Curriculum in Cardiology
A systematic review of statin-induced muscle problems in clinical trials

https://doi.org/10.1016/j.ahj.2014.03.019Get rights and content

Statin therapy is associated with muscle problems in approximately 10% to 25% of patients treated in clinical practice, but muscle problems have rarely been reported in controlled clinical trials. We performed a systematic search and review of statin clinical trials to examine how these studies evaluated muscle problems and to determine why there are apparent differences in muscle problems between clinical trials and practice. We initially identified 1,012 reports related to clinical trials of statin therapy, 42 of which qualified for analysis. Fifteen, 4, and 22 trials reported creatine kinase values only >10, 5, and 3 times the upper limits of normal, respectively, in both statin- and placebo-treated participants. Four trials reported average creatine kinase values, which increased with statin treatment in 3 instances. Twenty-six trials reported muscle problems, with an average incidence in statin- and placebo-treated participants of 13%, but only one trial specifically queried about muscle problems. Three trials used a run-in period to eliminate participants with statin intolerance and noncompliance. The percentage of muscle problems tended to be higher with statin treatment (12.7%) than with placebo group (12.4%, P = .06). This small difference probably reflects a high background rate of nonspecific muscle problems in both groups that could not be distinguished from statin-associated myalgia because most clinical trials did not use a standard definition for statin myalgia.

Section snippets

Methods

We searched PubMed, Ovid, and Google Scholar for English-language articles reporting the results of placebo-controlled trials of statin therapy using the terms hydroxymethylglutaryl CoA reductase inhibitors, statins, muscles, muscle injury, myalgia, myopathy, and creatine kinase alone and in combinations. Studies were required to be placebo controlled, to have a minimum follow-up of 6 months, and to be published from 1990 through November 2012. We initially identified 1,012 manuscripts but

Results

Fourteen studies examined pravastatin6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19; 6, lovastatin20, 21, 22, 23, 24, 25; 6, atorvastatin26, 27, 28, 29, 30, 31; 5, simvastatin32, 33, 34, 35, 36; 5, rosuvastatin37, 38, 39, 40, 41; 5, fluvastatin42, 43, 44, 45, 46; and 1, cerivastatin (Table I).47 The age (mean ± SD) of the statin and placebo groups was 60 ± 5.5 and 60 ± 5.6 years. The mean duration of statin exposure was 3 ± 1.6 years and ranged from 0.5 to 6.1 years. Only approximately half

Discussion

We examined the study design and results of 42 clinical trials of statin therapy to determine how statin-related muscle adverse effects are evaluated and reported. Only 26 trials (Table II) reported the frequency of muscle problems, and only 1 study37 actually queried participants systematically about muscle problems. Interestingly, among those 26 studies that reported these events, 12.7% of treated and 12.4% of placebo groups reported muscle problems. Ninety-eight percent of studies did not

Conclusion

Despite these potential problems, our review suggests that the impression that statin muscle adverse effects are rare in clinical trials is correct. The incidence in treated and placebo-treated participants in the clinical trials is nearly identical and is approximately 13% of participants. Most clinical trials, however, did not solicit muscle problems, use standard definitions of muscle problems or myalgia, or report the effect of statin therapy on average CK levels. We suggest that using

Disclosures

Harsha V Ganga: none.

Hanna B Slim: none.

Paul D Thompson has received grants from GlaxoSmithKline, Genomas, Roche,Sanolfi-Aventis, Regeneron, Esperion, and Amarin; has served as a consultant for Astra Zeneca, Amgen, Regeneron, Genomas, Merck, Abbott, Runner’s World, Genzyme, Sanolfi, GlaxoSmithKline, and Esperion; has received speaking honoraria from Merck, Astra Zeneca, Abbott, GlaxoSmithKline, and Kowa; owns stock in General Electric, JA Wiley Publishing, J&J, and Abbott; and has served as

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