Interventions for enhancing medication adherence

Abstract

Background

People who are prescribed self administered medications typically take only about half their prescribed doses. Efforts to assist patients with adherence to medications might improve the benefits of prescribed medications.

Objectives

The primary objective of this review is to assess the effects of interventions intended to enhance patient adherence to prescribed medications for medical conditions, on both medication adherence and clinical outcomes.

Search methods

We updated searches of The Cochrane Library, including CENTRAL (via http://onlinelibrary.wiley.com/cochranelibrary/search/), MEDLINE, EMBASE, PsycINFO (all via Ovid), CINAHL (via EBSCO), and Sociological Abstracts (via ProQuest) on 11 January 2013 with no language restriction. We also reviewed bibliographies in articles on patient adherence, and contacted authors of relevant original and review articles.

Selection criteria

We included unconfounded RCTs of interventions to improve adherence with prescribed medications, measuring both medication adherence and clinical outcome, with at least 80% follow‐up of each group studied and, for long‐term treatments, at least six months follow‐up for studies with positive findings at earlier time points.

Data collection and analysis

Two review authors independently extracted all data and a third author resolved disagreements. The studies differed widely according to medical condition, patient population, intervention, measures of adherence, and clinical outcomes. Pooling results according to one of these characteristics still leaves highly heterogeneous groups, and we could not justify meta‐analysis. Instead, we conducted a qualitative analysis with a focus on the RCTs with the lowest risk of bias for study design and the primary clinical outcome.

Main results

The present update included 109 new RCTs published since the previous update in January 2007, bringing the total number of RCTs to 182; we found five RCTs from the previous update to be ineligible and excluded them. Studies were heterogeneous for patients, medical problems, treatment regimens, adherence interventions, and adherence and clinical outcome measurements, and most had high risk of bias. The main changes in comparison with the previous update include that we now: 1) report a lack of convincing evidence also specifically among the studies with the lowest risk of bias; 2) do not try to classify studies according to intervention type any more, due to the large heterogeneity; 3) make our database available for collaboration on sub‐analyses, in acknowledgement of the need to make collective advancement in this difficult field of research. Of all 182 RCTs, 17 had the lowest risk of bias for study design features and their primary clinical outcome, 11 from the present update and six from the previous update. The RCTs at lowest risk of bias generally involved complex interventions with multiple components, trying to overcome barriers to adherence by means of tailored ongoing support from allied health professionals such as pharmacists, who often delivered intense education, counseling (including motivational interviewing or cognitive behavioral therapy by professionals) or daily treatment support (or both), and sometimes additional support from family or peers. Only five of these RCTs reported improvements in both adherence and clinical outcomes, and no common intervention characteristics were apparent. Even the most effective interventions did not lead to large improvements in adherence or clinical outcomes.

Authors' conclusions

Across the body of evidence, effects were inconsistent from study to study, and only a minority of lowest risk of bias RCTs improved both adherence and clinical outcomes. Current methods of improving medication adherence for chronic health problems are mostly complex and not very effective, so that the full benefits of treatment cannot be realized. The research in this field needs advances, including improved design of feasible long‐term interventions, objective adherence measures, and sufficient study power to detect improvements in patient‐important clinical outcomes. By making our comprehensive database available for sharing we hope to contribute to achieving these advances.

Plain language summary

Ways to help people follow prescribed medicines

Background

Patients who are prescribed medicines take only about half of their doses and many stop treatment entirely. Assisting patients to adhere better to medicines could improve their health, and many studies have tested ways to achieve this.

Question

We updated our review from 2007 to answer the question: What are the findings of high‐quality studies that tested ways to assist patients with adhering to their medicines?

Search strategy

We retrieved studies published until 11 January 2013. To find relevant studies we searched six online databases and references in other reviews, and we contacted authors of relevant studies and reviews.

Selection criteria

We selected studies reporting a randomized controlled trial (RCT) comparing a group receiving an intervention to improve medicine adherence with a group not receiving the intervention. We included trials if they measured both medicine adherence and a clinical outcome (e.g. blood pressure), with at least 80% of patients studied until the end.

Main results

The studies differed widely regarding included patients, treatments, adherence intervention types, medicine adherence measurement, and clinical outcomes. Therefore, we could not combine the results in statistical analysis to reach general conclusions, as it would be misleading to suggest that they are comparable. Instead, we provide the key features and findings of each study in tables, and we describe intervention effects in studies of the highest quality. The present update included 109 new studies, bringing the total number to 182. In the 17 studies of the highest quality, interventions were generally complex with several different ways to try to improve medicine adherence. These frequently included enhanced support from family, peers, or allied health professionals such as pharmacists, who often delivered education, counseling, or daily treatment support. Only five of these RCTs improved both medicine adherence and clinical outcomes, and no common characteristics for their success could be identified. Overall, even the most effective interventions did not lead to large improvements.

Authors' conclusions

Characteristics and effects of interventions to improve medicine adherence varied among studies. It is uncertain how medicine adherence can consistently be improved so that the full health benefits of medicines can be realized. We need more advanced methods for researching ways to improve medicine adherence, including better interventions, better ways of measuring adherence, and studies that include sufficient patients to draw conclusions on clinically important effects.

Background

Description of the condition

Low patient adherence is a major barrier to realizing the benefits of medications that have been shown to do more good than harm in clinical trials. Such trials are typically done among patients who are volunteers, and who are followed closely to assure high adherence. Benefits are greatly reduced or nullified in usual clinical practice where adherence rates are low. Interventions to improve adherence have the potential to multiply benefits for patients, but at the time of our previous review, Haynes 2008, no method of helping patients to follow self administered long‐term treatments had been proven effective, actionable, and affordable in usual care settings.

Many patients stop taking their medication in the first months following initiation, often without informing their provider, with further attrition over time. In addition, many patients who continue their medication do not consistently take it as prescribed. As a result, adherence rates average around 50% and range from 0% to over 100%, and there is no evidence for substantial change in the past 50 years (Sackett 1979; Gialamas 2009; Naderi 2012).

Medication non‐adherence is often defined as taking less than 80% of prescribed doses, although it has to be noted that non‐adherence can also include taking too many doses, and it is associated with an increased risk for poor health, adverse clinical events, and mortality. Thus many people who could benefit from medications do not, and much of the public and private investment in health research and health care is undermined. To make matters worse, low adherence, even to placebo, is independently associated with an increased risk of death ('healthy adherer' effect) (Simpson 2006). Therefore, enhancing medication adherence is a priority and could improve patient outcomes, primarily through the effect of medications, but also possibly through the overall 'healthy adherer' effect.

Description of the intervention

Our most recent update (search until January 2007) of this Cochrane review included 78 randomized controlled trials (RCTs) that had ≥ 80% follow‐up and tested the effect of adherence interventions on both adherence and clinical outcomes (Haynes 2008). We believe it is essential to have measures of both adherence and clinical outcomes, as ethical standards for adherence research dictate that attempts to improve adherence should be judged by their clinical benefits (NHLBI 1982). Studies that measure only adherence cannot show that patients are better off as a result, and studies that measure only clinical outcomes cannot verify that effects on adherence were important to achieving these outcomes.

Further, we described findings across disease conditions, as the clinical condition is not a major determinant of medication adherence, with the exception of psychiatric disorders (Haynes 1979a). Do note that studies targeting adherence for medications to treat psychiatric disorders are included in our review.

Our 2008 update found, besides the expected variety in medical conditions and regimens, a large diversity and complexity of interventions and of measures for adherence and patient outcomes (Haynes 2008). Although some intervention types tended to improve adherence, no specific recommendations could be given, especially since high‐quality evidence for consistent effects on both adherence and patient outcomes was lacking.

Why it is important to do this review

With increasing numbers of efficacious self administered treatments being available, the need for effective interventions to improve adherence is ever more apparent. In recent years, research efforts to better understand the multifactorial barriers that influence patient adherence and to refine theoretical frameworks have been increasing. However, whether these efforts have led to the emergence of more effective interventions needs to be assessed by summarizing the high‐quality RCT evidence to date. Many systematic reviews have been published after our 2008 update, but all focused on a specific (demographic, disease, or medication) population, intervention, or on an even more specific combination of both. Generally, these reviews reported similar conclusions: some intervention components are potentially effective, but small sample sizes and suboptimal methodology often prevented strong conclusions; the variety of adherence measures limited study comparability; and most studies lacked a theoretical underpinning (van Dulmen 2007).

Considering the substantial efforts in adherence research since 2007, and inconclusive evidence from other recent systematic reviews, we have updated our comprehensive systematic review. Based on publication rates over time in the previous review update, we predicted that we would find at least 50 additional RCTs, and thereby potentially improve our confidence for specific conclusions and recommendations.

Objectives

The primary objective of this review is to assess the effects of interventions intended to enhance patient adherence to prescribed medications for medical conditions, on both medication adherence and clinical outcomes.

Methods

Criteria for considering studies for this review

Types of studies

This systematic review is an update of the review by Haynes et al (Haynes 2008), which searched for studies until February 2007. As of 24 November 2013, no other comprehensive adherence reviews were registered in the Cochrane Database or PROSPERO, the International Prospective Register of Systematic Reviews (http://www.crd.york.ac.uk/prospero/). We used a web‐based database management system, developed by the Health Information Research Unit at McMaster University, to facilitate screening, data extraction, adjudication of disagreements, author review and confirmation of data, production of data tables, and production of data files for future research use. This system has been successfully used in conducting and completing several large, complex systematic reviews (Haynes 2010).

Studies for this review were included if they were RCTs that provided unconfounded tests of interventions expected to affect adherence. A confounder is a characteristic that is extraneous to the primary question being addressed in the study, but which can influence the outcome and is unequally distributed between the groups being compared in the trial. For example, in one study (Colcher 1972), two groups received the same prescription for phenoxymethyl penicillin, but different instructions, providing an unconfounded comparison for the instructions, but a third group in the same trial received a different drug (penicillin G benzathine) by a different route (intramuscularly) with a different dose (1.2 million units) and schedule (one dose), making it impossible to separate out independent adherence effects of this regimen. Thus, only the unconfounded comparison of instructions for phenoxymethyl penicillin was included in the review.

Types of participants

Patients who were prescribed medication for a medical (including psychiatric) disorder, but not for addictions (as these adherence problems are typically of a different nature and much more severe).

Types of interventions

Interventions of any sort intended to affect adherence with prescribed, self administered medications.

Types of outcome measures

We included studies if they reported at least one medication adherence measure and at least one clinical outcome. Regarding follow‐up completion, studies needed to have at least 80% follow‐up at the end of the recommended treatment period for short‐term treatments, and at least 80% follow‐up during at least six months for long‐term treatments with initially positive results. For long‐term regimens, we included negative trials with less than six months follow‐up and at least 80% data completion on the grounds that initial failure is unlikely to be followed by success (Sackett 1979). The 80% data completion was required for both adherence and clinical outcomes, and for any outcome other than mortality, the denominator for determining data completion excluded those patients who died before the outcome assessment.

Search methods for identification of studies

We searched: The Cochrane Library including CENTRAL (via http://onlinelibrary.wiley.com/cochranelibrary/search/), MEDLINE, EMBASE, PsycINFO (all via Ovid), CINAHL (via EBSCO), and Sociological Abstracts (via ProQuest). We completed database searches for relevant articles on 11 January 2013, updating previous searches that were undertaken on: 1 September 1993; 12 December 1993; 1 June 1994; 30 June 1995; 28 February 1997; 31 July 1998; 15 August 2001; 30 September 2004; and 1 February 2007. We searched new publications since 1 January 2007, that is, having a one‐month overlap with the previous search. All databases were originally searched from their start date.

The search filters for each database, and from the current and previous update, are shown in Appendix 1. We checked articles cited in reviews and original studies of patient adherence. We contacted authors of included RCTs to identify additional studies.

We re‐assessed all RCTs included in the 2008 update for eligibility to carry over into the current update. Retrieved citations from the updated search entered a first screening stage. Based on the title and abstract, studies moved to the second screening stage if they met all five eligibility criteria or if there was uncertainty about their eligibility. In the second screening stage, assessment of the full text determined if studies were included in the review. At both screening stages, two independent review authors assessed eligibility, and an adjudicator resolved disagreements. We recorded reasons for excluding citations in the second screening stage. The PRISMA flow chart showing the results for selection of papers is provided in Figure 1.

1.

Study flow diagram.

Data collection and analysis

We imported data from the 2008 review into the update database, and checked the data for accuracy. Extracted data included items as provided in the tables from the previous Cochrane review (Haynes 2008): the 'Characteristics of included studies' table (i.e. methods, participants, interventions, outcomes, additional notes pertaining to any one of the aforementioned items, detailed assessment of risk of bias), and the 'Adherence and outcome' table (i.e. clinical problem, intervention, control, effect on adherence outcome, effect on clinical outcome). We extracted the same items for new included studies. In addition, we extracted items from the Cochrane 'Risk of bias' tool for all included studies from the previous and current update (Higgins 2011). Two review authors independently extracted all new data, and an adjudicator resolved disagreements. We contacted primary or corresponding authors of all included RCTs to confirm extracted data and provide missing data.

We quantified review author agreement on study 'Risk of bias' criteria using the unweighted Cohen's kappa (k) coefficient (Fleiss 1981). We carried out all analyses using SPSS, version 20.0. When reporting results from individual studies, we cited the measures of association and P values reported in the studies. We interpreted P value < 0.05 as indicating statistical significance. Due to the extreme heterogeneity in clinical conditions, participant selection criteria, medical regimens, interventions, adherence measures, and clinical outcome measures, pooling results according to any of these characteristics would still leave highly heterogeneous groups. In support of this, we refer to the meta‐analysis reported by the Ascertaining Barriers for Compliance (ABC) project team, which exclusively focused on RCTs that measured adherence by means of electronic medication event monitoring systems (MEMS) and still found a very high heterogeneity of effects (I² = 98.88%) (ABC Project Team 2012). Pooling of effects in our review was further undermined by the frequent use of complex interventions, which was already problematic for categorizing intervention types in the previous update. Studies also had very heterogeneous clinical outcomes; they also often lacked clearly defined primary outcomes. We could not justify even plotting intervention effects without pooling in meta‐analysis, as this would imply some degree of comparability among the studies. Rather, as a best case alternative, we conducted a narrative analysis of the studies with the lowest risk of bias, using the Cochrane 'Risk of bias' tool (Higgins 2011), for study design (random sequence generation and concealment of allocation), and for their primary clinical outcome (blinding of outcome assessor, as relevant for the outcome in question). We did not require low risk of bias for the primary adherence measure, as this would have resulted in discussion of very few studies, as most adherence measures have a high or uncertain risk of bias, notably because of lack of blinding.

We reported intervention effects in individual RCTs for all outcomes for a) adherence and b) clinical outcomes. We reported effects in the RCTs identified as low risk of bias as described by the authors, with a focus on the primary outcomes, and with comments on methodological issues that might have influenced results, such as absence of correction for multiple comparisons. We considered adherence and clinical outcomes to be the primary outcome if they were:

1. indicated to be the primary outcome by the study author; OR

2. used in the study power calculation; OR

3. the first outcome described in the 'Results' section of the article.

Results

Description of studies

Results of the search

The new search identified 26,312 citations of which we assessed 1673 in full text. Of these, we included 109, based on a full‐text review in the second screening phase. The PRISMA flow chart shows the results for selection of papers and is provided in Figure 1.

Included studies

The previous update included 78 RCTs, of which 73 were carried over into the current update. We excluded five previously included RCTs: in the course of this review update, we identified that two did not address self administered medication (Canto De Cetina 2001; Ran 2003), one had less than 80% follow‐up (Van Servellen 2005), one reported no data for clinical outcome (van Es 2001), and one was confounded (Piette 2001). Therefore, we included a total of 182 RCTs in the current update. The overall number of RCT participants was 46,962. However, this overall number does not reflect the strength of the evidence base, considering that we could not meaningfully combine results of included studies. The newly added studies represent a growth in the knowledge base of 150% in the past six years, with more than twice the number of trials than we had predicted based on publication rates in the 2008 review.

Key features of all 182 RCTs are summarized in the table Characteristics of included studies. The most frequently targeted conditions in all RCTs were:

• HIV/AIDS (36);

• psychiatric disorders (29);

• chronic obstructive pulmonary disease (27);

• cardiovascular disease or cardiovascular risk (21);

• hypertension (17); and

• diabetes (16).

The remaining studies targeted:

• dyslipidemia (6);

• antibiotics (4);

• arthritis (3);

• complex chronic care (3);

• dyspepsia (3);

• glaucoma (2);

• oral anticoagulation (2);

• osteoporosis (2);

• tuberculosis (2);

• acne (1);

• cancer (1);

• hepatitis (1);

• iron supplementation during pregnancy (1);

• liver transplant (1);

• malaria (1);

• oral contraceptives (1);

• tonsillectomy/adenoidectomy (1); and

• ulcerative colitis (1).

Among the 109 new RCTs, 80 were from high‐income countries (44 from USA), 17 from middle‐income countries, five from low‐income countries, and seven from unknown geographic locations (World Bank classification, http://data.worldbank.org/about/country‐classifications/country‐and‐lending‐groups). In a majority of new RCTs (67) the adherence intervention targeted more than one medication, while 27 targeted one medication (the number of medications was unknown for the remaining 15 RCTs).

There were substantive differences across studies in settings, clinical disorders, treatment regimens, adherence interventions, adherence measures, and clinical outcome measures, so that there was insufficient common ground for quantifying differences between groups or estimating pooled effect sizes that would permit meaningful quantitative analysis of findings across studies. Instead, we indicated which differences were statistically significant for adherence or clinical outcomes between the groups compared in each RCT (see Analysis 1.1). Of note, some of the negative results were unconvincing because of low statistical power: 44 RCTs did not meet the minimal required sample size of 60 patients per treatment group to detect an absolute difference of 25% in adherence with 80% power (Haynes 2008).

1.1. Analysis.

Comparison 1 Studies that met criteria, Outcome 1 Adherence and outcome.

