Statin-Associated Rhabdomyolysis: Is There a Dose-Response Relationship?

Background: Statins have a well-established role in prevention of vascular events but are associated with muscle-related adverse events. The dose relationship with these adverse events is unclear. We present an original analysis of Canadian and US case reports of statin-associated rhabdomyolysis with a focus on dose response. A typical clinical case is also summarized. Methods: All cases of statin-associated rhabdomyolysis reported to Health Canada's Canadian Vigilance Program and to the US Food and Drug Administration's Adverse Event Reporting System from 20042008 were analyzed by severity and dose equivalence. Canadian national statin utilization data from 2002-2007 were used to estimate the dose-related incidence of rhabdomyolysis corrected for levels of utilization. Results: The clinical case illustrates well the potential severity of statin-induced rhabdomyolysis. Combined Canadian/US data revealed an average of 812 cases of statin-induced rhabdomyolysis reported annually with a mean patient age of 64.4 years (35.5% female). The worst outcomes reported were renal dysfunction in 17.0%, acute renal failure in 19.8%, dialysis in 5.2%, and death in 7.6%. Using 10 mg atorvastatin per day as the reference dose, the odds ratios of rhabdomyolysis were 3.8 (95% CI 2.3-6.6) for 40 mg/day atorvastatin dose equivalent and 11.3 (95% CI 6.4-20.4) for 80 mg/day atorvastatin dose equivalent. Conclusions: The results of our adverse drug analysis suggest a dose-response relationship. Given the widespread use of statins, the ability to predict which patients will experience serious muscle-related harm is a research priority.