Cardiovascular medication: improving adherence

Liam G Glynn; Tom Fahey

. 2009 Aug 24;2009:0220.

Cardiovascular medication: improving adherence

Liam G Glynn ^1,^#, Tom Fahey ^2,^#

PMCID: PMC2907813

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 review reports effects of intervention on adherence to cardiovascular medications however adherence has been measured.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions 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 April 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 39 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: patient health education; prescriber education; prompting mechanisms; reminder packaging (calendar [blister] packs; multi-dose pill boxes); and simplified dosing.

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 review, 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 makes it difficult to separate out any individual components that might be of benefit.

We found evidence that simplified dosing regimens may increase adherence compared with more complex regimens.

While simplifying the frequency of dosage may increase adherence, it is not known whether simplified regimens may increase adherence when someone is taking multiple drugs, as may be the case with cardiovascular medicines.
In altering a drug regimen simply to increase adherence, any changes could potentially affect the effectiveness of the treatment, and could also potentially increase adverse effects.

Prompting mechanisms may also 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.

Patient health education does not seem effective in increasing adherence.

Adherence behaviour is complex. Traditional education methods may fail to address this.
We found some evidence that a combination of strategies, for example, education plus prompting, may be more successful than a single educational strategy.

We found no evidence from one RCT that reminder packaging (a calendar blister pack) was effective, and found insufficient evidence on other types of reminder packaging such as multi-dose pill boxes.

We don't know whether prescriber education is effective, as we found no RCTs.

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 of adherence: 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, metabolite, or biological marker 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, it 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 they 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.

Incidence/ Prevalence

Not applicable for this review.

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 only been taken 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: prescriber education; prompting mechanisms; patient health education; simplified dosing; and reminder packaging (blister packs and pill boxes), and 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. Educational interventions can be directed at prescribers, patients, and their family members using written material, videotape, or individual or group training. Prompting mechanisms are intended to stimulate medication-taking through mailed or telephoned reminders or through the use of electronic medication-reminder caps. Simplified dosing is intended to improve adherence through the reduction of dosing frequency (e.g., once-daily regimens v twice-daily regimens, or twice-daily regimens v 3 times-daily regimens). 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 that 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′s treatment pre-packaged 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 1, 2007. 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 prescribed cardiovascular medication, however measured. Adherence is often measured by pill count, prescription renewal requests, self-reporting, and electronic monitoring. Adverse effects.

Methods

Clinical Evidence search and appraisal April 2007. The following databases were used to identify studies for this systematic review: Medline 1987 to April 2007, Embase 1987 to April 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Randomized Trials 2007, Issue 1. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the authors for additional assessment, using pre-determined criteria to identify relevant studies. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. Study-design criteria for evaluation in this review were: published systematic reviews and RCTs in any language undertaken in adults. Further studies were identified from a search of bibliographies of identified systematic reviews. We included RCTs whatever the level of blinding (whether double blind, single blind, or open). RCTs had to contain at least 20 people in total, or at least 10 per study arm, of whom more than 80% were followed up. The minimum length of follow-up for inclusion of an RCT was 6 weeks. We have included RCTs in people with 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. Difficulties in evaluating RCTs included analysing a multiplicity of different interventions and combinations of different elements that were not easily categorised. Therefore, in each treatment option, we have explicitly stated what we have included under that option heading. We have excluded RCTs that employed complex interventions (i.e., mixtures of different elements) in which the individual effects of our intervention of interest could not be separately assessed. We have also excluded RCTs that did not directly report adherence 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 identified a number of systematic reviews that employed different inclusion criteria, and that categorised interventions in different groupings. The systematic reviews did not pool data because of differences between included RCTs (including study designs, interventions employed, and outcome measures assessed). We have therefore reported each of the RCTs included in the systematic reviews separately. 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, e.g., anxiety in some people). In the harms section, we have reported harms data relating directly to the adherence intervention employed. We have not reported harms data relating to the drug treatments used, as adherence is our outcome of interest. The exception to this is in the simplified-dosing option, where we have reported drug adverse effects, as the intervention directly alters the drug regimen (e.g., to once-daily dosage, rather than twice-daily). Hence, in this case, differences in drug adverse effects between the regimens are due to the adherence intervention itself. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). 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).

Table.

GRADE evaluation of interventions for improving adherence to cardiovascular medication.

Important outcomes	Adherence to medication, adverse effects
Number of studies (participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of interventions to improve adherence to long-term medication for CVD in adults?
5 (1107)	Adherence to medication	Prompting mechanism v usual care	4	–2	0	–2	0	Very low	Quality points deducted for incomplete reporting of results and weak methods (method of randomisation not described, level of blinding not reported). Directness points deducted for diverse interventions affecting generalisability, and diverse range of outcome assessment and analysis
2 (432)	Adherence to medication	Prompting mechanism plus usual care v unit-of-use packaging plus usual care v unit-of-use packaging plus prompting mechanism plus usual care v usual care alone	4	–2	0	–1	0	Very low	Quality points deducted for incomplete reporting of results and weak methods (method of randomisation not described, level of blinding not reported). Directness point deducted for unclear intervention (unit-of-use intervention not fully defined)
1 (453)	Adherence to medication	Prompting mechanism plus patient health education v usual care	4	–1	0	–1	0	Low	Quality point deducted for weak methods (method of randomisation not described, level of blinding not reported). Directness point deducted for unclear validity of outcome assessment/single measure of adherence used
5 (7750)	Adherence to medication	Simplified dosing regimens v more complex dosing regimens	4	–2	0	–1	0	Very low	Quality points deducted for weak methods (method of randomisation not described, level of blinding not reported) and inclusion of 2 crossover RCTs. Directness point deducted for diverse range of outcome assessment and analysis
1 (180)	Adherence to medication	Calendar (blister) pack v usual care	4	–3	0	0	0	Very low	Quality points deducted for sparse data, incomplete reporting of results, and weak methods (method of randomisation not described, level of blinding for outcome assessment not reported)
10 (at least 4161)	Adherence to medication	Patient health education v usual care	4	–2	–1	–2	0	Very low	Quality points deducted for incomplete reporting of results and weak methods (method of randomisation not described, level of blinding not reported). Consistency point deducted for conflicting results. Directness points deducted for diverse interventions affecting generalisability, and diverse range of outcome assessment and analysis

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Type of evidence: 4 = RCT Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds 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.
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 G Glynn, National University of Ireland, Galway, Ireland.

Tom Fahey, RCSI Medical School, Dublin, Ireland.

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BMJ Clin Evid. 2009 Aug 24;2009:0220.

