Large-scale randomized trial evidence shows that statin therapy reduces the risk of heart attacks, ischaemic strokes and coronary revascularization procedures (“major vascular events”) by about one quarter for each mmol/L reduction in low density lipoprotein (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 (e.g. 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 (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”). 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 by large-scale randomized trials to be caused by long-term statin therapy – that is, are adverse effects of the statin – are myopathy (defined as muscle pain or weakness combined with large increases in blood levels of creatine kinase), new onset diabetes mellitus and, probably, haemorrhagic stroke. Typically, treatment of 10,000 patients for 5 years with an effective regimen (e.g. atorvastatin 40 mg daily) would cause about 5 cases of myopathy (1 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 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
results in the observational studies (e.g. that the wrong type of adjustment had been used or the timing of initiating treatment mattered),119,120 but these were eventually refuted.121,122 Likewise, randomized trials have not confirmed the 30% increased risk of breast cancer found in observational studies of estrogen-alone preparations, although the results for combined estrogen-progestin preparations appear similar.123-125 Despite these discrepancies, the similarity of the direction – but not the size126,127 – of the differences in the rates of stroke and pulmonary embolism in observational studies and in randomized trials of hormone replacement therapy has been used to justify continued reliance on observational evidence,2 rather than as an illustration of the difficulty of determining which – if any – associations with treatment in observational studies provide a reliable basis for safe and effective care of patients and the public. A number of reviews have been conducted to compare the estimates of treatment effects from observational studies and randomized trials, but their methods have been criticized (chiefly because of concerns about the methods used to select the studies and compare the results) and their findings have been inconsistent.106 It has been concluded that these reviews identified many examples where the results of the same intervention were on average the same, but also many examples where the results differed. For example, there have been many claims about the benefits of various vitamin supplements based on observational studies128,129 that have been reliably refuted by large-scale randomized trials.130-132 Similarly, when compared with the results from randomized trials of the effects of treatments for several different cancers, observational studies have generated improbable results despite controlling for comorbidity, extent of disease and many other characteristics that were recorded in detailed databases133-135 (as is also the case for reported