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. 2015 Sep 21;2015:0220.

Cardiovascular medication: improving adherence using prompting mechanisms

Liam Glynn 1,#, Tom Fahey 2,#
PMCID: PMC4577014  PMID: 26389860

Abstract

Introduction

Adherence to medication is generally defined as the extent to which people take medications as prescribed by their healthcare providers. It can be assessed in many ways (e.g., by self-reporting, pill counting, direct observation, electronic monitoring, or by pharmacy records). This overview reports effects of prompting mechanisms on adherence to cardiovascular medications, however adherence has been measured.

Methods and outcomes

We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of prompting mechanisms to improve adherence to long-term medication for cardiovascular disease in adults? We searched Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review).

Results

At this update, searching of electronic databases retrieved 174 studies. After deduplication and removal of conference abstracts, 80 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 45 studies and the further review of 35 full publications. Of the 35 full articles evaluated, one RCT was added at this update. We performed a GRADE evaluation of seven PICO combinations.

Conclusions

In this systematic overview, we categorised the efficacy for seven comparisons based on information relating to the effectiveness and safety of prompting mechanisms, alone and in combination with reminder packaging or patient education.

Key Points

Adherence to medication is generally defined as the extent to which people take medications as prescribed by their healthcare providers.

  • It can be assessed in many ways (e.g., by self-reporting, pill counting, direct observation, electronic monitoring, or through pharmacy records). In this overview, we have reported adherence to cardiovascular medications, however it has been measured.

The RCTs we found used a variety of different interventions in different populations, measured adherence differently, and expressed and analysed results differently.

  • The diversity and complexity of interventions employed in RCTs make it difficult to separate out any individual components that might be of benefit.

Prompting mechanisms may increase adherence to medication.

  • Some prompting mechanisms may be simple and inexpensive (e.g., mailed reminders), while others (e.g., daily telephone calls, installing videophones) seem impracticable for use in routine practice.

  • We don't know how prompting mechanisms compare to reminder packaging or patient education as we found insufficient evidence.

Reminder packaging or patient education in addition to prompting mechanisms may also increase adherence to medication, but more data are needed to enable conclusions to be drawn.

Clinical context

General background

Adherence is defined as the extent to which people take medications as prescribed by their healthcare providers. Adherence rates are variable, but are generally recognised to be low for long-term medication, which means that the majority of people on long-term medication regimens will not get the full benefit from what are often costly treatments. Healthcare providers are slow to identify poor adherence, and interventions to improve adherence have mixed results and are often very costly. This overview examines the effects of prompting mechanisms on adherence to cardiovascular medications in adults in the community.

Focus of the review

This overview included evidence on interventions to improve adherence to cardiovascular medication using prompting mechanisms alone or together with other interventions, namely reminder packaging and patient education. There is a specific focus on prompting mechanisms as there is new research emerging in this area taking advantage of newer technologies such as mobile and hand-held devices, which are now widespread.

Comments on evidence

We found 12 studies that met our inclusion criteria, at least one RCT on each of our treatments of interest. However, the diversity and complexity of interventions employed in RCTs makes it difficult to separate out any individual components that might be of benefit. There is a small amount of evidence for effect with prompting mechanisms alone versus control, but several of these interventions remain impracticable for use in routine clinical practice. Newer technologies, now widely available, may be able to provide cheap and scalable interventions, but the evidence base around effectiveness has yet to catch up with such developments.

Search and appraisal summary

The update literature search for this review was carried out from the date of the last search, April 2010, to May 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. Searching of electronic databases retrieved 174 studies. After deduplication and removal of conference abstracts, 80 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 45 studies and the further review of 35 full publications. Of the 35 full articles evaluated, one RCT was added at this update.

Additional information

With the widespread availability of mobile and handheld devices, the use of SMS and applications (or apps) focused on improving adherence to medication generally is an additional area of research. These developments hold some promise, but little evidence has so far emerged.