Prompting mechanisms

Summary

ADHERENCE TO MEDICATION Prompting mechanisms compared with usual care: Prompting interventions (including daily and weekly telephone calls, videotelephone calls, mailed reminders, and electronic medication-reminder caps) may be more effective than usual care 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). Prompting mechanism plus usual care compared with unit-of-use packaging plus usual care compared with unit-of-use packaging plus prompting mechanism plus usual care compared with usual care alone: A prompting intervention (mailed reminder 10 days before refill date), unit-of-use packaging, and combined prompting intervention plus unit-of-use packaging, may all be more effective than usual care at improving adherence to medication in people with mild-to-moderate hypertension; and the combined prompting intervention plus unit-of-use packaging may be more effective than the prompting intervention alone or unit-of-use packaging alone. However, the unit-of-use packaging intervention was not fully defined (a 30-day inventory tray in 1 RCT; not defined in another RCT), which makes drawing conclusions on it difficult. We don't know whether a mailed prompting reminder is more effective than unit-of-use packaging at improving adherence (very low-quality evidence). Prompting mechanism plus patient health education compared with usual care: A prompting intervention (including a telephone call and mailed reminder) plus patient health education (including an educational programme, newsletter, and general health advice) may be more effective than usual care at improving adherence to medication in people with newly diagnosed hypertension and in people with existing hypertension at 1 year (low-quality evidence).

Benefits

We found ten systematic reviews (search date 1996;search date 2000;search date 2002; search date 2003; search date 2004 ), which identified seven RCTs of sufficient quality. The reviews did not pool data. We found one subsequent RCT.

Prompting mechanism versus usual care:

We found five RCTs (30–636 people) undertaken in a variety of different populations, which employed a number of prompting mechanisms and assessed different measures of adherence (see table 2 ). Some of the RCTs had weak methods, and completeness of reporting varied widely among trials. Three of the five RCTs found that the prompting mechanism significantly increased adherence compared with usual care. The remaining two three-armed RCTs, which only assessed among-group differences, found a significant difference among groups, with higher rates of adherence in the prompting-mechanism groups compared with the usual-care group (see table 2 ).

Table 2.

Prompting mechanisms to increase adherence to medications

Population	Intervention	Outcome measurement	Results	Comments
304 people, previously untreated mild-to-moderate hypertension, less than 65 years old, on verapamil once daily, refill medication dispensed in 30-day supplies	(1) Standard care; (2) standard care plus mailed reminder 10 days prior to medication refill date; (3) standard care plus unit-of-use packaging; (4) standard care plus mailed reminder plus unit-of-use packaging	Mean number of days' supply of medication obtained over 360-day study period expressed as MPR	All active-intervention groups significantly increased MPR compared with standard care (mean MPR: 0.56 with [1] v 0.64 with [2] v 0.67 with [3] v 0.79 with [4]; each active groups v standard care, P less than 0.05). Intervention (4) significantly increased MPR compared with all other groups (intervention [4] compared with [1], [2], or [3], P less than 0.05). No significant difference between (2) and (3) (P value not reported)	100% follow-up. Method of randomisation not described. Level of blinding 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
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	(1) Standard care; (2) standard care plus mailed reminder 10 days prior to medication refill date; (3) standard care plus unit-of-use packaging; (4) standard care plus mailed reminder plus unit-of-use packaging	Mean number of days' supply of medication obtained over 360-day study period expressed as MPR	All active-intervention groups significantly increased MPR compared with standard care (mean MPR: 0.64 with [1] v 0.71 with [2] v 0.75 with [3] v 0.87 with [4]; all active groups v standard care, P less than 0.05). Intervention (4) significantly increased MPR compared with all other groups (intervention [4] compared with [1], [2], or [3], P less than 0.05). No significant difference between (2) and (3) (P value not reported)	100% follow-up. Method of randomisation not described. Level of blinding not reported. ‘Unit-of-use' packaging not further described
70 people with hypertension on long-term treatment, age 50 years or older, on one or more drugs	(1) Electronic cap on medication vial (digital timepiece displayed when last opened, alarm bleeped when dose due, flashed when a dose missed); (2) medication vial with normal cap	Number of remaining doses in each vial counted at 12 weeks; % compliance defined as doses consumed/doses prescribed x 100. Blood pressure measured	Electronic cap significantly increased compliance compared with normal cap (mean compliance: 95% with electronic cap v 78% with standard cap; P = 0.0002)	Participants blinded, investigators not blinded. Method of randomisation not described. Loss to follow-up not reported. Blood pressure results presented as baseline analysis, no between-group analyses reported. Factoral design: only first randomisation reported here
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	(1) 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; (2) no telephone contact	Short term: pill and packet counts at the 6- and 12-week clinic visits. Long term: pharmacies contacted at 1 and 2 years to document refill information	No significant difference in compliance between groups (1) and (2) at 6 or 12 weeks (6 weeks: lovastatin, 92% with [1] v 89% with [2]; colestipol, 93% with [1] v 90% with [2]; reported as not significant, P values not reported; 12 weeks: lovastatin, 88% with [1] v 86% with [2]; colestipol, 90% with [1] v 88% with [2]; reported as not significant, P values not reported). Telephone contact significantly increased compliance at 1 and 2 years compared with no telephone contact (1 year: lovastatin, 71% with [1] v 47% with [2]; colestpol, 54% with [1] v 27% with [2]; 2 years: lovastatin, 63% with [1] v 39% with [2]; colestpol, 48% with [1] v 23% with [2]; P less than 0.05 for all comparisons). 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	The method of randomisation was described, and follow up was 100%. Different measures of adherence at short (up to 12 weeks) and long term (up to 2 years). Small RCT (15 people in each group).
60 people age 65 years or older, diagnosis of chronic heart failure, had to have telephone socket, home not in high-crime area, Mini Mental-Status Examination (MMSE) score of 20 or better.	(1) Daily telephone calls; (2) daily videotelephone calls; (3) usual care. Daily calls lasted 3–5 minutes and were made by research assistant on Monday to Friday	Compliance monitored by electronic caps on medication bottles. 6-week intervention phase followed by 2-week post-intervention compliance monitoring period	Compliance (baseline to post-intervention): 76% to 74% with (1) v 82% to 84% with (2) v 81% to 57% with (3). Significant difference among groups (P less than 0.05). Direct statistical analysis of (1) v (3) or (2) v (3) not reported. No significant difference between (1) and (2) (reported as not significant, P value not reported)	Method of randomisation was described. Results based on 50/60 (83%) of those randomised. Withdrawals in each individual group not reported. Participants offered $20 to take part in study. Electronic caps placed on maximum of 4 medication bottles for each person
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	(1) Control group: did not receive a reminder; (2) sent postcard 2 working days before medication refill due; (3) telephone call 1 working day before refill due	Compliant events, which equalled the number of refills divided by the possible number of refills. Outcome measured for 3 months	Post hoc analysis found that the postcard (group 2) and telephone call (group 3) significantly increased mean compliant events compared with control (mean compliant events for 3 months: 0.58 with [1] v 0.65 with [2] v 0.64 with group [3]; [2] or [3] v [1], P less than 0.05). It found no significant difference between (2) and (3) in mean compliant events (P value not reported)	Method of randomisation not described. Level of blinding not reported. A telephone call was also made to all people in groups (1), (2), and (3) who were 3 days late obtaining the medication. This was to determine: if postcard group had received postcard; if medication obtained at 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 not contacted by telephone (unlisted or telephone disconnected). Hence, withdrawals varied between groups
636 people with newly diagnosed or uncontrolled mild-to-moderate hypertension, aged 18–80 years old, on single therapy	(1) Control group (usual care); (2) telephone intervention — 3 calls in total by nurses after scheduled visits to reinforce compliance, standard call, with good compliance praised; (3) mailed intervention — 3 mailed communications reinforcing compliance, health education, and reminding people of clinic visits	Assessed at 5 clinic visits: inclusion visit, and 4 follow-up visits at 26, 52, 106, and 155 days. Compliance assessed by counting tablets; % compliance defined as total number of consumed tablets/total number of tablets that should have been consumed x 100	Significant difference in mean % compliance between groups (90% with [1] v 99% with [2] v 97% with [3]; between-group analysis, P = 0.0001; direct statistical analysis of individual active treatment groups v usual care group not reported). Significant difference in the proportion of compliers (participants with 80–110% drug consumption) between groups (69% with [1] v 96% with [2] v 91% with [3]; between-group analysis, P = 0.0001). Significantly superior control of blood pressure with (2) compared with (1) (63% with [2] v 47% with [1]; P less than 0.05)	Method of randomisation was described. Results based on follow-up of 538/636 (86%) people

