ReviewInterpretation of the evidence for the efficacy and safety of statin therapy
Introduction
Used appropriately, modern medical therapies have the potential to prevent a large proportion of the burden of cardiovascular disease. However, their appropriate use relies on the availability of robust data on safety and efficacy, as well as on a sound understanding of the interpretation and application of such evidence.
Randomised controlled trials of adequate size are needed to be confident that any moderate benefits and any moderate harms of a treatment have been assessed sufficiently reliably.1, 2, 3, 4 In certain circumstances, available evidence from randomised trials about the effects of a treatment may be limited (perhaps because it is deemed not possible or too difficult to do adequate trials).2 However, the particular context that this Review addresses is the appropriate interpretation of evidence about the safety and efficacy of a treatment when randomised trials of it have been conducted in large numbers of many different types of patient (as is the case for statin therapy), as well as the additional value of information from observational studies based on cohorts, health-care databases, or other sources.3, 4, 5 Not only have the limitations of observational studies4, 6, 7, 8, 9 often been underestimated when attributing adverse effects to treatment (such as misleading claims that statins cause side-effects in one-fifth of patients10, 11, 12), but also the strengths of randomised trials with masked treatment allocation and systematic ascertainment of many different types of adverse event have been under-estimated for the reliable assessment of the safety and efficacy of treatment.3, 9, 13, 14, 15
This Review first considers the generic strengths and limitations of randomised trials and observational studies for assessing the effects of treatment, and then considers the specific evidence that is available on the efficacy and safety of statin therapy. It concludes by considering the public health implications of the failure to recognise the full benefits of using statin therapy and of the exaggerated claims that have been made about the rates of side-effects.
Section snippets
Like-with-like comparisons within randomised trials
The key strength of randomised controlled trials is that the process of randomisation results in groups of patients who differ from each other only by the play of chance with respect to their risks of having all types of health outcome (ie, the randomised treatment groups are balanced with respect to both known and unknown risk factors, irrespective of whether or not these have been assessed).3, 9, 13, 14, 15, 16 In addition, masking assignment of study treatment with a placebo minimises the
Observational studies: limited additional value for assessing the effects of treatment when large-scale evidence exists from randomised controlled trials (panel 2)
Observational epidemiological studies have been extremely valuable for identifying associations of risk factors with disease (eg, smoking with lung cancer; blood pressure and cholesterol with cardiovascular disease), but their value for the assessment of the effects of treatment is more limited.
Associations between LDL cholesterol and vascular disease
By contrast with observational studies of treatment, observational epidemiological studies are valuable for the assessment of causal risk factors. In particular, such studies have shown that there is a continuous positive association between blood concentrations of LDL cholesterol and the rates of coronary heart disease events in different populations, without any suggestion within the range that has been studied of a threshold below which a lower concentration is not associated with a lower
Proven beneficial effects of lowering LDL cholesterol concentration with statin therapy
In the pre-statin era, meta-analyses of randomised controlled trials of cholesterol-lowering diets, drugs, and ileal bypass surgery showed that, within a few years of reducing blood cholesterol concentrations, rates of non-fatal myocardial infarction and coronary death are reduced.174 In addition, the randomised trials that involved larger and more prolonged cholesterol reductions yielded larger reductions in the rates of coronary events. However, it was suggested that these beneficial effects
Proven adverse effects of statin therapy (panel 4)
The only excesses of adverse events that have been reliably demonstrated to be caused by statin therapy are myopathy and diabetes mellitus, along with a probable excess of haemorrhagic stroke. These excesses are larger in certain circumstances, but the absolute risks remain small by comparison with the absolute benefits.
Other adverse events that have been attributed to statin therapy
It has been claimed that statin therapy causes increased rates of other types of adverse health outcome, as well as symptomatic side-effects (chiefly muscle pain and weakness) that prevent a large proportion of patients from continuing to take statin therapy long term, often now referred to as “statin intolerance”.10, 11, 12, 22, 64, 73, 74, 75 These claims have been chiefly based on reports to regulatory authorities of adverse events that have been attributed to a statin and on non-randomised
Conclusions
There is an important need for greater recognition of the limitations of observational studies and case reports as a source of reliable information about the effects of a treatment on health outcomes (except in the special circumstances where both the effects are large and the outcome would not normally be expected to occur). By contrast, a better understanding is needed of the strengths of randomised controlled trials of adequate size with systematic assessment of adverse health outcomes and,
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