About this condition

Definition

Definition Adherence to a medication regimen is generally defined as the extent to which people take medications as prescribed by their healthcare providers. 'Adherence', 'compliance', and 'concordance' are often used interchangeably when studying health behaviour, but their meanings are in fact different, particularly in the context of RCTs examining interventions aimed at improving adherence. Adherence takes into account that people choose to take their medicines, have control over their use, and develop an agreement with healthcare professionals about their management. The main difference between the terms 'adherence' and 'compliance' is on a motivational level, with the latter suggesting that the patient is passively following the physician's orders, and that the treatment plan is not based on a therapeutic alliance or contract established between the patient and the physician. Unfortunately, the term 'concordance' has occasionally, and not always appropriately, replaced the terms 'compliance' or 'adherence'. 'Concordance' aims to describe an agreement between patient and healthcare professional about the whole process of medication-taking as part of a wider consultation, rather than describing the specific extent to which medication is taken. For the purposes of this review, 'adherence' will be defined as the extent to which people take medications as prescribed by their healthcare providers. The reporting of adherence varies, with some studies reporting adherence as a dichotomous outcome, and using an artificial cut-off point (e.g., 80% 'adherent'), whereas other studies compare study arms using continuous outcomes (e.g., a count of pills taken of 75% v 91%). Measurement The ideal measurement of adherence should: be usable over a prolonged period; be unobtrusive; be non-invasive; be practicable and cheap; yield immediate results; and not be open to manipulation. Based on these stringent criteria, the objective measurement of adherence is difficult and poses a challenge for researchers and clinicians. Measurement of adherence can be divided into 'direct' (which demonstrate drug ingestion) and 'indirect' (which do not demonstrate drug ingestion) methods. Direct methods include observing people taking medication, or the measurement of medicine, metabolites, or biological markers in the blood. Although objective and accurate, direct adherence measures are often impractical or too expensive for the RCT setting. A variety of indirect adherence measures are commonly employed in RCTs, and each one has strengths and weaknesses. These include self-reporting by patients, prescribing data, pill counting, measurement of physiological markers, and electronic monitoring. Patient self-reporting of adherence is simple, inexpensive, and probably the most practical and useful in the clinical setting. It is, however, subject to considerable bias, as the person may wish to please the investigator, be worried about admitting to not taking medication, or simply not accurately remember. Prescribing data, such as the rate of prescription refills or cessation of refills (discontinuation rate), are easy to obtain through pharmacies, but require a closed-pharmacy system to be accurate, and cannot be regarded as equivalent to ingestion of medication. However, this information affords a useful proxy, and may be easier to measure over long follow-up periods. Pill counts provide a direct measure of adherence. However, they may be manipulated by people if they are aware that the pills are being counted (e.g., pill dumping), and it does not necessarily mean that medication has been taken at the correct time. Measurement of physiological markers (e.g., measuring heart rate in patients taking beta-blockers) is easy to perform, but is greatly limited by its assumption of a cause-and-effect relationship, which is rarely applicable. Electronic monitoring methods have greatly advanced recently and allow recordings of the timing and frequency of drug ingestion, which make them the only method to provide data on drug-taking patterns. However, they are expensive, and there is no guarantee that opening of the medication container is followed by ingestion of the correct dose. It could also be argued that placing an electronic cap to measure compliance is an intervention in itself as people are aware that they are being monitored (Hawthorne effect). This effect may or may not persist in the longer term when people become used to the electronic cap. Although electronic monitoring is closest to a 'gold standard' in measuring adherence, it has so far been used mainly as a research tool owing to its relatively high cost. Prompting mechanisms A prompting mechanism is any tool (e.g., email, SMS, apps, or electronic medication cap) that is used to propel medication-taking via a reminder process.

Incidence/ Prevalence

Not applicable for this overview.

Aetiology/ Risk factors

The reasons for not adhering to prescribed cardiovascular medication are complex, and non-adherence may lead to various sequelae. For example, the prescribing clinician may alter or discontinue a regimen believing it not to be working when, in fact, it may have been taken only inconsistently or not at all. Failure to adhere to a prescribed regimen may increase adverse effects from the regimen, in that medication is taken incorrectly, and may fail to improve symptoms from the underlying condition for which it was prescribed. Interventions to improve adherence Interventions to improve adherence can potentially be divided into a variety of different categories or groupings. In this review we have grouped RCTs under the categories of: prompting mechanisms; prompting mechanisms plus reminder packaging (blister packs and pill boxes); and prompting mechanisms plus patient education. We have explained what we have included under each category where necessary. However, interventions to improve adherence are complex by nature and will often be combined in a multi-factorial or 'complex intervention' approach. This approach is necessary as there are many factors that contribute to poor adherence, although this does make it difficult to tease out the individual components of many adherence interventions. Prompting mechanisms are intended to stimulate medication-taking through mailed or telephoned reminders or through the use of electronic medication-reminder caps. Educational interventions can be written material, videotapes, or individual or group training. Reminder packaging falls into two distinct categories: those that are packaged in pill boxes (multi-compartment compliance aid, dose administration aid) or those that are pre-packaged into blister packs (calendar blister, unit dose, monitored dosage system). Definitions of terms relating to reminder packaging are reported in table 1 .

Table 1.

Definitions of different types of reminder packaging*

Definitions of different types of reminder packaging
Pill boxes 1 Monitored dosage system (MDS): medications are manually packed into blister/bubble trays under the supervision of a pharmacist and then cold- or heat-sealed with foil. Examples of these systems are the Nomad® and Manrex®. Patients using an MDS are provided with weekly or monthly blister packs
  2 Multi-compartment compliance aid (MCA) or dose administration aid: these are plastic trays or boxes that hold 7 days of a patient's medicine and are divided into days of the week. Each day of the week has a sliding lid, which covers compartments for different dosing times (usually 4 compartments for each day). They are commonly but not exclusively used for multiple medications. Examples of these are Dosett®, Medidos®, and the Mediset
Pre-packaged blister packs 1 Calendar blister: a blister package designed to aid a patient's memory by incorporating the day/time when each dose is to be taken into the package design
  2 Unit dose: the prescribed amount of each dosage in a package. This type of packaging can incorporate a reminder system
  3 Unit of use: the exact amount of a drug treatment prepackaged by the manufacturer or pharmacist in standardised amounts. This type of packaging can incorporate a reminder system
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* Source: Heneghan CJ, Glasziou P, Perera R. Reminder packaging for improving adherence to self-administered long term medication. In: The Cochrane Library, Issue 3, 2010. Chichester, UK: John Wiley & Sons, Ltd. Search date 2004. Copyright Cochrane Collaboration, reproduced with permission.

Prognosis

Patterns of medication-taking behaviour and adherence Patterns of medication-taking behaviour have been accurately described using electronic monitoring devices. Six general patterns of taking medication emerge among people treated for chronic illnesses who continue to take their medications: approximately one sixth come close to perfect adherence to a regimen; one sixth take nearly all doses, but with some timing irregularity; one sixth miss an occasional single day's dose and have some timing inconsistency; one sixth take drug holidays three to four times a year, with occasional omissions of doses; one sixth have a drug holiday monthly or more often, with frequent omissions of doses; and one sixth take few or no doses while giving the impression of good adherence. Most deviations in taking medication occur as omissions of doses (rather than additions) or delays in the timing of doses. Levels of adherence are poorly described, with those studies of higher quality limited by smaller numbers, and those studies of larger populations limited by crude measures of adherence. However, in terms of adherence to cardiovascular medication, most studies have examined adherence in relation to lipid-lowering drugs. It is evident that target cholesterol concentrations are only achieved in less than 50% of people receiving lipid-lowering drugs, and that only one in four people continue taking cholesterol-lowering drugs long-term. In adherence studies of people without CHD taking lipid-lowering drugs for the purposes of primary prevention, discontinuation rates are higher compared with people taking lipid-lowering drugs for the purpose of secondary prevention, indicating a possible relationship between adherence and awareness of illness.

