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

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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

Original languageEnglish
Pages (from-to)1210-1222
Number of pages13
JournalJournal of the American College of Cardiology
Volume78
Issue number12
DOIs
Published21 Sep 2021

Bibliographical note

Funding Information: The authors thank Heart UK and the British Heart Foundation for their help with recruitment; and Imperial Healthcare NHS Trust lipid, cardiology, and hypertension clinics for their help with recruitment to the SAMSON trial. The authors also thank the lipid clinics at St Mark's Hospital, Berkshire Healthcare NHS Foundation Trust, Wexham Park Hospital, Frimley Park Hospital, Aldershot Centre for Health, Frimley Health NHS Foundation Trust, Royal Surrey County Hospital, Royal Surrey NHS Foundation Trust, Darent Valley Hospital, Dartford and Gravesham NHS Trust, Princess Alexandra Hospital, Princess Alexandra Hospital NHS Trust, Medway Maritime Hospital, Medway NHS Foundation Trust, Royal Free Hospital, Royal Free London NHS Foundation Trust, Royal Sussex County Hospital, Brighton and Sussex University Hospitals NHS Trust, Basildon University Hospital, Basildon and Thurrock University Hospitals NHS Foundation Trust, University College Hospital, University College London Hospitals NHS Foundation Trust, Guy's Hospital, St Thomas? Hospital, Guys and St Thomas? NHS foundation Trust, University Hospital Lewisham, Lewisham and Greenwich NHS Trust, and St Bartholomew's Hospital, Barts Health NHS Trust for acting a participant identification centers for the trial. The authors are also grateful to the Hammersmith & Fulham GP Federation and the Clinical Research Network North West London for their assistance with recruitment. The authors thank the data monitoring committee, Prof Raymond MacAllister, Prof John Betteridge (deceased), Dr Tim Clayton, and Dr Neil Chapman, who have provided independent, expert professional advice throughout the study on patient safety data. Finally, the authors thank Juliet Holmes, who has been key to coordinating the trial, and Yousif Ahmad, who greatly assisted them in preparing the manuscript. Funding Information: 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. Publisher Copyright: © 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

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)

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