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on November 25, 2002

Circulation. 2002
Published online before print November 25, 2002, doi: 10.1161/01.CIR.0000047060.60595.CC
A more recent version of this article appeared on January 7, 2003
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© American Heart Association, Inc.

Clinical Investigation and Reports

Atorvastatin Reduces the Ability of Clopidogrel to Inhibit Platelet Aggregation

A New Drug–Drug Interaction

Wei C. Lau, MD; Lucy A. Waskell, MD, PhD; Paul B. Watkins, MD; Charlene J. Neer, BSN, MPA; Kevin Horowitz, BS; Amy S. Hopp, BS; Alan R. Tait, PhD; David G.M. Carville, PhD; Kirk E. Guyer, BS Eric R. Bates, MD

From the Department of Anesthesiology (W.C.L., L.A.W., C.J.N., K.H., A.S.H., A.R.T.) and Division of Cardiology, Department of Internal Medicine (E.R.B.), University of Michigan, Ann Arbor; General Clinical Research Center, University of North Carolina at Chapel Hill (P.B.W.); Division of Thrombosis, Department of Chemistry, Indiana University South Bend (D.G.M.C., K.E.G.); and Department of Anesthesiology, VA Medical Center, Ann Arbor, Mich (L.A.W.).

Correspondence to Wei C. Lau, MD, Department of Anesthesiology, University of Michigan Health System, 1500 East Medical Center Dr, 1G323 University Hospital, Box 0048, Ann Arbor, MI 48109-0048. E-mail weiclau{at}umich.edu

Background— We observed that the prodrug clopidogrel was less effective in inhibiting platelet aggregation with coadministration of atorvastatin during point-of-care platelet function testing. Because atorvastatin is metabolized by cytochrome P450 (CYP) 3A4, we hypothesized that clopidogrel might be activated by CYP3A4.

Methods and Results— Platelet aggregation was measured in 44 patients undergoing coronary artery stent implantation treated with clopidogrel or clopidogrel plus pravastatin or atorvastatin, and in 27 volunteers treated with clopidogrel and either erythromycin or troleandomycin, CYP3A4 inhibitors, or rifampin, a CYP3A4 inducer. Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of clopidogrel in a dose-dependent manner. Percent platelet aggregation was 34±23, 58±15 (P=0.027), 74±10 (P=0.002), and 89±7 (P=0.001) in the presence of clopidogrel and 0, 10, 20, and 40 mg of atorvastatin, respectively. Erythromycin attenuated platelet aggregation inhibition (55±12 versus 42±12% platelet aggregation; P=0.002), as did troleandomycin (78±18 versus 45±18% platelet aggregation; P<0.0003), whereas rifampin enhanced platelet aggregation inhibition (33±18 versus 56±20% platelet aggregation, P=0.001).

Conclusions— CYP3A4 activates clopidogrel. Atorvastatin, another CYP3A4 substrate, competitively inhibits this activation. Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel.


Key Words: drugs • pharmacology • platelets • statins




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