Adherence and outcome
Study	Clinical problem	Intervention	Control	Effect on adherence (Yes means a statistically significant effect in favor of the intervention; No means no effect or a negative effect)	Effect on clinical outcome (Yes means a statistically significant effect in favor of the intervention; No means no effect or a negative effect)
Abrahams 2010	Post‐exposure prophylaxis for HIV	TELEPHONE COUNSELING: Patients in the intervention group received standard care and telephone counseling sessions. The telephone counseling included 4 calls in the first week, 3 calls in the second and third week, and 2 calls in the last week, but more were made if necessary. The support included the application of basic counseling skills including listening and validating the traumatic events, encouraging participants to take their medication, to seek support from family and friends, to attend formal counseling services, to read the pamphlet, use the diary, and return to the clinic for follow‐up medication (n = 136)	STANDARD CARE: Standard care consisted of psychological containment, medical examination and collection of forensic evidence; HIV testing with pre‐ and post‐test counseling; providing emergency contraception, treatment of sexually transmitted infections and PEP for HIV. Follow‐up was arranged to collect further HIV PEP medication. All patients had an interactive information session to explain the content of the pamphlet, answer questions and demonstrate initiation of the use of the medication diary. The pamphlet contained specific information about taking PEP after a sexual assault; a diary for the 28‐day period on which pill taking was to be marked and contact information on support services. No further contact was made with participants in the control group until the final interview, but they continued to receive standard care from the service (n = 138)	No for improving adherence to prophylactic HIV treatment	No for depressive symptoms
Ahmadipour 2010	Type 2 diabetes	DIARY CHECKLIST: The intervention group was asked to complete a diary checklist about how they took their drugs during the study period.The duration was 12 weeks (n = 50)	COLLECTION OF MEDICATION SHELLS: The control group patients were asked to collect the shells of oral hypoglycemic agents after taking in a pocket. Duration was 12 weeks. (n = 50)	Yes for improving medication adherence in patients with type 2 diabetes with a diary check list intervention	No for improvement in HbA1c levels
Al Mazroui 2009	Type 2 diabetes mellitus	PHARMACIST CARE INTERVENTION: For all patients randomized to the intervention group, the research pharmacist had discussions with their physicians regarding drug therapy and, if necessary, treatment modification was recommended, e.g. more intensive management of hypertension or simplification of dosage regimens if deemed appropriate, taking account of the latest American Diabetes Association (ADA) recommendations. Patients who were randomized to the intervention group were educated on their illness and their medication in a structured fashion, including discussion on risk of diabetes complications, proper dosage, side effects and storage of medications, healthy lifestyle and management of diabetes mellitus signs and symptoms through self monitoring. A printed leaflet to assist with the education program was developed and the patient was given a copy to take home. Supplementary leaflets containing information about hypertension and hyperlipidemia were also given to the patients if they suffered from these conditions. The educational advice was reinforced when patients came to the hospital pharmacy to collect their prescribed medicines on their monthly schedule. In addition, behavioral modification aspects of the Pharmacist Care intervention involved advice on the following: self monitoring of glycemic control (patients were encouraged to monitor their blood glucose levels 3 times per day, to record these values and bring a record book to all subsequent appointments); physical exercise (this involved initiation of an exercise plan that could be incorporated into the patient’s daily schedule, after taking into consideration their level of fitness, e.g. 1‐hour walk daily; diet (the patient was assisted with the identification of dietary behavior that adversely influences blood glucose control, lipid levels, weight management, and of the times of day when the patient was most vulnerable to overeating, and given improved understanding of the relative effects of certain food choices on blood glucose control); medication adherence (patients were asked about any problems that they had encountered with regard to taking their medication and were offered education and practical help to encourage them to take the medicines prescribed for them by their physician); and smoking cessation (patients were encouraged to stop smoking by advising them about the danger of smoking to health, with emphasis on the increased dangers of smoking in diabetic patients) (n = 120)	USUAL CARE: Control group participants received normal care from medical and nursing staff. They did not receive any pharmacy clinical service but received advice on self monitoring their blood glucose by medical or nursing staff (n = 120)	Yes for improving adherence to medication at 12 months	Yes for BMI, blood glucose, HbA1c, blood pressure, cholesterol, quality of life, Framingham prediction scores, and British National Formulary risk prediction
Al‐Eidan 2002	Helicobacter pylori	Intervention patients (n = 38) received their medicines via the hospital pharmacy and were counseled (and followed up) by a hospital pharmacist	Control patients (n = 38) were given a standard advice sheet and referred to their GP who prescribed the same therapy	Yes for improving compliance with a 1‐week course of triple therapy to eradicate H. pylori	Yes for improving clinical outcomes for the intervention group who had a significantly higher rate of H. pylori eradication
Amado 2011	Hypertension	INTERVENTION (IG): Patients in the Intervention Group (IG) had 4 visits with specially trained nurses who used standardized guidelines and who had attended a 10‐hour workshop that focused on the antihypertensive medications. Each visit lasted for an average of 15 minutes. Information was personalized to the needs of the patient. Schedule sheets with the treatment plan were provided which contained information on the prescribed drugs and dosage schedule as well as basic advice on how to maximize the treatment schedule. The sheets were provided to reinforce the nurse's verbal instructions (n = 515 )	CONTROL GROUP (CG): Control patients received usual clinic care without any standardized intervention (n = 481 )	Yes for Haynes‐Sackett test; no for Morisky‐Green test, self declared 3‐month adherence, and pill count	No for systolic and diastolic blood pressure, hypertension control, BMI, and number of antihypertensive drugs taken
Anderson 2010	Schizophrenia	ADHERENCE TREATMENT: The intervention was 'Adherence Therapy' a manualized, patient‐centric approach that seeks to address a broad range of factors known to affect adherence. This individual therapy focuses on the needs, concerns, fears, values, goals, and experiences of the individual with the aim of encouraging people to take their medications. It was delivered by 4 therapists with Master's degree in social work. There were 8 one to one sessions of between 20 to 60 minutes, over 8 weeks. Follow‐up was conducted after the completion of the therapy. All intervention patients also received treatment as usual (n = 12)	TREATMENT AS USUAL: TAU included day treatment, case management, employment placement, medication monitoring, and individual counseling. During the trial, AT participants did not see their own therapist for therapy sessions, but continued their other treatment activities (n = 14)	No for improving adherence to antipsychotic medication in schizophrenia patients receiving adherence therapy and treatment as usual at 8 weeks	No for improving the PANSS positive, negative and general scores in schizophrenia patients receiving adherence therapy and treatment as usual at 8 weeks
Andrade 2005	HIV	Disease Management Assistant System (DMAS) device, programmed with verbal reminder messages and dosing times for medications in the highly active antiretroviral treatment (HAART) regimen with monthly adherence counseling and feedback (see Control; n = 29)	Monthly adherence counseling (education about barriers to adherence, hazards of non‐adherence, their prescribed HAART regimen) and adherence feedback (n = 29)	No for all adherence outcomes	No for CD4+ cell count. Yes for plasma HIV RNA (significant for 2 of 4 measures)
Ansah 2001	Malaria	The use of pre‐packed chloroquine tablets (n = 155)	The use of chloroquine syrup (n = 144)	Yes. The tablet form of medicine resulted in higher adherence rates, but it is not established whether this is due to the formulation or the lack of provision of a standard measuring device	No, there was no difference in the clinical outcomes
Antonicelli 2008	Congestive heart failure	HOME TELEMONITORING: Patients were in a 12‐month follow‐up period. Patients (or one of their relatives) were contacted by telephone at least once a week by the CHF team to obtain information on symptoms and adherence to prescribed treatment, as well as blood pressure, heart rate, bodyweight and 24‐hour urine output data for the previous day. A weekly ECG transmission was also required. Evaluation of these parameters was followed by reassessment of the therapeutic regimen and modification whenever needed. In addition, clinic visits were arranged as required on the basis of the data provided by telemonitoring or telephone interviews. Decisions on hospital re‐admission during follow‐up in both groups were made after consultation with a CHF team member (n = 29)	STANDARD CARE: Patients (or one of their relatives) in the control group were contacted monthly for 12 months of follow‐up by telephone to obtain data on new hospital admissions, cardiovascular complications and death. These patients were also routinely seen in the CHF outpatient clinic every 4 months, with additional visits being arranged whenever changes in clinical status made this necessary (n = 28)	Yes for improving adherence to beta‐blockers, HMG‐CoA reductase inhibitors and aldosterone receptor agonists at 12 months in elderly patients with CHF	Yes for composite endpoint of mortality and hospital readmission, hospital readmission (alone) and heart rate reduction. No for left ventricular ejection fraction change and mortality (alone)
Apter 2011	Asthma	PROBLEM‐SOLVING INTERVENTION: Participants met with a research co‐ordinator for 4 sessions of a problem‐solving (PS)intervention. PS comprised 4 30‐minute sessions. The individualized intervention involved 4 interactive steps, usually 1 per research session. For the 158 participants who reported missing doses of inhaled corticosteroids (ICS), the goal was to improve adherence. For the 7 participants who declared adherence to the prescribed regimen, the goal was to maintain adherence. The first PS step consisted of defining the problem: improving or preserving adherence to ICS use within the patient's unique context and orientation. Problem orientation facilitated the adoption of a rational, positive, and constructive appraisal of how to achieve adherence, with non‐adherence being presented as a problem to be solved. PS was presented as a means of coping with problems more generally and modifying attitudes or beliefs that inhibit or interfere with attempts to solve problems. It was a motivational technique to help the participant view the occurrence of problems as inevitable, normal, and solvable. This first step involved breaking problems into small achievable pieces. The second step was brainstorming for alternative solutions. The third step was choosing the best solution by weighing the consequences, both desirable and undesirable, of each candidate solution. Between the third and 4th meetings, the solution was tried. For the 4th step, the chosen solution was evaluated and revised. As part of this intervention, downloaded data from monitored ICSs were shared with the participant in a nonjudgmental fashion at each visit. At these sessions, subjects followed the same PS steps for addressing an additional problem of their own choosing, such as increasing physical activity. The problems were sometimes interrelated; for example, a father wants to play sports with his child, and improving asthma management makes this easier (n = 165)	ASTHMA EDUCATION: Patients attended 4 30‐minute sessions, conducted by a research co‐ordinator. Each session was about an asthma education (AE) topic unrelated to self management, adherence, or inhaled corticosteroid (ICS) therapy. The topics covered, 1 at each session, were the following: (1) the proper technique for using an albuterol rescue metered‐dose inhaler and a dry powder inhaler or spacer, depending on the patient's medications; (2) the use of peak flow meters; (3) common asthma triggers; and (4) the pathophysiology of asthma. These sessions did not involve discussion of problem‐solving or adherence, only didactic presentation of health information (n = 168)	No for improvement in medication adherence	No for improving asthma control, spirometry, emergency department visits and hospitalizations, and asthma‐related quality of life
Bailey 1990	Asthma	Pamphlet, workbook, counseling, phone follow‐up, support group, and reinforcement of adherence (n = 132)	Instructional pamphlet alone (n = 135)	Yes	Yes
Bailey 1999	Asthma	2 intervention groups: 1) Asthma Self Management Program (n = 78) ‐ a skill‐oriented self help workbook, which patients were counseled about in a one‐on‐one session and during 2 asthma support group meetings. Patients were also given peak flow meters and trained to use them for early detection of impending asthma attacks. They also received 2 telephone calls and a follow‐up letter at 1, 2, and 4 weeks, after the counseling session. 2) Core‐Elements Program (n = 76) ‐ a revised, shortened workbook that was reviewed in a 15 to 20 minutes one‐to‐one counseling session. Patients were trained to use inhalers and peak flow meters. They also received a follow‐up telephone counseling session a week later and a follow‐up letter 2 weeks later	Usual education from their physician, as well as a standardized set of pamphlets containing information about asthma. No steps were taken to ensure that patients read the pamphlets (n = 78)	No (medication adherence and inhaler use)	No for all clinical outcomes (asthma symptoms, respiratory illness, functional impairment, use of health services
Baird 1984	Hypertension	Once daily metoprolol (n = 196)	Twice daily metoprolol (n = 193)	Yes	No
Beaucage 2006	Acute infections	Pharmacist telephone follow‐up intervention (PTFI; n = 126)	Usual pharmacist intervention (UPI; n = 129)	No	No for all clinical outcomes
Becker 1986	Hypertension	Special "reminder" pill packaging (n = 86)	Separate vials for each medication (n = 85)	No	No
Berrien 2004	HIV	The intervention in intervention group (n = 20) consisted of 8 structured home visits over a 3‐month period by the same home care experienced registered nurse. The visits were designed to improve knowledge and understanding of HIV infection, to identify and resolve real and potential barriers to medication adherence, and ultimately to improve adherence. Spanish‐speaking case managers, incentives, notebooks with stickers and pill‐swallowing training were also part of the home visit training sessions	In the clinic setting for control group (n = 17), the physician, nurse and social worker provided standard medication adherence education at clinic appointments generally scheduled at 3‐month intervals. Phone follow‐ups and a single home visit were planned if the staff felt they were needed. Visual aids for remembering medications, medication boxes, beepers, and general technical and emotional support were regularly offered. The clinic nurse contacted the family by telephone when the patient was starting a new medication, was having difficulty with adherence, or needed clarification and support. A single home visit was planned when and if the clinic staff believed medication adherence was poor despite the implementation of the above listed techniques	Yes for pharmacy report of refill frequency; no for self reported	No
Boker 2012	Mild to moderate acne	TEXT MESSAGE REMINDERS: 20 patients were then randomized to receive daily, customized text‐message reminders at a predetermined time. The website LetterMeLater.com was used to create an automated and customized electronic reminder schedule for each patient in this group at their baseline visit. Individual texting schedules were chosen based on each patient's preference and the anticipated time of each medication use. Once the schedule was created, patients in the reminder group received a customized text message twice daily (morning and evening), reminding them to apply the Duac (Stiefel Laboratories) or Differin (Galderma) gels, respectively. The content of each text message was identical for each patient and varied only by including the recipient's first name at the start of the message. Patients in the reminder group were asked to text back a reply if and when each application was completed in an attempt to compare actual adherence (measured by MEMS caps opening/closing events) and self reported adherence. All medication tubes and their corresponding MEMS caps were clearly labeled to avoid mix‐ups (n = 20)	USUAL CARE: Control group patients received usual care and were not provided with text message reminders. (n = 20)	No for improving adherence to acne medication with daily, customized text messages	No for improvement in acne severity or quality of life with text messages
Bond 2007	Coronary heart disease	MEDICINE MANAGEMENT SERVICE (MEDMAN): The intervention was a comprehensive, community pharmacy‐led medicines management called MEDMAN. This intervention comprised of an initial consultation with a community pharmacist to review the appropriateness of therapy, compliance, lifestyle, social and support issues. Further consultations were provided according to pharmacist‐determined patient need. Recommendations were recorded on a referral form which was sent to the GP, who returned annotated copies to the pharmacists. The intervention lasted 12 months (n = 980)	STANDARD CARE: Control group patients not provided with MEDMAN intervention. Follow‐up data were collected at 12 months by audit clerks and postal questionnaire as at baseline. Intervention patients were also asked about their experience of the medicine management service (n = 513)	No for improving medication compliance in patients with coronary heart disease with a medicines management service	No statistically significant differences were found for any of the (adjusted) main outcome measures between the 2 groups at follow‐up
Bonner 2009	Asthma	INDIVIDUALIZED ASTHMA MANAGEMENT INTERVENTION: Families in the intervention group received asthma education by a trained Family Co‐ordinator who also provided individualized support in helping caregivers monitor their children's asthma using diaries. The Family Co‐ordinator helped caregivers interpret the diaries and communicate the contents to their doctors. 3 group education workshops were held at 1‐month intervals that followed the asthma self regulation model. Families were trained to use the diaries and peak flow meters. Family Co‐ordinators regularly called families to discuss their diary records. The second workshop used patients' diary records as illustrations of the relative effectiveness of controller medicines over rescue/quick‐relief drugs in preventing asthma symptoms over time. Participants reviewed their own records of medicines and symptoms. The third workshop described asthma management as a two‐pronged effort of pharmacotherapy and trigger control. Between the 1st and 2nd workshops, the Family Co‐ordinator prepared families for their doctor visit. The Family Co‐ordinator accompanied families to the doctor visit where he intervened if the family failed to communicate a thorough asthma history. The children in the intervention group were tested for allergies by an attending allergist at the hospital if they had not recently been tested by their own physician. Family Co‐ordinator conducted a home environment assessment and suggested strategies for reducing asthma triggers (n = 56)	USUAL CARE: Control patients (n = 63) received usual medical care at private or hospital‐affiliated community pediatric practice (n = 63)	Yes for family adherence to asthma medicines according to the frequency and dosage as prescribed on the labels and yes for prophylactic use of bronchodilators	Yes for improvements in self efficacy for management of asthma, phase of asthma regulation and symptom persistence
Brown 1997a	Hyperlipidemia and coronary artery disease	Controlled release niacin twice daily (n = 31)	Regular niacin 4 times a day (n = 31)	Yes	Yes
Brus 1998	Rheumatoid arthritis (RA)	6 patient education meetings. The education program focused on compliance with sulphasalazine therapy, physical exercises, endurance activities (walking, swimming, bicycling), advice on energy conservation, and joint protection. 4 (2‐hour) meetings were offered during the first months. Reinforcement meetings were given after 4 and 8 months. The program was implemented in groups and partners were invited to attend the meetings (n = 29)	The control group received a brochure on RA, as provided by the Dutch League against Rheumatism. This brochure gives comprehensive information on medication, physical and occupational therapy (n = 31)	No	No
Bruzzese 2011	Moderate to severe persistent asthma	ASTHMA SELF MANAGEMENT FOR ADOLESCENTS (ASMA): Students in the ASMA group receive an 8‐week intensive program. The intervention consists of 3 45‐ to 60‐minute group sessions, and individual tailored coaching sessions held at least once per week for 5 weeks. Sessions are delivered by trained health educators during the school day. In addition to teaching asthma management skills and ways to cope with asthma, the health educators encourage students to see their medical provider for a clinical evaluation and treatment. The individual sessions reinforce the educational messages taught in the group, help students identify and overcome barriers to managing their asthma, and coach students regarding their medical visits. The health educator offers to accompany the student to the medical visit to provide moral support, coaching, or advocacy when coaching fails. Medical providers received a presentation by experts in person or by telephone about a recommended change in therapy. The medical providers were first mailed a packet containing: a letter informing them that one of their patients was in the study and would be referred to him/her for a clinical evaluation; a blank asthma checklist the students complete throughout the intervention and bring to the visit with the provider; and a blank asthma action plan the provider is asked to complete. Within 2 weeks, a pediatric pulmonologist or adolescent medicine specialist called the students' medical providers to discuss the concepts presented in the program and to answer any questions regarding NHLBI Institute criteria for treating asthma (n = 175)	WAIT LIST CONTROL: The control group were kept on wait list until the completion of 12‐month interviews and then received the ASMA intervention (n = 170)	Yes for improving adherence in adolescents with asthma at 6 months; No for improving adherence in adolescents at 12 months	Yes for reducing night‐time awakenings in previous 2 weeks, and school absence in previous 2 weeks. No for reducing symptom days in prior 2 weeks. No for improving QOL at 6 months. Yes for QOL improvement at 12 months. Yes for reduction in urgent medical care use
Burgess 2007	Asthma	FUNHALER: Patients received a Funhaler for their daily asthma medication. The Funhaler is a small volume spacer that incorporates an incentive toy (spinning disk and whistle) that is driven by the child's expired breath (n = 26)	CONTROL SPACER: Patients received a standard spacer for administering asthma medication (n = 21)	No for improving adherence to medication at 3 months in asthma patients	No for exacerbations of asthma. No for reducing the frequency of wheeze or cough at 3 months
Chamorro 2011	Hypertension, dyslipidemia, cardiovascular disease, type 2 diabetes and coronary heart disease	PHARMACOTHERAPY FOLLOW‐UP: The intervention consisted in follow‐up of the patients by the pharmacist. He gave written and oral information about cardiovascular prevention and adherence to the patients in the first interview. The pharmacist adopted a pharmacotherapy follow‐up program, for 4 visits over 16 to 18 weeks. The final assessment was at 32 weeks (n = 44)	EDUCATION: This procedure consisted of health education, written and oral material all given in 1 session at enrollment (n = 41)	No for adherence at 8 months	No for all clinical health outcomes
Chan 2007	Persistent asthma	INTERNET‐BASED HOME MONITORING AND EDUCATION: Both groups had 6 visits scheduled at 0, 2, 6, 12, 26, and 52 weeks, with the study pediatrician and 1 of the 4 assigned nurse case managers or the pediatric clinical pharmacist case manager. The intervention group received 3 in‐person visits, at 0, 26, and 52 weeks, and the rest as virtual visits. Virtual visits included asthma education, a video recording of peak flow meter and inhaler use forwarded to the website, daily asthma diaries, and communication with the case manager electronically via the website. Patients were provided a home computer system, camera, and Internet access. On‐site in‐home instruction was provided by technical experts on equipment use and website capabilities and use. Each patient received the same models of computer and computer equipment, as well as broadband Internet access. Patients and their parents were taught how to use the equipment and how to record and to submit videos by using a computer‐mounted digital video camera, to capture the patient's peak flow meter and inhaler technique. A detailed asthma symptom diary and quality of life survey were included on the website. Patients and families were instructed regarding the submission of daily symptom diary entries. Videos were recorded and loaded on the site for the case manager, who scored them with standardized checklists and provided instruction through e‐mail back to the patient/family. Videos were sent 2 times per week for 6 weeks and then once‐weekly thereafter. Moreover, patients received the following same service as the control group: they were contacted (by e‐mail) by the case manager 2 times per week for 6 weeks and once per week thereafter, to review the asthma action and home management plans, to assess the symptom diary, to remind the patient to perform and to record peak flow measurements daily in the diary, to remind the patient to complete symptom diary information every day, to answer questions, and to intervene if needed. All patients were able to contact the case manager 24 hours per day, 7 days per week (n = 60)	OFFICE‐BASED VISITS: Patients were treated with an ambulatory asthma clinical pathway, with 6 visits scheduled 0, 2, 6, 12, 26, and 52 weeks after enrollment. At each visit, patients and their parents received in‐depth asthma education from the case manager, with specific subjects being determined by an asthma educational pathway. Office‐based group patients received all of their information in person at the pediatric clinic. Patients were able to contact their case manager by telephone (n = 60)	No for improving asthma controller medication adherence with internet‐based patient education and home monitoring for children with asthma	No for rescue medication use or emergency visits, symptoms, asthma knowledge and inhaler technique
Chaplin 1998	Schizophrenia	Individual semi‐structured educational sessions discussing the benefits and adverse effects of antipsychotic drugs, including tardive dyskinesia (n = 28)	Usual care (n = 28)	No	No
Charles 2007	Asthma	AUDIOVISUAL REMINDER: The intervention was an audiovisual reminder attached to the inhaler. When the alarm was switched on, it generated a single beep, which sounded once every 30 seconds for 60 minutes after the predesignated time, which was programmed into the device. The alarm stopped if the MDI was actuated or after 60 minutes if not taken. The device was programmed to emit the alarm at predetermined times twice a day. The AVRF also had a colored light, which was green before MDI use, changing to red once the MDI was taken. This function served to remind patients whether they had taken the MDI as scheduled. Follow‐up period was 12 weeks (n = 55)	SMART INHALER: Control participants received the same Smartinhaler as intervention participants, but it did not have the audiovisual reminder device (n = 55)	Yes for improving adherence to inhalers in adults and adolescents with asthma with an audiovisual reminder	No for improving clinical outcomes with an audiovisual timer device for inhalers in asthmatic adults and adolescents
Choudhry 2011	Myocardial infarction or coronary artery disease	FULL PRESCRIPTION COVERAGE: The intervention involved changing the pharmacy benefits of the intervention group patients so that they had no cost sharing for any brand or generic statin, beta‐blocker, ACE inhibitor or ARB for every prescription after randomization (n = 2845)	USUAL PRESCRIPTION COVERAGE: Control patients received usual prescription‐drug coverage (n = 3010)	Yes for improving adherence to prevention medications after MI by providing full coverage pharmacy plans	Yes for reduction in health expenditure and improving rates of first major vascular events
Chung 2011	HIV	COUNSELING: In the adherence counseling intervention, trained counselors administered 2 counseling sessions to participants prior to HAART initiation and a third session 1 month after HAART initiation. Counseling sessions around HAART initiation were based on a model of successful antiretroviral adherence promotion at a large University of Washington‐affiliated HIV treatment program in Seattle, Washington. All counseling sessions followed a written standardized protocol and lasted between 30 and 45 minutes. In the first session, counselors explored personal barriers to good adherence and taught participants about HIV, the virus that causes AIDS, antiretroviral medications, and the risks of treatment failure due to poor adherence. The second session occurred on a separate day and involved a review of a participant's understanding and readiness to begin antiretroviral medications. The third session allowed the counselor to examine practical and personal issues that the participant may have encountered on HAART. The adherence counseling intervention had been previously used and adapted at the same site in Kenya for over 2 years and was delivered in English and Kiswahili (n = 100) COUNSELING PLUS ALARM: Participants in counseling plus alarm group received both adherence counseling and alarm reminders. 3 adherence counseling sessions (2 prior to HAART initiation and 1 after HAART initiation) were conducted. All counseling sessions followed a written standardized protocol and lasted between 30 and 45 minutes. In the first session, counselors explored personal barriers to good adherence and taught participants about the HIV, the virus that causes AIDS, antiretroviral medications, and the risks of treatment failure due to poor adherence. The 2nd session occurred on a separate day and involved a review of a participant's understanding and readiness to begin antiretroviral medications. The 3rd session allowed the counselor to examine practical and personal issues that the participant may have encountered on HAART. The counseling session was delivered in English and Kiswahili. In addition, participants were given a small pocket digital alarm, which the individual was to carry at all times for 6 months. The device was programmed by the study staff to beep and flash twice a day at a time convenient to the participant when medications were to be taken. The digital alarm could not be reprogrammed or inactivated by the individual and was utilized for 6 months after HAART initiation before being disabled by study staff (n = 100) ALARM DEVICE: Participants in the alarm device intervention received a small pocket digital alarm which the individual was to carry at all times for 6 moths duration. The device was programmed by the study staff to beep and flash twice a day at a time convenient to the participant when medications were to be taken. The digital alarm could not be reprogrammed or inactivated by the individual and was utilized for 6 months after HAART initiation before being disabled by study staff (n = 100)	USUAL CARE: "At HAART initiation, the study pharmacist explained the side effects of medications and problems associated with poor adherence in a 15‐min session prior to dispensing drugs. All participants, including those in the control arm, received this educational message. Participants randomized to the control group did not receive adherence counseling or an alarm device." (pg 2‐3) (n = 100)	Yes for improving adherence to medication at 1 month in the counseling group; No for improving adherence to medication at 18 months in counseling group; No for improving adherence to HAART in alarm group at any time point	Yes for reducing viral failure in counseling group. No for improving mortality and CD4 cell count in counseling group. No for reducing viral failure, CD4 cell count and mortality in alarm group
Colcher 1972	Strep throat	Special counseling and written instructions on need to take all pills (n = 100)	Usual care (n = 100)	Yes	Yes
Collier 2005	HIV	Serial, scripted, and supportive telephone calls from a nurse plus usual adherence support (same as control group; n = 142)	Usual support measures including in‐person counseling by a nurse at start of therapy and discretionary phone calls (n = 140)	No	No
Cooper 2010	HIV	ONCE NIGHTLY REGIMEN: Patients in the once nightly regimen group received 1 x didanosine (DDI) enteric‐coated (EC) capsule 400 mg (250 mg if weight less than 60 kg), 2 x lamivudine (3TC) 150 mg tablet, 1 x efavirenz (Sustiva) 600 mg tablet each evening (n = 44)	TWICE DAILY REGIMEN: Patients in the control group received Combivir (zidovudine 300 mg + 3TC 150 mg): 1 tablet twice daily, 1 x efavirenz 600 mg tablet taken nightly (n = 43)	Yes for improving adherence with HAART with once nightly dosing versus twice daily dosing	Yes for viral load undetectable; No for HAART beliefs and intrusiveness
Costa 2008	Acute myocardial infarction	TRANSDISCIPLINARY APPROACH: The transdisciplinary intervention consisted of clinical follow‐up, smoking cessation assistance, dietary advice and life style modification advice. The intervention was delivered by a team consisting of an endocrinologist, a cardiologist, a nurse and a dietician. There were 2 follow‐up assessment ‐ at 60 to 90 days after MI and 120 to 180 days after MI. In diabetic patients, capillary glycemia was measured (Advantage reagent strips, Roche, Indianapolis, IN, USA), lower limbs were examined, and adherence to prescribed oral antidiabetic agents and insulin was reviewed. Those patients who were still smoking were advised to stop smoking by the nurse and also by the cardiologist. No oral medication was prescribed in this regard since these drugs are not routinely provided by the Public Health System in Brazil. After the above‐described procedures, the dietitian evaluated body weight and performed a nutritional review. This review was followed by reinforcement of healthy nutritional habits, which included information on the characteristics and amount of healthy meals according to each case and also lifestyle modification reinforcement. The management plan was formulated as an individualized therapeutic alliance among the patient and family, the physician, and other members of the health care team. Finally, patients were evaluated by the cardiologist, who completed the visit with the specific medical history, physical examination and specific complementary tests. Drug prescription by the cardiologist followed the AHA guidelines for both groups (statins, antiplatelet therapy, beta‐blockers and angiotensin‐converting enzyme inhibitors). Diabetic patients were evaluated by an endocrinologist. Drug prescription by the endocrinologist followed the American Diabetes Association (ADA) guidelines for both groups (n = 78)	CONVENTIONAL CARE: Conventional care group received regular care. Before discharge, they were visited by a dietitian who prescribed a post‐discharge diet plan after nutritional evaluation. Then they were referred to the conventional outpatient clinic for heart care, where the patients were seen only by the appointed cardiologist. Cardiologists kept a routine schedule with the patients and were seen for no more than 15 minutes. Then these participants were asked to be present at the clinic 180 days after AMI to perform a clinical examination and to obtain blood samples (n = 75)	No for improving adherence to medication in patients after myocardial infarction	No for improvement in clinical improvement index; No for reduction in rate of hospitalization and deaths; Yes for increasing compliance with diet; Yes for improving compliance with visits
Cote 1997	Asthma	Extensive asthma education program plus written self managed action plan based on peak expiratory flow (PEF) (n = 50) or based on asthma symptom monitoring (n = 45)	Basic information provided plus verbal action plan could be given by physician (n = 54)	No for each intervention	No for each intervention
Cote 2001	Asthma	Patients in Group Limited Education (LE) (n = 30) were given a self action plan that was explained by the on call physician. The action plan used "traffic lights" (green, yellow, red) to describe specific states of asthma control based on peak expiratory flow and symptoms and actions that the patient should take for each state. Subjects were all instructed by a respiratory therapist or study nurse in the proper use of an inhaler. In addition to what patients in Group LE received, the patients in Group Structured Education (SE n = 33) participated in a structured asthma educational program based on the PRECEDE model of health education within 2 weeks after their randomization	The patients in Group C (control, n = 35) received the usual treatment given for an acute asthma exacerbation	No	No
Coull 2004	Ischemic heart disease	Intervention consisted of participation in a mentor‐led group (n = 165), through attending monthly 2‐hour long meetings in community facilities over a 1‐year period. There was an average of 10 patients per group, each led by 2 mentors. The core activities covered in the program were lifestyle risk factors of smoking, diet and exercise; blood pressure and cholesterol; understanding of and ability to cope with IHD; and drug concordance. Each mentored group was also encouraged to develop its own agenda. Input was provided from a pharmacist, cardiac rehabilitation specialist nurse, dietician, welfare benefits advisor and Recreation Services. Volunteer lay health mentors, aged 54 to 74 recruited from the local community led the groups	Both intervention and control groups (n = 154) continued to receive standard care	Yes	No
Dejesus 2009	HIV/AIDS	SINGLE TABLET REGIMEN (EFV/FTC/TDF): Intervention group patients were prescribed a single‐tablet regimen consisting of efavirenz/ emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) (n = 203)	ART: Control group patients were prescribed regular multi‐drug ART (n = 97)	No for change in adherence to medication in EFV/FTC/TDF arm and SBR arm at 48 weeks	No for improving QOL; Yes for improving preference of medication and ease of the regimen; Yes for HIV symptom index
DiIorio 2008	HIV	MOTIVATIONAL INTERVIEWING: Intervention group receives usual adherence education and motivational interview. Participants received 5 individual MI counseling sessions with a study nurse counselor over a 3‐month period. The goal of these sessions was to help participants gain an understanding of their medication‐taking behaviors and the actions necessary to successfully maintain a high level of adherence. The counselor used a MI script to guide the interaction with the participants. During the session participants were encouraged to identify and discuss barriers to adherence, to express and resolve ambivalence about taking medications, and to support motivation to attain or maintain adherence. After each medication was discussed and an action plan developed, the counselor ended each session by summarizing the discussion and the action plan agreed upon by the participant and counselor. Session 1 was completed in‐person for all participants. Telephone sessions (for sessions 2 though 5) were conducted as needed for participants who were unable to meet the counselor in the clinic. Participants were paid USD 10 for completing the first MI session and USD 5 for each of the remaining 4 sessions. Participants in the intervention group also received a copy of the Get Busy Living video, a journal and a calendar (n = 125)	CONTROL: Participants randomized to the control group received the usual adherence education provided at the clinic. 3 nurse educators employed at the HIV clinic provided comprehensive adherence education to patients who are initiating or changing ART. They use a variety of teaching methods that were tailored for each individual based on factors such as education level, culture, type of regimen and time schedule. Patients were referred to the Get Busy Living staff when the nurse educators cleared them to begin taking their medications. Participants could continue to meet with the nurse educators for adherence assistance as needed after the initial education sessions (n = 122)	Yes for the per cent of prescribed doses taken on schedule; No for the per cent of doses taken	No for viral load and CD4 count
Druss 2010	Serious mental illness	HEALTH AND RECOVERY PROGRAM (HARP): Participants in the intervention group attended up to 6 group sessions led by mental health peer specialists. Sessions covered the following topics related to chronic disease self management: 1. Overview of self management 2. Exercise and physical activity 3. Pain and fatigue management 4. Healthy eating on a limited budget 5. Medication management and 6. Finding and working with a regular doctor. During the sessions, peer educators modeled appropriate behaviors and responses, and participation from each group member helped model behavior and improve motivation for other members. Attendees are taught to develop short‐term "action plans" for choosing domains of health behavior change. This process involves identifying a problem that is of particular concern, listing ideas for solving the problem, and then developing a plan outlining specific, short‐term goals for improvement. 2 certified mental health peer specialists participated in a community‐based, 5‐day CDSMP master training course to become master trainers in the CDSMP program. Subsequently, they received 3 additional days of training from the team's principal investigator and health educator in the Health and Recovery Peer (HARP) program (n = 41)	USUAL CARE: Subjects assigned to usual care continued to receive all medical, mental health, and peer‐based services that they were otherwise receiving prior to entry into the study (n = 39)	No for improving adherence to medication in patients with severe mental illness at 6 months	Yes for improving patient activation and primary care medical services use at 6 months. No for improving physical activity, physical health‐related quality of life, and mental health‐related quality of life at 6 months
Duncan 2012	HIV	MINDFULNESS‐BASED STRESS REDUCTION: MBSR aims to teach participants to respond to stressful situations ''mindfully'' ‐ a state in which one focuses on the present moment, accepting and acknowledging it without getting caught up in thoughts that are about the situation or emotional reactions. This enables people to respond to the situation by making conscious choices to respond instead of reacting automatically. The MBSR program consists of the following elements: (1) individual pre‐program intake interviews performed by the course instructor with each participant, lasting 30 minutes; (2) 8 weekly classes of 2.5 to 3 hours; (3) an all‐day silent retreat during the 6th week of the program; and (4) daily home assignments including a minimum of 45 minutes per day of formal mindfulness practice and 5 to 15 minutes of informal practice, 6 days per week for the entire duration of the course. The total in‐class contact is approximately 30 hours, and the total home assignments are a minimum of 42 to 48 hours. In addition, one to 2 additional individual interview sessions may be provided, at instructor discretion, to individual participants during the course. In addition to teaching mindfulness practices, the course includes didactic presentations that include information on stress physiology and stress reactivity. The course also addresses the effects of perception, appraisal, and attitude on health habits and behavior and on interpersonal communication (n = 40)	STANDARD CARE: Control group received standard care and went through the same assessment procedure as the intervention group (n = 36)	No for improving medication adherence in HIV patients with Mindfulness Based Stress reduction Therapy at 3 or 6 months	Yes for reducing frequency of symptoms attributable to ARTs at 3 and 6 months and distress associated with those symptoms at 3 months. No for reduction in perceived stress, depression, and positive and negative affect, at 3 and 6 months
Dusing 2009	Hypertension	MULTIFACTORIAL INTERVENTION: The set of supportive measures provided for selected centers and all patients recruited in these centers is listed below. It was up to the patients to select the tools they would like to use on an individual basis. For the patient: (a) 24‐hour timer: the timer can be set to an individual time and provides an acoustic signal every 24 hours at this point of time. (b) Set of 10 reminding stickers to be positioned at prominent places at home (e.g. refrigerator and bathroom mirror). (c) Information brochure for patients with hypertension published by the German Hypertension Society. (d) Information letter for the patient. (e) Information letter the patient can give to next of kin to receive support or his therapy (e.g. spouse reminding of drug intake). (f) Home BP measurement device. (g) Booklet to document home BP measurements (n = 101)	STANDARD CARE: At the baseline visit, all eligible patients were started on study treatment with valsartan 160 mg daily for 4 weeks. Patients with controlled BP were continued on treatment with valsartan 160 mg. Patients not achieving BP values less than 140/90 mmHg by week 4 were then up‐titrated to valsartan 160 mg and HCTZ 12.5 mg as a fixed‐dose combination. Follow‐up visits were scheduled after 2 (third visit), 4 (4th visit), 8 (fifth visit), 14 (6th visit), 24 weeks (7th visit), and at the end of the observation period at 34 weeks (8h visit). Dispensing of the study drugs was as follows. At baseline, patients received MEMS bottles containing 48 tablets of 160 mg valsartan. At 4th and 5th visits, that is, after 4 and 8 weeks, patients received further MEMS bottles containing 48 tablets of either 160 mg valsartan or 160 mg valsartan and 12.5 mg of HCTZ depending on their BP. At 6th and 7th visits, that is, after 14 and 24 weeks of treatment, patients received MEMS bottles containing 76 tablets. Patients were instructed to take their medication per mouth with water in the morning between 0700 and 1100 hours, regardless of meals. No supportive measures were given to patients (n = 105)	No for improving adherence outcome in patients with essential hypertension with the use of supportive measures	No for reduction in BP
El Miedany 2011	Rheumatoid arthritis	VISUAL FEEDBACK: The active group consisted of a visual feedback facility (visualization of computer charts showing the disease progression) that was added to their management protocol. Visual feedback is a relatively new tool that enables the patient to visualize as well as monitor a real‐time change of their disease activity parameters as well as the patient's reported outcome measures. Integrating electronic data recording in the standard rheumatology clinical practice facilitated the introduction of visual feedback into the standard rheumatology practice. During their visit, the patients were given the chance to view the progression of their disease on the computer, discuss the changes in their disease activity parameters, comorbidity risks, functional disability, and quality of life. The patients were assessed at 3‐month intervals for another 6 months (unless they sustained a flare up of their condition, at which time they would be reviewed earlier). Before every assessment in the clinic, every patient completed the multidimensional patient reported outcome measures questionnaire (n = 55)	ROUTINE MANAGEMENT: Control group patients continued their routine standard management and assessment every 3 months. All the patient's disease activity parameters, patient‐reported outcome measures (PROMs), medications, scores of falls, and cardiovascular risks were recorded and discussed verbally with the patient. Each patient was allowed to view his former completed forms and compare between his/her current scores in comparison to the earlier records (n = 56)	Yes for adherence to medication	Yes for improving pain score, patient global assessment, functional disability, quality of life, and disease activity score
Ellis 2005	Adolescents with type 1 diabetes	Standard medical care plus Multisystematic Therapy (MST), an intensive, family‐centered, community‐based psychotherapy treatment with tailored treatment goals and interventions for each family to best treat the adherence problem. MST interventions targeted adherence‐related problems within the family system, peer network, and the broader community systems within which the family was embedded (n = 64)	Standard medical care at a hospital‐based endocrine clinic where adolescents were cared for consisted of quarterly medical visits with a multidisciplinary medical team composed of an endocrinologist, nurse, dietician, social worker, and psychologist (n = 63)	No	No for all clinical outcomes
Ellis 2012	Type 1 or 2 diabetes	MULTISYSTEMIC THERAPY: Patients in the MST group received both standard medical care and treatment sessions by 5 masters‐level therapists trained to have sufficient knowledge regarding diabetes to enable them to conduct diabetes adherence interventions with families. Treatment included 1‐hour family treatment sessions, skills practice (e.g. spending 15 minutes in home to observe a caregiver implementing a reward or consequence as part of a behavior plan), attending school meetings to provide information to staff regarding diabetes care (e.g. 1‐2 hour staff training), and attending clinic visits with families (2 hours or more) (n = 74)	TELEPHONE SUPPORT: Control patients (telephone support) received an initial home visit where the program was explained to the adolescent and primary caregiver by either a master level therapists or doctoral students in clinical psychology or social work. Weekly phone calls (approximately 30 minutes each) focused on emotional support for diabetes care using client‐centered, nondirective counseling, assessing adherence to diabetes for the previous week, reviewing readings in the blood glucose meter, and helping the adolescent identify solutions to any barriers in their diabetes care. Non‐diabetes‐related problems such as peer, school, or family relationship problems were also addressed during the call if desired by the adolescent. Telephone support therapists completed the same formal diabetes education training completed by MST therapists (n = 72)	Yes for parent‐reported adherence at 7 and 12 months; No for youth‐reported adherence at 7 and 12 months	Yes for reduction in HB1Ac
Evans 2010	Coronary artery disease risk/cardiovascular risk	PHARMACIST FOLLOW‐UP: The pharmacist established goals for the patient. Goals were documented in the patient records. When any of the risk factors were uncontrolled, the pharmacist alerted the patient by telephone and mail, and the physician was notified through the patient's medical record and face to face (when possible). Patients received continuous follow‐up by the pharmacist at a minimum of every 8 weeks by telephone, mail, electronic mail, or face to face appointments. Mailed letters were reserved for patients who were successfully controlled or had been recently contacted. Information delivered during follow‐up was patient‐specific and did not require that a standard content be covered. Reasons for follow‐up included 1) To communicate relevant laboratory results, including proximity to individual targets; 2)To monitor clinical status within 7 to 10 days after the initiation or change of a drug; 3) To monitor clinical status within 7 to 10 days after experiencing an adverse event 4) To ensure that the patient was able to procure necessary follow‐up appointments 5) To provide patients with clinical goal reminders, disease‐specific information, or timely topics using periodic mailers. Emphasis was placed on conducting short follow‐up contacts that reminded and reinforced the importance of drug adherence and clinical targets. All patients were followed for a minimum of 6 months (n = 88)	SINGLE‐CONTACT GROUP: Patients met at the beginning of the study with the study pharmacist, and received a booklet about cardiovascular disease. After that meeting they received usual care and had no more contact with the study pharmacist (n = 88)	No for improving adherence to statin therapy	No for improving Framingham risk score (FRS), blood pressure, lipid profile (total cholesterol, HDL and triglycerides) and hemoglobin A1C value
Falces 2008	Heart failure	EDUCATIONAL INTERVENTION: A research team pharmacist carried out the intervention. It consisted of an interview at hospital release followed by telephone reinforcement. The intervention focused on information about the disorder, diet education, and information about the medication. Simple language adapted to the cultural needs of the patient was used. This was backed up by audiovisual and written material. Phone calls took place during the first 6 months and for 2 months following. Patient questions or issues we also discussed. Patients were also given a contact phone number which they could call if they had doubts about their treatment or illness (n = 53)	CONTROL GROUP: Visits were done at 6 and 12 months. A cardiologist provided treatment as usual and a pharmacist did a pill count (n = 50)	Yes for adherence to medication at 6 months; No for adherence to medication at 12 months	Yes for hospital readmission, number of readmissions and days in hospital at 6 months. Yes for number of hospital readmissons at 12 months. No for QoL and mortality at 6 and 12 months
Farber 2004	Asthma	Subjects in the intervention group (n = 28) received basic asthma education; instructions on use of a metered‐dose inhaler with holding chamber; a written asthma self management plan illustrated by zones colored green, yellow, and red; a sample age‐appropriate holding chamber; and prescriptions for medication needed to implement the plan. This medication included an inhaled corticosteroid drug for everyday use and a quick‐acting bronchodilator for use as needed. The importance of seeking urgent medical care in the red zone was emphasized. 3 brief follow‐up phone calls were placed to patients in the intervention group at 1 to 2 weeks, 4 to 6 weeks and 3 months after enrollment	The control group (n = 28) received routine care	Yes (based on dispensing)	No
Farooq 2011	Schizophrenia	STOPS: Participants in the STOPS arm received usual care plus specific education given to a key care supervisor about the illness and the importance of adherence; medications were provided 1 month at a time free of charge (n = 55)	TAU: Psychiatrists provided treatment as they would normally deliver in routine out‐patient settings. These included prescribing evidence‐based pharmacological treatments, out‐patient attendance in the psychiatry department as deemed appropriate by the consultant and brief counseling about the treatment and outcome. Participants who could not afford to buy medication had the option to seek free drug treatment from the social welfare department of the hospital (n = 55)	Yes for improving adherence to antipsychotic drugs at the end of 1 year	Yes for PANSS total scores, positive symptoms, and GAF scores
Fisher 2011	HIV	LIFEWINDOWS: The intervention was computer‐based, interactive ARV adherence promotion called LifeWindows developed based on the Information‐Motivation‐Behavioral skills (IMB) model. The nature of this intervention is to identify and address, through interventions, an individual's deficits in adherence‐related information, motivation, and behavioral skills. The intervention activities consisted of 20 different interactive activities that would be selected by the participants according to their goals. Patients on average spent 26 minutes to complete the full intervention with an average of 8 min dedicated to adherence intervention modules. Participants received USD 20 for completion of each session. Participants completed 1 session per month over 18 months (n = 277)	STANDARD OF CARE: Control patients received standard of care at the clinic they attended. Average total time spent to complete the full control session was 14 min. Participants received USD 20 for completion of the session per month over 18 months (n = 287)	Yes for increasing adherence to ARV in on protocol patients at the end of 18 months; No for increasing adherence to ARV in intent to treat at the end of 18 months	No for improving viral load at 18 months of intervention
Fortney 2007	Depression	TELEMEDICINE‐ENHANCED ANTIDEPRESSANT MANAGEMENT (TEAM): Patients at intervention sites received a stepped‐care model of depression treatment for up to 12 months. Treatment intensity was increased for patients failing to respond to lower levels of care by involving a greater number of intervention personnel with increasing mental health expertise. The intervention involved 5 types of providers: (1) PCPs located at CBOCs; 2) consult telepsychiatrists located at parent VAMCs; (3) an off‐site depression nurse care manager (RN); (4) an off‐site clinical pharmacist (PharmD); and 5) an off‐site supervising psychiatrist. The consult‐telepsychiatrist accepted consultations or referrals from PCPs. The supervising psychiatrist provided clinical supervision to the care manager and clinical pharmacist via weekly face‐to‐face meetings. Patients and providers could choose either watchful waiting or antidepressant treatment (Step 1). Nurse care manager encounters were conducted via telephone and were scripted to enhance standardization and reproducibility. During the initial care management encounter, patients were: (1) administered the PHQ9 symptom monitoring tool; (2) educated and activated using a semi‐structured script4; and 3) assessed for treatment barriers using semi‐structured scripts for endorsed barriers. Follow‐up encounters to monitor symptoms, medication adherence, and side effects were scheduled every 2 weeks during acute treatment and every 4 weeks during watchful waiting or continuation treatment. Non‐adherent patients or those experiencing severe side effects were administered semi‐structured scripts.3 A trial was considered to have failed in the acute phase if the patient: (1) was non‐adherent to the medication, (2) experienced severe side effects, (3) experienced 5‐point increase in their PHQ9 score, or (4) did not respond (50% decrease in PHQ9 score) after 8 weeks of antidepressant therapy. All feedback was provided to PCPs using the electronic medical record. Progress notes reporting failed trials requested an electronic co‐signature from the PCP. If the patient did not respond to the initial antidepressant, the pharmacist conducted a medication history and provided pharmacotherapy recommendations to PCPs via an electronic progress note (Step 2). The pharmacist also provided non‐scripted medication management over the phone to patients experiencing severe side effects or problems with non‐adherence. If the patient did not respond to 2 antidepressants trials, the protocol was to recommend a telepsychiatry consultation followed by additional treatment recommendations to the PCP (Step 3) (n = 177 patients (3 practices))	USUAL CARE: Control groups received usual care. Usual care patients like the intervention group were provided with provider education and patient education. Also, the screening results were entered into the electronic medical record (n = 218 patients (4 practices))	Yes for improving adherence to antidepressant medication in depressed patients at 6 and 12 months	Yes for increased response and no for remittance in the intervention group at 6 months. Yes for improving odds of remittance and no for response in intervention group at 12 months. Yes for improving satisfaction in intervention group at 12 months. No for improving physical health score at 6 and 12 months. Yes for improving mental health score at 12 months and not at 6 months
Friedman 1996	Hypertension	Telephone‐linked computer system (TLC) ‐ an interactive computer‐based telecommunications system that converses with patients in their homes between office visits to their physicians (n = 156)	Regular medical care (n = 145)	Yes	Yes
Gallefoss 1999	Asthma or chronic obstructive pulmonary disease (COPD)	An educational intervention consisting of a specially constructed patient brochure, 2 2‐hour group sessions (separate groups for asthmatics and patients with COPD) concentrating on pathophysiology, anti‐obstructive medication, symptom awareness, treatment plans, and physiotherapy. One or 2 40‐minute individual sessions were supplied by both a nurse and a physiotherapist. At the final teaching the patients received an individual treatment plan on the basis of the acquired personal information and 2 weeks of peak flow monitoring (n = 39 asthmatics, n = 32 COPD patients)	Usual care from GP (n = 39 asthmatics, n = 32 COPD patients)	No	No
Gamble 2011	Asthma	INTERVENTION: The intervention was individualized, provided psycho‐education and was led by an experienced registered nurse with basic level psychotherapy training for 12 months to improve adherence to medication. In addition to standard asthma care, intervention group subjects were offered up to 8 months of individual visits within a 12‐week period. Although the proposed intervention was unique in its design, to increase the internal validity of the study, the Compliance Therapy Model was used to provide the underpinning theoretical framework. This model encompassed the Transtheoretical Model of Change, Motivational Interviewing and Cognitive Behavioral Therapy principles, providing a flexible short‐term intervention using patient's individual reasons for non‐adherence as a guide to plan intervention content. The model used a non‐confrontational technique which elicited self motivation and provided a process to resolve ambivalence towards medication taking (n = 9)	STANDARD ASTHMA CARE: All participants received standard asthma care at the difficult asthma service but the control group did not receive any further intervention. Subsequent follow‐up visits for the control group was conducted at 6 months and 12 months post‐recruitment (n = 11)	Yes for percentage of prescriptions filled. Yes for number of participants in intervention group filling prescriptions	Yes for reducing the daily prescribed dose of maintenance prednisolone. No for improving hospital admissions, FEV % predicted, quality of life, asthma control score, anxiety, and depression
Gani 2001	Seasonal rhinitis and asthma	B group (n = 35) with drug therapy plus training on the use of nasal spray, and C group (n = 36) the same as B plus a lesson on rhinitis and asthma	A group (n = 30) with drug therapy alone	Yes for A versus B + C	Yes: between group A and group C in respiratory symptoms. Yes, in the use of inhaled albuterol (Fisher test) among the groups was observed (A versus B plus C: P value = 0.005; A versus C: P value = 0.005)
Gensichen 2009	Major depression	CASE MANAGEMENT: The intervention was in accordance with Chronic Care Model, which emphasizes proactive support for the patient by the entire practice team. 1 healthcare assistant from each practice assigned to the intervention group in 2 workshops (an 11‐hour and a 6‐hour workshop). This interactive training included information on depression, communication skills, telephone monitoring, and behavioral activation for the patient. The healthcare assistants contacted their patients by telephone twice a week in the first month and then once a month for the following 11 months. They monitored depression symptoms and adherence to medication by using the Depression Monitoring Context List. Healthcare assistants also encouraged patients to follow self management activities, such as medication adherence and activation for pleasant or social activities. The assistants provided this information to the family physician in a structured report that stratified the urgency of the contact by a robot scheme. Family physicians in both the intervention and control groups received training on evidence‐based depression treatment guidelines (n = 35 practices, 310 patients)	USUAL CARE: Patients in the control group were given usual care (n = 39 practices, 316 patients)	Yes for improving adherence to medication at 12 months	Yes for reducing depression symptoms score and increased response and remission in intervention group at 12 months. No for quality of life scores and number of family physician or mental health specialist contacts at 12 months
Ginde 2003	Macrolide antibiotic treatment	Patients in the ED group (n = 38) were provided a full course of azithromycin (6 x 250 mg) at no charge and given instructions on the proper dose and frequency before discharge from the ED	Patients in the pharmacy group (n = 36) received a written prescription for a full course of azithromycin before discharge from the ED	No	No. The prescription filling rate for the control group is based on the assumption that control patients used a participating pharmacy 8 blocks away that provided the drugs free of charge ‐ patients were apparently not asked if they filled their prescription elsewhere. The "course completed" rate is based on self report on a telephone call ‐ no indication that interviewers were blinded to group; nor was the exact question given (if there was one). Technically, this study qualified for the review, but the reliability and credibility of the measures are suspect. At least the question of the control group's filling of prescriptions could have been cleared up. The intervention is also impractical in any setting where giving drugs out for free is not possible
Girvin 1999	Hypertension	Enalapril 20 mg once daily (n = 27). Cross‐over study, with 4‐week study periods	Enalapril 10 mg twice daily (n = 27). Cross‐over study	Yes	No
Gould 2009	Acute cardiac event	DISCHARGE NURSING INTERVENTION (DNI): The discharge nursing intervention consisted of written discharge materials and telephone follow‐up by an expert cardiovascular nurse. Expert nurses were defined as those having advanced education and clinical expertise in the care and management of this population. Delivery of the intervention was time‐sensitive. The intervention was offered at discharge and continued within 24 hours of discharge. DNI group received a packet containing group instructions, medication review materials, a medication pocket card, suggested Internet sites, copies of the interview tools, and the Revised Illness Perception Questionnaire (IPQ‐R) instrument (n = 64)	USUAL CARE: Control group patients received routine discharge materials and usual care. Subjects in the control group received an envelope containing group instructions, copies of interview tools, and the IPQ‐R (n = 65)	No for improving adherence to medication in early discharge interventional cardiology patients	No for use of urgent care
Gray 2012	Ocular hypertension (OHT), open‐angle glaucoma (OAG)	INDIVIDUALIZED PATIENT CARE: Patients in the individualized care group received standard care plus an individualized care plan implemented by a glaucoma trained nurse. This included a 45‐minute assessment of health care needs and beliefs with supplied booklets and drop diaries, a 20‐minute educational session, and a 10‐minute training session on instilling eye drops. A 1‐year follow‐up care plan was designed and implemented according to healthcare needs, based on education and support, which was tailored to gaps in glaucoma knowledge, pre‐existing beliefs, and ability to manage an eye drop regimen. Patients were given the nurse's contact telephone for advice or assistance between consultation. Follow‐up involved ongoing training and support by both face‐to‐face and telephone consultations. This incorporated a review of drop diaries in the initial weeks of therapy (these were continued if found beneficial as a reminder tool), reminders to collect and use drops, and repetition of information as required. Needs were reassessed and the level of support adjusted accordingly at the end of each consultation. The intervention nurse was the same throughout, and the intervention was guided by prescriptive documentation (n = 64)	STANDARD CARE: Standard of care is not definitively described. Education, advice, and support varies from clinic to clinic within Manchester Royal Eye Hospital but is limited for many patients. No further contact after initial consultation (n = 63)	Yes for improving refill adherence at 12 months. Yes for improving self reported adherence at 12 month follow‐up	No for mean IOP, IOP fluctuation, and clinical management at 12 months and mean IOP at 24 months; Yes for IOP fluctuations and clinical management at 24 months
Hamann 2007	Schizophrenia or schizophreniform disorder	SHARED DECISION‐MAKING (SDM): The intervention was designed to inform patients about their treatment options and to prepare them for a planning talk with their physicians. A printed 16‐page booklet covering the pros and cons of oral versus depot formulation, first‐ versus second‐generation antipsychotics, psychoeducation, and type of socio‐therapeutic intervention was presented to the patients through the head nurse of the ward as soon as the psychiatrist in charge considered them able to cooperate. Trained nurses assisted the patient to work through the booklet. Within the decision aid, patients were asked to write down their experiences with previous antipsychotic medication and to indicate their preferences regarding the different options on each topic. Nurses were advised to answer any questions of the patients and to encourage them to state any point of view contrary to that of the doctor. They were also instructed to postpone the participation of patients in the study if serious thought disturbances or delusional misinterpretations were detected while working through the booklet. The average time for working through the booklet was 30 to 60 minutes. Patients met their physicians within 24 hours after having worked through the decision aid with their nurse. The aim of these meetings, "planning talks", was to reach an agreement between patient and psychiatrist on the further treatment according to the preferences indicated by the patient in the booklet. Like nurses, physicians were also trained about the SDM and required communication skills (n = 54)	USUAL CARE: "Patients in the control group were treated "as usual", thus they did not receive the decision aid and there was no arrangement for an extra planning talk" (n = 59)	No for improving adherence to antipsychotic medication at 6 and 18 months	No for reducing rehospitalizations within 6 and 18 months after discharge. No for improving CGI and GAF scores at 18 months
Haynes 1976	Hypertension	Tailoring, self monitoring of pills and blood pressure, rewards for higher adherence and lower blood pressure (n = 20)	Usual care (n = 18)	Yes	No
Hederos 2005	Children with asthma	Group meetings (weekly x 3, then 6 months later, 1.5 hours each) for parents of children with asthma held by a multidisciplinary team (pediatrician, nurse, psychologist) + usual care and basic education (see Control group strategy; n = 32)	Family received education about asthma at the first visit to the clinic. They received a written treatment plan that tailored the lowest effective dose. Treatment was stopped if the child had no asthma for 6 months (n = 28)	Yes for parents and doctors estimated adherence on a visual analogue scale (VAS), for poor adherence and for greater than or equal to 100% adherence. No for estimated adherence tracked from diaries, for good adherence, and for verified adherence from measured doses	No for all clinical outcomes
Heisler 2010	Diabetes	RECIPROCAL PEER SUPPORT: After the baseline assessment, patients in the RPS group attended a 3‐hour group session facilitated by a care manager and a research associate. In the first half of the session, patients' laboratory and blood pressure results were reviewed and action planning was introduced. In the 2nd half, patients received brief training in basic peer communication skills and were paired with another age matched patient in their cohort. Peer partners were encouraged to call each other at least once a week using an interactive, voice‐response–facilitated telephone platform that recorded call initiation, frequency, and duration; enabled partners to contact each other without exchanging telephone numbers and to set periods during which calls could be blocked; and generated automated reminders every 7 days if no peer calls were attempted. During a reminder call, patients could be transferred automatically to their peer partner's number. The system also allowed patients to leave voice messages for research staff or care managers. At the end of the initial session, patients were given a DVD that demonstrated peer communication skills and a diabetes self management workbook that they could use to help guide their peer telephone calls. Patients were also offered 3 optional 1.5‐hour group sessions at months 1, 3, and 6. These were completely patient‐driven sessions at which patients were encouraged to share concerns, questions, strategies, and progress on their action plans. Sessions were facilitated by a care manager and a research associate. Research associates were present to help maintain intervention fidelity by encouraging nondirective facilitation of group discussions and to complete a checklist of key areas covered and communication skills used in each session (n = 126)	NURSE CARE MANAGEMENT: At baseline and 6‐month follow‐up, all study patients had their HbA1c level and blood pressure checked and were informed of the results and the most recent cholesterol values were in their medical record. Patients in the NCM group then attended a 1.5‐hour session, led by a care manager, to review their laboratory and blood pressure results, ask questions, and receive information on VA care management services. They were provided their assigned care manager's contact information and encouraged to schedule follow‐up telephone calls or face‐to‐face visits with that care manager. Each patient was also provided with diabetes self management educational materials. Patients in the NCM group thus received enhanced usual care, because even though they would all be eligible for nurse care manager support at the study sites, many patients are not aware of and do not avail themselves of this service unless referred by their physician (n = 119)	No for improving adherence to medication at 6 months	Yes for reducing the mean HbA1c level and increasing social support score at 6 months. No for reducing blood pressure and diabetes‐related emotional distress at 6 months
Henry 1999	H. Pylori infection	10 days of omeprazole 20 mg twice daily, amoxicillin 500 mg 3 times a day and metronidazole 400 mg 3 times a day, verbal advice on medication use and its possible side effects in an initial 20‐minute consultation. Patients also received medication in dose‐dispensing units, an information sheet on H. Pylori treatment, and a medication chart. Compliance in intervention group patients was also encouraged by a phone call 2 days after the start of therapy (n = 60)	10 days of omeprazole 20 mg twice daily, amoxicillin 500 mg 3 times a day and metronidazole 400 mg 3 times a day, verbal advice on medication use and its possible side effects in an initial 20‐minute consultation (n = 59)	No	No
Hill 2001	Rheumatoid arthritis	The intervention group (n = 51) received 7 x 30 minute one to one sessions of patient education	The control group (n = 49) received standard management	Yes for improving adherence to D‐penicillamine (DPA) for rheumatoid arthritis	No for improving clinical outcomes of plasma viscosity, c‐reactive protein, articular index, morning stiffness and pain score
Holland 2007	Heart failure	HEARTMED PHARMACIST INTERVENTION: The pharmacist arranged a home visit, within 2 weeks of hospital discharge, at a time when they could meet the patient and any carer(s). Where appropriate, pharmacists educated the patient/carer about heart failure and their drugs and gave basic exercise, dietary, and smoking cessation advice. They also encouraged completion of simple sign and symptom monitoring diary cards (including monitoring body weight), removed discontinued drugs (with the patient's consent), fed back recommendations to the general practitioner, and fed back to the local pharmacist any need for a drug adherence aid (for example, a Medidos or Dosett container). We provided all pharmacists with a detailed manual describing the expected components of their visit and asked them to deliver education in line with advice given in the British Heart Foundation's booklet Living with Heart Failure, which they left with patients after the first visit. Pharmacists completed a standardized visit form during each visit. 1 follow‐up visit occurred at 6 to 8 weeks after discharge to review progress and reinforce original advice. We also recorded a selection of pharmacists' visits to investigate the intervention's delivery and the pharmacists' communication skills (n = 149)	USUAL CARE: The nature of the intervention meant that no clear "placebo" could be provided. Participants were told after randomization which group they were in. Those in the control group received usual care (n = 144)	No for improving medication adherence	No for improving quality of life and reducing ED visits and admissions
Holstad 2011	HIV	KHARMA INTERVENTION: The KHARMA intervention consisted of 8 group sessions using motivational interviewing delivered in a group format. It was designed to empower women to make decisions and develop strategies about taking ART as prescribed and consistently using risk reduction behaviors, such as condom use and to overcome resistance/ambivalence to both. The sessions lasted about 1.5 to 2 hours, and were led by trained MI nurses. The first and last session focused on both adherence and risk behavior, 3 sessions were devoted to adherence only and 3 to risk reduction behaviors only, including a session on disclosure which is important to risk reduction as well as adherence. Each session included a discussion of goals and goal setting related to the topic. MI techniques were incorporated into every session. In keeping with the autonomy support spirit of MI, participants as a group chose which topic they wanted to address first. The majority of groups (n = 14) chose medication adherence as the first topic (n = 104)	HEALTH PROMOTION PROGRAM: The control group sessions were equivalent in length and time to the MI group and were led by trained nurses and a health educator. This group used health education techniques of lecture/discussion/educational games and focused on nutrition, exercise, stress recognition, and women's health issues tailored to the HIV‐positive woman. Participants received a manual containing content and supplementary materials for each session. Adherence and RRB were not addressed in the HPP and facilitators were instructed to redirect the group if these issues came up (n = 103)	No for improved adherence to ART	Yes for CD4 counts at 9 months. No for all other outcomes
Hou 2010	oral contraceptive use	TEXT MESSAGING: Participants received daily text‐message reminders. During the 3‐month study period, each participant assigned the intervention received a daily text message, "Please remember to take your birth control pill," sent at a designated time chosen by the participant. (n=41)	USUAL CARE: Patients in the control group received usual care and were not offered additional medication reminders. (n=41)	No for improving adherence to oral contraceptives.	No for pregnancy at 3 months.
Howe 2005	Children with type 1 diabetes	2 intervention groups, standard care (see Control) plus: 1) Education (ED) ‐ One‐time session by the study co‐ordinator that aimed to provide families with basic diabetes management skills (n = 21). 2) Education and telephone case management group (ED and TCM) ‐TCM consisted of standardized telephone calls which reviewed blood sugars, safety issues, problem‐solving skills, diet and meal planning, and changing insulin dose, as well as parenting and behavior management skills with parents as needed (n = 26)	Standard care (SC) from a nurse practitioner and endocrinologist (n = 28)	Yes for the adherence questionnaire (ADH), in comparison between the ED and TCM group versus the SC group	No for both intervention groups
Howland 1990	Acute infections	Warnings about potential adverse effects of drugs (n = 50)	No warnings about adverse effects of drugs (n = 48)	No	No
Huguelet 2011	Schizophrenia or other non‐affective psychoses	RELIGIOUS AND SPIRITUAL ASSESSMENT: The intervention was delivered by psychiatrists who were trained by the researchers. Psychiatrist attended a 90‐minute training session during which they were informed about the rationale for taking into account the spiritual dimension in the treatment of patients with schizophrenia and how to conduct a spiritual assessment. They were made aware of how their own religious and spiritual experiences could influence their identity and world view, as well as how their attitudes toward such experiences might introduce biases into clinical assessment and treatment. Finally, psychiatrists were reminded to show respect for patients with different religious and spiritual backgrounds. Psychiatrists used a semi‐structured interview guided by the following topics: religious and spiritual history, effects of illness on spirituality or religiousness, current spiritual or religious beliefs and practices, subjective importance of religion in general, subjective importance of religion in coping with the illness, synergy of religion with psychiatric care. After each assessment the psychiatrist met with 2 of the authors, a psychiatrist and a psychologist of religion. In these sessions the individual patient was discussed for 10 to 40 minutes, depending on the clinical context. The participating psychiatrist reported the outcome of his or her spiritual assessment and was given guidance and advice, similar to clinical coaching; when needed, a more thorough discussion from a psychotherapeutic perspective was undertaken (n = 42)	USUAL CARE: "For the control group, psychiatrists were instructed to avoid speaking about religious issues during the 3‐month follow‐up period unless patients spontaneously brought up the subject." (pg 81) (n = 42)	No for improving medication adherence	No for improving positive and negative syndrome scale, global assessment of functioning, WHO quality of life instrument, recovery assessment scale, and social functioning questionnaire. Yes for improving the willingness to ask for help at 3 months follow‐up
Janson 2009	Moderate‐to‐severe persistent asthma	SELF MANAGEMENT EDUCATIONAL INTERVENTION: Participants in the individualized self management group received both the self monitoring of the control group plus an individualized self management component. Self management sessions were held by a certified asthma educator and respiratory therapist. The sessions consisted of asthma facts and medication actions and individualized components such as verbal and graphic interpretation of spirometric results, peak flow trends, metered dose inhaler technique error, and skin allergen results (with strategies to control specific personal environmental exposures). The peak flow monitor was modified for the intervention group to use a traffic light analogy and correlated to a simple written action plan (n = 45)	SELF‐MONITORING ALONE: Control patients attended the same number of visits as intervention patients, but control visits were only for data collection. During each phase of the trial, all participants measured morning peak flow with an electronic peak flowmeter (Airwatch; iMetrikus, Carlsbad, Calif) and also recorded their daily values in a diary. All participants were told that higher peak flow numbers meant their airways were more open and lower numbers meant their airways were more closed. An electronic medication monitor, which concealed readings from the subject (Doser CT; MediTrack, Hudson, Mass), was placed on each ICS inhaler. Participants also monitored daily symptoms, night‐time awakenings, and tabulated ICS and inhaled b‐agonist (IBA) use in the diary. Data from the electronic monitors and diary pages were collected at each study visit (n = 39)	Yes for maintaining > 60% adherence during the intervention period; No for mean adherence, mean change in adherence, and for maintaining > 60% adherence at the end of the study	Yes for night‐time awakenings during the study period, beta‐agonist use during the intervention period, and mean neutrophil count over the study period. No for FEV1, morning peak flow, perceived asthma control, quality of life, symptom score, ECP, symptom‐free days, night‐time awakenings during the intervention, beta‐agonist use over the entire study period, neutrophil counts during the intervention, and eosinophils and tryptase counts
Jarab 2012 a	Type 2 diabetes	PHARMACIST INTERVENTION: Patients in the pharmacist intervention group received structured patient education and discussion about type 2 diabetes, risks and complications from diabetes, the prescribed drug therapy, proper dosage, side effects, and the importance of medication adherence. The pharmacist also emphasized lifestyle management (changing unhealthy dietary habits that affect blood glucose, blood pressure and lipid levels; regular physical activity; and monitoring and record blood glucose levels). Smokers were referred to a hospital‐run smoking cessation program. A special booklet on diabetes and lifestyle changes was given to each patient. 8 weekly telephone calls were made by the pharmacist to discuss and review prescribed therapy, emphasize the importance of adherence, and to answer patient questions or address concerns. Each call average 20 minutes (n = 85)	USUAL CARE: Control patients (n = 85) received usual care by medical and nursing staff (patient assessment; 3‐ or 6‐month blood glucose and blood pressure measurements; advice on self monitoring blood glucose, and nutrition counseling) (n = 86)	Yes for improving medication adherence at 6 months	Yes for A1c values, systolic and diastolic blood pressure, and LDL‐C levels; No for HDL‐C levels and BMI
Jarab 2012 b	Chronic obstructive pulmonary disease	PHARMACIST INTERVENTION: Intervention participants received structured education about chronic obstructive pulmonary disease (COPD) and management of its symptoms from a clinical pharmacist in a separate room at the outpatient clinic. The pharmacist also completed a medication table designed specifically to discuss types, indications, doses, frequency of administration, and possible side effects for each prescribed medication. The importance of simple exercises symptoms control and the technique for expectoration were discussed with the intervention patients. A booklet on these techniques was prepared to assist in the education session and the patients were given a copy to take home with them. The clinical pharmacist used the motivational interviewing technique with the aim of improving adherence to the prescribed treatment. Patients who still smoked were referred to a special smoking cessation program within the hospital (n = 66)	TREATMENT AS USUAL: Controls did not receive pharmacists care (n = 67)	Yes for improving adherence to medication at 6 months	No for change in forced expiratory volume in 1 second (FEV1) and BMI at 6 months. No for difference in health‐related quality of life and emergency department visit for acute exacerbation of COPD at 6 months. Yes for reducing hospital admissions for acute exacerbation of COPD at 6 months
Jiang 2007	Coronary heart disease (angina pectoris or myocardial infarction)	CARDIAC REHABILITATION PROGRAM: Patients in the intervention group received a 12‐week, hospital‐initiated, home‐based multifaceted cardiac rehabilitation intervention led by a nurse. Phase I of the intervention involved in‐hospital individual and family education about CHD and self management principles, medication management, angina prevention and management, physical exercise, dietary management, smoking cessation, and family support. All sessions employed principles of adult learning and were short to facilitate time for discussion. All participants received a self help practical workbook. In Phase II of the intervention provided home‐based supervision, coaching and support by a experienced cardiac nurse over 12 weeks using home visits and telephone calls that included goal setting, practice, monitoring, problem‐solving and reinforcement, with iteration of this process to ensure the achievement of mutually set behavioral goals on a daily basis and used a log record for goal‐directed self reporting, self monitoring and self reinforcement of daily rehabilitative behaviors and mobilization of the family to join the behavioral change and provide appropriate support (n = 83)	ROUTINE CARE: Control patients received conventional care and were not offered any additional interventions (n = 84)	Yes for improving adherence to medication at 3 months. No for improving adherence to medication at 6 months	Yes for reducing serum lipids (TG, TC, LDL ‐ except for HDL) and systolic and diastolic BP at 3 months. No for body weight at any point and blood pressure at 6 months
Johnson 1978	Hypertension	(a) Self monitoring of blood pressure at home (n = 34); (b) Monthly home visits by a research assistant (n = 33); (c) Both a and b (n = 35)	Neither intervention (n = 34)	No for each intervention	No for each intervention
Johnson 2011	HIV/AIDS	BALANCE PROJECT EXPERIMENTAL INTERVENTION: The intervention was 5 60‐minute individual counseling sessions with each session designed around topics relevant to ART side effects coping. Intervention sessions followed a standard structure and set of activities, but were individually tailored to participants' specific life contexts, stressors, and goals. Participants received USD 30 at the 3‐month assessment if they completed all 5 sessions prior to that assessment interview. The intervention was delivered between months 3 and 6 of the study (n = 128)	USUAL CARE: Control group participants received treatment as usual and received no active psychosocial interventions prior to the final trial assessment interview (n = 121)	Yes for improving adherence to ART medication at 15 months	No for change in SECope Positive Emotion Focused Coping, Taking Side Effect Medications, and Non‐Adherence subscales
Kalichman 2011	HIV	INTEGRATED INTERVENTION: Intervention was an integrated risk reduction and adherence intervention based on the conflict theory of decision‐making. It consisted of a 45‐minute one to one orientation and goal setting with 1 of the group facilitators before 5 120‐minute group sessions and a 60‐minute post group one to one counseling session, conducted by facilitators/interventionists. Assessment was done at baseline, 3, 6, and 9‐month intervals for a total of 12 months of follow‐up (n = 217)	ATTENTION CONTROL CONDITION: Comparison intervention group received 45‐minute one‐on‐one orientation (with 1 facilitator), 120‐minute 5 group sessions (with male‐female facilitator pairs containing 8 to 10 participants of mixed gender and sexual orientation) and a 60‐minute one‐on‐one post‐group counseling session. The first group session focused on building group cohesion and discussed how to access quality health information. The remaining 4 group sessions covered detecting early warning signs of cancer, breast and testicular self examination, nutrition decision‐making, healthy food selection, planning exercise, and relaxation. The final individual counseling session set personalized health improvement goals (n = 219)	Yes improved adherence to ART over 12 months	Yes for sexual risk behavior and STI. Yes for adherence and prevention strategies and risk compensation beliefs. No for viral load
Kato 2008	Cancer	CANCER TARGETED VIDEO GAME: The intervention participants were given a mini‐computer containing commercial game plus the intervention game, which was a video PC game called Re‐Mission47. In this game, players control a nanobot, "Roxxi", in 3‐dimensional environments within the bodies of young patients with cancers that commonly are diagnosed in AYA. Game content was engineered to address behavioral issues that were identified in literature reviews and preproduction targeting studies as critical for optimal AYA patient participation in cancer treatment. Video‐game play includes destroying cancer cells and managing common treatment‐related adverse effects such as bacterial infections, nausea, and constipation by using chemotherapy, antibiotics, antiemetics, and a stool softener as ammunition. To win, players control the nanobot, Roxxi, to ensure strategically that virtual patients engage in positive self care behaviors, such as taking oral chemotherapy to fight cancer cells, taking antibiotics to fight infection, taking stool softeners to prevent bowel perforations, practicing good mouth care to combat mucositis, using relaxation techniques to reduce stress, and eating food to gain energy. Neither the nanobot nor any of the virtual patients "die" in the game. If players "fail" at any point in the game, then the nanobot powers down and players are given the opportunity to try the mission again. Players had to complete missions successfully before moving on to the next level. Participants were instructed to play for at least 1 hour per week during the 3‐month period (n = 197)	COMMERCIAL VIDEO GAME: The control patients were provided a commercial video game ‐ A PC version of Indiana Jones and the Emperor's Tomb served as the control game because the play structure and controller interface closely resembled that of Re‐Mission (n = 178)	No for self reported adherence. Yes for improving adherence to chemotherapy as evidence by 6MMP concentration alone or combined 6MMP and 6 TG concentrations	Yes for improving cancer knowledge and self efficacy; No for improving QOL, stress and control
Katon 2001	Depression	Patient education, 2 visits with a depression specialist, telephone monitoring and follow‐up (n = 194)	Usual care (n = 192)	Yes	Yes for SCL‐20 scores and depressive symptoms. No for episodes of relapse/recurrence
Kemp 1996	Acute psychosis	4 to 6 sessions of compliance therapy that focused on illness, conceptualization of the problem, symptoms, side effects of treatment, and the stigma of drug treatment (n = 25)	4 to 6 session non‐specific counseling (n = 22)	Yes	Yes for global functioning assessment. Yes for full version of the brief psychiatric rating scale. No for the abridged version of the brief psychiatric rating scale. No for dose of antipsychotic drug
Kemp 1998	Psychotic disorders	4 to 6 sessions of compliance therapy that focused on illness, conceptualization of the problem, symptoms, side effects of treatment, and the stigma of drug treatment (n = 39)	4 to 6 session non‐specific counseling (n = 35)	Yes, at 12 months.	No, at 12 months, for the 7‐item version of the Brief Psychiatric Rating Scale. Yes, at 12 months, for the Global Assessment of Function. Yes, at 6 months, for the Schedule for Assessment of Insight
Khdour 2009	Chronic obstructive pulmonary disease	PHARMACIST INTERVENTION: The intervention was individualized and tailored for each patient by the clinical pharmacist based on disease knowledge, smoking status, medication adherence, self efficacy in managing breathing difficulty, and exercise and diet habits. Intervention patients were educated individually by the clinical pharmacist (in a structured fashion) on COPD, their prescribed medication, the importance of adherence, inhaler technique (written information was provided) and the management of COPD symptoms. The clinical pharmacist ensured that the patient knew the indications and doses of each medicine, and was able and willing to use the inhaler devices prescribed. The clinical pharmacist also discussed with the intervention patients the importance of simple exercises that patients can do at home (e.g. upper and lower limb exercises and relaxation techniques), symptom control (pursed lip technique) and the technique for expectoration (huff and puff technique). The pharmacist demonstrated these techniques and then asked the patients to carry out the techniques to ensure that they fully understood how to perform them. A booklet on these techniques was prepared to assist in the education session and the patients were given a copy to take home with them. Advice, using the motivational interviewing technique, was provided to the patients who still smoked and referral to a special smoking cessation program run within the hospital was made. A customized action plan for acute exacerbations, including advice to GPs to provide a prescription for an antibiotic (amoxicillin/clavulanic acid) and an oral corticosteroid to be initiated promptly by patients for exacerbations,was developed for each patient. The clinical pharmacist through motivational interviewing attempted to increase the intervention patients' self efficacy to manage or avoid breathing difficulty while participating in certain activities. The interventions were tailored according to the preliminary assessment, i.e. checklists of patients' needs were prepared by the research pharmacist and forwarded to the clinical pharmacist to discuss with the patients. The initial intervention lasted for approximately 1 hour for non‐smoker patients and slightly longer for patients who currently smoked. At each outpatient clinic visit (every 6 months arranged by the hospital consultant), intervention group patients received reinforcement of the education on COPD and its treatment from the clinical pharmacist. In addition, follow‐up telephone calls by the clinical pharmacist to reinforce the education and motivate the patients to achieve their goals were made at 3 and 9 months, i.e. between outpatient clinic appointments (n = 86)	USUAL CARE: Control patients received usual hospital outpatient care from medical and nursing staff (n = 87)	Yes for improving adherence to medication at 6 and 12 months	Yes for reducing the number of exacerbations of COPD and hospitalizations at 12 months. Yes for improving symptoms and impact but no for improving activity at 6 and 12 months. No for change in forced expiratory volume in 1 second and body mass index at 12 months
Kimmel 2012	No specific clinical problems; patients just needed to be on warfarin	LOTTERY‐BASED INCENTIVES: Patients in the intervention group were offered financial incentives to remain adherent. All patients were provided with an Informedix Med‐eMonitor System, which has a display screen and separate medication compartments in which to place their warfarin. The monitor connects to an analog telephone line. They were enrolled in a daily lottery in a daily lottery, administered via the Med‐eMonitor, with an expected daily value of USD 3, or (2) no lottery intervention. participants had a 1 in 5 chance of a USD 10 reward and 1 in 100 chance of a USD 100 reward each day if they opened the monitor's pill compartment and confirmed that they took their warfarin as prescribed that day. If patients were told to not take warfarin on a particular day, they would only be eligible for the lottery if they did not take a pill that day (n = 53)	CONTROL: Patients in the control arm were set up with the Med‐eMonitor in order to measure medication adherence. Participants were also seen by their anticoagulation clinic practitioner as they normally would and by the study staff at baseline, 2 weeks, 3 months, and 6 months (n = 48)	No for improving overall adherence. No for improving adherence in a priori group with INR above target range	No for overall anticoagulation control. Yes for anticoagulation control in subjects below target range and no for subjects above target range
Klein 2009	Rejection episodes in liver transplanted patients	PHARMACEUTICAL CARE: In addition to routine clinical care, patients in the intervention group received pharmaceutical care services provided by a dedicated hospital pharmacist. The pharmaceutical care program usually started about 1 week before discharge from the transplant surgery unit. The hospital pharmacist met with the patient 3 to 4 times and educated him on different issues regarding immunosuppressive medication, for example, action of the drugs, side effects, interactions, vital signs, laboratory data, and discharge medication. On discharge, the hospital pharmacist handed out and explained written information, including a discharge medication plan, information regarding the immunosuppressive therapy, and a diary for documenting vital signs and laboratory data. During the first year after transplantation, the patient met the pharmacist at least once per quarter year and at maximum once per month. During these meetings the pharmacist discussed with the patient changes in medication, laboratory values, and drug‐related problems. Preferably, family members were involved. In addition, the hospital pharmacist reviewed the patients' drug therapy, to minimize drug‐related problems, and simplify drug regimens (n = 26)	CONTROL: Patients in the control group did not receive pharmaceutical care but they received routine clinical care. from the same hospital pharmacist as the intervention group (n = 24)	Yes for adherence	No for rejection episodes
Knobel 1999	HIV	Zidovudine + lamivudine + indinavir PLUS individualized counselling/assessments which consisted of adaptation of treatment to the patient's lifestyle and detailed information about highly active antiretroviral therapy (n = 60)	Zidovudine+ lamivudine + indinavir plus conventional care (n = 120)	Yes	Yes for reduction of viral load. No for detectable viral load.
Kunutsor 2011	HIV	TREATMENT SUPPORTER INITIATIVE: Patients in the TS arm received both the TS intervention and the standard adherence intervention package. Elements of the standard intervention package consisted of self monitoring of medication taking using adherence diaries; regular individual and group education by peer‐workers using patient education leaflets and tabletop flip‐charts; and late attendee tracing. The treatment supporters were usually family members—usually a partner, mother, daughter, sister, brother, friend, or neighbor/friend—who were chosen by the patient with the assistance of the health workers, had accepted the patient's HIV status and were confidantes. These individuals were committed to support the patient with ART for a long time, had gained the patient's trust over time, and commanded respect. Patients were asked to bring their chosen treatment supporter to the ART clinic for the health worker to explain about ART, adherence and treatment support. This includes commitment, confidentiality, knowledge on HIV and ART related needs, and perhaps emergency resource needs such as money, help with household, and children. Treatment supporters were educated with the following WHO Integrated Management of Adolescent and Adult Illness (IMAI) educational materials: Patient Education Flipchart, Patient Education Cards, and Caregiver Booklets. They were also educated on how to remind the patient to take their medicine, be present at the follow‐up appointments, remember all important test results and clinic history over time, and to accompany patient to support group meetings if possible. Treatment supporter meetings were also held at the clinic every 2 or more weeks to deal with issues of burn out, patient non‐adherence and other barriers to treatment and adherence (n = 87)	STANDARD ADHERENCE INTERVENTION: Patients randomized to the control arm did not have a treatment supporter but otherwise received the same standard adherence intervention package including the ongoing existing health education and adherence counseling support that all patients received during routine monthly clinic visits. These existing interventions are typical for HIV/ AIDS treatment programs in Uganda and the rest of sub‐Saharan Africa (n = 87)	No for mean adherence. Yes for proportion of patients who were at least 95% adherent	No for clinical attendance. No for number of deaths
Lai 2011	Post‐menopausal osteoporosis	PHARMACIST COUNSELING: The intervention was enhanced pharmacist care. Patients were followed over a 12‐month period that included 4 visits. All participants were given a 3‐month supply of their drugs at each visit, and instructed on how to take their medications. Intervention participants received an explanation on osteoporosis, risk factors, lifestyle modifications, goals of osteoporosis therapy, side effects and the importance of medication adherence. Verbal counseling was reinforced with an osteoporosis booklet. The pharmacist also reviewed participant's medications and conducted monthly follow‐up via telephone calls for the first 6 months, then every 3 months until month 12 (n = 100)	USUAL CARE: Participants were dispensed 3 months' supply of bisphosphonate and instructed on how to take their medications. Received no counseling (n = 98)	Yes for improving adherence based on pill counts at 6 months. Yes for improving adherence based on self recording at 6 and 12 months. No for all other adherence outcomes	No for bone turnover markers at 3 and 6 months
Laporte 2003	Compliance and stability of international normalized ratio (INR) of 2 oral anticoagulants with different half‐lives	The standard education group received the minimum information consistent with ethical oral anticoagulant therapy (OAT) with no particular emphasis on the necessity of strict compliance. Patients in the intensive education group received information about the causes of anticoagulation instability and the importance of strict adherence. The intensive education group were provided information through visual material, were visited daily by nurses and physicians to repeat some items, and were tested daily about their education. The education, either standard or intensive, was given until hospital discharge	A 2 by 2 factorial design with patients randomly allocated to warfarin (long half‐life, n = 43) or acenocoumarol (short‐half life, n = 43) and to either intensive education (n = 43) or standard education (n = 43)	No	No
Larrey 2011	Genotype 1 hepatitis C	NURSE EDUCATION: The nurse used a standardized questionnaire to evaluate the patient's understanding of the disease and the side effects of treatment. The nurse responded to any questions and informed the patient as thoroughly as possible with the means at his/her disposal, including by using explanatory texts and drawings. The nurse's goal during the consultation was to improve adherence. The following points were systematically covered: a) evaluation of the reasons for any eventual change in adherence; b) improvement of the quality of the patient‐medical team relationship; c) explanation of para‐clinical tests on therapeutic follow‐up and discussion of the positive aspects of the results; d) facilitation of the quality of the patient's relationship with his/her family and/or professional milieu; e) increasing if necessary social service support for the patient. This consultation with the nurse took place in a standardized fashion, which was set out in a document to guide the consultation. All the nurses involved in these consultations had received prior training in the field of viral hepatitis and its treatment, and on the details of this study. The consultation lasted between 30 and 45 minutes. At the end of the consultation, the nurse filled out a standardized questionnaire build for this study and comprising 34 items in 8 groups The patient could call the nurse free‐of‐charge if necessary outside the standard consultation dates (n = 123)	USUAL CARE: The control group received conventional clinical follow‐up. These patients did not receive consultation from the nurses (n = 121)	No for improving adherence	Yes for improving virological response
Lee 2006	Hypertension and hyperlipidemia	Comprehensive pharmacy care program consisting of 3 elements (n = 83): individualized medication education; medications dispensed using blister packs; follow‐ups every 2 months by clinical pharmacists	Usual care (n = 76); followed a 6‐month comprehensive care period; patients were then given a 90‐day supply of their medications with one repeat)	Yes	Yes for systolic blood pressure. No for diastolic blood pressure and LDL‐C
Lester 2010	HIV	SMS GROUP: All intervention group participants were given brief training about the use of SMS intervention by the study clinicians. On Monday morning of each week, the site nurse or clinical officer sent a text message via SMS to patients in the intervention group to inquire about their status and thus to remind them about the availability of phone‐based support. Regular, structured mobile phone communication between healthcare workers and patients could improve patient outcomes by both reminding patients to take their ART and by providing support to the patients. Patients in the intervention group were instructed to respond within 48 hours that either they were doing well or that they had a problem. The clinician then called patients who said they had a problem or who failed to respond within 2 days. Participants were instructed that healthcare workers were available to respond during clinic hours only (n = 273)	USUAL CARE: Control group is standard care. Standard care at Kijaiado study site included providing 1 counseling session at ART initiation and at the 2 Nairobi sites included providing 2 counseling sessions before and 1 session 1 month after ART initiation. Disclosure of HIV status, pairing up with a treatment adherence partner, and participation in support groups was encouraged but not insisted upon. Additional brief counseling was provided at each site during dispensation of the drugs in the clinic or pharmacy. Patients did not receive weekly SMS (n = 265)	Yes for improving adherence to ART medication at 6 and 12 months	Yes for viral loads at 12 months
Levy 2000	Acute asthma	1‐hour structured asthma consultation with study nurse 2 weeks after entry into study, followed by 2 or more 30‐minute consultations at 6‐weekly intervals (n = 103)	Usual care (n = 108)	Yes for use of inhaled topical steroids and rescue medication for severe attacks. Not statistically significant for use of inhaled topical steroids and rescue medication for mild attacks	Yes
Maitland 2008	HIV/AIDS	ONCE DAILY DOSING (QD): Patients were switched to a fixed‐dose combination tablet of ABC and 3TC dosed once a day. All other antiretroviral agent(s) in the patient's regimen were dosed once a day from or before screening (n = 48)	USUAL DOSING (TWICE A DAY): Patients remained on ABC and 3TC twice a day. All other antiretroviral agent(s) in the patient's regimen were dosed once a day from or before screening (n = 48)	Yes for adherence at 4 weeks	No for viral load at 4 weeks. No for HAD at 4 weeks
Margolius 2012	Hypertension	HOME TITRATION GROUP: Clinicians of patients in the home titration arm completed an algorithm of antihypertensive medication adjustments. Health coaches made weekly telephone calls to participants in both study arms to discuss overall well‐being, adherence to action plans, and blood pressure values. Patients in the home titration arm who reported blood pressure greater than 140 mm Hg systolic or greater than 90 mm Hg diastolic and excellent medication adherence could choose to increase their antihypertensive medication regimen according to the algorithm without a clinician appointment. In those cases, health coaches notified a physician investigator to fax the prescription to the pharmacy. Clinicians were notified of medication changes by e‐mail, and health coaches entered the change in the electronic health record. The duration of the intervention was 6 months (n = 129)	NO HOME TITRATION: Home monitoring and health coaching alone (no home titration arm), included health coaches made weekly telephone calls to participants in both study arms to discuss overall well‐being, adherence to action plans, and blood pressure values. The duration of the intervention was 6 months (n = 108)	No for adherence at 6 months	No for blood pressure at 6 months. No for change in number of primary care office visits
Marquez Contreras 2004	Hypercholesterolemia	The intervention group (IG) of 63 patients received the standard care given to control group, and in addition received a telephone call at 7 to 10 days, 2 months, and 4 months. The goal of the intervention was to establish the level of compliance, categorize this as adequate or inadequate, and make recommendations based on that. Level of compliance was determined by comparing the number of pills consumed to the number that should have been consumed (calculated using self reported information about the number of pills remaining, number of pills dispensed, and fill date of the prescription). Compliance was defined as taking 80% to 110% of the pills that should have been taken thus far. Compliant patients were congratulated and encouraged to continue their good level of compliance as it would lower their risk of heart disease. Non‐compliant patients were notified their behavior was considered non‐compliant and encouraged to better comply with therapy as it would lower their risk of heart disease	The control group (CG) of 63 patients, who received the doctor's normal treatment, which included oral information about hypercholesterolemia, advice about its control, brochures about dietary recommendations, 3 month‐long prescriptions for a cholesterol‐lowering medication, and titration of that medication if indicated at 3 months	Yes	Yes for the 6‐month decrease in total cholesterol and LDL‐C was significantly different between IG and CG (Table 3). No for the 6‐month decrease in triglycerides and HDL‐C
Marquez Contreras 2005	Hypertension	2 intervention groups (both receiving routine primary care plus 1 of): 1) Telephone intervention (TIG; n = 216) ‐ Patients received 3 telephone calls (15 days, 2 months, 4 months) by nurse to reinforce compliance and remind them of scheduled visits. The nurse gave feedback about compliance based on patient self report of pills consumed. 2) Mail intervention (MIG; n = 212) ‐ Patients received 3 mailed communications (15 days, 7 weeks, 15 weeks) to promote compliance through education in hypertension, medication compliance, and reminders of scheduled visits	Routine primary care for hypertension (n = 212)	Yes for pill count in both intervention groups in comparison to the control group	Yes for blood pressure control in both the TIG and the MIG in comparison to the control group. Yes for both SBP and DBP at 6 months for both the TIG and the MIG when compared to the control group. Yes for both SBP and DBP reduction from baseline to 6 months in the TIG in comparison to the control group
Marquez Contreras 2006	Hypertension	Usual care plus OMRON automatic monitor for home blood pressure monitoring (HBPM), a card to record pressures, with an instruction book and phone call to go over instructions (n = 100)	Usual care in a primary care setting at 40 sites (n = 100)	Yes	No for all clinical outcomes except the change in diastolic blood pressure from baseline to 6 months between groups
Marquez Contreras 2007	Hypercholesterolemia	CALENDAR REMINDER: The patients in the intervention group were mailed a calendar as a reminder of medication taking. The calendar is double sided. On one side, there is a calendar where the patient can make with an x the days of the months when they should be taking their medication. On the other side, there is information about the next visits, treatment recommendations and a place to insert lipid analysis info (n = 110)	USUAL TREATMENT: Patients received treatment as usual as provided by a family physician (n = 110)	Yes for adherence to lipid medication	Yes for cholesterol count at 24 weeks. Yes for triglyceride count at 24 weeks. No for HDL‐C count at 24 weeks; Yes for LDL‐C count at 24 weeks
Martins 2009	Tuberculosis	FOOD INCENTIVE: The intervention was a food incentive program in which the intervention group patients were provided with midday meals every time they attended the clinic. Patients were to report to the clinic 5 or 6 mornings a week to receive directly observed treatment in the intensive phase and fortnightly in the continuation phase (n = 137)	NUTRITIONAL ADVICE: Control participants received usual care. They were also given nutritional advice (verbal and written) about the types of locally available food that would constitute a balanced diet and would be likely to assist cure of tuberculosis (n = 133)	No for improvement of adherence in patients receiving directly observed treatment for TB with food incentives	No for completion of treatment. No for symptoms. No for cough clearance. Yes for weight gain