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Notes: Medication possession ratio (MPR) was 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. Optimal outcome was a ratio of 1:1 (e.g., 360-days' supply of therapy obtained over a 360-day period). A less desirable outcome being a ratio of less than 1. LDL = low-density lipoprotein cholesterol, HDL = high-density lipoprotein cholesterol

The first RCT (70 people) in people with hypertension found that an electronic medication-reminder cap significantly improved adherence compared with a normal cap at 12 weeks. The second small RCT (30 people) in people at high cardiovascular risk found no significant difference in adherence at 6 or 12 weeks between weekly telephone calls for 12 weeks and usual care, but found that telephone calls significantly improved adherence compared with usual care at 1 and 2 years.The third RCT (311 people on cardiovascular medication) found that both a mailed reminder sent 2 days before medication refill and a telephone call 1 day before medication refill significantly increased adherence compared with usual care at 12 weeks.The fourth RCT (60 people with chronic heart failure), which compared daily telephone calls, daily videotelephone calls, and usual care for 6 weeks, found a significant difference in adherence between groups at 6 months, with higher rates of adherence seen in the prompting-mechanism groups.The fifth RCT (636 people with hypertension) comparing three telephone calls, three mailed reminders, and usual care, found a significant difference in adherence between groups at 6 months, with higher rates of adherence seen in the prompting-mechanism groups. Adherence was measured in a variety of ways in the five RCTs (pill counts, pharmacy refill records, electronic caps) and overall compliance was calculated in different ways with no standard method employed.

Prompting mechanism plus usual care versus unit-of-use packaging plus usual care versus unit-of-use packaging plus prompting mechanism plus usual care versus usual care alone:

We found two RCTs (304 people; 128 people; previously untreated mild-to-moderate hypertension) undertaken by the same research group, which employed a similar methodology and compared: usual care alone; usual care plus mailed reminder 10 days prior to medication refill date; usual care plus unit-of-use packaging; and usual care plus mailed reminder plus unit-of-use packaging (see table 2 ). Both RCTs found that all the active interventions significantly improved adherence compared with usual care, found no significant difference in adherence between the prompting mechanism alone and unit-of-use packaging alone, and found that the combined mailed reminder plus unit-of-use packaging intervention significantly improved adherence compared with either active intervention alone. In one RCT, 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. In the other RCT, the unit-of-use packaging was reported to be specialised packaging, but was not defined. Hence, in this RCT, we were unable to draw reliable conclusions on the arms containing the unit-of-use packaging intervention.

Prompting mechanism plus patient health education versus usual care:

We found one RCT (453 people with newly diagnosed or existing hypertension) of an educational intervention (including educational programme, newsletter, and general health advice) plus a prompting intervention (telephone call and mailed reminder) significantly improved adherence compared with usual care at 1 year both in people with existing hypertension and in people with newly diagnosed hypertension (see table 3 ).

Table 3.

