Concerns related to the nocebo effect

We read with interest the finding of Ajay Gupta and colleagues (June 24, p 2473)1Gupta A Thompson D Whitehouse A et al.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.Lancet. 2017; 389: 2473-2481Summary Full Text Full Text PDF PubMed Scopus (238) Google Scholar of an absence of attributable risk of muscle-related adverse events to statin therapy in the blinded randomised controlled phase by contrast with an excess risk in the non-randomised, open-label extension phase in the same population. These results were attributed to the nocebo effect. We note that the overall proportion of participants reporting muscle-related adverse events was lower in the non-blinded, non-randomised phase than in the masked randomised phase. This might be explained by selective uptake or cessation of statins by participants in the follow-up phase, since 3364 (68%) of 4972 participants who had been randomly assigned to statin therapy made the choice to continue the drug in the open phase, whereas only 3045 (62%) of 4927 participants who had been randomly assigned to placebo opted to take atorvostatin. It would be interesting to know the proportion of those in the placebo group who reported muscle-related adverse events, because this is probably where the nocebo effect would be observed, since they are knowingly exposed to the drug for the first time. We declare no competing interests. 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 phaseThese 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. Full-Text PDF Concerns related to the nocebo effect – Authors' replyWe thank Zhen Zhou and colleagues for their comments on our Article.1 Full-Text PDF