Aims of intervention

To increase adherence to cardiovascular medication in order to achieve treatment goals; to prevent relapse of disease; to reduce morbidity; to reduce mortality; to improve quality of life, with minimal adverse effects.

Outcomes

Adherence to medication, however measured (adherence is often measured by pill count, prescription renewal requests, self-reporting, and electronic monitoring); adverse effects.

Methods

Search strategy BMJ Clinical Evidence search and appraisal May 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to May 2014, Embase 1980 to May 2014, The Cochrane Database of Systematic Reviews 2014, issue 8 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this review were systematic reviews and RCTs published in English. Open label studies were included. RCTs had to include 20 or more individuals (10 in each arm), and to follow up at least 80% of people enrolled. The minimum length of follow-up required for inclusion was 6 weeks. RCTs that used complex interventions (i.e., mixtures of different elements in which the individual effects of our intervention of interest could not be separately assessed) were excluded. Additionally, an RCT was excluded if it did not report adherence directly as an outcome, or reported an adherence outcome that was not clearly defined. There was a wide variation between RCTs in how adherence was measured (e.g., whether by pill count, self-reporting, electronic methods, or the number of repeat prescriptions obtained), with no standard method employed. We have, therefore, included RCTs however adherence was measured, but explicitly stated the adherence outcome measure employed in each RCT. We have included RCTs in people with cardiovascular disease (CVD) and excluded RCTs in mixed populations (i.e., RCTs that also included people with other diseases, in which people with CVD did not form the majority). We excluded RCTs in hospitalised people, and included RCTs in people in the community or seen as outpatients, who were responsible for administering their own medication. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our predefined criteria for inclusion in the benefits and harms section, may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects Measures to increase adherence may or may not have adverse effects (e.g., regular contact, and stressing the importance of medication and possible adverse effects of non-compliance, may increase anxiety in some people). For adverse events we have reported harms data relating directly to the adherence intervention employed. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Data and quality To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue which may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Cardiovascular medication: improving adherence using prompting mechanisms.

Important outcomes Adherence to medication
Studies (Participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of prompting mechanisms to improve adherence to long-term medication for cardiovascular disease in adults?
8 (1410) Adherence to medication Prompting mechanisms versus control 4 –2 0 –2 0 Very low Quality points deducted for incomplete reporting of results and weak methods (method of randomisation and level of blinding not reported in 7 out of 8 studies); directness points deducted for diverse interventions affecting generalisability, and diverse range of outcome assessment and analysis
1 (216) Adherence to medication Prompting mechanisms versus patient education 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results; directness point deducted for lack of statistical analysis
2 (222) Adherence to medication Prompting mechanisms versus reminder packaging 4 –2 0 –1 0 Very low Quality points deducted for incomplete reporting of results and weak methods (method of randomisation and level of blinding not reported); directness point deducted for unclear intervention (unit-of-use intervention not fully defined)
2 (210) Adherence to medication Prompting mechanisms plus reminder packaging versus control 4 –2 0 –1 0 Very low Quality points deducted for incomplete reporting of results and weak methods (method of randomisation and level of blinding not reported); directness point deducted for unclear intervention (unit-of-use intervention not fully defined)
2 (217) Adherence to medication Prompting mechanisms plus reminder packaging versus reminder packaging alone 4 –2 0 –1 0 Very low Quality points deducted for incomplete reporting of results and weak methods (method of randomisation and level of blinding not reported); directness point deducted for unclear intervention (unit-of-use intervention not fully defined)
2 (657) Adherence to medication Prompting mechanism plus patient education versus control 4 –2 0 –1 0 Very low Quality point deducted for weak methods (method of randomisation not described, level of blinding not reported) and incomplete reporting of results; directness point deducted for unclear validity of outcome assessment/single measure of adherence used
1 (228) Adherence to medication Prompting mechanisms plus patient education versus patient education alone 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results; directness point deducted for lack of statistical analysis
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We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Mini-Mental score

A score derived from the Folstein Mini Mental State Examination. This examination is used to evaluate dementia, and consists of a series of questions and tasks to assess a patient's orientation, attention, calculation, language, visuospatial, executive, and short-term memory abilities. The cut off for dementia is a score of less than 24 out of a possible 30.

Very low-quality evidence

Any estimate of effect is very uncertain.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Liam Glynn, National University of Ireland, Galway, Ireland.

Tom Fahey, RCSI Medical School, Dublin, Ireland.

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BMJ Clin Evid. 2015 Sep 21;2015:0220.

Prompting mechanisms versus control

Summary

Prompting mechanisms may increase adherence to medication.

Some prompting mechanisms may be simple and inexpensive (e.g., mailed reminders), while others (e.g., daily telephone calls, installing videophones) seem impracticable for use in routine practice.

Benefits and harms

Prompting mechanisms versus control:

We found 11 systematic reviews (search dates 1996; 2000; 2002; 2003; 2004; 2007; 2008; 2009), which identified seven RCTs of sufficient quality. We also found one subsequent RCT. The reviews did not synthesise data. Some of the RCTs had weak methods, and completeness of reporting varied widely among trials. Adherence was measured in a variety of ways in the seven RCTs (pill counts, pharmacy refill records, electronic caps) and overall compliance was calculated in different ways, with no standard method employed. For full details of prompting mechanisms used in RCTs, see Further information on studies.