Patient health education to increase adherence to medications

Population	Intervention	Outcome measurement	Results	Comments
230 male steelworkers, with hypertension, not on current treatment	(1) Educational programme on facts about hypertension, benefits of treatment, need for compliance, slide–audiotape format and booklet, and ‘”patient educator” (non-health professional) to reinforce messages; (2) no health education	6 months' follow-up. Assessment by pill count. Compliance defined as the % of medication prescribed for 6 months that was removed from the bottle. Defined ‘compliant' if compliance pill count of 80% or more	Of 115 in each group, 80 (70%) in education group and 64 (56%) in no education group received drug treatment. Similar compliance between these groups at 6 months (40/80 [50%] with (1) v 36/64 [56%] with (2); P value not reported)	Method of randomisation not described. Factoral design. Steelworkers also randomised to family doctor or industrial physician care at the same time to see if difference in outcome; these results not reported here. Interpretation complicated by factoral design and only 144 (62%) of those randomised received drug treatment — results based on these 144 men
110 people, with either newly diagnosed or established treated hypertension, mean age 59 years	(1) Group education (units of 15 people over 90 minutes, information about blood pressure management and importance of adherence) and additional postal education at 1, 3, and 5 months; (2) usual care	Pill count. 6 months' follow-up	Education significantly improved adherence compared with usual care (93% with (1) v 69% with (2); P less than 0.002)	Method of randomisation not described; not reported if outcome assessment blinded; withdrawal 15/110 (14%)
Long-term follow-up of RCT reported above	As above	Pill count. Follow-up for 2 years	Education significantly improved adherence compared with usual care (96% with (1) v 56% with (2); P less than 0.001)	Method of randomisation not described; not reported if outcome assessment blinded; withdrawal 18/110 (16%)
110 people, mean age 56 years, started on lipid-lowering medication (fluvastatin) mainly for primary prevention	(1) Small group training followed by postal information packages; (2) usual care	Pill count. Follow-up 4 months	No significant difference between groups in % of pills taken (88% with (1) v 84% with (2); P greater than 0.05). No significant difference between groups for mean total cholesterol (P = 0.26), mean LDL (P = 0.48), or mean HDL (P = 0.48). (1) significantly reduced triglyceride compared with (2) (P less than 0.05)	Final end points compared, not adjusted for baseline differences
115 people attending a primary care clinic, less than 70 years old, with hypertension, living near to clinic	(1) Health education. Four 90-minute meetings, emphasising importance of hypertension, including videotape and other standard material, and general health education; (2) daily self-monitoring of blood pressure; (3) both education and daily self-monitoring of blood pressure; (4) control	Self-reported compliance. Survey conducted by nurse, household medicated survey, which included questions on drugs and a count of all hypertensive medications	Absolute numbers of “good”, “fair”, and “poor” compliance: 8, 13, 8 with (1) v 7, 13, 5 with (2) v 9, 15, 6 with (3) v 7, 12, 10 with (4). RCT reported “no significant difference between groups on compliance” (P values not reported)	Randomisation procedure was described. Compliance categorised as “good”, “fair”, or “poor”, the basis of which not explained. Hence, difficult to interpret results
417 people with hypertension, on medication	(1) Printed messages — “threatening message” group. Informational tabloid contained material on hypertension, its effects, control measures, and instructions on following regimen. This version emphasised severity of hypertension and consequences; (2) printed messages — “positive message” group. Tabloid as above, but emphasised positive health aspects of treatment; (3) control group	Follow-up 4 months. Self-reporting at interview and analysis of number of tablets prescribed by pharmacy records	No significant difference between education and no education in compliance with medication (self-reported: 91% with education v 90% with no education; pharmacy score: 69% with education v 68% with no education; reported as not significant, P values not reported)	Factoral design — people sequentially allocated to different interventions. Only the first randomisation reported here. Method of randomisation not described. Level of blinding not reported. Intervention groups (1) and (2) were combined in analysis. At outset, 87% of participants were on medication. Follow-up for self-report scores and pharmacy scores unclear
34 people with hypertension on treatment, age 16 years or older (average age 51–56 years), at tertiary care medical centre	(1) 30- to 40-minute intervention with nurse practitioner and follow-up telephone call 4 weeks later, included reinforcement of regimen, brochure, 12-minute audiovisual presentation, and discussion of risk factors, and postcard reminder of next appointment; (2) usual care	Outcomes measured at 6 months. Self-reported compliance as assessed by interview with questionnaire, and the physician's assessment of adherence	No significant difference between groups in self-reported compliance (score measured on 6-point scale, where 0 = no adherence and 5 = all tablets taken: 27.53 with (1) v 24.46 with (2); P = 0.05). Group (1) significantly increased physician-rated compliance compared with (2) (score: 29.18 with (1) v 23.9 with (2); P = 0.003)	Method of randomisation not described. Level of blinding not described. Small study. Not clear on what basis the physician's assessment of compliance was made. Differential withdrawals — results based on 17/17 (100%) in intervention group and 13/17 (76%) in control group
453 outpatients, mild-to-moderate hypertension, on once-daily atenolol, either new cases or existing (previously treated)	(1) 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); (2) usual care	Follow-up 6 months. Results presented separately for new and existing cases. Mean number of days' supply of medication obtained over 360-day study period expressed as MPR	Both for existing cases (344 people) and new cases (109 people), education plus prompting intervention significantly increased MPR compared with usual care (existing: mean MPR, 0.82 with (1) v 0.48 with (2); new: 0.93 with (1) v 0.52 with (2); P less than 0.05 for both comparisons)	Method of randomisation not described. Level of blinding not described
Participants chosen from database by prescription (rather than diagnosis), 410 people taking benazepril, 1728 taking metoprolol, and 568 taking simvastatin, mean age 55 years old (range 20–97 years), with refill of medication every 30 days	(1) Mailed one relevant educational videotape on drug prescribed and inferred disease state, 30 minutes long, including advice on compliance (single mailing); (2) usual care	Outcome data collected over 9 months, refill data from pharmacy records. Index of compliance was MPR. Defined as compliant if MPR 0.80 or greater	No significant between-group differences in mean MPRs (benazepril: 0.71 with (1) v 0.72 with (2); metoprolol: 0.74 with (1) v 0.73 with (2); simvastatin: 0.73 with (1) v 0.70 with (2); reported as no significant difference between groups, P values not reported)	People selected by medication from computerised database. RCT inferred that people taking benazepril and metoprolol had hypertension and those taking simvastatin had hyperlipidaemia, which may or may not be the case. Also investigated people with transdermal oestrogen: these results not reported here. Method of randomisation, level of blinding, and loss to follow-up not reported. Not known if all participants in videotape group had access to a video player
100 people over 70 years of age with chronic stable heart failure, average age 85 years, excluded if mobility disorder or Folstein's Mental Health test score was less than 21	(1) Counselling programme including a standard written protocol employing verbal counselling, medication calendars, and information leaflets; (2) control group	Compliance measured by pill count at domiciliary visit and final outpatient appointment. 2 visits at 2–4-weekly intervals and final outpatient attendance at 2–4 weeks after last visit. Compliance expressed as % of maximum number of tablets that should have been consumed	Counselling programme significantly increased mean compliance compared with control (93% with [1] v 51% with [2]; P less than 0.001)	Method of randomisation not described. Follow-up 82/100 (82%)
245 people with hypertension, on 1 or more medications, attending primary care	(1) Adherence support session by practice nurse (20 minutes) followed by reinforcement session (10 minutes), which explored patient concerns regarding medication, whether person understood diagnosis, and strategies to resolve medication problems; (2) usual care	Adherence measured by electronic medication monitor (electronic lid that registered time and date of opening) for 6 months. 'Timing compliance' defined as number of doses taken at 24- or 12-hour intervals for a once- or twice-daily regimen respectively, divided by the total number of days x 100%	No significant difference at 6 months between groups (1) and (2) in mean timing compliance (87% with [1] v 90% with [2]; adjusted difference between means –1, 95% CI –5.1 to +3.1, P = 0.63; regression analysis). No significant difference between groups at 6 months with regard to systolic (P = 0.24) or diastolic (P = 0.85) blood pressure	Method of randomisation was described. Open label. Follow-up 204/245 (83%). Study noted that it found higher levels of adherence to medication than in previous studies in similar populations
314 people with heart failure, 50 years or older, attending primary care, on at least one medication	(1) Pharmacist-delivered intervention by protocol, included verbal and written material, exploring participant's understanding of disease or medication, addressing low medication adherence; (2) usual care. Intervention period 9 months	Adherence measured by electronic medication monitor (electronic lid that registered time and date of opening). Measured during intervention period (9 months) and post-intervention (3 months). “Taking adherence” was the % of prescribed medication taken, and “scheduling adherence” was defined as day-to-day deviation in timing of dose (e.g., once-daily within 2.4 hours of dose on previous day)	Group (1) significantly increased taking adherence and scheduling adherence compared with group (2) over the 9-month course of study (doses taken, taking adherence: 79% with (1) v 68% with (2), difference 11%, 95% CI 5.0% to 16.7%; scheduling adherence: 53% with (1) v 47% with (2), difference 6%, 95% CI 0.4% to 11.5%). No significant difference between groups (1) and (2) in taking adherence or scheduling adherence in the 3 months after the intervention had finished (doses taken, taking adherence: 71% with (1) v 67% with (2), difference +4%, 95% CI –2.8% to +10.7%; scheduling adherence: 48.9% with (1) v 48.6% with (2), difference +0.3%, 95% CI –5.9% to +6.5%)	Method of randomisation was described. Assessment blinded. Analysis based on 270/314 (86%) of those randomised. Found benefit when the intervention being applied over the study period, which dissipated over 3 months after the intervention had finished

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Notes: Medication possession ratio (MPR) was 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. Optimal outcome was a ratio of 1:1 (e.g., 360 days' supply of therapy obtained over a 360-day period). A less desirable outcome being a ratio of less than 1

Prompting mechanisms versus prescriber education, patient health education, or simplified dosing:

We found no RCTs.

