Background

High cholesterol is an important risk factor contributing to the global burden of disease. A WHO report estimated that it accounts for more than one-third of all deaths worldwide, and causes 18% of cerebrovascular disease (CVD) and 56% of ischaemic heart disease.1

The evidence that lipid-lowering drugs can reduce both lipid levels and the risk of heart attacks and strokes is well established. Lipid-lowering medications include statins, fibrates, niacin and bile acid resins. The effectiveness of statins is supported by large randomised trials and meta-analyses2 3 showing that the absolute reduction in LDL-cholesterol is linearly related to a reduction in the incidence of coronary and major vascular events.2 Statins are recommended as first-line therapy, whereas fibrates, niacin and bile acid resins are generally second-line therapy, alone or in combination with statins.4 5

Despite this evidence and the availability of guidelines, lipid-lowering therapy is still underused. Although recommendations about drug treatments vary between countries, most generally recommend statin treatment in people with clinical evidence of CVD to reduce further ischaemic events. In adults who have no history of a cardiovascular event, lipid-lowering medication is recommended if there is a 20% or greater risk of developing CVD in the next 10 years.4 Recommendations by the American College of Cardiology/American Heart Association have recently broadened the indications for lipid-lowering therapy, adding to the challenge of ensuring adequate treatment coverage.5

Adherence to treatment is important for optimal effectiveness. Adherence is defined as the extent to which people take medication as prescribed. A number of factors have been linked to poor adherence, such as lack of knowledge, denial, adverse effects, impaired memory and non-acceptance of treatment. Interventions to improve adherence to medication can focus on the person (patient education), the drug regimen (simplification of regimens), the physician (decision-making aids) or the health system (delivery of medication). A systematic review has shown that adherence to short-term drug treatment can be improved by written information, personal phone calls and counselling, but more complex interventions are needed for long-term treatments.6 Treating a symptomless condition like hyperlipidaemia poses a particular challenge. A previous version of this Cochrane review concluded that none of the interventions studied showed a clear benefit.7 We have updated this review with recent evidence to assess the effectiveness of these methods, including new interventions derived from advancements in technology, on clinical outcomes in patients prescribed lipid-lowering treatment.8

Review methods

We reviewed randomised controlled trials of interventions to increase adherence for lipid-lowering medication in adults in ambulatory settings looking at adherence to treatment (primary outcome) as well as changes to serum lipid levels, health outcomes such as quality of life, morbidity and mortality, and adverse effects (secondary outcomes). We searched the Cochrane Central Register of Controlled Trials, Medline, Embase, PsycINFO and Cumulative Index to Nursing and Allied Health Literature (CINAHL) up to 3 February 2016, and clinical trials registers (Australian New Zealand Clinical Trials Registry (ANZCTR) and ClinicalTrials.gov) up to 27 July 2016. We used standard Cochrane methods to select studies, extract data and assess risk of bias for each of the included studies. We used GRADEpro to rate the quality of the overall effect estimates. We reported dichotomous data as ORs with 95% CIs and continuous data as mean difference with SD of premeasurements and postmeasurements. Serum cholesterol values are reported in mg/dL using the formula: 1 mmol/L=38.66976 mg/dL.

We grouped the studies into seven types of interventions: (1) simplification of drug regimen; (2) patient education and information; (3) intensified patient care; (4) complex behavioural approaches; (5) decision support systems; (6) administrative improvements; and (7) pharmacy-led interventions. ‘Usual care’ was not defined as a separate intervention. We pooled data with a random-effects model, using a per-protocol analysis, as intention-to-treat analysis would yield misleading results by not showing an effect in many of these studies due to the pragmatic nature of the study designs.

We performed sensitivity analysis to assess the impact of heterogeneity and compared random-effects versus fixed-effects models to assess the robustness of the effect estimates. We also assessed the impact of attrition on the overall study outcome by removing studies with high attrition (>20%).

