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Adherence to statin therapy: the key to survival?

For example, several observational studies on the real-world effectiveness of statins estimated survival benefits attributed to statin therapy by comparing patients with good adherence vs. those with low adherence (Table 1). Most studies revealed a substantially higher reduction in all-cause mortality than meta-analyses of randomised controlled trials (RCTs) (3–7) on statins vs. placebo (Table 1, Figure 1). There are several reasons why one should interpret results such as these with scepticism (8–10) rather than enthusiasm: First, RCTs are designed to demonstrate drug efficacy. They are usually performed in a highly controlled environment (e.g. strict inclusion and exclusion criteria, high frequency and intensity of follow-up investigations, high completeness of follow up, methods to increase drug compliance, etc.) in which the detection of specific drug effects is much easier than in the complex real-world situation. If observational studies report higher drug benefits anyhow, plausible reasons for this discrepancy should be provided. Second, in the study of drug effects, one would like to see some kind of specificity. For instance, the effects of statins should be more pronounced with respect to specific endpoints (e.g. coronary revascularisation; cardiovascular events and cardiovascular deaths) than with respect to non-specific ones such as all-cause mortality. Two of the studies listed in Table 1 reported the effects of good adherence to statins not only on mortality but also on more specific endpoints. In the study by Ho et al. (11), the effects of statins were less pronounced in specific endpoints, such as coronary revascularisation (risk reduction of 10%) or cardiovascular hospitalisation (risk reduction of 26%), compared with the risk reduction observed for the unspecific endpoint all-cause mortality (risk reduction of 46%). Similarly, McGinnis et al. (12) reported no effect of adherence to statins on non-fatal cardiac events, but a 56% risk reduction with respect to allcause mortality. Patterns of drug effectiveness such as these seem implausible. Third, one should note that there are several different reasons of death, especially in heterogeneous populations. If it is reported that a single class of drugs such as statins can prevent approximately 50% of these deaths, this should trigger scepticism. For instance, Shalev et al. (13) reported that in primary prevention of coronary heart disease, patients adherent to statin treatment had a 45% lower risk of death compared with patients with poor adherence. To reach this level of effectiveness, statins would have to prevent not only all deaths resulting from cardiovascular causes (which is already implausible) but also a substantial number of deaths from other causes (8). An observational study on the effectiveness of influenza vaccination in elderly subjects (14) can serve as another example that certain levels of all-cause mortality reduction are not plausible. The study revealed an approximately 48% reduction in all-cause mortality attributable to influenza vaccination. It has been reported that in elderly subjects, the fraction of deaths attributable to influenza is, however, at the most 10% (15). Braun et al. (16) excellently summed up the main concern: ‘How can influenza vaccine prevent a much larger percentage of deaths than are caused by the disease that the vaccine is supposed to prevent?’ Why did most observational studies on adherence to statins seem to overestimate the effect on all-cause mortality? It is known for more than 25 years that adherence itself is a strong predictor of morbidity Adherence to drug therapy is a critical issue in ensuring optimal benefits of treatment. It is usually measured as the proportion of prescribed or recommended doses of a drug that was actually taken by the patient over a certain time period (1). Low drug adherence may thus represent a pattern of irregular or interrupted drug intake or complete drug discontinuation during the respective time period. In recent years, several observational studies have analysed the pattern of drug adherence of different important classes of drugs in clinical practice, and often reported a disappointingly low persistence to preventive drug therapy in patients with chronic conditions (1), with the greatest drop often occurring during the first 3–6 months of treatment (2). Studies on the clinical consequences of different levels of drug adherence, however, repeatedly revealed surprisingly pronounced benefits of good drug adherence. PERSPECT IVE