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N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects
Open accessAbstract
N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side EffectsTo the Editor: Statins are often discontinued because of side effects, 1,2 even though some blinded trials have not shown an excess of symptoms with statins as compared with placebo.3,4 Patients who had previously discontinued statins because of side effects that occurred within 2 weeks after the initiation of treatment were enrolled in a double-blind, three-group, n-of-1 trial to test whether symptoms would be induced by a statin or placebo.Details of the trial methods are provided in Section S2 in the Supplementary Appendix (available with the full text of this letter at NEJM.org); the trial protocol and statistical analysis plan are also available at NEJM.org.The patients received four bottles containing atorvastatin at a dose of 20 mg, four bottles containing placebo, and four empty bottles; each bottle was to be used for a 1-month period according to a random sequence.The patients used a smartphone application to report symptom intensity daily.Symptom scores ranged from 0 (no symptoms) to 100 (worst imaginable symptoms).If the patients determined that their symptoms were unacceptably severe, they could discontinue the tablets for that month.The primary end point was symptom intensity as assessed with the use of the nocebo ratio (i.e., the ratio of symptom intensity induced by taking placebo to the symptom intensity induced by taking a statin).This ratio was calculated as the symptom intensity with placebo minus the symptom intensity with neither statin nor placebo, divided by the symptom intensity with a statin minus the symptom intensity with neither statin nor placebo.From June 2016 through March 2019, a total of 60 patients underwent randomization.The screening data, the baseline characteristics of the
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“New evidence on the management of SAMS have since become available both from randomized control trials (RCTs) and from observational data [20–26].”
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“23 studies were included for data extraction [20–26,35–50], with 9 RCTs analyzed quantitatively.”
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“nine trials assessed statin against placebo [20–26,43]”
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“Most trials used statins with low to moderate intensity [20,21,24–26,40,43,46,48,49]”
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“two trials [24,26] used symptom intensity expressed as a nocebo ratio”
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“With suggestion of a nocebo effect, trials started reporting the nocebo ratio, e.g., the symptom intensity in placebo periods in relation to the symptom intensity when taking a statin [24,26].”
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“Insufficient information was provided regarding the methodology to address carryover effects during the data analysis in two crossover trials [24,43].”
From Safety outcomes of statin vs non-statin lipid-lowering interventions in patients with prior statin-associated muscle symptoms: A systematic review and meta-analysis (2025) · cites this paper as [24]
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Stroes, E. S., Thompson, P. D., Corsini, A., Vladutiu, G. D., Raal, F. J., Ray, K. K., Roden, M., Stein, E., Tokgözoğlu, L., Nordestgaard, B. G., et al. (2015) · European Heart Journal · doi:10.1093/eurheartj/ehv043 · Cited by 1,443
Gupta, A., Thompson, D., Whitehouse, A., Collier, T., Dahlof, B., Poulter, N., Collins, R., & Sever, P. (2017) · The Lancet · doi:10.1016/s0140-6736(17)31075-9 · Cited by 343
Self-citationFinegold, J. A., Manisty, C. H., Goldacre, B., Barron, A. J., & Francis, D. P. (2014) · European Journal of Preventive Cardiology · doi:10.1177/2047487314525531 · Cited by 214
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Metadata
- Authors
- Wood, F. A., Howard, J. P., Finegold, J. A., Nowbar, A. N., Thompson, D. M., Arnold, A. D., Rajkumar, C. A., Connolly, S., Cegla, J., Stride, C., Sever, P., Norton, C., Thom, S. A. M., Shun-Shin, M. J., & Francis, D. P.
- Affiliations
- Imperial College London (GB)
- Imperial College Healthcare NHS Trust (GB)
- University of Sheffield (GB)
- King's College London (GB)
- Imperial College London, London, United Kingdom
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2020-11-26
- Volume
- 383
- Issue
- 22
- Pages
- 2182-2184
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W3104495732
- Cited by
- 274
- References
- 4
- Citations by year
- 2026: 29 · 2025: 25 · 2024: 29 · 2023: 37 · 2022: 59 · 2021: 92 · 2020: 3
- FWCI
- 43.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- British Heart Foundation (PG/15/7/31235)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Keywords
- statins, atorvastatin, adverse drug reactions, nocebo effect, placebo response, symptom intensity, N-of-1 trials, statin discontinuation
- MeSH terms
- Atorvastatin, Adult, Double-Blind Method, Humans, Placebos, Confidence Intervals, Hydroxymethylglutaryl-CoA Reductase Inhibitors
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