Adherence to medication

Prompting mechanism compared with control Prompting interventions (including daily and weekly telephone calls, video-telephone calls, mailed reminders, and electronic medication-reminder caps) may be more effective than control at improving adherence in people taking cardiovascular medication. However, the practicality of some of these interventions in routine clinical practice is unclear (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adherence to medication

RCT
3-armed trial 		60 people aged 65 years or older, with a diagnosis of chronic heart failure; they had to have a telephone socket, home not in high-crime area, Mini-Mental State Examination (MMSE) score of 20 or better. Compliance (baseline to post-intervention) monitored by electronic caps on medication bottles 6-week intervention phase, followed by 2-week post-intervention compliance monitoring period
76% to 74% with daily telephone calls
82% to 84% with daily video-telephone calls
81% to 57% with control
Absolute numbers not reported
P <0.05 among groups
Direct statistical analysis of telephone group or video-telephone group versus control not reported, but higher rates of adherence in prompting mechanism groups

RCT		 70 people with hypertension on long-term treatment, aged 50 years or older, on 1 or more drugs Mean % compliance (defined as doses consumed/doses prescribed x 100) number of remaining doses in each vial counted at 12 weeks
95% with electronic cap on medication vial
78% with standard cap
P = 0.0002 		Effect size not calculated prompting intervention (electronic cap)

RCT		 30 people with coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA) in the last 7 to 30 days, baseline fasting LDL 130 mg/dL or higher, on lovastatin and colestipol, with a telephone in their home Compliance (measured by pill and packet counts) 6 weeks
92% for lovastatin and 93% for colestipol with telephone call
89% for lovastatin and 90% for colestipol with no telephone call
Absolute numbers not reported
Reported as not significant
P value not reported 		Not significant

RCT		 30 people with CABG or PTCA in the last 7–30 days, baseline fasting LDL 130 mg/dL or higher, on lovastatin and colestipol, with a telephone in their home Compliance (measured by pill and packet counts) 12 weeks
88% for lovastatin and 90% for colestipol with telephone call
86% for lovastatin and 88% for colestipol with no telephone call
Absolute numbers not reported
Reported as not significant
P value not reported 		Not significant

RCT		 30 people with CABG or PTCA in the last 7–30 days, baseline fasting LDL 130 mg/dL or higher, on lovastatin and colestipol, with a telephone in their home Compliance (measured by contacting pharmacies to obtain document refill information) 1 year
71% for lovastatin and 54% for colestipol with telephone call
47% for lovastatin and 27% for colestipol with no telephone call
Absolute numbers not reported
P <0.05 		Effect size not calculated prompting intervention (telephone call)

RCT		 30 people with CABG or PTCA in the last 7–30 days, baseline fasting LDL 130 mg/dL or higher, on lovastatin and colestipol, with a telephone in their home Compliance (measured by contacting pharmacies to obtain document refill information) 2 years
63% for lovastatin and 48% for colestipol with telephone call
39% for lovastatin and 23% for colestipol with no telephone call
Absolute numbers not reported
P <0.05 		Effect size not calculated prompting intervention (telephone call)

RCT
3-armed trial 		311 people on cardiovascular medications, attended primary care or speciality clinic at a university health centre, medication refill due in 2 days, people selected from a computer database Mean compliant events, which equalled the number of refills divided by the possible number of refills outcome measured for 3 months
0.58 with no reminder
0.65 with postcard reminder 2 working days before medication refill due
P <0.05
Post hoc analysis 		Effect size not calculated prompting intervention (reminder postcard)

RCT
3-armed trial 		311 people on cardiovascular medications, attended primary care or speciality clinic at a university health centre, medication refill due in 2 days, people selected from a computer database Mean compliant events, which equalled the number of refills divided by the possible number of refills outcome measured for 3 months
0.58 with no reminder
0.64 with telephone call 1 working day before medication refill due
P <0.05
Post hoc analysis 		Effect size not calculated prompting intervention (telephone call)

RCT
3-armed trial 		636 people with newly diagnosed or uncontrolled mild to moderate hypertension, aged 18–80 years, on single therapy Mean % compliance (compliance assessed by counting tablets; % compliance defined as total number of consumed tablets/total number of tablets that should have been consumed x 100) assessed at 5 clinic visits: inclusion visit, and 4 follow-up visits at 26, 52, 106, and 155 days
90% with control
99% with telephone intervention
97% with mailed intervention
P = 0.0001 for either intervention v control
No direct statistical comparison of telephone intervention alone or mailed intervention alone versus control reported, but higher rates of adherence in prompting mechanism groups 		Effect size not calculated prompting intervention

RCT
3-armed trial 		636 people with newly diagnosed or uncontrolled mild to moderate hypertension, aged 18–80 years, on single therapy Proportion of compliers (participants with 80%–110% drug consumption) (compliance assessed by counting tablets; % compliance defined as total number of consumed tablets/total number of tablets that should have been consumed x 100) assessed at 5 clinic visits: inclusion visit, and 4 follow-up visits at 26, 52, 106, and 155 days
69% with control
96% with telephone intervention
91% with mailed intervention
P = 0.0001 for either intervention v control
Between-group analysis
No direct statistical comparison of telephone intervention alone or mailed intervention alone versus control reported, but higher rates of adherence in prompting mechanism groups 		Effect size not calculated prompting intervention