Harms

Prompting mechanism versus usual care:

The RCTs did not report on adverse effects associated with the use of the prompting mechanism.

Prompting mechanism plus usual care versus unit-of-use packaging plus usual care versus unit-of-use packaging plus prompting mechanism plus usual care versus usual care alone:

The RCTs did not report on adverse effects.

Prompting mechanism plus patient health education versus usual care:

The RCT did not report on adverse effects associated with the use of the educational intervention.

Prompting mechanisms versus prescriber education, patient health education, or simplified dosing:

We found no RCTs.

Comment

In this option, we have included RCTs that included any form of prompting mechanism (e.g., telephone calls, mailed reminders, computer-generated prescription reminders).

Clinical guide:

As outlined above, 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, videotelephone calls, or electronic medication-reminder caps. There is a small amount of evidence for effect with all of the above mechanisms, but several (e.g., daily telephone calls, installing videophones, etc.) remain impracticable for use in routine clinical practice.

Substantive changes

Prompting mechanisms New option. Ten systematic reviews identified (search date 1996;search date 2000;search date 2002; search date 2003; search date 2004 ), which did not pool data. The reviews identified seven RCTs of sufficient quality and we found one subsequent RCT.Five RCTs compared various prompting mechanisms versus usual care; two RCTs compared a prompting mechanism plus usual care versus unit-of-use packaging plus usual care, unit-of-use packaging plus prompting mechanism plus usual care, or usual care alone; and the remaining RCT compared a prompting mechanism plus patient health education versus usual care. Prompting mechanisms categorised as Likely to be beneficial.

BMJ Clin Evid. 2009 Aug 24;2009:0220.

Simplified dosing

Summary

ADHERENCE TO MEDICATION Simplified dosing regimens compared with more complex dosing regimens: Simplified dosing regimens may be more effective than more complex dosing regimens (e.g., once-daily regimens compared with twice-daily regimens, or twice-daily regimens compared with three-times daily regimens) at increasing adherence to medication in people with hypertension, hyperlipidaemia, and angina (very low-quality evidence). NOTE We found no clinically important results from RCTs about simplified dosing regimens compared with patient health education, prompting mechanisms, prescriber education, or reminder packaging in relation to improving adherence to medication.

Benefits

We found 10 systematic reviews (search date 1996; search date 2000; search date 2002; search date 2003; search date 2004 ), which identified five RCTs of sufficient quality. The reviews did not pool data. We found no subsequent RCTs.

Simplified dosing regimens versus more complex dosing regimens:

We found five RCTs (27–7274 people) undertaken in a variety of different populations (people with hypertension, hyperlipidaemia, and angina) comparing either once-daily versus twice-daily medication, twice-daily versus three-times daily medication, or twice-daily versus four-times daily medication, and assessed different measures of adherence (see table 4 ). Three of the RCTs were small (27 people; 29 men; 31 people) and two of these were crossover studies, and the results should therefore be interpreted with caution. The larger RCTs (389 people; 7274 people) measured outcomes at 10 and 12 weeks, but not longer term. All five RCTs found that the simplified dosing regimen significantly improved adherence compared with the normal regimen.

Table 4.

Simplified dosing to increase adherence to medications

Population	Intervention	Outcome measurement	Results	Comments
389 people with mild or moderate hypertension, mean age 53–54 years, adequately controlled, on metoprolol or propranolol either as monotherapy or in conjunction with diuretic	(1) Once-daily metoprolol (slow-release); (2) twice-daily metoprolol. Participants continued their other medications as normal	2 weeks of baseline monitoring on original medication then 8 weeks of intervention. Assessment by pill count at 6 and 10 weeks during clinic visit. Compliance defined as those people taking at least 80% or 90% of their medications.	Once-daily regimen significantly increased the proportion of people taking at least 90% of tablets (93% with once-daily regimen v 81.5% with twice-daily regimen; P = 0.009). Once-daily regimen significantly increased tablet count compliance over test period compared with twice-daily regimen (mean rank: 123.38 with once daily v 100.92 with twice daily; P = 0.0089). No significant difference between groups in blood pressure control measured in clinic (P value not reported)	Method of randomisation not described. Level of blinding not reported. Loss to follow-up 50/389 (13%). Subgroup also participated in home blood pressure monitoring: these results not presented here
7274 people with hypertension, suitable for treatment with nicardipine, age 18 years and older, mean age 50 years, 60% on current treatment	(1) Nicardipine twice daily (slow-release); (2) nicardipine 3 times daily. Other concomitant antihypertensive therapies allowed	Adherence assessed at 3 months by standardised interview. Participants asked to rate their compliance as either 100%, 80%, 60%, 40%, 20%, or 0%	The twice-daily regimen significantly increased compliance compared with the 3-times daily regimen (self-reported compliance of 100%, 80%, 0–60%: 82%, 15%, and 3% with twice daily v 71%, 24%, and 4% with 3 times daily; reported as “all the differences were statistically significant, P less than 0.001"). No significant difference between groups in blood pressure control (P = 0.185)	Method of randomisation was described. Open RCT. Results based on 6813/7274 (94%) of those randomised. The treating physicians' estimates of participants' compliance were consistent with the participants' estimates. Adherence measured by self-reporting. Acceptability of twice-daily treatment was rated significantly higher by participants compared with 3 times daily (P less than 0.001)
29 men, participants in earlier study, mean age 49 years, on niacin 4 times daily plus lovastatin twice daily plus colestipol twice daily for 1 year, adjusted to maintain target cholesterol 150–175 mg/dL, high risk of cardiac events (elevated apoprotein B or stenosis or strong family history)	(1) Niacin continued at 4 times daily; (2) niacin given twice daily. Other medication (lovastatin and colestipol) continued as before. Intervention continued for 8 months then groups were crossed over for further 8 months	Compliance calculated using computer that accounted for drug supplies given, the recommended dosage, and a count of returned medication. Expressed as % of dose recommended	After 8 months, the compliance was significantly higher with twice-daily niacin compared with 4-times daily niacin (96% with twice daily v 85% with 4 times daily; P = 0.01)	Method of randomisation not described. Level of blinding not reported. Crossover RCT — results should be interpreted with caution
31 people with stable angina, mean age 63–64 years (range 47–74 years)	(1) Isosorbide mononitrate once daily; (2) isosorbide mononitrate twice daily	Follow-up 12 weeks. Compliance assessed by electronic bottle cap that measured date and time bottle opened. Also pill count	No difference between groups in manual pill count (tablets consumed, % of correct number: 98% with once daily v 98% with twice daily; statistical analysis not reported). By electronic measure, the once-daily regimen significantly increased the % of days with the correct number of openings (mean: 97% with once daily v 88% with twice daily; P less than 0.05) and the % of intervals between openings within the correct time range (mean: 88% with once daily v 69% with twice daily; P less than 0.05). No significant differences between groups in number of angina attacks or mean number of rescue GTN tablets taken (P value not reported)	Method of randomisation not described. Participants were aware cap was recording opening of bottle. Follow-up 29/31 (94%). Small RCT
27 people, mild hypertension, well controlled on monotherapy, mean age 62 years	(1) Enalapril once daily; (2) enalapril twice daily. Crossover design, given initial treatment for 4 weeks then groups crossed over	Follow-up at 8 weeks (after crossover). Compliance assessed by electronic bottle cap which measured date and time bottle opened, and also by pill count	Once-daily regimen significantly increased range of adherence measures compared with twice-daily regimen, including % of doses taken by pill count (P less than 0.01), % of doses taken by electronic count (P less than 0.001), % of days with correct number of doses taken (P less than 0.001). No significant difference between groups in blood pressure measurements, although differences approached significance in favour of the twice-daily regimen	Randomisation method not described. Evaluation blinded. Follow-up 25/27 (93%). All groups received home visits every 2 weeks for duration of study. Third 4-week treatment period incorporated into study design to detect carryover effects as no wash-out period between treatments. Crossover RCT — results should be interpreted with caution

