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Randomized Controlled Trial
. 2021 Sep 21;78(12):1210-1222.
doi: 10.1016/j.jacc.2021.07.022.

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

James P Howard  1 , Frances A Wood  1 , Judith A Finegold  1 , Alexandra N Nowbar  1 , David M Thompson  1 , Ahran D Arnold  1 , Christopher A Rajkumar  1 , Susan Connolly  1 , Jaimini Cegla  2 , Chris Stride  3 , Peter Sever  1 , Christine Norton  4 , Simon A M Thom  1 , Matthew J Shun-Shin  1 , Darrel P Francis  5
Affiliations
Randomized Controlled Trial

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

James P Howard et al. J Am Coll Cardiol. .

Abstract

Background: Most people who begin statins abandon them, most commonly because of side effects.

Objectives: The purpose of this study was to assess daily symptom scores on statin, placebo, and no treatment in participants who had abandoned statins.

Methods: Participants 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.

Results: A 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.

Conclusions: The 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).

Keywords: crossover trial; drug intolerance; nocebo; side effects; statins.

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Conflict of interest statement

Funding Support and Author Disclosures This study was funded by the British Heart Foundation (PG/15/7/31235), which had no role in study design, data collection, data analysis, data interpretation, or writing of the report. This study was supported by the National Institute for Health Research Imperial Biomedical Research Centre (BRC) and the Imperial Clinical Trials Unit. The views expressed are those of the author and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. Dr Howard is supported by the Wellcome Trust, grant number 212183/Z/18/Z. Dr Nowbar is supported by the National Institute for Health Research Academy. Dr Rajkumar is supported by the Medical Research Council, grant number MR/S021108/1. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
CONSORT Diagram Patient flow through the trial.
Figure 2
Figure 2
Every Daily Score for 6 Exemplar Patients From the Trial The vertical axes represent symptom scores; the horizontal axes represent time (days separated into 12 monthly intervals). Symptom intensity bars are colored gray in no-tablet months, blue in placebo months, and red in statin months. Lighter shaded regions indicate that patients have stopped tablets early for that month caused by intolerable symptoms. Each participant’s data is labeled by their trial number. Full data for all 60 randomized participants are shown in the Supplemental Appendix.
Central Illustration
Central Illustration
Symptom Scores and Cumulative Early Tablet Stopping Rates by Treatment (Left) The mean symptom scores across the 3 treatment types (statin, placebo, and no treatment). Whiskers indicate the associated 95% CIs. (Right) The cumulative rate of stopping tablets for patients starting a statin (red) or placebo (blue) after a no-tablet month. P value derived from a mixed-effects logistic regression model.
Figure 3
Figure 3
Symptom Time Course in Days Before and After Starting Tablets (Top) The symptom pattern averaged across all patients. (Bottom) The symptom scores during each unique 2-month period where a patient transitioned between a no-tablet month (gray) and a tablet month (red for statin, blue for placebo). The dotted vertical line shows the time of starting tablets. These periods are arranged so the largest increase in symptom scores on starting tablets is in the top left, and the lowest in the bottom right.
Figure 4
Figure 4
Symptom Time Course in Days Before and After Stopping Tablets (Top) The symptom pattern averaged across all patients. (Bottom) The symptom scores during each unique 2-month period where a patient transitioned between a tablet month (red for statin, blue for placebo) and no treatment (gray). The dotted vertical line shows the time of stopping tablets. These periods are arranged so the largest increase in symptom scores on starting tablets is in the top left, and the lowest in the bottom right. Because patients could stop tablets early if they experienced intolerable symptoms, some treatment periods are curtailed.
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Comment in

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