Main results

This updated review included 35 studies, randomising 925 171 participants (table 1). We pooled seven studies with 11 204 individuals that compared adherence rates of those in an intensification of patient care intervention (eg, combinations of the following: electronic reminders, pharmacist-led interventions, healthcare professional education of patients) versus usual care over the short term (≤6 months) (table 2). Adherence of participants in the intervention group was better than in the usual care group (OR 1.93, 95% CI 1.29 to 2.88; seven studies; 11 204 participants; moderate-quality evidence). Intensification of care also improved adherence rates in the long-term (>6 months) (OR 2.87, 95% CI 1.91 to 4.29; three studies; 663 participants; high-quality evidence). Similarly, total cholesterol and LDL-cholesterol levels were reduced in those allocated to the intensified interventions over both short-term and long-term follow-up. Measured at 6 months or less, total cholesterol decreased by a mean of 17.15 mg/dL (95% CI 1.17 to 33.14; four studies; 430 participants; low-quality evidence) and LDL-cholesterol by a mean of 19.51 mg/dL (95% CI 8.51 to 30.51; three studies; 333 participants; moderate-quality evidence). Measured on the long-term (>6 months) total cholesterol decreased by a mean of 17.57 mg/dL (95% CI 14.95 to 20.19; two studies; 127 participants; high-quality evidence). We could not assess the effect on quality of life, morbidity and mortality, adverse effects or costs as the included studies did not provide usable data. Sensitivity analyses confirmed the robustness of our findings.

Limitations of the evidence

We assessed the risk of bias as low for selection, attrition and reporting bias for the studies included in this review. Risk of bias relating to blinding was unclear for most studies, but blinding of participants was not possible due to the nature of most interventions (eg, reminder phone calls or education sessions). As this is acceptable in a pragmatic context, we have not downgraded the evidence for lack of blinding. In studies using a fixed dose combination or ‘polypill’, blinding is feasible, but we could not pool them in our review. We graded the evidence for long-term adherence and reduction in total cholesterol as high quality. We downgraded the evidence for short-term outcomes (patient adherence and LDL-cholesterol) to moderate quality due to heterogeneity and the short-term outcome of total serum cholesterol to low quality due to heterogeneity and a wide CI (imprecision).

Implication for practice

Our review indicates that interventions classified as intensification of patient care could improve both short-term and long-term adherence rates and serum cholesterol levels when compared with usual care.8 Given the importance of statin therapy, strategies to improve adherence rates could have significant benefit in those people for whom statins are recommended. The successful intensification of patient care interventions typically involved strategies beyond what a single clinician could provide. Instead, healthcare delivery systems might be better equipped to deliver a combination of these types of interventions, that is, pharmacist-led interventions, multidisciplinary education or counselling, and automated reminders, along with a focus on teamwork with the primary care physician to provide the best potential for effectiveness.

The results of our meta-analysis must, however, be seen in the context of the healthcare systems in which they were trialled. For instance, pharmacy-led interventions are applicable in systems with a strong and well-structured medication delivery system through pharmacies, but will not be feasible in, for instance, low-income countries where drug dispensing is much less controlled or not integrated into the healthcare system. Cultural and social context plays a role and the impact of automated reminders delivered as text messages may be less effective if patients’ beliefs regarding their medicines have not been addressed.

It is important to acknowledge the wide diversity of control interventions that we grouped as ‘usual care’, for example, pharmacy usual care, can include patient education in some settings but none at all in others. Likewise, usual care in the context of physician-delivered interventions can also vary extensively. The results of our comparisons therefore need to be interpreted with caution.

Implications for research

Adherence is a complex concept and perhaps a more patient-centred approach is the best way to address this complexity. This means that patients’ preferences, attitudes, beliefs and context must be taken into account when designing adherence-enhancing interventions. Combining strategies such as education, electronic or telephone reminders, adherence reinforcement and the patient’s personal context and perspective might be more effective. Future studies should use validated methods to measure adherence and assess the effects on serum lipid levels. As treatment with lipid-lowering medication is mostly lifelong, follow-up of 12 months and more will provide a more realistic picture of the impact of these interventions on adherence. Finally, studies evaluating outcomes such as morbidity, mortality, quality of life and cost-effectiveness are needed in order to provide guidance to clinicians and healthcare systems.