Matsumura 2012	Hypertension	COMBINATION PILL: The intervention was a combination pill instead of multiple pills. Patients assigned to the intervention group received a combination pill (losartan 50 mg/hydrochlorothiazide 12.5 mg). Follow‐up was done at 1, 3, and 6 months (n = 103)	MULTIPLE PILLS: Control patients were provided with an angiotensin receptor blocker and a diuretic. Follow‐up was done at 1, 3, and 6 months. Adherence outcomes and blood pressure were measured at the 1, 3, and 6‐month appointments; patient outcomes at before and 6 months after randomization (n = 104)	No for improving adherence to medication at 1, 3, and 6 months in patients with hypertension	No for improving blood pressure at 1, 3, and 6 months in patients with hypertension. No for difference in adverse events and blood variables (hematocrit, serum creatinine, serum sodium, serum potassium and serum uric acid) observed in 2 groups
Mehuys 2011	Type 2 diabetes	COMMUNITY PHARMACIST INTERVENTION: Patients in the intervention group received pharmacist‐led, individual education about type 2 diabetes and its complications, education about the correct use of oral hypoglycemic agents, facilitation of medication adherence, healthy lifestyle education (diet, physical exercise, and smoking cessation), and reminders about annual eye and foot examinations. These elements were implemented at the first visit and at each prescription‐refill visit of the patient during the 6‐month intervention period (n = 35 pharmacies and 153 patients)	USUAL PHARMACIST CARE: Patients in the control group received usual pharmacist care (n = 31 pharmacies and 135 patients)	No for adherence to oral hyperglycemics with high refill rates and self reported adherence in both groups	Yes for reduction in HbA1c. No for FPG. Yes for FPG and HbA1c in high risk group (FPG > 10.7)
Merinder 1999	Schizophrenia	8‐session psychoeducational program for schizophrenic patients and their relatives, conducted using a mainly didactic interactive method (n = 23)	Usual treatment provided in community psychiatry (n = 23)	No	Yes for knowledge of schizophrenia and for VSSS subscore satisfaction with relatives' involvement. There was also a trend towards reduced BPRS score in intervention group (P value = 0.07). No for time to relapse or insight into psychosis or psychosocial function (GAF)
Morgado 2011	Essential hypertension	PHARMACIST INTERVENTION PROGRAM: In sessions at baseline (30 minutes) and 3 and 6 months follow‐up (20 minutes) the clinical pharmacist thoroughly interviewed the patient to identify problems with medication adherence, provided patient education and counseling, and provided advice to physicians regarding pharmaceutical care. Pharmacists could schedule additional visits as needed, and patients were encouraged to bring all empty medication blisters and boxes to visits (n = 98)	USUAL CARE: Control group patients received usual care through the hospital clinic. Pharmacists were not involved in their care (n = 99)	Yes for improving adherence to antihypertensive medication at 9 months	Yes for patient knowledge of target BP values. Yes for proportion of patients achieving BP control. Yes for reduction in baseline SBP and DBP
Morice 2001	Asthma	Subsequent visits from the asthma nurse until discharge from hospital (n = 35)	'Routine care' from medical and nursing staff but no further intervention from the asthma nurse (n = 30)	No (on the contrary, medication compliance of beta‐agonist inhaler in intervention group was lower than in control group)	No for the total occasions of GP call‐out and re‐admission. Yes for patients percentage of claiming to have a writing management plan and self management
Moshkovska 2011	Ulcerative colitis	PERCEPTUAL (MOTIVATIONAL) INTERVENTIONS: Participants who were assigned to the intervention group attended a one‐on‐one education and motivation session conducted by the researcher. First, this session aimed to identify perceptual and practical barriers to 5‐ASA medication adherence and, second, to motivate, convince, and educate. The session was designed as a structured dialog allowing the patient to comment and ask questions. Educational topics included ulcerative colitis, 5‐ASA medication, and adherence. Participants were also encouraged to identify practical barriers to 5‐ASA medication use, as well as perceived barriers to adherence. Strategies for overcoming these barriers were also discussed. Sessions lasted for 20 to 30 minutes and were intended to deliver individualized support to each patient. At the end of the session patients were offered an educational leaflet to take away. Patients had the option of being accompanied to these educational sessions by a relative or friend and any accompanying person was also offered a leaflet specifically written for relatives and friends. During the session patients were offered a free choice of up to 3 practical adherence enhancing interventions; simplifying of dosing regime, medication reminder charts, visual medication reminders for refrigerators and bedside cabinets, daily electronic pill box organizers with alarms, weekly electronic pill box organizers, weekly non‐electronic pill box organizers, mobile telephone alarm set‐up, taking into consideration that practical problems and adherence may change over time. Participants had the option of changing these interventions at any time during the study and at weeks 4 and 24 they were formally asked whether they wished to change the interventions. 1 brief follow‐up telephone call was made to patients in the intervention group at week 4. During the mid‐study visit a 10‐minute reinforcement session was held during which the importance of adherence to prescribed 5‐ASA medication was reiterated, beliefs regarding medicine‐taking were reassessed, and any practical problems were discussed. All intervention group patients were given a telephone number which enabled them to obtain advice at specified times or leave a message for a return call (n = 43)	USUAL CARE: Patients in the control group received standard prescribed care from their clinical team. The treatment regime for these patients was not changed in any way as a result of involvement in the study and no reminders or other additional adherence support was offered by the research team. Participants in the control group provided 3 urine samples at 0, 24, and 48 weeks and completed questionnaires during baseline and end‐of‐study visits. At the end of the study, control group participants were given the educational leaflets that intervention group participants received at the beginning of study. (n = 41)	Yes for improving adherence to 5‐ASA at 12 months to reduce the risk of disease flare‐ups.	No difference for disease flare‐ups at 12 months.
Mullan 2009	type 2 diabetes mellitus	DIABETES MEDICATION CHOICE DECISION AID TOOL: The intervention was the use of a decision aid tool in one appointment with the patient. The tool is designed to enable clinicians to discuss with patients the potential advantages and disadvantages of adding an agent from 1 of the following antihyperglycemic classes to their regimen: metformin, insulin, thiazolidinediones, exenatide, and sulfonylureas. The tool consists of 6 cards that describe the possible effects of the medications on 6 outcomes: "Weight Change," "Low Blood Sugar," "Blood Sugar," "Daily Routine," "Daily Sugar Testing," and "Side Effects". After reviewing and discussing the cards that the patient and the clinician choose to discuss, they arrive at the medication that best matches the patient's circumstances and preferences. The patient receives a copy of the cards in the form of a take‐home pamphlet. (n = 48)	USUAL CARE: Participants in the usual care arm discussed anti‐hyperglycemic medication in the usual manner. In addition, patients received a professionally produced (by the Mayo Clinic Patient Education Center) 12‐page general pamphlet on oral anti‐hyperglycemic medications to take home (n = 37)	Yes for adherence judged by pharmacy records. Yes for self reported adherence	No for HbA1c levels
Muniz 2010	Acute coronary syndrome	POST DISCHARGE EDUCATIONAL INTERVENTION: Intervention is an educational intervention consisting of a signed agreement between patient and physician on the objectives to be reached. The intervention includes a personalized interview at discharge with patient and nearest next‐of‐kin, in which physician and patient discuss and sign an agreement with the patient‐specific secondary prevention procedures and therapeutic aims. Both physician and patient keep a copy of the signed agreement. Written back‐up information (about heart attack, controlling cholesterol, body weight, and blood pressure, and effects of smoking), and a phone number as to where to call in case of questions were given. Intervention also included an interview with the patient 2 months after discharge in order to review the agreement, adapt treatment if needed, and reinforce the intervention. Informative materials are given once again.The visits took an average of 30 to 40 minutes each. (n = 867)	USUAL CARE: Control group participants received usual care. Follow‐up was at 6 months (n = 890)	Yes for significant difference between intervention and control groups at 6 month for improving adherence to statins. No for difference between intervention and control groups for medication adherence to aspirin, clopidogrel, beta‐blockers, ACE‐inhibitors, and Angiotensin receptor blocking agent Type II at 6 month	Yes for reduction in BMI. Yes for reduction in lipid level and waist circumference at 6 months in intervention group with an educational program at discharge following acute coronary episode. No for blood pressure control
Murray 2007	Heart failure	PHARMACIST INTERVENTION: A pharmacist delivered the intervention by using a protocol that included a baseline medication history of all prescription and over‐the‐counter drugs and dietary supplements taken by patients, which patients brought with them to the baseline interview, and the results of an assessment of patient medication knowledge and skills. The pharmacist dispensed enough of the patient's medications to last approximately 2 months. The intervention lasted 9 months. When medications were dispensed, the pharmacist provided patient‐centered verbal instructions and written materials about the medications. Each medication category had an icon associated with it. The same icon appeared on the container label and lid and on the written patient instructions. The pharmacist monitored patients' medication use, health care encounters, body weight, and other relevant data by using a study database. Information about patients was communicated as needed to clinic nurses and primary care physicians by face‐to‐face visits, telephone, paging (physician only), and e‐mail (physician only). An interdisciplinary team of investigators trained the intervention pharmacist. The intervention pharmacist also studied guidelines for treating heart failure, key concepts in the pharmaceutical care of older adults, communication techniques, and the pharmacotherapy of the cardiovascular drugs for heart failure (n = 122)	USUAL CARE: Control groups received usual care. Usual care participants were aware of the purpose of the study. They received their prescription services from the same pharmacy as the intervention participants, but the pharmacists who attended the usual care participants were not trained by the interdisciplinary team (n = 192)	Yes for adherence based on MEMS and pharmacy refill records. No for self reported adherence	Yes for exacerbations. No for improving the quality of life in heart failure patients receiving pharmacy intervention at 6 and 12 months compared to usual care
Nazareth 2001	Complex regimens in the elderly (aged 75 years and older on 4 or more medicines who had been discharged)	The hospital pharmacist developed discharge plans which gave details of medication and support required by the patient. A copy was given to the patient and to all relevant professionals and carers. This was followed by a domiciliary assessment by a community pharmacist. (n = 165)	In the control group, patients were discharged from hospital following standard procedures that included a discharge letter to the general practitioner listing current medications (n = 151)	No	No
Nguyen 2008	Gastrointestinal irritability due to prenatal multivitamins	SMALL LOW IRON DOSE TABLET: Small low dose iron tablets were used as the intervention in this study. PregVit a prenatal multivitamin that contains 35 mg elemental iron, as ferrous fumarate was prescribed for intervention group patients. The multiple vitamins and minerals are formulated into 2 small tablets, and is taken as 2 tablets per day. After enrolment, subjects received a 1‐week follow‐up telephone call and then were interviewed by telephone on a monthly basis until the end of pregnancy. Each interview documented obstetrical and medical information, adherence based on pill intake recall, and any reported adverse events. The date(s) of discontinuation at any time(s) during study participation was documented as the date(s) reported by the subject during the monthly interview (n = 92)	SMALL 60 MG MULTIVITAMIN TABLET: A small‐sized high‐dose (60 mg) multivitamin administered once daily was used as the control in this study (n = 75)	No for improving adherence to multivitamin in pregnant women	No for reduced adverse effects in pregnant women
Nieuwkerk 2012	Increased cardiovascular risk	EXTENDED CARE: Subjects in Extended Care (EC) received multifactorial risk‐factor counseling, in addition to Routine Care (RC). During the counseling the nurse practitioner explained the presence of unmodifiable risk factors, such as age, gender, and family history, and modifiable risk factors, such as lipid levels, diabetes mellitus, blood pressure, overweight, smoking habits, and physical activity. The study nurse was not blinded to the purpose of the study. The counseling focused on changing modifiable risk factors such as increasing medication adherence, reducing overweight, smoking cessation, and increasing physical activity. All obtained data were summarized in a personal risk‐factor passport: a graphical presentation of the patient's calculated 10‐year cardiovascular disease risk. It also showed the target risk that could be reached if all the patient's modifiable risk factors were optimally treated, as well as the standard age‐ and gender‐related risk. 10‐year risk and target risk were calculated using the Framingham risk score. The risk‐factor passport contained the most recent ultrasound image of the patient's carotid artery, as well as an example of a healthy and an unfavorable image of the carotid artery, which were both explained and discussed by the nurse practitioner. This risk‐factor passport was updated during each follow‐up visit (n = 101)	ROUTINE CARE: Routine care consisted of measuring body weight and blood pressure and performing a capillary lipid profile at each visit. Initially, all participants received atorvastatin 10 mg, unless baseline cholesterol levels were severe and more aggressive therapy was needed. Dose escalation during the study period was allowed if deemed appropriate by the treating physician (n = 100)	Yes for improving adherence to lipid‐lowering medication in patients with increased cardiovascular risk	Yes for lowering the low‐density lipoprotein cholesterol, improving intima‐media thickness and anxiety. No for improving body weight, body mass index, blood pressure, adverse events and quality of life
O'Donnell 2003	Schizophrenia	The experimental group (n = 28) received 5 sessions of compliance therapy, each session lasting 30 to 60 minutes. The sessions covered a review of the patient's illness history, understanding of the illness and his or her ambivalence to treatment, maintenance medication and stigma. Compliance therapy is a cognitive behavior intervention with techniques adapted from motivational interviewing, other cognitive therapies and psychoeducation	The control group (n = 28) received non‐specific counseling comprising of 5 sessions lasting 30 to 60 minutes	No	No
Odegard 2005	Poorly controlled type 2 diabetes, on oral medications	Usual care (see Control) plus: Pharmacist‐led intervention (n = 43): Pharmacist‐patient communication on diabetes progress; pharmacist‐provider communication on the subject's progress; medication‐related problems ‐ the pharmacists were not formally affiliated with the clinic	Usual care (primary care, university‐based, medical clinics) (n = 34)	No	No for all clinical outcomes
Ogedegbe 2012	Hypertension	POSITIVE AFFECT INTERVENTION: Patients in the Positive Education (PE) control group received a culturally tailored educational workbook designed (1) to enhance patients' knowledge about hypertension, (2) to improve self management behaviors, and (3) to support goal‐setting. Patients randomized to the Positive Affect (PA) intervention group were given the same workbook as those in the PE group but with an additional chapter that addresses the benefits of positive moments in overcoming obstacles to medication adherence. Also, these patients received 2 forms of PA during bimonthly telephone calls. First, they were asked to identify small things in their lives that invoke positive feelings in them and were then instructed to incorporate these positive thoughts into their daily routine. The positive thoughts were further reinforced during subsequent bimonthly telephone calls. Second, the patients received unexpected small gifts mailed to them before each telephone call. This strategy was based on the potential of the receipt of unexpected gifts to induce positive feelings. For self affirmation induction, the patients were asked to remember their core values and proud moments in their lives whenever they encounter situations that make it difficult for them to take their medications (n = 125)	PATIENT EDUCATION: Patient Education (PE) control group received a culturally tailored educational workbook designed (1) to enhance patients' knowledge about hypertension, (2) to improve self management behaviors, and (3) to support goal‐setting. On receipt of the workbook, trained Research Assistants (RAs) reviewed each chapter with the patients and then asked them to sign a behavioral contract that asked them to make a commitment to taking their medications as prescribed. Subsequent to this session, each patient received bimonthly telephone calls, during which the RAs assessed the patient's behavioral contract and confidence to take their medications as prescribed. These assessments served as the basis for reviewing and counseling the patient on perceived barriers to medication adherence. The intervention lasted for 12 months (n = 131)	Yes for improving adherence to medication at 12 months	No for reducing systolic and diastolic blood pressure at 12 months
Okeke 2009	Glaucoma	INTERVENTION: The intervention consisted of 4 components. (1) a 10‐minute educational video created through Alcon, Inc. marketing branch for the DA device, which stressed the importance of regular drop‐taking, its rationale and expected effects, alternatives to eyedrops, and methods to maximize co‐operation, such as linking drops to a daily activity, keeping a drop‐taking calendar diary, and using family members to help in reminding them; (2) a structured discussion with the study co‐ordinator to develop a strategy for improving adherence that included finding the best time of day to take the medication, distributing a blank calendar diary and going over details of how to keep it, and discussing individual patient barriers to taking the medication; (3) reminder telephone calls from the co‐ordinator, including administration of a questionnaire about drop‐taking behavior, difficulty with drops, side effects, and eliciting questions about therapy (this call was made once per week for the first follow‐up month and then every other week for the next 2 months); and (4) activation of the audible and visible alarms on the DA (n = 35)	USUAL CARE: Usual care group were told that it is important to take their eyedrops as prescribed but had no other intervention (n = 31)	Yes for improving eyedrop adherence at 6 months	No for lowering intraocular pressure between 3 and 6 months
Otsuki 2009	Asthma	ASTHMA BASIC CARE (ABC): ABC intervention received 5 30‐ to 45‐minute home visits by trained asthma educators (AEs) 1, 2, 3, 4, and 8 weeks after randomization. The ABC intervention is a home‐based asthma education program with 5 core components: (1) review of the prescribed asthma regimen and training in medication, spacer, and peak flow technique; (2) development of an asthma action plan; (3) identification of barriers to accessing health care and problem‐solving to reduce barriers; (4) discussion of beliefs and concerns about asthma and medications; and (5) provision of written asthma education materials (n = 84) ADHERENCE MONITORED FEEDBACK (AMF): The intervention included ABC + AMF. AMF stands for adherence monitoring with feedback and ABC stands for asthma basic care. These patients received 1. Objective feedback of medication adherence: electronic medication feedback. The AEs were trained to provide non‐threatening, supportive feedback on adherence to encourage a partnership with the family; 2. Goal‐setting: families were encouraged to set asthma control goals (e.g. no coughing at night) and weekly adherence goals. The AEs assisted families in setting age‐appropriate expectations regarding the child's ability to self manage asthma; 3. Reinforcement for attaining adherence goals: the importance of positive reinforcement. When the child attained the adherence goal, the AE provided a small reward (e.g. crayons). When it was not achieved, the AE worked with the family to identify barriers and taught problem‐solving skills. 4. Strategies for self monitoring medication use: families were taught to monitor adherence and asthma symptoms by using behavioral charts and symptom diaries. When possible, the AE highlighted the relationship between improvements in adherence and asthma outcomes (n = 83)	USUAL CARE: Patients received an asthma education booklet and resource guide that provided information about low‐cost asthma care providers, social services, legal services, and other resources. Participants were encouraged to receive care from their primary care provider (n = 83)	Yes for pharmacy refills both AMF versus UC and Combined intervention group versus UC were significant but declined after active intervention was removed. No difference for ABC versus UC or AMF versus ABC. No for self report	Yes for reduction of ED visits between AMF and UC group. No for reduction in oral corticosteroids between AMF and UC groups. No for asthma symptom frequency and hospitalizations between AMF and UC group. No for reduction of ED visits between ABC and UC groups. Yes for improvement in asthma symptom frequency between ABC and UC groups. Yes for decrease in oral corticosteroid use between ABC and UC group. No for hospitalization rate between ABC and AMF groups. No for improvement in any clinical health outcome between AMF and ABC group. Yes for ED visit reduction and use of oral corticosteroids between combined intervention groups and UC group. No for asthma symptom frequency and hospitalization between combined intervention groups and UC
Parienti 2007	HIV	ONCE A DAY DOSING: Patients were switched from 2 a day nevirapine to a 1 a day formula (n = 31)	TWICE A DAY DOSAGE: Control participants continued to take nevirapine twice a day (n = 31)	No for adherence rates. Yes for increased monthly days without dose. No for monthly drug holidays	No for viral control
Parsons 2007	HIV	PROJECT PLUS INTERVENTION: Intervention was 8, 60‐minute individual sessions based on Information Motivation Behavioral Skills model delivered by delivered by master's degree–prepared counselors. 2 complementary techniques—motivational interviewing (MI) and cognitive‐behavioral skills training (CBST)—were integrated, allowing trained counselors to match targeted information and skill‐building techniques to the particulars of each client's motivation for change.The first session was delivered immediately on completion of the baseline assessment, thereby ensuring that each participant has a minimum dose of 1 session. Follow‐ups were conducted at 3 and 6 months (n = 65)	EDUCATION CONDITION: 8 education sessions of 60 minutes facilitated by a health educator was the intervention. Sessions were designed to be completed weekly, but participants had 12 weeks to complete all 8 sessions. The first session was delivered immediately on completion of the baseline assessment, thereby ensuring that each participant had a minimum dose of 1 session. The sessions were video taped to ensure that motivational interview or cognitive‐behavioral skills training was not used (n = 78)	Yes for improving percentage dose adherence and percentage day adherence at 3 months. No for improving percentage dose adherence and percentage day adherence at 6 months	Yes for reducing viral load and increasing CD4 count at 3 months. No for reducing viral load at 6 months and No for increasing CD4 count at 6 months
Pearson 2007	HIV	PEER DELIVERED MODIFIED DIRECTLY OBSERVED THERAPY (MDOT): The participants in the MDot intervention group received both the standard of care and a 6‐week peer intervention to monitor their morning weekday dose. Peers also provided daily social support, information about the benefits and side effects of HAART, and help to address barriers to adherence. Peers were also a link between participants and other members of the HIV clinic team and the community (n = 175)	STANDARD CARE: Includes no‐cost medications, clinical and laboratory follow‐up, psychosocial adherence support by a trained social worker, and referral to community‐based peer support groups. Mandatory pre‐HAART counseling involves education about dosing, side effects, nutritional requirements, and the importance of adherence. Patients were encouraged to identify a treatment partner to help with adherence, provided with information on community‐based support groups and nutritional resources, and instructed to contact their medical provider, nurse, pharmacist, or peer if they have any difficulties or concerns about their medication regimen. Peers were HIV‐positive, chosen from among patients at the clinic and participants in community‐based groups through self nomination or nominations by clinic staff, and were paid a small stipend for their work. Patients met with the pharmacist and peer for pharmacy refills at week 2, 4, and 6 for the first 2 months and monthly thereafter (n = 175)	Yes for improving 7‐ and 30‐day adherence at 6‐ and 12‐month follow‐up	No for mean CD4 cell count at 6 and 12 months. No for mortality rate at 6 months
Perrin 2010	Asthma	COMBINATION METERED DOSE INHALER (MDI): Subjects received the intervention treatment regimen for a duration of 24 weeks that involved 125 mg FP and 25 mg salmeterol in a combination Smartinhaler, 2 actuations twice daily. Participants were seen in the clinic on 5 occasions. At the first visit, subjects were randomized and issued the appropriate Smartinhalers, and inhaler technique was checked. Subjects were instructed to take 2 actuations of the study medications twice daily, resulting in a daily dose of 500 mg FP and 100 mg salmeterol with both regimens. Subjects were advised that the study was designed to compare the efficacy of the 2 regimens but were not informed that adherence would be monitored. They were told that the MDI casing looked different because it was possible to program it with a reminder alarm, but that this function would not be used in this study (n = 57)	SEPARATE METERED DOSE INHALER (MDI): Subjects received a treatment regimens for a duration of 24 weeks of 125 mg FP and 25 mg salmeterol in separate Smartinhalers, 2 actuations twice daily. Participants were seen in the clinic on 5 occasions. At the first visit, subjects were randomized and issued the appropriate Smartinhalers, and inhaler technique was checked. Subjects were instructed to take 2 actuations of the study medications twice daily, resulting in a daily dose of 500 mg FP and 100 mg salmeterol with both regimens. Subjects were advised that the study was designed to compare the efficacy of the 2 regimens but were not informed that adherence would be monitored (n = 54)	No for improving compliance during the final 6 weeks of the study, for the first 3 6‐week periods, percentages of days that subjects were adherent, or for the proportion of subjects who took > 50%, 80%, or 90% of their prescribed inhaler medication	No for Asthma Control Questionnaire score and lung function (FEV1)
Peterson 1984	Epilepsy	Counseling, leaflet, self monitoring of pill‐taking and seizures, mailed reminders for appointments and missed drugs refills (n = 27)	Usual care (n = 26)	Yes	No
Peterson 2004	Dyslipidemia	Patients in the intervention group (n = 45) were visited at home monthly by a pharmacist, who educated the patients on the goals of lipid‐lowering treatment and the importance of lifestyle issues in dyslipidemia and compliance with therapy, assessed patients for drug‐related problems, and measured total blood cholesterol levels using point‐of‐care testing	Patients in the control group (n = 49) received standard medical care. There was no further contact with patients in the control group after the initial collection of baseline data, until 6 months had lapsed. At that time, their final total blood cholesterol level was measured, and the current medication regimen and self reported compliance were recorded	No	No
Peveler 1999	Depression	Treatment information leaflet (n = 53), drug counseling (n = 52) or both leaflet and counseling (n = 53)	Usual care (n = 55)	Yes for counseling (at 12 weeks). No for leaflet	No for counseling. No for leaflet
Phumipamorn 2008	Diabetes	EXTRA PHARMACIST SERVICE: Patients received their usual scheduled care by a primary care physician every 4 to 8 weeks. At each visit, fasting blood glucose was checked by the laboratory. Blood pressure and weight were recorded by a qualified nurse. A research pharmacist checked the pill count. Each patient then met a physician who assessed the patient and issued a repeat or modified prescription which the dispensing pharmacist filled and they also gave general advice on the medication uses. This was done over the dispensary counter on a routine basis. In addition to the usual care, each patient of the study group had a scheduled meeting with the research pharmacist for 4 consecutive visits at 2‐month intervals. Each visit was on the same date as the physician's appointment and in addition, to avoid a missed appointment, a health personnel co‐ordinator attached to the primary health care centre in the area, where a patient was living, reminded the patients of the scheduled visit 3 days prior to each visit date. At each visit, the research pharmacist refilled prescriptions, discussed the uses of medication and checked the pill count. Education on diabetes which included appropriate lifestyles and correct diet was also provided apart from a companion diabetic pamphlet which covered the diabetic complications, the targets of treating diabetes, lifestyle change, and antidiabetic medications (n = 67)	USUAL CARE: The control group received their usual scheduled care by a primary care physician every 4 to 8 weeks. At each visit, fasting blood glucose was checked by the laboratory. Blood pressure and weight were recorded by a qualified nurse. A research pharmacist checked the pill count. Each patient then met a physician who assessed the patient and issued a repeat or modified prescription which the dispensing pharmacist filled and they also gave general advice on the medication uses. This was done over the dispensary counter on a routine basis (n = 68)	Yes for improving adherence to medication in Muslim diabetic patients	No for A1C. Yes for change in total cholesterol. No for changes in triglycerides. Yes for change in LDL. Yes for change in HDL. No for change in non HDL
Portsmouth 2005	HIV	Participants were assigned to take Stavudine (d4T), which is a prolonged‐release once‐daily formulation of a thymidine‐based nucleoside reverse transcriptase inhibitor (NRTI). Both groups continued their other medications (n = 22)	Participants in the control group were assigned to continue the twice daily version of d4T (IR/3TC/EFV or Combivirs/EFV) as per their screening regimen (n = 21)	No for all adherence outcomes	No for all clinical outcomes
Powell 2010	Heart failure	SELF MANAGEMENT PLUS EDUCATION: In the self management plus education treatment, patients received group base heart failure education plus counseling to help patients develop mastery in problem‐solving skills and in 5 self management skills. 18 2‐hour group meetings of approximately 10 patients were spread over the course of 1 year. At each meeting, education in the form of 18 heart failure tip sheets summarized basic elements of patient management. A problem‐solving format was used. Groups were led by health professionals (n = 451)	EDUCATION ONLY: Patients randomized to receive education received the same 18 Heart Failure Tip Sheets, on the same schedule as the self management group meetings but delivered by mail. To ensure receipt and check comprehension, a study co‐ordinator contacted the patient by telephone within 2 to 3 days of each mailing. If the tip sheet had not been read, the call was rescheduled. All questions about the tip sheets were answered. For concerns unrelated to the tip sheets, the patient was referred to his or her primary care clinician (n = 451)	No for adherence in patients with mild to moderate heart failure	No for reduction in death or heart failure hospitalization in patients with mild to moderate heart failure. Yes for decreased major depressive symptoms, restricting sodium intake with time (2 to 3 years). No for difference in NYHA class, 6‐minute walk, heart rate, respiratory rate, blood pressure, body mass index, quality of life, emotional support, or purpose in life
Powers 2011	Coronary heart disease and stroke	PERSONALIZED RISK COMMUNICATION: Patients in the personalized risk communication arm received standard risk factor education (control) as well as personalized information based on their Framingham CHD and stroke risk score, presented verbally and in graphic form as vertical bar charts. Patients' average and optimal CHD and stroke risks based on published estimates for their 5‐year age group were also presented in graphical form alongside their estimated risk. To achieve optimal risk, patients were presented with potential strategies to improve their risk through risk factor modification such as medication and patient lifestyle factors. A copy of the patient's personal risk information was also provided to the primary care provider (n = 45)	STANDARD RISK FACTOR EDUCATION: Control patients received written patient education materials from the American Heart Association/American Stroke Association entitled "Are You at Risk of Heart Attack or Stroke?" which reviewed risk factors and how these factors can be improved but did not provide personalized estimates of individual risk. The research assistant verbally reviewed the information with all patients and answered any questions at the initial visit (n = 44)	No for improving medication adherence with personalized stroke risk communication in coronary heart disease patients	No for risk factor knowledge, beliefs and health behaviors, or estimated vascular risk
Pradier 2003	HIV	Patients (n = 100) in the intervention group (IG) were offered 3 individual sessions by trained nurses.	No mention was made of the care that was provided for the control group (n = 102).	Yes	No. The clinical significance of these findings is unclear ‐ adherence rate was on self report in an unblinded trial, the mean HIV RNA was no different at 6 months for the 2 groups and no actual clinical outcomes were reported.
Purcell 2007	HIV with injection drug use	PEER MENTORING INTERVENTION: The peer mentoring intervention sessions were delivered twice a week for 5 weeks and included 7 group sessions, 2 individual sessions, and 1 ''peer volunteer activity'' (PVA), during which participants went to a local service organization for 2 to 4 hours to observe, participate, and practice peer mentoring skills. The first session focused on setting group rules and the power of peer mentoring, 2 group sessions and 1 individual session focused on utilization of HIV primary care and adherence, and 3 group sessions and 1 individual session focused on sex and drug risk behaviors. Risk messages were communicated using posters and handouts with risk hierarchies that helped to form individualized risk plans discussed during the individual session focusing on sex and injection behaviors. The final group session focused on review and reinforcement of motivation and skills for behavior change and ended with a graduation ceremony. For both treatment groups, a resource table that provided information about local services available for medical care, support groups, drug treatment, and prevention resources such as pamphlets and male and female condoms was available during and after every session (n = 486)	VIDEO DISCUSSION INTERVENTION: Control participants had similar access to general information resources and risk reduction information and resources Intervention participants, and received equal attention during the study regarding groups sessions, but not the 2 individual sessions as for Intervention. Participants in the Control group took part in 8 group sessions over 5 weeks. For all but session 1, the Control sessions were led by the same 2 facilitators who led the Intervention sessions. Participants in the Control group watched documentary or self help videos focused on issues relevant to HIV‐positive intravenous drug users, followed by facilitated discussion. Topics directly related to the intervention outcomes were avoided or minimized. Community resources and risk reduction information and tools were available at every Control session (n = 480)	No for improving the proportion of patients adherent with HIV therapy after 12 months	No for reduction in hospital utilization, sexual risk behavior, and injection drug risk behavior with a peer mentoring intervention
Pyne 2011	HIV with depression	HIV TRANSLATING INITIATIVES FOR DEPRESSION INTO EFFECTIVE SOLUTIONS (HITIDES): The purpose of the HITIDES intervention was to support HIV and mental health clinicians in delivering evidence‐based depression treatment. The HIV depression care team consisted of a registered nurse depression care manager, a clinical pharmacist, and a psychiatrist. This team was located offsite and convened once a week and as needed by telephone or in person. The depression care team communicated with treating clinicians via electronic medical record progress notes. The DCM communicated with patients via telephone. The HITIDES depression care team made treatment suggestions. Treatment decisions were made by the HIV or mental health clinicians at each site. The DCM delivered the following intervention components: participant education and activation, assessment of treatment barriers and possible resolutions, depression symptom and treatment monitoring, substance abuse monitoring, and instruction in self management. The DCM used prewritten scripts, which are standardized instruments that were supported by the Web‐based decision support system during these telephone encounters. The intervention used a stepped‐care model for depression treatment. At any time, HIV health care providers were free to refer participants directly to specialty mental health care. The DCM conducted telephone‐based monitoring every 2 weeks during acute treatment and every 4 weeks during watchful waiting or continuation treatment. The NetDSS system identified potential treatment non‐response as (1) antidepressant regimen adherence of less than 80% during the past 14 days, (2) counseling non‐adherence of less than 75% during the past month, (3) participant report of severe adverse effects during 2 consecutive DCM encounters, (4) participant report of a 5‐point increase in depression severity from the enrollment PHQ‐9 score based on 2 consecutive DCM encounters, or (5) lack of participant response during an 8‐week antidepressant or 12‐week counseling trial (n = 138)	USUAL CARE: Usual care depression treatment was provided by HIV or mental health clinicians without involvement of the HITIDES depression care team. Before starting the study, all HIV health care providers received 1 hour of HIV and depression training (n = 138)	No for improving adherence to antidepressant medication regime. No for improving adherence of HIV medications	No for reduction of depression severity score. No for improvement in health‐related quality of life. Yes for treatment response improvement at 6 months. Yes for intervention effect in remission rates at 6 months. No for treatment response at 12 months. No for remission rates at 12 months. Yes for depression free days
Rawlings 2003	HIV	4 modules of the Tools for Health and Empowerment HIV education intervention (EI) plus routine counseling (RC) (EI + RC; n = 96)	Routine counseling alone (RC) (n = 99)	No	No
Razali 2000	Schizophrenia	Culturally modified family therapy (CMFT), which consists of a sociocultural approach of family education, drug intervention program and problem‐solving skills (n = 80)	Behavior Family Therapy (BFT) (n = 86)	Yes	No at 6 months. Yes at 12 months for all variables (exacerbation, GAF score, SBS score, rehospitalization, family burden)
Remien 2005	HIV	Usual care (see Control) plus a 4‐session (45 to 60 minutes each, over 5 weeks), couple‐focused adherence intervention consisting of treatment and adherence education, identifying adherence barriers, developing communication and problem‐solving strategies, optimizing partner support, and building confidence for optimal adherence, with each partner receiving USD 20 for each session attended (n = 106)	Usual care from a multidisciplinary treatment team, including monthly visits with provider if nonadherent (n = 109)	No	No for all clinical outcomes
Rickles 2005	Depression	Usual care (see Control) plus: Pharmacist‐guided education and monitoring (PGEM) ‐ to address concerns, educate, and help patients increase adherence to medication (n = 31)	Usual care ‐ no special counseling or monitoring of adherence (n = 32)	No for all adherence outcomes	No
Riesen 2008	Primary hypercholesterolemia	10 MG PLUS: Patients received a daily oral treatment with rosuvastatin and access to compliance enhancement tools (10 mg Plus group) for 24 weeks. Patients were assessed at week 4 and at week 12 to review fasting levels of TC, LDL‐C, HDL‐C, and triglycerides. For patients not achieving the 1998 European target for LDL‐C at week 12, the daily dose of rosuvastatin was increased to 20 mg for the remainder of the study. Patients in the 10 mg Plus group received a starter pack containing a videotape and educational leaflets concerning their condition. These patients also received newsletters at regular intervals and had access to both a telephone helpline and an Internet website, all designed to reinforce the initial message in the starter pack (n = 527)	10 MG: Patients received a daily oral treatment with rosuvastatin alone (10 mg group) for 24 weeks. Patients were assessed at week 4 and at week 12 to review fasting levels of TC, LDL‐C, HDL‐C, and triglycerides. For patients not achieving the 1998 European target for LDL‐C at week 12 the daily dose of rosuvastatin was increased to 20 mg for the remainder of the study (n = 601)	No for improving adherence to rosuvastatin medication at 12 and 24 weeks	Yes for reducing low‐density lipoprotein cholesterol level at 24 weeks below 3.0 mm/mol (European 1998 goal) and not below 2.5 mm/mol (European 2003 goal). No for reducing total cholesterol and plasma lipid levels at 12 and 24 weeks. No for changes in heart rate, blood pressure, and body weight at 24 weeks
Rosen 2007	HIV	CONTINGENCY MANAGEMENT: The intervention group participants were provided with 16 weeks of weekly CM‐based counseling followed by 16 additional weeks of data collection and adherence feedback to providers followed by 16 additional weeks of data collection and adherence feedback to providers. The CM intervention provided by bachelor's level staff involved review of data generated by electronic pill‐bottle caps that record bottle opening (MEMS) and brief substance abuse counseling. CM participants were reinforced for MEMS measured adherence with drawings from a bowl for prizes and bonus drawings for consecutive weeks of perfect adherence (n = 28)	SUPPORTIVE COUNSELING CONDITION: The supportive counseling condition was an attention control condition. Participants were encouraged to meet with counselors weekly. In these sessions, participants were asked about their adherence, and offered support for their efforts to improve adherence. However, the counselors did not review MEMS data with the participants or conduct urine toxicology testing. There was an initial review of self reported substance abuse and referral to available treatment. In addition, providers were sent monthly letters stating the participant's self reported adherence. The same staff members delivered both interventions (n = 28)	Yes for improving adherence to reinforced antiretroviral therapy during the intervention period (1 to 16 weeks) but no during the follow‐up period (17 to 32 weeks). No for improving adherence to non‐reinforced antiretroviral therapy during the intervention and follow‐up period	Yes for reducing viral load at 16 weeks but not at 32 weeks. No for reducing the viral load below 400 HIV‐RNA copies per milliliter at 16 and 32 weeks
Rubak 2011	Type 2 diabetes	MOTIVATIONAL INTERVIEWING: The courses in "motivational interviewing" (MI) for the GPs in the intervention group were conducted by a trained teacher introducing a manual which together with "Motivational interviewing, preparing people to change addictive behaviour" constituted the theoretical part of the course curriculum. The intervention group was coached in the key points of MI. The training also included the use of specific skills, e.g. empowerment, ambivalence, the decisional balance schedule, the visual analogue scale, stage of change, and reflective listening, all of which are described in detail in the book MI. The intervention group courses consisted of a 1½ ‐day training sessions with a half‐day follow‐up twice during the first year. None of the GPs in I‐ and control group had previously participated in an MI course. All GPs in the I‐ and the control group participated in the same half‐day course on intensive treatment of type 2 diabetes. During these diabetes training sessions, it was stressed that GPs should act as counselors for the patients, allowing treatment decisions to be based on mutual understanding between the patient and the GP. In Denmark, GPs' consultation encounters average 15 minutes and the County Health Insurance has agreed to one longer preventive consultation encounter of 45 minutes per patient. In this study the County Health Insurance agreed to allow the GPs in the I‐ and control group to undertake 3 consultations of 45 minutes per patient, in which the intervention group could use MI (n = 37 practices and 307 patients)	CONTROL: None of the GPs in the control group had previously participated in an MI course. All GPs in the control group participated in the same half‐day course on intensive treatment of type 2 diabetes. During these diabetes training sessions, it was stressed that GPs should act as counselors for the patients, allowing treatment decisions to be based on mutual understanding between the patient and the GP. In Denmark, GPs' consultation encounters average 15 minutes and the County Health Insurance has agreed to one longer preventive consultation encounter of 45 minutes per patient. In this study the County Health Insurance agreed to allow the GPs in the control group to undertake 3 consultations of 45 minutes per patient. (n = 41 practices and 321 patients)	No for improved adherence to blood glucose‐lowering drugs, BP or lipid‐lowering drugs at 1 year in type 2 diabetes patients	Yes for improved blood pressure, blood lipid measurement, HbA1c, and BMI at 12 months in both controls and intervention groups. No for improvement in blood pressure, blood lipid measurement, HbA1c, and BMI in intervention group compared to control groups
Rudd 2004	Hypertension	A nurse care manager conducted baseline counseling on the correct use of the automated blood pressure (BP) device, regular return of the automatically printed BP reports, tips for enhancing adherence, and recognition of drug side effects; the nurse phoned patients at 1 week, 1, 2, and 4 months. The nurse changed doses on own and called physician for medication changes (n = 74)	Usual care (n = 76)	Yes	Yes for changes in both systolic and diastolic blood pressure from baseline to 6 months between groups
Sabin 2010	HIV/AIDS	COUNSELING BASED ON ELECTRONIC DRUG MONITORING DATA: When intervention participants came to the clinic monthly, a study member downloaded and reviewed the subject's previous month's electronic drug monitoring device (EDM) data. Each subject found to be less than 95% adherent according to the EDM data was 'flagged' for counseling with a clinic physician or nurse utilizing the EDM information immediately following regular clinic visit activities. The data were provided to both the subject and his/her clinician as a printout summarizing the percent of doses taken, the percent of doses taken on time, and a visual display of doses taken by time. This process of flagging and counseling was specific to each clinic visit. In each counseling session, the clinician reviewed the EDM printout with the subject, explored reasons for missed or off‐time doses, and inquired about problems or challenges the subject might be having. Beyond this, counseling sessions did not follow a script. This was designed to accommodate each clinician's counseling style, allow for an individually‐focused discussion of adherence behavior, and encourage each subject‐clinician pair to devise personalized strategies to improving adherence. In this regard, the EDM feedback provided data to inform and thereby enhance the counseling, but did not dictate precisely how the counseling should be performed. In the event that subjects did not immediately offer reasons for missed or off‐time doses, clinicians were advised to say: "Let's talk more about any problems that you had last month".' Most counseling sessions were completed within 10 to 15 minutes. The intervention period was 7 to 12 months (n = 34)	STANDARD CARE: Control group participants provided their electronic drug monitors (EDM) data at their monthly visits to the study team members and received standard care. Standard care in China included completing self reports of adherence and attending counseling session with clinician if self reported adherence indicated less than 95% adherence. In the counseling sessions with control subjects, which were guided by self reported adherence and clinicians inquired about recent problems that might have affected dose‐taking (n = 34)	Yes for improving adherence to ART at 12 months in the intervention group	No for improvement in markers of HIV progression with electronic drug monitoring based counseling in HIV positive patients in China
Sackett 1975	Hypertension	(a) Care at work site by occupational health physicians (n = 37); (b) Detailed 'programmed' instructions about hypertension and adherence (n = 28); (c) Both a and b (n = 44)	Neither intervention (n = 25)* * numbers provided by author	No	No
Sadik 2005	Heart failure	Usual care plus: Booklets and education on heart failure (HF) and training on a self monitoring program (daily weights and symptom diary, to share with physician and pharmacist; extra dose of diuretic if weight rose). Research pharmacist interacted with physicians to simplify drug regimens, with patients on follow‐up visits to clinic (n = 109)	Usual care in a medical or cardiology clinic (n = 112)	Yes	Yes for 2‐minute walk test, blood pressure and pulse, HF symptoms, forced vital capacity and both quality of life measures ‐ the MLHFQ and SF36
Samet 2005	HIV	Usual medical care plus nurse‐led intervention (60 minute session + 3 follow‐up visits) with 4 parts (n = 74): a) assessment of the alcohol and substance use b) a watch to time medications and improve adherence c) enhancement of perceived efficacy of medications d) individualized HIV counseling	Patients received regular medical care for HIV infection. This included verbal or written instructions about optimal medication strategies (n = 77)	No	Yes for CD4 count
Sarna 2008	HIV	MODIFIED DIRECTLY OBSERVED THERAPY (M‐DOT): Patients in the intervention arm received M‐DOT services for the first 24 weeks of ART, in addition to standard care. Although consideration was given to provision of home‐based M‐DOT, formative research revealed that patients were concerned this would undermine their privacy and confidentiality. They also believed that clinic visits would provide beneficial access to health care workers, so M‐DOT services were provided during twice weekly clinic visits. To enhance convenience, participants could select 1 of 6 health centers for their M‐DOT visits. At each visit, participants met with M‐DOT observers (nurses) who observed ingestion of the patient's ART dose, inquired about difficulties encountered, and provided individualized adherence support. Used medication containers were also collected, pill counts recorded, and medication dispensed for the subsequent 3 or 4 days. During the monthly clinic visits, efforts were made to ensure that participants in the M‐DOT and control group received equal contact time with study staff to minimize the likelihood that any differences observed would be due to nonspecific effects of increased attention given to the intervention group. CHW traced M‐DOT participants who missed visits and brought medications to participants who were unable to visit the facility. After cessation of M‐DOT at week 24, patients had no further contact with M‐DOT observation centers. Like the control group, they collected monthly medication refills at recruitment clinics and received standard adherence support during weeks 25 to 72. No compensation was given for study participation, though travel costs were reimbursed for 21 M‐DOT participants with financial constraints (USD 0.65 per visit) (n = 116)	STANDARD CARE: As standard care, all participants attended 3 one‐on‐one adherence counseling sessions before initiating ART. In these, trained nurse counselors emphasized the importance of adherence; educated patients on the treatment regimen, dosing instructions, side effects, and dietary considerations; tailored the regimen to daily activities; and identified social issues like living conditions and family support. After ART initiation, patients visited treatment centers every 4 weeks for follow‐up. At the first 2 follow‐up visits, general adherence counseling was provided, as was discussion of specific emerging problems with side effects or medication intake; thereafter, counseling was tailored to individual needs. All patients were encouraged to bring a family member or friend to clinic visits and counseling sessions (n = 118)	Yes for 24‐week adherence. No for 48 and 72‐week adherence	No for suppression of viral load at 48 weeks. No for increase in CD4 cell count and immunological improvements. Yes for larger mean increase in BMI during the intervention period
Schaffer 2004	Asthma	(a) Audiotape alone (n = 10); (b) National Heart Lung and Blood Institute (NHLBI) booklet alone (n = 12); (c) Audiotape plus NHLBI booklet (n = 11)	Standard provider education (control) (n = 13)	Yes for positive effect on adherence by pharmacy‐refill measure for booklet versus control, and for booklet + audiotape versus control, but not for audiotape versus control, at 6 months. No for self reported adherence	No
Schroeder 2005	Hypertension	Usual care (see Control) plus nurse‐led adherence support sessions (20 minutes initially, 10 minutes 2 months later) with the following goals (n = 128): patients address problems with blood pressure lowering medication; explain diagnosis and the treatment process; address patient concerns with their medication and tailor strategies to resolve any problems	Usual care at their doctors' practices, other than blood pressure checks at similar intervals as the intervention group (n = 117)	No for all adherence outcomes	No for all clinical outcomes
Sherrard 2009	Adverse events post‐cardiac surgery (coronary bypass grafts/valvular surgery)	INTERACTIVE VOICE RESPONSE (IVR): Patients in the IVR follow‐up group received automated telephone calls for 6 months, at 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 weeks after discharge. The telephone interview contained an algorithm of 11 questions addressing medication compliance, reporting of adverse events, providing information on common medications, and offering general medication safety tips. The intent of the IVR algorithm was to provide early identification of issues permitting timely intervention, provide a mechanism for tracking medication compliance, and provide medication information at the time deemed most valuable by the patient at his or her request and to provide longer‐term follow‐up as the patient transitioned from hospital to home. Patients were asked questions about medication compliance such as, "Did you fill the prescriptions given to you at discharge?" and were offered additional information on 8 common medications prescribed to cardiac surgical patients on discharge. The answers to the questions were captured in a database. Depending on the response, a colored flag appears in the database next to the question indicating no action is needed, the call was not answered, or alerting the nurse to intervene by calling the patient to provide education and counseling (n = 164)	USUAL CARE: Patients in the control group received the standard of care provided to all patients discharged from post‐cardiac surgery. This included receiving an IVR call on day 3 and 10 after discharge to screen common symptoms. This current surgical follow‐up algorithm does not contain questions or information on medications. They were contacted at 6 months to answer questions on medication compliance and outcomes (n = 167)	Yes for improving compliance at 6 months in IVR group compared to UC in post‐cardiac surgery patients	Yes for composite outcome. No for ER visits and hospitalizations
Simon 2011	Depression	CARE MANAGEMENT: Intervention group received care management intervention in addition to usual care by the treating physician. The intervention was delivered online but the structure was similar to the telephone programs tested in earlier studies. After randomization, participants received a welcome letter describing the program and it contained general advice about the antidepressants medication and self care for depression. Monitoring contacts were scheduled 2, 6, and 10weeks later. At each monitoring contact, there was an outreach message from the nurse containing a link to an online assessment. The assessment included the PHQ depression questionnaire and questions regarding use of antidepressant medication, side effects, and reasons for medication discontinuation. Those not responding were sent up to 2 reminder messages. For each assessment completed, an algorithm generated a suggested response based on PHQ depression score, current antidepressant use, and side effects. The care manager could tailor this suggested response using information in the medical record or in messages since the last contact. The care manager communicated with the treating physician using an electronic messaging system within the electronic medical record. In consultation with the physician, the care manager might facilitate follow‐up visits, support changes in medication, or facilitate referral for specialty care (including urgent referrals in case of suicidal ideation or severe symptoms). Each of the 3 care management contacts included this cycle: outreach message from the care manager, patient completion of online assessment, structured response from the care manager, and follow‐up communication with the patient and physician as needed. The care manager's messages to patients included brief support but no formal psychotherapy. Patients were free to send additional messages or telephone the care manager if needed. The care manager was expected to make outreach telephone calls in case of suicidal ideation or other urgent clinical need. All outgoing messages were in English. The care manager in this trial was a registered nurse with added certification in psychiatry and 15 years of experience in mental health (n = 106)	USUAL CARE: Controls received usual care and did not receive any additional care other than what was normally available, which included follow‐up in primary care or specialty referral for psychotherapy or medication management. Online patient‐provider messaging was available to all patients in the usual care (n = 102)	Yes for increasing use of antidepressant over 90 days for patients with depressive disorder	Yes for improving SCL depressive scores and satisfaction with depression treatment. No for increased hospitalization or suicide attempts
Simoni 2007	HIV/AIDS	PEER SUPPORT: Patients in the peer support group had 6 twice‐monthly meetings during the 3‐month peer support intervention where peers and participants met with other peers and participants to discuss shared experiences, barriers to HAART adherence, life issues, etc. The group meetings were facilitated by an RA but were predominately peer‐led. Between group meetings, peers were instructed to call each of their study participants 3 times weekly to provide more in‐depth one‐on‐one attention and feedback (n = 71)	STANDARD CARE: Standard of care (control) patients received no additional adherence assistance beyond the clinic's typical offerings (consultation with primary providers and social and mental health referrals when requested) (n = 65)	No for medication adherence by self report and EDM at 3 and 6 months	No for HIV‐1 RNA viral load and depressive symptomatology
Simoni 2009	HIV/AIDS	PEER SUPPORT: The 3‐month peer support intervention consisted of 2 parts: (a) 6 twice monthly 1‐hour gatherings held at the clinic, consisting of all peers and actively enrolled participants in the peer support arm and (b) weekly phone calls from peers to participants. At the time of enrollment, participants were assigned to individual peers by study staff based on peer availability and presumed compatibility. In the group setting, participants had the opportunity to interact face‐to‐face with their assigned peer and meet the other peers and participants, with the goal of benefiting from the discussion of the shared experiences of the group. The meetings were designed to identify barriers to HAART adherence and generate problem‐solving strategies to overcome them. Other emerging themes included life issues that impact adherence, including HIV status disclosure, dating, substance use, and struggles with mental health issues. One of several research staff members coordinated the groups by making reminder phone calls, preparing the meeting room, and providing refreshments. With assistance from the peers, they facilitated the meetings by refocusing the discussion on adherence‐related topics when appropriate. Otherwise, they refrained from interfering with the group process and the exchange of support among peers and participants, resulting in predominantly peer led groups. Participants received a $15 incentive for attending each of the 6 sessions. All were welcomed to continue attending thereafter but were provided neither reminder phone calls nor monetary incentives for additional meetings. Between group meetings, peers were instructed to call each of their study participants weekly to provide more in‐depth one‐on‐one attention and feedback. Phone calls also were better suited for participants with confidentiality concerns and those who had difficulty traveling to the clinic or had scheduling conflicts with the set meeting times. Peers were instructed not to initiate contact with participants after the 3‐month intervention period, but they were allowed to respond to requests for contact from the participants at their own discretion (n = 57) PAGER MESSAGING: The 3‐month pager intervention consisted of a customized pager system that combined the communicating abilities of the world‐wide web and 2‐way pagers. A computer program allowed for the timing of all text messages to be specified up front and then sent automatically without any further intervention from study staff. At randomization, the study co‐ordinator distributed a 2‐way pager and customized a message schedule to the participant's daily medication regimen, which was confirmed by the clinic pharmacist. In addition to dose reminders, 3 other types of text messages were sent: (1) educational; (2) entertainment (jokes or thoughts for the day); and (3) adherence assessments. There was some flexibility in the frequency and content of messages to accommodate participants' differing needs and schedules, but there was a minimum of 3 pager messages sent daily to participants for the first 2 months. Pages gradually tapered in the last month of the 3‐month intervention to avoid a rebound in non‐adherence. A confirmation return page was requested for every message sent. Project staff periodically reviewed the return page log and if no responses were received, the participant could be called to determine if they were having any problems with the pager. Between the first contact and the end of the 3‐month intervention, the participants were asked to wear the pager at all waking moments. Participants had to use the study pagers and could not substitute with their own pager or cell phone. They were instructed not to use the devices for personal use. Participants could select from a variety of auditory alarms or a vibrate‐only option if desired. If the pager was lost or failed, it was promptly replaced at no cost to the subject (n = 56) 56 participants in Pager Messaging and Peer Support	USUAL CARE: Before initiation of HAART, all clinic patients who are naive patients or off HAART for more than 6 months are required to complete the HAART protocol, a clinic‐based program designed to provide education regarding HAART and adherence and to identify and correct adherence barriers before HAART initiation. The HAART protocol involves a series of 3 separate appointments with a pharmacist, nutritionist, and case manager after an initial meeting with a provider and before a final meeting when the provider decides whether to prescribe HAART. During these preliminary interviews, patients are given social and mental health referrals as appropriate, a daily medication schedule, and information on medication side effects and techniques to help manage them. All participants in each of the study's 4 arms participated in the HAART protocol if they had not received it in the last 6 months. There were no time or attention‐control activities ( n= 57)	Yes for improving self reported adherence at 3 month in peer intervention. No for improving self reported adherence at 6 and 9 months. No for improving EDM adherence for peer intervention at 3, 6, or 9 months. No for improving self reported and EDM adherence at 3, 6, and 9 months in pager intervention	No for improvements in viral loads and CD4 cell counts at 3, 6, or 9 months in the peer intervention arm or pager intervention arm
Simoni 2011	HIV/AIDS	ENHANCED INTERVENTION ARM: Patients assigned to the intervention arm could choose an alarm device, counseling or both. The alarm device was either a cell phone (if the patient so chose) or a small battery powered electronic alarm device. In either case, the project staff helped the patient set up the device of their choice. Counseling was delivered by a bachelor level nurse. In accordance with a manualized protocol, the counseling sessions involved a cognitive‐behavioral and problem‐solving approach to: (1) enhancing motivation for treatment continuation, (2) learning about antiretroviral medication and the prescribed regimen, (3) keeping appointments, (4) communicating with healthcare providers, (5) formulating a daily medication schedule, (6) storing medications, (7) setting reminder strategies, (8) coping with side effects, (9) securing family and social support, (10) handing adherence lapses, and (11) addressing additional barriers. Participants could also invite a treatment partner to attend the counseling sessions with them. A ''treatment partner'' was defined as someone to whom the participant had already disclosed their HIV status and who was available to assist the participant on a daily basis. Participants who opted to have counseling, either individually or with a treatment adherence partner, had 3 counseling sessions of up to 1 hour each with the study nurse. The first session occurred either at the enrollment interview or within the first 2 weeks of initiating ART; additional counseling sessions occurred at 5 and 9 weeks. If necessary, the later sessions were replaced with counseling provided over the telephone (n = 36)	MINIMAL INTERVENTION ARM: At the baseline appointment and before initiation of ART, all participants completed a 1‐hour interviewer‐administered paper‐and‐pencil baseline survey. They then participated in a 30‐minute educational session facilitated with a flip‐chart, which was designed to provide information regarding their treatment plans, likely side effects, and the importance of adherence. All patients also were given a daily medication schedule, a plastic pill box to organize daily doses, and a referral card to the hospital‐based peer support group. Participants assigned to the minimal intervention were to receive no further adherence‐promotion intervention beyond the usual care at the clinic, which involved monthly medication pick‐ups and any conversations patients initiated with their healthcare providers. All participants continued to receive medical care as usual at the clinic (n = 34)	Yes for improving self reported 7‐day adherence and dichotomous 30‐day adherence at 19 weeks. No for improving self reported or EDM based adherence at 7, 13, and 25 weeks	No for improvement in viral load and CD4 cell count at 13 and 25 weeks
Sirey 2010	Major depression	TREATMENT INITIATION AND PARTICIPATION PROGRAM (TIP): The Treatment Initiation and Participation Program (TIP) included 3 30‐minute individual meetings between the TIP counselor and older adult patient during the first 6 weeks of pharmacotherapy, followed by 2 follow‐up telephone calls at 8 and 10 weeks after study entry. During these sessions the TIP counselor and older adult would review symptoms and antidepressant therapy regimen, and conduct a barriers assessment, define a personal goal that could be achieved with adherence, provide education about depression and antidepressant therapy, collaborate to address barriers to treatment participation, create an adherence strategy and facilitate and empower the older adult to talk directly with the PCP about the treatment. A "contact sheet" listed barriers in each domain and specific intervention techniques and served as the guide for sessions and a record of the interventions administered (n = 33)	TREATMENT AS USUAL (TAU): Patients in the control group continued with treatment as usual (n = 37)	Yes for improved self reported adherence to antidepressant medication throughout all time points	Yes for reduction in depressive symptoms
Solomon 2012	Osteoporosis	TELEPHONE BASED COUNSELING: Subjects in both groups started receiving educational material regarding osteoporosis 30 days after randomization. In addition the intervention group subjects received motivational intervening based counseling administered by a health educator. 10 sessions were targeted per subject (n = 1050)	CONTROL: Approximately 30 days after randomization, all subjects received mailings regarding osteoporosis. During the study, all subjects received 7 informational mailings covering topics such as exercise, fall prevention, and recommended calcium intake (n = 1047)	No for medication adherence measured using MPR during 12 months	No for self reported falls. No for poor or fair general health
Sorensen 2007	HIV	VOUCHER INTERVENTION: Patients in the voucher intervention group began with a 4 week baseline phase, where they received a MEMS monitor for one of their HAART medications. Patients met with a registered nurse or trained research assistant who provided medication coaching once during the baseline phase and then every 2 weeks throughout the study. Patients were provided with a hard copy of their MEMS data throughout the study. During baseline, patients met a research assistant twice weekly to provide the MEMS data. At the end of the baseline phase, patients in the voucher phase continued to meet twice weekly with a research assistant, for a total of 24 visits. When patients opened their medication caps as scheduled, they received vouchers that were exchangeable for goods and services for each correctly taken medication dose. The value of the voucher increased for each correctly taken dose in a row, but reset to the original value if a dose was missed. Patients could earn up to USD 1172.40 if they took all their medication correctly throughout the study (n = 34)	COMPARISON: Patients in the comparison group began with a 4‐week baseline phase, where they received a MEMS monitor for one of their HAART medications. Patients met with a registered nurse or trained research assistant who provided medication coaching once during the baseline phase and then every 2 weeks throughout the study. Patients were provided with a hard copy of their MEMS data throughout the study. During baseline, patients met a research assistant twice weekly to provide the MEMS data. During the intervention phase, comparison group participants continued to meet twice weekly with the research assistant, for a total of 24 visits, and received medication coaching every 2 weeks. As several of the initial comparison group participants expressed dissatisfaction with their treatment compared to the voucher group, a reward system was implemented for the comparison group. A fishbowl prize system was used to reinforce attendance at scheduled interviews. Patients could pick a number from the fishbowl which would give them either a small or large prize (n = 32)	Yes for improving adherence while intervention was active. No for maintaining that adherence during the follow‐up phase	No for all patient health indices
Staring 2010	Psychotic disorders	TREATMENT ADHERENCE THERAPY: Initial sessions assess individual determinants of non‐adherence. According to the clusters of determinants detected, therapists fill out a decision form and chose from the 3 modules available for the subsequent patient appoints. Modules are motivational interviewing, medication optimization, and behavioral training. If more than one cluster of problems was present in an individual, the modules were completed in order. The duration and number of sessions varied per patient, in general taking no more than 6 months. Most of the therapists were psychiatric nurses who were not the patients own mental health professionals. All sessions were recorded and used in supervision (n = 54)	TREATMENT AS USUAL: Treatment as usual generally consisted of sessions with a psychiatric nurse and a psychiatrist when indicated. The sessions varied in frequency and duration, but mostly consisted of one or 2 sessions per month. The contents reflected overall problems the participant might encounter such as symptoms, social participation, work, daily activities, and medication issues. Some participants received psychoeducation individually or in group sessions. This was recorded (n = 55)	Yes for improving adherence to antipsychotic medications in the intervention group at the end of intervention and at 6‐month follow‐up	No for decrease in hospital admissions and improvement in symptoms and quality of life for participants in TAT group compared to controls at 6‐month follow‐up
Stevens 2002	Helicobacter pylori	A longer adherence counseling session and a follow‐up phone call from the pharmacist during drug treatment (n = 163). All subjects were given the same 7‐day course of omeprazole, bismuth subsalicylate, metronidazole, and tetracycline hydrochloride (OBMT)	A standard antibiotic regimen and randomly assigned to receive usual care counseling from a pharmacist (n = 162). All subjects were given the same 7‐day course of omeprazole, bismuth subsalicylate, metronidazole, and tetracycline hydrochloride (OBMT)	No	No. (The big problems with this study are that a) both groups got blister packs with daily doses clearly marked; b) both groups got counseling, although this was longer and more detailed for the IC than CG; c) self report was used for measuring adherence (insensitive). All these factors would bias towards no difference)
Strang 1981	Schizophrenia	Family therapy (n = 17)	Individual supportive therapy (n = 15)	Yes	Yes
Taiwo 2010	HIV	TREATMENT PARTNER INTERVENTION: In addition to standard care, patients randomized to the treatment partner intervention (TPA) arm chose a treatment partner who was aware of the patient's HIV infection and resided in the same house or in close proximity. Treatment partners attended one adherence education session similar to that for study participants. They were asked to observe the ingestion of HIV drugs at least once daily, assist with the reporting and management of adverse effects, and remind participants of drug pickup. No compensation was provided for participation, but treatment partners with financial constraints received travel stipends of USD 2–14 (total) (n = 248)	STANDARD CARE: All participants were given a 2‐hour interactive adherence session in English and local language conducted by a nurse who was openly HIV positive trained as adherence counselor. Content included information on ART, HIV drug resistance, symptom management, and emphasis on the importance of adherence and benefits of disclosure. Each patient was given a pillbox and educated on proper use. The study pharmacist, who was blinded to treatment arm, provided one‐on‐one reinforcement of the education provided by the adherence counselor plus information specific to each participant's regimen. The pharmacist had formal training in adherence counseling and more than 3 years experience at study clinic. At each drug pickup visit, the pharmacist provided targeted counseling based on the participant's self report of adherence and adverse effects. Patients who had detectable viremia at week 24 underwent intensive adherence retraining with the adherence counselor. This retraining was aimed at identifying individualized obstacles to adherence and practical tips for overcoming them. Follow‐ups were conducted at 12, 24, and 48 weeks after baseline (n = 251)	Yes for improving medication adherence in HIV patients undergoing ART with Treatment Partner Intervention at 12 and 48 weeks	No for viral load of HIV, CD4 count, or mortality
Tuldra 2000	HIV	Psychoeducative intervention to implement adherence, i.e. explanations about reasons for starting treatment and the relevance of appropriate adherence, development of a dosage schedule with patients' input, patients were taught how to manage various other aspects of medication taking in highly active antiretroviral treatment (HAART) (i.e. forgetting, side effects, changes in daily routine). Phone number was given should patients have any questions before next interview. Verbal reinforcement of adherence at follow‐up visits (n = 55)	Usual medical follow‐up (n = 61)	No	No
Udelson 2009	Chronic HF and left ventricular (LV) dysfunction	ONCE DAILY DOSING: The intervention was an open‐label, once daily regimen of controlled release carvedilol CR (n = 136)	TWICE A DAY DOSAGE: Participants received their usual twice daily dose of carvedilol IR, but in a double‐blinded fashion (n = 133) ONCE A DAY DOSING PLUS PLACEBO: Participants received once daily dose of controlled‐release carvedilol CR in the morning with a placebo substituted for the second daily dose in a double blinded manner (n = 136)	No for improving adherence to carvedilol in patients with HF and LVF with simplified dosing	No improvement in quality of life (QOL), PHQ‐8 Depressive Symptoms Questionnaire (PHQ‐8), and Treatment Satisfaction Questionnaire with Medication. No for BNP levels and hospital and emergency services utilization
Valencia 2007	Schizophrenia	PSYCHOSOCIAL SKILLS TRAINING (PSST): PSST is psychosocial skills training. It is composed of 7 treatment areas: (1) symptom management, (2) medication management, (3) social relations, (4) occupational, (5) money management, (6) couple relations, and (7) family relations. A therapist's manual describes all the areas, the skills corresponding to each area, and the training strategies for each session. The trainers were 2 psychologists who used 6 learning activities to teach patients skills acquisition: (1) introduction and explanation of the skills to be taught, including preparing and motivating patients to participate actively in the learning activities; (2) demonstration of the skills by one of the therapists, followed by a question‐and‐answer segment that allowed for clarification; (3) role playing: patients practiced the skills by role playing during sessions; (4) role playing feedback to allow patients to identify the resources needed to perform the skills in the real world; (5) practice of skills in their natural environment; and (6) at the beginning of the following session a segment was dedicated to verifying the practice of the skills in the community; this information was registered in a skills learning check‐up list. The learning activities were similar to the 7 instructional techniques proposed for teaching social and instrumental skills to the severely mentally ill. These were modified to 6 learning activities for the participants of the present study. Patients participated in group sessions, 8 patients per group, with a time limit of 1 hour 15 minutes, once a week for a total of 48 sessions during 1 year of PSST. To verify that each treatment area was being covered systematically and adequately, a therapist fidelity evaluation form was used. Family therapy (FT) consists of 2 parts: the first was psychoeducation, which included 8 group sessions where all the patients' relatives received information about the illness, symptoms and medication management. The second part consisted of 4 sessions for each family, including the patient, oriented to problem‐solving as needed by each family to improve communication skills, the recognition and management of warning signs of relapse, the importance of medication and its side effects, compliance with AP medication, and keeping appointments with physicians. 2 family therapists conducted the FT. Recreational activities for the patients, conducted by an arts teacher, included singing, musical games, creative movement, and arts and crafts, once a week for 2 hours. Recreational activities were not considered as a therapeutic modality (n = 49)	TREATMENT AS USUAL: Control group was treatment as usual, which was provided at the Schizophrenia Clinic of the INPRF by 2 clinical psychiatrists, who were blind to the 2 treatment conditions.They provided 20‐minute monthly appointments during a 1‐year period, controlled the prescription of their AP medication based upon the assessment of their psychotic symptoms, checked their medication compliance, recorded their attendance to the consultations, and registered all this information in their clinical files (n = 49)	Yes for improving adherence to antipsychotic medication at 12 months in patients with schizophrenia	Yes for improvement in symptomatology, psychosocial and global functioning, reducing relapse, rehospitalization and dropout rates
Valenstein 2011	Serious mental illness (SMI) including schizophrenia, schizoaffective and bipolar disorders	MEDS‐HELP INTERVENTION: A composite intervention consisting of: 1) unit‐of‐use packaging that included all patients' medications for psychiatric and general medical conditions; 2) a medication and packaging education session; 3) refill reminders mailed 2 weeks before scheduled refill dates; and 4) notification of clinicians when patients failed to fill antipsychotic prescriptions within 7 to 10 days of a fill date. The medication education session was conducted by a pharmacist, usually in‐person, but occasionally by telephone. During this session, the pharmacist reviewed patients' prescribed medications, including treatment indications. The pharmacist also explained unit‐of‐use medication packaging and plans for interim use of pill boxes when medication changes were made by clinicians before the next shipment of medication packages (n = 58)	USUAL CARE: Usual care was treatment in Veterans Affairs outpatient mental health clinics and included psychiatrist visits, non‐MD mental health visits, and group visits. During the study period, patients completed an average of 8 visits with psychiatrists; 49% had visits with non‐MD mental health clinicians and 23% had group visits (n = 60)	Yes for improving the medication possession ratio (MPR) of antipsychotic drugs among patients with serious mental illness	No for improving psychological symptoms, quality of life, patient satisfaction, and reducing hospitalizations at 6 and 12 months in patients with serious mental illness
van der Meer 2009	Asthma	INTERNET‐BASED SELF MANAGEMENT: An internet based self management program consisting of a specially designed website which allowed monitoring through the website or text messaging, use of an internet‐based treatment plan, online education and web communications with a specialized asthma nurse was administered to the intervention group. Patients monitored their asthma weekly by completing an electronic version of the Asthma Control Questionnaire on the website and instantly received feedback on the current state of their asthma control along with advice on how to adjust their treatment according to a predefined algorithm and treatment plan. Self‐management education consisted of both web‐based and face‐to‐face, group‐based education. Web‐based education included asthma information, news, frequently asked questions, and interactive communication with a respiratory nurse specialist. All patients were offered 2 group‐based education sessions, which lasted 45 to 60 minutes, for patients in the Internet‐based self management group within 6 weeks after entering the trial. Both sessions included exploration of a patient's interests and previous knowledge, personalized feedback, and empowerment of self management. The first educational session also included pathophysiology of asthma, information on the web‐based action plan, and information and review of inhalation technique. The second educational session gave information about the mechanisms and side effects of medication and explained trigger avoidance (n = 101)	USUAL CARE: Website access for usual care patients was restricted to a diary page for patients to keep during assessments (n = 99)	No for improvement of self reported adherence with an internet‐based self management program for asthma	Yes for asthma control and lung function. No for other clinical outcomes (exacerbations, inhaled corticosteroid dose)
Velligan 2008	Schizophrenia	FULL‐CAT: Cognitive Adaptation Training (CAT) uses manual‐driven compensatory strategies and supports such as pill containers with alarms, organization of belongings, and activity checklists to prompt and sequence adaptive behaviors in an individual's home environment. CAT strategies are tailored to the specific cognitive impairments and behavioral approaches to goal‐directed activity exhibited by each participant. Environmental supports in Full‐CAT treatment were based upon an assessment of neurocognitive function, behavior, adaptive functioning, and the environment. Interventions for each functional deficit were based on 2 dimensions, (1) level of impairment in executive functions and (2) whether the overt behavior of the individual during performance of goal‐directed activity was characterized more by apathy, disinhibition, or a combination of these styles. According to the CAT model, individuals with poor executive functioning need high levels of structure and more obviously placed environmental cues, while those with somewhat better executive functioning need less structure and more subtle cues. Individuals with apathetic behavior benefit from environmental supports that cue and sequence behavior, those with disinhibition benefit most from the removal of distracting stimuli, and those with mixed behavior benefit from a combination of these strategies. Assessment results yield one of 6 CAT classifications for which interventions can be targeted. Once an individual's CAT classification was determined, strategies for specific functional problems were chosen from the manual. CAT interventions were established, trained, and maintained in the home during weekly visits from a CAT therapist/trainer. Patients in Full‐CAT were seen once weekly for 30 to 45 minutes. The treatment lasted for 9 months and then the patients were followed up for 6 months after the withdrawal of home visits. CAT therapists were individuals with bachelor's or master's degrees in psychology or related fields trained using a combination of didactic and in vivo strategies. (n = 37) PHARM‐CAT: Pharm‐CAT is a subset of the Full‐CAT program, which is a manual‐driven treatment using environmental supports. Patients received assessments of neurocognitive function, behavior, adaptive functioning, and the environment. Interventions in Pharm‐CAT are individualized in the same manner as those in Full‐CAT treatment. However, only interventions that specifically target adherence are used. Additional issues such as transportation are addressed only if they relate to taking medication or making it to clinic appointments. Patients in Full‐CAT and Pharm‐CAT were seen once weekly for 30 to 45 minutes. Visits in Pharm‐CAT were necessarily shorter in duration because the focus of treatment was circumscribed around the issue of adherence. Pharm‐CAT is a subset of the Full‐CAT program, which is a manual‐driven treatment using environmental supports. Patients received assessments of neurocognitive function, behavior, adaptive functioning, and the environment. Interventions in Pharm‐CAT are individualized in the same manner as those in Full‐CAT treatment. However, only interventions that specifically target adherence are used. Additional issues such as transportation are addressed only if they relate to taking medication or making it to clinic appointments. Patients in Full‐CAT and Pharm‐CAT were seen once weekly for 30 to 45 minutes. Visits in Pharm‐CAT were necessarily shorter in duration because the focus of treatment was circumscribed around the issue of adherence. Pharm‐CAT therapists were individuals with bachelor's or master's degrees in psychology or related fields trained using a combination of didactic and in vivo strategies. (n = 36)	TAU: Patients are seen monthly to every 3 months for brief medication visits. They have case managers with high case loads who have little ongoing contact with patients not in crisis (n = 32)	Yes for improving adherence in Full‐CAT and Pharm‐CAT compared to TAU throughout treatment and follow‐up. No difference between Full‐CAT and Pharm‐CAT. Yes for improving pill refill rates in Full‐CAT. No difference between Pharm‐CAT and TAU for improving pill refill rates	No for improving symptoms. Yes for increased percentage of participants with higher time to relapse in Full‐CAT and Pharm‐CAT compared to TAU. Yes for improved functional outcome in CAT compared to TAU and Pharm‐CAT at 15 months. Yes for improved functional outcome in Pharm‐CAT compared to TAU at 6 months and not thereafter
Vergouwen 2005	Depression	Depression Care Program targeted both patients and their GPs. Participants received a newsletter with information about depression, the need to continue antidepressant medication for 6 months, and the importance of social support, and had homework assignments. Their GPs received newsletter summaries and copies of the homework and were to use motivational interviewing with patients (n = 81)	Patients and doctors did not have the program, but patient follow‐ups were scheduled at the same frequency as for the intervention group, and GPs did the same assessments for depression and compliance (n = 96)	No	No for all clinical outcomes
Volume 2001	Ambulatory elderly (> or = 65 years of age)	Pharmacists (in n = 8 pharmacies, 159 patients) used the Pharmacist's Management of Drug‐Related Problems (PMDRP) instrument to summarize the information collected during the patient interview and the subjective, objective, assessment, and plan record to document actions and follow‐up	Pharmacists at control pharmacies (n = 8 pharmacies, 204 patients) continued to provide traditional pharmacy care	No	No
Wakefield 2011	Type 2 diabetes mellitus and hypertension	HIGH‐INTENSITY GROUP: In the high‐intensity group, subjects were instructed to measure BP daily and BG as directed by their physician, that is, frequency of home BG monitoring was not changed. The study team developed a branching disease management algorithm based on DM and HTN guidelines from the VA, American Diabetes Association, and the American Heart Association. The algorithm was programmed into the device and focused on diet, exercise, smoking cessation, foot care, advice for sick days, medications, weight management, preventive care, and behavior modification and lifestyle adjustments. A schedule was established for each prompt set so that subjects received both standard prompts each day and a rotation of questions and educational content. Follow‐up was for a period of 12 months (n = 93) LOW‐INTENSITY GROUP: In the low‐intensity group, subjects were instructed to measure BP daily and BG as directed by their physician. Subjects in this group responded to a small subset of questions from the larger set of questions used with the high‐intensity group. Every day, subjects in this group were asked, ''Have you taken all your medications as prescribed?'' In addition, subjects were prompted with one additional question each day focused on diet, exercise, foot care, or medication side effects. These questions did not use the branching algorithm used for the high‐intensity group, rather they used yes/no or multiple choice responses (n = 102)	USUAL CARE: Usual care subjects scheduled follow‐up appointments with the primary care clinic in the usual manner. Subjects had access to their nurse care manager employed by the medical center (n = 107)	No for improving adherence to medication in diabetes patients with hypertension with a nurse management program	Yes for decreasing A1c at 6 months. No for decreasing A1c at 12 months. Yes for decreasing SPB at 6 and 12 months in high intervention group
Walley 2001	Tuberculosis	170 were assigned DOTS with direct observation of treatment by health workers; 165 were assigned DOTS with direct observation of treatment by family members	162 were assigned self administered treatment	No	No
Wang 2010 a	HIV with substance addiction	NURSE‐DELIVERED HOME VISITS: 4 home visits (every 2 months) were delivered by a qualified nurse and included 1) the provision of information about HIV/AIDS, 2) ART medication and adherence, and 3) skills to facilitate adherence, reinforcing motivation, mobilizing family support. Patients were provided with a pamphlet, electric pillbox with alarm, drug rehabilitation, methadone therapy, and stress management. In addition, tailored interventions were made based on the previous home visit and addressed barriers identified. Similarly, telephone calls were every 2 weeks including following each home visit to reinforce the effect of home visit and varied from 10 to 20 minutes to 1 hour during which adherence level, barriers and general emotional, sleeping, and eating conditions were discussed (n = 58)	USUAL CARE: As part of the Chinese national ART management program, patients are seen twice in the first month of ART and receive medication for half a month at each visit and in the absence of side effects and presence of normal liver and renal function, visits are reduced to once a month. The clinic's pharmacy dispenses medication monthly. Clients on ART also receive free laboratory test for CD4+ T cell counts every 3– 6 months for evaluating the effectiveness of the treatment. HIV viral load test is not routinely provided in the national treatment program because of the limited fund. The patients visit the clinic once they have side effects or other health problems and need a laboratory test. The service of home visits or phone calls from health care providers are not routinely provided (n = 58)	Yes for improving adherence to ART in heroin‐addicted HIV‐positive patients	Yes for improving quality of life and depressive symptoms in heroin‐addicted HIV‐positive patients
Wang 2010 b	Asthma	PHARMACIST COUNSELING: Patients participated in the standard nurse administered asthma education program with additional pharmacist counseling with the pharmacist. A detailed workbook prepared by chest physicians was used for each session. The asthma education program covered 4 topics taught in sequence in 3 1‐hour sessions offered during monthly clinic visits (at months 1, 2, and 3). Topics covered were: (1) definition, etiology, diagnosis, disease progress, and complications of asthma; (2) instruction to monitor disease severity, especially skills needed to use the peak expiratory flow (PEF) meter and the format to record symptoms in a diary; (3) introduction on medications for asthma therapy, including protocol of a stepwise treatment plan, pharmacology of leading asthma drugs and correct inhaler techniques; and (4) guidelines for self management, including understanding potential environmental triggers and irritant factors, environmental control and standard procedure for coping with asthma attacks. Pharmacist counseling covered information related to the action and side effects of asthma medications, treatment plans for individualized medication, and modification of medications in response to progressive asthma (n = 34) NURSE ADMINISTERED ASTHMA EDUCATION PROGRAM: Patients participated in the standard nurse administered asthma education program. A detailed workbook prepared by chest physicians was used for each session. The asthma education program covered 4 topics taught in sequence in 3 1‐hour sessions offered during monthly clinic visits (at months 1, 2, and 3). Topics covered were: (1) definition, etiology, diagnosis, disease progress, and complications of asthma; (2) instruction to monitor disease severity, especially skills needed to use the peak expiratory flow (PEF) meter and the format to record symptoms in a diary; (3) introduction on medications for asthma therapy, including protocol of a stepwise treatment plan, pharmacology of leading asthma drugs and correct inhaler techniques; and (4) guidelines for self management, including understanding potential environmental triggers and irritant factors, environmental control and standard procedure for coping with asthma attacks (n = 35)	CONTROL: Patients in the control group received only routine asthma care (n = 35)	No for improving adherence to asthma medication at 6 months	No for quality of life at 6 months
Weber 2004	HIV	Intervention group participants (n = 32) received cognitive behavior therapy in addition to usual care, while control group participants (n = 28) received usual care alone. Intervention group participants were assigned to a psychotherapist and given the contact information to schedule their own first appointment. Protocol defined a minimum of 3 and a maximum of 25 sessions within the 1‐year study period. Participant and psychotherapist determined the frequency of appointments and set their own goals for future interventions	Both intervention and control groups continued to receive standard care. Standard care included monthly visits for 12 months with assessments of clinical and laboratory data, course of treatment, drug adverse events and HIV‐1 RNA	No	No
Weinberger 2002	Asthma or chronic obstructive pulmonary disease (COPD)	The pharmaceutical care program provided pharmacists with recent patient‐specific clinical data (peak expiratory flow rates (PEFRs), emergency department (ED) visits, hospitalizations, and medication compliance), training, customized patient educational materials, and resources to facilitate program implementation (n = 447)	The PEFR monitoring control group received a peak flow meter, instructions about its use, and monthly calls to elicit PEFRs. However, PEFR data were not provided to the pharmacist. Patients in the usual care group (n = 303) received neither peak flow meters nor instructions in their use; during monthly telephone interviews, PEFR rates were not elicited. Pharmacists in both control groups had a training session but received no components of the pharmaceutical care intervention (n = 363)	Yes, for within‐group at 6 and 12 months; no for between‐group	Yes. At 12 months, patients receiving pharmaceutical care had significantly higher peak flow rates than the usual care group (P value = 0.02) but not than PEFR monitoring controls (P value = 0.28). There were no significant between‐group differences in HRQOL, but patients participating in the program were significantly more satisfied with their pharmacists than the other 2 groups
Wiggins 2009	Postoperative pain after tonsillectomy and adenoidectomy	AROUND‐THE‐CLOCK INTERVENTION: The intervention was alarms to remind administering analgesic 4 hours after going to bed on the night of surgery and next 2 postoperative nights as instructed by the research nurse. In addition to the study procedure, all children and families received discharge education from their ear, nose, and throat (ENT) physician/clinic and from the professional nurses in each of the ambulatory centers. Discharge education in both ambulatory settings included use of around‐the‐clock prescribed analgesia for pain during the early days of recovery; increased fluid intake; monitoring for infection and bleeding; and returning to their specialist at a designated time in the recovery process. In addition, all ENT specialists encouraged families to contact them with concerns. All families received a phone call from a registered nurse from their ambulatory surgery center 24 hours after discharge (n = 7)	USUAL CARE: The usual care group (UCG) was not given any specific intervention, but was offered the same discharge education as the intervention group. Discharge education materials included information about ear pain and the length of the recovery, mothers and children expressed self doubt about their ability to provide adequate symptom management when painful experiences continued (n = 6)	Yes for improving adherence to analgesic in children after tonsillectomy or adenoidectomy	No for improved pain intensity and fluid intake until postoperative day 2
Wilson 2010	Asthma	SHARED DECISION‐MAKING : Session 1 involved setting the stage, gathering patient information, providing information and negotiating a treatment plan. In session 2 (1 month after session 1), and in 3 brief phone calls 3, 6, and 9 months later, patient progress was assessed and medications were adjusted, as necessary, using the assigned care management approach. Researchers used identical standardized interventionist scripts and materials. The patient's asthma history was elicited using a standardized patient information form, the patient's level of asthma control was classified, and asthma education was provided. Once treatment was negotiated, patients were instructed in the correct use of the relevant inhaler medication devices using methods previously shown by this team to improve inhaler technique and eliminate common usage errors. At the end of session 1, a written asthma management and action plan was created, and potential barriers to medication adherence were elicited and addressed using motivational interviewing techniques. Any subsequent changes made at session 2 or in a follow‐up phone call were documented in the plan. The SDM model implemented the 4 key defining features. The care manager elicited the patient's goals for treatment and relative priorities regarding symptom control, regimen convenience, avoidance of side effects, and cost. The patient was then shown a list of the full range of regimen options for all levels of asthma severity, based on the then‐current national asthma guidelines and KP pharmacopeia. These options differed with respect to the number and type(s) of medications, dosing, and schedule. Using a simple worksheet, the patient and clinician then compared the pros and cons of all of the options the patient wished to consider, which included the option of continuing the patient's current regimen to arrive at a treatment that best accommodated the patient's and care manager's goals. A SABA was always prescribed for rescue use as needed. If indicated, treatment of allergic rhinitis and/or gastroesophageal reflux disease was negotiated (n = 204) CLINICIAN DECISION‐MAKING: Session 1 of the intervention involved prescribing the patient a therapy rather than negotiating a therapy. In session 2 (1 month after session 1), and in 3 brief phone calls 3, 6, and 9 months later, patient progress was assessed and medications were adjusted, as necessary, using the assigned care management approach. Researchers used identical standardized interventionist scripts and materials. The patient's asthma history was elicited using a standardized patient information form, the patient's level of asthma control was classified, and asthma education was provided. Once treatment was decided (CDM), patients were instructed in the correct use of the relevant inhaler medication devices using methods previously shown by this team to improve inhaler technique and eliminate common usage errors. At the end of session 1, a written asthma management and action plan was created, and potential barriers to medication adherence were elicited and addressed using motivational interviewing techniques. Any subsequent changes made at session 2 or in a follow‐up phone call were documented in the plan. In the CDM model, the care manager prescribed an appropriate regimen based on the patient's level of asthma control, and explained that decision to the patient. A SABA was always prescribed for rescue use as needed. If indicated, treatment of allergic rhinitis and/or gastroesophageal reflux disease was prescribed (n = 204)	USUAL CARE: Usual asthma care at KP medical centers was based on a stepped‐care approach to pharmacotherapy with the aim of long‐term asthma control, as recommended by the National Asthma Education Prevention Program's Expert Panel Report 2. At some KP sites, physicians also had the option to refer patients to an asthma care management program, typically of less than 6 months' duration, in which a licensed health professional (non‐physician) provided asthma education and addressed adherence and other medication use and self management issues in a manner similar to, but less structured than, the CDM intervention. However, asthma care management was neither a required aspect of usual care nor necessarily available at all BOAT sites, and current participation in that program was an exclusion criterion for the study. Once enrolled in BOAT, usual care and SDM or CDM patients (after the intervention phase) still had access to KP's existing care management services, if available, based on their physician's referral (n = 204)	Yes for improving compliance for all asthma controller medication and ICS at 1 year and no at 2 years in SDM group compared to CDM and UC and CDM compared to UC. Yes for improving compliance for beclomethasone canister equivalents in SDM group than CDM and UC at 1 year and 2 year. Yes for improving compliance to LABA use at 1 and 2 years for both SDM and CDM compared to UC	Yes for asthma‐related quality of life in both SDM and CDM compared to UC at 1 year. No for increased health care utilization in SDM and CDM than UC at 1 year. Yes for better asthma control in SDM than UC and CDM than UC. No for SABA use in SDM compared to UC and CDM at 1 year. No for SABA use in CDM compared to UC at 1 year. Yes for lung function at 1 year in SDM group compared to UC and in CDM compared to UC at 1 year
Wolever 2010	Type 2 diabetes	INTEGRATIVE HEALTH (IH) COACHING: 2 coaches provided the coaching intervention. Both had substantial training in coaching methods as well as masters‐level degrees in social work or psychology. Coaches each had over 100 hours of experience of individualized coaching with type 2 diabetes patients and had previously facilitated diabetes coaching groups. Participants randomized to the coaching condition had an initial telephone session with their coach within 2 weeks of the baseline visit. They were then offered 30‐minute coaching sessions by telephone (8 weekly calls, 4 biweekly calls, and a final call 1 month later) for a total of 14 sessions. Participants were paired with the same coach throughout the intervention. During the initial telephone call, participants were asked what was important to them in terms of diabetes care, how well they were managing their health, and what they perceived to be their challenges or areas of required support. Patients were guided in creating a vision of health, and long‐term goals were discussed that aligned with that vision. To facilitate learning, participants randomized to IH coaching received a binder of educational materials at the initial assessment visit. Contents included materials from GlaxoSmithKline's Adherence Starts with Knowledge® (ASK‐20) and Essential Connections® as well as information from Duke Integrative Medicine. These were referenced throughout the interactions of the study. The ASK‐20 is a brief survey that helps practitioners quickly identify and target reasons patients may not be adhering to prescribed medication regimens. It is accompanied by materials on topics relevant to self management such as symptom recognition, self care, and disease risk factors. Duke Integrative Medicine provided information regarding nutrition, stress management, and tips on how to best utilize time with the coach. Additional materials came from Essential Connections, a resource of tools for coaches to facilitate motivational interviewing techniques and behavior change, linking topics of interest with patients' readiness to change and relevant education content (n = 30)	USUAL CARE: Control group participants received usual care, with no additional materials or correspondence (n = 26)	No for self reported adherence on the Morisky questionnaire	No for A1C at 6 months. No for stress at 6 months. No for quality of life between integrative health coaching and usual care patients at 6 months
Wu 2006	Chronic illnesses receiving polypharmacy	INCREASED SUPERVISION BY PHARMACIST: Patients in the intervention group received 10‐ to 15‐minute telephone calls from the pharmacist at the midpoint between clinic visits, normally scheduled at intervals of 2 to 4 months, throughout the study period. During the telephone calls the pharmacist asked about the patient's current medication regime, clarified misconceptions, explained the nature of side effects, reminded patients of next appointment, reinforced importance of compliance with medications and relevant aspects of self care and encouraged patients to share side effects, self initiated change in regimen, or other concerns with the doctors at next follow‐up (n = 219)	USUAL CARE: Patients in the control group continued with usual care, which for clinically stable patients meant follow‐up at intervals of 2 to 4 months, with each consultation lasting 10 to 15 minutes (n = 223)	Yes for improving compliance to polypharmacy for chronic conditions	Yes for mortality, ER visits, and hospitalization
Wu 2012	Chronic heart failure	LITE: The intervention was delivered by a cardiovascular nurse expert in delivery of the education and counseling intervention. Patients received the counseling intervention individually every other week for a total of 4 sessions. The first and third sessions were face‐to‐face education and counseling lasting 1 hour. The 2nd and 4th sessions were delivered by telephone and lasted 20 minutes each. The intervention was designed to influence medication adherence by creating a more positive attitude toward medication adherence, incorporating significant others into the patient education and counseling sessions to build a positive subjective norm, and providing needed information and skills to overcome barriers to adherence to increase the patient's perceived behavioral control (n = 27) PLUS: In addition to what was received by the LITE group, participants received feed‐back on their medication taking behavior from the MEMS at each of the 2 face‐to‐face sessions. MEMS feedback was used to show the patients their own medication‐taking behavior and identify problematic areas. A visual display was shared by the nurse with the participant (n = 27)	USUAL CARE: Received usual care. Participants completed a baseline survey, were contacted monthly to collect outcome, and completed a 9‐month questionnaire. In addition their MEMS data were downloaded at 1, 2, and 9 months (n = 28)	Yes for improving adherence to heart failure medication at 9 months in PLUS and LITE groups compared to control. Yes for improving adherence at 2 months in PLUS compared to control. No for improving adherence at 9 months in PLUS compared to LITE	Yes for improving cardiac event‐free survival in both interventions compared to controls at 9 months. No for improved quality of life over the 9‐month period
Wysocki 2001	Diabetes	Behavioral‐Family Systems Therapy (BFST) ‐10 sessions consisting of 4 therapy components: problem‐solving training, communication skills training, cognitive restructuring and functional and structural family therapy, plus USD 100 monetary incentive for attending all 10 intervention sessions (n = 38) Education and Support (ES) ‐ families attended 10 group diabetes education and social support meetings (45‐minute educational presentation by diabetes professional + 45‐minute interaction among the families), plus USD 100 monetary incentive for attending all 10 intervention sessions (n = 40)	Current therapy ‐ standard pediatric endocrinology follow‐up and self management training (n = 41)	No for BFST and ES at post‐treatment. Yes for BFST at 6 and 12 months. No for ES at 6 and 12 months	No for BFST in diabetic control or adjustment to diabetes. Yes for BFST on PARQ scales at post‐treatment, 6, and 12 months. No for ES
Xiong 1994	Schizophrenia	Family counseling and close follow‐up (n = 34)	Prescription of medication without formal follow‐up (n = 29)	No	Yes
Yopp 2004	Adolescents with type 1 diabetes	Usual care (see Control) plus Multisystemic Therapy (MST; n = 27) ‐ a home‐based psychotherapy, the goal of which is to understand which factors are maintaining poor health status	Usual care in a multidisciplinary children's endocrinology clinic (n = 26)	No for the Diabetes Management Scale. Yes for the 24‐Hour Recall Interview, specifically the insulin adherence	No
Zhang 1994	Schizophrenia	Family intervention (n = 42)	Prescription of medication without formal follow‐up (n = 41)	No	Yes
Zolfaghari 2012	Type 2 diabetes	SHORT MESSAGE SYSTEM (SMS) GROUP: Participants in both groups received 3 days of diabetes self care education sessions. Before the intervention, the SMS group received 10 minutes of instruction on how to use their cell phones and check their ability to read the SMS. The intervention was provided for 3 months. Patients in the SMS group received about 6 messages every week (excluding holidays) that consisted information about taking a diet, exercising, diabetic medication taking, frequent self monitoring of blood glucose levels, and stress management. Overall, 72 messages were sent to patients during intervention, and the length of each message was not more than 160 features. Participants in the SMS group could receive messages at any place where access was possible by cellular phone. The researcher sent optimal recommendations back to each patient, 6 times by SMS of a cellular phone weekly (n = 38)	TELEPHONE INTERVENTION GROUP: The intervention for the Telephone Group was provided via telephone for 3 months. The intervention was provided by counseling scheduled appointments – whenever the time was convenient to the subject. The content of intervention consisted of counseling on the nature of the disease, risk factors, importance of maintaining blood glucose levels within a near‐normal range, continuous education and reinforcement of diet, exercise, medications taking, hypoglycemia management, illness management, how to record daily blood glucose and frequent self monitoring of blood glucose levels. The researcher contacted the telephone group at least twice a week for the first month and then weekly for the 2nd and 3rd month. The total frequency of telephone counseling averaged 16 times per subject. The average length of these contacts was 20 minutes per call. "The researcher asked questions about the diet: 'Did you eat salad and vegetable before every meal?', 'How many days did you follow your recommended diet over the past days?' 'Did you eat your meals at regular times?' and…some recommendations about exercising such as: 'How many times did you do physical exercising or walking during the last days?' 'When is the best time to exercise'? 'Did you feel better after exercising?' 'Do you know that exercising is as important as diabetic medication?' and medication‐related questions were: 'Did you take your recommended diabetic medication?' 'When did you consume your prescribed tablet? 'Do you know how your consuming medications, act in your body?'…and so on" (n = 39)	No for improving medication adherence in diabetic patients with an SMS intervention at 6 months	No for improving HbA1C levels at 6 months. No difference in HbA1c levels between the groups

