Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial

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. Clopidogrel for the Reduction...

Full description

Saved in:

Bibliographic Details
Published in:	Circulation (New York, N.Y.) N.Y.), 2003-08, Vol.108 (8), p.921-924
Main Authors:	SAW, Jacqueline, STEINHUBL, Steven R, BERGER, Peter B, KEREIAKES, Dean J, SEREBRUANY, Victor L, BRENNAN, Danielle, TOPOL, Eric J
Format:	Article
Language:	eng
Subjects:	Angioplasty, Balloon, Coronary Atorvastatin Biological and medical sciences Clopidogrel Coronary Artery Disease - mortality Coronary Artery Disease - prevention & control Coronary Artery Disease - therapy Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System - metabolism Drug Interactions Drug Therapy, Combination Female General and cellular metabolism. Vitamins Hemorrhage - etiology Heptanoic Acids - adverse effects Heptanoic Acids - therapeutic use Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use Male Medical sciences Middle Aged Myocardial Infarction - prevention & control Pharmacology. Drug treatments Platelet Aggregation Inhibitors - adverse effects Platelet Aggregation Inhibitors - therapeutic use Pyrroles - adverse effects Pyrroles - therapeutic use Randomized Controlled Trials as Topic - statistics & numerical data Retrospective Studies Risk Assessment Stroke - prevention & control Ticlopidine - adverse effects Ticlopidine - analogs & derivatives Ticlopidine - therapeutic use Treatment Outcome
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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. 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. 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.
ISSN:	0009-7322 1524-4539