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

Circulation. 2003 Aug 26;108(8):921-4. doi: 10.1161/01.CIR.0000088780.57432.43. Epub 2003 Aug 18.


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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angioplasty, Balloon, Coronary
  • Atorvastatin
  • 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
  • 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
  • Middle Aged
  • Myocardial Infarction / prevention & control
  • 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


  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Platelet Aggregation Inhibitors
  • Pyrroles
  • Cytochrome P-450 Enzyme System
  • Atorvastatin
  • Clopidogrel
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Ticlopidine