This review compared the effects of fixed-dose combination pills and unit-of-use packaging with medications as usually presented on adherence and clinical outcomes. The authors concluded that combination pills and unit-of-use packaging were likely to improve adherence, but the effect size was uncertain. This was a well-conducted review and the authors' conclusions are likely to be robust.

To assess the effects on adherence and clinical outcomes of fixed-dose combination pills and unit-of-use packaging compared with medications as usually presented.

MEDLINE (from 1966), EMBASE (from 1980), CINAHL (from 1981) and International Pharmaceutical Abstracts (from 1970) were searched to May 2003. The Cochrane Library (Issue 2, 2003) and the meta Register of Controlled Trials were also searched. The search terms were reported. The bibliographies of retrieved studies were checked, and websites of institutes involved in research, policy and regulations relating to pharmaceuticals were searched. No restrictions on language, date or publication status were applied.

Study designs of evaluations included in the review

Quasi-randomised and randomised controlled trials (RCTs) were eligible for inclusion.

Specific interventions included in the review

Studies comparing combination pills or unit-of-use packaging with usual pill containers were eligible for inclusion. Bioequivalence studies were excluded, while studies of mixed interventions were only included if the groups differed only by one of the interventions compared. The included studies were conducted in economically developing and economically developed countries.

Participants included in the review

Studies of adults taking more than one oral self-administered medication were eligible for inclusion. The included studies were of participants receiving treatment for a variety of conditions (e.g. communicable diseases, hypertension and diabetes), vitamin supplements, and multiple medications in the elderly.

Outcomes assessed in the review

Studies that assessed clinical measures related to adherence or the pharmacological goal of the medication or cost were eligible for inclusion. The included studies assessed outcomes using a variety of measures including pill counting, self-report and urine tests for adherence (details of the measures used were reported).

How were decisions on the relevance of primary studies made?

Two reviewers independently assessed studies for relevance. How consensus was reached was not reported.

Aspects of validity were discussed in the review and presented in tables. These included study design, method of treatment allocation, sample size, study duration, drop-outs, methods used for statistical analysis and the use of intention-to-treat analysis. Two reviewers independently assessed validity. How consensus was reached was not reported.

Two reviewers independently extracted the data. How consensus was reached was not reported.

How were the studies combined?

The studies were grouped by type of intervention and combined in a narrative.

How were differences between studies investigated?

Differences between the studies were discussed in the text. Tables of study details and results were available on the World Health Organization website (accessed 06/01/2006). See Web Address at end of abstract.

Fifteen studies (n=3,561) were included. There were 12 RCTs (n=3,381), of which one was a factorial design (n=183) and two were multicentre cluster designs (n=1,671), as well as two crossover trials (n=96) and one non-randomised repeat crossover trial (n=84). The duration of the studies ranged from 3 days to 2 years, and the sample size ranged from 9 to 564.

Overall methodological limitations included small sample sizes, lack of blinding, short duration, losses to follow-up and inappropriate analysis (study design or clusters not taken into account in the analysis).

Fixed-dose combination (3 studies).

One study (n=701) of anti-tuberculosis medications found that combination tablets significantly increased the proportion of tuberculosis patients with sputum conversion at 8 weeks, but found no difference in compliance at 8 weeks or 6 months. Another study (n=105) found combination tablets improved sputum conversion at 8 weeks and radiological improvement and compliance at 2 years, but the improvements were not statistically significant. The third study (n=223) found that combination pills significantly increased self-reported adherence and non-statistically significantly improved clinical outcomes in patients with human immunodeficiency virus.

Unit-of-use packaging (12 studies).

One study (n=1,017) of infectious disease medications found no statistically significant difference between interventions in adherence, but found that packaging eased storage, handling and preservation, while a second (n=654) found that packaging significantly improved adherence. Two of three studies of hypertension medications found that calendar-blister packaging or a pill organiser plus patient education significantly reduced blood-pressure compared to education alone (n=162), while the third (n=171) found no difference between interventions. One study (n=68) in patients with poorly controlled diabetes found that calendar blister packs plus written instructions significantly reduced glycated haemoglobin and diastolic blood-pressure. One study (n=183) found high levels of adherence for both pill organisers and standard bottles over 2 months. The five studies (n=277) of medication aids in the elderly were all of a poor quality. Three found the medication aid improved adherence.

One study reported that pre-packing of a 3-day course for malaria reduced the total costs for treatment by 50%.

Evidence suggested that fixed-dose combination pills and unit-of-use packaging were likely to improve adherence, but the effect size was uncertain.

The review question was clear in terms of the study design, intervention, participants and outcomes. Several relevant sources were searched and attempts were made to minimise language and publication bias. Two reviewers independently selected the studies and extracted the data, thus reducing the potential for bias and errors. Aspects of validity were reported, and adequate information on the included studies was presented either in the text or in tables available online. Given the small number of heterogeneous studies, a narrative synthesis was appropriate. The narrative took methodological limitations of the studies into consideration. The authors' conclusions are likely to be robust.

Practice: The authors did not state any implications for practice.

Research: The authors stated that there is a need to develop and evaluate fixed-dose combination products, particularly in developing countries.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.