Clinical Research Statin-Associated Rhabdomyolysis: Is There a Dose-Response Relationship? Anne Holbrook, MD, PharmD, MSc, FRCPC, a,b,c Mitchell Wright, b Melani Sung, PharmD, d Christine Ribic, MD, c and Steven Baker, MSc, MD, FRCPC c a Division of Clinical Pharmacology and Therapeutics, McMaster University, Hamilton, Ontario, Canada b Centre for Evaluation of Medicines, McMaster University, Hamilton, Ontario, Canada c Department of Medicine, McMaster University, Hamilton, Ontario, Canada d Faculty of Pharmaceutical Sciences, University of Toronto, Toronto, Canada ABSTRACT Background: Statins have a well-established role in prevention of vascu- lar 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 2004- 2008 were analyzed by severity and dose equivalence. Canadian na- tional 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 sta- tin-induced rhabdomyolysis. Combined Canadian/US data revealed an average of 812 cases of statin-induced rhabdomyolysis reported an- nually 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 rhabdo- myolysis 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. RÉSUMÉ Introduction : Les statines ont un rôle bien établi dans la prévention d’évènements vasculaires, mais sont associées à des évènements musculaires indésirables pour lesquels la relation avec la dose est obscure. Nous présentons une analyse originale de rapports de cas canadiens et américains de rhabdomyolyse associée aux statines qui porte particulièrement sur la dose-réponse. Un résumé d’un cas clinique typique est aussi présenté. Méthodes : Tous les cas de rhabdomyolyse associée aux statines rapportés par le Programme Canada Vigilance de Santé Canada et par le U.S. Food and Drug Administration’s Adverse Event Reporting System de 2004-2008 étaient analysés selon la gravité et l’équivalence de dose. Les données nationales canadiennes sur l’utilisation des statines de 2002-2007 ont été utilisées pour évaluer l’incidence corrigée de rhabdomyolyse liée à la dose selon les niveaux d’utilisation. Résultats : Les cas cliniques démontrent bien la gravité potentielle de la rhabdomyolyse induite par les statines. Les données canadiennes et américaines combinées rapportent annuellement une moyenne de 812 cas de rhabdomyolyse induite par les statines dont l’âge moyen des patients est de 64,4 ans (35,5 % de sexe féminin). Les résultats les plus graves rapportés étaient des dysfonctions rénales dans 17,0 % des cas, des insuffisances rénales aiguës dans 19,8 % des cas, des dialyses dans 5,2 % des cas et des décès dans 7,6 % des cas. En Statins are one of the top selling prescription drug families in the world, with estimated sales of $22 billion and climbing. 1 Their widespread use is supported by high-quality evidence for vascular risk reduction. 2 Recent large randomized controlled trials (RCTs) showed additional cardiovascular event reductions of 11%- 20% with high daily doses (80 mg atorvastatin daily) versus low to moderate doses (10 mg atorvastatin, 20 mg simvastatin, or 40 mg pravastatin) for patients with coronary heart disease. 3-5 This ap- proach also appears to be cost-effective in high-risk populations. 6 Although generally well tolerated, statins are associated with muscle-related pathology ranging from mild, transient myal- gias (muscle aches only), myopathy (muscle aches and weak- ness), and myositis (muscle symptoms with elevation of crea- tine kinase [CK] 10 times upper limit of normal [ULN]) to rhabdomyolysis (elevated levels of CK 10 times ULN, often with renal impairment). 7 Received for publication April 19, 2010. Accepted August 19, 2010. Corresponding author: Dr Anne Holbrook, Division of Clinical Pharma- cology and Therapeutics, Centre for Evaluation of Medicines, McMaster Uni- versity, 105 Main St E, Level P1, Hamilton, ON, L8N 1G6, Canada. Tel.: +1-905-522-1155, ext. 35269; fax.: +1-905-528-7386. E-mail address: holbrook@mcmaster.ca See page 150 for disclosure information. Canadian Journal of Cardiology 27 (2011) 146 –151 0828-282X/$ – see front matter © 2011 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.cjca.2010.12.024