Background
People who are prescribed self-administered medications typically take less than half the prescribed doses. Efforts to assist patients with adherence to medications might improve the benefits of prescribed medications, but also might increase their adverse effects.

Objectives
To update a review summarizing the results of randomized controlled trials (RCTs) of interventions to help patients follow prescriptions for medications for medical problems, including mental disorders but not addictions.

Search methods
We updated searches of The Cochrane Library, MEDLINE, CINAHL, EMBASE, International Pharmaceutical Abstracts (IPA), PsycINFO (all via OVID) and Sociological Abstracts (via CSA) in January 2007 with no language restriction. We also reviewed bibliographies in articles on patient adherence and articles in our personal collections, and contacted authors of relevant original and review articles.

Selection criteria
Articles were selected if they reported an unconfounded RCT of an intervention to improve adherence with prescribed medications, measuring both medication adherence and treatment outcome, with at least 80% follow-up of each group studied and, for long-term treatments, at least six months follow-up for studies with positive initial findings.

Data collection and analysis
Study design features, interventions and controls, and results were extracted by one review author and confirmed by at least one other review author. We extracted adherence rates and their measures of variance for all methods of measuring adherence in each study, and all outcome rates and their measures of variance for each study group, as well as levels of statistical significance for differences between study groups, consulting authors and verifying or correcting analyses as needed. The studies differed widely according to medical condition, patient population, intervention, measures of adherence, and clinical outcomes. Therefore, we did not feel that quantitative analysis was scientifically justified; rather, we conducted a qualitative analysis.

Main results
For short-term treatments, four of ten interventions reported in nine RCTs showed an effect on both adherence and at least one clinical outcome, while one intervention reported in one RCT significantly improved patient adherence, but did not enhance the clinical outcome. For long-term treatments, 36 of 83 interventions reported in 70 RCTs were associated with improvements in adherence, but only 25 interventions led to improvement in at least one treatment outcome. Almost all of the interventions that were effective for long-term care were complex, including combinations of more convenient care, information, reminders, self-monitoring, reinforcement, counseling, family therapy, psychological therapy, crisis intervention, manual telephone follow-up, and supportive care. Even the most effective interventions did not lead to large improvements in adherence and treatment outcomes.

Authors' conclusions
For short-term treatments several quite simple interventions increased adherence and improved patient outcomes, but the effects were inconsistent from study to study with less than half of studies showing benefits. Current methods of improving adherence for chronic health problems are mostly complex and not very effective, so that the full benefits of treatment cannot be realized. High priority should be given to fundamental and applied research concerning innovations to assist patients to follow medication prescriptions for long-term medical disorders.

Interventions for enhancing medication adherence.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(04)17670-8.pdf

External validity of randomised controlled trials: “To whom do the results of this trial apply?”

Objective To evaluate the relation between adherence to drug therapy, including placebo, and mortality. Design Meta-analysis of observational studies. Data sources Electronic databases, contact with investigators, and textbooks and reviews on adherence. Review methods Predefined criteria were used to select studies reporting mortality among participants with good and poor adherence to drug therapy. Data were extracted for disease, drug therapy groups, methods for measurement of adherence rate, definition for good adherence, and mortality. Results Data were available from 21 studies (46 847 participants), including eight studies with placebo arms (19 633 participants). Compared with poor adherence, good adherence was associated with lower mortality (odds ratio 0.56, 95% confidence interval 0.50 to 0.63). Good adherence to placebo was associated with lower mortality (0.56, 0.43 to 0.74), as was good adherence to beneficial drug therapy (0.55, 0.49 to 0.62). Good adherence to harmful drug therapy was associated with increased mortality (2.90, 1.04 to 8.11). Conclusion Good adherence to drug therapy is associated with positive health outcomes. Moreover, the observed association between good adherence to placebo and mortality supports the existence of the “healthy adherer” effect, whereby adherence to drug therapy may be a surrogate marker for overall healthy behaviour.

https://www.bmj.com/content/bmj/333/7557/15.full.pdf

A meta-analysis of the association between adherence to drug therapy and mortality

ADHERENCE MAY BE DEFINED AS the extent to which a patient’s behavior (in terms of taking medication, following a diet, modifying habits, or attending clinics) coincides with medical or health advice. If a patient is prescribed an antibiotic for an infection to be taken as 1 tablet 4 times a day for a week but takes only 2 tablets a day for 5 days, the adherence would be 36% (10/28). The term adherence is intended to be nonjudgmental, a statement of fact rather than of blame of the prescriber, patient, or treatment. Compliance and concordance are synonyms for adherence. This simple definition of adherence belies the difficulties that many medical regimens present for patients. For example, the regimen described for type 2 diabetes mellitus in a previous article includes a special diet, increased exercise, smoking cessation, oral hypoglycemic drugs, and risk factor management, usually involving additional drugs. Such regimens fulfill theoretical, physiological, and empirical considerations about optimal care, while ignoring practical patient-centered concerns, such as the nature, nurture, culture, and stereotyping of the patient, and the inconvenience, cost, and adverse effects of the treatment. Indeed, low adherence with prescribed treatments is very common. Typical adherence rates for prescribed medications are about 50% with a range of 0% to more than 100%.

Interventions to Enhance Patient Adherence to Medication Prescriptions

ContextLow adherence with prescribed treatments is ubiquitous and undermines
treatment benefits.ObjectiveTo systematically review published randomized controlled trials (RCTs)
of interventions to assist patients' adherence to prescribed medications.Data SourcesA search of MEDLINE, CINAHL, PSYCHLIT, SOCIOFILE, IPA, EMBASE, The Cochrane
Library databases, and bibliographies was performed for records from 1967
through August 2001 to identify relevant articles of all RCTs of interventions
intended to improve adherence to self-administered medications.Study Selection and Data ExtractionStudies were included if they reported an unconfounded RCT of an intervention
to improve adherence with prescribed medications for a medical or psychiatric
disorder; both adherence and treatment outcome were measured; follow-up of
at least 80% of each study group was reported; and the duration of follow-up
for studies with positive initial findings was at least 6 months. Information
on study design features, interventions, controls, and findings (adherence
rates and patient outcomes) were extracted for each article.Data SynthesisStudies were too disparate to warrant meta-analysis. Forty-nine percent
of the interventions tested (19 of 39 in 33 studies) were associated with
statistically significant increases in medication adherence and only 17 reported
statistically significant improvements in treatment outcomes. Almost all the
interventions that were effective for long-term care were complex, including
combinations of more convenient care, information, counseling, reminders,
self-monitoring, reinforcement, family therapy, and other forms of additional
supervision or attention. Even the most effective interventions had modest
effects.ConclusionsCurrent methods of improving medication adherence for chronic health
problems are mostly complex, labor-intensive, and not predictably effective.
The full benefits of medications cannot be realized at currently achievable
levels of adherence; therefore, more studies of innovative approaches to assist
patients to follow prescriptions for medications are needed.

https://jamanetwork.com/journals/jama/articlepdf/195605/JSR20016.pdf

Renato Dantes

Papers

Patient compliance and the conduct and interpretation of therapeutic trials.