Published online before print August 18, 2003, doi: 10.1161/01.CIR.0000088780.57432.43
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(Circulation. 2003;108:921.)
© 2003 American Heart Association, Inc.
Brief Rapid Communications |
Lack of Adverse Clopidogrel–Atorvastatin Clinical Interaction From Secondary Analysis of a Randomized, Placebo-Controlled Clopidogrel Trial
From the Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (J.S., D.B., E.J.T.); University of North Carolina, Chapel Hill, North Carolina (S.R.S.); Mayo Clinic, Rochester, Minn (P.B.B.); University of Cincinnati, Cincinnati, Ohio (D.J.K.); and Johns Hopkins University, Baltimore, Md (V.L.S.).
Correspondence to Eric J. Topol, MD, Cleveland Clinic Foundation, 9500 Euclid Ave, Desk F25, Cleveland, Ohio, 44195. E-mail topole{at}ccf.org
Received March 4, 2003; de novo received May 29, 2003; revision received July 7, 2003; accepted July 8, 2003.
Background— Statins primarily metabolized by cytochrome P450 3A4 (CYP3A4) reportedly reduce clopidogrel’s metabolism to active metabolite, thus attenuating its inhibition of platelet aggregation ex vivo. However, the clinical impact of this interaction has not been evaluated.
Methods and Results— Clopidogrel for the Reduction of Events During Observation (CREDO) was a double-blind, placebo-controlled, randomized trial comparing pretreatment (300 mg) and 1-year (75 mg/d) clopidogrel therapy (clopidogrel) with no pretreatment and 1-month clopidogrel therapy (75 mg/d) (control) after a planned percutaneous coronary intervention. All patients received aspirin. The 1-year primary end point was a composite of death, myocardial infarction, and stroke. We performed a post hoc analysis to evaluate the clinical efficacy of concomitant clopidogrel and statin administration, categorizing baseline statin use to those predominantly CYP3A4-metabolized (atorvastatin, lovastatin, simvastatin, and cerivastatin) (CYP3A4-MET) or others (pravastatin and fluvastatin) (non-CYP3A4-MET). Of the 2116 patients enrolled, 1001 received a CYP3A4-MET and 158 a non-CYP3A4-MET statin. For the overall study population, the primary end point was significantly reduced in the clopidogrel group (8.5% versus 11.5%, RRR 26.9%; P=0.025). This clopidogrel benefit was similar with statin use, irrespective of treatment with a CYP3A4-MET (7.6% clopidogrel, 11.8% control, RRR 36.4%, 95% CI 3.9 to 57.9; P=0.03) or non-CYP3A4-MET statin (5.4% clopidogrel, 13.6% control, RRR 60.6%, 95% CI -23.9 to 87.4; P=0.11). Patients given atorvastatin or pravastatin had similar 1-year event rates. Additionally, concomitant therapy with statins had no impact on major or minor bleeding rates.
Conclusions— Although ex vivo testing has suggested a potential negative interaction when coadministering a CYP3A4-metabolized statin with clopidogrel, this was not clinically observed statistically in a post hoc analysis of a placebo-controlled study.
Key Words: drugs • metabolism • statins
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|
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|
|
|
|
 |
|
 E. Lim Reply to the Editor: J. Thorac. Cardiovasc. Surg., February 1, 2005; 129(2): 475 - 476. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
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|
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|
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|
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|
|
|
|
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|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
A Mugge and H Neubauer Do statins really interfere with clopidogrel-induced platelet function?: Reply Eur. Heart J., March 1, 2004; 25(5): 449 - 449. [Full Text] [PDF]
|
|
|
|
 |
|
 Clopidogrel-Atorvastatin Interaction Revisited Journal Watch Cardiology, October 31, 2003; 2003(1031): 5 - 5. [Full Text]
|
|
|
|
 |
|
 Does Clopidogrel Interact with Certain Statins? Journal Watch (General), October 3, 2003; 2003(1003): 4 - 4. [Full Text]
|
|
|
|
|
|
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|
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