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N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects


to the Editor:

Statins are often discontinued due to side effects,1,2 Even though some blind trials have not shown an exacerbation of symptoms with statins compared to placebo.3,4 Patients who had previously discontinued statins due to a side effect occurring within 2 weeks of initiation of treatment were tested for double-blind, three to test whether a statin or placebo would be induced. -Groups were enrolled in the N-to-1 trial. Details of the test methods are provided in section S2 Supplementary appendix (Available at NEJM.org with full text of this paper); testing Draft a contract And the statistical analysis plan is also available at NEJM.org.

The patients received four bottles containing atrovastatin at a dose of 20 mg, four bottles with placebo and four empty bottles; Each bottle was to be used in random order for a period of 1 month. The patients used a smartphone application to report daily symptom intensity. Symptom scores range from 0 (no symptoms) to 100 (worst symptoms). If 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 Nosco ratio (i.e., the ratio of symptom intensity induced by taking a placebo to symptom intensity induced by taking a statin). This ratio was calculated as symptom intensity with placebo minus divided by symptom intensity with neither statin nor placebo, nor symptom intensity with statin and placebo.

From June 2016 to March 2019, a total of 60 patients randomized. Screening data, baseline characteristics of patients and diagrams showing screening, randomization, intervention, and follow-up are given in S1 through S3 to S3. Supplementary appendix. A total of 49 patients completed all 12 months of the trial.

Symptom scores for patients on all tests.

The mean shown is the symptom score for 49 patients who completed all 12 months of testing (left) and for 11 patients who did not complete all 12 months (right). Each cycle represents one month for each patient. Symptoms were reported daily, and the mean symptom score was calculated for the month to determine if the bottle assigned to the patient was closed at any time during the month.

The original primary end-point analysis showed a Nosco ratio of 2.2 (95% confidence interval) [CI],, 62.3 to 66.7). This value was high and there was a wide confidence interval because in some patients symptom intensity with statins neither reduced symptom intensity with statins nor placebo was unexpectedly small or negative. Therefore an independent statistician recommended a separate analysis (see section S2) Supplementary appendix) In which individual patient data were submitted prior to the ratio calculation. This analysis showed a ratio of 0.90. In all 60 patients, the mean symptom intensity was 8.0-tablet months (95% CI, 4.7 to 11.3), compared to 15.4 (95% CI, 12.1 to 18.7; P Figure 1). Adverse events are listed in section S4 Supplementary appendix.

Six months after the completion of the trial, 30 patients (50%) successfully resumed statins, 4 planned to do so, and 1 could not be contacted. The remaining 25 patients were not receiving statins and were not planning to restart statins. The reasons given by these 25 patients for not resuming statins are listed in Section S3. Supplementary appendix.

In patients discontinuing statin therapy due to side effects, 90% of the symptom burden associated with a statin challenge was also removed by placebo. Half the test patients were able to successfully resume statins.

Francis A. Wood, M.Phil.
James P. Howard, Ph.D.
Judith A. Finegold, Ph.D.
Alexandra Ann. Nauber, MB, B.S.
David M. Thompson, Ph.D.
Ahran d. Arnold, MB, B.S.
Christopher A. Rajkumar, MB, B.S.
Susan Connolly, Ph.D.
Imperial College London, London, United Kingdom

Jaimini Cegla, MRCP
Imperial College Healthcare NHS Trust, London, United Kingdom

Chris Stride, Ph.D.
Sheffield University Management School, Sheffield, United Kingdom

Peter Saver, FRCP
Imperial College London, London, United Kingdom

Christine Norton, Ph.D.
King’s College London, London, United Kingdom

Simon AM Thomas, MD
Matthew J. Shun-Shin, Ph.D.
Darrell P. Francis, Ph.D.
Imperial College London, London, United Kingdom

Supported by grant (PG / 15/7/31235) British Heart Foundation; A grant from the Wellcome Trust (212183 / Z / 18 / Z, to Dr. Howard); Grant from Medical Research Council (MR / S021108 / 1, to Dr. Rajkumar); National Institute for Health Research Imperial Biomedical Research Center; And the Imperial Clinical Testing Unit.

Disclosure forms The full text of this paper is available at NEJM.org provided by the authors.

The views expressed in this paper are those of the author and are not necessarily those of the National Institute of Health Research or the Department of Health and Social Care.

The paper was published on November 15, 2020 on NEJM.org.

Ms. Wood and Drs. Howard contributed equally to this paper.

  1. 1. Stroke n, Thompson PD, Corsini A, and others. Statin-associated muscle symptoms: effects on statin therapy – European Atherosclerosis Society consensus panel statement on assessment, etiology and management. You heart jay 2015; 36:10121022.

  2. 2. Stoolk tea, Ceška r., Gotam AM Junior. Statin Intolerance: The Doctor’s Viewpoint. Karr Atheroscler Rape 2015; 17:6969.

  3. 3. Lalit took J.A., Manistee CH, Goldcare Bee, Baron AJ, Francis DP. In what proportion are symptomatic side effects caused by the drug in patients taking statins? Systematic review of randomized placebo-controlled trials to aid individual patient’s choice. Ur j pre cardiol 2014; 21:464474.

  4. 4. Gupta A, Thompson D, Whitehouse a, and others. Incidents associated with unrelated events, but not blinded with statin therapy, in a trial of Anglo-Scandinavian cardiac outcomes, the trial-lipid-lowering arm (ASCOT-LLA): a randomized double-blindbo-controlled trial and its nonrandom. Non-blind extension. Phase. Knife 2017; 389:24732481.



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