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Side-Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment
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The authors performed a randomized trial of statin therapy versus placebo to assess perceived negative side effects. Patients taking placebo and statin both reported an increase in symptoms, but there was no difference between the two groups. Symptom relief from stopping medication was similar when stopping placebo and statin.
- The majority of symptoms caused by statin tablets were nocebo, with no difference between placebo and statin.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBackground
Most people who begin statins abandon them, most commonly because of side effects.
Objectives
The purpose of this study was to assess daily symptom scores on statin, placebo, and no treatment in participants who had abandoned statins.
Methods
Participants received 12 1-month medication bottles, 4 containing atorvastatin 20 mg, 4 placebo, and 4 empty. We measured daily symptom intensity for each using an app (scale 1-100). We also measured the “nocebo” ratio: the ratio of symptoms induced by taking statin that was also induced by taking placebo.
Results
A total of 60 participants were randomized and 49 completed the 12-month protocol. Mean symptom score was 8.0 (95% CI: 4.7-11.3) in no-tablet months. It was higher in statin months (16.3; 95% CI: 13.0-19.6; P < 0.001), but also in placebo months (15.4; 95% CI: 12.1-18.7; P < 0.001), with no difference between the 2 (P = 0.388). The corresponding nocebo ratio was 0.90. In the individual-patient daily data, neither symptom intensity on starting (OR: 1.02; 95% CI: 0.98-1.06; P = 0.28) nor extent of symptom relief on stopping (OR: 1.01; 95% CI: 0.98-1.05; P = 0.48) distinguished between statin and placebo. Stopping was no more frequent for statin than placebo (P = 0.173), and subsequent symptom relief was similar between statin and placebo. At 6 months after the trial, 30 of 60 (50%) participants were back taking statins.
Conclusions
The majority of symptoms caused by statin tablets were nocebo. 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.
Additional Info
Disclosure statements are available on the authors' profiles:
Are statin-associated muscle complaints real?
I recently reviewed the 3 available “N-of-1” statin-associated muscle symptom (SAMS) trials.1 N-of-1 trials randomly and repetitively assign patients with SAMS to short trials of statin or placebo to determine if there is a difference in the occurrence of SAMS between the active and placebo periods. All 3 studies found that SAMS was as frequent on placebo as on statin, suggesting that SAMS are more psychological than physiological. The implication is that clinicians should tell patients (sympathetically) to “suck it up.”
I lamented that these trials do not really know if their study subjects have SAMS. I readily agree that most patients have other causes of their discomfort, but do all? We have advocated for pretrial, run-in protocols where subjects are randomized to placebo or statin to ensure that only patients who report pain only on the statin, and not on placebo, are allowed to participate.
One of the 3 studies was published as a research letter, has been expanded, and is now published in JACC.2,3 The study is unique because it is the only N-of-1 trial that had a no pill period. Overall, 60 subjects who had previously developed SAMS within 2 weeks of statin initiation were randomly assigned to 12 x 1-month trials of atorvastatin 20 mg daily, placebo tablets, or no tablets. Only 49 subjects completed the trial. Symptom scores were significantly higher on both statin and placebo than on no tablets, but not different between the statin and placebo.
Such studies show that many patients with SAMS wrongly blame statins as the source of their discomfort. But these studies do not show that all SAMS is spurious because they do not first verify that the patients really had SAMS. We have advocated for pretrial, run-in protocols that randomize subjects to placebo or statin to ensure that only patients with pain only on the statin are allowed to participate. In addition, this is a very small study with only 49 completers. The patients got symptoms within 2 weeks of statin initiation, suggesting that they were a twitchy group. Finally, the central figure shows no difference in the cumulative percentage of patients who stopped the tablets (P = .173), but the statin group is consistently higher in a very small study. What would a larger study show?
I wonder why statins have so many muscle complaints versus other drugs. Could it be the statin? Why do clinicians and epidemiologists differ on the physiological reality of SAMS? N-of-1 studies are useful because they encourage patients to stay on these life-saving drugs, but they do not prove that all SAMS is imaginary.
References