Excluded studies

Of the 26,312 unique citations detected, we excluded 24,639 studies during the title and abstract screen (Figure 1). We excluded an additional 1,564 studies during the full‐text screen (Figure 1), of which 374 were excluded at the data extraction stage for the reasons indicated in Characteristics of excluded studies. There are also eight studies awaiting assessment, as noted in Characteristics of studies awaiting classification.

Risk of bias in included studies

Although all included studies were RCTs, their risk of bias varied considerably because of study design or conduct. Review author agreement was good for determining risk of bias for random sequence generation (kappa = 0.71; 95% confidence interval (CI) 0.61 to 0.80), moderate for the risk of bias for allocation concealment (kappa = 0.47; 95% CI 0.34 to 0.59), and fair for the risk of bias for blinding of the primary clinical outcome assessor (kappa = 0.32; 95% CI 0.16 to 0.45). A third adjudicator resolved differences in the duplicate independent assessments. Authors responded to our requests to review our extractions and provide additional information on 126 occasions out of 182 attempts (69%).

Allocation

The risk of bias for random sequence generation was low in 105 RCTs and unclear in 77 RCTs. For concealment of allocation, risk of bias was high in two RCTs, low in 58 RCTs, and unclear in 122 RCTs.

Blinding

Also taking into account the risk of bias for the primary clinical outcome, 17 RCTs had a low risk of bias for both study design (random sequence generation and concealment of allocation) and for the primary clinical outcome (blinding of the outcome assessor): six from the previous update (Haynes 1976; Walley 2001; Nazareth 2001; Stevens 2002; Laporte 2003; Weber 2004), and 11 from the current update (Wu 2006; Simoni 2007; Martins 2009; Simoni 2009; Lester 2010; Chung 2011; Farooq 2011; Morgado 2011; Ellis 2012; Gray 2012; Solomon 2012). Only four RCTs also had a low risk of bias for the primary adherence outcome, since most adherence measures had a high or uncertain risk of bias (Haynes 1976; Chung 2011; Gray 2012; Solomon 2012).

We chose to focus our narrative on the 17 RCTs with low risk of bias for study design and primary clinical outcome to provide insights from the highest‐quality evidence of adherence intervention. Details for all 182 RCTs are reported in the table Characteristics of included studies.

A summary of the risk of bias in all 182 studies is shown in Figure 2.

2.

'Risk of bias' summary: review authors' judgments about each risk of bias item for each included study.

Effects of interventions

Intervention effects

The diversity and complexity of interventions precluded a taxonomy of simple labels that would accurately summarize efficacy per intervention type. We also avoided the classification in general themes and groups as done for the previous update, as this would be more cumbersome and less helpful with the current volume of included randomized controlled trials (RCTs). Detailed information regarding treatment arms and outcomes for all 182 RCTs is provided in both the Characteristics of included studies and the Analysis 1.1 tables. To provide a reasonable sampling of the details and diversity of included adherence intervention RCTs, we chose to provide a narrative focused strictly on the RCTs with the lowest risk of bias.

Summary of the RCTs with the lowest risk of bias

Of all included RCTs, 17 had a low risk of bias for both the study design (random sequence generation and concealment of allocation) and the primary clinical outcome (blinding of outcome assessor, as relevant for the outcome). Four of these trials also had low risk of bias for measuring adherence, so we discuss these first, with the most recently published studies first, then the remaining 13 studies, again, with newest studies first.

Gray 2012 randomized 127 patients with newly diagnosed ocular hypertension or open‐angle glaucoma to an individually tailored adherence intervention or care as usual. The intervention was delivered by a glaucoma trained nurse with an initial session to assess patient needs, beliefs, and potential solutions, and to devise a one‐year individualized care plan that involved education, training, liaising with and training for informal caregivers and professional health care providers, and planning approximately five face‐to‐face or phone follow‐up contacts with the nurse for reassessment. From 12 to 24 months follow‐up no intervention was provided and both groups had usual care. The intervention group had a higher proportion of patients with 100% refill adherence (70% versus 43%; P value = 0.002) as measured by low risk of bias practitioner and pharmacist report at 12 months. Intraocular pressure values and changes in management were recorded from routine medical care charts. The mean intraocular pressure, and fluctuations in ocular pressure and changes in management, were not different at 12 months. At 24 months, adherence was not measured. The mean intraocular pressure was almost identical in the two groups, but the fluctuation of intraocular pressure was higher and changes in management more frequent in the control group. It is possible that the differences at 24 months were found due to chance, especially as it is unlikely that a significant effect would be observed one year after stopping the intervention, while no effect was observed after one year of intensive intervention.

Solomon 2012 sent seven informational mailings addressing osteoporosis to 2097 low‐income older adults who were initiating osteoporosis medication, and randomized them to receive eight phone counseling sessions by health educators using motivational interviewing techniques to promote adherence, or the mailings alone. The phone counseling intervention did not significantly improve the primary outcome, adherence as measured by the median medication possession ratio using low risk of bias pharmacy claims data. Further, secondary outcomes including medication persistence, and proportions with self reported fractures or falls were not improved. The authors indicated that the 113‐day time lag between identifying persons initiating therapy in the database and making the first phone call in the intervention group was a missed opportunity, since many eligible or recruited persons had already stopped therapy before the first call.

Chung 2011 randomized 400 newly diagnosed HIV patients who were candidates for highly active antiretroviral therapy to one of four treatment groups in a 2 x 2 factorial design: 1) three adherence counseling sessions within one month of therapy initiation, or 2) a visual and audible alarm device, programmed by staff, to carry at all times during six months, or 3) both adherence counseling and the alarm device, or 4) neither counseling nor the alarm device (control). Counseling sessions, which followed a written standardized protocol and lasted between 30 and 45 minutes, had no significant effect on the proportion of participants who achieved adherence ≥ 80% or ≥ 95%, as determined using low risk of bias pill counts at pharmacy refill visits, but resulted in a lower hazard rate of viral failure. The authors hypothesized that the clinical benefit of counseling could relate to providing the sessions in advance of, and just after, therapy initiation. The alarm device did not improve the adherence or viral outcomes.

Haynes 1976 randomly allocated, through the minimization method, 38 patients who were both hypertensive and non‐adherent (less than 80% of prescribed pills) at the end of a six‐month trial to an intensive adherence intervention or control. The intervention included care provided at the work site, special pill containers, counseling, reminders, self monitoring of adherence and blood pressure, support groups, feedback and reinforcement for adequate adherence and blood pressure‐lowering, all administered with bi‐weekly contacts by a lay program co‐ordinator who was supported from study funds. At six months follow‐up, there was a significantly higher adherence in the intervention group, as measured by low risk of bias unobtrusive home pill count. The change in diastolic blood pressure after six months was not statistically significantly different between groups (difference in change 3.5 mm Hg; P value = 0.12), although the small sample size might have meant insufficient power to detect a clinically meaningful difference. The authors discussed the possibility that simply the increased attention for intervention patients could have contributed to the improved adherence, rather than the specific intervention components. It has to be noted that medical therapy for intervention patients was more often intensified at the end of the study, while the intervention co‐ordinator was not allowed to contact treating physicians.

Ellis 2012 tested whether an average of 5.6 months of multi‐systemic therapy (MST), a highly intensive, home‐based, tailored family intervention, improved treatment adherence and HbA1c levels compared with weekly phone support during 4.9 months, among 146 poorly controlled adolescent diabetics (mean HbA1c = 11.7%, where good control would be an A1c of 7% for most patients). In MST, therapists were expected to meet with families, their related contacts (e.g. extended family, physicians, and school personnel), or both, a minimum of two times per week at the beginning of treatment with an option for a reduced number of sessions at the end of treatment based on family progress toward treatment goals. Treatment was planned to last for approximately six months. All participants in the trial received standard medical care in addition to MST or telephone support. At seven and 12 months follow‐up, the intervention lowered HbA1c and improved adherence (Diabetes Management Scale) as reported by the parent, but not as reported by the adolescent. As the authors acknowledged, it has to be evaluated whether such an intensive intervention is cost‐effective, especially as the difference in improvements in HbA1c were relatively small (e.g. A1c ‐0.74%, 95% confidence interval (CI) ‐1.48% to ‐0.01%, at 12 months) in view of the poor control at baseline (A1c 11.7%).

Farooq 2011 randomized 110 patients with schizophrenia or schizoaffective disorder to receive family supervised treatment (STOPS) or care as usual. In addition to usual care, participants in the STOPS arm each had a key care supervisor, defined as any family member living with the individual for at least six months and providing support for the treatment as identified by the participant. Education was provided to the key care supervisor about the nature of the illness, misconceptions about treatment, the relationship between supernatural and biological causes of illness (some people believing in supernatural causes might think they cannot do anything about the disease), and the importance of continuing the medication, as well as basic skills in how to administer and supervise the medication. It was emphasized that participants should not be antagonized and violence should never be used in case of refusal to accept the treatment. Steps involved in collecting medicine from the treatment center, storage at home, administering tablets and their ingestion by the participant and how to confirm this were demonstrated. Intervention participants also received free medicines while control group members were left to their own means to obtain their medications. The proportion of patients with perfect adherence, as measured by a five‐point self report scale supplemented by pill count data, was higher at three and 12 months in the intervention group, but not at six months. Supervised therapy also improved symptoms as measured by the Global Assessment of Functioning Scale and Positive And Negative Syndrome Scale. However, it was unclear to what extent free provision of medication in the intervention group for the study contributed to the effect, since control patients could only apply for free drugs through a regular care process (not for the study), if eligible.

Morgado 2011 randomized 197 patients with arterial hypertension, who had been on antihypertensive therapy for at least six months, to receive either counseling from a hospital pharmacist at a specialized outpatient clinic, or regular care at a traditional hospital clinic without a hospital pharmacist. Hospital pharmacists interviewed patients, assessed problems with blood pressure control, educated patients, advised physicians on medication changes, and provided intervention patients with written educational material. Patients in the intervention group were also encouraged to bring all empty blisters and boxes of antihypertensive medication to clinic visits for recycling and to verify compliance with therapy. The intervention improved the primary outcome of proportion of patients with blood pressure controlled to target, and reduced the proportion of patients with low medication adherence as measured by a five‐item questionnaire. The medical therapy advice from pharmacists to physicians might have contributed to the improved blood pressure control in addition to the improved adherence, although the authors report that there were no marked differences compared with the control group regarding therapy changes.

Lester 2010 randomized 538 patients newly initiating antiretroviral therapy, and who had access to a mobile phone and, if required, a partner able to read educational materials, to receive interactive short message service (SMS) or care as usual. Patients in the intervention group received a short education session on the intervention from clinicians, received an SMS every Monday asking "How are you?", and were required to respond within 48 hours to indicate that everything was fine or they had a problem. In case of no response within 48 hours or an indicated problem, the clinician called the patient. The intervention was based on existing mobile phone services and SMS messages were sent by available nurses or clinical officers; no personnel or SMS credits were provided specifically for the study. In the intention‐to‐treat analysis, the intervention improved the proportion of patients with self reported adherence greater than 95% as well as viral suppression (HIV‐1 RNA < 400 copies/ml). Of note, the intervention was reported to function well during a period of political turmoil and population displacement, directing patients to alternative health resources using interactive SMS.

Martins 2009 randomized 270 patients with pulmonary tuberculosis from urban community clinics in Timor‐Leste, which had a well‐functioning tuberculosis treatment program including direct observation of medication taking, to receive the intervention with supplementary food or nutritional advice only. Intervention patients were required to attend the clinic daily for routine tuberculosis treatment, and additionally were offered nutritious daily meals at the clinic during the first eight weeks with direct observation of consumption by clinic personnel, and received daily meal packages to take home during weeks 9 to 32. Control group patients were also required to attend the clinic daily for routine care, and additionally received advice regarding a nutritious diet, but did not receive food. The intervention did not improve the primary outcome of proportion of patients completing treatment (sputum clearance) or completion of eight months of treatment, nor did it improve medication adherence or clinical symptoms including cough. The significant weight gain in the intervention group could be beneficial for the tuberculosis patient group, but was not achieved through better medication adherence and therefore not pertinent to the research question of this review. Of note, a civil conflict arose during the last months of the study, which caused displacement of a large population and complicated adequate completion of the study.

Simoni 2009 randomized 226 HIV‐positive patients initiating or switching to a new antiretroviral medication in a factorial design to either peer support, pager messaging, both peer support and paper messaging, or care as usual only. Regarding peer support, clinic staff selected peer supporters who were also HIV patients on antiretroviral therapy, and had a high therapy adherence, regularly attended clinic visits, were socially skilled, and were able to participate in training and supervision. Peers were, as much as possible, matched to participants based on race/ethnicity, sex, and sexual orientation. During three months, aiming to use twice‐monthly group meetings and thrice‐weekly phone calls, peer supporters addressed barriers to medication adherence and potential solutions. Patients could choose to continue attending meetings and seeking assistance after three months. The three months pager intervention involved automated individually tailored interactive messaging, addressing medication adherence, education, entertainment, and adherence measurement. Messaging frequency could be tailored to the patient's preference with a minimum of three daily messages in the first two months, which was tapered in the third month. At three months, the only significant effect was for self reported adherence in the peer support group, compared with care as usual. No effects were found of either peer support or the pager intervention on self reported adherence, electronically monitored adherence, and viral load and CD4 count as reported in routine medical charts, at six and nine months. The one significant effect was likely a chance finding, considering the testing of multiple outcomes at different time points and the absence of confirmation by Medication Event Monitoring System (MEMS). The authors discussed that the lack of an effect could be related to the poor use of the intervention by participants, the high quality of usual care in this HIV‐specialized clinic, and the inclusion of all patients on therapy rather than those with adherence problems only.

Simoni 2007 randomized 136 HIV‐positive patients with prescribed antiretroviral therapy to receive a peer‐led social support intervention or standard care. The three months peer support intervention was of similar design to the intervention for Simoni 2009, with the difference that in the present study patients could not choose to continue attending meetings and seeking assistance after three months. The intervention did not improve adherence as measured by self report and MEMS, nor did it lower HIV‐1 RNA viral load values as routinely reported in medical charts, at three and six months follow‐up. The authors discussed the possibility that the lack of an effect could relate to the poor use of the intervention by participants due to multiple barriers—including poverty, substance abuse, and insufficient time to establish trust between patient and peer supporter—limiting consistent attendance at meetings and receiving phone calls for adherence.

Wu 2006 tested the effect on adherence and mortality of pharmacist phone counseling, addressing medication adherence, lifestyle, and the next follow‐up visit, versus usual care, among non‐adherent stable patients on five or more chronic medications. Of 442 randomized patients, 236 had become adherent since screening. Adherence was measured by pharmacists using a structured questionnaire in combination with medication dispensing information: taking 80% to 120% of prescribed pills was considered adherent. A proportion of all medications for which the patient was adherent was calculated, but it was unclear how this was used since the authors only distinguished adherent and non‐adherent. After receiving six to eight pharmacist calls during two years, the intervention group had fewer baseline non‐adherent patients who remained non‐adherent, and more baseline adherent patients who remained adherent. The phone counseling intervention also reduced the risk of all‐cause mortality from 18% to 11% (relative risk 0.59, 95% CI 0.35 to 0.97; P value = 0.039). Considering that mortality is hard to improve solely with an adherence intervention, and the confidence interval for the relative risk is wide, this result needs to be replicated.

Weber 2004 randomized 60 HIV patients, who were stable on a combination of at least three antiretroviral medications and had a viral load of less than 50 copies/ml, to a cognitive behavioral intervention or standard care. Patients in the intervention group were given contact information for a psychotherapist, and asked to schedule a first appointment. The psychotherapist and patient determined a visit schedule for the year, with a minimum of two sessions and maximum of 25 (median was 11). In addition, they would identify at least two treatment goals, of which medication adherence was one, which would be targeted with treatment based on cognitive behavioral therapy principles. The proportion of patients with adherence of 95% or greater as measured by MEMS, and self reported adherence as measured on a visual analog scale, was higher in the intervention group at 10 to 12 months, but the regression coefficients for change in MEMS adherence during the study were not different between intervention and control. Viral load and CD4 count were not different between groups, but the intervention group showed an improvement in mental state, as measured by a standardized questionnaire on experience and behavior. This study was designed as a feasibility study, with no reported sample size calculation, and it is unclear to what extent the study was powered to detect differences in clinical outcomes, or if significant effects would remain after correction for multiple comparisons.

Laporte 2003 randomized 86 patients who were hospitalized for a thromboembolic disease and needed oral anticoagulation for at least three months, to either intensive education or standard education on anticoagulation. Patients in the intervention group received visual educational material, daily visits from healthcare providers, and daily tests on their education for the duration of the hospitalization, all aimed at the importance of medication adherence and causes of anticoagulation instability. Control group patients received standard education without any of these features for the entire duration of hospitalization. Following discharge, no differences were found regarding correct bottle openings, timing of bottle openings or pill count, all measured using MEMS. In addition, no differences were found regarding the clinical effect of anticoagulants, e.g. proportion of values or the proportion of days the INR (international normalized ratio) values were within the therapeutic target range. The study used a factorial design and also randomized patients to anticoagulation with either warfarin or acenocoumarol, but these medication groups did not differ regarding adherence and no statistical interaction was found between the medication and educational interventions.

Stevens 2002 randomized 335 patients with dyspepsia and confirmed Helicobacter pylori infection, who were prescribed seven‐day treatment with omeprazole, bismuth subsalicylate, metronidazole, and tetracycline hydrochloride, to either an intensive pharmacist counseling intervention or regular pharmacist counseling. Intervention patients received a detailed 15‐minute pharmacist counseling session at the start of therapy, addressing side effects, the importance of completing therapy, potential barriers and coping strategies related to adherence, and encouragement to call the pharmacist in case of problems, as well as a standard phone call by the pharmacist after two to three days. Patients in the control group received a standard five‐minute pharmacist counseling session at therapy initiation, describing the proper protocol to take the medication and providing an opportunity to ask questions. Self reported medication adherence and Helicobacter pylori eradication rate, as measured by carbon¹⁴ urea breath test, were not different between the intervention and control groups at three months. The authors indicated that the lack of an effect could relate to enrolment of motivated patients who were doing well at baseline, the use of daily blister packs in all patients, which might have enhanced adherence, or spill‐over of the intervention to the control group due to the same pharmacists applying the two treatments, both of which included counseling.

Nazareth 2001 randomized 362 hospitalized patients over 75 years, who were taking more than four medications at discharge, to either an intensive or a standard pharmacist discharge plan. Patients in the intervention group received an assessment by a hospital pharmacist, who evaluated therapy appropriateness and the patient's ability to manage the medications, and educated patients on appropriate adherence and how to liaise with important healthcare providers. An individualized discharge plan was devised containing the patient's medications and required adherence support, and copies were given to the patient and an assigned community pharmacist, family physician and other involved providers. After 7 to 14 days the community pharmacist visited the patient at home to reassess therapy adherence and barriers, and intervene and schedule additional follow‐up visits as deemed appropriate. Control group patients received standard discharge procedures by a hospital pharmacist, including a letter to the family physician. No differences were found at three and six months for hospital readmission, death, outpatient clinic visits, and family physician visits, nor for self reported measures including general well‐being, satisfaction, adherence, medication knowledge, and medication hoarding. This study included old and high‐risk patients, of whom 11% had a Mini‐Mental State Examination score of 15 or less at baseline and 15% died during six months, leaving 74% of participants for interview on self reported measures at six months.

Walley 2001 tested the effect of direct observation of therapy, and randomized 497 new sputum‐positive tuberculosis patients to one of three arms: 1) direct observation by health workers six days per week during two months, 2) direct observation by family members, 3) self administered therapy, obtained by bi‐weekly visits to a health facility. At seven to eight months, both direct observation intervention groups had comparable rates to the control group for the outcomes of cure (sputum‐negative on two most recent occasions) and cure or treatment completion (no smear results on at least two occasions, but treatment completed). The authors indicated that the lack of an effect might be due to challenges such as the high rate of patients not being able to comply with direct observation of therapy by health workers, and the implementation of interventions for this study on top of a recently strengthened tuberculosis care system.

Discussion

Summary of main results

The current review updated our 2008 version, Haynes 2008, with 109 new RCTs, a substantially larger number than expected from previous publication rates. To our knowledge this is the only comprehensive (not restricted to specific settings, medications, or diseases) systematic review of interventions to improve medication adherence based on randomized controlled trials (RCTs) that assessed both adherence and clinical outcomes. Despite the more than two‐fold increase in the knowledge base, the interventions and findings of these RCTs only slightly alter the conclusions of the previous version of our review. Compared with the previous update, we now: 1) report a lack of convincing evidence among studies with the lowest risk of bias; 2) no longer try to classify studies according to intervention type; 3) make our database available for collaboration on sub‐analyses. The wide variety of settings, participants, intervention types, medications, adherence measures, and clinical outcomes precluded summarizing findings to reach reliable general conclusions. RCTs included in the current review reported effects that were inconsistent from study to study. A minority of lowest risk of bias RCTs reported improving both adherence and clinical outcome, but these typically had very complex interventions that would be difficult to implement in usual practice setting. Thus, as a qualitative generalization, methods of improving medication adherence for chronic health problems tested to date are mostly complex and not very effective, so that the full benefits of treatment cannot be realized. Therefore, the quest for effective and practical interventions to promote medication adherence and improve clinical outcomes must continue. In acknowledgement of the need for collective advancement, we make our database available for collaboration on sub‐analyses.

To the extent that they represent true innovation, the increase of trials is most encouraging. Even when outcomes were improved, however, the effects were generally small. Effects were seldom assessed on major clinical events such as death or hospitalization, and when done these were rarely significant, albeit possibly due to insufficient study power. The diversity, complexity, and uncertain effects of the interventions, as well as the often uncertain risk of bias for blinding treatment allocation and outcomes assessment, make generalizations about which interventions work and which do not problematic.

Quality of the evidence

Our narrative focused on the RCTs with the lowest risk of bias, to provide a reasonable sampling of the details and diversity of included trials. We identified only 17 studies as having a low risk of bias for study design and clinical outcome assessment. Their interventions were generally complex, trying to overcome multiple barriers to adherence by several means of tailored ongoing support. The lowest risk of bias RCTs primarily involved enhanced support from family, peers, or allied health professionals such as pharmacists, who often delivered intense education, counseling (including motivational interviewing or cognitive behavioral therapy by professionals), and/or daily treatment support. Of these RCTs, five improved both adherence and clinical outcomes, three improved only adherence outcomes, one improved only clinical outcomes, and eight did not improve adherence or clinical outcomes. This was a similar success rate to that found in the 21 newly included studies in the 2008 update (Haynes 2008). Whether these numbers reflect the actual proportion of studies that had an important effect is uncertain, and simple 'vote counting' is not informative because:

1. a large variety of often complex interventions would be inappropriately treated as equal;

2. many studies tested multiple outcomes without statistical correction, thereby increasing the risk of false positives findings;

3. many studies were underpowered thereby potentially hiding a true effect;

4. most outcomes were surrogate measures (e.g. blood pressure) rather than patient‐important outcomes.

No common intervention characteristics for success were apparent among these studies. Therefore, even in the studies with the strongest methodology, no consistent evidence exists that medication adherence can be improved within the resources usually available in clinical settings, and that this will predictably lead to important improvements in treatment outcomes. The results might have been different with more relaxed criteria for participant loss to follow‐up, but this would further muddy the water with even lower‐quality RCTs, and we prefer to stand by our criteria of at least 80% follow‐up in all treatment groups. In addition, most studies enrolled patients who were willing to participate, rather than those that had low adherence. This makes it harder to show an effect, as opposed to applying the intervention only to those in need of adherence support. Although we were not able to assess potential publication bias, as we did not pool results, we estimate that some publication bias is likely due to the widespread lack of power to pick up potentially meaningful effects. If so, our low estimate of the benefits of interventions to date would likely only be reinforced by unpublished studies.

Interventions

New developments

Since the last update, some new or little studied intervention types have been reported. Although the technologies have been around for a while, we were now able to include several RCTs testing the effect of mobile text messages (Simoni 2009; Hou 2010; Lester 2010; Boker 2012; Zolfaghari 2012), and remote internet‐based treatment support (Chan 2007; van der Meer 2009). Of the five RCTs testing the effect of mobile text messages, two were included in the lowest risk of bias group. Only Lester 2010 showed a significant effect, on antiretroviral therapy adherence and the clinical outcome of viral load in HIV patients. There may be potential to build on the opportunities provided by text messaging, including in low‐resource settings. Simoni 2009 also targeted HIV patients, but did not show an effect of pager messages on adherence or viral load. The remaining three RCTs testing mobile text messages for oral contraceptives, acne therapy, and diabetes were not included in the lowest risk of bias group, and none had an effect on both adherence and the clinical outcome (Hou 2010; Boker 2012; Zolfaghari 2012). Further, Chan 2007, a study not included in the lowest risk of bias group, tested internet‐based asthma telemonitoring for patients of 6 to 17 years, but found no effect on adherence or clinical outcomes. van der Meer 2009 tested internet‐based asthma self management plus education among adults, whereby communication could also be done using mobile text messaging if preferred, and found no improvement in medication adherence, only moderate improvements in asthma control and lung function, and no clinically significant improvements in asthma‐related quality of life and exacerbations. Further, no other RCTs testing the effect of internet‐based disease telemonitoring made it through our selection process. Although both technologies have great potential to reach large population groups to improve adherence, further rigorous testing is necessary. Ongoing studies might strengthen the knowledge base and provide more details on how they could be better utilized. The present examples overall do not change our conclusion from the previous update that adherence research is lagging behind the rapid developments in technology, and that research methodology and evidence on their optimal use remain weak.

Allied healthcare providers such as nurses and pharmacists are increasingly delivering part of, or the entire intervention. In our previous update we advised further exploration of their role, and hypothesized that if their roles can be expanded to include counseling patients to enhance medication adherence, this may be feasible in practice. Considering that physicians have limited time, and sometimes skills, to counsel patients on medication adherence repeatedly, shifting these tasks to allied providers seems reasonable and potentially cost‐effective. Several complex interventions involving allied providers were effective, but since they were often only part of the intervention and delivered a variety of intervention enhancing services, their efficacy has to be determined for specific roles and tasks. In addition to the role of allied health professionals, several studies tested family/social interventions, lay health mentoring, or group meetings. It seems worthwhile to explore further involving non‐professional personnel, since the patient's social context is important to optimize chronic care, and might improve cost‐effectiveness.

As mentioned, complex interventions were often used in the new RCTs, typically involving intensive ongoing allied health care provider and social support, sometimes facilitating transitions in care. This seems logical considering that adherence is generally a complicated matter caused by multi‐factorial barriers (ABC Project Team 2012; Kardas 2013), but also raises three primary concerns:

1. complex interventions are usually compared with care as usual, while it remains to be seen if they are more effective than a simple intervention;

2. if effective, the entire complex intervention should be implementable in other settings, without requirement of excessive additional personnel and costs (implementation flexibility and external validity); and

3. if the latter is not feasible, the effects of individual components should be teased out, such as by a factorial design, in order to be able to determine if all components were required or to select the most effective ones.

Related to complexity, many RCTs used personnel and resources supported by research funds. For example, pharmacists would be specifically allocated to the intervention and reimbursed accordingly, but outside this research setting they might not be able or willing to dedicate this time to the intervention. Even if a small effect on clinical outcomes was observed, it remains to be seen whether such interventions can be translated to other settings in a cost‐effective manner. Regarding this, few adequate full cost‐effectiveness evaluations of adherence RCTs are being published (Oberje 2013). These will be needed if clinically important effects are documented.

Process evaluation of an effective complex intervention can be very useful to hypothesize which components were most effective and to identify individual or contextual barriers and facilitators to adherence (Craig 2008). However, we believe that this eventually requires direct comparison in an RCT, compared with usual care or a simple intervention. Two RCTs in the lowest risk of bias group, Simoni 2009 and Chung 2011, applied two different adherence interventions in a factorial design. This design allows testing of the separate effects of multiple intervention components, while also observing their additive effect. This will better inform which components are independently effective, or whether an effect is due to the combination of two components that individually might not be (very) effective. It has to be noted that to be able to test several components and their interactions with sufficient power, the required sample size has to be increased accordingly (McAlister 2003).

Of note, the European Ascertaining Barriers for Compliance project published its final report in 2013 (Demonceau 2013), which also included a comprehensive systematic review including intervention RCTs assessing adherence outcome by means of electronically compiled measures. The authors used a taxonomy to label intervention components and tried to tease out the effect of each component, although they acknowledged that many interventions were complex, highly variable, and not easily summarized. Of the 65 included RCTs, 32 also assessed clinical outcome, with only four showing an effect on clinical outcome.

Promising interventions not included in our review

There are likely many potential areas for which interventions are either in development or lacked high‐quality RCT evidence with adherence and clinical outcomes at the time of our search. We will illustrate this with a selected example regarding cardiovascular prevention single‐pill combination therapies, also since a recent Cochrane systematic review by Ryan et al showed promise for simplified dosing (Ryan 2014). Several of these combination pills, containing multiple proven cardiovascular medications, have already been developed and tested versus the same medications as individual therapies (Working Group on the Summit of Combination Therapy). These pills simplify therapy to only one pill per day, where most cardiovascular patients currently have to take at least four to five separate pills daily. The RCTs testing combination pills typically assessed effects on therapy persistence (e.g. not explicitly discontinuing), rather than daily pill adherence while still on medications, in addition to intermediate clinical outcomes such as blood pressure. However, an RCT published after our search showed that self reported adherence as well as intermediate clinical outcomes (blood pressure, lipid levels) were somewhat improved with a cardiovascular combination pill (Thom 2013). That said, medication was provided free to the combination pill intervention group, while control group participants had to fend for themselves in acquiring their medications (almost half lacked insurance coverage), leaving uncertainty as to whether the improved adherence was due to simplified therapy or facilitated access to medication and cost‐lowering. This study would be a candidate to make it into our next update, but the provision of polypills free of charge constitutes a more complex intervention than the authors highlighted. As a related example, in our previous review we indicated that there is some evidence that a dose frequency of one to two times per day may be associated with better adherence than three to four times per day, and advised better exploration of this dose frequency. None of the new RCTs with the lowest risk of bias addressed this issue, and we would like to highlight this important issue.

Measuring adherence and clinical outcomes

To determine applicability to patient care, we only selected studies that measured both adherence and treatment outcome. This requirement has received the criticism that this resulted in a more negative message than some would like to see. It has been suggested that the findings would be more upbeat and positive if we included studies that measured only adherence. This criticism does not pertain to the purpose of this review, that is, to determine whether adherence interventions make a difference to clinical outcomes. It simply cannot be assumed that measures to increase adherence do more good than harm, even if they increase adherence. Nevertheless, we do agree that investigators who seek to advance the methods for enhancing adherence may find promising leads from studies that do not meet our criteria for measurement of both adherence and clinical outcomes.

Attempts to increase adherence can have adverse effects (loss of privacy and autonomy, increased adverse effects of treatments) (Simpson 2006), and so on. Few RCTs assessed such potential adverse effects. Further, many interventions with an effect on adherence and surrogate clinical outcomes measured relatively short‐term outcomes, typically at 6 to 12 months, which does not mean that their effect would be sustained or that they would lead to important clinical outcomes in the long run.

Adherence measures

A well‐known problem with adherence studies is the inability to measure adherence accurately and reliably, making it harder to pick up true differences, which could have contributed to the variable effects we observed among RCTs. Most studies used patient self report measures, which are known to overestimate adherence (Gordis 1979; Haynes 1980; Stephenson 1993); these studies are at especially high risk of bias when the patient is not blinded to the treatment allocation, which is usually the case. Some validated questionnaires are available, and should be used as much as possible if self report is chosen, but their accuracy and reliability are often limited and depend on the context they are used in.

Increasingly, studies are using Medication Event Monitoring System (MEMS) pill bottle caps. These caps contain a microchip that measures the date and time at which the bottles are opened, but do not register if the patient actually took the medication on those occasions. Although this method is more objective than self report, it could also function as an intervention (patients feel monitored) (Christensen 2009), and increase adherence in both groups, thus diminishing or concealing a true difference. It can also be 'gamed' by the patient who is aware of the MEMS function and wishes to keep non‐adherence private.

A potentially more objective measure that was used in some studies was pill count, which is especially appealing if it is done unannounced, at home, and in an unobtrusive way, in order to prevent patient awareness and anticipation of pill count. However, most pill counts are done on containers that the patient brings with them to a visit to a health professional, and in this circumstance counts can clearly be altered by the patient.

A method that was regularly used, and that probably has the highest likelihood of maintaining blinding of patients and providers, was the use of routine pharmacy refill records. Although this method depends on the assumption that the patient is actually consuming the medication, and the only one doing so, it better allows adequate blinding of outcome assessors. In our view, using more objective measures such as pharmacy records is a productive step forward in the field of adherence research, as it will lead to further valid and reliable results. With electronic records available in most pharmacies, this option is increasingly available, inexpensive, and acceptable, providing that patient consent is obtained.

It is important to note that our review may miss the most severe form of non‐adherence, among those who do not attend for needed care or enter trials. Patients dropping out of care are unlikely to be receiving any medication, and if those in care average about 50% adherence, keeping patients in care is arguably the most important adherence intervention at present. The same rationale can be used for keeping patients on medication, even if they do not attend clinic visits. Both assume, however, that for those who are prevented from dropping out or discontinuing medication, or who are returned to care or restart medication by intervention, adherence rates are sufficient to achieve clinically important benefits. This merits further testing.

Clinical outcomes

Consistent with the large variety in diseases and medications, many different clinical outcomes were reported. Most RCTs measured intermediate biological outcomes, such as blood pressure, serum cholesterol or HIV‐1 RNA, or patient‐reported outcomes such as quality of life, knowledge, beliefs, or attitudes. Very few studies examined major, patient‐important, clinical endpoints such as death or hospitalization. The latter have the lowest risk of bias, as they are obvious and can easily be verified. Intermediate biological outcomes also often have a low risk of bias, although this could be compromised if measurement methods differ among subjects, and outcome assessors are not blinded. For example, measuring blood pressure requires a protocol whereby a fixed number of measurements are taken according to a standardized process, and a provider who is aware of a participant being in the intervention group might (subconsciously or otherwise) alter this process or interpret readings differently. Self reported outcomes such as symptoms and quality of life are more prone to bias, even if using well‐validated general and disease‐specific tools to assess them. Finally, many studies reported self reported knowledge, beliefs, and attitudes, often in addition to more objective clinical outcomes. Although these types of outcomes can be used to further clarify mechanisms of effects, they are often not validated or inadequately validated, are prone to self report or observer bias, and their measurement varies with time and clinical care experiences which limits their reliability.

Study power

Many RCTs had inadequate power to detect a meaningful difference in adherence, and this did not seem to be improved among newly identified RCTs. As a general guide, studies with a single intervention group and control group would need to include at least 60 participants per group if they are to have at least 80% power to detect an absolute difference of 25% in the proportion of patients judged to have adequate adherence. According to this rule, the new RCTs were as likely to be underpowered (40% (44/109)) as RCTs in the previous update, and even among the 17 lowest risk of bias RCTs in the present update, four had insufficient power (Haynes 1976; Laporte 2003; Weber 2004; Farooq 2011). For example, in a study of 38 patients (Haynes 1976), there was a significant increase in adherence associated with the intervention and an interesting within‐group reduction of blood pressure within the intervention group. However, the difference between the intervention and control groups for blood pressure change was not statistically significant. Underpowered studies are more likely to miss a meaningful difference in adherence, even when improving adherence substantially, and showing an effect on clinical outcomes is likely even harder. This is especially true for major events. If RCTs with hundreds or thousands of participants are needed to show that the medication has an effect on major outcomes compared with usual care, it is unlikely that improving adherence among patients who are prescribed the medication will have a substantial effect on major outcomes in a small sample size.

Quality of reporting

Many articles did not provide sufficient detail to allow the risk of bias to be determined, or for the exact nature of what the study tested to be understood. In particular, details of the methods of random sequence generation, concealment of treatment allocation, and blinding of the outcome assessors as relevant for the outcomes were often not reported, and therefore we could not determine the risk of bias. As a consequence, it is possible that some of RCTs that we excluded from our narrative actually had a low risk of bias, but we were unable to determine this based on the manuscript, supplements, and (absence of) author response. The importance of adequate reporting is further illustrated by the initially included RCTs that were eventually discarded due to less than 80% follow‐up after repeated detailed review. The way these studies were reported was sometimes confusing for something as simple as follow‐up rate, and the full picture was only revealed after reading all the details, tables, figures, or supplements. Examples appear in the listing of studies excluded for cause in this review.

Treatment arms, both intervention and control, were also not always described in sufficient detail. For example, while the report might state clearly that patients received reminders, the method of administering the reminder program might not be described, or might be described in some part of the text other than the section on the intervention. Most studies paid research staff to administer interventions, raising issues in generalizability to usual practice settings. This also raised the issue of attribution in many studies: if the control group received 'usual care', there would be no 'attention control' in the study and any effects observed could be due to either the intervention proper or simply the non‐specific effects of increased attention paid to the intervention group. Furthermore, some studies reported that the patients in the control group received 'usual care', but did not describe what that encompassed. If the standard medical care is already performing relatively well, it will be harder to show an improvement with the intervention. Therefore, to understand the trial results better, it is recommended to provide sufficient details on the intervention design and delivery, the assumed change process the intervention aims to deliver, and the care process for the control group, whether this was an active control or usual care (Michie 2009).

Potential biases in the review process

Missed studies

Despite extensive searching, we may have missed some trials that met all of our criteria. The literature on patient adherence is not well indexed because the number of studies is quite small relative to the literature published on other topics, and because it is spread across traditional disease boundaries. We invite readers to send us any studies, published or unpublished, which may meet our criteria.

Study eligibility criteria and 'Risk of bias' assessment

We chose our eligibility criteria to summarize the current best evidence of unconfounded RCTs, with adequate follow‐up completion in all treatment groups, assessing the effect on both adherence and clinical outcome. With other eligibility criteria, such as allowing a larger loss to follow‐up or not requiring clinical outcome, the review results might have been different. In addition, in the absence of clear study details, we could have made judgment calls in our 'Risk of bias' assessment to avoid too many 'uncertain risk' assignments. This might have resulted in more studies being considered 'low risk', and therefore eligible for discussion in our main text. However, we anticipate that the quality of evidence in these trials would be even lower than the moderate study quality which was found in both the overall review and among the RCTs with the lowest risk of bias, and would lead us further from an accurate overview of the current best evidence in a field with a large number of small and low quality studies.

Other reviews

Our review is restricted to prescribed medications, excluding those prescribed for addiction, and to studies that assessed both adherence and treatment outcomes. There are many other systematic reviews of adherence interventions, too numerous to list, especially for specific clinical conditions, and also for non‐medication interventions (e.g. diet, exercise, addictions, and so on). We acknowledge that systematic reviews focusing on specific clinical conditions, medications, or intervention types might draw different conclusions. We chose to focus on all RCTs testing adherence interventions for any self administered therapy, to get a complete overview of the field and to account for the fact that adherence problems are often comparable for different medications. This resulted in the inclusion of a large variety of heterogeneous RCTs that could not reliably be pooled, but we encourage reviewers and researchers who find a signal for effective interventions for a specific condition or medication to share their findings with us and other reviewers. In addition, we invite reviewers interested in specific conditions, medications, or interventions to propose such a specific analysis in our comprehensive database.

Sharing of review data

As indicated, we did not feel it scientifically justified to summarize data across studies, but provided all the details on included RCTs in the tables, as well as a narrative of the RCTs with the lowest risk of bias. For this review we collected a wealth of information, and we invite readers to propose specific analyses of interest. Access to our database for additional analyses will be considered, based on requests to the corresponding author. Please e‐mail your analysis proposal to par@mcmasterhkr.com.

Authors' conclusions

Implications for practice.

Among 109 newly identified randomized controlled trials (RCTs), interventions were often complex, involving allied health care providers such as nurses and pharmacists, presumably attempting to overcome multifactorial barriers and to tailor support to individual patient needs. Only 17 RCTs had a low risk of bias for randomization and allocation concealment, and clinical outcome assessment; this low number is likely partly due to the fact that there was often insufficient detail provided to determine risk of bias. Among these 17 RCTs, only five improved both adherence and clinical outcome, which is comparable to the rate found among the 21 new RCTs in our previous update. If there is a common thread to these interventions, it is that they are complex and use frequent interaction with patients with a focus on adherence. However, these complex strategies for improving adherence with long‐term medication prescriptions are not very effective, despite the amount of effort and other resources they can consume. There is insufficient evidence at present to conclude that newer intervention types, such as mobile text messaging and Internet‐based care, can assist in improving adherence. There is no evidence that low adherence can be 'cured'. Thus, effective methods to improve adherence must be maintained for as long as the treatment is needed, requiring interventions that can be integrated into the care system in a cost‐effective manner.

Implications for research.

Low adherence affects all self administered treatments, and as the numbers of efficacious treatments continue to grow, investments in fundamental and applied adherence research are likely to pay large dividends. It is possible that interventions to date are not very effective since we do not understand in sufficient detail exactly what the adherence problems are. Frameworks to assist in the development of complex interventions therefore advise preparatory qualitative assessments involving patients and other stakeholders, to understand better the problems and context (Craig 2008).

Despite the steep increase in number of RCTs, the field of adherence improvement research has persistent methodological weaknesses. Rather than increasing the volume of research while repeating weaknesses, several study methodology issues need to be addressed to ensure that we are not missing any true effects or creating false positive findings. Investigators should make use of best‐in‐class adherence measures, such as prescription monitoring. More objective measures for adherence are needed to accurately determine intervention effects. Patients should be recruited because their adherence is low, not just because they are willing to participate. Researchers should design studies to minimize risk of bias as much as possible and clearly report their procedures, especially concerning co‐interventions, such as additional staff supported by research funds. Another priority is attaining sufficient study power for clinical outcomes that are important to patients. Around 40% of all studies were underpowered, with less than 60 patients per treatment group, and this was a comparable rate to the previous update. Smaller studies may be appropriate until an innovation appears to have clinically useful effects. At that point, the innovation should be tested in more substantial trials to document effects on clinically important outcomes (including adverse effects), feasibility in usual practice settings, and sustainability. If complex interventions show positive effects, it would be appropriate to test their components in factorial studies.

A cure for non‐adherence is nowhere to be seen, but treatments that obviate the need for ongoing adherence, such as implantable treatments with minimal adverse effects (e.g. intrauterine devices) could be worth pursuing. Intervention components that could be explored further include well‐established and newer information and communication technologies on top of regular care, and specific or co‐ordinated roles for allied health professionals.

Finally, it is essential that researchers stop re‐inventing the poorly performing 'wheels' of adherence interventions that we have seen to date. It seems that most adherence research is performed by clinicians and others who discover adherence problems while working within the context of the management of a specific disease condition, such as cardiovascular risk, diabetes, HIV/AIDS, and the like. Low adherence with medications is a ubiquitous problem, found with self administered treatments for all medical conditions. Without considering what has been studied across disease conditions, researchers will find themselves with inadequate knowledge of what does not work, and will be unable to avoid repeating the painful lessons of adherence research to date. Rather, we need to begin with interventions that have shown some promise, or at least have not been tested with repeatedly negative results. The methods and innovations of adherence research must advance if we are to be able to help patients enjoy the benefits of modern therapeutics.

What's new

Date	Event	Description
18 December 2013	New citation required but conclusions have not changed	The conclusions of the review have not changed. Characteristics and effects of interventions to improve medication adherence varied among studies, with only 5 of the 17 highest quality trials providing convincing evidence for improvement. Current methods of improving adherence for chronic health problems are mostly complex and not very effective, so that the full benefits of treatment cannot be realized.
18 December 2013	New search has been performed	We added 15 new authors in addition to RB Haynes, who was an author on the previous version of the review. The research objectives and inclusion criteria remain the same as in the previous review. We added the assessment of the risk of bias to the outcome measures. We updated the search filters for detecting relevant studies. We added 109 new studies in this 2013 update from searches run in January 2013.

History

Review first published: Issue 3, 1999

Date	Event	Description
14 February 2008	New search has been performed	Twenty‐one new studies were added in the 2007 update (published in Issue 2, 2008 of The Cochrane Library).
13 February 2008	New citation required and conclusions have changed	There are now 78 studies meeting our criteria for testing interventions to help patients to follow prescribed, self administered medications. Despite the new studies, our conclusions remain the same: most people do not follow self administered medical treatments as prescribed and interventions to help them follow treatments are marginally effective at best, especially for long‐term medical regimens. Strategies that appear to have some effect for long‐term regimens involve combinations of counseling, reminders, self monitoring, feedback, family therapy, psychological therapy, manual telephone follow‐up, and supportive care. For short‐term treatments, high adherence can be achieved by simpler means, including counseling, written information about the importance of taking all doses, and personal phone calls. The authorship changed to: Haynes RB, Ackloo E, Sahota N, McDonald HP, Yao X.
29 August 2005	New citation required and conclusions have changed	The title changed to 'Interventions for enhancing medication adherence.' The authorship changed to: Haynes RB, Yao X, Degani A, Kripalani S, Garg A, McDonald HP.
29 August 2005	New search has been performed	Twenty‐five new studies were added (Issue 4, 2005), bringing to 57 the number of randomized trials meeting our criteria for testing interventions for helping patients to follow prescribed, self administered medications. Despite the new studies, conclusions remained essentially the same: most people do not follow self administered medical treatments as prescribed and interventions to help them follow treatments are marginally effective at best, especially for long‐term medical regimens. Strategies that appear to have some effect for long‐term regimens involve combinations of counseling, reminders, self monitoring, feedback, family therapy, psychological therapy, manual telephone follow‐up, and supportive care. For short‐term treatments, high adherence can be achieved by simpler means, including counseling, written information about the importance of taking all doses, and personal phone calls.
7 February 2002	New search has been performed	Fourteen new studies were added (Issue 2, 2002), bringing to 33 the number of randomized trials meeting our criteria for testing interventions for helping patients to follow prescribed, self administered medications. Despite the new studies, conclusions remain the same: most people do not follow self administered medical treatments as prescribed and interventions to help them follow treatments are marginally effective at best, especially for long‐term medical regimens. Strategies that appear to have some effect for long‐term regimens involve combinations of counseling, reminders, self monitoring and feedback, and supportive care. For short‐term treatments, high adherence can be achieved by simpler means, including reminders and instruction about the importance of taking all doses.
7 February 2002	New citation required but conclusions have not changed	The updated citation reflects the updated search and new authorship: Haynes RB, McDonald H, Garg AX, Montague P.

Appendices

Appendix 1. Search filters used in the previous review and this update

MEDLINE and CINAHL database search filters used in the 2008 version of the review:

1. ((patient compliance (mh) OR patient adjacent to compliance (title and abstract) AND (clinical trials (pt) OR clinical trial (mh) OR all random: (textword))

2. ((random: or control:) AND (patient compliance/ or patient dropouts/ or psychotherapy or treatment refusal/ or patient education/ or regimen:.tw.) AND (intervention:.tw. or outcome:.tw.) AND (medicat:.tw. or drug therapy))

MEDLINE search filters used in this update using the Ovid interface:

1. ((exp patient compliance/ OR (patient adj compliance).tw. OR (patient adj adherence).tw. OR (medication adj compliance).tw. OR (medication adj adherence).tw.) AND ((clinical trial OR random:).mp. OR tu.xs.)) NOT ((qualitative OR retrospective OR mice OR rat OR rats).tw. OR editorial.pt. OR letter.pt. OR comment.pt.) NOT (animals NOT humans).sh. (Note: clinical trial.mp. picks up clinical trial.pt.)

2. ((random: OR control:).mp. AND (exp patient compliance/ OR patient dropouts/ OR psychotherapy/ OR treatment refusal/ OR patient education/ OR regimen:.tw.) AND (intervention: OR outcome:).tw. AND (medicat:.tw. OR drug therapy/)) NOT ((qualitative OR retrospective OR mice OR rat OR rats).tw. OR editorial.pt. OR letter.pt. OR comment.pt.) NOT (animals NOT humans).sh.

CINAHL search filters used in this update using the EBSCO interface:

1. MH patient compliance+ OR TI "patient compliance" OR AB "patient compliance” OR TI "patient adherence” OR AB “patient adherence” OR TI “medication compliance” OR AB “medication compliance” OR TI “medication adherence” OR AB “medication adherence” NOT PT editorial or PT letter or TI qualitative or AB qualitative or TI retrospective or AB retrospective or TI mice or AB mice or TI rat or AB rat or TI rats or AB rats (limited by Clinical Queries therapy sensitive search filter and date ‐ 2007 to 2012 )

2. MH patient compliance OR MH medication compliance OR MH patient dropouts OR MH treatment refusal OR MH patient education OR TI psychotherapy OR AB psychotherapy AND TX ( (random* OR control*) ) AND TX ( (medicat* OR drug therapy) ) NOT PT editorial or PT letter or TI qualitative or AB qualitative or TI retrospective or AB retrospective or TI mice or AB mice or TI rat or AB rat or TI rats or AB rats

EMBASE search filter used in the 2008 version of the review:

((random$ or control$) AND (patient adherence or patient dropouts or illness behavior or psychotherapy or treatment refusal or patient education or regimen$) AND (intervention$ or outcome$ or treatment outcome) AND (medicat$ or drug therapy) AND (clinical trial or controlled study or randomized controlled trial))

EMBASE search filter used in this update using the Ovid interface:

(random: or control:).mp. AND (patient compliance or patient dropouts or illness behavior or psychotherapy or treatment refusal or patient education or regimen:).mp. AND (intervention: or outcome: or treatment outcome).mp. AND (medicat: or drug therapy).mp. AND (clinical trial or controlled study or randomized controlled trial).mp.

PsycINFO search filter used in the 2008 version of the review:

((random$ or clinical or control or trial) AND (adherence or compliance or noncompliance or dropouts or patient education) AND (drug therapy or drug or medicat$ or treatment or regimen) AND (intervention or outcomes or treatment outcomes))

PsycINFO search filter used in this update using the Ovid interface:

(((control: or random:).tw. or exp treatment/) and (adherence or compliance or noncompliance or dropouts or patient education).mp. and (drug therapy or drug or medicat: or treatment or regimen).mp. and (intervention or outcomes or treatment outcomes).mp.) not (qualitative or retrospective or mice or rat or rats).tw.

The Cochrane Library search filter used in the 2008 version of the review:

((random$) AND (complian$ or adheren$ or pharmacotherapy or regimen$ or educat$) AND (medicat$)); patient adherence; patient adherence; medication adherence.

The Cochrane Library search filter used in this update (http://onlinelibrary.wiley.com/cochranelibrary/search/):

((random*) AND (complian* or adheren* or pharmacotherapy or regimen* or educat*) AND (medicat*)) (Note: Searched using all text tag; Search by product: Cochrane Database of Systematic Reviews, DARE (Other Reviews), Central; Search by record: all)

Sociological Abstracts search filter used in the 2008 version of the review:

((patient or treatment or dropouts) AND (clinical trials or control) AND (drugs or medicine))

Sociological Abstracts search filter used in this update using the ProQuest interface (http://search.proquest.com/socabs/advanced):

((patient or treatment or dropouts) AND (clinical trials or control) AND (drugs or medicine or medication)) (Searched using all fields; all(medication) retrieves su(medication adherence)

ClinicalTrials.gov search filter used in this update (http://clinicaltrials.gov/ct2/search/advanced):

"patient compliance" OR "patient adherence" OR "medication compliance" OR "medication adherence" | Closed Studies | Studies With Results |

International Clinical Trials Registry Platform search filter used in this update (http://apps.who.int/trialsearch/AdvSearch.aspx):

patient compliance or patient adherence or medication compliance or medication adherence (Note: recruitment status all used)

International Pharmaceutical Abstracts (IPA) was searched during the previous review; however, this database is no longer available through McMaster University library services. We did not search this database for the update.

Data and analyses

Comparison 1. Studies that met criteria.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adherence and outcome			Other data	No numeric data

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Abrahams 2010.

Methods	Randomized controlled trial
Participants	The study location was Sinawe sexual assault service, Mthatha, South Africa, and Karl Bremer Hospital, Victoria Hospital, and the Simelela Centre; all in Khayelitsha, South Africa 136 participants were randomized to the intervention group and 138 participants were randomized to the control group The inclusion criteria were women and girl children; girls under 16 years of age were eligible if accompanied by a care giver The exclusion criteria were rape victims who did not get post‐exposure prophylaxis (PEP) (due to being HIV positive or because they did not take an HIV test), those unable to give consent for reason of severe injury or severe mental distress (including severely distressed guardians), and those who were not contactable telephonically
Interventions	Intervention: TELEPHONE COUNSELING Patients in the intervention group received standard care and telephone counseling sessions. The telephone counseling included 4 calls in the first week, 3 calls in the 2nd and 3rd week, and 2 calls in the last week, but more were made if necessary. The support included the application of basic counseling skills including listening and validating the traumatic events, encouraging participants to take their medication, to seek support from family and friends, to attend formal counseling services, to read the pamphlet, use the diary, and return to the clinic for follow‐up medication Control: STANDARD CARE Standard care consisted of psychological containment, medical examination, and collection of forensic evidence; HIV testing with pre‐ and post‐test counseling; providing emergency contraception, treatment of sexually transmitted infections and PEP for HIV. Follow‐up was arranged to collect further HIV PEP medication. All patients had an interactive information session to explain the content of the pamphlet, answer questions, and demonstrate initiation of the use of the medication diary. The pamphlet contained specific information about taking PEP after a sexual assault; a diary for the 28‐day period on which pill taking was to be marked and contact information on support services. No further contact was made with participants in the control group until the final interview, but they continued to receive standard care from the service
Outcomes	The measures of adherence were assessed within 5 days of the 28‐day treatment period ending in a face to face interview conducted by a fieldworker. Non‐adherence was defined as missing 3 or more doses of medication (of 56 doses). Patients who did not return to the facility to collect the full 28 days of medication, or who were found to have more than 3 doses remaining when pills were counted/volume of syrup was assessed, were considered non‐adherent. If medication containers were not available at the interview, participants were asked to estimate the number of pills or volume of syrup remaining The patient outcomes were depressive symptomatology, measured by the Centre for Epidemiological Studies Depression Scale, measured 4 weeks after the beginning of treatment (within 4 days of treatment ending). The scale was administered by a fieldworker
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A computer‐generated randomization list was generated by the study statistician and random block sizes of 4, 6 and 8 were used to ensure balance in the 2 arms (pg 1176)
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not specified; (pg 1176) a computer‐generated randomization list was generated by the study statistician and random block sizes of 4, 6 and 8 were used to ensure balance in the 2 arms. Participants were allocated to an arm by the study co‐ordinator after the initial data had been collected and leaflet explained
Selective reporting (reporting bias)	Unclear risk	No protocol available, therefore unable to determine if everything was reported
Other bias	Unclear risk	There appears to be weaknesses in the intervention delivery such as variations in the number of telephone calls, which may have attenuated the differences between the intervention and the control group
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT/SYRUP MEASURE ‐ fieldworkers who did the final interview were blinded to study arm, but this may have been disclosed by the participants during the final interviews. Participants could not be blinded to the study arm(pg 1176)
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) DEPRESSIVE SYMPTOMOLOGY ‐ fieldworkers were blind to condition but blinding could have been broken by the patients (pg 1176)
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) PILL COUNT/SYRUP MEASURE ‐ participants could not be blinded to the study arm
Blinding of participants (performance bias) Patient outcome	Unclear risk	(PRIMARY) DEPRESSIVE SYMPTOMOLOGY ‐ patients could not be blinded (pg 1176), but unclear if this might have affected their responses to the scale
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) PILL COUNT/SYRUP MEASURE ‐ outcome unlikely to be affected if other personnel were not blinded
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) DEPRESSIVE SYMPTOMOLOGY ‐ not specified, but other personnel are unlikely to have influenced the data collection
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT/SYRUP MEASURE ‐ not enough detail given on reasons for loss to follow‐up. Number is small and balanced across groups but still unclear what impact this would have
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) DEPRESSIVE SYMPTOMOLOGY ‐ not enough detail given on reasons for loss to follow‐up. Number is small and balanced across groups but still unclear what impact this would have

Ahmadipour 2010.