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The first RCT (389 people with hypertension) found that once-daily metoprolol significantly increased adherence measured by pill count compared with twice-daily metoprolol at 10 weeks; while a second RCT (7274 people with hypertension) found that twice-daily nicardipine significantly increased adherence measured by self-reporting compared with three-times daily nicardipine at 12 weeks.

The third RCT (27 people with hypertension, crossover design) found that enalapril once daily significantly increased adherence compared with twice-daily enalapril at 8 weeks. The RCT found no significant differences between groups in blood pressure measurements, although differences between groups approached significance in favour of the twice-daily regimen.

The fourth RCT (29 men with high risk of cardiac events, crossover design) found that twice-daily niacin significantly improved adherence compared with four-times daily niacin at 8 months.

The fifth RCT (31 people with stable angina) found that once daily isosorbide mononitrate significantly increased adherence compared with twice-daily isosorbide mononitrate measured by an electronic bottle cap at 12 weeks, but found no significant difference between groups in adherence measured by pill count.

Simplified dosing versus patient health education, prompting mechanisms, prescriber education, or reminder packaging:

We found no RCTs.

Harms

Simplified dosing regimens versus more complex dosing regimens:

The first RCT found no significant difference in adverse effects between once-daily and twice-daily metoprolol.

The second RCT found a significantly higher occurrence of pruritus (P = 0.043), palpitations (P = 0.033), hot flushes (P = 0.024), and people with at least one adverse event (P = 0.004) with three-times daily nicardipine versus twice-daily nicardipine (absolute numbers not reported).

The third RCT gave no information on adverse effects.

The fourth RCT found that twice-daily niacin was associated with significantly fewer episodes of flushing compared with four-times daily niacin (14 people with twice-daily niacin v 6 people with 4-times daily niacin; P less than 0.005).

The fifth RCT reported that none of the differences in tolerability were significantly different between once- and twice-daily isosorbide mononitrate (absolute numbers and P value not reported).

Simplified dosing versus patient health education, prompting mechanisms, prescriber education, or reminder packaging:

We found no RCTs.

Comment

In this option we have included any RCTs that compared any form of simplified dosing (that is, a reduction in the number of tablets taken daily). All included RCTs compared different regimens of the same drug. We excluded RCTs that compared different drugs in each arm (e.g., one drug once daily v a different drug twice daily), as the different drugs in each arm may have different acceptabilities, which may affect adherence in each arm, making interpretation of adherence between groups difficult.

Clinical guide:

The relatively limited evidence (small number of RCTs and short follow-up period) supports the strategy of simplifying the frequency of dosage of medication when prescribing cardiovascular medicines. Whether simplification of dosage influences adherence when a patient is taking multiple drugs (the usual situation in secondary prevention of CHD) is not known. Similarly, the trade-off between simplification of dosage to enhance adherence balanced against the risk of altered pharmacodynamics and pharmacokinetics, particularly in elderly patients at risk of adverse drug reactions, is also unknown. Nevertheless, provision of simple, clear instructions alongside simplification of the dosage regimen seems a sensible and pragmatic strategy.

Substantive changes

Simplified dosing New option. Ten systematic reviews identified (search date 1996; search date 2000; search date 2002; search date 2003; search date 2004 ), which did not pool data. The reviews identified five RCTs of sufficient quality, and we found no subsequent RCTs. Three RCTs compared once-daily versus twice-daily medication, one RCT compared twice-daily versus three-times daily medication, and the remaining RCT compared twice-daily versus four-times daily medication. Simplified dosing categorised as Likely to be beneficial.

BMJ Clin Evid. 2009 Aug 24;2009:0220.

Prescriber education

Summary

We found no clinically important results from RCTs about adherence to medication from a prescribing clinician who had been given a directed educational intervention to increase adherence compared with a prescribing clinician who had not been given a directed educational intervention.

Benefits

We found eight systematic reviews (search date 1996;search date 2000;search date 2002; search date 2003; search date 2004 ).

Prescriber education versus usual care:

The systematic reviews identified no RCTs of sufficient quality. We found no subsequent RCTs.

Prescriber education versus prompting mechanisms, patient health education, simplified dosing, or reminder packaging:

The systematic reviews identified no RCTs of sufficient quality. We found no subsequent RCTs.

Harms

Prescriber education versus usual care:

We found no RCTs.

Prescriber education versus prompting mechanisms, patient health education, simplified dosing, or reminder packaging:

We found no RCTs.

Comment

In this option, prescriber education refers to a prescribing clinician who has received a directed intervention (educational) aimed at improving medication adherence in people to whom he or she has prescribed; this is compared with adherence achieved by another clinician of a similar overall training level, but who has not received the educational intervention.

Clinical guide:

Prescribers play a key initial role in the process of adherence to medication within the setting of a therapeutic alliance between clinician and patient. However, they still remain removed from the process of medication-taking, which is the ultimate determinant of adherence. Despite this, educational interventions can be directed at prescribers with the aim of improving adherence, but such studies of sufficient methodological rigour have yet to be carried out.

