Technical interventions
Technical adherence interventions, for example on dosage and packaging, are usually directed at simplifying the medication regimen. Most adherence interventions in this domain are aimed either at reducing the number of doses per day, for example through extended release formulations, or at reducing the number of different drugs in the regimen, for example by using fixed dose combination pills. Fixed dose combination pills are pills that include two or more drugs in fixed proportions in the same formulation, or blister packaging of several medications in a fixed combination, to be taken together.
The effects of technical adherence interventions have been assessed in several single-focus and comparative reviews [
15,
36‐
40]. Most reviewers arrive at the same conclusion that a less frequent dosage results in better adherence. These results are found across a variety of medical disorders and diseases such as peptic ulcer, hypertension, diabetes and cardiovascular disorders. Depression is an exception to this rule; the number of anti-depressant drugs does not seem to be related to the number of drop-outs [
40].
Buring et al. performed a meta-analysis on adherence to antibiotic regimens for peptic ulcer disease caused by H. pylori [
36]. The number of doses a day of such regimens may range from one to 16. Their analysis of 56 primary studies showed that adherence rates were higher with regimens containing three or fewer doses a day, compared to four to six doses a day (p = 0.001), seven to eleven (p = 0.009) or 12 or more (p < 0.0001). In this review the magnitude of effect was not mentioned.
The meta-analysis of Iskedjian et al. [
38] also showed that the average adherence rate to antihypertension drugs was significantly higher for single daily dosage than for multiple daily dosage (91.4% versus 83.2%, p < 0.001). However, the longer the therapy lasted, the lower the adherence rates. For patients taking antihypertensive medication pill organizers and calendar packaging were also found to improve medication adherence [
41]. Electronic vial caps improved adherence in a trial among elderly patients. These medication containers display the time when the container was last opened and beep when a dose is due to be taken. The odds ratios in the experimental group were about six times higher than those in the control groups [
41].
The effectiveness of electronic devices on adherence was also investigated by Claxton et al. [
15]. In their review they selected studies (N = 76) that used Electronic Monitoring (EM) devices to measure adherence. Adherence appeared to decline as the number of daily doses increased. Adherence to one dose was 79%, two doses 69%, three doses 65% and four doses 51%. Simplification of regimen by unit-of-use packaging also seems to improve adherence, but uncertainty remains about the size of these benefits [
37]. All in all, there is consistent and robust evidence that simplifying medication dosage schedules leads to improved adherence [
32] and, where feasible, reducing dose frequency may offer health outcome and cost benefits for the patients [
39]. However, there are indications that the effects of this simplification become less the longer the treatment lasts.
Behavioural interventions
The most common behavioural interventions provide patients with memory aids and reminders, whether by mail, telephone, computer, or by home visits. Other classes of interventions consist of monitoring, by means of calendars or diaries, and providing feedback, support or rewards.
Giuffrida et al. reviewed 11 randomised trials, conducted in the United States, in which patients were paid for adherence in cash, gifts or vouchers. The incentives ranged from $5 to gifts worth nearly $1000. The results showed improved adherence in ten out of 11 studies (Odds ratios > 1.0). It remained unknown whether a cash payment or payment in kind was more effective. The authors argued that incentives can be cost-effective, if substantial benefits accrue, not only to the patient, but also to society at large. An example is to prevent the development of drug-resistant strains of infectious diseases or, in transplant patients, to prevent re-transplantation when patients adhere to their anti-rejection drugs [
42].
Macharia et al. found that mailed reminders and telephone prompts were consistently useful for reducing the number of missed clinical appointments for the supervised administration of medical care [
43]. The conclusions are based on their meta-analytic calculations of 23 randomised trials covering a fairly wide range of interventions and clinical settings. The most common intervention was simply a letter or telephone call a few days prior to the appointment to remind patients of the pending appointment. This proved to be effective in general medical populations (pooled Odds ratio 2.2). According to the authors, computerised reminders can be highly cost-effective. Van Eijken et al. found that a telephone-linked reminder system increased medication adherence among elderly people [
44]. A review of 49 randomised trials in cardiac care found that enhancing self-efficacy, skill-training and self-monitoring are also successful strategies [
9].
These reviews show that behavioural interventions not only have relevance for improving medication adherence, like most technical interventions have, but enhance adherence to other types of treatments as well.
Educational interventions
Education is a cognitive didactic approach that includes teaching and providing knowledge. There are different ways to educate patients: individual versus group education, face to face contact, audio-visually, in writing, by telephone, by e-mail or via home visits.
Three meta-analytic reviews focused on patient education in relation to chronic diseases. These included both types of diabetes, hypertension and asthma [
45‐
47]. Together they cover 202 primary studies. The authors' main conclusions are that their analyses lend support to the effectiveness of patient education on knowledge, adherence and patient outcome. Knowledge showed the largest effect with a mean effect size of d
+ 1.05 in diabetes education [
45] (the effect size 'd' represents the standardised mean difference between treatment and control groups, measured in standard deviation units; d
+ is the average unbiased weighted effect size). The effects of knowledge, however, appear to diminish over time. Measured at two weeks after the intervention, hypertension education showed a large effect size on knowledge of d
+ 0.98, but declined to a medium effect size of d
+ 0.46 when measured at four weeks [
47]. The reviews did not provide enough information about the educational programme to determine what types of programmes and educational strategies are most effective [
45]. Zygmunt et al. found that educating patients in concrete problem solving and motivational techniques increased medication adherence among schizophrenic patients [
48]. In their review of 39 studies, the authors also found that psycho-educational programmes, which are common in clinical practice, were typically ineffective [
48]. Education did appear to increase patient adherence in asthma (effect size d
+ 0.70) and hypertension (effect size d
+ 0.49). In diabetes, adherence to dietary regimens also improved with education (effect size d
+ 0.57), but the effects on weight loss were much smaller (effect size d
+ 0.17) [
45].