Methods	Randomized controlled trial
Participants	The study location was the Isfahan Diabetes Institute, Isfahan, Iran 50 participants were randomized to the intervention group and 50 participants were randomized to the control group The inclusion criteria were patients with type 2 diabetes mellitus taking oral hypoglycemic agents for at least 1 year and had given informed consent
Interventions	Intervention: DIARY CHECKLIST The intervention group was asked to complete a diary checklist about how they took their drugs during the study period. The duration was 12 weeks Control: COLLECTION OF MEDICATION SHELLS The control group patients were asked to collect the shells of oral hypoglycemic agents after taking in a pocket. Duration was 12 weeks
Outcomes	The measures of adherence were a diary checklist about how the drugs were taken The patient outcome was HbA1c level measured using a chromatographic method
Notes	There is a discrepancy between the abstract and the text of the article in terms of the number of participants in the control and intervention groups. According to abstract there are 100 participants divided equally into 2 groups, but in figure 1, as well as in methods, there are 30 participants in the intervention group and 57 in the control
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information on method of randomization (pg 1 Abstract). A number of 100 type 2‐diabetic patients were selected through systematic sampling method and then were randomly allocated to 2 groups of equal number (pg 3 Methods)
Allocation concealment (selection bias)	Unclear risk	Not described. Participants were selected from the patients list of the Institute through a systematic sampling method and then they were randomly allocated to 2 groups
Selective reporting (reporting bias)	Unclear risk	No protocol and no details about what outcomes would be looked at, only that HbA1c was measured in each group
Other bias	Unclear risk	Intervention and control not adequately described. Discrepancy in sample size description
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) MEDICINE SHELLS ‐ Insufficient information. Blinding not mentioned
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) CHECKLIST DIARY ‐ Insufficient information. Blinding not mentioned
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) HBA1C LEVEL ‐ Insufficient information. Blinding not mentioned
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) CHECKLIST DIARY ‐ Patients would have been aware due to the nature of the intervention
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) MEDICINE SHELLS ‐ Patients likely to be aware of the intervention due to its nature
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) HBA1C LEVEL ‐ Blinding not mentioned but lack of blinding of the participant is not likely to affect this outcome
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) MEDICINE SHELLS ‐ Insufficient information. Blinding not mentioned
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) CHECKLIST DIARY ‐ Insufficient information. Blinding not mentioned
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) HBA1C LEVEL ‐ Insufficient information. Blinding not mentioned
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) CHECKLIST DIARY ‐ Insufficient information provided. However, there appears to be an error in paper regarding the number of participants randomized to each group. States in Abstract Methods (pg 1): "A number of 100 type 2‐diabetic patients were selected through systematic sampling method and then were randomly allocated to two groups of equal number" but then states twice in the article (pg 4 under Results), including Figure 1, that there were 57 at the end of the study in the "reference" (control) group
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) MEDICINE SHELLS ‐ Insufficient information provided. However, there appears to be an error in paper regarding the number of participants randomized to each group. States in Abstract Methods (pg 1): "A number of 100 type 2‐diabetic patients were selected through systematic sampling method and then were randomly allocated to two groups of equal number" but then states twice in the article (pg 4 under Results), including Figure 1, that there were 57 at the end of the study in the "reference" (control) group
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) HBA1C LEVEL ‐ Insufficient information provided. However, there appears to be an error in paper regarding the number of participants randomized to each group. States in Abstract Methods (pg 1): "A number of 100 type 2‐diabetic patients were selected through systematic sampling method and then were randomly allocated to two groups of equal number" but then states twice in the article (pg 4 under Results), including Figure 1, that there were 57 at the end of the study in the "reference" (control) group

Al Mazroui 2009.

Methods	Randomized controlled trial
Participants	The study location was Zayed Military Hospital, United Arab Emirates 120 participants were randomized to the intervention group and 120 participants were randomized to the control group The inclusion criteria were diagnosis of type 2 diabetes mellitus, receiving oral hypoglycemic therapy, hospital consultant consented to patient entering trial, patient provided written informed consent to their participation in the research The exclusion criteria were secondary forms of hypertension, serum creatinine > 184 mmol l‐1, macroalbuminuria > 300 mg 24 h‐1, history of cerebrovascular accidents, convulsive disorder, diabetic proliferative retinopathy or diabetic autonomic neuropathy
Interventions	Intervention: PHARMACIST CARE INTERVENTION For all patients randomized to the intervention group, the research pharmacist had discussions with their physicians regarding drug therapy and, if necessary, treatment modification was recommended, e.g. more intensive management of hypertension or simplification of dosage regimens if deemed appropriate, taking account of the latest American Diabetes Association (ADA) recommendations. Patients who were randomized to the intervention group were educated on their illness and their medication in a structured fashion, including discussion on risk of diabetes complications, proper dosage, side effects and storage of medications, healthy lifestyle and management of diabetes mellitus signs and symptoms through self monitoring. A printed leaflet to assist with the education program was developed and the patient was given a copy to take home. Supplementary leaflets containing information about hypertension and hyperlipidemia were also given to the patients if they suffered from these conditions. The educational advice was reinforced when patients came to the hospital pharmacy to collect their prescribed medicines on their monthly schedule. In addition, behavioral modification aspects of the Pharmacist Care intervention involved advice on the following: self monitoring of glycemic control (patients were encouraged to monitor their blood glucose levels 3 times per day, to record these values and bring a record book to all subsequent appointments); physical exercise (this involved initiation of an exercise plan that could be incorporated into the patient's daily schedule, after taking into consideration their level of fitness, e.g. 1‐hour walk daily; diet (the patient was assisted with the identification of dietary behavior that adversely influences blood glucose control, lipid levels, weight management, and of the times of day when the patient was most vulnerable to overeating, and given improved understanding of the relative effects of certain food choices on blood glucose control); medication adherence (patients were asked about any problems that they had encountered with regard to taking their medication and were offered education and practical help to encourage them to take the medicines prescribed for them by their physician); and smoking cessation (patients were encouraged to stop smoking by advising them about the danger of smoking to health, with emphasis on the increased dangers of smoking in diabetic patients) Control: USUAL CARE Control group participants received normal care from medical and nursing staff. They did not receive any pharmacy clinical service but received advice on self monitoring their blood glucose by medical or nursing staff
Outcomes	The measures of adherence were self report. Adherence was measured at baseline and 12 months using a standard protocol for questionnaire administration to reduce potential bias. Patients who reported forgetting doses, intentionally missing or taking extra doses were classed as non‐adherent. No account was taken of intelligent non‐adherence, i.e. when a patient decides for good reason, for example, to take an extra dose or miss a dose The patient outcomes were BMI, fasting blood glucose, HbA1c, blood pressure, cholesterol, health‐related QoL, and 10‐year risk assessments. BMI, blood work, and QoL scores were collected by the research pharmacist and/or clinical pharmacy staff at baseline and then every 4 months until the study was completed (12 months). 10‐year risk assessments were done at the end of the study using British National Formulary (BNF) prediction charts and the Framingham scoring method. These methodologies take account of age, gender, smoking status, total cholesterol, HDL, and systolic blood pressure
Notes	It is unclear what information was gathered at the face to face interview and what was gathered from a review of the medical charts
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information about the process of randomization: "After recruitment, patients were randomly assigned to one of two groups: intervention group or control group. The group allocations were carried out using restricted randomization with both groups being matched as closely as possible for gender and presence of hypertension i.e. diastolic blood pressure > = 90 mmHg (hypertensive) or < 90 mmHg (normotensive)" (pg 548)
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the allocation process: "After recruitment, patients were randomly assigned to one of two groups: intervention group or control group. The group allocations were carried out using restricted randomization with both groups being matched as closely as possible for gender and presence of hypertension i.e. diastolic blood pressure > = 90 mmHg (hypertensive) or < 90 mmHg (normotensive)" (pg 548)
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No limitations are given
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Insufficient information to permit judgment of 'Low risk' or 'High risk' of bias. No information about the blinding of data collectors is given
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) BMI AND BLOOD TESTS CHART REVIEW ‐ Outcomes collected through a chart review. Unclear if staff extracting the data were blind
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Patient self report ‐ subject to bias. No mention of patient blinding
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) BMI AND BLOOD TESTS CHART REVIEW ‐ The lack of blinding of the study participant is not likely to affect this outcome
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Insufficient information to permit judgment of 'Low risk' or 'High risk' of bias. No indication of blinding of key study personnel
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) BMI AND BLOOD TESTS CHART REVIEW ‐ Outcomes collected through a chart review. Unclear if study personnel were blind
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Few dropouts; evenly across groups
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) BMI AND BLOOD TESTS CHART REVIEW ‐ Few dropouts; evenly distributed across groups

Al‐Eidan 2002.

Methods	Patients were randomly assigned to the intervention or control group using a sealed envelope technique
Participants	76 dyspeptic patients, who at endoscopy were found to have gastritis, duodenitis, or ulceration, and a positive Helicobacter pylori (H. pylori) urease test, were recruited. Patients were excluded if they were unsuitable for eradication therapy or hypersensitive to its ingredients
Interventions	After diagnosis and enrolment, all patients were to be prescribed a 1‐week regimen of lansoprazole 30 mg daily, amoxicillin 1 g twice a day (bid), and clarithromycin 500 mg bid. Patients in the intervention group received their medication from the hospital pharmacy and were counseled by the hospital pharmacist (average 9.5 minutes) on: their disease and the importance of eradication of the organism; the medicines to be taken and possible side effects, the importance of compliance with the prescribed dosage. Intervention patients received a patient information leaflet about their medication and the need for H. pylori eradication. They were also given a compliance diary chart and telephoned 3 days after the initiation of therapy to provide further counseling about the importance of complying to the medication regimen. Control patients were treated according to normal hospital procedures. They were given a letter to be given to their GP with the recommendation to start triple‐therapy and a letter explaining the nature of infection, the need for treatment, and the importance of compliance (ambiguous in the article, but it seems that the latter letter went to the patient rather than (just) their doctor)
Outcomes	Compliance measurements 1) Patient interview by telephone (structured questionnaire) by the same pharmacist for both groups, after the intended end of the eradication course 2) Pill counts on returned medication when patients returned for a urea breath test. Patient clinical outcome measures included: H. pylori status: assessed with a urea breath test 4 to 6 weeks post‐eradication therapy. Eradication was defined as an absence of H. pylori. Adverse effects: contacted by hospital pharmacist 10 days post‐endoscopy and asked about any adverse effects experienced from the eradication therapy. Modified version of the Gastrointestinal Symptom Rating Scale: to assess the presence and severity of dyspeptic symptoms. The presence and severity symptoms was judged by the patient. They were assessed at the time of endoscopy, at 1 month and 6 months
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Minimal information given: (pg 164) Using a sealed envelope technique patients were randomly assigned to either the control group or the intervention group
Allocation concealment (selection bias)	Low risk	Minimal information given: (pg 164) Using a sealed envelope technique patients were randomly assigned to either the control group or the intervention group
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No other biases noted in discussion section or otherwise obvious but difficult to determine if the study if free of other types of bias
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) PATIENT INTERVIEW BY TELEPHONE ‐ No mention of blinding of study staff collecting the data
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) UREA BREATH TEST TO ASSESS H. PYLORI ERADICATION RATE ‐ objective measure
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) PATIENT INTERVIEW BY TELEPHONE ‐ Patient would know if they saw the hospital pharmacist or not
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) UREA BREATH TEST TO ASSESS H. PYLORI ERADICATION RATE ‐ Objective measure
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) PATIENT INTERVIEW BY TELEPHONE ‐ No mention of blinding of staff
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) UREA BREATH TEST TO ASSESS H. PYLORI ERADICATION RATE ‐ objective measure
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) PATIENT INTERVIEW BY TELEPHONE ‐ Not enough information about how the data were collected or analyzed (used 2 methods to measure compliance, but no explanation of how they took and combined the data)
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) UREA BREATH TEST TO ASSESSH. PYLORI ERADICATION RATE ‐ Not enough information given to judge if the study is free of other types of bias

Amado 2011.

Methods	Randomized controlled trial
Participants	The study location was Primary Health Care Centres (PHCC), Barcelona and its metropolitan area, Spain 515 participants were randomized to the intervention group and 481 participants were randomized to the control group The inclusion criteria were patients between 18 and 80 years old with hypertension who were visiting the clinic for at least 6 months for long‐term follow‐up and control of hypertension using anti‐hypertensive drug therapy The exclusion criteria were serious psychiatric, physical, or sensory alterations
Interventions	Intervention: INTERVENTION (IG) Patients in the Intervention Group (IG) had 4 visits with specially trained nurses who used standardized guidelines and who had attended a 10‐hour workshop that focused on the antihypertensive medications. Each visit lasted for an average of 15 minutes. Information was personalized to the needs of the patient. Schedule sheets with the treatment plan were provided, which contained information on the prescribed drugs and dosage schedule as well as basic advice on how to maximize the treatment schedule. The sheets were provided to reinforce the nurse's verbal instructions Control: CONTROL GROUP (CG) Control patients received usual clinic care without any standardized intervention
Outcomes	The measures of adherence were self reported adherence and pill counts. The Haynes‐Sackett and Morisky‐Green tests were used to collect self reported adherence over the previous 3 months The patient outcomes were systolic and diastolic blood pressure, hypertension control, BMI, and number of hypertensive drugs at 12 months compared with baseline measures
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information about sequence generation. "The study was designed as multi‐centre, prospective, cluster randomised, controlled clinical trial, using the primary healthcare centre as a randomization unit." (pg 63)
Allocation concealment (selection bias)	Unclear risk	Method of allocation not described. "The study was designed as multi‐centre, prospective, cluster randomised, controlled clinical trial, using the primary healthcare centre as a randomization unit." (pg 63)
Selective reporting (reporting bias)	Unclear risk	No protocol
Other bias	Unclear risk	Most adherence measures were by self report (pg 66). Authors mention the possibility of contamination between intervention and control groups
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRES ‐ Not stated whether the nurses collecting the data were blinded
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE ‐ Not stated whether nurse collecting data was blinded
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) BMI ‐ Not stated whether nurse collecting data was blinded
Blinding of participants (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRES ‐ subjective outcome; no mention of blinding
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) BLOOD PRESSURE ‐ Lack of blinding is not likely to affect the outcome
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) BMI ‐ No blinding of patients mentioned but lack of blinding not likely to affect this outcome
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRES ‐ Insufficient information about the blinding of key personnel
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) BMI ‐ No blinding of other study personnel mentioned
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE ‐ No blinding of other study personnel mentioned
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRES ‐ Reasons for dropouts were similar in both groups
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) BLOOD PRESSURE ‐ Reasons for dropouts similar in both groups
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) BMI ‐ Reasons for dropouts similar in both groups

Anderson 2010.

Methods	Randomized controlled trial
Participants	The study location was a community mental health center in the southeast of the USA 12 participants were randomized to the intervention group and 14 participants were randomized to the control group The inclusion criteria were male and female patients aged over 18 years with a diagnosis of schizophrenia or schizoaffective disorder, and were able to read and understand English The exclusion criteria were (i) a comorbid axis I diagnosis of moderate or severe learning disability or organic brain disorder; (ii) a comorbid axis I diagnosis of drug or alcohol dependence; (iii) inpatient status at the start of the study; and (iv) suicidal or homicidal ideation at the start of the study
Interventions	Intervention: ADHERENCE TREATMENT The intervention was 'adherence therapy' a manualized, patient centric approach that seeks to address a broad range of factors known to affect adherence. This individual therapy focuses on the needs, concerns, fears, values, goals, and experiences of the individual with the aim of encouraging people to take their medications. It was delivered by 4 therapists with Master's degree in social work. There were 8 one to one sessions of between 20 to 60 minutes, over 8 weeks. Follow‐up was conducted after the completion of the therapy. All intervention patients also received treatment as usual Control: TREATMENT AS USUAL TAU included day treatment, case management, employment placement, medication monitoring, and individual counseling. During the trial, AT participants did not see their own therapist for therapy sessions, but continued their other treatment activities
Outcomes	The measures of adherence were the Personal Evaluation of Transitions in Treatment (PETiT; Voruganti & Awad 2002), a 30‐item, self rated measure of patients' subjective evaluation of treatment with 6 questions specifically addressing medication adherence. The 30 items are rated on a 3‐point scale, with higher scores indicating greater satisfaction and adherence. Voruganti and Awad (2002) report high internal consistency, with a Cronbach's alpha of 0.96 and good split‐half reliability; they describe the scale as an indicator of medication adherence.The follow‐up was conducted after therapy completion (8 weeks) The patient outcomes were severity of schizophrenia symptoms, measured with PANSS (Positive and negative syndrome scale), administered at baseline and completion of the 8‐week therapy by a researcher who was trained to administer the measure
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization by an independent randomization service(pg 342)
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk' of bias. "Written, informed consent was obtained from patients prior to randomization. Randomization was performed by an independent randomization service."
Selective reporting (reporting bias)	Unclear risk	Protocol unavailable
Other bias	Unclear risk	Follow‐up period is not clearly defined in the article; it says after completion of therapy only(pg 348). Several factors during this pilot study had the potential to influence the study results negatively. They included: (i) the small sample size, making the study underpowered and increasing the risk of type II errors; (ii) the possibility of outliers in a sample this size might have skewed the data; (iii) selection bias, considering the high rate of refusal to participate and a possibility of those who agreed already were more medication adherent; (iv) time constraints, as follow‐up was conducted only 6 to 8 weeks after the beginning of the intervention and within 1 to 2 days of the last counseling session; and (v) therapists' knowledge level of psychotropic medication could mean that cues from patients might have been missed
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ This is a single masked trial (pg 340). "Ratings were conducted masked" (pg 346)
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) POSITIVE AND NEGATIVE SYNDROME SCALE (PANSS) ‐ This is a single masked trial (pg 340). "The PANSS structured clinical interview rating was completed by a researcher (SF) who was trained to administer the measure." (pg 343). "Ratings were conducted masked" (pg 346)
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Patients not blind due to the nature of the intervention
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) POSITIVE AND NEGATIVE SYNDROME SCALE (PANSS) ‐ Patients not blind due to the nature of the intervention
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Insufficient information to permit judgment of 'Low risk' or 'High risk' of bias
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) POSITIVE AND NEGATIVE SYNDROME SCALE (PANSS) ‐ Insufficient information to determine if study personnel were blinded
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Missing data not balanced; dissimilar reasons but difficult to determine what impact this would have on the study
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) POSITIVE AND NEGATIVE SYNDROME SCALE (PANSS) ‐ Missing data not balanced; dissimilar reasons but difficult to determine what impact this would have on the study

Andrade 2005.

Methods	64 patients were randomized in this study with 32 in the intervention group and 32 in the control group. Allocation concealment and method of randomization were not described
Participants	Enrolled patients who were 18 years of age or older, able to self medicate, and currently receiving care at the Johns Hopkins Moore (HIV) Clinic. Subjects eligible for inclusion were either previously treatment‐naive and initiating highly active antiretroviral therapy (HAART) for the first time or antiretroviral experienced and switching HAART regimens. Among subjects in the latter group, we included only those who had received 3 or less HAART regimens before study enrolment. Exclusion criteria were inability to self medicate, presence of severe dementia, and institutionalization
Interventions	All subjects participated in an individualized, 30‐minute adherence counseling session each month and received adherence feedback from a standardized transcript that provided general education about the barriers to adherence, the hazards of non‐adherence, and their prescribed HAART regimen. A clinical pharmacist with extensive experience in the field of Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) provided adherence counseling and feedback. Patients in the intervention group were also given the Disease Management Assistance System (DMAS) device for 24 weeks. The DMAS device was programmed with reminder messages and dosing times for each medication in the HAART regimen. Devices were inspected monthly and reprogrammed when the HAART regimen was changed or replaced if they were lost or malfunctioning. Patients in the control group did not receive the DMAS
Outcomes	Adherence was assessed monthly with the DMAS, data from the electronic drug‐exposure monitoring (eDEM) caps and completion of the AIDS Clinical Trials Group (ACTG) Baseline Adherence Questionnaire during the initial study visit and the ACTG Follow‐up Adherence Questionnaire during subsequent visits. 4‐day average adherence was calculated as the number of prescribed doses minus the number of missed doses, divided by the number of prescribed doses. For the DMAS device, adherence was calculated as the number of times the response button was pressed divided by the number of medication prompts during the 4‐day period preceding the study visit. Clinical endpoints included CD4+ cell count and plasma HIV RNA load were assessed at baseline and at weeks 12 and 24 of follow‐up. Validated neuropsychological (NP) tests were used to assess attention, memory, new learning, psychomotor speed, and executive functions and administered twice during the study, at baseline and after 24 weeks of HAART. Symptoms of depression were assessed using the Center for Epidemiologic Studies Depression (CES‐D) scale. Patients were also questioned about active illicit drug use and alcohol use during the past 4 days
Notes	The DMAS prompting device improved adherence for memory‐impaired subjects but not for memory‐intact subjects; this was shown at 24 weeks with a 20% increase in adherence for the memory‐impaired group compared with 6% for the memory‐intact patients. Although the DMAS resulted in improved adherence, the overall mean adherence score was only 77% for DMAS users with memory deficits. This is lower than the optimal adherence rate of 95% required for optimal viral suppression
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Author note: Subjects were randomized using a random number generator that produced a list of treatment slots
Allocation concealment (selection bias)	Unclear risk	No mention of allocation concealment. (pg 876) "Subjects were randomly assigned to intervention or control groups."
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	High risk	Low external generalizability. (pg 881) "Third, substance abuse was relatively uncommon in our study, and therefore the results might not be generalizable to populations in which drug abuse is more prevalent."
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) ELECTRONIC DRUG EXPOSURE MONITORING ‐ No mention of blinding of outcome assessors
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) CD4 CELL COUNT ‐ Author note: Laboratory staff were blind
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) ELECTRONIC DRUG EXPOSURE MONITORING ‐ Participants would have known they were in the intervention group
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) CD4 CELL COUNT ‐ No mention of blinding but this outcome is objective
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) ELECTRONIC DRUG EXPOSURE MONITORING ‐ No mention of blinding of study staff
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) CD4 CELL COUNT ‐ No mention of blinding of study staff
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) ELECTRONIC DRUG EXPOSURE MONITORING ‐ Even dropouts but imputation method was unclear
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) CD4 CELL COUNT ‐ Even dropouts but the imputation method was unclear

Ansah 2001.

Methods	If children coming in on Monday received pre‐packed tablets, those who came in on Tuesday received syrup. The formulation assigned to a particular day changed from week to week. 155 received pre‐packed chloroquine tablets, and 146 received syrup
Participants	Children aged 0 to 5 years diagnosed with malaria at the clinic over a 6‐week period received either pre‐packed tablets or syrup by random assignment (n = 301)
Interventions	Chloroquine tablets were dispensed in polythene packages divided into 3 parts each containing the daily dose. The brand of tablets used for this study easily dissolved in water to form a homogenous suspension. Caregivers were advised at the dispensary to crush the tablets and to add a little honey or sugar to the mixture to mask its bitter taste. Staff of the health centers pre‐packed the chloroquine on a weekly basis. Packages were available for 8 treatment regimes based on weight. The other group got chloroquine syrup
Outcomes	The measure used to dispense the medication (in the case of syrups), frequency, and duration of administration. A standard graded measuring syringe was used to assess the volume of the implement used for measuring the dose at home, and then compared adherence to treatment and its cost between the 2 groups
Notes	The investigators varied which day of the week was assigned to which intervention, making this trial closer in methodology to a cluster‐randomized trial
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomization based on day of the week. (pg 497) "All caregivers visiting the two health centres over a 6‐week period whose children had malaria received either pre‐packed chloroquine tablets or chloroquine syrup by random assignment..... Thus if children coming in on Monday received pre‐packed tablets, those who came in on Tuesday received syrup. The formulation assigned to a particular day changed from week to week."
Allocation concealment (selection bias)	Unclear risk	(pg 497) "Thus if children coming in on Monday received pre‐packed tablets, those who came in on Tuesday received syrup. The formulation assigned to a particular day changed from week to week."
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	Insufficient information provided
Blinding of outcome assessment (detection bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ No blinding of staff and personnel
Blinding of outcome assessment (detection bias) Patient outcome	High risk	(PRIMARY) RECOVERY ‐ No mention of blinding of data collectors
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ Patients could not be blinded due to the intervention
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) RECOVERY ‐ Patients were not blinded to study groups
Blinding of personnel (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ No blinding of key study personnel
Blinding of personnel (performance bias) Patient outcome	High risk	(PRIMARY) RECOVERY ‐ No mention of blinding of study staff
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ Insufficient information provided
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) RECOVERY ‐ No reasons given for missing outcome data

Antonicelli 2008.

Methods	Randomized controlled trial
Participants	The study location was the Italian National Research Centre on Aging, Ancona, Italy 29 participants were randomized to the intervention group and 28 participants were randomized to the control group The inclusion criteria were patients with congestive heart failure of NYHA class II‐IV The exclusion criteria were lack of co‐operation and/or of reliable family assistance at home, severe dementia or debilitating psychiatric disorders, inability to access a home telephone line, end‐stage heart failure requiring regular inotropic drug infusions, cachexia, chronic renal failure, requiring dialysis treatment, and unstable angina
Interventions	Intervention: HOME TELEMONITORING Patients were in a 12‐month follow‐up period. Patients (or one of their relatives) were contacted by telephone at least once a week by the chronic heart failure (CHF) team to obtain information on symptoms and adherence to prescribed treatment, as well as blood pressure, heart rate, bodyweight, and 24‐hour urine output data for the previous day. A weekly ECG transmission was also required. Evaluation of these parameters was followed by reassessment of the therapeutic regimen and modification whenever needed. In addition, clinic visits were arranged as required on the basis of the data provided by telemonitoring or telephone interviews. Decisions on hospital re‐admission during follow‐up in both groups were made after consultation with a CHF team member Control: STANDARD CARE Patients (or one of their relatives) in the control group were contacted monthly for 12 months of follow‐up by telephone to obtain data on new hospital admissions, cardiovascular complications, and death. These patients were also routinely seen in the CHF outpatient clinic every 4 months, with additional visits being arranged whenever changes in clinical status made this necessary
Outcomes	The measures of adherence were in the telemonitoring group, patients (or one of their relatives) were contacted by telephone at least once a week by the CHF team to obtain information on adherence to prescribed treatment. It is not clear how adherence was measured in the control group The patient outcomes were new hospital admissions, cardiovascular complications and death, and symptoms, which were assessed by telephone contact at least once a week by the CHF team with patients (or one of their relatives). These calls also assessed blood pressure, heart rate, bodyweight, and 24‐hour urine output data for the previous day. A weekly ECG transmission was also required. The primary composite endpoint was the combined rate of mortality and re‐admission to hospital because of CHF. The secondary endpoints were rates of mortality and re‐hospitalization considered separately over the follow‐up period.
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Author's note: All randomization steps were done by the statistician
Allocation concealment (selection bias)	Low risk	Author's note: All randomization steps were done by the statistician. All envelopes were concealed; there was no possibility for investigator bias
Selective reporting (reporting bias)	Low risk	Author note: We followed the protocol from the previous study, published at Journal of Telemedicine and Telecare 2008;14:300‐5. All outcomes were reported
Other bias	High risk	Limitations noted by author: small sample size and short follow‐up period
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) TELEPHONE SURVEY ‐ No information about blinding is provided
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Author note ‐ Yes, outcome assessors were blind
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) TELEPHONE SURVEY ‐ No information about blinding in the manuscript, but likely that patients were not blinded because it is impossible to blind participants to the study group
Blinding of participants (performance bias) Patient outcome	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Author note ‐ Patients were blind to the intervention
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) TELEPHONE SURVEY ‐ No mention of blinding study staff or note on role in study; unclear how this would impact the outcome
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Author note ‐ Yes, study personnel were blind
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) TELEPHONE SURVEY ‐ No mention of dropouts; thus may have 100% follow‐up but not sure
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ No mention of dropouts; thus assume 100% follow‐up but this is unclear

Apter 2011.

Methods	Randomized controlled trial
Participants	The study location was primary care and asthma specialty practices serving low‐income, inner‐city neighborhoods in Pennsylvania, USA 165 participants were randomized to the intervention group and 168 participants were randomized to the control group The inclusion criteria were (1) age of 18 years or greater; (2) physician's diagnosis of asthma; (3) prescription for an ICS‐containing medication for asthma; and (4) evidence of reversible airflow obstruction (i.e. either an increase of 15% or greater and 200 ml in FEV1 with asthma treatment over the previous 3 years or an increase in FEV1 or forced vital capacity (FVC) of 12% or greater and 200 ml in FEV1 within 30 minutes of inhaled albuterol) The exclusion criteria were patients with severe psychiatric problems, such as obvious mania or schizophrenia, which would make it impossible for them to understand or carry out problem solving
Interventions	Intervention: PROBLEM SOLVING INTERVENTION Participants met with a research co‐ordinator for 4 sessions of a problem solving (PS) intervention. PS comprised 4 30‐minute sessions. The individualized intervention involved 4 interactive steps, usually 1 per research session. For the 158 participants who reported missing doses of inhaled corticosteroids (ICS), the goal was to improve adherence. For the 7 participants who declared adherence to the prescribed regimen, the goal was to maintain adherence. The first PS step consisted of defining the problem: improving or preserving adherence to ICS use within the patient's unique context and orientation. Problem orientation facilitated the adoption of a rational, positive, and constructive appraisal of how to achieve adherence, with non‐adherence being presented as a problem to be solved. PS was presented as a means of coping with problems more generally and modifying attitudes or beliefs that inhibit or interfere with attempts to solve problems. It was a motivational technique to help the participant view the occurrence of problems as inevitable, normal, and solvable. This first step involved breaking problems into small achievable pieces. The second step was brainstorming for alternative solutions. The third step was choosing the best solution by weighing the consequences, both desirable and undesirable, of each candidate solution. Between the third and fourth meetings, the solution was tried. For the fourth step, the chosen solution was evaluated and revised. As part of this intervention, downloaded data from monitored ICSs were shared with the participant in a nonjudgmental fashion at each visit. At these sessions, subjects followed the same PS steps for addressing an additional problem of their own choosing, such as increasing physical activity. The problems were sometimes interrelated; for example, a father wants to play sports with his child, and improving asthma management makes this easier Control: ASTHMA EDUCATION Patients attended 4 30‐minute sessions, conducted by a research co‐ordinator. Each session was about an asthma education topic unrelated to self management, adherence, or inhaled corticosteroid (ICS) therapy. The topics covered, 1 at each session, were the following: (1) the proper technique for using an albuterol rescue metered‐dose inhaler and a dry powder inhaler or spacer, depending on the patient's medications; (2) the use of peak flow meters; (3) common asthma triggers; and (4) the pathophysiology of asthma. These sessions did not involve discussion of problem solving or adherence, only didactic presentation of health information
Outcomes	The measures of adherence were electronic monitoring. Date and time of ICS actuation was monitored. The electronic monitor can record multiple actuations over a short time period and thus can detect medication 'dumping', multiple actuations of an ICS unaccompanied by inhalation. Only 2 electronic monitors that measure the time and date of ICS use were available at the time of the study. Although no commercial monitor was available for fluticasone‐salmeterol, the most frequent ICS prescribed to subjects during the study period, we were able to use the Diskus Adherence Logger (DAL). Fluticasone and beclomethasone administered by means of metered‐dose inhalers were the next most frequently prescribed; for these, we used a commercial monitor, MDILog (Life Link Monitoring, Inc, Kingston, NY). Approximately 90% of study participants were prescribed an ICS that could be monitored with the DAL or MDILog. 14 patients were initially prescribed inhaled mometasone, but they were switched to a medication that could be monitored, fluticasone, during the study period with their physician's permission. We truncated adherence at 100% for each monitoring period to control for multiple actuations over a very short period of time and to provide a better measure of adherence The patient outcomes were asthma‐related quality of life, asthma control, FEV1, hospitalizations and emergency room visits. Asthma‐related quality of life (AQOL) was measured at visits 1, 5, and 8 with the Mini‐Asthma Quality of Life Questionnaire. This 15‐item questionnaire, reflecting well‐being over the past 2 weeks, has a 7‐point response scale that provides a mean summary score. A 0.5‐unit change is considered clinically meaningful. The Asthma Quality of Life Questionnaire has been shown to be a useful indicator of AQOL in low‐income adults. Asthma control was measured at each visit by using the 7‐item version of the Asthma Control Questionnaire, which asks about symptoms over the past week. The score is the mean of all responses (0, total control; 6, extremely uncontrolled). The minimal important clinical difference is 0.5. A score of greater than 1.5 is considered inadequate control. Spirometry was obtained by using American Thoracic Society procedures for FEV1 and FVC. At each research visit, participants reported hospitalizations and emergency department (ED) visits for asthma or any cause that had occurred since the previous meeting. Measures were taken by research co‐ordinators at each study visit, at monthly visits, for 8 months
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	2 weeks later (visit 2), subjects were randomized according to a computer‐generated algorithm in a 1:1 ratio to intervention or control group
Allocation concealment (selection bias)	Unclear risk	Allocation concealment is not specified. Only state: 2 weeks later (visit 2), subjects were randomized according to a computer‐generated algorithm in a 1:1 ratio to either the intervention or control group
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified
Other bias	High risk	The authors indicate on pg 522 that "The limitations of our study are informative. As noted, electronic monitoring of adherence cannot be achieved divorced from the Hawthorne effect. Because of monitoring, many members of the asthma education group (control group) (66%) thought researchers were teaching about adherence. Thus the interventions might have been perceived similarly by participants. Although the intervention was complicated and labor intensive, it focused only on the patient's behavior and did not consider the environment of the practice site or that of the patient's larger social context."
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) ELECTRONIC MONITORING ‐ Objective measure/research co‐ordinator who collected the data was not blinded (was the one who delivered the intervention) but probably would not affect electronic monitor data
Blinding of outcome assessment (detection bias) Patient outcome	High risk	(PRIMARY) ASTHMA CONTROL QUESTIONNAIRE ‐ Open‐label trial/no mention of blinding of study staff/Subjective measure
Blinding of participants (performance bias) Adherence measure	Low risk	(PRIMARY) ELECTRONIC MONITORING ‐ Objective measure/data dumping is accounted for(pg 518) "We electronically monitored the date and time of ICS actuation. The electronic monitor can record multiple actuations over a short time period and thus can detect medication "dumping", multiple actuations of an ICS unaccompanied by inhalation."
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) ASTHMA CONTROL QUESTIONNAIRE ‐ Open‐label trial/no mention of blinding of patients/Subjective measure
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) ELECTRONIC MONITORING ‐ Objective measure
Blinding of personnel (performance bias) Patient outcome	High risk	(PRIMARY) ASTHMA CONTROL QUESTIONNAIRE ‐ Open‐label trial/no mention of blinding of study personnel/Subjective measure
Incomplete outcome data (attrition bias) Adherence measure	High risk	(PRIMARY) ELECTRONIC MONITORING ‐ A large amount of missing data for this measure. (pg 520) Monitor downloads failed in 380 (20%) of 2360 downloads, 18% of the PS group and 22% of the AE group. Failures were attributed to monitor failure, battery failure, and proximity to other batteries or magnets
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) ASTHMA CONTROL QUESTIONNAIRE ‐ Insufficient information

Bailey 1990.

Methods	Random allocation by sealed envelope technique. Blinding of patients or staff to the experimental treatment that individual patients were receiving was not performed, however, contacts/care givers of control patients were kept separate from those of the intervention group
Participants	Patients meeting the following diagnostic criteria were included in the study: recurrent episodes of wheezing or dyspnea, objective evidence of significantly increased airflow resistance during episodes, objective evidence of improvement in airflow when symptom free. Patients excluded from the study were those less than 18 years of age, those who refused to participate, or those with another pulmonary or severely debilitating disease that may have confused result interpretation
Interventions	Patients randomized to the control or usual care group were provided with a standardized set of asthma pamphlets, which contained comprehensive information about asthma. No special steps, however, were taken to ensure that patients actually read the pamphlets, and no special counseling, support groups, or systematic encouragement beyond routine physician encouragement were provided. While patients in the interventional self management group were also provided with the standardized asthma pamphlets, they in addition were provided with a skill‐oriented self help workbook, a one‐to‐one counseling session, and were subject to several adherence‐enhancing strategies, such as attending an asthma support group and receiving telephone calls from a health educator. Physicians emphasized these skills at regular clinic visits. A standard protocol for classifying patients in terms of level of severity and for relating their treatment regimen to their level of severity was employed
Outcomes	Measurement of adherence: 3 outcome measures directly assessed adherence to recommended regimens: a 10‐item observational checklist to assess inhaler use skills, self report scales to determine adherence to medications and inhaler use, and subjective assessment on a 3‐point scale by a project staff member. Measurement of healthcare outcomes: 4 status scales were employed in assessing healthcare outcomes: the first assessed the severity of asthma symptoms during the past 7 days, the next focused on psychological/psychosomatic aspects of asthma (whether the patients were 'bothered' by asthma in the past 7 days), the next scale assessed the number of episodes of respiratory problems/diseases experienced in the last 3 months, and the final scale measured whether asthma had interfered with the patients' lives in the last 3 months (prevented them from doing something)
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Closed envelope method used. Physicians treating the patients were involved in stratification. (pg 1666) "Patients were then randomized to two groups by using the closed envelope method. Patients were then stratified by 11 UAB pulmonary physicians based on severity of asthma. Randomization envelopes were prepared in advance, using a separate schedule for each strata".
Allocation concealment (selection bias)	Low risk	(pg 1666) "Patients were then randomized to two groups by using the closed envelope method."
Selective reporting (reporting bias)	Unclear risk	All the 9 pre‐specified outcome measures reported. Protocol required for further evaluation (Table 2pg 1667). (pg 1666) "Nine outcome measures assessed at baseline and at the 12‐month"
Other bias	Unclear risk	Insufficient information to determine if other bias occurred
Blinding of outcome assessment (detection bias) Adherence measure	High risk	(PRIMARY) 10‐ITEM OBSERVATION CHECKLIST ‐ (pg 1666) "It proved impossible to blind either patients or project staff to the experimental treatment that individual patients were receiving. To minimize the contamination of the usual care condition with the Self management group all contacts with the usual care group were limited to a staff member who had no part in implementing the intervention program".
Blinding of outcome assessment (detection bias) Patient outcome	High risk	(PRIMARY) ASTHMA SEVERITY SCALE ‐ (pg 1666) "It proved impossible to blind either patients or project staff to the experimental treatment that individual patients were receiving. To minimize the contamination of the usual care condition with the Self management group all contacts with the usual care group were limited to a staff member who had no part in implementing the intervention program".
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) 10‐ITEM OBSERVATION CHECKLIST ‐ (pg 1666) "It proved impossible to blind either patients or project staff to the experimental treatment that individual patients were receiving. To minimize the contamination of the usual care condition with the Self management group all contacts with the usual care group were limited to a staff member who had no part in implementing the intervention program"
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) ASTHMA SEVERITY SCALE ‐ (pg 1666) "It proved impossible to blind either patients or project staff to the experimental treatment that individual patients were receiving."
Blinding of personnel (performance bias) Adherence measure	High risk	(PRIMARY) 10‐ITEM OBSERVATION CHECKLIST ‐ (pg 1666) "It proved impossible to blind either patients or project staff to the experimental treatment that individual patients were receiving. To minimize the contamination of the usual care condition with the Self management group all contacts with the usual care group were limited to a staff member who had no part in implementing the intervention program".
Blinding of personnel (performance bias) Patient outcome	High risk	(PRIMARY) ASTHMA SEVERITY SCALE ‐ (pg 1666) "It proved impossible to blind either patients or staff to the experimental treatment that individual patients were receiving. To minimize the "contamination" of the usual care condition with the Self‐Management Program, all contacts with usual care patients were limited to a Staff member who had no part in implementing the intervention program."
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) 10‐ITEM OBSERVATION CHECKLIST ‐ 34 patients from the usual care and 8 from the self management program were lost at the 12‐month follow‐up and were excluded from data analysis. Originally the groups were balanced ‐ 135 and 132 to usual care and SMP groups and were closely matched at baseline. Excluding the dropouts analysis was carried out for 101 patients from the usual care and 123 from intervention group. It is stated in the paper (pg 1666) that "Analyses of baseline data indicated that dropouts were highly similar to subjects who persisted in the study, and that there was no dropout". However, not sure whether the imbalance in numbers could have affected the results
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) ASTHMA SEVERITY SCALE ‐ 34 patients from the usual care and 8 from the self management program were lost at the 12‐month follow‐up and were excluded from data analysis. Originally the groups were balanced ‐ 135 and 132 to usual care and SMP groups and were closely matched at baseline. Excluding the dropouts analysis was carried out for 101 patients from the usual care and 123 from intervention group. It is stated in the paper (pg 1666) that " Analyses of baseline data indicated that dropouts were highly similar to subjects who persisted in the study, and that there was no dropout". However, not sure whether the imbalance in numbers could have affected the results.

Bailey 1999.

Methods	Patients (n = 236) were stratified by asthma severity (moderate or severe) and randomly assigned to the 3 groups using the closed‐envelope technique: University of Alabama at Birmingham (UAB) Asthma Self Management group (n = 78), UAB Core‐Elements group (n = 76) and usual care group (n = 78). As well, standard computer procedures were employed to create a stratified, blocked randomization schedule, which consisted of block sizes of 6 to ensure 2 out of every 6 patients in each stratum were assigned to each group. Immediately following randomization, staff collected baseline data and implemented the designated educational treatment
Participants	All subjects were patients in the clinics of the UAB Division of Pulmonary and Critical Care Medicine with a primary diagnosis of asthma who met the following diagnostic criteria: (1) recurrent episodes of dyspnea or wheezing, (2) objective evidence of significantly increased resistance to airflow during episodes, (3) objective evidence of improvement in airflow when symptom‐free, and (4) moderate to severe (rather than mild) asthma as assessed by their asthma care physician. New and current patients were included in the study; although patients who had participated in the earlier self management study were excluded
Interventions	UAB Asthma Self Management Program (n = 78): the core component of the UAB Asthma Self Management Program (ASMP) was a skill‐oriented self help workbook, which patients were counseled about in a one‐on‐one session and during 2 asthma support group meetings. The workbook included information on physiology of asthma, asthma medications, identification and avoidance of triggers, detection of and response to asthma attacks, and asthma care services. The 1‐hour counseling session included reviewing the workbook content and skills, identifying personal expectations, asthma triggers, and barriers to adherence, and practicing inhaler use until patients were able to do so correctly. Patients were also given peak flow meters and trained to use them for early detection of impending asthma attacks. Asthma support groups, facilitated by a health educator, consisted of 4 to 6 patients with asthma and, if possible, asthma control partners (spouses or close friends). Support group meetings were held once each month many patients came every month. Patients were encouraged to share asthma concerns, discuss adherence problems, and exchange patient‐initiated solutions. Patients received 2 telephone calls and a follow‐up letter at 1, 2, and 4 weeks, after the counseling session. The first telephone call allowed the discussion of problems and to collect baseline peak flow readings and to help determine their expected peak flow rates. The letter reinforced actions to take at different levels of peak flow readings. The second telephone call provided closure for the intervention. Overall, the intervention spanned about 6 to 8 weeks for patients. UAB Core‐Elements Program (n = 76): this program consisted of a revised, shortened workbook that was given to patients. It was reviewed in a brief (15 to 20 minutes) one‐to‐one counseling session. Patients were trained to use inhalers and peak flow meters and rehearsed until these devices were used correctly. A follow‐up telephone counseling session was conducted approximately one week later to review the patient's medication regimen and inhaler and peak flow meter skills. 2 weeks later, a follow‐up letter was sent to patients, stressing the importance of adhering to the prescribed regimen and responding immediately to a drop in peak flow rate or other early signs of an attack Usual‐care control group (n = 78): patients received the education that was the standard practice of their physician. They also received a standardized set of pamphlets that contained information about asthma. No steps were taken to ensure that patients read the pamphlets, and no special counseling, support groups, or telephone calls were provided
Outcomes	Compliance was measured using 2 4‐item self reports, which were based on the prototype self report scale described by Morisky et al but were modified to be more applicable to asthma. The psychometric characteristics of the asthma therapy adherence scales were good to excellent. Adherence was analyzed in terms of the percentage of subjects with the highest possible scores on these scales. 4 clinical outcome measures addressed asthma status, specifically, the impact of asthma on respiratory symptoms and illnesses, functional status, and use of healthcare services. 2 scales addressed the severity of asthma symptoms in the past 7 days and the number of respiratory illnesses in the past 3 months. The functional impairment scale assessed the extent to which asthma had a negative impact on daily activities in the past 3 months. The scale for measurement of use of healthcare services classified patients as users if they had visited an emergency department for asthma and/or been hospitalized for asthma in the past 6 months. Other patients were classifies as nonusers. These measures also analyzed the percentage of subjects who obtained the highest possible score as users
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Stratified randomization using computer‐generated numbers, closed envelopes (pg 2424)
Allocation concealment (selection bias)	Low risk	Central randomization using computer‐generated numbers, closed envelopes
Selective reporting (reporting bias)	Unclear risk	Insufficient information; no protocol available
Other bias	Low risk	No other obvious biases noted
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ INTERVIEW (ASTHMA THERAPY ADHERENCE SCALE) ‐ Author note: data collectors were blind
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) ASTHMA STATUS QUESTIONNAIRES ‐ Author note: data collectors were blind
Blinding of participants (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ INTERVIEW (ASTHMA THERAPY ADHERENCE SCALE) ‐ Patients were blind to allocation, but it is possible that they became aware of their group later on during one‐to‐one sessions. If the patients came to know about their group they might exaggerate responses during the telephone interview. The authors have not mentioned about any measure taken to ensure that patients remained blinded throughout the study. Author's note: the only effect was not to discuss which intervention was being used
Blinding of participants (performance bias) Patient outcome	Unclear risk	(PRIMARY) ASTHMA STATUS QUESTIONNAIRES ‐ Patients were blind to allocation, but it is possible that they became aware of their group later on during one‐to‐one sessions. If the patients came to know about their group they might exaggerate responses during the telephone interview. Authors have not mentioned about any measure taken to ensure that patients remained blinded throughout the study. Author's note: the only effect was not to discuss which intervention was used
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ INTERVIEW (ASTHMA THERAPY ADHERENCE SCALE) ‐ Author's note: study staff were blind
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) ASTHMA STATUS QUESTIONNAIRES ‐ Author's note: study staff were blind
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ INTERVIEW (ASTHMA THERAPY ADHERENCE SCALE) ‐ Unclear whether the missed data could have changed the outcome, hence marked unclear. However, attrition is fairly low, possibly low bias
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) ASTHMA STATUS QUESTIONNAIRES ‐ Unclear whether the missed data could have changed the outcome, hence marked unclear. However, attrition is fairly low, possibly low bias

Baird 1984.

Methods	Random allocation without indication of concealment.
Participants	Mild‐moderate hypertensive patients who, at the time of study entry, were adequately controlled with a regimen of metoprolol 200 mg (range 150 to 250 mg) daily, or propranolol 160 mg (range 120 to 200 mg) daily, either as monotherapy or in conjunction with a diuretic were included in the study. Patients excluded from the study were those with a condition in which beta‐blockade was contraindicated
Interventions	Patients were taken off whatever beta‐blocker they were taking at entry and then allocated to one of the 2 interventional groups: (1) Betaloc tablets 100 mg in the morning (0600 to 0900 hours), and in the evening (12 hours later), or (2) Betaloc Durules 200 mg every morning (0600 to 0900 hours)
Outcomes	2 measurements of adherence were utilized: (1) tablet counts at 6 and 10 weeks, and (2) spot checks of metoprolol concentration in the urine at 6 and 10 weeks. The mean heart rate, systolic and diastolic blood pressures were assessed before, during, and after the trial, and compared between the 2 treatment regimens
Notes	Outcome assessments were not blinded to study group
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No discussion of randomization process. "Patients were allocated randomly" (pg 96)
Allocation concealment (selection bias)	Unclear risk	No mention of allocation concealment. "Patients were allocated randomly" (pg 96)
Selective reporting (reporting bias)	Unclear risk	Unclear. No protocol available
Other bias	Unclear risk	Not enough details provided in the article
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT ‐ No mention of blinding of study staff
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE AND HEART RATE ‐ No information is provided in the article on blinding
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) PILL COUNT ‐ No blinding and outcome is possibly affected
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) BLOOD PRESSURE AND HEART RATE ‐ No information in provided in the article, but non‐blinding of the patient is unlikely to affect this outcome
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT ‐ No mention of blinding of study staff
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE AND HEART RATE ‐ No mention of blinding of staff
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT ‐ Unclear how many patients withdrew from this portion of the trial, otherwise reasons for dropouts are provided in Table 3
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE AND HEART RATE ‐ Unclear how many patients withdrew from this portion of the trial, otherwise reasons for dropouts are provided in Table 3

Beaucage 2006.

Methods	Patients (n = 255) were randomly assigned to (1) Pharmacist telephone follow‐up intervention (PTFI; n = 126) or (2) usual pharmacist intervention (UPI; n = 129). Randomization was stratified by pharmacy in balanced blocks of 10 patients (1:1 ratio) using a computer‐generated random number table and provided to the pharmacist investigators in sealed envelopes identified by patient number. Patients were randomized sequentially by patient number
Participants	Patients had an expected duration of antibiotic treatment of 5 to 14 days, spoke French or English, were able to converse over the telephone, and were available for a telephone call during and at the expected end of antibiotic treatment and for up to 48 hours thereafter. Patients were excluded from the trial if they were initiating prophylactic antibiotic treatment, were not self managing their medication, were already participating in a clinical trial, in the opinion of the pharmacist, required intense clinical follow‐up, or would benefit from more intensive follow‐up in a special medical hospital clinic
Interventions	Pharmacist telephone follow‐up intervention (PTFI) patients received a telephone call from a pharmacist on day 3 of their antibiotic treatment. The pharmacist documented the patient's general condition, checked for adverse effects and the patient's understanding of the dosage, stressed the importance of adherence to treatment, and offered encouragement. Patients were invited to ask questions and to contact their pharmacist if needed. At the initial pharmacy visit, Usual Pharmacist Intervention (UPI) patients were invited to contact their pharmacist if needed. They received no telephone calls during their treatment
Outcomes	Compliance was measured by patients reporting the number of antibiotic tablets or capsules left. Compliance was defined as the percentage of tablets consumed of the total number of tablets provided. Patients receiving azithromycin treatment and those who had a change in antibiotics during their treatment were excluded from this analysis. The clinical outcomes of patients were measured by asking for the number of infectious symptoms and their descriptions; in addition, a 5‐point Likert scale was used to evaluate the severity of the infections. This was measured at baseline and upon completion of the treatment
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Low bias because "Randomization was stratified by pharmacy in balanced blocks of 10 patients (1:1 ratio) using a computer‐generated random‐number table and provided to the pharmacist investigators in sealed envelopes identified by patient number. Patients were randomized sequentially by patient number." (pg 558)
Allocation concealment (selection bias)	Low risk	Allocation concealment detailed and appropriate. (pg 558) "... using a computer‐generated random‐number table and provided to the pharmacist investigators in sealed envelopes identified by patient number. Patients were randomized sequentially by patient number."
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	Some limitations noted in discussion ‐ (pg 562) "because the access to clinical data was limited, the main study outcome consisted of a patient's subjective evaluation rather than microbiological cultures... Moreover, a significant proportion of the patients included in the study were probably suffering from viral infections. Because antibiotics are not efficacious against such infections, it is unlikely that optimizing antibiotic treatment would affect the symptoms of these patients. Indeed, in a secondary analysis, by excluding patients suffering from upper‐ or lower‐respiratory tract infections (the patients most likely to have viral infections), we observed a larger reduction in the number of infectious symptoms among PTFI patients."
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ The pharmacist that contacted patients to discuss adherence were blinded to group (pg 559) "The final evaluation was conducted over the telephone by a pharmacist blinded to the patient's assignment group."
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) NUMBER OF INFECTIOUS SYMPTOMS ‐ Pharmacist collecting data blinded to patient group (pg 559) "The final evaluation was conducted over the telephone by a pharmacist blinded to the patient's assignment group. The interview was scheduled for the expected last day of antibiotic treatment, except for patients on azithromycin treatment for five days, who were contacted on day 10; due to long tissue half‐life and large volume of distribution, therapeutic concentrations are maintained over a 10‐day period. 15 of the patient could not be reached, additional telephone calls were made at least three times a day for up to three days. To maintain blinding, the pharmacist who performed the final evaluation was different from the recruiting pharmacist and had access only to the patient's name and telephone number and the name and dosage of his or her antibiotic treatment. At the end of the interview, the pharmacist was asked if, in her opinion, blinding was maintained. If a DRP was identified at the final evaluation, the patient was referred to his or her treating pharmacist. The number of infectious symptoms and the infection severity score were evaluated as in the initial evaluation. The interviewing pharmacist did not have access to the initial evaluation and was unaware of the patient's diagnosis".
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ Open‐label trial and self report of adherence is highly subjective
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) NUMBER OF INFECTIOUS SYMPTOMS ‐ Patient symptom severity and number of symptoms is subjective and patients were likely aware of their study group allocation
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ No mention of blinding of study personnel
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) NUMBER OF INFECTIOUS SYMPTOMS ‐ No mention of blinding of other study personnel
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ 21 patients had missing data across the 2 groups. 7 and 15 each in intervention and control groups. Reasons for missing data not reported individually for 2 groups. Unable to predict if it would have made a difference. Hence, marked unclear
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) NUMBER OF INFECTIOUS SYMPTOMS ‐ The reasons for dropouts are unclear

Becker 1986.

Methods	Random allocation without an indication of concealment
Participants	Patients between the ages of 20 and 80 years who were already taking medication for previously diagnosed hypertension, and who had already demonstrated poor blood pressure control (diastolic blood pressure > 90 mm Hg) on at least 1 visit during the preceding 2 years were included in the study. Patients who had significant visual, auditory, or mental problems that could interfere with their adherence were excluded
Interventions	Patients in the control group received all of their antihypertensive medications in the traditional pill vials (separate vials for each pill that were labeled with the drug name, the dosage, the medication instructions, and the physician's name), whereas patients assigned to the experimental group received all their medications in the special packaging format (all pills taken together were packaged in a single plastic blister sealed with a foil backing on which was printed the day of the week and the time of day at which each medication was to be taken). All medications for both groups were provided free of charge to ensure that all patients would receive their medications
Outcomes	Patient self reports of adherence, where patients were asked non‐threatening, non‐judgmental questions about their adherence behavior (patients who admitted less than perfect adherence were considered non‐adherent), pill counts (patients were considered adherent if they had taken 80% or more of their prescribed medication) and the Hybrid model were employed in order to assess adherence. Blood pressure was taken 3 times during each visit. The first measure was discarded and an average of the second and third measures was used as the blood pressure measurement for that visit. Blood pressure control was defined as diastolic blood pressure less than 90 mm Hg
Notes	All data collection was done by a nurse research assistant prior to regular office visits. Physicians caring for patients were aware that adherence studies were in progress, but were not told the aims of the study nor the group to which an individual patient had been assigned
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not described in the article. (pg 358) "Patients who agreed were randomly assigned into either the experimental of the control group."
Allocation concealment (selection bias)	Unclear risk	(pg 358) "Patients who agreed were randomly assigned into either the experimental or the control group..." No description of allocation concealment
Selective reporting (reporting bias)	Unclear risk	Probably all outcomes reported, but insufficient information in the article to judge
Other bias	Low risk	Authors identify possible co‐intervention effect, but similar in both arms, so unlikely to have introduced bias. (pg 361) "The magnitude of this cointervention effect is suggested by the increase in the proportion of patients in both groups whose (...) pressure was controlled between the time of the pre‐enrollment and the baseline visit (i.e. before the special packaging intervention was initiated)." This co‐intervention appears to have affected both groups equally and is thus unlikely to have biased the results
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ Unclear if nurses were blinded. (pg 358) "All data collection was done by a nurse research assistant immediately before a regular office visit. Physicians caring for these patients were aware that compliance study was in progress but were not told the aims of the study or informed of whether any individual patient was in the experimental or control group."
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) BLOOD PRESSURE ‐ Blinding. (pg 358) "Physicians caring for these patients were aware that a compliance study was in progress but were not told the aims of the study of informed of whether any individual patient was in the experimental or control group."
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ No blinding and likely to affect the outcome
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) BLOOD PRESSURE ‐ Patients not blinded but likely would not impact outcome
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ Physicians were blinded. (pg 358) "All data collection was done by a nurse research assistant immediately before a regular office visit. Physicians caring for these patients were aware that compliance study was in progress but were not told the aims of the study or informed of whether any individual patient was in the experimental or control group."
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) BLOOD PRESSURE ‐ Physicians were blinded. (pg 358) "Physicians caring for these patients were aware that compliance study was in progress but were not told the aims of the study or informed of whether any individual patient was in the experimental or control group."
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ Not enough information to judge. We do not know to which arm the drop outs belong. (pg 359) "Most of these patients did not show up for appointments and could not be contacted by telephone. Other reasons for dropouts included death (1) and discontinuation of medications (1). No patients indicated that problems with the medication packaging were involved in their reasons for dropping out."
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE ‐ Not enough information to judge. We do not know to which arm the dropouts belong. (pg 359) "Most of these patients did not show up for appointments and could not be contacted by telephone. Other reasons for dropouts included death (1) and discontinuation of medications (1). No patients indicated that problems with the medication packaging were involved in their reasons for dropping out."

Berrien 2004.

Methods	37 patients were randomized 1:1 to either the home intervention or control group using the Small Table of Random Digits. The randomization process was number‐based, with patient names not identified. The randomization list was held by the clinical co‐ordinator of the HIV program and kept in a locked file
Participants	All eligible HIV‐positive patients (n = 37) followed in the program. Informed consent was obtained from each participant's legal guardian. Children ranged in age between 1.5 to 12 years of age (mean 8.7 years) for the intervention group and 5 to 11 years (mean 8.4 years) in the control group. Assent was obtained from all minors older than 7 years of age
Interventions	The intervention group received 8 structured home visits over a 3‐month period by the same home care experienced registered nurse. The visits were designed to improve knowledge and understanding of HIV infection, to identify and resolve real and potential barriers to medication adherence, and ultimately to improve adherence. Spanish‐speaking case managers, incentives, notebooks with stickers, and pill‐swallowing training were also part of the home visit training sessions. In the clinic setting for control group, the physician, nurse, and social worker provided standard medication adherence education at clinic appointments generally scheduled at 3‐month intervals. Phone follow‐ups and a single home visit were planned if the staff felt they were needed. Visual aids for remembering medications, medication boxes, beepers, and general technical and emotional support were regularly offered. The clinic nurse contacted the family by telephone when the patient was starting a new medication, was having difficulty with adherence, or needed clarification and support. A single home visit was planned when and if the clinic staff believed medication adherence was poor despite the implementation of the above listed techniques
Outcomes	Knowledge and adherence were measured at the beginning of the study and at the end of the intervention. These were measures via self report and pharmacy fill record. Changes in viral load and CD4 counts were measured at baseline and after treatment, or for 6 to 11 months beyond the initial study period
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number table was used. Hence low bias. (pg 356) "Patients were randomized 1:1 to either the home intervention or control group using the Small Table of Random Digits. The randomization process was number based, with patient names not identified".
Allocation concealment (selection bias)	Low risk	(pg 356) "Patients were randomized 1:1 to either the home intervention or control group using the Small Table of Random Digits. The randomization process was number based, with patient names not identified. The randomization list was held by the clinical coordinator of the HIV Program and kept in a locked file."
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes were explicitly stated. (pg 356) "Primary study outcomes included changes in patient knowledge of HIV and their medications, and changes in adherence, the latter being measured by self report and by pharmacy drug refill history". (pg 357) "Secondary outcomes included changes in viral load (Roche Amplicor HIV‐1 Monitor Test) and CD4= T‐cell percentages and counts". All those have been accounted in the results
Other bias	Unclear risk	None noted but insufficient information provided
Blinding of outcome assessment (detection bias) Adherence measure	High risk	(PRIMARY) PHARMACY FILL RECORD ‐ Non‐blinded trial. (pg 356) "a randomized, nonblinded, pilot clinical study at CCMC's pediatric and youth HIV program."
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) CD4+ T CELL PERCENTAGES AND COUNTS ‐ No details given about how these measures were collected
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) PHARMACY FILL RECORD ‐ Non‐blinded trial. (pg 356) "a randomized, nonblinded, pilot clinical study at CCMC's pediatric and youth HIV program."
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) CD4+ T CELL PERCENTAGES AND COUNTS ‐ No blinding but patient lack of blinding unlikely to impact this outcome
Blinding of personnel (performance bias) Adherence measure	High risk	(PRIMARY) PHARMACY FILL RECORD ‐ Intervention provider was involved in evaluation steps also. Non‐blinded trial. (pg 356) "a randomized, non‐blinded, pilot clinical study at CCMC's pediatric and youth HIV program."
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) CD4+ T CELL PERCENTAGES AND COUNTS ‐ No details given about how these measures were collected
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) PHARMACY FILL RECORD ‐ 3 patients were not included in analysis ‐ either dead or withdrew from the study; one from the intervention group and two from the control group. Missing data are accounted for and excluded from analysis. It is not known whether missing data would have made a plausible size effect. However, intention‐to‐treat analyses results were similar to the analysis which excluded the 3 missing data
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) CD4+ T CELL PERCENTAGES AND COUNTS ‐ 3 patients were not included in analysis ‐ either dead or withdrew from the study; one from the intervention group and two from the control group. Missing data are accounted and excluded from analysis. It is not known whether missing data would have made a plausible size effect. However, intention‐to‐treat analyses results were similar to the analysis which excluded the 3 missing data

Boker 2012.

Methods	Randomized controlled trial
Participants	The study location was University of Texas Southwestern Medical Center, Texas, and University of California at Davis, California, USA 20 participants were randomized to the intervention group and 20 participants were randomized to the control group The inclusion criteria were healthy patients 12 to 35 years of age with mild to moderate facial acne suitable for treatment with topical medications; male or female of any ethnic background; a clinical diagnosis of acne vulgaris with facial involvement for at least 6 months; a minimum of 30 non‐inflammatory facial lesions (open and/or closed comedones) and at least 20 inflammatory lesions (papules or pustules); a score of 2 or 3 on the Investigator Global Assessment (IGA) scale; and possession of a personal mobile telephone with SMS text messaging capabilities. Women of childbearing potential were required to use an acceptable birth control measure such as abstinence, condoms, or vaginal diaphragms. Hormonal‐based oral contraception was only allowed if treatment had been initiated at least 5 months before study enrollment and was given for reasons other than specific treatment of acne. Minors (less than 18 years) were required to have parental or legal guardian consent to participate The exclusion criteria were known pregnancy, the presence of nodular or cystic acne, acne conglobata or acne fulminans, exposure to environmental or chemical comedogenic agents, women with hyperandrogenism (polycystic ovarian syndrome) or on any form of specific acne‐directed hormonal therapy, a history of Cushing syndrome or congenital adrenal hyperplasia, and use of tanning beds within 4 weeks of enrollment. All female patients of childbearing potential were required to undergo a baseline urine pregnancy test that was repeated at each follow‐up visit. Required washout periods included: acne‐specific systemic antibiotics, 2 months; isotretinoin, 6 months; and topical acne medications (prescription or over the counter), 4 weeks
Interventions	Intervention: TEXT MESSAGE REMINDERS 20 patients were then randomized to receive daily, customized text‐message reminders at a predetermined time. The website LetterMeLater.com was used to create an automated and customized electronic reminder schedule for each patient in this group at their baseline visit. Individual texting schedules were chosen based on each patient's preference and the anticipated time of each medication use. Once the schedule was created, patients in the reminder group received a customized text message twice daily (morning and evening), reminding them to apply the Duac (Stiefel Laboratories) or Differin (Galderma) gels, respectively. The content of each text message was identical for each patient and varied only by including the recipient's first name at the start of the message. Patients in the reminder group were asked to text back a reply if and when each application was completed in an attempt to compare actual adherence (measured by MEMS caps opening/closing events) and self reported adherence. All medication tubes and their corresponding MEMS caps were clearly labeled to avoid mix‐ups Control: USUAL CARE Control group patients received usual care and were not provided with text message reminders
Outcomes	The measures of adherence were MEMS. Patients were given medication tubes. Each medication tube was fitted with a customized Medication Event Monitoring System (MEMS) cap(MEMS, Aardex Group, Sion, Switzerland) that has the ability to record the date and time of every opening/closing of the medication cap. Each opening/closing is recorded as one individual event (date/time stamp). Patients were not informed that their adherence was monitored electronically. Data were downloaded at the 12‐week exit visit The patient outcomes were acne severity assessed by Investigator Global Assessment, Patient Global Assessment, and quality of life assessed by Dermatology Quality of Life Index questionnaire. All questionnaires were administered by a blinded investigator at baseline 6 and 12 weeks
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not enough information given. Patients were randomized in a 1:1 ratio and assigned in a sequential manner to either receive electronic text message reminders or to serve as control subjects
Allocation concealment (selection bias)	Unclear risk	Not enough information provided. ('sequential manner' = possibly high bias?). Patients were randomized in a 1:1 ratio and assigned in a sequential manner to either receive electronic text message reminders or to serve as control subjects
Selective reporting (reporting bias)	Unclear risk	None detected. Protocol not available
Other bias	Low risk	None noted
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) MEMS ‐ Unblinded, but MEMS data unlikely to be biased by the data collectors
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) ACNE SEVERITY ‐ it is unclear from description if the investigator was only blinded at baseline or was blinded at follow‐up as well
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) MEMS ‐ Patients were not informed that their adherence was monitored electronically, but nature of intervention might have unblinded them
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) ACNE SEVERITY ‐ it is unlikely patient could bias this measure
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) MEMS ‐ Unblinded, but MEMS data unlikely to be biased by the study staff
Blinding of personnel (performance bias) Patient outcome	High risk	(PRIMARY) ACNE SEVERITY ‐ study co‐ordinator was not blinded
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) MEMS ‐ Attrition not balanced between groups; not enough information provided on reasons for dropout
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) ACNE SEVERITY ‐ Attrition rates imbalanced; not enough information provided to judge

Bond 2007.