Substantive changes

Prescriber education New option. We found eight systematic reviews (search date 1996;search date 2000;search date 2002; search date 2003; search date 2004 ), which found no RCTs of sufficient quality. We found no subsequent RCTs. Prescriber education categorised as Unknown effectiveness.

BMJ Clin Evid. 2009 Aug 24;2009:0220.

Reminder packaging (calendar [blister] packs; multi-dose pill boxes)

Summary

ADHERENCE TO MEDICATION Calendar (blister pack) compared with usual care: We don't know whether packaging medication in calendar (blister) packs is more effective than packaging medication in traditional (usual) vials at improving adherence to medication at 12 weeks in people with hypertension (very low-quality evidence). Multi-dose pill box (unit-of-use packaging) plus usual care compared with usual care alone compared with prompting mechanism plus usual care compared with multi-dose pill box (unit-of-use packaging) plus prompting mechanism: Unit-of-use packaging, a prompting intervention (mailed reminder 10 days before refill date), and combined unit-of-use packaging plus prompting intervention, may all be more effective than usual care at improving adherence to medication in people with mild-to-moderate hypertension; and the combined unit-of-use packaging plus prompting intervention may be more effective than unit-of-use packaging alone or than the prompting intervention alone. However, the unit-of-use packaging intervention was not fully defined (a 30-day inventory tray in 1 RCT; not defined in another RCT), which makes drawing conclusions on it difficult. We don't know whether unit-of-use packaging is more effective than a mailed prompting reminder at improving adherence (very low-quality evidence). NOTE We found no clinically important results from RCTs about calendar (blister) packs compared with simplified dosing, patient health education, prompting mechanisms, prescriber education, or multi-dose pill boxes in relation to improving adherence to cardiovascular medication. We found no clinically important results from RCTs about multi-dose pill boxes compared with calendar (blister) packs, simplified dosing, patient health education, or prescriber education in relation to improving adherence to cardiovascular medication.

Benefits

We found 10 systematic reviews (search date 1996; search date 2000;search date 2002; search date 2003; search date 2004 ), which identified three RCTs. We found no subsequent RCTs.

Calendar (blister) pack versus usual care:

One RCT included in the reviews (180 people with previously diagnosed hypertension, aged 20–80 years, poor blood pressure control on at least one visit in the last 2 years) compared medications dispensed in special packaging versus medications dispensed in traditional (usual) pill vials (see table 5 ). The special packaging was a commercially available system comprising 28 doses of medication. All pills were enclosed in a single plastic blister sealed with foil, on which was printed the day of week and time of day the medication was due. Adherence was assessed both by self-reports of compliance and by pill counts. Results were based on people who completed the study, and varied between analysis because of missing data. The RCT found no significant difference between groups in adherence (people taking above 80% of pills) at 3 months however measured (self-reported: 169/180 [94%] people analysed, adherence 56% with special packaging v 54% with traditional packaging; pill count: 158/180 [88%] people analysed, adherence 84% with special packaging v 75% with traditional packaging; both comparisons reported as not significant, P values not reported). The RCT also found no significant difference between groups in average diastolic blood pressures at 3 months.

Table 5.

Reminder packaging to increase adherence to medications

Population	Intervention	Outcome measurement	Results	Comments
180 subjects with elevated diastolic blood pressure greater than 90 mm Hg in the 2 years prior to the study; recruited from people getting care at a community hospital-based family medicine practice	(1) People received antihypertensive medication in special unit dose-reminder packaging; (2) people received antihypertensive medication in usual vials. Participants continued their other medications as normal	Follow-up interviews, pill counts, and blood pressure measurements at 3-month intervals.	On 165 participants completing the first follow-up visit. RCT found no significant improvements in blood pressure control or compliance (by pill count or self-reporting) for people receiving special medication packaging (P values not reported)	Method of randomisation not described. Physicians treating people were blinded to the study group, it was not reported whether assessment was blinded. Loss to follow-up at first follow-up visit was 15/180 (8%). In contrast to previously reported work, this RCT did not demonstrate any significant improvement in compliance with special packaging of antihypertensive medications

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Calendar (blister) packs versus simplified dosing, patient health education, prompting mechanisms, prescriber education, or multi-dose pill boxes:

We found no RCTs.

Multi-dose pill box (unit-of-use packaging) plus usual care versus usual care alone versus prompting mechanism plus usual care versus multi-dose pill box (unit-of-use packaging) plus prompting mechanism plus usual care:

See benefits of prompting mechanisms.

Multi-dose pill boxes versus calendar (blister) packs, simplified dosing, patient health education, or prescriber education:

The systematic reviews identified no RCTs of sufficient quality. We found no subsequent RCTs.

Harms

Calendar (blister pack) versus usual care:

The RCT did not report on adverse effects associated with the use of calendar (blister) packs.

Calendar (blister) packs versus simplified dosing, patient health education, prompting mechanisms, prescriber education, or multi-dose pill boxes:

We found no RCTs.

Multi-dose pill box (unit-of-use packaging) plus usual care versus usual care alone versus prompting mechanism plus usual care versus multi-dose pill box (unit-of-use packaging) plus prompting mechanism plus usual care:

See harms of prompting mechanisms.

Multi-dose pill boxes versus calendar (blister) packs, simplified dosing, patient health education, or prescriber education:

We found no RCTs.

Comment

Clinical guide:

Reminder packaging now appears commonly in clinical practice as more and more drug companies produce their medications in calendar packs, and the use of multi-dose pill boxes, especially for the elderly, continues to rise. Although the benefit seems self-evident, there are few data published on the subject. The only RCT of sufficient quality included here on calendar (blister) packs, which compared medications dispensed in special packaging versus medications dispensed in traditional pill vials, found no significant difference between groups in adherence.

Substantive changes

Reminder packaging (calendar [blister] packs; multi-dose pill boxes) New option. We identified ten systematic reviews (search date 1996; search date 2000;search date 2002; search date 2003; search date 2004 ), which did not pool data. The reviews identified three RCTs. We found no subsequent RCTs. One RCT compared a calendar (blister) pack versus usual care, while two RCTs compared unit-of-use packaging plus usual care versus a prompting mechanism plus usual care, unit-of-use packaging plus prompting mechanism plus usual care, or usual care alone. Reminder packaging categorised as Unknown effectiveness.

BMJ Clin Evid. 2009 Aug 24;2009:0220.

Patient health education

Summary

ADHERENCE TO MEDICATION Compared with usual care: Patient health education may be no more effective than usual care at improving adherence in people taking cardiovascular medication. However, the education interventions used were diverse, and results varied by the specific educational intervention employed (very low-quality evidence). Patient health education plus prompting mechanism compared with usual care: Patient health education (including an educational programme, newsletter, and general health advice) plus a prompting intervention (including a telephone call and mailed reminder) may be more effective than usual care at improving adherence to medication in people with newly diagnosed hypertension, and in people with existing hypertension at 1 year (low-quality evidence).

