ArticlesAdverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase
Introduction
Large-scale evidence from randomised placebo-controlled trials has shown that statin therapy reduces the incidence of major vascular events (ie, coronary deaths or myocardial infarctions, ischaemic strokes, and coronary revascularisation procedures) by about one quarter for each 1 mmol/L LDL cholesterol concentration reduction during each year (after the first) that it continues to be taken.1 The proportional reductions in risk have been shown to be similar in secondary and primary prevention and somewhat greater among individuals at a lower risk (although the absolute benefits are smaller). These findings have resulted in guidelines recommending that statin therapy be considered for all patients who have had an atherosclerotic event and, in primary prevention, for those who have a 10 year risk of having a cardiovascular event (defined as coronary death, myocardial infarction, angina, stroke, or transient ischaemic attack) of at least 10%, as well as for those with high LDL cholesterol concentrations or relevant comorbidities (such as diabetes).2, 3
Concerns have been expressed about the expansion in statin use produced by lowering of risk thresholds for offering of statin therapy to patients.4, 5 In making the argument against so-called over-medicalisation of the population, statin therapy has been claimed to cause increased rates of adverse events (AEs) and symptomatic side-effects (chiefly muscle pain and weakness); claims that prevent as many as one fifth of patients from continuing to take statin therapy in the long term.5, 6 These claims are usually derived from observational studies using health-care databases which, since they are neither randomised nor blinded, are subject to potential biases in assessment of causation.7 By contrast, in double-blind randomised controlled trials of statin therapy, the reported rates of different types of AE have generally been similar between patients receiving statin or placebo treatment (except for reductions in atherosclerotic events), with no differences between groups in the rates of treatment cessation in association with advere events.7, 8, 9, 10
The absence of a difference in AEs in randomised controlled trials of statin therapy has been suggested to be due to their ascertainment not being sufficiently specific or sensitive.5, 11 The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)12 provides a unique opportunity to assess the effect of blinded and unblinded ascertainment of AEs identified with the same approach during blinded randomised statin therapy in the Lipid-Lowering Arm (LLA) of the trial13 and the subsequent follow-up period when a proportion of patients were taking open-label statins.14 We prespecifed four AEs of interest (AEOIs) because of the public health effect of widespread claims about muscle-related side-effects and the additions to the drug label of erectile dysfunction, sleep disturbance, and cognitive impairment as possible side-effects on the basis of reviews by the Medicines and Healthcare Products Regulatory Agency15 and US Food and Drug Administration.16
Section snippets
Study design and patients
Details of the ASCOT protocol, including study design, organisation, clinical measurements, power calculations, recruitment rates, and baseline characteristics, have been previously published.12 Men and women aged between 40 years and 79 years were eligible if they had three or more risk factors for cardiovascular disease but had no history of myocardial infarction and were not being treated for angina. They were randomly assigned in an open-label comparison between two blood pressure-lowering
Results
The blinded randomised phase was done between February, 1998, and December, 2002; 10 305 patients were randomly allocated in the LLA (5168 [50%] to atorvastatin and 5137 [50%] to placebo), but 65 were withdrawn soon after randomisation because of concerns about source documentation validation. Of the remaining 10 240 (99%) eligible randomised patients, 60 (1%) patients (33 [55%] in the atorvastatin group vs 27 [45%] in the placebo group) were excluded from these analyses as they were missing
Discussion
The ASCOT-LLA provides a unique opportunity to compare the rate of reporting of AEs with use of an identical follow-up procedure and AE ascertainment process in the same individuals during blinded randomised and non-blinded non-randomised statin therapy. We noted no excess of reports of muscle-related AEs among patients assigned statin therapy during the blinded randomised phase, but we noted a significant excess when patients knew that they were taking a statin during the subsequent
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