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Clopidogrel-Precipitated Rhabdomyolysis in a Stable Heart Transplant Patient

Professor of Medicine, Faculty of Medicine and Dentistry; Medical Director, Cardiac Transplant Program; Interventional Cardiologist, Division of Cardiology, University of Alberta, Edmonton, AB, Canada

Ilene Burton, RN

Outpatient Nurse Coordinator, Cardiac Transplant Program, University of Alberta Hospital, Edmonton

Glen J Pearson, PharmD FCSHP

Associate Professor of Medicine, Faculty of Medicine and Dentistry; Co-Director, Cardiac Transplant Clinic; Deputy Medical Director and Director of Research, Cardiovascular Risk Reduction Clinic, Division of Cardiology, University of Alberta

Reprints: Dr. Pearson, Division of Cardiology, University of Alberta, Suite 2C2, Walter Mackenzie Health Sciences Centre, 8440–112th St., Edmonton T6G 2B7, AB, Canada, fax 780/407-1496, Glen.Pearson{at}ualberta.ca

OBJECTIVE: To report the case of an orthotopic heart transplant recipient who developed rhabdomyolysis precipitated by the addition of clopidogrel to the existing regimen of cyclosporine and atorvastatin, which had been tolerated for more than 3 years without adverse effects or laboratory evidence of myositis.

CASE SUMMARY: Fourteen years after cardiac transplantation, a 58-year-old woman began a planned 4 week course of clopidogrel 75 mg/day following coronary angioplasty and placement of a stent in the left circumflex coronary artery. Almost 4 weeks later, she presented with severe muscle pain and weakness and laboratory evidence of rhabdomyolysis, with marked elevations of plasma creatine kinase (96 000 U/L) and urine myoglobin (332 872 µg/L) as well as early acute renal failure (serum creatinine 2.9 mg/dL). Symptoms and laboratory abnormalities resolved with cessation of cyclosporine, atorvastatin, and clopidogrel. Clopidogrel was not restarted, while atorvastatin and cyclosporine were; the patient had no recurrence of symptoms up to 15 months later.

DISCUSSION: Both atorvastatin and cyclosporine, as well as clopidogrel's active thiol derivative, are metabolized by the cytochrome P450 3A4 isoenzyme. Cyclosporine is also a moderate inhibitor of this isoenzyme. We postulate that competition between atorvastatin and clopidogrel for CYP3A4 receptors, already partially inhibited by cyclosporine, led to increased atorvastatin concentrations, resulting in the acute onset of rhabdomyolysis. This theory is further supported by the patient's continued ability to tolerate the combination of atorvastatin and cyclosporine, without clopidogrel, on rechallenge. Use of the Naranjo probability scale revealed that rhabdomyolysis was probably precipitated by the addition of clopidogrel to the stable baseline regimen of cyclosporine and atorvastatin.

CONCLUSIONS: Practitioners must be conscious of the potential for adverse effects when prescribing clopidogrel to heart transplant patients who are concomitantly receiving cyclosporine and a statin. If concomitant administration is required, careful clinical and laboratory monitoring of the patient is necessary.

Key Words: cyclosporine, heart transplant, hydroxymethylglutaryl coenzyme A reductase inhibitor, rhabdomyolysis

Published Online, January 2, 2007. www.theannals.com, DOI 10.1345/aph.1H394