Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment

James P Howard,Frances A Wood,Judith A Finegold,Alexandra N Nowbar,David M Thompson,Ahran D Arnold,Christopher A Rajkumar,Susan Connolly,Jaimini Cegla,Chris Stride,Peter Sever,Christine Norton,Simon A.M Thom,Matthew J Shun-Shin,Darrel P Francis

doi:10.1016/j.jacc.2021.07.022

Abstract

BackgroundMost people who begin statins abandon them, most commonly because of side effects. ObjectivesThe purpose of this study was to assess daily symptom scores on statin, placebo, and no treatment in participants who had abandoned statins. MethodsParticipants received 12 1-month medication bottles, 4 containing atorvastatin 20 mg, 4 placebo, and 4 empty. We measured daily symptom intensity for each using an app (scale 1-100). We also measured the “nocebo” ratio: the ratio of symptoms induced by taking statin that was also induced by taking placebo. ResultsA total of 60 participants were randomized and 49 completed the 12-month protocol. Mean symptom score was 8.0 (95% CI: 4.7-11.3) in no-tablet months. It was higher in statin months (16.3; 95% CI: 13.0-19.6; P < 0.001), but also in placebo months (15.4; 95% CI: 12.1-18.7; P < 0.001), with no difference between the 2 (P = 0.388). The corresponding nocebo ratio was 0.90. In the individual-patient daily data, neither symptom intensity on starting (OR: 1.02; 95% CI: 0.98-1.06; P = 0.28) nor extent of symptom relief on stopping (OR: 1.01; 95% CI: 0.98-1.05; P = 0.48) distinguished between statin and placebo. Stopping was no more frequent for statin than placebo (P = 0.173), and subsequent symptom relief was similar between statin and placebo. At 6 months after the trial, 30 of 60 (50%) participants were back taking statins. ConclusionsThe majority of symptoms caused by statin tablets were nocebo. Clinicians should not interpret symptom intensity or timing of symptom onset or offset (on starting or stopping statin tablets) as indicating pharmacological causation, because the pattern is identical for placebo. (Self-Assessment Method for Statin Side-effects Or Nocebo [SAMSON]; NCT02668016)

Highlights

Most people who begin statins abandon them, most commonly because of side effects
In the individual-patient daily data, neither symptom intensity on starting (OR: 1.02; 95% CI: 0.98-1.06; P 1⁄4 0.28) nor extent of symptom relief on stopping (OR: 1.01; 95% CI: 0.98-1.05; P 1⁄4 0.48) distinguished between statin and placebo
Cessation of tablets was almost as frequent for placebo as for statin (17.2% vs 21.6%). These results of SAMSON lie in between those from GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3) [14] (15% vs w22% at 28 days) and the recently published StatinWISE (A series of randomized controlled N-of-1 trials in patients who have discontinued or are considering discontinuing statin use due to muscle related symptoms to assess if atorvastatin treatment causes more muscle symptoms than placebo) [15] (19.5% vs 17%)