Methods	Randomized controlled trial
Participants	The study location was 9 primary care organizations, England, UK 980 participants were randomized to the intervention group and 513 participants were randomized to the control group The inclusion criteria were registered with the general practices, aged over 17 years, and with CHD (previous myocardial infarction, angina, coronary artery bypass graft, and/or angioplasty) The exclusion criteria were illiterate/innumerate, history of alcohol/drug misuse, terminal/serious illness, severe mental illness, and unable to provide informed consent or otherwise unsuitable for the trial
Interventions	Intervention: MEDICINE MANAGEMENT SERVICE (MEDMAN) The intervention was a comprehensive, community pharmacy‐led medicines management called MEDMAN. This intervention comprised of an initial consultation with a community pharmacist to review the appropriateness of therapy, compliance, lifestyle, social, and support issues. Further consultations were provided according to pharmacist‐determined patient need. Recommendations were recorded on a referral form which was sent to the GP, who returned annotated copies to the pharmacists. The intervention lasted 12 months Control: STANDARD CARE Control group patients not provided with MEDMAN intervention. Follow‐up data were collected at 12 months by audit clerks and postal questionnaire as at baseline. Intervention patients were also asked about their experience of the medicine management service
Outcomes	The measures of adherence were self reported compliance. 12 statements about medicine taking were included and summated to derive a self reported compliance score. Data were collected from participants at baseline and at 12 months. Baseline and follow‐up data were collected by audit clerks and postal questionnaire The patient outcomes were health status, 5‐year risk of cardiovascular death, and patient satisfaction. Health status was assessed using SF‐3619 Euro‐Quality of Life questionnaire. 5‐year risk of cardiovascular death was assessed based on an existing score modified to allow for the absence of data on history of stroke and creatinine concentration. The final satisfaction score included experience of and satisfaction with the community pharmacy service and was assessed by measuring response to 15 positive and negative statements regarding their most recent pharmacy visit. Possible responses ranged from 5 to 1 for strongly agree to strongly disagree for positive statements and from 1 to 5 for negative statements, summated to give an overall satisfaction score. Data were collected at baseline and 12 months by audit clerks and research assistants who were blinded
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were randomized in a ratio of 2:1, intervention to control group. This was done independently of the research team using a password protected computer programme in permuted blocks stratified by practice." (pg 190)
Allocation concealment (selection bias)	Unclear risk	Insufficient information provided ‐ (pg 190) Community pharmacists were given an indicative allocation of 20 patients. If more than 20 patients chose 1 pharmacy, the pharmacist could choose to go 'over quota', or refuse the patient who was asked to choose another pharmacy, or was excluded (designated over quota in Figure 1)
Selective reporting (reporting bias)	Unclear risk	None detected but protocol not available
Other bias	Unclear risk	Insufficient information provided
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ "Audit clerks performing data extraction were blind to the randomization status of participants, as were the researchers conducting the statistical analyses." (pg 193)
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) HEALTH STATUS ‐ "Audit clerks performing data extraction were blind to the randomization status of participants, as were the researchers conducting the statistical analyses." (pg 192)
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE (pg 192) "Patients could not be blind to trial intervention because of its nature."
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) HEALTH STATUS ‐ "Patients could not be blind to trial intervention because of its nature." (pg 193)
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Except participants, community pharmacists, audit clerks performing data extraction, and researchers conducting the statistical analyses were blinded. "Community pharmacists were not informed which control patients had nominated their pharmacy. Audit clerks performing data extraction were blind to the randomization status of participants, as were the researchers conducting the statistical analyses." (pg 190)
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) HEALTH STATUS ‐ Except participants, community pharmacists, audit clerks performing data extraction, and researchers conducting the statistical analyses were blinded. "Community pharmacists were not informed which control patients had nominated their pharmacy. Audit clerks performing data extraction were blind to the randomization status of participants, as were the researchers conducting the statistical analyses." (pg 190)
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Missing data not balanced, especially with regards to withdrawn patients. ITT analysis done, but bias is unclear
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) HEALTH STATUS ‐ Missing data not balanced, especially with regards to withdrawn patients. ITT analysis done, but the potential for bias is unclear

Bonner 2009.

Methods	Randomized controlled trial
Participants	The study location was not stated 56 participants were randomized to the intervention group and 63 participants were randomized to the control group The inclusion criteria were pediatric patients who had been treated for asthma in either the general pediatric practice or the pulmonary clinic of a university hospital during the previous 12 months
Interventions	Intervention: INDIVIDUALIZED ASTHMA MANAGEMENT INTERVENTION Families in the intervention group received asthma education by a trained Family Co‐ordinator who also provided individualized support in helping caregivers monitor their children's asthma using diaries. The Family Co‐ordinator helped caregivers interpret the diaries and communicate the contents to their doctors. 3 group education workshops were held at 1‐month intervals that followed the asthma self regulation model. Families were trained to use the diaries and peak flow meters. Family Co‐ordinators regularly called families to discuss their diary records. The second workshop used patients' diary records as illustrations of the relative effectiveness of controller medicines over rescue/quick‐relief drugs in preventing asthma symptoms over time. Participants reviewed their own records of medicines and symptoms. The third workshop described asthma management as a 2‐pronged effort of pharmacotherapy and trigger control. Between the first and second workshops, the Family Co‐ordinator prepared families for their doctor visit. The Family Co‐ordinator accompanied families to the doctor visit where he intervened if the family failed to communicate a thorough asthma history. The children in the intervention group were tested for allergies by an attending allergist at the hospital if they had not recently been tested by their own physician. Family Co‐ordinator conducted a home environment assessment and suggested strategies for reducing asthma triggers Control: USUAL CARE Control patients (n = 63) received usual medical care at private or hospital‐affiliated community pediatric practice
Outcomes	The measures of adherence were family's adherence to frequency and dosage of prescribed medication and prophylactic bronchodilator use measured at 3 months in face‐to‐face at‐home interviews by the trained Family Co‐ordinator The patient outcomes were self reported symptom persistence and activity restriction as reported in a diary by the caregiver
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Sequence generation not described. (pg 169) "After the baseline interview, families were randomly assigned to control or intervention conditions."
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not described. (pg 169) "After the baseline interview, families were randomly assigned to control or intervention conditions."
Selective reporting (reporting bias)	Unclear risk	None detected; protocol not available
Other bias	Unclear risk	The authors note (pg 177) "A limitation of this study was that a single Family Coordinator delivered the intervention. This precluded any measurement of the Family Coordinator's personal characteristics that may have contributed to patients' skill development. Only 28% of the patients who were originally contacted finally consented to participate in the study, which precludes generalization to the entire population of urban clinic patients. Another limitation is that an intervention period of three months was insufficient to measure how lasting were the gains in patient behavior or how robust was relationship between patient and physician. Another limitation of the study is that reliance on self reported data without confirmation by objective measures may overestimate the impact of the intervention because of participants' response bias towards success." However, it is not clear what impact these limitations would have had on this study
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) FAMILY'S SELF REPORTED ADHERENCE ‐ No blinding mentioned
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) SELF EFFICACY FOR MANAGING ASTHMA ‐ Insufficient information regarding blinding of the research assistant
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) FAMILY'S SELF REPORTED ADHERENCE ‐ Patients likely to be aware of the intervention due to it's nature
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) SELF EFFICACY FOR MANAGING ASTHMA ‐ Patients likely to be aware of the intervention due to it's nature
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) FAMILY'S SELF REPORTED ADHERENCE ‐ Blinding of other personnel to study group not mentioned
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) SELF EFFICACY FOR MANAGING ASTHMA ‐ Insufficient information about blinding
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) FAMILY'S SELF REPORTED ADHERENCE ‐ (pg 174) Control: 50/63 (13 families dropped out) Intervention: 50/56 (6 families dropped out). "There were no significant differences between the dropout rates in the two groups (i.e., 13 control families and 6 intervention families). Nor was there a significant demographic difference at baseline between those who did or did not drop out of either the control group, F(3, 59) = 1.57, n.s., or the intervention group, F(3, 52) = 0.05, n.s. Finally, there was no significant difference at baseline in the health outcome measures between those who did or did not drop out of either the control group, F(10, 52) = 0.57, n.s., or the intervention group, F(10, 45) = 1.08, n.s."
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) SELF EFFICACY FOR MANAGING ASTHMA ‐ (pg 174) Control: 50/63 (13 families dropped out) Intervention: 50/56 (6 families dropped out). "There were no significant differences between the dropout rates in the two groups (i.e., 13 control families and 6 intervention families). Nor was there a significant demographic difference at baseline between those who did or did not drop out of either the control group, F(3, 59) = 1.57, n.s., or the intervention group, F(3, 52) = 0.05, n.s. Finally, there was no significant difference at baseline in the health outcome measures between those who did or did not drop out of either the control group, F(10, 52) = 0.57, n.s., or the intervention group, F(10, 45) = 1.08, n.s."

Brown 1997a.

Methods	The method of random allocation was not described
Participants	Patients were men < or = 65 years of age at high risk for future cardiac events by virtue of: 1) an elevated apoprotein B > or = 125 mg/dl, 2) at least 1 coronary lesion > or = 50% stenosis or 2 lesions > or = 30% stenosis as documented by baseline angiogram, and 3) a family history of premature cardiovascular events
Interventions	Regular niacin (4 times each day) versus polygel controlled release niacin (twice‐daily dosage (bid)). All patients received lovastatin 20 mg bid, colestipol 10 g bid, and niacin 500 mg 4 times each day for 12 months, with dosage adjustment to target cholesterol of 150 to 175 mg/dl, and to minimize side effects. At 12 months, patients were randomly assigned to 1) continue with regular niacin at a dose identical to that established during the 12‐month dose‐finding period, or 2) change to polygel controlled‐release niacin at that daily dosage, but given twice rather than 4 times/day. At 20 months, groups 1) and 2) were reversed (cross‐over). This regimen continued for 8 more months
Outcomes	Compliance with the recommended (and variable) dosage was calculated for each drug using a computer program that accounted for all drug supplies given, the recommended dosage, and a count of returned medication. It is expressed as a percentage of the dose recommended for the patient at the time Clinical outcome measurements included plasma very low‐density lipoprotein (VLDL), low‐density lipoprotein (LDL), and high‐density lipoprotein (HDL) cholesterol, triglycerides, apolipoprotein B, and asparate aminotransferase measured at baseline and every 4 months. Other laboratory measurements included uric acid, fasting glucose, fasting insulin, creatinine kinase and fibrinogen at entry (before treatment), 6 months, 12 months, 20 months, 28 months, and 6 weeks after stopping the triple‐drug regimen
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details on randomization provided in article. (pg 112) At 12 months, patients were randomly assigned to: (1) continue with regular niacin at a dosage identical to that established in the 12‐month dose‐finding period, or (2) change to polygel controlled‐release niacin at that daily dosage, but given twice rather than 4 times/day. At 20 months, groups (1) and (2) were reversed (cross‐over). This regimen continued for 8 more months
Allocation concealment (selection bias)	Unclear risk	No details on allocation concealment provided in article. (pg 112) At 12 months, patients were randomly assigned to: (1) continue with regular niacin at a dosage identical to that established in the 12‐month dose‐finding period, or (2) change to polygel controlled‐release niacin at that daily dosage, but given twice rather than 4 times/day. At 20 months, groups (1) and (2) were reversed (cross‐over). This regimen continued for 8 more months
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No apparent bias but unclear
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT ‐ No information given in article about who collected the data
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) LIPID LEVELS ‐ BLOOD TEST ‐ Probably unblinded ‐ trial is open‐label; there is insufficient information, but marked low risk because blood test is an objective measure not affected by blinding
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) PILL COUNT ‐ Patient would have been aware of their study group; open‐label trial
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) LIPID LEVELS ‐ BLOOD TEST ‐ Laboratory outcomes are unlikely to be influenced by lack of blinding of participants
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT ‐ No information given in the article about general blinding to study group
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) LIPID LEVELS ‐ BLOOD TEST ‐ Probably unblinded ‐ trial is open‐label; there is insufficient information, but marked low risk because blood test is an objective measure not affected by blinding
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) PILL COUNT ‐ Reason for missing data unlikely to be related to the outcome (2 patients left the study because of time constraints)
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) LIPID LEVELS ‐ BLOOD TEST ‐ Reason for missing data unlikely to be related to the outcome (2 patients left the study because of time constraints)

Brus 1998.

Methods	Patients were allocated at random to experimental (n = 29) or control group (n = 31). The randomization was carried out block‐wise per rheumatologist. No statement concerning concealment of allocation. Outcome assessors were blinded for allocation
Participants	Patients suffering from rheumatoid arthritis (RA), based on ACR criteria, for less than 3 years. Active disease defined by an erythrocyte sedimentation rate (ESR) greater than 28 mm 1st hour, the presence of 6 or more painful joints, and the presence of 3 or more swollen joints. Disease‐modifying anti‐rheumatic drug (DMARD) therapy with sulphasalazine had to be indicated by the attending rheumatologist and agreed for by the patients. Patients who had used any DMARD other than hydroxychloroquine were excluded
Interventions	The experimental group attended 6 patient education meetings. The education program focused on compliance with sulphasalazine therapy, physical exercises, endurance activities (walking, swimming, bicycling), advice on energy conservation, and joint protection. 4 (2‐hour) meetings were offered during the first months. Reinforcement meetings were given after 4 and 8 months. The program was implemented in groups and partners were invited to attend the meetings. 1 instructor (HB) provided information on RA, attendant problems, and basic treatment. The related beliefs of the patients were discussed and, when necessary, corrected. If patients anticipated problems with the applications of any of the treatments, these were discussed, including possible solutions. A training was given in proper execution of physical exercise. Patients were encouraged to plan their treatment regimens. Their intentions were discussed and help was given in recasting unrealistic ones. Patients made contracts with themselves regarding their intentions. Feedback on the eventual implementation of therapeutic advice was included in each meeting. The control group received a brochure on RA, as provided by the Dutch League against Rheumatism. This brochure gives comprehensive information on medication, physical, and occupational therapy. Sulphasalazine in the form of 500 mg enteric coated tablets was prescribed to all patients. The daily dose was increased in 4 weeks by steps of 1 tablet, until a daily dose of 4 tablets was reached. In individual cases, this could be increased to 6 tablets a day, reduced as deemed necessary, or stopped in case of inefficacy or toxicity, at the description of the attending rheumatologist. All patients obtained the sulphasalazine tablets from the pharmacists according to the local Health Care System
Outcomes	Compliance with sulphasalazine therapy was evaluated at 3, 6, and 12 months. Medical records and pharmacy records were the source of data on the number of tablets prescribed and the number of tablets obtained. At each evaluation, the number of remaining tablets were counted. Compliance was defined as the number of tablets that had been taken during the preceding period divided by the number of tablets prescribed. Disease activity was measured by the disease activity score (DAS). This is a function of ESR, Ritchie score (0 to 78), and number of swollen joints (0 to 52). The DAS ranges from 0 to 10, where 0 represents the lowest level of disease activity possible, and 10 the highest. Physical function was measured by a Dutch version of the M‐HAQ. The Dutch‐AIMS questionnaire was used to assess physical function, psychological function, pain, and social activities. Compliance rates with prescriptions for physical exercise and with endurance activity regiments (walking, swimming, bicycling) were measured by questionnaire. Compliance with prescriptions for energy conservation was measured by questioning whether patients spread their activities over the day to prevent fatigue. A test for joint protection performance was used as an indication for the level of compliance with the prescription of joint protection. Patients were asked to perform actions, representing relevant ergonomic principles. The test score ranges from 0 to 10, where 0 represents a poor performance and a 10 good performance
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details provided in the article. (pg 147) Patients were allocated at random to the experimental or control group. The randomization was carried out block‐wise per rheumatologist
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not detailed. (pg 147) "randomised, controlled, assessor blinded, clinical trial. It was intended to follow up all patients for one year. Patients were allocated at random to the experimental or control group. The randomisation was carried out blockwise per rheumatologist."
Selective reporting (reporting bias)	Unclear risk	Reasons for missing data unclear. (pg 148) "Sixty five patients were selected. Thirty two were randomised to the experimental condition. Three patients in the experimental group and two in the control group refused informed consent. Sixty patients entered the study: 29 in the experimental condition and 31 in the control. Ten groups of patients received the education programme. Eleven partners attended the meetings. From each group one patient refused the evaluation at six months. Another three patients refused the final evaluation. The results presented here concern the available data on the remaining 25 experimental and 30 control subjects."
Other bias	High risk	Inappropriate co‐intervention. (pg 148) "Three patients of these 10 received another DMARD together with a low dose prednisone, four another DMARD alone, and three used neither of these. (...) One of these seven patients was using another DMARD in combination with a low dose prednisone, one was using only prednisone, and five were using neither of these." Inclusion/Exclusion criteria were not systematically applied. p.149 "According to the described randomisation procedure the attending rheumatologists selected the patients. Therefore, at inclusion, the data on disease activity as scored by the independent measurement technician, did not always fulfill the selection criteria, but according to the protocol patients were included because they were selected previously."
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) PILL COUNT ‐ (pg 147) "Evaluations were made by the same assessor, a measurement technician. He was blinded for the allocation". Blinding was done for assessor who collected data
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) DISEASE ACTIVITY SCORES ‐ Blinding done for outcome assessor. (pg 147) "Evaluations were made by the same assessor, a measurement technician. He was blinded for the allocation."
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) PILL COUNT ‐ No blinding and could have influenced pill count over long periods of time (3, 6, 12 months)
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) DISEASE ACTIVITY SCORES ‐ No blinding of patient
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT ‐ No information on whether the rest of the study group was blinded
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) DISEASE ACTIVITY SCORES ‐ No information provided
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT ‐ see 1.5. Uneven attrition, with more dropouts in the intervention group, among a small numbers, but insufficient information provided to make a judgment
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) DISEASE ACTIVITY SCORES ‐ Balanced loss to follow‐up but reasons for loss to follow‐up not clear

Bruzzese 2011.

Methods	Randomized controlled trial
Participants	The study location was 5 high schools in New York City, New York, USA 175 participants were randomized to the intervention group and 170 participants were randomized to the control group The inclusion criteria were 9th or 10th graders with diagnosed moderate to severe persistent asthma (defined by NHLBI guidelines) and taking prescribed asthma medication in the past 12 months
Interventions	Intervention: ASTHMA SELF MANAGEMENT FOR ADOLESCENTS (ASMA) Students in the ASMA group receive an 8‐week intensive program. The intervention consists of 3 45‐ to 60‐minute group sessions, and individual tailored coaching sessions held at least once per week for 5 weeks. Sessions were delivered by trained health educators during the school day. In addition to teaching asthma management skills and ways to cope with asthma, the health educators encouraged students to see their medical provider for a clinical evaluation and treatment. The individual sessions reinforced the educational messages taught in the group, helped students identify and overcome barriers to managing their asthma, and coached students regarding their medical visits. The health educator offered to accompany the student to the medical visit to provide moral support, coaching, or advocacy when coaching failed. Medical providers received a presentation by experts in person or by telephone about a recommended change in therapy. The medical providers were first mailed a packet containing: a letter informing them that one of their patients was in the study and would be referred to him/her for a clinical evaluation; a blank asthma checklist the students complete throughout the intervention and bring to the visit with the provider; and a blank asthma action plan the provider is asked to complete. Within 2 weeks, a pediatric pulmonologist or adolescent medicine specialist called the students' medical providers to discuss the concepts presented in the program and to answer any questions regarding NHLBI Institute criteria for treating asthma Control: WAIT LIST CONTROL The control group were kept on wait list until the completion of 12‐month interviews and then received the ASMA intervention
Outcomes	The measures of adherence were use of asthma controller medication at 6 and 12 months measured by trained staff The patient outcomes were self reported quality of life, asthma symptom days in prior 2 weeks, night awakening in prior 2 weeks, days with activity restriction in the prior 2 weeks, school absences in prior 2 weeks and urgent healthcare usage. All the outcomes were self reported except for school absences where data were obtained from the school board. Outcome evaluations were done at 6 and 12 months by blinded interviewers
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	(pg 1000) "On completion of baseline surveys, students were randomized to ASMA or a wait‐list control group. Within each school, we stratified students by asthma severity (moderate vs. severe persistent asthma). Within each stratum, we randomized students to control or intervention using computerized randomization lists generated in advance by the data manager who concealed them until randomization."
Allocation concealment (selection bias)	Unclear risk	Allocation is unclear. (pg 1000) "...we randomized students to control or intervention using computerized randomization lists generated in advance by the data manager who concealed them until randomization. Interviewers were blind to group assignment."
Selective reporting (reporting bias)	Unclear risk	None detected, protocol unavailable
Other bias	Unclear risk	Author's note: possibility of contamination of sample; control students from same schools. (pg 1004) "The study has several limitations. We relied primarily on self reported data and did not corroborate self report data with objective data. Therefore, the potential self report bias found in our school attendance data may also be present in our other outcome data. Similarly, our case detection was by self report and thus has the potential for misclassification bias. Because we targeted those with moderate and severe persistent asthma, the chance of enrolling a student who did not have asthma was low. However, we may have had false‐negatives, missing students in need. Although recruitment of eligible students exceeded that in other asthma trials with urban adolescents (15), just less than 40% of eligible youth were not enrolled; this limits the extrapolation of study results to a larger population of urban, minority high school students with moderate to severe persistent asthma. We are also unable to extrapolate study results to other populations of high school students with asthma (e.g., white suburban adolescents with mild asthma) because we limited enrollment to minority youth with moderate to severe persistent asthma. The control group was a wait‐list control group who received no attention. Although unlikely, it is possible that treatment benefits of ASMA were due to "nonspecific therapeutic factors", including the effects of attention and positive regard received by those in the intervention condition. At the same time, treatment differences may have been mitigated (1) if the consent process and/or surveys fostered attention to treating asthma in the control students; (2) if participants received interim treatments from other sources, which we did not assess; and/or (3) if there was contamination of control subjects by the treated adolescents. However, we had sufficient power to control for contamination, and our informal interviews with control subjects regarding their contact with other students in the program suggest that such contamination did not occur. Although cigarette use is prevalent among adolescents, and smoke is an asthma trigger, we did not assess the impact of smoking behavior nor exposure to second hand smoke."
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) USE OF CONTROLLER MEDICATION ‐ (pg 1000) "Interviewers were blind to group assignment."
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) SYMPTOM DAYS ‐ (pg 1000) "Interviewers were blind to group assignment."
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) QUALITY OF LIFE ‐ (pg 1000) "Interviewers were blind to group assignment."
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) USE OF CONTROLLER MEDICATION ‐ Patients highly likely to know group allocation because of the nature of the intervention
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) SYMPTOM DAYS ‐ Patients likely to be non‐blinded due to the nature of intervention; subjective outcome
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) QUALITY OF LIFE ‐ Patients likely to be non‐blinded due to the nature of intervention; subjective outcome
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) USE OF CONTROLLER MEDICATION ‐ Author's comment: some key personnel were blind. The project director was not. However, the PI and statistician were blind, as were the senior advisors
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) SYMPTOM DAYS ‐ interviewers blinded. Author's note: other study staff were also blind
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) QUALITY OF LIFE ‐ interviewers blinded. Author's note: other study staff were also blind
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) USE OF CONTROLLER MEDICATION ‐ (pg 1001) "Attrition, which was primarily attributable to truancy or no longer being enrolled in the school, did not differ by group assignment at any follow‐up time point (P = 0.26–0.99); 12‐month retention was 81% (Figure 1)."
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) QUALITY OF LIFE ‐ (pg 1001) "Attrition, which was primarily attributable to truancy or no longer being enrolled in the school, did not differ by group assignment at any follow‐up time point (P = 0.26–0.99); 12‐month retention was 81%."
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) SYMPTOM DAYS ‐ (pg 1001) "Attrition, which was primarily attributable to truancy or no longer being enrolled in the school, did not differ by group assignment at any follow‐up time point (P = 0.26–0.99); 12‐month retention was 81%."

Burgess 2007.

Methods	Randomized controlled trial
Participants	The study location was Australia 26 participants were randomized to the intervention group and 21 participants were randomized to the control group The inclusion criteria were children diagnosed with asthma, aged 18 months to 7 years, taking preventive asthma medication on a daily basis
Interventions	Intervention: FUNHALER Patients received a Funhaler for their daily asthma medication. The Funhaler (FH) is a small‐volume spacer that incorporates an incentive toy (spinning disk and whistle) that is driven by the child's expired breath Control: CONTROL SPACER Patients received a standard spacer for administering asthma medication
Outcomes	The measures of adherence were collected using a Smartinhaler. Adherence was evaluated as a percentage of prescribed doses registered by the Smartinhaler either between midnight and midday or between midday and midnight for morning and evening doses, respectively, or at any time during the day for once daily dosing.The child was provided with preventive medication loaded into a Smartinhaler. The parent was informed that the Smartinhaler would "count" the number of doses dispensed but that the data would remain confidential. The subjects were reviewed every 4 weeks for 3 months. During each review the parent was provided with a clean spacer and Smartinhaler containing a new canister of medication The patient outcome was exacerbation of asthma. The subjects were reviewed every 4 weeks for 3 months. During each review the parent completed a symptom questionnaire. An exacerbation of asthma was defined as the child having received a course of prednisolone either initiated by the parent in response to an escalation of symptoms requiring regular reliever medication more than 4th hourly for 24 hours as per their asthma management plan or prescription of prednisolone by the child's primary care physician
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	(pg 737) "All subjects were then randomized to either the FH or a control spacer (Aerochamber Plus; ACP; Trudell Medical International, London, Canada) using a minimization computer program (Minim) with equal weighting for age, sex and level of maternal education."
Allocation concealment (selection bias)	Unclear risk	No information about allocation concealment is given in the paper. "All subjects were then randomized to either the FH or a control spacer (Aerochamber Plus; ACP; Trudell Medical International, London, Canada) using a minimization computer program (Minim) with equal weighting for age, sex and level of maternal education." (pg 737)
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified
Other bias	Low risk	None noted
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) SMARTINHALER ‐ Objective measure, unlikely to be biased
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) ASTHMA EXACERBATION ‐ No mention of blinding of staff
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SMARTINHALER ‐ Unlikely that patients/parents were blind
Blinding of participants (performance bias) Patient outcome	Unclear risk	(PRIMARY) ASTHMA EXACERBATION ‐ self report questionnaire, parents could bias results depending on condition
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) SMARTINHALER ‐ Objective measure, unlikely to be biased
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) ASTHMA EXACERBATION ‐ No mention of blinding of key personnel
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) SMARTINHALER ‐ Few missing data; does not appear likely to be biased
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) ASTHMA EXACERBATION ‐ Limited dropouts, balanced across the groups

Chamorro 2011.

Methods	Randomized controlled trial
Participants	The study location was in 9 community pharmacies of Granada, Spain 44 participants were randomized to the intervention group and 41 participants were randomized to the control group The inclusion criteria were patient presenting to the pharmacy to file a prescription in their name for one or more of antihypertensives, anti‐dyslipidemia, cardiovascular prevention, antidiabetics at moderate or high CV risk The exclusion criteria were BP > 180/110, history of MI within 3 months, on cardiac rehabilitation, terminally ill, low CV risk, refusing consent. They were excluded if their physician prescriber did not see fit to include them in the pharmacotherapy follow‐up
Interventions	Intervention: PHARMACOTHERAPY FOLLOW‐UP The intervention consisted of follow‐up of the patients by the pharmacist. He gave written and oral information about cardiovascular prevention and adherence to the patients in the first interview. The pharmacist adopted a pharmacotherapy follow‐up program, for 4 visits over 16 to 18 weeks. The final assessment was at 32 weeks Control: EDUCATION This procedure consisted of health education, written and oral material all given in 1 session at enrollment
Outcomes	The measure of adherence was the Morisky‐Green‐Levine (MGL) test. A patient was considered adherent when they answered all questions correctly. Adherence was measured at baseline, 16 weeks, and 32 weeks in the control group and the intervention group by a pharmacist. Adherence in each group was calculated in terms of the percentage of patients who were achievers with the therapy The patient outcomes were blood pressure and cholesterol level. Blood pressure was considered to have achieved the therapeutic goal when values were under 140/90 mm Hg, or under 130/80 mm Hg in patients with diabetes, renal failure and acute myocardial infarction. Cholesterol levels were considered to have achieved the therapeutic goal in primary prevention when values were under 200 mg/dl and in secondary prevention under 175 mg/dl. The measures were made for control group at baseline, 16 weeks, and 32 weeks. The intervention group was assessed at the baseline, 2 to 4 weeks, 6 to 8 weeks, 16 to 18 weeks, and 32 weeks.They were made by the same pharmacist
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information provided about the sequence generation process
Allocation concealment (selection bias)	Low risk	Centralized randomization
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	Unclear risk	The information in the article was insufficient to determine if there were other types of bias
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE MGL ‐ Blinding not mentioned; self report
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE ‐ No blinding statement
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE MGL ‐ self report ‐ subjective measure ‐ patient not blinded
Blinding of participants (performance bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE ‐ No blinding statement
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE MGL ‐ Blinding not mentioned; self report
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE ‐ No blinding statement
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE MGL ‐ Missing data not reported
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE ‐ Not reported

Chan 2007.

Methods	Randomized controlled trial
Participants	The study location was the island of Oahu, Hawaii, USA 60 participants were randomized to the intervention group and 60 participants were randomized to the control group The inclusion criteria were children 6 to 17 years of age with persistent asthma, dependents of US military personnel, not moving from Oahu for 12 months, ability to receive cable modem connections in the home, willing to learn to record and to send inhaler technique and peak flow data 2 times per week, willing to attend asthma education follow‐up visits either in person or electronically (virtually) at 2‐week, 6‐week, 3‐month, and 6‐month intervals after initiation into the study, willing to complete satisfaction and education surveys at the end of the study period, and willing to sign informed written consent forms
Interventions	Intervention: INTERNET‐BASED HOME MONITORING AND EDUCATION Both groups had 6 visits scheduled at 0, 2, 6, 12, 26, and 52 weeks, with the study pediatrician and 1 of the 4 assigned nurse case managers or the pediatric clinical pharmacist case manager. The intervention group received 3 in‐person visits, at 0, 26, and 52 weeks, and the rest as virtual visits. Virtual visits included asthma education, a video recording of peak flow meter and inhaler use forwarded to the Web site, daily asthma diaries, and communication with the case manager electronically via the Web site. Patients were provided a home computer system, camera, and Internet access. On‐site in‐home instruction was provided by technical experts on equipment use and Web site capabilities and use. Each patient received the same models of computer and computer equipment, as well as broadband Internet access. Patients and their parents were taught how to use the equipment and how to record and to submit videos by using a computer‐mounted digital video camera, to capture the patient's peak flow meter and inhaler technique. A detailed asthma symptom diary and quality of life survey were included on the website. Patients and families were instructed regarding the submission of daily symptom diary entries. Videos were recorded and loaded on the site for the case manager, who scored them with standardized checklists and provided instruction through e‐mail back to the patient/family. Videos were sent 2 times per week for 6 weeks and then once‐weekly thereafter. Moreover, patients received the following same service as the control group: they were contacted (by e‐mail) by the case manager 2 times per week for 6 weeks and once per week thereafter, to review the asthma action and home management plans, to assess the symptom diary, to remind the patient to perform and to record peak flow measurements daily in the diary, to remind the patient to complete symptom diary information every day, to answer questions, and to intervene if needed. All patients were able to contact the case manager 24 hours per day, 7 days per week Control: OFFICE‐BASED VISITS Patients were treated with an ambulatory asthma clinical pathway, with 6 visits scheduled 0, 2, 6, 12, 26, and 52 weeks after enrollment. At each visit, patients and their parents received in‐depth asthma education from the case manager, with specific subjects being determined by an asthma educational pathway. Office‐based group patients received all of their information in person at the pediatric clinic. Patients were able to contact their case manager by telephone
Outcomes	The measures of adherence were total number of inhalers refilled (assessed by pharmacy refill data fro the entire study duration of 52 weeks), controller inhaler use (assessed by metered dose inhalers) and inhaler videos (to be submitted twice weekly for 6 weeks and once weekly thereafter until 52 weeks). Controller inhaler use was calculated as inhalers per patient ‐ month, inhaler videos were also converted to number per patient‐months The patient outcomes were 1) lung function tests (spirometry performed at intake and study exit at 1 year) 2) peak flow (percentage of personal best), 3) patient and caregiver pediatric asthma quality of life questionnaires (analyzed at intake and study exit at 1 year), 4) utilization of services (emergency department visits, hospitalizations, and unscheduled acute visits because of asthma, from centralized medical chart database and case manager records), 5) rescue therapy use (beta‐receptor agonist use and refills and use of oral prednisone rescue therapy, from computerized pharmacy records), 6) symptom control (diary symptom score)
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Explicitly refers to table of random numbers. (pg 570) "Patients underwent block randomization with a table of random numbers and were enrolled in either the "virtual" group (60 subjects) or the office‐based group (60 subjects)."
Allocation concealment (selection bias)	Unclear risk	No mention of allocation concealment in the article
Selective reporting (reporting bias)	Unclear risk	Insufficient information. Many outcomes are reported, but only broad categories are specified in the methods (pg 570) "to improved outcomes, including therapeutic and diagnostic adherence and disease control (quality of life, lung function, utilization of services, rescue therapy, symptom control, patient education, and patient satisfaction)"
Other bias	Unclear risk	The different number of dropouts between intervention and comparison may lead to bias, but insufficient evidence to judge it. (pg 573) Table 1: 13 dropouts in the virtual group versus 5 in the office‐based group
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) CONTROLLER REFILL ‐ Objective measure
Blinding of outcome assessment (detection bias) Patient outcome	High risk	(PRIMARY) LUNG FUNCTION TEST ‐ staff and personnel were not blinded to allocation group and assessment of lung function could have been biased
Blinding of participants (performance bias) Adherence measure	Low risk	(PRIMARY) CONTROLLER REFILL ‐ Patients are not blinded to the information, but it is unlikely that this may bias pharmacy refill
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) LUNG FUNCTION TEST ‐ Patient not blinded, but unlikely bias of the assessment of lung function
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) CONTROLLER REFILL ‐ Objective measure
Blinding of personnel (performance bias) Patient outcome	High risk	(PRIMARY) LUNG FUNCTION TEST ‐ staff and personnel were not blinded to allocation group and assessment of lung function could have been biased
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) CONTROLLER REFILL ‐ Number of lost data imbalanced across groups; not clear how this would have impacted results
Incomplete outcome data (attrition bias) Patient outcome	High risk	(PRIMARY) LUNG FUNCTION TEST ‐ Differential dropout may be associated with prognosis in lung functions

Chaplin 1998.

Methods	Patients were randomly assigned to 2 groups of 28 patients each. No statement concerning concealment of randomization
Participants	Patients were included if they had an ICD‐10 diagnosis of functional psychosis, were clinically stable, living in the community, and receiving antipsychotic medication for at least 6 months. Patients were excluded if they were prescribed clozapine or were hospital in‐patients. 60 patients were approached. 56 patients agreed to participate
Interventions	The study group participated in a discussion about the risks and benefits of neuroleptic medications based on individual semi‐structured educational sessions with reference to a standardized information sheet modified from Kleinman et al (1989). The patients were asked whether they had heard of tardive dyskinesia (TD). The common movements of TD were modeled and the patients were asked whether they thought they had the condition or had seen others with it. They were informed that they were receiving an antipsychotic drug and were given information about extrapyramidal symptoms and TD, its risk factors, prevalence, treatment, potential irreversibility and the 1% risk of TD in non‐antipsychotic‐treated patients. They were told that gradual discontinuation of antipsychotic medication was the best way to prevent the condition but if done abruptly carries a high risk of relapse and of precipitating TD. It was stated that the optimum maintenance treatment, taking into account its risks and benefits, was to use the lowest dose of antipsychotic drug that would keep them well. Most importantly, they were asked not to make any changes to their treatment without discussion with their psychiatrist. Finally, they were given the opportunity to ask questions in an informal interactive session lasting 30 minutes, and were given an information sheet for reference. The control group received usual care
Outcomes	1. Relapse, defined as a period of hospitalization, evidence of clear clinical deterioration in the case notes or in discussion with the keyworker, or evidence of deterioration at follow‐up interview. 2. Increase in antipsychotic dose of > 200 mg chlorpromazine equivalents. 3. If the patient missed more than 2 weeks of their antipsychotic medication they were considered non‐compliant
Notes	In this study, the intent was not to increase compliance, rather to test whether information about benefits and adverse effects of the treatment would decrease compliance
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random number sequence generation not described. (pg 79) "Those who agreed to be interviewed were randomly assigned to two groups, each of 28 patients."
Allocation concealment (selection bias)	Unclear risk	Allocation not described
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	High risk	Authors note in discussion that control participants might have inquired and received education. Potential Hawthorne effect noted (pg 3). In the community teams and control patients, there was surprisingly little opposition to the study. All consultant psychiatrists gave agreement for a researcher to recruit patients but some team members declined permission. It was essential to brief the teams about the nature of the study and how previous work had shown good clinical outcome, because key workers or psychiatrists were likely to be asked by patients or their relatives to explain about tardive dyskinesia. The modest gain in knowledge by the control patients could have resulted from the community teams' awareness of the study (the Hawthorne effect) or enquiry about tardive dyskinesia after exposure to the questionnaire
Blinding of outcome assessment (detection bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ (pg 80) "The researcher was not blind to the study and control groups."
Blinding of outcome assessment (detection bias) Patient outcome	High risk	(PRIMARY) RELAPSE ‐ (pg 80) "The researcher was not blind to the study and control groups."
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ No blinding; subjective outcome
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) RELAPSE ‐ it is unlikely that this measure could be influenced by patient's knowledge of their group membership
Blinding of personnel (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ (pg 80) "The researcher was not blind to the study and control groups."
Blinding of personnel (performance bias) Patient outcome	High risk	(PRIMARY) RELAPSE ‐ (pg 80) "The researcher was not blind to the study and control groups."
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ Insufficient reporting of details regarding missing data
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) RELAPSE ‐ Insufficient missing data information

Charles 2007.

Methods	Randomized controlled trial
Participants	The study location was Wellington, New Zealand 55 participants were randomized to the intervention group and 55 participants were randomized to the control group The inclusion criteria were age 12 to 65 years with a diagnosis of asthma, required to take regular inhaled corticosteroid (ICS) at a fixed dose, no exacerbation in the previous month or run‐in period, not pregnant or lactating, and if of child‐bearing potential, using contraception The exclusion criteria were a diagnosis of chronic obstructive pulmonary disease, the use of a long‐acting beta‐agonist, or a history of other clinically significant disease
Interventions	Intervention: AUDIOVISUAL REMINDER The intervention was an audiovisual reminder function (AVRF) attached to the inhaler. When the alarm was switched on, it generated a single beep, which sounded once every 30 seconds for 60 minutes after the predesignated time, which was programmed into the device. The alarm stopped if the MDI was actuated or after 60 minutes if not taken. The device was programmed to emit the alarm at predetermined times twice a day. The AVRF also had a colored light, which was green before MDI use, changing to red once the MDI was taken. This function served to remind patients whether they had taken the MDI as scheduled. Follow‐up period was 12 weeks Control: SMARTINHALER Control participants received the same Smartinhaler as intervention participants, but it did not have the audiovisual reminder device
Outcomes	The measures of adherence were a covert electronic monitor inside the asthma inhaler used by participants during the study. Participants were not aware of the monitor, which recorded each time the inhaler was used. Adherence was calculated based on the percentage of prescribed doses that were taken. Participants were prescribed 2 separate doses each day, taken at least 6 hours apart. A correction was applied to dose dumping (when 10 or more doses were actuated within a 3‐hour period). The patient outcomes were Asthma Control Questionnaire (ACQ) scores and Peak Expiratory Flow (PEF). Measures were taken at clinic visits at weeks 0, 6, 12, 18, and 24. At the clinic visits, subjects completed the ACQ and had 3 measurements of PEF with the highest value recorded. Subjects were instructed not to take their short‐acting beta‐agonist for 6 hours before the clinic visits
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	(pg 813) The randomization was by reference to a computer‐generated random code concealed from the researcher, who opened an envelope at the time of randomization. After a 2‐week run‐in period, subjects were randomized to receive 1 of the 2 fluticasone propionate (FP) treatment regimens for a 24‐week period
Allocation concealment (selection bias)	Unclear risk	Does not specify opaque envelopes; description not clear enough to permit judgment of low risk. The randomization was by reference to a computer‐generated random code concealed from the researcher who opened an envelope at the time of randomization. After a 2‐week run‐in period, subjects were randomized to receive 1 of the 2 FP treatment regimens for a 24‐week period
Selective reporting (reporting bias)	Unclear risk	None detected, protocol not available
Other bias	Unclear risk	None noted but insufficient information provided
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) SMARTINHALER ‐ ELECTRONIC MONITORING ‐ Data are objective; no indication staff were involved in altering data
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) PEAK EXPIRATORY FLOW ‐ The article does not provide information on the staff who collected the data, but it is an objective measure
Blinding of participants (performance bias) Adherence measure	Low risk	(PRIMARY) SMARTINHALER ‐ ELECTRONIC MONITORING ‐ Patients were not aware that adherence was being measured or that the study was about adherence
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) PEAK EXPIRATORY FLOW ‐ The patients were not aware of the purpose of the study
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) SMARTINHALER ‐ ELECTRONIC MONITORING ‐ Data are objective; procedures outlined for applying correction factors (i.e. dose dumping)
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) PEAK EXPIRATORY FLOW ‐ Objective measure, unlikely to be biased
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SMARTINHALER ‐ ELECTRONIC MONITORING ‐ Dropouts are relatively balanced across conditions, but there are a significant number of them. Insufficient information to made a judgment
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) PEAK EXPIRATORY FLOW ‐ Not enough information provided to judge

Choudhry 2011.

Methods	Randomized controlled trial
Participants	The study location was Harford, Connecticut, USA 2845 participants were randomized to the intervention group and 3010 participants were randomized to the control group The inclusion criteria were having received both medical and prescription drug benefits through Aetna, discharged from the hospital with a principal or secondary diagnosis code of International Classification of Diseases, 9th Revision, Clinical Modification (ICD‐9‐ CM) 410 (except when the fifth digit was 2) and a length of stay of 3 to 180 days The exclusion criteria were enrollment in a health savings account, 65 years of age or older, plan sponsor has opted out of the study, and receive only medical services or pharmacy coverage but not both through Aetna
Interventions	Intervention: FULL PRESCRIPTION COVERAGE The intervention involved changing the pharmacy benefits of the intervention group patients so that they had no cost sharing for any brand or generic statin, beta‐blocker, ACE inhibitor or ARB for every prescription after randomization Control: USUAL PRESCRIPTION COVERAGE Control patients received usual prescription‐drug coverage
Outcomes	The measures of adherence were medication possession ratios (i.e. the number of days a patient had a supply of each medication class available, divided by the number of days of eligibility for that medication) and proportion of patients with full adherence (defined as a medication possession of = 80%). The data were sourced from the medical coverage provider's database The patient outcomes were "a composite of the first readmission for a major vascular event or coronary revascularization, first major revascular event and health expenditure". All the data were sourced from the insurance company database
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Use of random number generator. (pg 2089) "...randomly assigned to full coverage (full‐coverage group) or usual pharmacy benefits (usual‐coverage group) with the use of a random‐number generator, and all subsequently eligible patients of that plan sponsor were assigned to the same group."
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk' of bias ‐ (pg s33) "When a newly eligible post‐MI patient is identified, an investigator blinded to the identity of the plan sponsor will determine whether that patient's plan sponsor has previously been randomized, and if not, the plan sponsor's block assignment. Plan sponsors will be randomly assigned in a 1:1 ratio to intervention or control using a random number generator. All subsequent patients of that plan sponsor will be assigned to the same group."
Selective reporting (reporting bias)	Low risk	None detected, protocol available
Other bias	Unclear risk	(pg 2096) "Several limitations of our study should be acknowledged. We relied on administrative claims to identify patients and evaluate outcomes. The use of such data for the outcomes that were studied has been validated, and we did not adjudicate study events with medical records. We recruited patients with hospital discharge claims that take time to become available in administrative databases. During the resultant delay, some patients may have become nonadherent to their prescribed therapies. Although this approach increases the generalizability of our findings to other insurers that seek to institute similar plans, it may have diminished the observed effect of the intervention. We evaluated relatively young patients who had been discharged from the hospital after myocardial infarction and who were covered by a large national insurer, and our results may not be generalizable to patients with other conditions or to those who receive health benefits through other means. We do not report the effect of eliminating copayments on the rate of out‐of‐hospital deaths from cardiovascular causes, since such rates will be ascertained by means of data from death certificates recorded in the Centers for Disease Control and Prevention National Death Index (NDI), for which there is a lag between the date of death and its documentation in the NDI. The clinical outcomes we report include only verifiable deaths from cardiovascular causes (i.e., those that occurred during the course of a hospital admission)."
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) MEDICATION ADHERENCE RATE ‐ Data sourced from electronic database of the drug coverage company. Objective outcome
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) COMPOSITE OF FIRST MAJOR VASCULAR EVENT OR CORONARY REVASCULARIZATION ‐ Objective data retrieved from health records
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) MEDICATION ADHERENCE RATE ‐ Participants were not blinded to the study. "Patients in the full‐coverage group were also informed of the change in their pharmacy benefits." (pg 2090)
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) COMPOSITE OF FIRST MAJOR VASCULAR EVENT OR CORONARY REVASCULARIZATION ‐ Objective data retrieved from health records
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) MEDICATION ADHERENCE RATE ‐ Data sourced from electronic database of the drug coverage company. Objective outcome
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) COMPOSITE OF FIRST MAJOR VASCULAR EVENT OR CORONARY REVASCULARIZATION ‐ Objective data retrieved from health records
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) MEDICATION ADHERENCE RATE ‐ Rate of missing data balanced. ITT analysis done
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) COMPOSITE OF FIRST MAJOR VASCULAR EVENT OR CORONARY REVASCULARIZATION ‐ Rate of missing data balanced. ITT analysis performed

Chung 2011.

Methods	Randomized controlled trial
Participants	The study location was Coptic Hope Center for Infectious Diseases in Nairobi, Kenya Patients were randomized as follows: 100 patients to counseling,100 patients to the alarm device, 100 patients to counseling plus the alarm device, and 100 patients to the control group The inclusion criteria were a CD4 count < 250 cells/mm3, World Health Organization (WHO) clinical stage IV disease, or a CD4 count < 350 cells/mm3 with WHO clinical stage III disease. In addition, patients had to be 18 or older, antiretroviral naive, agree to home visits, and plan to live in Kenya for at least 2 years
Interventions	Intervention: COUNSELING In the adherence counseling intervention, trained counselors administered 2 counseling sessions to participants prior to HAART initiation and a third session one month after HAART initiation. Counseling sessions around HAART initiation were based on a model of successful antiretroviral adherence promotion at a large University of Washington‐affiliated HIV treatment program in Seattle, Washington. All counseling sessions followed a written standardized protocol and lasted between 30 and 45 minutes. In the first session, counselors explored personal barriers to good adherence and taught participants about HIV, the virus that causes AIDS, antiretroviral medications, and the risks of treatment failure due to poor adherence. The second session occurred on a separate day and involved a review of a participant's understanding and readiness to begin antiretroviral medications. The third session allowed the counselor to examine practical and personal issues that the participant may have encountered on HAART. The adherence counseling intervention had been previously used and adapted at the same site in Kenya for over 2 years and was delivered in English and Kiswahili Intervention: COUNSELING PLUS ALARM Participants in counseling plus alarm group received both adherence counseling and alarm reminders. 3 adherence counseling sessions (2 prior to HAART initiation and 1 after HAART initiation) were conducted. All counseling sessions followed a written standardized protocol and lasted between 30 and 45 minutes. In the first session, counselors explored personal barriers to good adherence and taught participants about the HIV, the virus that causes AIDS, antiretroviral medications, and the risks of treatment failure due to poor adherence. The second session occurred on a separate day and involved a review of a participant's understanding and readiness to begin antiretroviral medications. The third session allowed the counselor to examine practical and personal issues that the participant may have encountered on HAART. The counseling session was delivered in English and Kiswahili. In addition, participants were given a small pocket digital alarm, which the individual was to carry at all times for 6 months. The device was programmed by the study staff to beep and flash twice a day at a time convenient to the participant when medications were to be taken. The digital alarm could not be reprogrammed or inactivated by the individual and was utilized for 6 months after HAART initiation before being disabled by study staff Intervention: ALARM DEVICE Participants in the alarm device intervention received a small pocket digital alarm which the individual was to carry at all times for 6 months duration. The device was programmed by the study staff to beep and flash twice a day at a time convenient to the participant when medications were to be taken. The digital alarm could not be reprogrammed or inactivated by the individual and was utilized for 6 months after HAART initiation before being disabled by study staff Control: USUAL CARE "At HAART initiation, the study pharmacist explained the side effects of medications and problems associated with poor adherence in a 15‐min session prior to dispensing drugs. All participants, including those in the control arm, received this educational message. Participants randomized to the control group did not receive adherence counseling or an alarm device." (pg 2)
Outcomes	The measures of adherence were pill counts and pharmacy refill visits. After initiating HAART, participants returned to the study clinic monthly with their pill bottles to pick up antiretroviral medications. At each monthly visit, the study pharmacist counted and recorded the number of pills remaining in the bottle, the visit date, whether the participant took his or her morning dose, and the number of pills dispensed that day. Adherence was calculated as the percentage of dispensed doses that were taken since the previous visit to the study pharmacy. Total time between the last date the participant visited the pharmacy and the participant's subsequent pharmacy visit included any missed visits to the pharmacy or time when the participant was not attending the clinic. This calculated adherence was assumed to be constant and the same as daily adherence throughout this time period. Continuous adherence and time to monthly adherence < 80% and < 95% were calculated The patient outcomes were viral failure, mortality, and change in CD4 count. Participants had blood drawn at 6, 12, and 18 months. RNA was measured using the Gen‐Probe quantitative HIV‐1 viral load assay. CD4 counts were determined using flow cytometry. Viral failure was defined as the first plasma HIV‐1 RNA level greater than or equal to 5000 copies/ml measured at least 4 months after HAART initiation
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	(pg 2) "In a 262 factorial design, participants were randomized in a 1:1:1:1 ratio to one of four arms prior to initiating HAART: (1) adherence counseling alone; (2) alarm device alone; (3) both adherence counseling and alarm device together; and (4) a control group that received neither adherence counseling nor alarm device. Randomization was performed at enrollment by the study nurse who opened a sealed envelope containing a computer‐generated block randomization code that was developed by the study biostatistician."
Allocation concealment (selection bias)	Low risk	Randomization was performed at enrollment by the study nurse who opened a sealed envelope containing a computer‐generated block randomization code that was developed by the study biostatistician. Study investigators and participants were not blinded to the interventions
Selective reporting (reporting bias)	Low risk	All relevant results appear to be reported; protocol is available
Other bias	Unclear risk	The authors note several limitations of the study but insufficient information is provided to make a judgment
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) PHARMACY REFILL RECORDS ‐ Not blinded, but refill records are unlikely to be biased
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) CD4 CELL COUNT AND VIRAL LOAD ‐ This an objective outcome
Blinding of participants (performance bias) Adherence measure	Unclear risk	(PRIMARY) PHARMACY REFILL RECORDS ‐ No mention of blinding of study participants. Possible bias that participants might discard medicine instead of taking it
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) CD4 CELL COUNT AND VIRAL LOAD ‐ This an objective outcome
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) PHARMACY REFILL RECORDS ‐ No mention of blinding of study personnel
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) CD4 CELL COUNT AND VIRAL LOAD ‐ This an objective outcome
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) PHARMACY REFILL RECORDS ‐ Missing data appear relatively balanced across groups but insufficient information provided to make a judgment
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) CD4 CELL COUNT AND VIRAL LOAD ‐ Losses to follow‐up relatively balanced across the groups

Colcher 1972.

Methods	Random allocation without an indication of concealment
Participants	All children (aged 1 to 15) presenting to a pediatric outpatient clinic with streptococcal pharyngitis were included except those known to have received previous antimicrobial therapy of any type during the previous month, or those known to be allergic to penicillin
Interventions	The parents of the 'normally informed' group were given instructions that the penicillin was to be taken 3 times per day for 10 days, and any questions that they had were answered. Parents of the 'optimally informed' group received specific counseling stressing the necessity that the penicillin be taken for the full 10 days in order to achieve the best cure/prevent relapse, and further, were given written instructions
Outcomes	There was a single measurement of adherence: Sarcina lutea growth inhibition by urine (a test for the presence of antimicrobial activity). Throat cultures were obtained at 9 days, 3, and 6 weeks post‐treatment. In addition, the incidence of relapse was estimated in the various patient groups
Notes	There was no indication of blinding of the outcome measures
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No mention of method of randomization. (pg 657) "...during this period were randomly assigned to one of three treatment groups."
Allocation concealment (selection bias)	Unclear risk	No mention of allocation concealment
Selective reporting (reporting bias)	Low risk	Clear the studies report all prestated outcomes; although, protocol is not available. (Study is from 1972)
Other bias	Low risk	No obvious other types of bias
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) URINE DRUG CONCENTRATION ‐ Not enough information in the article to assess blinding, but assessment is unlikely to be affected by lack of blinding
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) FAILURE AND RELAPSES ‐ Not enough information in the article to assess blinding, but assessment is unlikely to be affected by lack of blinding
Blinding of participants (performance bias) Adherence measure	Low risk	(PRIMARY) URINE DRUG CONCENTRATION ‐ Not blinded, but assessment is unlikely to be affected by lack of blinding
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) FAILURE AND RELAPSES ‐ No blinding, but assessment is unlikely to be affected by lack of blinding
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) URINE DRUG CONCENTRATION ‐ Not enough information in the article to assess blinding, but assessment is unlikely to be affected by lack of blinding
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) FAILURE AND RELAPSES ‐ Not enough information in the article to assess blinding, but assessment is unlikely to be affected by lack of blinding
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) URINE DRUG CONCENTRATION ‐ Reasons and losses to follow‐up not described
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) FAILURE AND RELAPSES ‐ We do not know to which study arms the dropouts belong

Collier 2005.

Methods	Patients (n = 282) were randomized upon entry to receive either each study site's usual adherence support measures (n = 140) or each study site's usual adherence support measures and scripted serial telephone calls from study site staff members (n = 142). Exact method of allocation concealment was not described
Participants	Patients had < or = to 200 CD4+ T cells/mm3 or >80,000 HIV RNA copies/ml of plasma at screening, no or limited previous antiretroviral therapy (no previous use of lamivudine, nonnucleoside reverse transcriptase inhibitors, or protease inhibitors), hemoglobin > or = to 9.1 g/dl (for men) or > or = to 8.9 g/dl (for women), > or = to 850 neutrophils/mm3, > 65,000 platelets/mm3, hepatic aminotransferase levels < 5 times the upper limit of reference values, and amylase levels < 1.5 times the upper limit of reference values, and could not be pregnant or breast‐feeding
Interventions	The intervention group received serial, supportive telephone calls. Study site staff members (mostly nurses) followed a standardized script for telephone calls and received training by the study team. Spanish and Italian translations of the English script were provided. The telephone calls focused on each subject's medication‐taking behavior, and study site staff members identified barriers to adherence and developed individualized strategies to increase adherence. During the telephone calls, the study site staff members also provided social support and assistance with the management of side effects. The telephone calls were to be made at specific times: 1 to 3 days after the initiation of the study regimen and at weeks 1, 2, 3, 6, 12, and every 8 weeks thereafter, as long as the subject continued to receive the assigned study regimen, for a maximum of 16 telephone calls over the course of 96 weeks. For each telephone call, a minimum of 2 attempts were made to contact the patient before leaving a counseling or general message. Also, a complete telephone call was one where all the topics described above were discussed, however, if that did not occur, calls were categorized as being only partially completed. The usual adherence support measures included an average of 35 minutes of in‐person counseling provided by a study site nurse or pharmacist at the start of treatment. According to a study site survey, 67% of study sites reported providing written materials to study subjects as part of their usual adherence support measures. As well, 41% reported making at least 1 telephone call to selected subjects (deemed at being high risk for low adherence) as part of their usual support measures; however, the telephone calls were made to a minority of patients, the number of calls per patient was limited, and the content was not standardized
Outcomes	Compliance was measured at baseline using a standardized adherence questionnaire and a follow‐up questionnaire evaluating medication‐taking behavior during the preceding 4 days at weeks 8, 16, 24, 48, 72, and 96 The primary health outcome was a measure of antiretroviral drug activity, specifically, the time to virologic failure. Virologic failure was defined as (1) having > than or = to 200 HIV RNA copies/ml of plasma at or after week 24 or (2) having an increase of > 1.0 log10 above nadir levels or an increase to or above baseline levels before week 24 or (3) having 2 consecutive HIV RNA levels > than or = to 200 copies/ml at any time after having 2 consecutive HIV RNA levels < 200 copies/ml
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random number generation was not described. (pg 1399) "Subjects in the substudy were randomized at entry to receive either each study site's usual adherence support measures (usual support measures group) or each study site's usual adherence support measures and scripted serial telephone calls from study site staff members (calls group)."
Allocation concealment (selection bias)	Unclear risk	No mention of allocation concealment ‐ (pg 1399) "Subjects in the substudy were randomized at entry to receive either each study site's usual adherence support measures (usual support measures group) or each study site's usual adherence support measures and scripted serial telephone calls from study site staff members (calls group). Study site staff members (mostly nurses) followed a standardized script for telephone calls and received training by the study team by conference call before the study started."
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	Some limitations were noted by the authors but insufficient information to make a judgment
Blinding of outcome assessment (detection bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Adherence assessors (not explicitly stated) were apparently not blinded. The original trial, of which this is a substudy was open‐labeled. The phone calls were made by nurses; no statement regarding their blinding. (pg 1399) "Study site staff members (mostly nurses) followed a standardized script for telephone calls and received training by the study team by conference call before the study started."
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) VIRAL LOAD ‐ Objective outcome
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ No blinding done in this study, subjective outcome. (pg 1399) "open‐label study"
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) VIRAL LOAD ‐ Objective outcome
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ No blinding done in this study; not clear how study personnel might influence outcome ‐ (pg 1399) "open‐label study"
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) VIRAL LOAD ‐ Objective outcome
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Groups for dropouts not clear. Of the 282 enrollees, 239 (85%) completed ACTG 746, 35 (12%) prematurely discontinued ACTG 388 (and, thus, ACTG 746), 6 (2%) died, and 2 discontinued for other reasons. The categories were similar between the groups but insufficient information to make a judgment
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) VIRAL LOAD ‐ Unclear whether the missing data would have changed the results

Cooper 2010.

Methods	36 patients were randomized to the Cognitive Adaptation Training (PharmCAT), which was focused only on medication and appointment adherence; 37 were randomized to the Cognitive Adaptation Training (Full‐CAT), which focused on many aspects of community adaptation; 32 participants were randomized to the control group. Randomized controlled trial
Participants	The study location was 9 sites across UK (Brighton, Birmingham Heartlands, Kings College London, Birmingham Whittall Street, Newcastle General, Leicester, St. Mary's London, Oxford, Newham) UK 44 participants were randomized to the intervention group and 43 participants were randomized to the control group The inclusion criteria were being HIV positive, age > 18 years, able to give informed consent, being antiretroviral naive, with CD4 lymphocyte count, < 350 cells per cubic millimeter and/or HIV viral load > 20,000 copies per milliliter and/or AIDS‐defining illness, and likely to live more than 2 years with antiviral therapy The exclusion criteria were alkaline phosphatase or hepatic transaminases > 5 times upper limit of normal, neutrophil count of < 0.5 X 10 9/L, medical history of pancreatitis, prior exposure to any antiretroviral agent, pregnancy or female patient trying to become pregnant, patients who do not self medicate, those unwilling or unable to use Medication Event Monitoring Systems (MEMS) monitors, patients who are unable to comprehend the written questionnaires with the help of a clinician or interpreter, and those needing medication other than their proposed antiretrovirals that is either more than 3 additional tablets or capsules per day, that cannot be taken at the same time as their antiretrovirals, or that may have a significant pharmacological interaction with their proposed antiretrovirals
Interventions	Intervention: ONCE NIGHTLY REGIMEN Patients in the once nightly regimen group received 1 x Didanosine (DDI) enteric‐coated (EC) capsule 400 mg (250 mg if weight less than 60 kg), 2 x lamivudine (3TC) 150 mg tablet, 1 x efavirenz (Sustiva) 600 mg tablet each evening Control: TWICE DAILY REGIMEN Patients in the control group received Combivir (zidovudine 300 mg + 3TC 150 mg): 1 tablet twice daily, 1 x efavirenz 600 mg tablet taken nightly
Outcomes	The measures of adherence were persistence with treatment and execution of the dosing regimen and measured using MEMS 6 to collect 3TC drug dosing histories. Persistence was defined as the length of time during which the medication is taken, that is, the time from the first‐taken dose to the last taken dose, measured using MEMS. Execution of the Dosing Regimen measured how closely the patient's dosing history corresponds to the prescribed drug‐dosing regimen by reporting the proportion of prescribed doses taken and was summarized as binary time series where for each consecutive day that the patient was still engaged with treatment, the variable indicated whether or not the patient had taken at least the prescribed number of doses. MEMS data were downloaded at 4, 12, 24, 36, and 48 weeks after each patient initiated treatment The patient outcomes were measured in the clinic before patients initiated treatment (baseline) and each subsequent time point (4, 12, 24, 36, and 48 weeks). Patient outcomes included: 1) Beliefs about HAART measured using the Beliefs about Medicines Questionnaire–HAART specific version, which comprises 2 scales: HAART necessity scale which consists of 8 items assessing individuals' beliefs about their personal need for HAART for controlling their HIV, maintaining their health, and preventing illness, and HAART concerns scale which consists of 11 items which bring together a range of separate concerns about the potential adverse effects of HAART that have been identified across studies. Participants were presented with a series of statements about which they were told "these are statements that other people have made about combination therapy". They were then asked to rate their level of agreement with each item on a scale, where responses ranged from strongly agree (scored 5) to strongly disagree (scored 1). Scores for the individual items within each scale were summed to give a total scale score. A mean scale score was computed by dividing each scale by the number of items, giving a range of 1 to 5 for both necessity and concerns scales. This was done to facilitate comparison of scores between scales and to calculate a necessity–concerns differential (NCD) by subtracting concerns scores from necessity scores. The NCD score can be thought of as a crude indicator of the way the individual rates their perceived need for the treatment relative to their concerns about taking it. 2) HAART Intrusiveness Scale Consists of 10 items addressing the degree to which HAART is perceived to interfere with 10 aspects of daily life, each ranked on a scale from 1 to 5, where 1 indicates low interference and 5 indicates high interference. A total score was computed by adding up responses to each item. For comparison with other scales, an average score was computed by dividing the total score by the number of items. Possible responses ranged from 1 to 5 with higher scores indicating higher perceived intrusiveness. 3) Viral load was assessed at 4, 12, 24, 36, and 48 weeks after each patient initiated treatment using locally available method in each case. Viral load failure was defined as viral load >50 copies per milliliter at 48 weeks
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number table used (pg 370) ‐ The sequential allocation of consecutive patients was predetermined by random number tables
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk'
Selective reporting (reporting bias)	Unclear risk	None detected but protocol unavailable
Other bias	Unclear risk	Insufficient information provided to make a judgment. But noted that the study was not powered to compare the effect on viral load between the 2 dose regimens (pg 375)
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) MEMS ‐ Not likely to be affected by staff and personnel collecting the data
Blinding of outcome assessment (detection bias) Patient outcome	High risk	(PRIMARY) HAART BELIEFS AND INTRUSIVENESS ‐ Open‐label study; subjective measure; no mention of blinding
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) MEMS ‐ Patients likely to be non‐blinded because of the nature of the intervention
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) HAART BELIEFS AND INTRUSIVENESS ‐ Open‐label study; subjective measure; no mention of blinding
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) MEMS ‐ Not likely to be affected key study personnel collecting the data
Blinding of personnel (performance bias) Patient outcome	High risk	(PRIMARY) HAART BELIEFS AND INTRUSIVENESS ‐ Open‐label study; subjective measure; no mention of blinding
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) MEMS ‐ Low dropout rate and excellent follow‐up
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) HAART BELIEFS AND INTRUSIVENESS ‐ Low dropout, high follow‐up

Costa 2008.