RCT
4-armed trial 		304 people, previously untreated mild to moderate hypertension, aged <65 years, on verapamil once-daily, refill medication dispensed in 30-day supplies Mean number of days' supply of medication obtained over 360-day study period, expressed as "medication possession ratio" (defined as the number of days' supply of medication obtained throughout the study period expressed as a ratio against the number of days that should have been supplied)
0.64 with mailed reminder 10 days prior to medication refill date
0.56 with control
P <0.05 		Effect size not calculated prompting intervention (mailed reminder)

RCT
4-armed trial 		128 people with previously untreated mild to moderate hypertension, on verapamil once-daily, mean age approximately 54 years, refill medication dispensed in 30-day supplies Mean number of days' supply of medication obtained over 360-day study period, expressed as "medication possession ratio" (defined as the number of days' supply of medication obtained throughout the study period expressed as a ratio against the number of days that should have been supplied)
0.71 with mailed reminder 10 days prior to medication refill date
0.64 with control
P <0.05 		Effect size not calculated prompting intervention (mailed reminder)

RCT		 440 people with established coronary heart disease in an inner-city primary care clinic Adherence to cardiovascular medication refills (determined by the calculation of the cumulative medication gap; using refill data from the health system pharmacy) 1 year
28% with refill reminder postcards
31% with control
Absolute numbers not reported
Significance not assessed
See Further information on studies
Open in a new tab

Adverse effects

No data from the following reference on this outcome.

Further information on studies

RCT methods Follow-up of 100%. Method of randomisation was not described. Level of blinding was not reported.

Prompting mechanism Daily calls, which lasted 3 to 5 minutes and were made by research assistant on Monday to Friday. RCT methods The method of randomisation was described. Results were based on 50/60 (83%) of those randomised. Withdrawals in each individual group were not reported. Participants were offered $20 to take part in the study. Electronic caps were placed on a maximum of 4 medication bottles for each person. No significant difference in adherence was reported between telephone and video-telephone groups (reported as not significant; P value not reported).

Prompting mechanism Electronic cap on medication bottles: digital timepiece displayed when last opened, alarm bleeped when dose was due, flashed when dose was missed. RCT methods Participants were blinded; investigators were not blinded. The method of randomisation was not described. Loss to follow-up was not reported. Blood pressure results were measured but presented as baseline analysis; no between-group analyses were reported. Factoral design: only the first randomisation was reported here.

Prompting mechanism Telephone calls: the same pharmacist telephoned people in their homes every week for 12 weeks. Standard set of questions, with emphasis on the importance of therapy, and asking reasons for non-compliance where appropriate. RCT methods The method of randomisation was described, and follow-up was 100%. Different measures of adherence were used in the short term (up to 12 weeks) and the long term (up to 2 years). Small RCT (15 people in each group). Changes in total cholesterol, LDL, HDL, and triglyceride level were not significantly different between groups at 6 or 12 weeks. Compared with the no-telephone group, the telephone intervention significantly reduced total cholesterol (P = 0.03), LDL (P = 0.02), and triglyceride levels (P = 0.04) at 1 and 2 years.

RCT methods The method of randomisation was not described. The level of blinding was not reported. A telephone call was also made to people in all three groups who were 3 days late obtaining the medication. This was to determine: if the postcard group had received the postcard; if medication had been obtained at a different pharmacy; and reasons for not refilling. Calls made to all groups (including control) may have influenced the results. Of 40/311 (13%) total withdrawals, 35 were in group (1). These people were excluded from analysis as they had not been contacted by telephone (unlisted number or telephone disconnected). Hence, withdrawals varied between groups. The RCT found no significant difference between the postcard and telephone groups in mean compliant events (P value not reported).

Prompting mechanism Telephone intervention: three calls in total by nurses after scheduled visits to reinforce compliance, standard call, with good compliance praised. Mailed intervention: three mailed communications reinforcing compliance, supplying health education, and reminding people of clinic visits. RCT methods The method of randomisation was described. Results were based on follow-up of 538/636 (86%) people. There was significantly superior control of blood pressure with telephone intervention compared with control (63% with telephone intervention v 47% with control; P <0.05).

Prompting mechanism Medications were dispensed in a 30-day supply. Patients were randomised to: (i) reminder postcards mailed to their homes approximately 25 days after their last fill; (ii) illustrated medication schedules that visually depicted medication regimens; (iii) reminder postcard plus illustrated medication schedule; or (iv) a control group of usual pharmaceutical care (not further defined). RCT methods The RCT had a 2 x 2 factorial design to compare four treatments in people with established coronary heart disease. The method of randomisation was described. Outcome assessors were masked to treatment, but patients and treating physicians were aware of treatments. The primary outcome was cardiovascular medication refill adherence, assessed by the cumulative medication gap (CMG). Patients with CMG less than 0.20 were considered adherent. No statistical comparisons between groups were carried out. Statistical significance of rate of adherence across all four treatments identified no statistically significant difference across groups (P = 0.58).

Comment

Clinical guide

There is a variety of potential prompting mechanisms, from the simple and relatively low-cost mailed reminder to the more expensive and labour-intensive use of telephone calls, video-telephone calls, or electronic medication-reminder caps (and we have included RCTs that assessed any form). There is a small amount of evidence for effect with all of the above mechanisms, but several (e.g., daily telephone calls, installing videophones) remain impracticable for use in routine clinical practice.

Substantive changes

Prompting mechanisms versus control Overview re-structured. One RCT added. Categorisation unchanged (likely to be beneficial).

BMJ Clin Evid. 2015 Sep 21;2015:0220.

Prompting mechanisms versus patient education

Summary

We don't know how prompting mechanisms and patient education compare at increasing adherence to cardiovascular medication, as we found insufficient evidence.

Benefits and harms

Prompting mechanisms versus patient education:

We found 11 systematic reviews (search dates 1996; 2000; 2002; 2003; 2004; 2007; 2008; 2009), which identified no RCTs of sufficient quality. We found one subsequent RCT.

