Physicians' Academy for Cardiovascular Education

Statin-related adverse events a nocebo effect?

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

Background

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 is 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

Conclusion

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.

References

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Find this article online at The Lancet