Methods	Randomized controlled trial
Participants	The study location was a tertiary outpatient clinic in Brazil 78 participants were randomized to the intervention group and 75 participants were randomized to the control group The inclusion criterion was hospitalization because of first acute myocardial infarction
Interventions	Intervention: TRANSDISCIPLINARY APPROACH The transdisciplinary intervention consisted of clinical follow‐up, smoking cessation assistance, dietary advice and lifestyle modification advice. The intervention was delivered by a team consisting of an endocrinologist, a cardiologist, a nurse, and a dietician. There were 2 follow‐up assessments ‐ at 60 to 90 days after MI and 120 to 180 days after MI. In diabetic patients, capillary glycemia was measured (Advantage reagent strips, Roche, Indianapolis, IN, USA), lower limbs were examined, and adherence to prescribed oral antidiabetic agents and insulin was reviewed. Those patients who were still smoking were advised to stop smoking by the nurse and also by the cardiologist. No oral medication was prescribed in this regard since these drugs are not routinely provided by the Public Health System in Brazil. After the above‐described procedures, the dietitian evaluated body weight and performed a nutritional review. This review was followed by reinforcement of healthy nutritional habits, which included information on the characteristics and amount of healthy meals according to each case and also lifestyle modification reinforcement. The management plan was formulated as an individualized therapeutic alliance among the patient and family, the physician, and other members of the healthcare team. Finally, patients were evaluated by the cardiologist, who completed the visit with the specific medical history, physical examination and specific complementary tests. Drug prescription by the cardiologist followed the AHA guidelines for both groups (statins, antiplatelet therapy, beta‐blockers, and angiotensin‐converting enzyme inhibitors). Diabetic patients were evaluated by an endocrinologist. Drug prescription by the endocrinologist followed the American Diabetes Association (ADA) guidelines for both groups Control: CONVENTIONAL CARE Conventional care group received regular care. Before discharge, they were visited by a dietitian who prescribed a post‐discharge diet plan after nutritional evaluation. Then they were referred to the conventional outpatient clinic for heart care, where the patients were seen only by the appointed cardiologist. Cardiologists kept a routine schedule with the patients and were seen for no more than 15 minutes. Then these participants were asked to be present at the clinic 180 days after AMI to perform a clinical examination and to obtain blood samples
Outcomes	The measures of adherence were a questionnaire administered to the patient/family members twice during the follow‐up period, 60 to 90 days after MI and 120 to 180 days after MI The patient outcomes were clinical improvement, which was evaluated by means of a constructed index comprising lowering of body weight (> 5% from baseline), lowering of blood pressure levels (< 135/85 mm Hg), cessation of smoking (yes or no), increased physical activity and compliance with medication. Reduction in smoking was not counted as cessation. Blood pressure was measured with the patient seated for 5 minutes and using an aneroid or mercury sphygmomanometer, periodically calibrated according to the recommendations of the VII Joint National Committee (JNC). Body weight and height were measured on a manual balance (Filizzola, SP, Brazil), with a maximum capacity for a 150 kg load and 1.90 m height. Compliance with medication was evaluated by asking questions directly to the patient/family members. For each item with a positive change, 1 point value was assigned. A final sum of greater than or equal to 4 points was considered very good. In addition blood samples were collected at the outpatient clinic for the measurement of total plasma cholesterol and triglycerides. All the measurements were performed during the 2 follow‐up visits, first one between days 60 to 90 post MI and the second 120 to 180 days post MI
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	(pg 490) "This randomized clinical trial contained two groups, control and intervention, which were distributed randomly in blocks of 20 by randomization software (Random, PEPI 4.0)."
Allocation concealment (selection bias)	Unclear risk	Insufficient information was provided. "This randomized clinical trial contained two groups, control and intervention, which were distributed randomly in blocks of 20 by randomization software (Random, PEPI 4.0)." (pg 490)
Selective reporting (reporting bias)	High risk	Fasting plasma glucose was measured using the automated enzymatic method. (pg 491) This outcome is not reported anywhere
Other bias	High risk	Self reporting bias. Large amount of data are missing. E.g. for primary outcome 48 and 51 missing from CC and TC groups
Blinding of outcome assessment (detection bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ The patients and health professionals involved in outpatient treatment were not blinded as to their allocation (pg 490)
Blinding of outcome assessment (detection bias) Patient outcome	High risk	(PRIMARY) CLINICAL EXAMINATION ‐ The patients and health professionals involved in outpatient treatment were not blinded as to their allocation (pg 490)
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Participants were aware of the intervention due to its nature
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) CLINICAL EXAMINATION ‐ The patients and health professionals involved in outpatient treatment were not blinded as to their allocation
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ The patients and health professionals involved in outpatient treatment were not blinded as to their allocation (pg 490)
Blinding of personnel (performance bias) Patient outcome	High risk	(PRIMARY) CLINICAL EXAMINATION ‐ The patients and health professionals involved in outpatient treatment were not blinded as to their allocation (pg 490)
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ ITT analysis used, missing data not balanced between groups, reasons unknown. Not sufficient information to make a judgment
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) CLINICAL EXAMINATION ‐ Refer to Table 2: there are 3 dead in CC group and 1 from the TC group. Refer to Table 3. The reasons for missing information are not available

Cote 1997.

Methods	The method of random allocation was not described
Participants	Patients were 16 years of age or older, with moderate to severe asthma and the need to take daily anti‐inflammatory agent. The diagnosis of asthma was confirmed by either a documented reversibility greater than 15% in FEV1 or a PC20 methacholine less than or equal to 8 mg/ml when determined by the method described by Cockcroft and coworkers
Interventions	The intervention is an asthma education program with an action plan based on peak‐flow monitoring (Group P) or an action plan based on asthma symptoms (Group S). The Control group (Group C) received instructions from their pulmonologists regarding medication use and influence of allergenic and non‐allergenic triggers. They were taught how to use their inhaler properly by the educator. A verbal action plan could be given by the physician. Groups P and S received the same education as the controls plus individual counseling with the specialized educator during a 1‐hour session. All participants received a book entitled "Understand and Control Your Asthma" at no extra charge. Group P received a self management plan based on peak expiratory flow (PEF). They were asked to continue measuring PEF twice a day and to keep a diary of the results. Each time, subjects only recorded the best of 3 measurements. Every attempt was made to ensure that patients knew how to interpret the measurement and how to respond to a change in PEF. At each follow‐up visit, the patient's diary card was reviewed, and if the action plan had not been implemented when required, further explanations were given regarding when treatment should be modified. Group S received a self management plan based on asthma symptom monitoring. These patients were asked to keep a daily diary of asthma symptom scores, using a scale of 0 (no symptoms) to 3 (night‐time asthma symptoms, severe daily symptoms preventing usual activities), and adjust their medications according to the severity of respiratory symptoms using the guidelines of the action plan
Outcomes	Adherence was assessed at each follow‐up by weighing the used medication canisters. Patients were unaware of this. Treatment outcome was assessed, in terms of asthma morbidity, by a count of the days missed from work or school, the number of hospitalizations or visits to the emergency room for asthma, and the number of oral corticosteroids courses used since their last visit. These were self reported in a diary and recorded at each of the 1, 3, 6, 9, and 12‐month visits after randomization. Data regarding the number of visits to the emergency room, number of hospitalizations, and absenteeism at work or school during the 12 months prior to enrollment in the study were also collected for all patients by administering a questionnaire and reviewing the medical charts. Knowledge of asthma was also measured pre‐run‐in, at randomization, and at the final visit using a questionnaire
Notes	To reduce financial barriers to treatment adherence, the investigators supplied asthma medication at no charge throughout the trial
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details given. (pg 2) Visit R (randomization). Randomization into one of the 3 groups was done in each center, taking into account the name of the participating physician
Allocation concealment (selection bias)	Unclear risk	No information given. No details given. (pg 2) Visit R (randomization). Randomization into one of the 3 groups was done in each center, taking into account the name of the participating physician
Selective reporting (reporting bias)	Unclear risk	Protocol not found
Other bias	High risk	In the discussion section, the authors note that the fact that the patients were provided with free medication and sustained care may have contributed to the success of the study. All patients also received some sort of asthma education that may have influenced the results. Also, the inhaled corticosteroid therapy was adjusted prior to randomization and this may have had an effect on the success of the intervention. (pg 4) "The results of this study surprised us, as we had expected to find a greater decrease in asthma morbidity among patients who took part in the structured educational program. It can probably be explained by the fact that the control group may have been influenced by facilitating and reinforcing factors such as free medication and sustained care, including several follow‐up visits with the educator, as described in the PRECEDE model contrary to what happened in one of our previous studies. In the present study, however, control patients were instructed on how to use their inhalers properly, and physicians could give information regarding allergenic and nonallergenic triggers if judged important. To differentiate the benefits of optimal asthma treatment from those of asthma education, inhaled corticosteroid therapy was adjusted prior to randomization using peak‐flow monitoring. We agree that all patients received some degree of education during the run‐in period, as optimization of therapy itself requires interaction with the patient to document symptoms and adjust or change medication if necessary, an inherently educational process. Although the control group received more than the usual care treatment, there were marked differences between control and educated patients, as none of the patients from Group C received the book Understand and Control Asthma, none were given a written action plan, and none took part in a structured educational program. Finally, none of these patients had a peak‐flow meter at home after completion of the run‐in period. Apart from physician's recommendations, no reinforcement was given by the specialized educator with regard to compliance in patients in Group C. Enrolled in this study were patients with moderate to severe asthma (daily respiratory symptoms) who required chronic use of inhaled corticosteroids to maintain good control of their illness. We did not select a very high‐risk group of patients: these subjects did not have socioeconomic problems, nor had they had several visits to the emergency room or hospitalizations related to asthma in the year prior to enrollment. Previous studies have already shown that asthma morbidity can be decreased by education in these specific subgroups of patients. The results of our study do not rule out the possibility that education could decrease asthma morbidity under other circumstances. Indeed, this study was conducted in a tertiary care setting by asthma specialists, and had we conducted this study in patients with less optimal care or in high‐risk populations, we might have obtained different results. Furthermore, referring the patient to a specialized asthma educator may help physicians to complete the educational interventions, sometimes difficult to provide in a busy clinic. In order to assess compliance with treatment, we supplied the medication at no charge throughout the study. As inhaled corticosteroids are expensive, some patients, particularly those receiving high dosages, cannot afford this treatment. Had the asthmatic subjects paid for their own medication, it is possible that compliance with treatment would have been lower among control patients than among patients from the two educated groups, and this might have biased the outcome of the control group."
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) WEIGHT OF USED CANISTERS ‐ Blinding information not provided
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) DAYS LOST FROM WORK OR SCHOOL ‐ Insufficient information about blinding provided
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) WEIGHT OF USED CANISTERS ‐ Although it states that canisters were weighed without patients knowing, the patient was still asked to bring in the canister. Any blinding could have been broken due to the nature of the intervention
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) DAYS LOST FROM WORK OR SCHOOL ‐ subjective measure; blinding could have been broken due to the nature of the intervention
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) WEIGHT OF USED CANISTERS ‐ Blinding information not provided
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) DAYS LOST FROM WORK OR SCHOOL ‐ Insufficient information about blinding provided
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) WEIGHT OF USED CANISTERS ‐ Dropouts/missing information accounted for. Missing outcomes not enough to have an impact on the effect size
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) DAYS LOST FROM WORK OR SCHOOL ‐ incomplete data are accounted for

Cote 2001.

Methods	All patients were stratified for treatment center. The first 45 patients among 126 patients were recruited in the control group to avoid contamination. Subsequent eligible patients were randomized in the 2 educated groups. Only the randomized groups are eligible for our review
Participants	126 patients were enrolled in the study, but 105 attended for randomization. Patients (aged > 18 years) with an acute exacerbation of asthma who had not previously taken part in any asthma educational program. Patients older than 40 years of age in whom the best forced expiratory volume in 1 second (FEV1) was lower than 80% of predicted were excluded. All patients with concurrent medical illnesses that in the judgment of the investigators contraindicated study participation were also excluded
Interventions	The patients in Group C (control) received the usual treatment given for an acute asthma exacerbation. In addition to standard treatment as for Group C treatment, patients in Group Limited Education (LE) were given a self action plan that was explained by the on call physician. The action plan used "traffic lights" (green, yellow, red) to describe specific states of asthma control based on Peak Expiratory Flow and symptoms and actions that the patient should take for each state (pages 1415 to 1416). Subjects were all instructed by a respiratory therapist or study nurse in the proper use of an inhaler. In addition to what patients in Group LE received, the patients in Group Structured Education participated in a structured asthma educational program based on the PRECEDE model of health education within 2 weeks after their randomization. Structured educational intervention group Group SE. In addition to what patients in Group LE received, the patients in Group SE participated in a structured asthma educational program based on the PRECEDE model of health education within 2 weeks after their randomization. Briefly, this model takes into consideration 3 different issues that are important when dealing with health‐related behaviors: predisposing factors (belief, attitude, knowledge); enabling factors (community resource, family support); and reinforcement. The teaching was provided individually or in small groups according to patient preference. The intervention focused mainly on self management. To increase patient self confidence in making his or her own treatment decisions, the interaction with the patient was based on the self efficacy theory of Bandura. Reinforcement was provided at the 6‐month follow‐up visit
Outcomes	Compliance with inhaled corticosteroids was evaluated according to the patient's own estimation at 2 weeks and 12 months. Patient outcome measures included number of urgent visits for an acute exacerbation of asthma, lung function tests, knowledge, use of an action plan, compliance with inhaled corticosteroids, quality of life score
Notes	The method of measuring adherence is very insensitive because it only indicates whether the person had a prescription for inhaled corticosteroids, not whether they used it
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No mention of process of randomization. (pg 1415) "All patients were stratified for treatment center. To avoid contamination of the control group, the first 45 patients were recruited in the control group. Subsequent eligible patients were randomized in the two educated groups. At this point in time, physicians unfamiliar with the prescription of self action plans were given information either by the study coordinator or the investigator".
Allocation concealment (selection bias)	Unclear risk	No information provided on allocation concealment. (pg 1) "All patients were stratified for treatment center. To avoid contamination of the control group, the first 45 patients were recruited in the control group. Subsequent eligible patients were randomized in the two educated groups."
Selective reporting (reporting bias)	Unclear risk	Apparently, all declared outcomes were reported but protocol was not available. Hence, marked uncertain
Other bias	Unclear risk	No limitations noted in discussion and no clear biases
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ No information provided
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) URGENCY VISITS ‐ No information provided
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ Subjective outcome
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) URGENCY VISITS ‐ Patients kept track of this information. Any blinding could have been broken
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ No information provided
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) URGENCY VISITS ‐ No information provided
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ Compliance data collected from 48 only. No group‐wise distribution available: thus, unable to predict the effect
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) URGENCY VISITS ‐ No dropout information provided

Coull 2004.

Methods	319 patients were randomized by the researchers after giving informed consent. 165 patients were in the mentoring group and 154 in the control group. Eligible patients were stratified by sex, disease modality (myocardial infarction or angina), and location (5 areas identified)
Participants	Patients aged 60 or over that had been either admitted to hospital, or had attended the outpatient department, with a clinical diagnosis of ischemic heart disease (IHD). Exclusion criteria were terminal illness, an abbreviated mental health test score < 8, inability to complete 3 minutes of Bruce Protocol exercise tolerance testing, awaiting angioplasty or coronary artery bypass grafting, participation in another clinical study involving coronary risk factor modification or at the request of their consultant or general practitioner
Interventions	Intervention consisted of participation in a mentor‐led group, through attending monthly 2‐hour‐long meetings in community facilities over a 1‐year period. There was an average of 10 patients per group, each led by 2 mentors. Both intervention and control groups continued to receive standard care. The core activities covered in the program were lifestyle risk factors of smoking, diet and exercise; blood pressure and cholesterol; understanding of and ability to cope with IHD; and drug concordance. Each mentored group was also encouraged to develop its own agenda. Input was provided from a pharmacist, cardiac rehabilitation specialist nurse, dietician, welfare benefits advisor, and Recreation Services. Volunteer lay health mentors, aged 54 to 74 recruited from the local community, led the groups
Outcomes	Perceived change in taking of medication was measured using a 5‐point Likert scale in the exit questionnaire. Outcome measures were changes in blood pressure, cholesterol and medication, and cardiovascular events; non‐medical support requirement, health status and psychological functioning, and social inclusion
Notes	This is self reported concordance and there was no attempt to standardize the regimens, so this may be explained by differences in medications, insensitive/biased measure of adherence, or low power
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was done appropriately. (pg 350) "Patients were randomised by the researchers after giving informed consent. Eligible patients were stratified by sex, disease modality (myocardial infarction or angina) and location (five areas identified). They were allocated using computer‐generated sealed envelopes supplied by the University of Edinburgh Medical Statistics Unit."
Allocation concealment (selection bias)	Unclear risk	Allocation concealment via sealed envelopes but unclear if opaque or ordered. (pg 350) "...They were allocated using computer‐generated sealed envelopes supplied by the University of Edinburgh Medical Statistics Unit."
Selective reporting (reporting bias)	Unclear risk	No reporting bias detected but protocol not available
Other bias	High risk	Some major limitations were noted in discussion. (pg 353) "We recognise limitations of our study due to potential referral bias introduced by focussing on fitter individuals who could complete exercise testing. The inclusion of food and physical activity diaries was open to recall bias but changes were biologically consistent in a beneficial direction. The widespread community interest in this study and subsequent increased awareness of risk factors for coronary heart disease may have diluted the effect of mentoring. Our study was not sufficiently powered to elicit differences in clinical events and mortality. We also recognise that a small number of our significant results may be explained by multiple testing."
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Outcome assessors were blinded. (pg 349) "Exit evaluation was blinded."
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) HEALTH QUESTIONNAIRES ‐ (pg 349) "Exit assessments were by blinded staff". Health status and food data were collected separately; no mention about blinding
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ No mention of patient blinding and interviews are subjective. Likely high risk due to the nature of the intervention
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) HEALTH QUESTIONNAIRES ‐ Likely high risk due to the nature of the intervention. No mention of blinding of patients and subjective interviews
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ No mention of study personnel blinding
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) HEALTH QUESTIONNAIRES ‐ No mention of blinding of other study personnel
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Balanced dropouts and reasons provided
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) HEALTH QUESTIONNAIRES ‐ Low rate of completion for food diary but likely to be low bias for other outcomes in the questionnaire list

Dejesus 2009.

Methods	Randomized controlled trial
Participants	The study location was 53 sites in the United States and 2 sites in Puerto Rico 203 participants were randomized to the intervention group and 97 participants were randomized to the control group The inclusion criteria were male or nonpregnant female patients 18 years or older with adequate renal function, documented HIV‐1 seropositivity, demonstrated maintenance of virologic suppression for at least 3 months on their current regimen and patients have a life expectancy of greater than or equal to 1 year The exclusion criteria were taking an nonnucleoside reverse transcriptase inhibitor (NNRTI)‐based regimen consisting of EFV plus TDF and FTC, had taken NRTI‐only therapy for > 7 days before their current therapy, individuals with known hypersensitivity to any of the components of EFV/FTC/TDF, have resistance to any of the study agents at any time in the past, a new AIDS defining condition (with the exception of CD4 criteria) diagnosed within 30 days of baseline, taking nephrotoxic medications or agents known to interact with EFV
Interventions	Intervention: SINGLE TABLET REGIMEN (EFV/FTC/TDF) Intervention group patients were prescribed a single‐tablet regimen consisting of efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) Control: ART Control group patients were prescribed to be on regular multi‐drug ART
Outcomes	The measures of adherence were self reported adherence and pill count. Visual analog scale (VAS) was used to measure self reported adherence. Subjects were required to estimate adherence to their antiretroviral therapy regimen by marking a linear scale. Both the measures were taken at baseline and 48 months The patient outcomes were virologic suppression, health‐related quality of life (assessed by SF‐36 questionnaire), and HIV symptom index. The measurements were performed at 4, 12, 24, 36, and 48 weeks
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk' of bias. (pg 164) "Patients on stable ART with HIV‐1 RNA < 200 copies per milliliter for > or = 3 months were stratified by prior nonnucleoside reverse transcriptase inhibitor‐based or protease inhibitor‐based therapy and randomized (2:1) to simplify treatment to EFV/FTC/TDF or to stay on their baseline regimen (SBR)."
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk' of bias. (pg 164) "Patients on stable ART with HIV‐1 RNA < 200 copies per milliliter for > or = 3 months were stratified by prior nonnucleoside reverse transcriptase inhibitor‐based or protease inhibitor‐based therapy and randomized (2:1) to simplify treatment to EFV/FTC/TDF or to stay on their baseline regimen (SBR)."
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified
Other bias	Unclear risk	(pg 173) Authors indicate that there are certain limitations to this study. In general, studies that involve switching therapy tend to attract patients motivated to make a change in treatment, and such studies can have an intrinsic bias toward favoring the switch strategy under evaluation. More than 90% of subjects cited regimen simplification as a reason for participation. This is not surprising given that the median duration of prior ART was 3 years, and individuals showing poor regimen tolerability would be much less likely to be receiving such long‐term therapy. Thus, the motivation to simplify therapy in this stable population could have affected patients reporting of AEs, adherence, and/or medication preference
Blinding of outcome assessment (detection bias) Adherence measure	High risk	(PRIMARY) VISUAL ANALOG SCALE (VAS) ‐ This is an open‐label study and the outcome is subjective. Therefore, lack of blinding is likely to have an impact on the outcome results
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) VIROLOGIC SUPPRESSION ‐ Blood test are objective. The lack of blinding of data collectors in this study is not likely to affect the outcome
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) VISUAL ANALOG SCALE (VAS) ‐ This is an open‐label study and the outcome is subjective. Therefore, lack of blinding is likely to have an impact on the outcome results
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) VIROLOGIC SUPPRESSION ‐ Blood test are objective. The lack of blinding of data collectors in this study is not likely to affect the outcome
Blinding of personnel (performance bias) Adherence measure	High risk	(PRIMARY) VISUAL ANALOG SCALE (VAS) ‐ This is an open‐label study and the outcome is subjective. Therefore, lack of blinding is likely to have an impact on the outcome results
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) VIROLOGIC SUPPRESSION ‐ Blood tests are objective. The lack of blinding of data collectors in this study is not likely to affect the outcome
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) VISUAL ANALOG SCALE (VAS) ‐ Author's note: this is a 2:1 randomization to intervention arm:control arm, so the percentage of attrition is 11% versus 12%; there is no imbalance
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) VIROLOGIC SUPPRESSION ‐ Author's note: this is a 2:1 randomization to intervention arm:control arm, so the percentage of attrition is 11% versus 12%; there is no imbalance

DiIorio 2008.

Methods	Randomized controlled trial
Participants	The study location was a HIV/AIDS clinic in Atlanta, Georgia, USA 125 participants were randomized to the intervention group and 122 participants were randomized to the control group The inclusion criteria were 1) infected with HIV, (2) referred to the nurse educator for adherence education, (3) prescribed for the first time a multi‐drug regimen or had a recent change in their regimen, (4) 18 years of age or older, (5) able to speak English and (6) willing to talk with a Get Busy Living recruiter
Interventions	Intervention: MOTIVATIONAL INTERVIEWING Intervention group receives usual adherence education and motivational interview. Participants received 5 individual MI counseling sessions with a study nurse counselor over a 3‐month period. The goal of these sessions was to help participants gain an understanding of their medication‐taking behaviors and the actions necessary to successfully maintain a high level of adherence. The counselor used a MI script to guide the interaction with the participants. During the session participants were encouraged to identify and discuss barriers to adherence, to express and resolve ambivalence about taking medications, and to support motivation to attain or maintain adherence. After each medication was discussed and an action plan developed, the counselor ended each session by summarizing the discussion and the action plan agreed upon by the participant and counselor. Session 1 was completed in‐person for all participants. Telephone sessions (for sessions 2 though 5) were conducted as needed for participants who were unable to meet the counselor in the clinic. Participants were paid USD 10 for completing the first MI session and USD 5 for each of the remaining 4 sessions. Participants in the intervention group also received a copy of the Get Busy Living video, a journal and a calendar Control: CONTROL Participants randomized to the control group received the usual adherence education provided at the clinic. 3 nurse educators employed at the HIV clinic provide comprehensive adherence education to patients who are initiating or changing ART. They use a variety of teaching methods that are tailored for each individual based on factors such as education level, culture, type of regimen and time schedule. Patients were referred to the Get Busy Living staff when the nurse educators cleared them to begin taking their medications. Participants could continue to meet with the nurse educators for adherence assistance as needed after the initial education sessions
Outcomes	The measure of adherence was a Medication Event Monitoring System (MEMS) as the primary measure of adherence. MEMS consist of a microprocessor that is contained within the cap of the medication bottle. When the cap is opened, the date and time of opening are recorded and stored. These data are downloaded to a computer and used to calculate a variety of adherence measures. For the present study, 2 MEMS adherence rates were calculated. The first was based on the correspondence between the number of doses prescribed per day and the number of cap openings per day. The second was based on the number of cap openings occurring within one hour of the prescribed time for the dose. Each was converted to a percentage, i.e. per cent of doses taken and per cent of doses taken on schedule. Only one medication per person was monitored using MEMS. The staff selected the medication for monitoring using a predetermined list of possible medication combinations. MEMS caps have been used in a number of research studies assessing ART adherence and have been found to be a reliable and valid measure of adherence. The patient outcomes were viral load and CD4 counts, assessed based on medical records, where viral load was measured by the AMPLICOR HIV‐1 MONITOR Test, and CD4 cell count was determined by the BD FACSCalibur system. All tests were conducted by the medical center laboratory, which used appropriate techniques to ensure reliability and validity of the results of the tests
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The study was a randomized controlled trial in which participants were randomized by use of computer‐generated codes to either the usual care or intervention condition(pg 274)
Allocation concealment (selection bias)	Unclear risk	No mention of allocation concealment ‐ (pg 274) "The study was a randomized controlled trial in which participants were randomized by use of computer‐generated codes to either the usual care or intervention condition."
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	Some questions on generalizability; no other serious or apparent bias in trial. (pg 281‐2) "...there are several limitations of this study. First, the sample was composed primarily of low‐income African American men. Thus, the results cannot be generalized to those in other groups who are also prescribed ART. Future research should focus on other groups affected by HIV, including women and gay men and other cultural groups, including Hispanic and Asian men and women. Second, all men and women who were initiating or changing ART were eligible to participate provided they met other study criteria. We did not limit participants to those who were reported difficulties taking their medications. We found that many participants maintained a high level of adherence throughout the study, limiting our ability to fully test the usefulness of MI in promoting behavioral change. Finally, we asked participants to use MEMS † caps throughout the one‐year study. This proved difficult for some individuals. In future studies, researchers might consider limiting the use of these caps to short periods of time around the follow‐up assessment periods. Finally, cost of lab tests limited our ability to fully test the effect of the intervention on viral load and CD4 counts. Although there was some indication that those in the intervention group had more favorable lab values, future research should include systematic assessment of these indices. Finally, the types and doses of medications changed over the course of the study..."
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) MEMS ‐ No mention of blinding but MEMS is unlikely to be affected by outcome assessors
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) VIRAL LOAD ‐ The information about CD4 cell count was collected from medical records. No mention of blinding
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) MEMS ‐ No mention of patient blinding
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) VIRAL LOAD ‐ The data were abstracted from medical records; it is unlikely the patient would influence data
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) MEMS ‐ No mention of blinding of staff. Insufficient information to permit judgment of 'Low risk' or 'High risk
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) VIRAL LOAD ‐ it is unclear from the paper whether key personnel were blinded or not
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) MEMS ‐ Dropouts fairly balanced and reasons for withdrawals noted "A total of 23 participants actively withdrew, were withdrawn from the study at various points or died: 14 in the control and nine in the intervention group. Most of these participants had died (70%). Other reasons for withdrawal included: moved, time constraints and loss of interest. Because the primary measures of adherence were based on data obtained from MEMS cap use, participants with at least one month (4 weeks) of monitored days beyond the date of baseline assessment were included in the main analyses."
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) VIRAL LOAD ‐ Missing outcome data are balanced in numbers across intervention groups, with similar reasons for missing data across groups

Druss 2010.

Methods	Randomized controlled trial
Participants	The study location was an urban Community Mental Health Center (CMHC) 41 participants were randomized to the intervention group and 39 participants were randomized to the control group The inclusion criteria were to be on the active patient roster at the CMHC, have a severe mental illness, have one or more chronic medical condition, and have the capacity to provide informed consent
Interventions	Intervention: HEALTH AND RECOVERY PROGRAM (HARP) Participants in the intervention group attended up to 6 group sessions led by mental health peer specialists. Sessions covered the following topics related to chronic disease self management: 1. Overview of self management 2. Exercise and physical activity 3. Pain and fatigue management 4. Healthy eating on a limited budget 5. Medication management and 6. Finding and working with a regular doctor. During the sessions, peer educators modeled appropriate behaviors and responses, and participation from each group member helped model behavior and improve motivation for other members. Attendees are taught to develop short‐term "action plans" for choosing domains of health behavior change. This process involves identifying a problem that is of particular concern, listing ideas for solving the problem, and then developing a plan outlining specific, short‐term goals for improvement. 2 certified mental health peer specialists participated in a community‐based, 5‐day chronic disease self‐management program (CDSMP) master training course to become master trainers in the CDSMP program. Subsequently, they received 3 additional days of training from the team's principal investigator and health educator in the Health and Recovery Peer (HARP) program Control: USUAL CARE Subjects assigned to usual care continued to receive all medical, mental health, and peer‐based services that they were otherwise receiving prior to entry into the study
Outcomes	The measures of adherence were a validated self report measure of problems in adherence to medication The patient outcomes were patient activation, which reflects an individual's perceived ability to manage his or her illness and health behaviors, and act as an effective patient. This construct was measured using the 13‐item Patient Activation Measure (PAM). Patient activation is calculated on a 0 to 100 score, with 100 as the highest possible degree of activation. Disease self management was assessed using questions about physical activity, health services use. Questions about physical activity and source of a primary care provider were drawn from the Behavioral Risk Factor Surveillance System (BRFSS). Health‐related quality of life (HRQOL) was measured by the SF‐36, constructed for use in the Medical Outcomes Study. A Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were constructed from the survey, scored between 0 (poor health) and 100 (perfect health)
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer randomization program. (pg 266) "Using a computerized algorithm, patients were randomized to the intervention or usual care group by the project manager. After randomization, interviews were administered at baseline and again at 6 months post‐baseline. Interviewers were blinded to subjects' randomization status."
Allocation concealment (selection bias)	Unclear risk	No mention of allocation concealment. (pg 266) "Using a computerized algorithm, patients were randomized to the intervention or usual care group by the project manager. After randomization, interviews were administered at baseline and again at 6 months post‐baseline. Interviewers were blinded to subjects' randomization status."
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	High risk	Several limitations and it is a pilot study. (pg 268) "As a pilot study, the study had several limitations, including reliance on self report outcome measures, a relatively brief follow‐up period, and lack of adequate power to assess statistical significance for many of the study outcomes. Further testing using a broader range of outcome measures, longer follow‐up periods, and larger sample sizes will be needed to establish the HARP program as an evidence‐based practice."
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) SELF REPORTED ADHERENCE ‐ Outcome assessors blinded. (pg 266) "Interviewers were blinded to subjects' randomization status"
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) PATIENT ACTIVATION ‐ Outcome assessors blind. (pg 266) "Interviewers were blinded to subjects' randomization status"
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORTED ADHERENCE ‐ No mention of patient blinding and this is a subjective self report measure
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) PATIENT ACTIVATION ‐ No mention of blinding of patients and subjective questionnaire
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORTED ADHERENCE ‐ No mention of blinding of other study staff
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) PATIENT ACTIVATION ‐ No mention of blinding study staff
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORTED ADHERENCE ‐ More dropouts in control group; unclear if reasons related to intervention
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) PATIENT ACTIVATION ‐ Unequal dropouts and reasons for loss to follow‐up unclear if related to intervention

Duncan 2012.

Methods	Randomized controlled trial
Participants	The study location was not available 40 participants were randomized to the intervention group and 36 participants were randomized to the control group The inclusion criteria were currently taking a recognized ART regimen and reporting a level of side effect‐related bother for the previous 30 days at or above 8 (corresponding to the 40th percentile in another sample) on the side effect and symptom distress scale The exclusion criteria were enrollment in another behavioral coping or HIV adherence intervention research study or MBSR program, severe cognitive impairment, active psychosis, or active substance abuse that would interfere with capacity to participate in MBSR
Interventions	Intervention: MINDFULNESS‐BASED STRESS REDUCTION MBSR aims to teach participants to respond to stressful situations "mindfully" ‐ a state in which one focuses on the present moment, accepting and acknowledging it without getting caught up in thoughts that are about the situation or emotional reactions. This enables people to respond to the situation by making conscious choices to respond instead of reacting automatically. The MBSR program consists of the following elements: (1) individual pre‐program intake interviews performed by the course instructor with each participant, lasting 30 minutes; (2) 8 weekly classes of 2.5 to 3 hours; (3) an all‐day silent retreat during the 6th week of the program; and (4) daily home assignments including a minimum of 45 minutes per day of formal mindfulness practice and 5 to 15 minutes of informal practice, 6 days per week for the entire duration of the course. The total in‐class contact is approximately 30 hours, and the total home assignments are a minimum of 42 to 48 hours. In addition, one to 2 additional individual interview sessions may be provided, at instructor discretion, to individual participants during the course. In addition to teaching mindfulness practices, the course includes didactic presentations that include information on stress physiology and stress reactivity. The course also addresses the effects of perception, appraisal, and attitude on health habits and behavior and on interpersonal communication Control: STANDARD CARE Control group received standard care and went through the same assessment procedure as the intervention group
Outcomes	The measures of adherence were AIDS Clinical Trials Group self report adherence measure to assess pills and doses skipped in the last 3 days for each ART medication and a visual analog scale (VAS) developed by Walsh et al to assess 30‐day adherence. The instruments were administered as audio computer‐administered self interview (ACASI) and computer‐assisted personal interviewing (CAPI) at 3 time points: baseline, 3 and 6 months The patient outcomes were side effects, perceived stress, depression, positive and negative affect, and mindfulness assessed at baseline, 3 and 6 months. Side effects was measured using a AIDS clinical trial group checklist in which respondents were asked whether they had experienced each of 25 possible symptoms in the preceding 30 days, and whether they attributed these to their ART medications, their HIV infection, or to other causes. Symptoms were coded as: 0 = did not experience the symptom versus 1 = experienced the symptom; the individual symptoms were then summed to create overall counts of symptoms and symptoms attributable to ART medications. To measure severity, participants were asked how much each symptom bothered them (on a Likert‐type scale: 0 = not present; 1 = present but does not bother me; ranging to 4 = present and bothers me terribly). Average symptom bother scores were computed as the mean of these individual Likert items to quantify the overall average bother and bother attributable to ART medications. Residual plots of the sum of symptoms attributable to ART medications variable appeared skewed and heteroskedastic in our data, so log transformation was applied to this outcome. The residual plots of log‐transformed symptoms attributable to ART and their average related bother/distress appeared close to normal and homoskedastic. Depression was assessed using the Beck Depression Inventory (BDI). Perceived stress was assessed using the Perceived Stress Scale (PSS). The Positive and Negative Affect Schedule (PANAS), was used to assess the intensity of positive and negative affect during the previous week. Mindfulness was assessed using a 5‐factor mindfulness questionnaire. The instruments were administered as audio computer‐administered self interview (ACASI) and computer‐assisted personal interviewing (CAPI) at 3 time points: baseline, 3, and 6 months
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	(pg 163) "Randomization was performed in blocks of six using the SAS system's PLAN procedure (SAS Institute, Cary, NC). Groups of six participant IDs were sorted in ascending order and aligned with the treatment output from the procedure. When less than six participants were available, dummy participant IDs were used to complete the block."
Allocation concealment (selection bias)	Unclear risk	Insufficient information about allocation concealment
Selective reporting (reporting bias)	Unclear risk	None detected; protocol not available
Other bias	Unclear risk	(pg 8) Authors report: low level of intervention participation with only one third sample completing the 5 or more of the 8 sessions
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) AIDS CLINICAL TRIALS GROUP SELF REPORT ADHERENCE MEASURE ‐ No mention of outcome assessor blinding
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) SIDE EFFECTS ‐ No mention of outcome assessor blinding
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) AIDS CLINICAL TRIALS GROUP SELF REPORT ADHERENCE MEASURE ‐ Patients likely to be aware of interventions
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) SIDE EFFECTS ‐ Insufficient information about the blinding of participants. The outcome is self reported. Thus, the outcome could be biased
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) AIDS CLINICAL TRIALS GROUP SELF REPORT ADHERENCE MEASURE ‐ No mention of study staff blinding
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) SIDE EFFECTS ‐ No mention of study staff blinding
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) AIDS CLINICAL TRIALS GROUP SELF REPORT ADHERENCE MEASURE ‐ The number of missing participants is similar in both groups and for similar reasons. Refer to Figure 1: at 3‐month assessment, 6 participants in the intervention group and 5 participants in the control group were lost to follow‐up because they were unable to contact/schedule. At 6‐month follow‐up, 3 from the intervention and 3 from the control group were lost to follow‐up because unable to contact/schedule, move outs, or health problems(pg 166)
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) SIDE EFFECTS ‐ The number of missing participants is similar in both groups and for similar reasons

Dusing 2009.

Methods	Randomized controlled trial
Participants	The study location was not provided 101 participants were randomized to the intervention group and 105 participants were randomized to the control group The inclusion criteria were patients at least 18 years of age who were either newly diagnosed or not treated for at least 1 year. Except for hypertension, patients had to be healthy and not requiring any regular long‐term drug treatment (e.g. for asthma, chronic obstructive pulmonary disease (COPD), diabetes, rheumatoid arthritis, pain medication, depression, psychotropic drugs, inflammatory bowel disease, estrogen replacement therapy, thyroid hormones, hypercholesterolemia, and oral contraception)
Interventions	Intervention: MULTIFACTORIAL INTERVENTION The set of supportive measures provided for selected centers and all patients recruited in these centers is listed below. It was up to the patients to select the tools they would like to use on an individual basis. For the patient: (a) 24‐hour timer: the timer can be set to an individual time and provides an acoustic signal every 24 hours at this point of time; (b) Set of 10 reminding stickers to be positioned at prominent places at home (e.g. refrigerator and bathroom mirror); (c) Information brochure for patients with hypertension published by the German Hypertension Society; (d) Information letter for the patient; (e) Information letter the patient can give to next of kin to receive support or his therapy (e.g. spouse reminding of drug intake); (f) Home BP measurement device; (g) Booklet to document home BP measurements Control: STANDARD CARE At the baseline visit, all eligible patients were started on study treatment with valsartan 160 mg daily for 4 weeks. Patients with controlled BP were continued on treatment with valsartan 160 mg. Patients not achieving BP values less than 140/90 mm Hg by week 4 were then uptitrated to valsartan 160 mg and hydrochlorothiazide (HCTZ) 12.5 mg as a fixed‐dose combination. Follow‐up visits were scheduled after 2 (3rd visit), 4 (4th visit), 8 (5th visit), 14 (6h visit), 24 weeks (7th visit), and at the end of the observation period at 34 weeks (8h visit). Dispensing of the study drugs was as follows. At baseline, patients received MEMS bottles containing 48 tablets of 160 mg valsartan. At 4th and 5th visits, that is, after 4 and 8 weeks, patients received further MEMS bottles containing 48 tablets of either 160 mg valsartan or 160 mg valsartan and 12.5 mg of HCTZ depending on their BP. At the 6th and 7th visits, that is, after 14 and 24 weeks of treatment, patients received MEMS bottles containing 76 tablets. Patients were instructed to take their medication per mouth with water in the morning between 0700 and 1100 hours, regardless of meals. No supportive measures were given to patients
Outcomes	The measures of adherence were electronic MEMS, which compiled date and time of drug intake through the opening of the medication bottle for every day. The MEMS monitors were drug containers designed to compile the dosing history of ambulatory patients prescribed oral medications. Each monitor consisted of a conventional medicine bottle filled with a special closure that recorded the time and date of each opening and closing of the container through integrated microcircuitry. Monitors were designed to be used by one patient with one drug. A communicator transferred the dose‐timing data from the MEMS monitor to a computer. At the 2nd and 6th visits, MEMS monitors were to be provided for all patients. At the 6th and 8h visits, the monitors used by the patients were collected by the investigator for data analysis The patient outcomes were blood pressure response and normalization in the 2 randomized groups
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No mention of randomization methods. (pg 895) "...cluster‐randomized (by center), open‐label, multicenter parallel‐group study... Centers were assigned to one of the following two treatment arms in a ratio of 1 : 1, centers providing their patients with supportive measures and centers not providing their patients with supportive measures. To avoid any investigator bias in treating one patient with and another patient without supportive measures, investigators rather than patients were randomized to provide only treatment with or without supportive measures for all patients at a single participating center."
Allocation concealment (selection bias)	Unclear risk	No mention of allocation concealment. (pg 895) "...cluster‐randomized (by center), open‐label, multicenter parallel‐group study... Centers were assigned to one of the following two treatment arms in a ratio of 1 : 1, centers providing their patients with supportive measures and centers not providing their patients with supportive measures. To avoid any investigator bias in treating one patient with and another patient without supportive measures, investigators rather than patients were randomized to provide only treatment with or without supportive measures for all patients at a single participating center."
Selective reporting (reporting bias)	Unclear risk	None detected but protocol not available
Other bias	Unclear risk	No clear other biases and no limitations mentioned in article
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) MEMS ‐ Outcome not likely to be affected by outcome assessors
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE AND NORMALIZATION ‐ Method of data collection not detailed in the article and no mention of blinding
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) MEMS ‐ Patients aware of intervention and the measure
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) BLOOD PRESSURE AND NORMALIZATION ‐ Patients not being blinded is unlikely to affect this outcome
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) MEMS ‐ It seems other staff were blind. (pg 896) "The centers providing standard care were blinded with regard to the content of the 'supportive measures'"
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) BLOOD PRESSURE AND NORMALIZATION ‐ Other staff were blinded. (pg 895) "The centers providing standard care were blinded with regard to the content of the 'supportive measures'." Also, open‐label but cluster RCT and objective outcome
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) MEMS ‐ Uneven loss to follow‐up and not all reasons for dropout are clear; adverse events was one reason for dropouts
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE AND NORMALIZATION ‐ Uneven loss to follow‐up and not all reasons for dropout are clear; adverse events was one reason for dropouts

El Miedany 2011.

Methods	Randomized controlled trial
Participants	The study location was not available 55 participants were randomized to the intervention group and 56 participants were randomized to the control group The inclusion criteria were to have early inflammatory arthritis according to the new ACR/EULAR criteria
Interventions	Intervention: VISUAL FEEDBACK The active group consisted of a visual feedback facility (visualization of computer charts showing the disease progression) that was added to their management protocol. Visual feedback is a relatively new tool that enables the patient to visualize as well as monitor a real‐time change of their disease activity parameters as well as the patient's reported outcome measures. Integrating electronic data recording in the standard rheumatology clinical practice facilitated the introduction of visual feedback into the standard rheumatology practice. During their visit, the patients were given the chance to view the progression of their disease on the computer, discuss the changes in their disease activity parameters, comorbidity risks, functional disability, and quality of life. The patients were assessed at 3‐month intervals for another 6 months (unless they sustained a flare up of their condition, at which time they would be reviewed earlier). Before every assessment in the clinic, every patient completed the multidimensional patient reported outcome measures questionnaire Control: ROUTINE MANAGEMENT Control group patients continued their routine standard management and assessment every 3 months. All the patient's disease activity parameters, patient‐reported outcome measures (PROMs), medications, scores of falls, and cardiovascular risks were recorded and discussed verbally with the patient. Each patient was allowed to view his former completed forms and compare between his/her current scores in comparison to the earlier records
Outcomes	The measures of adherence were measured using the Electronic Recording of Outcome Measures for Inflammatory arthritis and Ankylosing spondylitis ‐ EROMIA. Using this system, medication intake could be recorded and downloaded when needed. Adherence to drug therapy was monitored every month for a 6‐month period and then every 3 months for another 6 months. The patient outcomes were disease activity score (DAS‐28) and PROMS domains: pain score, patient global assessment, functional disability, and quality of life
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information given in article. This was a double‐blind, randomized controlled study, which included 111 patients diagnosed to have early inflammatory arthritis according to the new ACR/EULAR criteria
Allocation concealment (selection bias)	Unclear risk	No information given in article. This was a double‐blind, randomized controlled study, which included 111 patients diagnosed to have early inflammatory arthritis according to the new ACR/EULAR criteria
Selective reporting (reporting bias)	High risk	No protocol available
Other bias	Unclear risk	Did not report any limitations in the manuscript, but there is a lot of missing information in the study, such as percentage of participants who were retained in the study, the randomization details etc., so more information is needed
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) EROMIA ‐ This was a double‐blinded study (pg 3061)
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) DISEASE ACTIVITY SCORE (DAS‐28) AND PROMS DOMAINS ‐ Double‐blind, randomized controlled study (pg 3061)
Blinding of participants (performance bias) Adherence measure	Low risk	(PRIMARY) EROMIA ‐ This was a double‐blinded study (pg 3061)
Blinding of participants (performance bias) Patient outcome	Unclear risk	(PRIMARY) DISEASE ACTIVITY SCORE (DAS‐28) AND PROMS DOMAINS ‐ Not enough information in article to judge
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) EROMIA ‐ Insufficient information to permit judgment of 'Low risk' or 'High risk'
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) DISEASE ACTIVITY SCORE (DAS‐28) AND PROMS DOMAINS ‐ Insufficient information to permit judgment of 'Low risk' or 'High risk
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) EROMIA ‐ Refer to Table 1: total number of participants who stopped the medication in active group is 4 and in control group is 17. Reasons for stopping are intolerance and side effects. Based on the data in Table 1, it seems that there is a large imbalance between control and active groups, but it is not clear whether there are more missing data due to other reasons
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) DISEASE ACTIVITY SCORE (DAS‐28) AND PROMS DOMAINS ‐ Refer to Table 1: total number of participants who stopped the medication in the active group is 4 and in the control group is 17. Reasons for stopping are intolerance and side effects. Based on the data in Table 1, it seems that there is a large imbalance between the control and active groups, but it is not clear whether there are more missing data due to other reasons

Ellis 2005.

Methods	Randomization was completed immediately after baseline data collection by the project statistician. To ensure equivalence across treatment condition, randomization was stratified by level of glycosylated hemoglobin levels (HbA1c) at the baseline visit. A total of 127 adolescents and their families were randomized to either receive the multisystemic therapy (MST) (intervention group) (n = 64) or to the control group (n = 63)
Participants	Patients were 1) diagnosed with type 1 diabetes for at least 1 year; 2) had an average HbA1c (A1C) > or = to 8% during the year before study entry, as well as a most recent A1C > or = to 8%; 3) aged 10 to 17 years, and 4) sufficient mastery of English to communicate with therapists and complete study measures. Patients were excluded from the study if they possessed moderate/severe mental retardation or psychosis
Interventions	Adolescents assigned to the intervention condition received multisystemic therapy (MST) plus standard medical care. MST is an intensive, family‐centered, community‐based treatment. Therapists conducted a multisystemic assessment of the strengths and weaknesses of the family, then tailored treatment goals and interventions to each family to best treat the adherence problem. MST interventions targeted adherence‐related problems within the family system, peer network, and the broader community systems within which the family was embedded. The therapists drew upon evidence‐based intervention techniques that included cognitive behavioral therapy, parent training, and behavioral family systems therapy; the various interventions were incorporated at home, school, with peers, and within the healthcare system. Therapists were expected to meet with families a minimum of 2 to 3 times per week at the beginning of treatment. Treatment was terminated when treatment goals were met and the mean length of treatment in the study was 5.7 months. Adolescents in the control condition received standard medical care. Standard care at the hospital where adolescents were cared for consisted of quarterly medical visits with a multidisciplinary medical team composed of an endocrinologist, nurse, dietitian, social worker, and psychologist
Outcomes	Patients completed the 24‐Hour Recall Interview to assess adherence behaviors for the previous day Clinical outcomes included HbA1c values, number of ER visits, and number of hospitalizations
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not enough information about randomization process. (pg 1605) "Randomization to the treatment condition was completed immediately after baseline data collection by the project statistician"
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not described
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No other apparent bias but insufficient information provided
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) 24‐HOUR RECALL INTERVIEW ‐ No blinding measure described. Not clear who collected the data
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) A1C ‐ Outcome less likely to be influenced by lack of blinding. No blinding measures described in the text
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) 24‐HOUR RECALL INTERVIEW ‐ No evidence of blinding, subjective outcome
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) A1C ‐ Outcome less likely to be influenced by lack of blinding. No blinding measures described in the text
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) 24‐HOUR RECALL INTERVIEW ‐ No blinding measure described
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) A1C ‐ Outcome less likely to be influenced by lack of blinding. No blinding measures described in the text
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) 24‐HOUR RECALL INTERVIEW ‐ 6 (9%) of intervention group used insulin pumps ‐ they were not evaluated for insulin adherence; 4 of the same group did not receive intervention. Not known whether this had an effect. Also "Data were collected at 7, 12, 18, and 24 months after baseline data collection. The present study reports on data from 7 months posttest, as data collection at later time points is not yet complete."
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) A1C ‐ 6 (9%) of intervention group used insulin pumps ‐ they were not evaluated for insulin adherence; 4 of the same group did not receive intervention. Not known whether this had an effect. Also "Data were collected at 7, 12, 18, and 24 months after baseline data collection. The present study reports on data from 7 months posttest, as data collection at later time points is not yet complete."

Ellis 2012.

Methods	Randomized controlled trial
Participants	The study location was Children's Hospital of Michigan, Detroit, Michigan, USA 74 participants were randomized to the intervention group and 72 participants were randomized to the control group The inclusion criteria were between 10 and 18 years old with type 1 or 2 diabetes for at least 1 year that required management with insulin, a current HbA1c of 8% or higher, a mean HbA1c of 8% or higher during the year before the study entry, and residing in a home setting The exclusion criteria were moderate or severe mental retardation, psychosis, not English speaking, or unable to complete study measures in English
Interventions	Intervention: MULTISYSTEMIC THERAPY Patients in the MST group received both standard medical care and treatment sessions by 5 masters‐level therapists trained to have sufficient knowledge regarding diabetes to enable them to conduct diabetes adherence interventions with families. Treatment included 1‐hour family treatment sessions, skills practice (e.g. spending 15 minutes in home to observe a caregiver implementing a reward or consequence as part of a behavior plan), attending school meetings to provide information to staff regarding diabetes care (e.g. 1 to 2‐hour staff training), and attending clinic visits with families (2 hours or more) Control: TELEPHONE SUPPORT Control patients (telephone support) received an initial home visit where the program was explained to the adolescent and primary caregiver by either a master level therapists or doctoral students in clinical psychology or social work. Weekly phone calls (approximately 30 minutes each) focused on emotional support for diabetes care using client‐centered, nondirective counseling, assessing adherence to diabetes for the previous week, reviewing readings in the blood glucose meter, and helping the adolescent identify solutions to any barriers in their diabetes care. Non‐diabetes‐related problems such as peer, school, or family relationship problems were also addressed during the call if desired by the adolescent. Telephone support therapists completed the same formal diabetes education training completed by MST therapists
Outcomes	The measures of adherence were parent‐reported adherence and patient‐reported adherence using the Diabetes Management Scale, a questionnaire that measures a broad range of diabetes management behaviors (insulin, diet, blood glucose, symptom response). The questionnaires were administered to parents and patients by a trained research assistant in the participants' homes at baseline and at 7 and 12 months (6‐month follow‐up) The patient outcome was hemoglobin A1c (HbA1c), as measured by a pediatric endocrinologist every 3 to 4 months
Notes	ClinicalTrials protocol found
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	(pg 208) Minimization used: "Randomization... using a permuted block algorithm to ensure equivalence across treatment condition. The project statistician generated the randomization sequence..."
Allocation concealment (selection bias)	Low risk	The project statistician generated the randomization sequence ‐ randomization controlled by independent administration group
Selective reporting (reporting bias)	High risk	They do not report on diabetic ketoacidosis (DKA) admissions and emergency room (ER) visits as noted in NCT00372814
Other bias	Unclear risk	Limitations: Adherence measures: self report and by primary caregiver not always present to verify adherence. Intervention (MST) had more contacts per week than control (telephone): 2 to 3/week compared with 1/week. "In addition, the follow‐up period in the current study was limited to 6 months after the conclusion of treatment. While still significant, reductions in average blood glucose levels were attenuated at 6 months follow‐up. Longer‐term follow‐up is needed to better assess the sustainability of MST effects over time. MST and telephone support were not matched on dose (e.g., two to three contacts per week versus one contact per week). Therefore, the possibility that a higher intervention dose in the MST condition accounted for better health outcomes for youth receiving MST cannot be ruled out."
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) SELF REPORTED QUESTIONNAIRE ‐ (pg 209) "All measures were collected by a trained research assistant in the participants' homes. The research assistant was blind to treatment assignment to the extent possible in a behavioral trial"
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) HBA1C ‐ Blinding not mentioned but this an objective measure
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORTED QUESTIONNAIRE ‐ Participant (primary caregiver/parent) blinding not mentioned and likely to affect outcome
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) HBA1C ‐ Blinding not mentioned but this an objective measure
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) SELF REPORTED QUESTIONNAIRE ‐ The study does not mention blinding of other personnel but unlikely to affect outcome; intervention and control involved different study personnel
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) HBA1C ‐ Blinding not mentioned but this an objective measure
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) SELF REPORTED QUESTIONNAIRE ‐ Low rate of missing data, reasons not related to outcome, ITT analysis used
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) HBA1C ‐ Low rate of missing data, reasons not related to outcome, ITT analysis used

Evans 2010.

Methods	Randomized controlled trial
Participants	The study location was Saskatoon, Saskatchewan, Canada 88 participants were randomized to the intervention group and 88 participants were randomized to the control group The inclusion criteria were patients who exhibited any cardiovascular risk factors (hypertension, dyslipidemia, diabetes mellitus, or a previous cardiovascular event), a calculated Framingham risk score (FRS) of at least 15% or a coronary artery disease risk equivalent (coronary artery disease, peripheral artery disease, cerebrovascular disease, or diabetes mellitus) The exclusion criteria were severe psychiatric conditions or dementia, symptomatic heart failure (New York Heart Association class III or IV), terminal illness, concurrent participation in an investigational study, or were pregnant or breastfeeding
Interventions	Intervention: PHARMACIST FOLLOW‐UP The pharmacist established goals for the patient. Goals were documented in the patient records. When any of the risk factors were uncontrolled, the pharmacist alerted the patient by telephone and mail, and the physician was notified through the patient's medical record and face to face (when possible). Patients received continuous follow‐up by the pharmacist at a minimum of every 8 weeks by telephone, mail, electronic mail, or face to face appointments. Mailed letters were reserved for patients who were successfully controlled or had been recently contacted. Information delivered during follow‐up was patient specific and did not require that a standard content be covered. Reasons for follow‐up included 1) To communicate relevant laboratory results, including proximity to individual targets; 2) To monitor clinical status within 7 to 10 days after the initiation or change of a drug; 3) To monitor clinical status within 7 to 10 days after experiencing an adverse event; 4) To ensure that the patient was able to procure necessary follow‐up appointments; 5) To provide patients with clinical goal reminders, disease‐specific information, or timely topics using periodic mailers. Emphasis was placed on conducting short follow‐up contacts that reminded and reinforced the importance of drug adherence and clinical targets. All patients were followed for a minimum of 6 months Control: SINGLE‐CONTACT GROUP Patients met at the beginning of the study with the study pharmacist, and received a booklet about cardiovascular disease. After that meeting they received usual care and had no more contact with the study pharmacist
Outcomes	The measures of adherence were calculated based on pharmacy refill records using the proportion of days covered; that is, the sum of the days supply for all statin prescription fills during the study period, divided by the number of days between the index date and the end of the study period The patient outcomes were global cardiovascular risk status as measured by the 10‐year FRS, systolic and diastolic blood pressure, hemoglobin A1C, and cholesterol. FRS was measured by the study pharmacist based on medical record review and a patient interview. Laboratory values were taken from the patient's medical charts
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization lists were stratified by each physician and were created by using a table of random numbers in permuted blocks of 4 (pg 768)
Allocation concealment (selection bias)	Low risk	Randomization codes were kept in individually sealed envelopes and opened by the study pharmacist at the end of the initial visit (pg 768)
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon)
Other bias	Low risk	Author's note: we present evidence for bias towards the null
Blinding of outcome assessment (detection bias) Adherence measure	High risk	(PRIMARY) PHARMACY RECORDS ‐ The pharmacist was not blinded and was the lead investigator of the study
Blinding of outcome assessment (detection bias) Patient outcome	High risk	(PRIMARY) FRAMINGHAM RISK SCORE ‐ Collected by staff pharmacist who was not blinded and was also lead investigator for the study
Blinding of participants (performance bias) Adherence measure	Low risk	(PRIMARY) PHARMACY RECORDS ‐ Patients were not blinded but pharmacy refill records unlikely to be affected
Blinding of participants (performance bias) Patient outcome	Unclear risk	(PRIMARY) FRAMINGHAM RISK SCORE ‐ Patients were not blinded; unknown how this may affect this outcome
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) PHARMACY RECORDS ‐ Unclear if other personnel were blind
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) FRAMINGHAM RISK SCORE ‐ Unclear if any other personnel were blind
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) PHARMACY RECORDS ‐ There is not enough information given about the missing data, or if there were additional missing data due to participants not picking up prescription
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) FRAMINGHAM RISK SCORE ‐ Incomplete data evenly spread across conditions; does not seem likely to bias the results

Falces 2008.

Methods	Randomized controlled trial
Participants	The study location was a cardiology clinic, Hospital General de Vic, Osona, Barcelona, Spain 53 participants were randomized to the intervention group and 50 participants were randomized to the control group The inclusion criteria were over 70 years and hospitalized at the General de Vic hospital. The Framingham criteria were employed; 2 major criteria or 1 major and 2 minor criteria had to be present The exclusion criteria were residence outside the hospital area bounds, nursing home residence, waiting on surgery, another center, dementia or psychological instability, or refusal to participate
Interventions	Intervention: EDUCATIONAL INTERVENTION A research team pharmacist carried out the intervention. It consisted of an interview at hospital release followed by telephone reinforcement. The intervention focused on information about the disorder, diet education, and information about the medication. Simple language adapted to the cultural needs of the patient was used. This was backed up by audiovisual and written material. Phone calls took place during the first 6 months and for 2 months following. Patient questions or issues we also discussed. Patients were also given a contact phone number which they could call if they had doubts about their treatment or illness Control: CONTROL GROUP Visits were done at 6 and 12 months. A cardiologist provided treatment as usual and a pharmacist did a pill count
Outcomes	The measures of adherence were pill count ‐ a pharmacist did a pill count at 6 and 12 months. He/she then categorized patients as 1) adherent if the patient had taken 95% to 100% of prescribed dose; 2) partially adherent (85% to 95% of dose taken); 3) not adherent if < 85% of dose taken The patient outcomes were 1) Time to rehospitalization, 2) percentage and 3) total number of patients rehospitalized, 4) total number of days in the hospital during the study period. Also 5) quality of life and 6) mortality during the follow‐up period
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Software‐assisted block randomization was used
Allocation concealment (selection bias)	Low risk	Allocation was handled by an admissions service
Selective reporting (reporting bias)	Unclear risk	None noted but protocol not available
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists
Blinding of outcome assessment (detection bias) Adherence measure	High risk	(PRIMARY) PILL COUNT ‐ Open study
Blinding of outcome assessment (detection bias) Patient outcome	High risk	(PRIMARY) QUALITY OF LIFE (QLS) ‐ Open study; subjective measure
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) PILL COUNT ‐ Open study. Does not mention if the pill count was done unbeknownst to patient
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) QUALITY OF LIFE (QLS) ‐ Open study; subjective measure
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) PILL COUNT ‐ Outcome not likely to be affected by key study personnel
Blinding of personnel (performance bias) Patient outcome	High risk	(PRIMARY) QUALITY OF LIFE (QLS) ‐ Open study; subjective measure
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) PILL COUNT ‐ Loss to follow‐up similar in the 2 groups
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) QUALITY OF LIFE (QLS) ‐ Loss to follow‐up similar in the 2 groups

Farber 2004.

Methods	Randomization was accomplished using a randomized block design in which block size was randomly allocated between 2 and 4 to ensure that the size of the intervention and control groups was equivalent. Randomization was not balanced on any other variables. Random group assignments were generated and were placed in sequentially numbered envelopes. Envelopes were not opened to reveal group assignments until informed consent was obtained and enrolment (baseline) interviews were completed
Participants	56 subjects to be included in the study; subjects were between the ages of 2 to 18 years, had State of Louisiana Medicaid insurance, had a telephone at home, had a history of asthma, had not been intubated or mechanically ventilated for asthma, did not have other clinically significant (i.e. moderate to severe) chronic illness, presented to the ED when an investigator was available, had informed consent provided by a parent or guardian, child voluntarily assents to participation in the study if older than 12 years
Interventions	Subjects in the intervention group received basic asthma education; instructions on use of a metered‐dose inhaler with holding chamber; a written asthma self management plan illustrated by zones colored green, yellow, and red; a sample age‐appropriate holding chamber; and prescriptions for medication needed to implement the plan. This medication included an inhaled corticosteroid drug for everyday use and a quick‐acting bronchodilator for use as needed. The importance of seeking urgent medical care in the red zone was emphasized. 3 brief follow‐up phone calls were placed to patients in the intervention group at 1 to 2 weeks, 4 to 6 weeks, and 3 months after enrolment
Outcomes	Self reported method to measure the compliance plus pharmacy refills. Medicaid claims files used to assess frequency of medication dispensing, dates of asthma‐related hospital admissions, and dates of ED visits (identified by ICD‐9) discharge diagnosis)
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No mention of method of random number creation. (pg 108) "Randomization was accomplished using a randomized block design in which block size was randomly allocated between 2 and 4 to ensure that the size of the intervention and control groups was equivalent. Randomization was not balanced on any other variables. Random group assignments were generated and were placed in sequentially numbered opaque (manila) envelopes by someone not associated with the study. Envelopes were not opened to reveal group assignments until informed consent was obtained and enrollment (baseline) interviews were completed."
Allocation concealment (selection bias)	Low risk	(pg 108) "Randomization was accomplished using a randomized block design in which block size was randomly allocated between 2 and 4 to ensure that the size of the intervention and control groups was equivalent. Randomization was not balanced on any other variables. Random group assignments were generated and were placed in sequentially numbered opaque (manila) envelopes by someone not associated with the study. Envelopes were not opened to reveal group assignments until informed consent was obtained and enrollment (baseline) interviews were completed."
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Low risk	No important risks of bias noted in limitations; no obvious risks of bias in trial
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) MEDICATION DISPENSING EVENTS ‐ No blinding reported for outcome assessment of frequency of medication dispensing
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) FUNCTIONAL SEVERITY OF ASTHMA ‐ (pg 109) "The telephone interviewer was blinded as to study group assignment." Outcome assessor was blinded
Blinding of participants (performance bias) Adherence measure	Unclear risk	(PRIMARY) MEDICATION DISPENSING EVENTS ‐ No blinding reported for outcome assessment of frequency
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) FUNCTIONAL SEVERITY OF ASTHMA ‐ Blinding of patient was not reported and mostly likely not feasible. This may introduce recall bias since the parents in the intervention group will have more knowledge on asthma and may likely to pay more attention to children symptoms as a result. Since the measurement is purely based on the recall of the parents, there is a high risk of bias
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) MEDICATION DISPENSING EVENTS ‐ No mention of blinding for this outcome
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) FUNCTIONAL SEVERITY OF ASTHMA ‐ No report of blinding for other key study personnel. Risk of bias cannot be determined
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) MEDICATION DISPENSING EVENTS ‐ Missing data were balanced in number across groups and missing outcomes were not enough to have a clinically relevant impact on observed effect size
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) FUNCTIONAL SEVERITY OF ASTHMA ‐ Missing data were balanced in number across groups and missing outcomes were not enough to have a clinically relevant impact on observed effect size

Farooq 2011.