Adherence to medication

Prompting mechanisms compared with patient education We don't know whether refill reminder postcards are more effective than illustrated medication schedules at improving adherence to medication in people with coronary heart disease taking cardiovascular medication (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adherence to medication

RCT		 440 people with established coronary heart disease in an inner-city primary care clinic Adherence to cardiovascular medication refills (determined by the calculation of the cumulative medication gap [CMG]; using refill data from the health system pharmacy) 1 year
28% with refill reminder postcards
34% with illustrated medication schedules
Absolute numbers not reported
Significance not assessed
See Further information on studies
Open in a new tab

Adverse effects

No data from the following reference on this outcome.

Further information on studies

Prompting mechanism Medications were dispensed in a 30-day supply. Patients were randomised to: reminder postcards mailed to their homes approximately 25 days after their last fill; illustrated medication schedules that visually depicted medication regimens; reminder postcard plus illustrated medication schedule; or a control group of usual pharmaceutical care (not further defined).

RCT methods The RCT had a 2 x 2 factorial design to compare four treatments in people with established coronary heart disease. The method of randomisation was described. Outcome assessors were masked to treatment, but patients and treating physicians were aware of treatments. The primary outcome was cardiovascular medication refill adherence, assessed by the cumulative medication gap (CMG). Patients with CMG less than 0.20 were considered adherent. No statistical comparisons between groups were carried out. Statistical significance of rate of adherence across all four treatments identified no statistically significant difference across groups (P = 0.58).

Comment

Only one RCT comparing prompting mechanisms with patient education was identified. It used a paper-based approach and it showed no statistically significant difference across groups. Further RCTs are required, perhaps taking advantage of newer technologies to provide robust evidence in this area.

Substantive changes

Prompting mechanisms versus patient education New option. One RCT added. Categorisation as 'unknown effectiveness'.

BMJ Clin Evid. 2015 Sep 21;2015:0220.

Prompting mechanisms versus reminder packaging

Summary

We don't know how prompting mechanisms and reminder packaging compare at increasing adherence to cardiovascular medication as the evidence was weak.

Benefits and harms

Prompting mechanisms versus reminder packaging:

We found 11 systematic reviews (search dates 1996; 2000; 2002; 2003; 2004; 2007; 2008; 2009), which identified two RCTs of sufficient quality. The reviews did not synthesise data. The two RCTs were undertaken by the same research group and employed a similar methodology.

Adherence to medication

Prompting mechanisms compared with reminder packaging We don't know whether mailed reminders 10 days prior to medication refill are more effective than unit-of-use reminder packaging at improving adherence to medication in people with mild to moderate hypertension taking verapamil once daily (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adherence to medication

RCT
4-armed trial 		304 people, previously untreated mild to moderate hypertension, aged <65 years, on verapamil once-daily, refill medication dispensed in 30-day supplies Mean number of days' supply of medication obtained over 360-day study period, expressed as "medication possession ratio" (defined as the number of days' supply of medication obtained throughout the study period expressed as a ratio against the number of days that should have been supplied)
0.64 with mailed reminder 10 days prior to medication refill date
0.67 with unit-of-use packaging
Reported as not significant
P value not reported
The unit-of-use packaging was reported to be "a sequentially numbered 30-day supply inventory tray with easy-access compartments" but was not further defined 		Not significant

RCT
4-armed trial 		128 people with previously untreated mild to moderate hypertension, on verapamil onc- daily, mean age approximately 54 years, refill medication dispensed in 30-day supplies Mean number of days' supply of medication obtained over 360-day study period, expressed as "medication possession ratio" (defined as the number of days' supply of medication obtained throughout the study period expressed as a ratio against the number of days that should have been supplied)
0.71 with mailed reminder 10 days prior to medication refill date
0.75 with unit-of-use packaging
Reported as not significant
P value not reported
The unit-of-use packaging was not further defined 		Not significant
Open in a new tab

Adverse effects

No data from the following reference on this outcome.

Further information on studies

RCT methods Follow-up was 100%. The method of randomisation was not described. The level of blinding was not reported. 'Unit-of-use' packaging was reported to be "a sequentially numbered 30-day supply inventory tray with easy-access compartments". It was not further described.

Comment

Only two RCTs were identified that compared prompting mechanisms with reminder packaging. These were of low quality and showed no statistically significant difference across groups. Higher-quality RCTs are required, perhaps taking advantage of newer technologies to provide robust evidence in this area.

Substantive changes

Prompting mechanisms versus reminder packaging New option. No new evidence. Categorised as 'unknown effectiveness'.

BMJ Clin Evid. 2015 Sep 21;2015:0220.

Prompting mechanisms plus reminder packaging versus control

Summary

We don't know how prompting mechanisms plus reminder packaging compare with control at increasing adherence to cardiovascular medication, as the evidence was weak.

Benefits and harms

Prompting mechanisms plus reminder packaging versus control:

We found 11 systematic reviews (search dates 1996; 2000; 2002; 2003; 2004; 2007; 2008; 2009), which identified two RCTs of sufficient quality. The reviews did not synthesise data. The two RCTs were undertaken by the same research group and employed a similar methodology.

