but by the expectation of such adverse effects, conclude researchers behind the randomized SAMSON trial, now fully published .
It’s common for patients to stop taking their statin because of muscle pain and their belief that the drug itself is to blame. That can sometimes be true, but the SAMSON trial, owing to its unusual design, makes a strong case that such symptoms are usually a nocebo effect.
That is, most statin-related muscle symptoms are likely “driven by the act of taking tablets rather than whether the tablets contain a statin,” concludes the report, which appears in the September 21 issue of the Journal of the American College of Cardiology, with lead authors James P. Howard, PhD, and Frances A. Wood, MPhil, Imperial College London.
SAMSON had been presented at the American Heart Association Scientific Sessions 2020 virtual meeting, covered at the time by this news organization, and simultaneously published in abbreviated form as correspondence in the New England Journal of Medicine.
“SAMSON suggests that the bulk of statin-related intolerable side effects arise from the taking of a tablet, not from statin therapy per se,” agrees an editorial accompanying the new publication.
“The study also demonstrates that the informal experimentation of stopping and restarting a statin to evaluate symptom resolution and reinduction without use of a placebo leads to nocebo symptoms misattributed to the statin,” writes Peter P. Toth, MD, PhD, Johns Hopkins University, Baltimore.
Statin intolerance, he continues, “warrants considerable further investigation, because it undermines standard of care for a very large number of patients worldwide,” leaving them vulnerable to atherosclerotic cardiovascular disease events. “Aches and pains are a fact of life; just because a patient has them does not mean they should be attributed to their statin.”
SAMSON assigned 35 men and 25 women to take atorvastatin 20 mg/day, its matching placebo, or neither pill each for 1 month in randomly alternating order for 12 months, with double-blinding, such that each of the three regimens was maintained for a total of 4 months.
The patients, 77% of whom were prescribed statins for primary prevention and all of whom had a history of stopping the drugs because of adverse effects, documented the severity of any perceived adverse effects on a smartphone app, with a “symptom score” ranging from 0 to 100.
The symptom score averaged 8.0 in months when no tablet was taken, but it was much higher in other months: 15.4 in placebo-pill months and 16.3 in months when atorvastatin was taken. The no-tablet score was significantly lower (P < .001) than either of the two other scores, which themselves were not significantly different from each other.
Eleven patients were unable to complete all 12 one-month segments of the trial, including five because of severe symptoms, but discontinuation was no more likely to occur in the atorvastatin group than in the placebo group.
The authors calculated an overall 0.90 “nocebo ratio” for the study, defined as the difference between symptom intensity on placebo and on no pill, divided by the difference between symptom intensity on atorvastatin and on no pill.
That means, the authors propose, that 90% of the symptom burden felt by patients receiving atorvastatin was also felt on the placebo pill and could be attributed to the nocebo effect.
“Prompt onset and offset of symptoms after starting and stopping tablets is often interpreted by patients and clinicians as evidence of causation. Our data indicate that this is true,” the authors write, but “the causation is from taking a tablet, rather than from the tablet being a statin.”
SAMSON was funded by the British Heart Foundation and supported by the National Institute for Health Research Imperial Biomedical Research Centre and the Imperial Clinical Trials Unit. Dr. Howard is supported by the Wellcome Trust. Dr. Wood declared no conflicts. Disclosures for the other authors are in the report. Dr. Toth discloses serving as a consultant to Amarin, Amgen, AstraZeneca, nio89, Kowa, Merck, Resverlogix, and Theravance; and serving on a speaker’s bureau for Amarin, Amgen, Esperion, and NovoNordisk.
A version of this article first appeared on Medscape.com.