Methods	Randomized controlled trial
Participants	The study location was the psychiatry department of Lady Reading Hospital, Peshawar, Pakistan 55 participants were randomized to the intervention group and 55 participants were randomized to the control group The inclusion criteria were (a) aged 17 to 60 years; (b) a diagnosis of schizophrenia or schizoaffective disorder based on the ICD‐10 Research Diagnostic Criteria (RDC); and (c) residence in Peshawar district The exclusion criteria were evidence of organic disorder, ICD‐10 'mental retardation', and severe drug dependence requiring in‐patient treatment and/or detoxification
Interventions	Intervention: Supevised Treatment in Out‐patients for Schizophrenia (STOPS) Participants in the STOPS arm received usual care plus specific education given to a key care supervisor about the illness and the importance of adherence, medications were provided 1 month at a time free of charge Control: TAU Psychiatrists provided treatment as they would normally deliver in routine out‐patient settings. These included prescribing evidence‐based pharmacological treatments, out‐patient attendance in the psychiatry department as deemed appropriate by the consultant and brief counseling about the treatment and outcome. Participants who could not afford to buy medication had the option to seek free drug treatment from the social welfare department of the hospital
Outcomes	The measures of adherence were measurement by interview using a questionnaire with a 5‐point scale (where 1 is always and 5 is never). The assessments for adherence to treatment were done quarterly from baseline with the help of information provided by participants and relatives. All assessments were carried out by doctors with at least 2 years' training in psychiatry. These researchers were masked to participant group assignment and instructed not to enquire about a participant's treatment during interviews The patient outcomes were Global Assessment of Functioning (GAF) ratings and Positive and Negative Syndrome Scale (PANSS) for schizophrenia, taken at 3, 6 months, and 1 year by doctors with psychiatry training and researchers masked to participant group
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Author's note: to us there was low risk of bias as an epidemiologist was contacted for the same and she used random number tables for it. However, this was not explicitly mentioned in the article as is mentioned in 3.1.1
Allocation concealment (selection bias)	Low risk	Opaque, sealed, sequential envelopes. (pg 468) "Individuals who met inclusion criteria were randomly assigned to each treatment group. The random allocations of patients to each group were enclosed in opaque envelopes which were sealed and numbered sequentially. These allocations were placed away from the site of assessment. After assessment and satisfying the inclusion criteria, the staff which were not part of the study were asked to open the sealed envelope and reveal the treatment arm for each patient."
Selective reporting (reporting bias)	Unclear risk	Author's note: tablet counts are not reported in the article although this was stated in the protocol
Other bias	Unclear risk	Mention risk that not paying for control medications might skew results. (pg 471) "It can be argued that the provision of free drugs could have contributed to the better outcome in the STOPS group. The average cost of medication for a month using atypical drugs is about 900 rupees (£1 is equivalent to approximately 136 rupees), which can be quite costly for patients and families from lower socioeconomic backgrounds presenting in a public hospital such as Lady Reading Hospital. The DOTS is a complex intervention and free access to medication is an essential component of the DOTS programme as applied in tuberculosis control. The participants in the TAU group had the option of accessing free drugs from the social welfare department. Providing free medication as part of the trial would have grossly distorted the TAU condition in these settings. The evidence, however, suggests that even if drugs were free, non‐adherence persists. One recent study showed that even among people who have health plans with no cost‐sharing for medication, rates of non‐adherence were nearly 40%."
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ It states outcome assessors were masked. (pg 469) "The follow‐up assessments were done by researchers who were masked to participant group assignment and instructed not to enquire about a participant's treatment during interviews. To ensure this, the administration of STOPS was kept completely separate from the research team assessing adherence and administering questionnaires for the trial and they were not associated with clinical care of the participants in the trial. The participants and relatives were briefed not to discuss their treatment with the assessors."
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) GAF AND PANSS SCORES ‐ it states outcome assessors were blind. pg 469 "The same team of psychiatrists carried out all the follow‐up assessments. The follow‐up assessments were done by researchers who were masked to participant group assignment and instructed not to enquire about a participant's treatment during interviews. To ensure this, the administration of STOPS was kept completely separate from the research team assessing adherence and administering questionnaires for the trial and they were not associated with clinical care of the participants in the trial. The participants and relatives were briefed not to discuss their treatment with the assessors."
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ No mention of patient blinding; questionnaire responses would be influenced by lack of blinding. Since patients were receiving free pills in the STOPS intervention, it is probably easy for the patients to figure out which group they belonged to
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) GAF AND PANSS SCORES ‐ Author's note: patients/participants were blinded
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Insufficient information to permit judgment of 'Low risk' or 'High risk'. No mention of study staff blinding or role in study
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) GAF AND PANSS SCORES ‐ Author's note: although not mentioned explicitly in the write up, there was "low risk of bias" as the blinding was maintained for all the staff used to assess the patients on various scales. Only the co‐ordinator was aware of the participants' respective group
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Nearly equal dropouts across groups, reasons for dropouts seemingly unrelated to intervention
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) GAF AND PANSS SCORES ‐ Nearly equal dropouts across groups; reasons for dropouts seemingly unrelated to intervention

Fisher 2011.

Methods	Randomized controlled trial
Participants	The study location was 5 large HIV care clinics in Connecticut, USA 277 participants were randomized to the intervention group and 287 participants were randomized to the control group The inclusion criteria were 1) 18 years of age or older; 2) have English language comprehension; 3) free of marked cognitive impairment; 4) prescribed ARV therapy at study inception
Interventions	Intervention: LIFEWINDOWS The intervention was computer‐based, interactive ARV adherence promotion called LifeWindows developed based on the Information‐Motivation‐Behavioral skills (IMB) model. The nature of this intervention is to identify and address, through interventions, an individual's deficits in adherence‐related information, motivation, and behavioral skills. The intervention activities consisted of 20 different interactive activities that would be selected by the participants according to their goals. Patients on average spent 26 minutes to complete the full intervention with an average of 8 minutes dedicated to adherence intervention modules. Participants received USD 20 for completion of each session. Participants completed 1 session per month over 18 months Control: STANDARD OF CARE Control patients received standard of care at the clinic they attended. Average total time spent to complete the full control session was 14 minutes. Participants received USD 20 for completion of the session per month over 18 months
Outcomes	The measures of adherence were the AIDS Clinical Trials Group (ACTG) 3‐day recall measure of doses taken, and a visual analog scale (VAS) 3 to 4‐week ARV adherence assessment adapted for computer delivery. These data were collected at each LifeWindows session from both intervention and control groups. Adherence to regimen was calculated as the total number of pills taken over 3 days divided by the total number of pills prescribed for all agents for that period (ACTG) and as the average per cent adherence over 3 to 4 weeks for all agents (VAS) The patient outcome was HIV viral load, measured as per standard of care, and data were extracted from patient charts at the conclusion of the research period
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization at enrollment to control and intervention conditions involved use of randomly generated numbers, which were sequentially assigned." (pg 1637)
Allocation concealment (selection bias)	Unclear risk	No information about the concealment of allocation is given. "Randomization at enrollment to control and intervention conditions involved use of randomly generated numbers, which were sequentially assigned." (pg 1637)
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk'. No protocol available
Other bias	Unclear risk	Insufficient information provided to make a judgment
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ (pg 1643) All outcome data for adherence were collected using a computer. While this limits bias of staff and personnel, they did not mentioned who had access to these data. Author's note: the research assistant at the site did not have access to the data generated by the research participant
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) VIRAL LOAD ‐ Outcome not likely influenced by lack of blinding
Blinding of participants (performance bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Author's note: the participant was blind
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) VIRAL LOAD ‐ Outcome not likely influenced by lack of blinding
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Author's note: only staff at the central office had access to the research data; the research assistant at the study site did not have access
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) VIRAL LOAD ‐ Outcome not likely influenced by lack of blinding
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ (pg 5, Figure 1 and Table 2) Baselined participants (N = 594) completed from one to 18 LifeWindows sessions (Mode = 6 sessions) during their clinical care visits over approximately 18 months, taking part in an overall total of 4155 sessions of which 3924 included assessments of ARV adherence. Of 594 baselined participants, 328 (55%) met the inclusion criteria for the on protocol (OP) sample (see Figure 1). Participant characteristics for the ITT, OP‐included, and OP‐excluded samples are presented in Table 2. Those included in the OP sample are similar in most respects to those excluded with the exception that those included reflected larger numbers of women, unemployed, individuals on disability, and were slightly older. The OP sample also had a higher number of individuals with undetectable viral load at baseline. Note that these elements did not differ by study arm within the OP sample. No differences in baseline values by study arm assignment were noted in the ITT sample; study arm was not related to inclusion or exclusion in the OP sample, and the only differences between study arm in the OP sample were total income (lower income in the intervention arm) and self reported sexual orientation (lower proportion of gay participants in the intervention arm)
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) VIRAL LOAD ‐ While not mentioned, the authors undertook adequate procedures to take missing data into account in analyses

Fortney 2007.

Methods	Randomized controlled trial
Participants	The study location was Veterans Affairs (VA) community‐based outpatient clinics (CBOCs), South Central Veterans Healthcare Network, USA 177 patients (3 practices) were randomized to the intervention group and 218 patients (4 practices) were randomized to the control group The inclusion criteria were patients with depression that PCPs would be comfortable treating. Patients were screened with a Patient Health Questionnaire depression scale (PHQ9) The exclusion criteria were diagnosis of schizophrenia, current suicide ideation, recent bereavement, pregnancy, a court‐appointed guardian, substance dependence, bipolar disorder, cognitive impairment, or receiving specialty mental health treatment
Interventions	Intervention: TELEMEDICINE ENHANCED ANTIDEPRESSANT MANAGEMENT (TEAM) Patients at intervention sites received a stepped‐care model of depression treatment for up to 12 months. Treatment intensity was increased for patients failing to respond to lower levels of care by involving a greater number of intervention personnel with increasing mental health expertise. The intervention involved 5 types of providers: (1) PCPs located at CBOCs; 2) consult telepsychiatrists located at parent Veterans Affairs Medical Centers (VAMCs); (3) an off‐site depression nurse care manager (RN); (4) an off‐site clinical pharmacist (PharmD); and 5) an off‐site supervising psychiatrist. The consult‐telepsychiatrist accepted consultations or referrals from PCPs. The supervising psychiatrist provided clinical supervision to the care manager and clinical pharmacist via weekly face‐to‐face meetings. Patients and providers could choose either watchful waiting or antidepressant treatment (Step 1). Nurse care manager encounters were conducted via telephone and were scripted to enhance standardization and reproducibility. During the initial care management encounter, patients were: (1) administered the PHQ9 symptom monitoring tool; (2) educated and activated using a semi‐structured script4; and 3) assessed for treatment barriers using semi‐structured scripts for endorsed barriers. Follow‐up encounters to monitor symptoms, medication adherence, and side effects were scheduled every 2 weeks during acute treatment and every 4 weeks during watchful waiting or continuation treatment. Non‐adherent patients or those experiencing severe side effects were administered semi‐structured scripts. A trial was considered to have failed in the acute phase if the patient: (1) was non‐adherent to the medication, (2) experienced severe side effects, (3) experienced = 5‐point increase in their PHQ9 score, or (4) did not respond (50% decrease in PHQ9 score) after 8 weeks of antidepressant therapy. All feedback was provided to PCPs using the electronic medical record. Progress notes reporting failed trials requested an electronic co‐signature from the PCP. If the patient did not respond to the initial antidepressant, the pharmacist conducted a medication history and provided pharmacotherapy recommendations to PCPs via an electronic progress note (Step 2). The pharmacist also provided non‐scripted medication management over the phone to patients experiencing severe side effects or problems with non‐adherence. If the patient did not respond to 2 antidepressants trials, the protocol was to recommend a telepsychiatry consultation followed by additional treatment recommendations to the PCP (Step 3) Control: USUAL CARE Control groups received usual care. Usual care patients like the intervention group were provided with provider education and patient education. Also, the screening results were entered into the electronic medical record
Outcomes	The measures of adherence were assessed using an instrument specifically designed for the study. Prior to administering the follow‐up survey, a study psychiatrist examined the patients VA electronic medical records to determine what antidepressants had been prescribed (or refilled) during the previous 6 months. The most recently prescribed/refilled antidepressant medication was recorded prior to the follow‐up interview and the adherence questions referred to the antidepressant explicitly by name. Research assistants asked all patients with an active prescription if they were currently taking the medication. If the patient was currently taking the medication, the interviewers asked how frequently they took the medication in the previous month and if they took the dosage prescribed. Patients were classified as adherent if item responses indicated they took the full dosage > = 80% of the days in the previous month The patient outcomes were treatment response, remission, health status, and quality of life. Treatment response and remission were measured using the Hopkins Symptom Checklist. Response is measured dichotomously as a 50% improvement in depression severity between baseline and follow‐up. Remission is defined dichotomously as SCL‐20 < 0.5. Health status was measured by the change in the physical health and mental health component scores (PCS and MCS) of the Short Form (SF12V) between baseline and follow‐up. Improvement in health‐related quality of life was measured by the change in the Quality of Well Being (QWB) score. Measures were taken at 6 months and 12 months follow‐up.
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The article gives no details on the randomization process. Protocol paper does not provide any additional information. (pg 1087) The 7 eligible CBOCs in the South Central Veterans Healthcare Network were matched by parent VAMC, and one CBOC within each pair was randomized to the intervention
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk' of bias. (pg 1087) "The 7 eligible CBOCs in the South Central Veterans Healthcare Network were matched by parent VAMC, and one CBOC within each pair was randomized to the intervention. Five of the CBOCs had on‐site midlevel mental health specialists (e.g. social workers)."
Selective reporting (reporting bias)	Low risk	All relevant results from the methods paper seem to be reported
Other bias	Unclear risk	None noted but insufficient information provided to judge
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ "Data were collected via blinded telephone interview." (pg 1087)
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRES ‐ "Data were collected via blinded telephone interview." (pg 1087)
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ Patients were not blinded to the intervention. This is a subjective measure
Blinding of participants (performance bias) Patient outcome	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRES ‐ Insufficient information about patient blinding to permit judgment of 'Low risk' or 'High risk'. Patients would have been aware if they received the intervention; might have affected their questionnaire responses
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ "Data were collected via blinded telephone interview." (pg 1087)
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRES ‐ Author note: due to the nature of the intervention, it was not possible to blind primary care providers to randomization status. However, I do not believe that this introduces bias because the care management intervention was specifically designed to support primary care providers treating depression (e.g. alerting them to side effects and non‐adherence)
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ INTERVIEW ‐ Author indicated that this is low risk of bias
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRES ‐ Missing outcome data approximately balanced in numbers across intervention groups, with similar reasons for missing data across groups. Refer to Figure 1 in the article. Plus author note: missing data from completed follow‐up interviews were imputed using multiple imputation

Friedman 1996.

Methods	Random allocation using a paired randomization protocol
Participants	Patients were 60 years or older, under the care of a physician for hypertension, and prescribed an antihypertensive medication. They needed to have systolic blood pressure greater than or equal to 160 mm Hg or a diastolic blood pressure greater than or equal to 90 mm Hg based on an average of 2 determinations taken 5 minutes apart. Individuals were excluded if they had a life‐threatening illness, were not English‐speaking, did not have a telephone or could not use one, or refused to consent to participate
Interventions	Control patients received regular medical care. The intervention group received regular medical care plus the telephone‐linked computer system (TLC). TLC is an interactive computer‐based telecommunications system that converses with patients in their homes, using computer‐controlled speech, between office visits to their physicians. The intervention patients would call the TLC on a weekly basis. Before calling, subjects would record their own blood pressure using an automated sphygmomanometer with a digital readout. During the conversation, subjects would answer a standard series of questions and the TLC would provide education and motivational counseling to improve medication adherence. The TLC then transmitted the reported information to the subject's physician
Outcomes	Antihypertensive medication adherence was assessed by home pill count conducted by the field technicians Clinical outcome measures included change in systolic and diastolic blood pressure. Outcome measures were recorded by the field technicians, at the 2 home visits performed 6 months apart. The measures were also reported on a weekly basis by the participant
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No description regarding random sequence generation. (pg 286) "after which participants were randomly assigned to either the TLC or usual care groups using a paired randomization protocol"
Allocation concealment (selection bias)	Unclear risk	No description of allocation concealment. (pg 286) "... after which participants were randomly assigned to either the TLC or usual care groups using a paired randomization protocol. The field technicians were blinded to the group assignments…"
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	Unclear risk	No major biases noted in the discussion but insufficient information provided to make a judgment
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT ‐ Unclear if data collectors were blinded the entire study. (pg 286) "The field technicians were blinded to the group assignments until after baseline measurements were complete..."
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE ‐ Unclear if data collectors blinded the entire study. (pg 286) "The field technicians were blinded to the group assignments until after baseline measurements were completed"
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) PILL COUNT ‐ Patients not likely to be blind due to the nature of the intervention
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) BLOOD PRESSURE ‐ Lack of blinding of the study participant is unlikely to affect this outcome
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT ‐ No mention of blinding of other study staff
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE ‐ No mention of blinding study personnel
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT ‐ The attrition rate for the TLC group was 15% (n = 23), and for the usual care group it was 8% (n = 11). TLC group lost double patients to attrition than usual care. Not sure if that could have induced a change in the result
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE ‐ The attrition rate for the TLC group was 15% (n = 23), and for the usual care group it was 8% (n = 11). TLC group lost double patients to attrition than usual care. Not sure if that could have induced a change in the result

Gallefoss 1999.

Methods	At inclusion, patients signed a written consent and were then randomized to an intervention group or a control group. Concealment of allocation was unclear. Technical staff assessing bronchodilator spirometry were blinded to control and intervention patients. (Study reported in 2 papers)
Participants	Eligible subjects were patients with bronchial asthma or chronic obstructive pulmonary disease (COPD) between 18 and 70 years of age, not suffering from any serious disease such as unstable coronary heart disease, heart failure, serious hypertension, diabetes mellitus, or kidney or liver failure. Participants with stable asthma were to have a pre‐bronchodilator FEV1 equal to or higher than 80% of predicted value "in stable phase". Furthermore, either a positive reversibility test, a documented 20% spontaneous variability (PEF or FEV1) or a positive methacholine test (provocative dose causing a 20% decrease in FEV1 (PD20) was required. A positive reversibility test required at least a 20% increase (FEV1 or PEF) after inhalation of 400 µg salbutamol. Subjects with COPD were to have a pre‐bronchodilator FEV1 equal to or higher than 40% and lower than 80% of predicted
Interventions	The control group participants were followed by their GPs and the intervention group received an education program and were then also transferred to a 1‐year follow‐up by their GPs The educational intervention consisted of a specially constructed 19‐page patient booklet with essential information about asthma/COPD, medication, compliance, self care, and self management plan. Instructions in the recoding of PEF and symptoms in a diary were given to both asthmatics and patients with COPD. There were also two 2‐hour group sessions (separate groups for asthmatics and patients with COPD) of 5 to 8 people on 2 separate days. The COPD group received more information about tobacco weaning, but besides this the educational interventions were comparable The first session was given by a medical doctor, concentrating on pathophysiology, symptom awareness, prevention of attacks and factors causing exacerbations, especially smoking. The second group session was given by a pharmacist, focusing on drugs and their appropriate use. One or two 40‐minute individual sessions were then supplied by a nurse, and another one or two 40‐minute individual sessions, by a physiotherapist. With regard to anti‐obstructive medication the following was emphasized: the components of obstruction were explained together with the site of action of the actual medication. The patient's pulmonary symptoms were registered and discussed with emphasis on the early symptoms experienced at exacerbations. The individual factors causing attacks/exacerbations and concerns regarding adverse effects of medication were discussed and inhalation technique was checked. At the final teaching the patients received an individual treatment plan on the basis of the acquired personal information and 2 weeks of peak flow monitoring. The personal understanding of the treatment plan with regard to changes in PEF and symptoms was discussed and tested
Outcomes	One paper reported compliance of regular medication, calculated as a % age: (dispensed Defined Daily Dosage/Prescribed Defined Daily Dosage) x 100 during the 1‐year follow‐up. Patients were defined as compliant when dispensed regular medication was greater than 75% of prescribed regular medication during the study period. Pre‐bronchodilator spirometry was performed before randomization and at 12‐month follow‐up by standard methods The other paper reported that 4 simple health‐related quality of life (HRQoL) questions were asked at baseline. HRQoL as measured by the St George's Respiratory Questionnaire (SGRQ) at 12 months plus the same 4 questions asked at baseline. FEV measured via spirometry prior to randomization and at 12 months
Notes	Patients who failed to attend all group sessions or who failed to meet at individual sessions were withdrawn. There was no similar "faintness of heart" procedure for the control group. Thus, 38 of 39 control asthma patients were included in the compliance assessment but only 30 of 39 intervention group patients
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information given in article. "We performed a randomized, controlled intervention study in patients with mild to moderate asthma or COPD using a standardized education program and a self management plan."
Allocation concealment (selection bias)	Unclear risk	No information given in article. "We performed a randomized, controlled intervention study in patients with mild to moderate asthma or COPD using a standardized education program and a self management plan."
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No other biases noted or obvious but insufficient information provided to make a judgment
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) PHARMACY FILL RECORD ‐ No mention of blinding of personnel. (pg 2001) "Dispensed medication was reported from all local pharmacies through monthly print‐outs from the pharmacy data registers. At the 1‐yr follow‐up all patients were asked whether they had received medication elsewhere."
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) SPIROMETRY ‐ (pg 2002) "The technical staff did not know whether the patients belonged to the control or intervention groups."
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) PHARMACY FILL RECORD ‐ Patients would have known if they received the educational intervention
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) SPIROMETRY ‐ Unlikely that lack of patient blinding would affect this outcome
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) PHARMACY FILL RECORD ‐ No mention of blinding of personnel collecting data. (pg 2001) "Dispensed medication was reported from all local pharmacies through monthly print‐outs from the pharmacy data registers. At the 1‐yr follow‐up all patients were asked whether they had received medication elsewhere."
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) SPIROMETRY ‐ No mention of study personnel blinding
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) PHARMACY FILL RECORD ‐ Reasons for missing data are noted but unclear whether unequal missing data effects outcome
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) SPIROMETRY ‐ Not enough information provided

Gamble 2011.

Methods	Randomized controlled trial
Participants	The study location was Northern Ireland Regional Difficult Asthma Service, Northern Ireland 9 participants were randomized to the intervention group and 11 participants were randomized to the control group The inclusion criteria were 18 years of age, attending the Difficult Asthma Service, a Juniper Asthma Control Score =317 and remained non‐adherent despite participating in Phase 1 The exclusion criteria were current tobacco smoking or significant other co‐morbidity, which contributed to persisting respiratory symptoms
Interventions	Intervention: INTERVENTION The intervention was individualized, provided psycho‐education and led by experienced registered nurse with basic level psycho therapy training for 12 months to improve adherence to medication. In addition to standard asthma care, intervention group subjects were offered up to 8 months of individual visits within a 12‐week period. Although the proposed intervention was unique in its design, to increase the internal validity of the study, the Compliance Therapy Model was used to provide the underpinning theoretical framework. This model encompassed the Transtheoretical Model of Change, Motivational Interviewing and Cognitive Behavioral Therapy principles, providing a flexible short‐term intervention using patient's individual reasons for non‐adherence as a guide to plan intervention content. The model used a non‐confrontational technique which elicited self motivation and provided a process to resolve ambivalence towards medication taking Control: STANDARD ASTHMA CARE All participants received standard asthma care at the difficult asthma service but the control group did not receive any further intervention. Subsequent follow‐up visits for the control group was conducted at 6 months and 12 months post‐recruitment
Outcomes	The measures of adherence were GP refill records. All prescribed medication was obtained via prescription from a single General Practitioner (GP) and prescription refills for inhaled combination therapy (ICT) were obtained for the previous 6 months and expressed as a percentage of prescribed medication. Non‐adherence was defined as prescription filling of >= 50%. Data were collected at 6 and 12 months The patient outcomes were daily prescribed dose of inhaled corticosteroid (ICS), courses of rescue oral corticosteroids, total inhaled and nebulised beta‐agonist doses, hospital admissions, and lung function (spirometry), as well as Asthma Control Questionnaire (ACQ), Asthma Quality of Life Score (AQLQ) and Hospital Anxiety and Depression Scale/State Trait Anxiety Scale (HADS). Outcomes for follow‐up visits were obtained from the patient or medical notes, and lung function, questionnaires were obtained during the patient visit
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not enough information to judge. (pg 1309) Patients were randomly allocated to either the intervention or control group
Allocation concealment (selection bias)	Low risk	Author's note: patients were randomly allocated using pre‐sealed, sequentially numbered, opaque envelopes
Selective reporting (reporting bias)	Low risk	No protocol available
Other bias	Low risk	None noted
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) PRESCRIPTION REFILL RECORDS ‐ Appear to be low risk of bias. (pg 1309) Adherence was measured as previously described and validated, using prescription refill records. In Northern Ireland, all prescribed medication is obtained via prescription from a single General Practitioner (GP) and prescription refills for inhaled combination therapy (ICT) were obtained for the previous 6 months and expressed as a percentage of prescribed medication
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) SPIROMETRY ‐ Objective measure of outcome
Blinding of participants (performance bias) Adherence measure	Unclear risk	(PRIMARY) PRESCRIPTION REFILL RECORDS ‐ Appear to be low risk of bias
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) SPIROMETRY ‐ Objective measure of outcome
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) PRESCRIPTION REFILL RECORDS ‐ Appear to be low risk of bias
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) SPIROMETRY ‐ Objective measure of outcome
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) PRESCRIPTION REFILL RECORDS ‐ Only 2 withdrawals
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) SPIROMETRY ‐ Only 2 withdrawals

Gani 2001.

Methods	101 patients were randomized into 3 groups: A (n = 30) with drug therapy alone, B (n = 35) with drug therapy plus training on the use of nasal spray, and C (n = 36) the same as B plus a lesson on rhinitis and asthma. All patients received mometasone furoate nasal spray for 8 weeks as regular therapy, plus rescue medications on demand. Symptoms and drug consumption were evaluated during the pollen season
Participants	101 patients (62 male, 39 female, age range 12 to 60 years) had suffered for at least 2 years from seasonal asthma and rhinitis (SAR) solely due to pollens (grasses, birch, Parietaria, and Compositae). Patients with sensitization to multiple pollens were included, whereas sensitization to cat dander, mites, or mold was a reason for exclusion. Exclusion criteria were as follows: anatomical abnormalities of the upper respiratory airways (septal deviation, polyposis), previous or ongoing immunotherapy, pregnancy/lactation, chronic treatment with systemic corticosteroids, malignancies, and major psychiatric disorders
Interventions	The first group of patients (group A = 30 patients) was given only the drug with the instructions provided by the manufacturer. The second group (group B = 35 patients) received a brief training on how to use the nasal spray and were given simplified written instructions on the use of the device. The third group (group C = 36 patients) also attended a 1‐hour informal lesson on the clinical and pathogenic aspects of SAR, the treatment strategy, the correct use of medications, and the possible side effects of drugs. A trained allergist (1 per clinic) gave the lesson to patients, and the set of slides used was the same in the 3 clinics
Outcomes	All patients completed a symptom diary, recording the presence and severity of their symptoms (self reported). The compliance with therapy was evaluated on the basis of the returned diaries and canisters. Symptoms were subdivided as follows: nasal (itching, sneezing, rhinorrhea, and blockage), ocular (itching, redness, lacrimation, and swelling), and respiratory (cough, wheezing, and chest tightness). The severity of symptoms was graded on a 10 cm visual analog scale (0: no symptoms, 10: severe symptoms). Patients were also required to record carefully each dose of each drug taken, in addition to the nasal corticosteroid
Notes	8‐week follow‐up during the whole pollen season is satisfactory for the seasonal disease
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated ‐ no details given. The study was designed to use 3 randomized, open‐controlled parallel groups. "One hundred and one patients suffering from SAR were randomly allocated into three groups receiving a written prescription of drug therapy alone, or training on how to use the nasal spray, or a detailed lesson on the nature of their disease." The presence and severity of symptoms were assessed during the whole pollen season, as was the intake of drugs(pg 66)
Allocation concealment (selection bias)	Unclear risk	(pg 66) Allocation concealment technique not mentioned "One hundred and one patients suffering from SAR were randomly allocated into 3 groups receiving a written prescription of drug therapy alone, or training on how to use the nasal spray, or a detailed lesson on the nature of their disease."
Selective reporting (reporting bias)	Unclear risk	No information given, no protocol available
Other bias	Unclear risk	Nothing noted but insufficient data provided to make a judgment
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ DIARY ‐ intervention does not mention blinding. (pg 66) "The first group of patients (group A = 30 patients) was given only the drug with the instructions provided by the manufacturer. The second group (group B = 35 patients) received a brief training on how to use the nasal spray and were given simplified written instructions on the use of the device. The third group (group C = 36 patients) also attended a 1‐h informal lesson on the clinical and pathogenic aspects of SAR, the treatment strategy, the correct use of medications, and the possible side‐effects of drugs. A trained allergist (one per clinic) gave the lesson to patients, and the set of slides used was the same in the three clinics".
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) SELF REPORTED SYMPTOMS ‐ Blinding not mentioned. (pg 66) "The first group of patients (group A = 30 patients) was given only the drug with the instructions provided by the manufacturer. The second group (group B = 35 patients) received a brief training on how to use the nasal spray and were given simplified written instructions on the use of the device. The third group (group C = 36 patients) also attended a 1‐h informal lesson on the clinical and pathogenic aspects of SAR, the treatment strategy, the correct use of medications, and the possible side‐effects of drugs. A trained allergist (one per clinic) gave the lesson to patients, and the set of slides used was the same in the three clinics."
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ DIARY ‐ Subjective measure and patients likely were not blind
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) SELF REPORTED SYMPTOMS ‐ Subjective measure; patients likely were not blind
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ DIARY ‐ Intervention does not mention blinding. (pg 66) "The first group of patients (group A = 30 patients) was given only the drug with the instructions provided by the manufacturer. The second group (group B = 35 patients) received a brief training on how to use the nasal spray and were given simplified written instructions on the use of the device. The third group (group C = 36 patients) also attended a 1‐h informal lesson on the clinical and pathogenic aspects of SAR, the treatment strategy, the correct use of medications, and the possible side‐effects of drugs. A trained allergist (one per clinic) gave the lesson to patients, and the set of slides used was the same in the three clinics."
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) SELF REPORTED SYMPTOMS ‐ Blinding not mentioned. (pg 66) "The first group of patients (group A = 30 patients) was given only the drug with the instructions provided by the manufacturer. The second group (group B = 35 patients) received a brief training on how to use the nasal spray and were given simplified written instructions on the use of the device. The third group (group C = 36 patients) also attended a 1‐h informal lesson on the clinical and pathogenic aspects of SAR, the treatment strategy, the correct use of medications, and the possible side‐effects of drugs. A trained allergist (one per clinic) gave the lesson to patients, and the set of slides used was the same in the three clinics."
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ DIARY ‐ Unclear if amount of missing data would alter event rates. 6 patients dropped out because they did not attend the final visit(pg 66)
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) SELF REPORTED SYMPTOMS ‐ Unclear if missing data will impact the event rates

Gensichen 2009.

Methods	Randomized controlled trial
Participants	The study location was 74 small primary care practices in Hesse, Germany 35 practices, 310 participants were randomized to the intervention group and 39 practices, 316 participants were randomized to the control group The inclusion criteria were diagnosis of major depression with indication for any antidepressive treatment, age 18 to 80 years, access to a private telephone, ability to give informed consent, and ability to communicate in German The exclusion criteria were confirmed pregnancy, severe alcohol or illicit drug consumption, or acute suicidal ideation assessed by the family physician
Interventions	Intervention: CASE MANAGEMENT The intervention was in accordance with Chronic Care Model, which emphasizes proactive support for the patient by the entire practice team. One healthcare assistant from each practice assigned to the intervention group in 2 workshops (an 11‐hour and a 6‐hour workshop). This interactive training included information on depression, communication skills, telephone monitoring, and behavioral activation for the patient. The healthcare assistants contacted their patients by telephone twice a week in the first month and then once a month for the following 11 months. They monitored depression symptoms and adherence to medication by using the Depression Monitoring Context List. Healthcare assistants also encouraged patients to follow self management activities, such as medication adherence and activation for pleasant or social activities. The assistants provided this information to the family physician in a structured report that stratified the urgency of the contact by a robot scheme. Family physicians in both the intervention and control groups received training on evidence‐based depression treatment guidelines Control: USUAL CARE Patients in the control group were given usual care
Outcomes	The measures of adherence were a modified Morisky patient self report scale, in which patients are scored from 0 to 3 on the basis of their answers to the following 3 questions (coded higher values indicate higher adherence): Did you ever forget to take your medicine during the last 2 weeks? During the last 2 weeks, did you sometimes stop taking your medicine when you felt better? During the last 2 weeks, did you stop taking your medicine when you felt worse? This questionnaire was given to patients at 6 and 12 months The patient outcome was depression symptoms as the primary outcome, which was assessed by using the primary care–validated PHQ‐9. Each item is scored from 0 (not at all) to 3 (nearly every day), for a total score that ranges from 0 to 27 (high scores indicate more severe depression). Response (50% improvement in PHQ‐9 score) and remission status (PHQ‐9 score=5) were secondary outcomes. Data for the following secondary outcomes were also recorded: quality of life, patient assessment of chronic illness care, and medication adherence. Health‐related quality of life was measured by using the Medical Outcomes Study Short Form 36 (SF‐36) and the EuroQol‐5D. The SF‐36 allows the calculation of scores for physical health and mental health (range, 0 to 100; higher scores indicate better status). The EuroQol‐5D is a generic instrument that measures health‐related quality of life with a visual analog scale (range, 0 to 100; higher ratings indicate higher quality of life). The number of physical comorbid conditions was determined by counting the documented diagnoses from different diagnostic groups listed in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, and International Classification of Diseases, 10th Edition, excluding all psychiatric diagnoses in the patient record. Severity of chronic physical diseases was assessed by using the Chronic Disease Score, on the basis of prescription data from the patient record. All outcomes were assessed at 6 and 12 months
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer randomized. (pg 370) "The data safety and monitoring board stratified the practices according to the size of the city and performed computer‐based randomization. Patient random assignment status was nested within the practice status. The data safety and monitoring board was responsible for allocation concealment by keeping the randomization results in a secure database."
Allocation concealment (selection bias)	Low risk	Allocation concealment done. (pg 370) "The data safety and monitoring board stratified the practices according to the size of the city and performed computer‐based randomization. Patient random assignment status was nested within the practice status. The data safety and monitoring board was responsible for allocation concealment by keeping the randomization results in a secure database."
Selective reporting (reporting bias)	Unclear risk	Did not report some prespecified outcomes from the protocol of Beck Depression Inventory and days out of work
Other bias	Unclear risk	Some risk of bias noted by the author ‐ (pg 369) "Patients, health care assistants, family physicians, and researchers were not blinded to group assignment, and 12‐month follow‐up of patients was incomplete". However, overall risk of bias is unclear
Blinding of outcome assessment (detection bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Outcome assessors were not blind. (pg 370) "Because of the practice staff training required for the behavioral intervention, patients, health care assistants, family physicians, and researchers were not blinded to assignment once the trial was started."
Blinding of outcome assessment (detection bias) Patient outcome	High risk	(PRIMARY) DEPRESSION SYMPTOMS AND QUALITY OF LIFE QUESTIONNAIRES ‐ Outcome assessors were not blinded. (pg 370) "Because of the practice staff training required for the behavioral intervention, patients, health care assistants, family physicians, and researchers were not blinded to assignment once the trial was started."
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Patients were not blind. (pg 370) "Because of the practice staff training required for the behavioral intervention, patients, health care assistants, family physicians, and researchers were not blinded to assignment once the trial was started."
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) DEPRESSION SYMPTOMS AND QUALITY OF LIFE QUESTIONNAIRES ‐ Patients were not blinded. (pg 370) "Because of the practice staff training required for the behavioral intervention, patients, health care assistants, family physicians, and researchers were not blinded to assignment once the trial was started."
Blinding of personnel (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Study staff were not blind. (pg 370) "Because of the practice staff training required for the behavioral intervention, patients, health care assistants, family physicians, and researchers were not blinded to assignment once the trial was started."
Blinding of personnel (performance bias) Patient outcome	High risk	(PRIMARY) DEPRESSION SYMPTOMS AND QUALITY OF LIFE QUESTIONNAIRES ‐ Study staff were not blinded. (pg 370) "Because of the practice staff training required for the behavioral intervention, patients, health care assistants, family physicians, and researchers were not blinded to assignment once the trial was started."
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Reasons for dropouts not noted, dropouts were not balanced across ‐ but not clear how this would have affected the results
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) DEPRESSION SYMPTOMS AND QUALITY OF LIFE QUESTIONNAIRES ‐ Reasons for dropouts not noted; dropouts were not balanced across groups, but unclear how this would have affected the results

Ginde 2003.

Methods	Randomized controlled trial: consenting patients were randomized to the ED (intervention) or pharmacy (control) group
Participants	The study was conducted from November 2001 to May 2002. During the 6‐month study period, all adult patients (> 18 years old) presenting to the ED for whom an outpatient prescription for a macrolide antibiotic was being considered in discharge planning were eligible for the study. The need for outpatient treatment with an antibiotic was determined by the attending Emergency Physician who was primarily responsible for the patient. Patients who were unwilling or unable to give informed consent or were unavailable for telephone follow‐up were excluded from the study. In addition, all females of childbearing potential were given urine pregnancy tests, and pregnant or breast‐feeding females were excluded. 77 patients were recruited
Interventions	Patients in the ED group were provided a full course of azithromycin (6 x 250 mg) at no charge and given instructions on the proper dose and frequency before discharge from the ED. Patients in the pharmacy group received a written prescription for a full course of azithromycin before discharge from the ED. To minimize the potential for economic bias, the patients were able to fill their prescriptions free of charge at a 24‐hour pharmacy located 8 blocks from the hospital
Outcomes	The primary outcome was compliance of obtaining medication as determined by pharmacy records. A secondary outcome was compliance in completing the course of medication as determined by a telephone survey Measurement of clinical health outcomes: return visits to the ED and hospitalization
Notes	The prescription filling rate for the control group is based on the assumption that control patients used a participating pharmacy 8 blocks away that provided the drug free of charge and patients were apparently not asked if they filled their prescription elsewhere. The prescription filling rates could have been clarified for the control group. The "course completed" rate is based on self report on a telephone call and there was no indication that interviewers were blinded to group or if the exact question given. Technically, this study qualified for the review, but the reliability and credibility of these measures is suspect. This intervention may be impractical in any setting where giving drugs out for free is not possible
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Author's note: patients were randomized by random sequence generation through pharmacy who opened the envelope to determine if the subject was in the intervention or control group
Allocation concealment (selection bias)	Unclear risk	No mention of allocation concealment. (pg 313) "Patients who were enrolled in the study were randomized into the ED (intervention) or pharmacy (control) group."
Selective reporting (reporting bias)	Low risk	Author's note: We reported all outcomes that we measured: compliance by self report, compliance by pharmacy records, return ED visits, or hospitalization within 2 weeks
Other bias	Unclear risk	Limitations in discussion note other risks of bias. (pg 315) "The most important limitation of this study is the poor reliability of patient self reported compliance. This makes it difficult to draw conclusions on patient compliance beyond filling the prescription. Another limitation was the choice of a study medication, which is often prescribed for relatively benign, self limiting conditions, because spontaneous improvement in the patient's condition could further decrease compliance. The benign nature of disease in this population could have also limited the ability to find differences in patient morbidity and use of hospital resources as a result of noncompliance. Finally, small sample size and our urban setting limit the ability to generalize the results to larger populations or other ED settings." Author note: these limitations present an unclear risk of bias
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) PHARMACY RECORD ‐ No mention of blinding of outcome assessors ‐ not possible given the groups in this study (only one group received medicine from the pharmacy). (pg 313) "Pharmacy records were reviewed to determine whether patients in the pharmacy group had filled their prescriptions". No mention of other details like whether the records were electronic or paper‐based
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) RETURN VISIT TO ED/HOSPITAL ADMISSION ‐ No mention of blinding of outcome assessors, though this is unlikely to impact this outcome given its objective nature. (pg 313‐4) "The hospital's computerized record system was searched to identify enrolled patients who returned to the ED or were admitted to the hospital within 2 weeks of the index visit....as well as return visits to the ED and hospital admissions within 2 weeks of the index visit."
Blinding of participants (performance bias) Adherence measure	Unclear risk	(PRIMARY) PHARMACY RECORD ‐ No explicit statement on blinding. Pharmacy group patients were required to fill their prescriptions at a pharmacy 8 blocks away and ED patients from ED itself. It is not known whether the fact that some of the patients were obtaining medicines from ED was concealed from the pharmacy group, a fact which could alter the outcome; hence unclear
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) RETURN VISIT TO ED/HOSPITAL ADMISSION ‐ No mention of blinding of outcome assessors, though this is unlikely to impact this outcome given its objective nature
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) PHARMACY RECORD ‐ True blinding impossible because medicines were dispensed from 2 different sites. There is no statement regarding the blinding; hence adjudged uncertain
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) RETURN VISIT TO ED/HOSPITAL ADMISSION ‐ No mention of blinding of outcome assessors, though this is unlikely to impact this outcome given its objective nature
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) PHARMACY RECORD ‐ Incomplete data is evenly spread across the groups ‐ 4 in the ED group and 3 in the pharmacy group
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) RETURN VISIT TO ED/HOSPITAL ADMISSION ‐ Incomplete data is evenly spread across the groups ‐ 4 in the ED group and 3 in the pharmacy group

Girvin 1999.

Methods	Randomization was conducted by an independent advisor by resampling without replacement after the placebo run‐in period. The study was not double‐blind because one outcome was the difference in compliance between once‐daily and twice‐daily regimens. However, the investigator responsible for analyzing the results was blinded as to the treatment phase
Participants	27 patients with a history of mild hypertension (well controlled on monotherapy), with a diastolic BP between 90 to 110 mm Hg were included. Patients were excluded if they had secondary hypertension or significant end organ damage, were pregnant or lactating mothers, had cardiovascular complications in addition to hypertension (e.g. MI within the past 6 months), stroke, congestive heart failure, angina pectoris, had poor renal function, a history of renal artery stenosis, were obese (weighing over 125% of ideal body weight), had hyperkalemia, had a history of angioneurotic edema, had any contraindication or hypersensitivity to ACE inhibitors, or if they were taking non‐steroidal anti‐inflammatory drugs, corticosteroids or any other medication that would significantly alter blood pressure
Interventions	Patients were randomly assigned to a sequence of enalapril 20 mg once daily or 10 mg twice daily in 3 4‐week periods following a 4‐week run‐in period. Treatment A comprised enalapril 20 mg once daily, and treatment B comprised enalapril 10 mg twice daily. The first 2 periods in each group constituted a conventional 2‐period cross‐over design. The third treatment period was included to detect any carryover effects between the periods without having to incorporate a washout phase between treatments. The 4 study arms were organized as follows (each period lasted 4 weeks): ABB BAA ABA BAB
Outcomes	Measurement of compliance: patient compliance was measured via pill counts and electronic monitoring using medication electronic monitoring system (MEMS), which record the exact date and time of each opening and closing of the drug container. Measurement of clinical health outcomes: blood pressure reduction was measured at each visit. Patients were asked not to take their blood pressure tablet on the morning of the clinical visit until after the investigator had measured their blood pressure so that the blood pressure (BP) readings were trough values. 2 readings were taken after 10 minutes rest in the seated position. The arm was supported at heart level and the diastolic blood pressure taken as the disappearance of the Korotkoff sounds (phase V). Ambulatory blood pressure was measured at the end of the placebo run‐in period and at the end of periods 1 and 2
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No mention of method of randomization. (pg 1628) "Randomization was conducted by an independent advisor (by resampling without replacement) after the placebo run‐in period."
Allocation concealment (selection bias)	Unclear risk	No mention of allocation concealment, though reference to an "independent advisor" may have meant allocation was concealed from study staff. (pg 1628) "Randomization was conducted by an independent advisor (by resampling without replacement) after the placebo run‐in period."
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	No biases noted in discussion, no other obvious risks of bias in study
Blinding of outcome assessment (detection bias) Adherence measure	High risk	(PRIMARY) PILL COUNT ‐ (pg 1628) "The study could not be double‐blind since an important outcome was the difference in compliance between the once daily and twice daily regimens. However, the investigator responsible for analysing the results was blinded as to the treatment phase."
Blinding of outcome assessment (detection bias) Adherence measure	High risk	(PRIMARY) MEMS ‐ No mention of blinding outcomes assessors, but (pg 1628) "The study could not be double‐blind since an important outcome was the difference in compliance between the once daily and twice daily regimens. However, the investigator responsible for analysing the results was blinded as to the treatment phase."
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) BLOOD PRESSURE ‐ (pg 1628‐9) "Blood pressure was measured at each visit using the Hawksley Random‐Zero Sphygmomanometer (Lancing, UK)"
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) MEMS ‐ Patients would have been aware that their pills were being tracked
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) PILL COUNT ‐ Patients would have been aware that their pills were being counted
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) BLOOD PRESSURE ‐ (pg 1628‐9) "Blood pressure was measured at each visit using the Hawksley Random‐Zero Sphygmomanometer (Lancing, UK)"
Blinding of personnel (performance bias) Adherence measure	High risk	(PRIMARY) MEMS ‐ (pg 1628) "The study could not be double‐blind since an important outcome was the difference in compliance between the once daily and twice daily regimens. However, the investigator responsible for analysing the results was blinded as to the treatment phase."
Blinding of personnel (performance bias) Adherence measure	High risk	(PRIMARY) PILL COUNT ‐ (pg 1628) "The study could not be double‐blind since an important outcome was the difference in compliance between the once daily and twice daily regimens. However, the investigator responsible for analysing the results was blinded as to the treatment phase."
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) BLOOD PRESSURE ‐ (pg 1628) "Blood pressure was measured at each visit using the Hawksley Random‐Zero Sphygmomanometer (Lancing, UK)."
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) MEMS ‐ No mention of groups missing data were from. (pg 1629) "Twenty‐seven patients were recruited into the study, two of whom had to be withdrawn after experiencing headache, nausea and dizziness upon commencing enalapril therapy. The remaining 25 patients completed".
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT ‐ No mention of groups missing data were from. (pg 1629) "Twenty‐seven patients were recruited into the study, two of whom had to be withdrawn after experiencing headache, nausea and dizziness upon commencing enalapril therapy. The remaining 25 patients completed."
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE ‐ No mention of groups missing data were from. (pg 1629) "Twenty‐seven patients were recruited into the study, two of whom had to be withdrawn after experiencing headache, nausea and dizziness upon commencing enalapril therapy. The remaining 25 patients completed."

Gould 2009.

Methods	Randomized controlled trial
Participants	The study location was not specified 64 participants were randomized to the intervention group and 65 participants were randomized to the control group The inclusion criteria were adult male and female patients between the ages of 30 and 80 years treated for an acute cardiac event with percutaneous coronary intervention (PCI) and discharged from a hospital setting within 72 hours of the procedure The exclusion criteria were if the patients were not accessible by telephone, had conditions that may impair telephone communication, or were enrolled in clinical trials or other research activity requiring telephone follow‐up
Interventions	Intervention: DISCHARGE NURSING INTERVENTION (DNI) The discharge nursing intervention consisted of written discharge materials and telephone follow‐up by an expert cardiovascular nurse. Expert nurses were defined as those having advanced education and clinical expertise in the care and management of this population. Delivery of the intervention was time‐sensitive. The intervention was offered at discharge and continued within 24 hours of discharge. DNI group received a packet containing group instructions, medication review materials, a medication pocket card, suggested Internet sites, copies of the interview tools, and the Revised Illness Perception Questionnaire (IPQ‐R) instrument Control: USUAL CARE Control group patients received routine discharge materials and usual care. Subjects in the control group received an envelope containing group instructions, copies of interview tools, and the IPQ‐R
Outcomes	The measures of adherence were the Self‐Reported Medication Taking Scale and the Machtinger and Bansberg visual analog scale. They were given the patients at discharge, with responses collected 1 to 3 days later via telephone The patient outcome was urgent care visits. This was measured via questions in a telephone interview 3 days after hospital discharge. Patients were asked if they had placed an urgent call to their physician or to the hospital or visited an ER since discharge
Notes	The authors got consent from 154 patients but only 129 were included in the analysis. It is not clear whether the 154 patients were randomized and then they dropped out or whether they dropped out prior to randomization
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to judge. (pg 120) Following consent, patients were randomly assigned into 2 groups: control and experimental, determined by selection of sealed envelopes containing group assignment and study materials
Allocation concealment (selection bias)	Low risk	Additional info provided by author: the PI completed the consent process and delivered the intervention. Allocation concealment was done as patients were assigned to groups using a sealed envelope technique. The envelopes were identical visually and physically. Envelopes were prepared by the primary investigator but were shuffled and placed in a container by 2 adults without the PI present. The PI had no knowledge of group assignment until the patient opened the envelope. At that point both patient and PI became aware of group assignment. The staff caring for the patient was not aware of group assignment
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	None noted but unclear
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Additional info provided by author: the PI completed the consent process and delivered the intervention. Allocation concealment was done as patients were assigned to groups using a sealed envelope technique. The envelopes were identical visually and physically. Envelopes were prepared by the primary investigator but were shuffled and placed in a container by 2 adults without the PI present. The PI had no knowledge of group assignment until the patient opened the envelope. At that point both patient and PI became aware of group assignment. The staff caring for the patient was not aware of group assignment
Blinding of outcome assessment (detection bias) Patient outcome	High risk	(PRIMARY) USE OF URGENT CARE ‐ Author's note: the staff in the cardiovascular department, caring for the patients, were not aware of group assignment. The PI was aware of patient assignment during the interviews and patients were aware of assignment during interview
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Author's note: the PI and patients were blinded only during the enrollment stage. Following consent, both patients and PI became aware of group assignment
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) USE OF URGENT CARE ‐ Author info: patients were aware of assignment during interviews
Blinding of personnel (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Author's note: the PI and patients were blinded only during the enrollment stage. Following consent, both patients and PI became aware of group assignment
Blinding of personnel (performance bias) Patient outcome	High risk	(PRIMARY) USE OF URGENT CARE ‐ Author's note: the PI was aware of patient assignment during the interviews
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ No information given about the group membership of the dropouts, or if they were disproportionate in one group over the other
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) USE OF URGENT CARE ‐ There is a low risk of bias; there seems to be no missing information. Refer to Table 3, 4 and 5: there seems to be no data missing for use of urgent care data, and patient satisfaction. 1 participant's data are missing from the control group for illness perception (because there are only 64/65)

Gray 2012.

Methods	Randomized controlled trial
Participants	The study location was Manchester Royal Eye Hospital (MREH) clinics in Manchester, UK 64 participants were randomized to the intervention group and 63 participants were randomized to the control group The inclusion criteria were patients with newly diagnosed ocular hypertension (OHT), open‐angle glaucoma (POAG), normal tension glaucoma (NTG), pigment dispersion, or pseudo‐exfoliation glaucoma The exclusion criteria were inability to make an informed decision about participating in the study and having a co‐existing eye condition requiring a drop regimen
Interventions	Intervention: INDIVIDUALIZED PATIENT CARE Patients in the individualized care group received standard care plus an individualized care plan implemented by a glaucoma trained nurse. This included a 45‐minute assessment of healthcare needs and beliefs with supplied booklets and drop diaries, a 20‐minute educational session, and a 10‐minute training session on instilling eye drops. A 1‐year follow‐up care plan was designed and implemented according to healthcare needs, based on education and support, which was tailored to gaps in glaucoma knowledge, pre‐existing beliefs, and ability to manage an eye drop regimen. Patients were given the nurse's contact telephone for advice or assistance between consultation. Follow‐up involved ongoing training and support by both face‐to‐face and telephone consultations. This incorporated a review of drop diaries in the initial weeks of therapy (these were continued if found beneficial as a reminder tool), reminders to collect and use drops, and repetition of information as required. Needs were reassessed and the level of support adjusted accordingly at the end of each consultation. The intervention nurse was the same throughout, and the intervention was guided by prescriptive documentation Control: STANDARD CARE Standard of care is not definitively described. Education, advice, and support varies from clinic to clinic within Manchester Royal Eye Hospital but is limited for many patients. No further contact after initial consultation
Outcomes	The measures of adherence were refill adherence, measured by contacting general practitioners and pharmacists for prescription dispensing information during the 1‐year follow‐up period, and self report adherence using the Revised Glaucoma Adherence Questionnaire (GAQ‐R) The patient outcomes were mean intraocular pressure (IOP), difference in IOP fluctuations at 12 months, and changed in clinical management at 12 months
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	(pg 408) Computer‐generated randomization was conducted by a statistician with no involvement in data collection
Allocation concealment (selection bias)	Low risk	(pg 409, Figure 1) Allocations were concealed in opaque, sealed envelopes by personnel with no involvement in the study, and opened by a research co‐ordinator with no other involvement in the study
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified
Other bias	Unclear risk	Author noted limitations in the article. (pg 415) "...refill adherence does not capture all aspects of refill behavior" ‐ refilling does not necessarily mean the previous bottle was used; could have been lost ‐ changes in visual field or optic nerve head not likely to reach significance during study length
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) REFILL ADHERENCE ‐ "The researcher and outcome assessor were masked to allocations until study completion." (pg 409, Figure 1)
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) MEAN IOP, IOP FLUCTUATION, AND CHANGE IN CLINICAL MANAGEMENT ‐ IOP level recordings and decisions regarding clinical management were made at routine clinic visits and were the responsibility of clinicians with no involvement in the study
Blinding of participants (performance bias) Adherence measure	Low risk	(PRIMARY) REFILL ADHERENCE ‐ The lack of blinding of participants is not likely to affect the outcome
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) MEAN IOP, IOP FLUCTUATION, AND CHANGE IN CLINICAL MANAGEMENT ‐ The data were collected from the hospital records. The lack of blinding is not likely to affect the outcome
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) REFILL ADHERENCE ‐ "The researcher and outcome assessor were masked to allocations until study completion." (pg 409, Figure 1)
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) MEAN IOP, IOP FLUCTUATION, AND CHANGE IN CLINICAL MANAGEMENT ‐ The data were collected from the hospital records. The researcher and outcome assessor were masked to allocations until study completion
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) REFILL ADHERENCE ‐ 10 in intervention group did not receive full intervention but an ITT analysis was done; 9 intervention arm patients who did not receive the full intervention were classed as having poor refill adherence
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) MEAN IOP, IOP FLUCTUATION, AND CHANGE IN CLINICAL MANAGEMENT ‐ Few dropouts and balanced across intervention and control

Hamann 2007.

Methods	Randomized controlled trial
Participants	The study location was 12 acute psychiatric wards of 2 German state hospitals (Bezirkskrankenhaus Haar, Klinikum Agatharied) 54 participants were randomized to the intervention group and 59 participants were randomized to the control group The inclusion criteria were all men and women aged 18 to 65 years who had an ICD‐10 diagnosis of schizophrenia or schizophreniform disorder (F20/F23) The exclusion criteria were (i) severe mental retardation, (ii) lack of fluency in German, and (iii) refusal to give written informed consent
Interventions	Intervention: SHARED DECISION MAKING (SDM) The intervention was designed to inform patients about their treatment options and to prepare them for a planning talk with their physicians. A printed 16‐page booklet covering the pros and cons of oral versus depot formulation, first versus second generation antipsychotics, psychoeducation, and type of socio‐therapeutic intervention was presented to the patients through the head nurse of the ward as soon as the psychiatrist in charge considered them able to co‐operate. Trained nurses assisted the patient to work trough the booklet. Within the decision aid, patients were asked to write down their experiences with previous antipsychotic medication and to indicate their preferences regarding the different options on each topic. Nurses were advised to answer any questions of the patients and to encourage them to state any point of view contrary to that of the doctor. They were also instructed to postpone the participation of patients in the study if serious thought disturbances or delusional misinterpretations were detected while working through the booklet. The average time for working through the booklet was 30 to 60 minutes. Patients met their physicians within 24 hours after having worked through the decision aid with their nurse. The aim of these meetings (planning talks) was to reach an agreement between patient and psychiatrist on the further treatment according to the preferences indicated by the patient in the booklet. Like nurses, physicians were also trained about the SDM and required communication skills Control: USUAL CARE "Patients in the control group were treated "as usual", thus they did not receive the decision aid and there was no arrangement for an extra planning talk
Outcomes	The measures of adherence were the Medication Adherence Rating Scale (MARS) adherence questionnaire and a measurement of plasma levels. Patients were followed‐up at 6 and 18 months. To rate compliance with medication, patients were requested to fill in a questionnaire on their compliance (MARS). MARS is a previously validated 10‐item questionnaire derived from the Drug Attitude Inventory (DAI) and the MAQ (Medical Adherence Questionnaire). Physicians were requested to rate compliance of their patients on a 4‐point scale ranging from "poor compliance" to "very good compliance". MARS rating below the median score of 8 were considered to indicate poor compliance; rating of 8 or above were considered to indicate good compliance. Physicians were requested to rate compliance of their patients on a 4‐point scale ranging from "poor compliance" to "very good compliance". Physicians were requested to make unannounced measurements of plasma levels of the prescribed antipsychotics at 6 months and 18 months after discharge. The estimates of compliance by patients and physicians as well as results of the plasma levels were dichotomized into good and poor compliance. A "conservative" algorithm was applied in order to obtain an overall measure of compliance for every patient and point in time. Overall compliance was considered "good" if patients and physicians agreed in their (positive) estimates. In all other cases (incongruence of ratings, both rating poor compliance), compliance was rated as "poor". Results were corrected in the direction toward the results of the plasma evaluation if plasma levels indicated compliance or noncompliance difference from that derived from self rating/physicians' rating (in 2 cases) The patient outcome was rehospitalization due to schizophrenia, which was recorded for the periods of 0 to 6 and 6 to 18 months after discharge from the hospital. Rehospitalization within 18 months after discharge was defined as the main outcome measure. The variable was dichotomized into scores of 1 (rehospitalization occurred with in 18 months after discharge) and 0 (no rehospitalization occurred within 18 months after discharge). At 6 and 18 months after discharge, patients' global functioning (Global Assessment of Functioning Score) and severity of illness (Clinical Global Impression scale) were assessed
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No mention of randomization method. (pg. 993) "... were randomly included in a decision aid program or received usual care"
Allocation concealment (selection bias)	Unclear risk	No mention of allocation concealment. (pg. 993) "... were randomly included in a decision aid program or received usual care"
Selective reporting (reporting bias)	Low risk	No protocol available, refers to another study (ref 11) for details on the intervention but that does not appear to be a protocol for this study
Other bias	High risk	The authors note several limitations to their study: "There are certainly limitation to our study, including the relatively low sample size, a considerable proportion of patients dropping out of the study because they were lost to follow‐up, a one time intervention without iteration or "booster sessions" and the well‐known difficulty of measuring compliance of outpatients." (pg 996) "Limitations and strengths of the study... Since we placed emphasis on studying the topic under real‐world conditions (state hospitals) and tried to avoid a study with highly selected patients, many of the limitations from the one point of view (internal validity) are thus strengths from another point of view (external validity): • We abstained from individual randomization to avoid contamination of the verum and control conditions and to avoid the situation that the same physician had to practice SDM and routine care at the same time. We believe, however, that our study does not suffer from the limitations of classical cluster trials (e.g. selection bias), since individual patients were 'randomly' sent to that ward of a pair that had free beds available and were not selected according to any patient characteristics. • We used broad inclusion criteria, which resulted in many patients being included who were afterward considered incapable of making reasonable decisions, but which shed light on the percentage of patients that can successfully be reached with this intervention. • This trial was not performed in a university setting but in state hospitals, which led on the one hand to a higher amount of lacking (selfreport) values and which limited the amount of questionnaires that could be administered (e.g. an objective measure of the decision making capacity), but which on the other hand now enables us to argue that the intervention is feasible in normal patient care and with 'normal', non‐selected patients. • The intervention took place as 'soon as possible'. An intervention shortly before discharge might have more adequately addressed the needs of the patients in regard to long‐term care. On the other hand, many decisions concerning maintenance therapy (e.g. drug choice) are made early during hospitalization." (pg 271 (supplement))
Blinding of outcome assessment (detection bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ No mention of blinding of outcome assessors
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) REHOSPITALIZATIONS ‐ No mention of blinding of outcome assessors but an objective outcome
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ No mention of blinding of patients and subjective outcome
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) REHOSPITALIZATIONS ‐ No mention of blinding of patients but an objective outcome
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ No mention of blinding of study staff
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) REHOSPITALIZATIONS ‐ No mention of blinding of study staff but an objective outcome
Incomplete outcome data (attrition bias) Adherence measure	High risk	(PRIMARY) SELF REPORT ‐ QUESTIONNAIRE ‐ Reasons for incomplete data unclear and high losses to follow‐up by 18 months
Incomplete outcome data (attrition bias) Patient outcome	High risk	(PRIMARY) REHOSPITALIZATIONS ‐ Reasons for dropouts unclear; large number of dropouts

Haynes 1976.

Methods	Random allocation by 'minimization', a method stated to be impervious to bias
Participants	This was the second phase of a 2 phase study. Male steel company employees with high blood pressure (when sitting quietly on 3 separate days, a standard series of fifth phase diastolic blood‐pressures were > 95 mm Hg) who were treated with antihypertensive medications during the first phase of the study were included in the second phase if they were non‐adherent with prescribed antihypertensive therapy (pill counts less than 80%), and not at goal blood pressures (fifth phase < 90 mm Hg) in the 6th month of treatment of phase 1.
Interventions	Patients in the experimental group were all taught the correct method to measure their own blood pressures, were asked to chart their home blood pressures and pill taking, and taught how to tailor pill taking to their daily habits and rituals. These men also visited fortnightly at the work site a high‐school graduate with no formal health professional training who reinforced the experimental maneuvers and rewarded improvements in adherence and blood pressure. Rewards included allowing participants to earn credit, for improvements in adherence and blood pressure, that could be applied towards the eventual purchase of the blood pressure apparatus they had been loaned for the trial. Control patients received none of these interventions
Outcomes	An unobtrusive pill count done in the patient's home by a home visitor was the method of determining medication adherence. Adherence rates are reported as the proportion of pills prescribed for the 12th month of therapy which were removed from their containers and, presumably, swallowed by the patients. In the 12th month of treatment, patients were evaluated for adherence and blood pressure both at home and at the mill by examiners who were 'blind' to their experimental group allocation
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Minimization used. (pg 1265) "39 such men were allocated by "minimisation" either to a control group or to an experimental group. Minimisation allows the simultaneous consideration of a large series of matching characteristics when allocating subjects to experimental and control groups, thereby minimising (using randomisation in the case of ties) between‐group differences. The method is immune to experimenter bias and has been shown to substantially outperform simple randomisation in reducing the imbalance between treatment groups that has troubled several earlier randomised trials."
Allocation concealment (selection bias)	Low risk	Minimization used. (pg 1265) "39 such men were allocated by "minimisation" either to a control group or to an experimental group. Minimisation allows the simultaneous consideration of a large series of matching characteristics when allocating subjects to experimental and control groups, thereby minimising (using randomisation in the case of ties) between‐group differences. The method is immune to experimenter bias and has been shown to substantially outperform simple randomisation in reducing the imbalance between treatment groups that has troubled several earlier randomised trials."
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	High risk	Possible confounding bias identified by the authors in the Discussion portion of the paper. (pg 1268) "We are not satisfied, however, that this investigation is free from a fourth potential source of bias, and this is the confounding of the compliance‐improving strategies with the amount of attention shown to these patients. By design, phase‐II experimental patients received more attention (five hours, spread over six months) than phase‐II controls, and our review of the compliance literature suggests that simply spending more time with patients, regardless of the content of the interchange, is associated with increased compliance."
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) PILL COUNT ‐ Blinding was accounted for. (pg 1266) "At the end of phase 2 (in the twelfth month of treatment) patients were evaluated both at home and at the mill by examiners who were "blind" to their experimental group allocation."
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) BLOOD PRESSURE ‐ Outcome assessors were blinded to treatment group. (pg 1266) "At the end of phase II (in the twelfth month of treatment) patients were evaluated both at home and at the mill by examiners who were "blind" to their experimental group allocation."
Blinding of participants (performance bias) Adherence measure	Low risk	(PRIMARY) PILL COUNT ‐ Pill count done unobtrusively once, while patient not in room. (pg 1266) "...The home visitor verified each patient's doses while the patient was supplying a urine specimen (requested without prior warning), did an unobtrusive pill‐ count and compared it with a baseline established one month earlier."
Blinding of participants (performance bias) Patient outcome	Unclear risk	(PRIMARY) BLOOD PRESSURE ‐ Patient blinding is not reported
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT ‐ No mention of blinding other study personnel
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) BLOOD PRESSURE ‐ Blinding of the outcome assessor is accounted for. (pg 1266) "At the end of phase II (in the twelfth month of treatment) patients were evaluated both at home and at the mill by examiners who were "blind" to their experimental group allocation."
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) PILL COUNT ‐ There are few missing outcome data; reason for missing data unrelated to intervention. (pg 1266) "1 control developed deep vein thrombosis and his hypotensive drugs were stopped; this patient was removed from the study, leaving 20 experimental patients and 18 controls."
Incomplete outcome data (attrition bias) Patient outcome	Low risk	(PRIMARY) BLOOD PRESSURE ‐ There are few missing outcome data; reason for missing data unrelated to intervention. (pg 1266) "1 control developed deep vein thrombosis and his hypotensive drugs were stopped; this patient was removed from the study, leaving 20 experimental patients and 18 controls."

Hederos 2005.

Methods	The parents of the 60 children were randomized consecutively in groups of 4 to either the intervention or the control group by the nurses. This resulted in 32 children in the intervention group and 28 children in the control group. The 3 doctors that were involved in the group sessions also performed the follow‐up visits. Blinding could not be completed since the intervention was led by their physicians
Participants	Patients were 60 children aged between 3 months to 6 years and had been given a diagnosis of asthma in the region, 1 to 2 months earlier. Asthma was defined by 3 or more episodes of wheezing before 2 years of age, or the first wheezing episode after the age of 2, or the first episode of wheezing in a child with other atopic diseases. The patients also had fulfilled the following criteria implying high risk for permanent asthma: wheezing without symptoms of upper respiratory tract infection (URTI) and/or proven allergy and/or atopic heredity
Interventions	The intervention consisted of meetings in a group setting with the parents. The sessions took place in the afternoon and lasted about 1.5 hours. Shortly after the children were diagnosed as an asthmatic, 3 meetings (one every week for 3 weeks) took place and a follow‐up meeting took place 6 months later. 3 pediatricians, 3 nurses and 2 psychologists were involved in these sessions: one nurse was present on all occasions, and the doctors and psychologists on 3 each. The goal of all the meetings was to reach the parents' "main worry" and, apart from teaching about asthma, the following key question was asked: "What is asthma to you?" The use of dialogue and peer education, whereby the group was encouraged to share personal experiences was emphasized. The control group, as well as the intervention group, received basic education about asthma and its treatment, including how to use the Nebunette, and information on environmental control at the first visit to the clinic. They received a written treatment plan where the principle was high dose (0.2 mg x 4 of budesonide for 3 days) initially and then, in association with URTI, stepping down the therapy to the lowest po