Interpretation of the Evidence for Statin Therapy

Collins R, Reith C, Emberson J, et al.
Interpretation of the Evidence for the Efficacy and Safety of Statin Therapy. Lancet 2016;Sep 6:[Epub ahead of print].

The following are key points from this review, which is intended to help clinicians and patients make informed decisions about statin therapy for the prevention of myocardial infarctions (MIs) and strokes:

  1. Randomization trials with masking of subjects are necessary to establish that differences in health outcomes, beneficial and harmful, can generally be attributed causally to differences in study treatment.
  2. Trials with different eligibility criteria that involve large numbers of different types of patients (ideally combined in meta-analyses of individual patient data) can provide reliable information about treatment effects that can be widely generalized to different circumstances.
  3. Large numbers of individuals in observational studies based on health care databases enable large treatment effects (adverse or beneficial) to be detected even when rare. Observational studies can have prolonged exposure to a treatment that can reveal untoward effects not observed in the limited time of the trials, although data may be incomplete.
  4. Application of the proportional effects of treatment on specific outcomes derived from randomized trials to the absolute rates of the outcomes derived from observational studies can be used to yield generalizable estimates of its absolute benefits and harms.
  5. Randomized trials show that statin therapy reduces the risk of major vascular events (i.e., coronary deaths, MIs, strokes, and coronary revascularization procedures) by about 25% for each 40 mg/dl reduction in low-density lipoprotein cholesterol (LDL-C) per year. The absolute benefits of statin therapy depend on an individual’s absolute risk of cardiovascular events and the absolute reduction in LDL-C. For example, lowering LDL-C by about 80 mg/dl with an effective low-cost statin regimen (e.g., atorvastatin 40 mg daily, costing about $4 per month) for 5 years in 10,000 patients would typically prevent major vascular events from occurring in about 1,000 patients (i.e., 10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (i.e., 5% absolute benefit) who are at increased risk, but have not yet had a vascular event (primary prevention). Larger absolute benefits accrue with more prolonged therapy, and these benefits persist long-term.
  6. Serious adverse events have been shown to be caused by long-term statin therapy. Typically, treatment of 10,000 patients for 5 years with an effective regimen (e.g., atorvastatin 40 mg daily) would cause about five cases of myopathy (muscle symptoms with elevated creatine kinase, that might progress, if the statin therapy is not stopped, to rhabdomyolysis), 50–100 new cases of diabetes, and 5–10 hemorrhagic strokes. Any adverse impact of these side effects on major vascular events has already been taken into account in the estimates of the absolute benefits.
  7. Statin therapy may cause symptomatic adverse events (e.g., muscle pain or weakness) in up to about 50–100 patients (i.e., 0.5–1.0% absolute harm) per 10,000 treated for 5 years. However, placebo-controlled randomized 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 (i.e., they represent misattribution).
  8. Based on large-scale randomized trial evidence, it is unlikely that large absolute excesses in other serious adverse events are present that would materially alter the balance of benefits and harms. It is concerning that exaggerated claims about side-effect rates with statin therapy may be responsible for its underuse among individuals at increased risk of cardiovascular events. 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 MIs or strokes that may occur if statin therapy is stopped unnecessarily can be devastating.
  9. Perspective: The authors are an international group of experts in prevention and treatment of atherosclerotic disease who are clearly concerned that so many persons with or at risk for vascular disease are stopping their statins because of poorly documented side effects or fears, and seeking alternatives that may not be as effective and considerably more expensive.

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