Adherence to medication

Prompting mechanism plus reminder packaging compared with control We don’t know how prompting mechanisms (mailed) plus unit-of-use reminder compare with control at improving adherence to medication in people with mild to moderate hypertension taking verapamil once daily (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adherence to medication

RCT
4-armed trial 		304 people, previously untreated mild to moderate hypertension, aged <65 years, on verapamil once-daily, refill medication dispensed in 30-day supplies Mean number of days' supply of medication obtained over 360-day study period, expressed as "medication possession ratio" (defined as the number of days' supply of medication obtained throughout the study period expressed as a ratio against the number of days that should have been supplied)
0.79 with mailed reminder plus unit-of-use packaging
0.56 with control
P <0.05
The unit-of-use packaging was reported to be "a sequentially numbered 30-day supply inventory tray with easy-access compartments" but was not further defined 		Effect size not calculated prompting mechanism (mailed reminder) plus reminder packaging (unit-of-use-packaging)

RCT
4-armed trial 		128 people with previously untreated mild to moderate hypertension, on verapamil once-daily, mean age approximately 54 years, refill medication dispensed in 30-day supplies Mean number of days' supply of medication obtained over 360-day study period, expressed as "medication possession ratio" (defined as the number of days' supply of medication obtained throughout the study period expressed as a ratio against the number of days that should have been supplied)
0.87 with mailed reminder plus unit-of-use packaging
0.64 with control
P <0.05
The unit-of-use packaging was not further defined 		Effect size not calculated prompting mechanism (mailed reminder) plus reminder packaging (unit-of-use-packaging)
Open in a new tab

Adverse effects

No data from the following reference on this outcome.

Further information on studies

RCT methods Follow-up was 100%. The method of randomisation was not described. The level of blinding was not reported. 'Unit-of-use' packaging was reported to be "a sequentially numbered 30-day supply inventory tray with easy-access compartments". It was not further described.

Comment

Although the use of prompting mechanisms with reminder packaging holds potential promise in the improvement of adherence, little research has been undertaken in this area. Only two RCTs were identified that compared prompting mechanisms plus reminder packaging with a control. These were of low quality and showed no statistically significant difference across groups. Higher-quality RCTs are required, perhaps taking advantage of newer technologies to provide robust evidence in this area.

Substantive changes

Prompting mechanisms plus reminder packaging versus control New option. No new evidence. Categorised as 'unknown effectiveness'.

BMJ Clin Evid. 2015 Sep 21;2015:0220.

Prompting mechanisms plus reminder packaging versus reminder packaging alone

Summary

We don't know how prompting mechanisms plus reminder packaging compare to reminder packaging alone at increasing adherence to cardiovascular medication, as the evidence was weak.

Benefits and harms

Prompting mechanisms plus reminder packaging versus reminder packaging alone:

We found 11 systematic reviews (search dates 1996; 2000; 2002; 2003; 2004; 2007; 2008; 2009), which identified two RCTs of sufficient quality. The reviews did not synthesise data. The two RCTs were undertaken by the same research group and employed a similar methodology.

Adherence to medication

Prompting mechanism plus reminder packaging compared with reminder packaging alone Prompting mechanism (mailed reminder) plus unit-of-use reminder packaging may be more effective than unit-of-use reminder packaging alone at improving adherence to medication in people with mild to moderate hypertension taking verapamil once daily (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adherence to medication

RCT
4-armed trial 		304 people, previously untreated mild to moderate hypertension, aged <65 years, on verapamil once-daily, refill medication dispensed in 30-day supplies Mean number of days’ supply of medication obtained over 360-day study period, expressed as "medication possession ratio" (defined as the number of days' supply of medication obtained throughout the study period expressed as a ratio against the number of days that should have been supplied)
0.67 with unit-of-use packaging
0.79 with mailed reminder plus unit-of-use packaging
P <0.05
The unit-of-use packaging was reported to be "a sequentially numbered 30-day supply inventory tray with easy-access compartments" but was not further defined 		Effect size not calculated prompting mechanism (mailed reminder) plus reminder packaging (unit-of-use-packaging)

RCT
4-armed trial 		128 people with previously untreated mild to moderate hypertension, on verapamil once-daily, mean age approximately 54 years, refill medication dispensed in 30-day supplies Mean number of days' supply of medication obtained over 360-day study period, expressed as "medication possession ratio" (defined as the number of days' supply of medication obtained throughout the study period expressed as a ratio against the number of days that should have been supplied)
0.75 with unit-of-use packaging
0.87 with mailed reminder plus unit-of-use packaging
P <0.05
The unit-of-use packaging was not further defined 		Effect size not calculated prompting mechanism (mailed reminder) plus reminder packaging (unit-of-use-packaging)
Open in a new tab

Adverse effects

No data from the following reference on this outcome.

Further information on studies

RCT methods Follow-up was 100%. The method of randomisation was not described. The level of blinding was not reported. 'Unit-of-use' packaging was reported to be "a sequentially numbered 30-day supply inventory tray with easy-access compartments". It was not further described.

Comment

There is a small amount of evidence for effect when comparing prompting mechanisms with control. It is not surprising then, that when comparing prompting mechanisms plus reminder packaging with reminder packaging alone, we are seeing a statistically significant effect size. This is the case with the two RCTs identified; however, these were of low quality. Higher-quality RCTs are required to answer this question definitively, but such interventions do seem to hold promise in adherence to cardiovascular medication.

Substantive changes

Prompting mechanisms plus reminder packaging versus reminder packaging alone New option. No new evidence. Categorised as 'unknown effectiveness'.

BMJ Clin Evid. 2015 Sep 21;2015:0220.

Prompting mechanism plus patient education versus control

Summary

We don't know how prompting mechanisms plus patient education compare with control at increasing adherence to cardiovascular medication, as the evidence was weak.

Benefits and harms

Prompting mechanism plus patient education versus control:

We found 11 systematic reviews (search dates 1996; 2000; 2002; 2003; 2004; 2007; 2008; 2009), which identified one RCT of sufficient quality. See Further information on studies for full details on interventions. We found one subsequent RCT.