Benefits

We found nine systematic reviews (search date 1996; search date 2000;search date 2002; search date 2003; search date 2004 ), which identified nine RCTs of sufficient quality published in 10 reports. The reviews did not pool data. We found two subsequent RCTs.

Patient health education versus usual care:

We found 10 RCTs (34–2618 people) including one extended follow-up report of an RCT undertaken in a variety of different populations (people with hypertension, hyperlipidaemia, and heart failure), which employed a number of educational interventions and assessed different measures of adherence (see table 3 ; see comment below). The content and method of delivery of the educational intervention varied widely. Some RCTs used written material only,or videotape only, while others used a mixture of different material delivered at group training, or individually administered, sometimes directly by a nurse or pharmacist. The intensity of the educational intervention varied from a single mailing of an educational videotape through to group education over 90 minutes followed by additional postal education over 5–24 months, or a pharmacist-delivered educational intervention over 9 months. Some of the RCTs were of poor methodological quality, and completeness of reporting varied widely between studies.

Of the 10 RCTs, six RCTs (34–2618 people) found no significant difference between patient health education and usual care in adherence at 6–9 months, and a seventh RCT (230 men) found similar adherence between health education and usual care at 6 months, but did not test the significance of differences between groups.

One RCT (110 people with hypertension) found that group education and additional postal education over 5 months significantly improved adherence compared with usual care at 6 months, and this difference persisted at 2 years; while another RCT (100 people with chronic heart failure) found that a counselling programme including information leaflets and medication calendars significantly increased adherence compared with usual care.

A third large, well-conducted RCT (314 people with heart failure), comparing a pharmacist-delivered intervention including verbal and written material over 9 months versus usual care, found that the educational intervention significantly improved adherence compared with usual care over the 9 months duration of the intervention, but found no significant difference in adherence between groups at 3 months after the intervention had ended.

Patient health education plus prompting mechanism versus usual care:

See benefits of prompting mechanisms.

Patient health education versus prompting mechanisms, prescriber education, simplified dosing, or reminder packaging:

We found no RCTs.

Harms

Patient health education versus usual care:

The RCTs did not report on adverse effects associated with the use of the educational intervention.

Patient health education plus prompting mechanism versus usual care:

See harms of prompting mechanisms.

Patient health education versus prompting mechanisms, prescriber education, simplified dosing, or reminder packaging:

We found no RCTs.

Comment

Clinical guide:

Most factors known to affect adherence to medication — such as knowledge, health beliefs, perception of risk, convenience, and memory — relate to the patient. It is therefore not surprising that interventions to address adherence should focus on patient education but what is perhaps surprising is that such interventions do not seem to have greater influence on adherence. However, the phenomenon of adherence is complex, and traditional educational methods may fail to recognise this. People's beliefs and preferences need to be acknowledged and incorporated into adherence-enhancing interventions. A combination of strategies including prompting mechanisms, simplified dosing, alongside patient education with emphasis on the patient's perspective, may have a more successful impact on adherence. The rationale that the complexity of adherence behaviour may respond better to a multi-factorial approach is supported by an RCT of an educational intervention plus a prompting intervention that significantly improved adherence compared with usual care, and by an RCT that used a combination of face-to-face education and follow-up postal education.

Substantive changes

Patient health education New option. We identified nine systematic reviews (search date 1996; search date 2000;search date 2002; search date 2003; search date 2004 ), which did not pool data. The reviews identified nine RCTs of sufficient quality published in 10 reports, and we found two subsequent RCTs. Ten RCTs, including one extended follow-up report of an RCTcompared various patient health education interventions versus usual care; and one RCT compared patient health education plus a prompting mechanism versus usual care.Patient health education categorised as Unlikely to be beneficial.

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PERMALINK

Cardiovascular medication: improving adherence

Liam G Glynn

Tom Fahey

Roles

Abstract

Introduction

Methods and outcomes

Results

Conclusions

Key Points

About this condition

Definition

Incidence/ Prevalence

Aetiology/ Risk factors

Table 1.

Prognosis

Aims of intervention

Outcomes

Methods

Table.

Glossary

Disclaimer

Contributor Information

References

Prompting mechanisms

Summary

Benefits

Prompting mechanism versus usual care:

Table 2.

Prompting mechanism plus usual care versus unit-of-use packaging plus usual care versus unit-of-use packaging plus prompting mechanism plus usual care versus usual care alone:

Prompting mechanism plus patient health education versus usual care:

Table 3.

Prompting mechanisms versus prescriber education, patient health education, or simplified dosing:

Harms

Prompting mechanism versus usual care:

Prompting mechanism plus usual care versus unit-of-use packaging plus usual care versus unit-of-use packaging plus prompting mechanism plus usual care versus usual care alone:

Prompting mechanism plus patient health education versus usual care:

Prompting mechanisms versus prescriber education, patient health education, or simplified dosing:

Comment

Clinical guide:

Substantive changes

Simplified dosing

Summary

Benefits

Simplified dosing regimens versus more complex dosing regimens:

Table 4.

Simplified dosing versus patient health education, prompting mechanisms, prescriber education, or reminder packaging:

Harms

Simplified dosing regimens versus more complex dosing regimens:

Simplified dosing versus patient health education, prompting mechanisms, prescriber education, or reminder packaging:

Comment

Clinical guide:

Substantive changes

Prescriber education

Summary

Benefits

Prescriber education versus usual care:

Prescriber education versus prompting mechanisms, patient health education, simplified dosing, or reminder packaging:

Harms

Prescriber education versus usual care:

Prescriber education versus prompting mechanisms, patient health education, simplified dosing, or reminder packaging:

Comment

Clinical guide:

Substantive changes

Reminder packaging (calendar [blister] packs; multi-dose pill boxes)

Summary

Benefits

Calendar (blister) pack versus usual care:

Table 5.

Calendar (blister) packs versus simplified dosing, patient health education, prompting mechanisms, prescriber education, or multi-dose pill boxes:

Multi-dose pill box (unit-of-use packaging) plus usual care versus usual care alone versus prompting mechanism plus usual care versus multi-dose pill box (unit-of-use packaging) plus prompting mechanism plus usual care:

Multi-dose pill boxes versus calendar (blister) packs, simplified dosing, patient health education, or prescriber education:

Harms

Calendar (blister pack) versus usual care:

Calendar (blister) packs versus simplified dosing, patient health education, prompting mechanisms, prescriber education, or multi-dose pill boxes:

Multi-dose pill box (unit-of-use packaging) plus usual care versus usual care alone versus prompting mechanism plus usual care versus multi-dose pill box (unit-of-use packaging) plus prompting mechanism plus usual care:

Multi-dose pill boxes versus calendar (blister) packs, simplified dosing, patient health education, or prescriber education:

Comment

Clinical guide: