Circulation. 2003;107:32-37
Published online before print November 25, 2002, doi: 10.1161/01.CIR.0000047060.60595.CC
Published online before print November 25, 2002, doi: 10.1161/01.CIR.0000047060.60595.CC
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(Circulation. 2003;107:32.)
© 2003 American Heart Association, Inc.
Clinical Investigation and Reports |
Atorvastatin Reduces the Ability of Clopidogrel to Inhibit Platelet Aggregation
A New Drug–Drug Interaction
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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I. Muller, F. Besta, C. Schulz, Z. Li, S. Massberg, and M. Gawaz Effects of Statins on Platelet Inhibition by a High Loading Dose of Clopidogrel Circulation, November 4, 2003; 108(18): 2195 - 2197. [Abstract] [Full Text] [PDF]
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E. R Bates, D. Mukherjee, and W. C Lau Drug-drug interactions involving antiplatelet agents Eur. Heart J., October 1, 2003; 24(19): 1707 - 1709. [Full Text] [PDF]
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H. Neubauer, B. Gunesdogan, C. Hanefeld, M. Spiecker, and A. Mugge Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function -- a flow cytometry study Eur. Heart J., October 1, 2003; 24(19): 1744 - 1749. [Abstract] [Full Text] [PDF]
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M. Di Napoli Editorial Comment--C-Reactive Protein and Vascular Risk in Stroke Patients: Potential Use for the Future Stroke, October 1, 2003; 34(10): 2468 - 2470. [Full Text] [PDF]
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P. Damkier, V. L. Serebruany, S. R. Steinhubl, and C. H. Hennekens Atorvastatin and Clopidogrel * Response Circulation, September 30, 2003; 108 (13): e96 - e96. [Full Text] [PDF]
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A. I. Schafer Genetic and Acquired Determinants of Individual Variability of Response to Antiplatelet Drugs Circulation, August 26, 2003; 108(8): 910 - 911. [Full Text] [PDF]
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P. T. Martin, R. Denman, W. C. Lau, L. A. Waskell, C. J. Neer, K. Horowitz, A. S. Hopp, A. R. Tait, E. R. Bates, P. B. Watkins, et al. Atorvastatin-Clopidogrel Interaction * Response Circulation, June 24, 2003; 107 (24): e223 - e223. [Full Text] [PDF]
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M. Shechter, W. C. Lau, L. A. Waskell, C. J. Neer, K. Horowitz, A. S. Hopp, A. R. Tait, E. R. Bates, P. B. Watkins, D. G.M. Carville, et al. Atorvastatin and the Ability of Clopidogrel to Inhibit Platelet Aggregation * Response Circulation, June 10, 2003; 107 (22): e210 - e210. [Full Text] [PDF]
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V. L. Serebruany, S. R. Steinhubl, and C. H. Hennekens Are Antiplatelet Effects of Clopidogrel Inhibited by Atorvastatin?: A Research Question Formulated but Not Yet Adequately Tested Circulation, April 1, 2003; 107(12): 1568 - 1569. [Full Text] [PDF]
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C. Mueller, H. Roskamm, F.-J. Neumann, P. Hunziker, S. Marsch, A. Perruchoud, and H. J. Buettner A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary artery stents J. Am. Coll. Cardiol., March 19, 2003; 41(6): 969 - 973. [Abstract] [Full Text] [PDF]
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