Other reviewers found that education had positive effects on metabolic control [
45], blood pressure [
47] and asthma [
46]. According to Devine the positive effect of education is probably attributable to the fact that many of the educational programmes included instructions on appropriate medication usage as well as self-care activities [
46]. However, Schroeder et al. compared four types of adherence interventions in hypertension patients from 38 trials and found that the most effective intervention was not education but dosage simplification. Reducing the number of daily doses of blood pressure lowering medication increased adherence by eight to twenty percent [
49].
An effective adherence intervention in primary care turned out to be collaborative care [
50]. Collaborative care was defined as a systematic approach that improves patient education through mental health professionals or other care providers, such as nurses in primary care, playing an active role [
50]. Collaborative care was tested against patient education in a review of 19 randomised trials, of which 13 were in primary care. Nine of the 13 primary care studies showed significant differences in adherence between intervention and usual care groups, with an increased adherence of approximately 25%. Better depression outcomes were achieved as well, especially in patients suffering from major depression, who were prescribed adequate dosages of antidepressant medication [
50].
Mullen's meta-analysis included 28 controlled trials on cardiac patient education programmes [
51]. Patient education was broadly defined and encompassed didactic, as well as, behavioural approaches. Many cardiac programmes were intensive and consisted of large numbers of contacts, for example in supervised cardiac exercise programmes. The effects were seen in clinical and behavioural outcomes. The average sizes of the effect were 0.51 for blood pressure, 0.24 for mortality, 0.19 for diet and 0.18 for exercise. Smoking cessation and drug adherence did not change significantly. The trend was for behaviourally-oriented interventions to have larger effects [
51]. However, the difference with didactic interventions did not reach statistical significance, because, according to Mullen, intensive affective interventions were applied in the didactic programmes.
Unfortunately, no comparison of two or more types of interventions was carried out within the studies in order to test the effectiveness of different types or components of interventions [
46]. Besides, subgroup analyses or pooling of the results were not always allowed due to the heterogeneity of the samples as defined by Hedges' test of homogeneity. A major weakness of the existing research is under-reporting of key aspects of the studies, for example, the duration of the treatment [
47].
Structural interventions
An example of a structural or organizational intervention is a programme of care at the place of work to manage hypertension, administered by specially trained nurses as described by Morrison et al. [
41]. They found a small but significant improvement in adherence and blood pressure. Additional strategies, such as a disease management programme aimed exclusively at the non-adherent patients, yielded no significant improvements [
41]. Another example of structural interventions is provided in the review by Zygmunt et al. on community-based rehabilitative intervention programmes for schizophrenic patients [
48]. The authors found that such interventions, targeted specifically to non-adherence problems, were twice as effective as more broadly based interventions.
Complex or multi-faceted interventions
Among the category of complex interventions, the findings of Haynes et al. deserve special attention [
6]. They updated their review of 2002 and added 25 recent studies. They came to three conclusions on the basis of 57 un-confounded randomised trials that reported adherence and treatment outcomes with a follow-up period of at least six months. Firstly, less than half (45%) of the interventions resulted in improved adherence and only 33% in better treatment outcomes. Secondly, those interventions that were effective for long-term care were exceedingly complex and labour-intensive. Thirdly, even the most effective interventions did not lead to large improvements in adherence and treatment outcomes [
6].
Roter et al. conducted meta-analytic computations in their review (153 studies) [
31]. They found that no single strategy or programmatic focus showed any clear advantage over the other. Comprehensive interventions, combining cognitive, behavioural and affective components, were more effective than single-focus ones (ES 0.34). Affective components concern the provider-patient relationship and refer to issues such as empathy, attentiveness, care, concern or support. The same results were reported by Dolder et al. in a review on schizophrenia [
53]. Among schizophrenic patients, interventions of a purely educational nature were the least successful at improving adherence to anti-psychotic medication [
53], and behavioural components seem to be needed [
54]. The intensity and duration of the interventions did matter, according to Dolder et al. Interventions reporting an improvement in adherence had a median of eight sessions, while those interventions without gains in adherence had a median of three sessions [
53]. Written materials were weaker (ES 0.12) than other educational interventions in Roter's review, but written, mailed, reminders (ES 0.21) were as effective as telephone reminders (ES 0.19) in keeping appointments.
Roter et al. concluded that behavioural and educational approaches were equally effective but they also suggested that the addition of affective components enhances the effectiveness of the interventions [
31]. The variability in study design, along with the multitude of adherence definitions and assessments, precluded reviewers from performing a meaningful meta-analysis [
53]. Besides, the differences in adherence measures and definitions of adherence, create complications when trying to compare changes in adherence among studies and when calculating mean, non-adherence, rates.