Statin-related adverse events only observed in unblinded and not in blinded trials; a nocebo effect?

9-5-2017 • Gupta A, The Lancet, 2017

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

Gupta A, Thompson D, Whitehouse A, et al.
The Lancet 2017, Epub ahead of print


Statin use has been associated with increased rates of adverse events (AEs) and symptomatic side-effects, including muscle pain and weakness. This withdraws many patients from statin therapy [1,2].  However, this increase in AEs are mainly derived from observational studies, in which patients were neither randomized nor blinded, whereas double-blind randomized controlled trials did not show such results, as different types of AEs were generally similar between patients in these studies [3-6]. The absence of AEs has been explained by the statin not being sufficiently specific or sensitive [1,7].
In this study, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) data of the Lipid-Lowering Arm (LLA) had been used to assess the effect of blinded (1998-2002, median follow-up 3.3yrs) and unblinded (2002-2005, median follow-up 2.3yrs) therapy on AEs in the same individuals. Four AEs of interests (AEOIs) were prespecified: muscle-related side-effects, erectile dysfunction, sleep disturbance and cognitive impairment. In ASCOT-LLA, 5101 patients were blinded to atorvastatin, of which 3364 were assigned to atorvastatin in the extension phase again and 1608 were assigned to non-use of atorvastatin. On the other hand, 5079 were placebo-treated, of which 3045 were assigned to atorvastatin and 1882 were assigned to non-use in the extension phase.

Main results

  • In total, 60 612 distinct AEs occurred.
  • In the blinded randomized phase, definite or probably muscle-related AEOIs were reported in 298 statin- and 283 placebo-treated patients (HR 1.03, 95% CI 0.88-1.21, P=0.72), erectile dysfunction in 272 statin- and 302 placebo-treated patients (HR 0.88, 95% CI 0.75-1.04, P=0.13) and sleep disturbance in 149 statin- and 210 placebo-treated patients (HR 0.69, 95% CI 0.56-0.85, P=0.0005). As too few cases of cognitive impairment were reported, analyses were not statistically reliable regarding this AE (31 vs 32, HR 0.94, 95% CI 0.57-1.54, P=0.81).
  • Findings were similar in sensitivity analyses based on only definite AEOIs or when more possible AEOIs were included.
  • Regarding other AEs, renal and urinary disorders occurred more among patients on atorvastatin (HR 1.23, 95% CI 1.08-1.41, P=0.002).
  • In the non-blinded non-randomized phase, overall less AEOIs were reported compared to the blinded phase. However, muscle-related AEOIs were reported more often in statin users than non-users (HR 1.41, 95% CI 1.10-1.79, P=0.006), which proportional excess was similar between atorvastatin- or placebo-assigned patients of blinded phase (P interaction=0.63).
  • There was no significance difference of other prespecified AEs between statin-users and non-statin-users in non-blinded phase (erectile dysfunction HR 0.89, 95% CI 0.66-1.20, P=0.44, sleep disturbance HR 0.87, 95% CI 0.63-1.20, P=0.40, cognitive impairment HR 0.59, 95% CI 0.34-1.02, P=0.06). Findings were similar in sensitivity analyses.
  • When non-blinded comparisons were adjusted for baseline age, sex, race, smoking, diabetes, left ventricular hypertrophy, total cholesterol and systolic blood pressure, HRs were minimally affected. For muscle-related AEs, HR changed to 1.43 (95% CI 1.12-1.83).
  • Regarding other AEs in unblinded phase, only musculoskeletal and connective tissue disorders (HR 1.17, 95%C CI 1.06-1.29, P=0.001) and blood and lymphatic system disorders (HR 1.40, 95% CI 1.04-1.88, P=0.03) occurred more often among statin users.


In the blinded randomized phase of the ASCOT-LLA trial, the number of muscle-related AEs were comparable between statin-treated and placebo-treated patients. However, these AEs were significantly more often reported when these same patients knew that they were taking a statin during the extended non-blinded non-randomized phase. This observation is consistent with a nocebo effect, whereby subjective AEs are probably a result of a treatment thought that causes some particular side-effects. These data suggest that muscle-related AEOIs are not causally related to statin-use and therefore, the benefits of statins in reducing cardiovascular events should override concerns about reports of side-effects.  
Find this article online at The Lancet


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