Adherence to medication

Prompting mechanism plus patient education compared with control A prompting intervention (including a telephone call and mailed reminder) plus patient education (including an educational programme, newsletter, and general health advice) may be more effective than control at improving adherence to medication in people with newly diagnosed hypertension and in people with existing hypertension at 1 year (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adherence to medication

RCT		 453 outpatients, mild to moderate hypertension, on once-daily atenolol, either new cases or existing (previously treated) Results expressed as "medication possession ratio" (defined as mean number of days' supply of medication obtained over 360-day trial period) follow-up at 6 months
0.82 with prompting intervention plus patient education
0.48 with control
P <0.05 		Effect size not calculated prompting intervention plus patient education

RCT		 453 outpatients, mild to moderate hypertension, on once-daily atenolol, either new cases or existing (previously treated) Results expressed as "medication possession ratio" (defined as mean number of days' supply of medication obtained over 360-day study period) follow-up at 6 months
0.93 with prompting intervention plus patient education
0.52 with control
P <0.05 		Effect size not calculated prompting intervention plus patient education

RCT		 440 people with established coronary heart disease in an inner-city primary care clinic Adherence to cardiovascular medication refills (determined by the calculation of the cumulative medication gap [CMG]; using refill data from the health system pharmacy) 1 year
37% with refill reminder postcards plus illustrated medication schedules
31% with control
Absolute numbers not reported
Significance of between-group difference not assessed
See Further information on studies
Open in a new tab

Adverse effects

No data from the following reference on this outcome.

Further information on studies

Prompting mechanism Active intervention consisted of health education (educational programme, newsletter discussing importance of compliance, nutrition, and lifestyle advice) plus prompting intervention (telephone conversation 1 week prior to next medication refill initially, and then mailed reminder 10 days prior to refill each month). RCT methods The method of randomisation was not described. The level of blinding was not described.

Prompting mechanism Medications were dispensed in a 30-day supply. Patients were randomised to: (i) reminder postcards mailed to their homes approximately 25 days after their last fill; (ii) illustrated medication schedules that visually depicted medication regimens; (iii) reminder postcard plus illustrated medication schedule; or (iv) a control group of usual pharmaceutical care (not further defined). RCT methods RCT had a 2 x 2 factorial design to compare four treatments in people with established coronary heart disease. The method of randomisation was described. Outcome assessors were masked to treatment, but patients and treating physicians were aware of treatments. The primary outcome was cardiovascular medication refill adherence, assessed by the cumulative medication gap (CMG). Patients with CMG less than 0.20 were considered adherent. No statistical comparisons between groups were carried out. Statistical significance of rate of adherence across all four treatments identified no statistically significant difference across groups (P = 0.58).

Comment

There is a small amount of evidence for effect when comparing prompting mechanisms with control. It is not surprising then, that when comparing prompting mechanisms plus patient education versus control, we are seeing a statistically significant effect size. This is the case with the two RCTs identified. Further RCTs are required to answer this question definitively, but such interventions do seem to hold promise in adherence to cardiovascular medication, particularly when newer technologies such as hand-held devices are used. One additional RCT that was identified used text messaging to promote medication adherence for patients with coronary heart disease and provided some evidence of efficacy, but follow-up was too short for this RCT to be included in this review.

Substantive changes

Prompting mechanisms plus patient education versus control New option. One RCT added. Categorised as 'unknown effectiveness'.

BMJ Clin Evid. 2015 Sep 21;2015:0220.

Prompting mechanisms plus patient education versus patient education alone

Summary

We don't know how prompting mechanisms plus patient education compare to patient education alone at increasing adherence to cardiovascular medication as the evidence was weak.

Benefits and harms

Prompting mechanisms plus patient education versus patient education alone:

We found 11 systematic reviews (search dates 1996; 2000; 2002; 2003; 2004; 2007; 2008; 2009), which identified no RCTs. We found one subsequent RCT.

Adherence to medication

Prompting mechanism plus patient education compared with patient education alone We don't know whether a prompting intervention (mailed reminder) plus patient education (illustrated medication schedules) is more effective than patient education alone at improving adherence to medication in people with established coronary heart disease (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adherence to medication

RCT		 440 people with established coronary heart disease in an inner-city primary care clinic Adherence to cardiovascular medication refills (determined by the calculation of the cumulative medication gap [CMG]; using refill data from the health system pharmacy) 1 year
37% with refill reminder postcards plus illustrated medication schedules
34% with illustrated medication schedules
Absolute numbers not reported
Significance of between-group difference not assessed
See Further information on studies
Open in a new tab

Adverse effects

No data from the following reference on this outcome.

Further information on studies

Prompting mechanism Medications were dispensed in a 30-day supply. Patients were randomised to: (i) reminder postcards mailed to their homes approximately 25 days after their last fill; (ii) illustrated medication schedules that visually depicted medication regimens; (iii) reminder postcard plus illustrated medication schedule; or (iv) a control group of usual pharmaceutical care (not further defined). RCT methods The RCT had a 2 x 2 factorial design to compare four treatments in people with established coronary heart disease. The method of randomisation was described. Outcome assessors were masked to treatment, but patients and treating physicians were aware of treatments. The primary outcome was cardiovascular medication refill adherence, assessed by the cumulative medication gap (CMG). Patients with CMG less than 0.20 were considered adherent. No statistical comparisons between groups were carried out. Statistical significance of rate of adherence across all four treatments identified no statistically significant difference across groups (P = 0.58).

Comment

We only found one RCT comparing prompting mechanisms plus patient education with patient education alone, and this study did not assess significance of between-group difference. Therefore, further RCTs are required to answer this question definitively.

Substantive changes

Prompting mechanisms plus patient education versus patient education alone New option. One RCT added. Categorised as 'unknown effectiveness'.

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