Elsevier

The Lancet

Volume 388, Issue 10059, 19–25 November 2016, Pages 2532-2561
The Lancet

Review
Interpretation of the evidence for the efficacy and safety of statin therapy

https://doi.org/10.1016/S0140-6736(16)31357-5Get rights and content

Summary

This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the efficacy and safety of statin therapy. In addition, it discusses how claims that statins commonly cause adverse effects reflect a failure to recognise the limitations of other sources of evidence about the effects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. The absolute benefits of statin therapy depend on an individual's absolute risk of occlusive vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol by 2 mmol/L (77 mg/dL) with an effective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about £2 per month) for 5 years in 10 000 patients would typically prevent major vascular events from occurring in about 1000 patients (ie, 10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (ie, 5% absolute benefit) who are at increased risk but have not yet had a vascular event (primary prevention). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken, so larger absolute benefits would accrue with more prolonged therapy, and these benefits persist long term. The only serious adverse events that have been shown to be caused by long-term statin therapy—ie, adverse effects of the statin—are myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment of 10 000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of rhabdomyolysis), 50–100 new cases of diabetes, and 5–10 haemorrhagic strokes. However, any adverse impact of these side-effects on major vascular events has already been taken into account in the estimates of the absolute benefits. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about 50–100 patients (ie, 0·5–1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised trials have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by it (ie, they represent misattribution). The large-scale evidence available from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events still await discovery. Consequently, any further findings that emerge about the effects of statin therapy would not be expected to alter materially the balance of benefits and harms. It is, therefore, of concern that exaggerated claims about side-effect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if statin therapy is stopped unnecessarily can be devastating.

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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