Elsevier

The Lancet

Volume 389, Issue 10088, 24–30 June 2017, Pages 2473-2481
The Lancet

Articles
Adverse 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

https://doi.org/10.1016/S0140-6736(17)31075-9Get rights and content

Summary

Background

In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials.

Methods

In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40–79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest—muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment—and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum.

Results

The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7–3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2–2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88–1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75–1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56–0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57–1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08–1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10–1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06–1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04–1·88]; p=0·03), which were reported more commonly by statin users than by non-users.

Interpretation

These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects.

Funding

Pfizer, Servier Research Group, and Leo Laboratories.

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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