Identification and assessment of adherence-enhancing interventions in studies assessing medication adherence through electronically compiled drug dosing histories: a systematic literature review and meta-analysis

Abstract

Background: Non-adherence to medications is prevalent across all medical conditions that include ambulatory pharmacotherapy and is thus a major barrier to achieving the benefits of otherwise effective medicines.

Objective: The objective of this systematic review was to identify and to compare the efficacy of strategies and components thereof that improve implementation of the prescribed drug dosing regimen and maintain long-term persistence, based on quantitative evaluation of effect sizes across the aggregated trials.

Data sources: MEDLINE, EMBASE, CINAHL, the Cochrane Library, and PsycINFO were systematically searched for randomized controlled trials that tested the efficacy of adherence-enhancing strategies with self-administered medications. The searches were limited to papers in the English language and were included from database inception to 31 December 2011.

Study selection: Our review included randomized controlled trials in which adherence was assessed by electronically compiled drug dosing histories. Five thousand four hundred studies were screened. Eligibility assessment was performed independently by two reviewers. A structured data collection sheet was developed to extract data from each study.

Study appraisal and synthesis methods: The adherence-enhancing components were classified in eight categories. Quality of the papers was assessed using the criteria of the Cochrane Handbook for Systematic Reviews of Interventions guidelines to assess potential bias. A combined adherence outcome was derived from the different adherence variables available in the studies by extracting from each paper the available adherence summary variables in a pre-defined order (correct dosing, taking adherence, timing adherence, percentage of adherent patients). To study the association between the adherence-enhancing components and their effect on adherence, a linear meta-regression model, based on mean adherence point estimates, and a meta-analysis were conducted.

Results: Seventy-nine clinical trials published between 1995 and December 2011 were included in the review. Patients randomized to an intervention group had an average combined adherence outcome of 74.3 %, which was 14.1 % higher than in patients randomized to the control group (60.2 %). The linear meta-regression analysis with stepwise variable selection estimated an 8.8 % increase in adherence when the intervention included feedback to the patients of their recent dosing history (EM-feedback) (p < 0.01) and a 5.0 % increase in adherence when the intervention included a cognitive-educational component (p = 0.02). In addition, the effect of interventions on adherence decreased by 1.1 % each month. Sensitivity analysis by selecting only high-quality papers confirmed the robustness of the model. The random effects model in the meta-analysis, conducted on 48 studies, confirmed the above findings and showed that the improvement in adherence was 19.8 % (95 % CI 10.7-28.9 %) among patients receiving EM-feedback, almost double the improvement in adherence for studies that did not include this type of feedback [10.3 % (95 % CI 7.5-13.1 %)] (p < 0.01). The improvement in adherence was 16.1 % (95 % CI 10.7-21.6 %) in studies that tested cognitive-educational components versus 10.1 % (95 % CI 6.6-13.6 %) in studies that did not include this type of intervention (p = 0.04). Among 57 studies measuring clinical outcomes, only 8 reported a significant improvement in clinical outcome.

Limitations: Despite a common measurement, the meta-analysis was limited by the heterogeneity of the pooled data and the different measures of medication adherence. The funnel plot showed a possible publication bias in studies with high variability of the intervention effect.

Conclusions: Notwithstanding the statistical heterogeneity among the studies identified, and potential publication bias, the evidence from our meta-analysis suggests that EM-feedback and cognitive-educational interventions are potentially effective approaches to enhance patient adherence to medications. The limitations of this research highlight the urgent need to define guidelines and study characteristics for research protocols that can guide researchers in designing studies to assess the effects of adherence-enhancing interventions.

Fig. 1

Flow diagram of study selection process. CI confidence interval, SD standard deviation

Fig. 2

Combination of adherence-enhancing components for each intervention group (n = 87). Each column stands for one intervention group. Intervention groups are ranked by number and types of components tested. In each intervention group, the tested intervention components are illustrated by red boxes. TRT simpl Interventions based on treatment simplification, Cogn-Educ cognitive-educational interventions, Behav-Counsel behavioral-counseling interventions, Soc-Psych social-psycho-affective intervention, EM-feedback interventions based on electronic-monitoring adherence feedback, Tech rem interventions based on a technical reminder use, Tech equip interventions based on a technical equipment use, Rewards any kind of rewards for adhering to medications

Fig. 3

Improvement in adherence outcome (percentage points) by study duration (linear regression model) (n = 86) *Loess: locally weighted scatterplot smoothing

Fig. 4

Difference in the combined adherence outcome (expressed as percentages) between intervention and control group by adherence-enhancing component. The point near the middle of the box is the median. The lower and upper bounds of the box are the 25th and 75th percentile of the distribution. The ends of the whiskers represent the minimum and the maximum of the distribution after taking out the outliers. A point is considered as an outlier if it is above the 75th percentile of the distribution plus 1.5 of the interquartile range or if it is below the 25th percentile of the distribution minus 1.5 of the interquartile range. The reported p values are based on the Wilcoxon rank sum test to evaluate if there is any significant difference in adherence amelioration outcome between studies that included the corresponding intervention component and studies that did not include this type of intervention component. TRT simpl Interventions based on treatment simplification, Cogn-Educ cognitive-educational interventions, Behav-Counsel behavioral-counseling interventions, Soc-Psych social-psycho-affective intervention, EM-feedback interventions based on electronic-monitoring adherence feedback, Tech rem interventions based on a technical reminder use, Tech equip interventions based on a technical equipment use, Rewards any kind of rewards for adhering to medications. The number of studies that reported a statistical comparison between the groups (p value) and the proportion of them that were statistically significant at the 5 % level are depicted on the right-hand side

Fig. 5

Percentage point differences in adherence outcomes (ordered by year of publication)

Fig. 6

Funnel plot to assess any publication bias across studies