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

To 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 patients, and a diagram showing screening, randomization, intervention, and follow-up are provided in Sections S1 through S3 in the Supplementary Appendix. A total of 49 patients completed all 12 months of the trial.

Symptom Scores for All the Trial Patients.

Shown are mean symptom scores for the 49 patients who completed all 12 months of the trial (left) and those for the 11 patients who did not complete all 12 months (right). Each circle represents a single month for each patient. Symptoms were reported daily, and the mean symptom score was calculated for the month regardless of whether the patient discontinued the assigned bottle at any time during that month.

The original primary end-point analysis showed a nocebo ratio of 2.2 (95% confidence interval [CI], −62.3 to 66.7). This value was high and had a wide confidence interval because in some of the patients the value of the symptom intensity with statins minus the symptom intensity with neither statin nor placebo was unexpectedly small or negative. An independent statistician therefore recommended a different analysis (see Section S2 in the Supplementary Appendix) in which individual patient data were pooled before calculation of the ratio. This…

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