The majority of symptoms caused by statin tablets in the British Heart Foundation’s 60-patient SAMSON trial were “nocebo,” driven by the act of taking tablets, regardless of whether the pill contained a statin, said the researchers.
The findings – published Monday online ahead of the Sept. 21 issue of the Journal of the American College of Cardiology – suggest the “cues and informal experiments patients and clinicians use to test causation can paradoxically confirm a non-existent association” between statins and side effects, the researchers added. SAMSON’s top-line results were presented as a late-breaking trial at the American Heart Association Virtual Scientific Sessions 2020 in November.
“Most people who begin statins abandon them, most commonly because of side effects,” Imperial College London’s James P. Howard, PhD, and Frances A. Wood, MPhil, noted, together with colleagues. This means that more than one-half of the potential benefit of this group of drugs is being lost, they stressed.
Yet the researchers reviewed placebo-controlled trials of over 80,000 participants, which show no evidence of an increment in symptoms on statins vs. placebo. “If symptoms disappear and reappear on stopping and restarting, does this prove the statin is the cause?” the researchers asked.
The SAMSON (Self-Assessment Method for Statin Side-effects Or Nocebo) trial was, therefore, established, randomizing 60 participants from 17 U.K. referral centers with intolerable side effects and who had no intention of restarting. The most common side effects leading to statin abandonment were muscle ache (60%), fatigue or tiredness (15%), and cramps (10%).
The trial was a multiple-crossover three-arm, double-blind, placebo-controlled design, and included two study visits at Hammersmith Hospital in London.
Many had tried different statin drugs or doses, with 12 of the participants having tried four or more previous regimens.
The participants had a mean age of 65.5 ±8.6 years, were majority male (58.3%), mostly white (90%)and had a mean body mass index of 29.1 ± 6.7 kg/m2. Patients with fibrates or dangerous previous side effects, such as rhabdomyolysis, were excluded.
Each was given a 12-month protocol with 4 months of statins (atorvastatin 20 mg), 4 months of placebo and 4 no-tablet months in indistinguishable bottles, randomly ordered for sequential allocation.
Daily symptom scores on a 1-to-100 scale were collected via a smartphone app and the “nocebo” ratio – the ratio of symptoms induced by taking statin that was also induced from taking placebo – was measured.
Of the 60 enrolled participants, 49 completed the full 12-month protocol. The mean symptom score was 8 (95% confidence interval [CI]: 4.7 – 11.3; P < 0.001) in no-tablet months, and was higher in both statin months (16.3; 95% CI: 12 – 19.6; P < 0.001) and placebo months (15/4; 95% CI: 12.1-18.7; P < 0.001).
There was no significant difference between mean symptom score on statin and placebo months (P = 0.388). The corresponding nocebo rate from pooled patient data was 0.90. When calculated using individual patient nocebo ratios, the nocebo ratio was 2.2 (95% CI: - 62.3 to 66.7).
In individual patient daily data, there was no difference between statin and placebo when it came to symptom intensity when starting (odds ratio [OR]: 1.02; 95% CI: 0.98-1.06; P = 0.28) or extent of symptom relief when stopping (OR: 1.01; 95% CI: 0.98-1.05; P = 0.48).
Furthermore, stopping was no more frequent for statin than for placebo (P = 0.173), while subsequent symptom relief was similar between the two groups.
Of the 11 participants who withdrew, five pulled out because of severe symptoms.
The researchers added that at 6 months after the trial, 30 of the 60 participants were back taking statins.
“Despite having permanently abandoned statin tablets because of intolerable side effects, most participants could nevertheless complete a 12-month multiple-crossover protocol intended to verify these side effects and identify their origins. These side effects predominantly arose from taking a tablet, rather than from the statin within it,” the researchers said.
“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,” they concluded.
The researchers added that useful future trials could include multiple-crossover designs with a no-treatment arm as well as an active drug and placebo, to isolate side effect profiled related to nonpharmacological factors.
In an accompanying editorial, Peter P. Toth, MD, PhD, from CGH Medical Center, Sterling, Illinois, branded the study innovative and stressed that: “The issue of statin intolerance warrants considerable further investigation, because it undermines standard of care for a very large number of patients worldwide and leaves them vulnerable to [atherosclerotic cardiovascular disease] related 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.”
Howard JP, Wood FA, Finegold JA, et al. Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment. J Am Coll Cardiol 2021;78:1210- 1222.
Toth PP. That Myalgia of Yours Is Not From Statin Intolerance. J Am Coll Cardiol 2021;78:1223-1226.
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