Calcium-channel blockers reduce the antiplatelet effect of clopidogrel

J Am Coll Cardiol. 2008 Nov 4;52(19):1557-63. doi: 10.1016/j.jacc.2008.07.055.


Objectives: Because of the known CYP3A4 inhibition by calcium-channel blockers (CCBs), we hypothesized that there might be a drug-drug interaction between clopidogrel and dihydropyridines in patients with coronary artery disease.

Background: Clopidogrel is activated by CYP3A4, which also metabolizes CCBs of the dihydropyridine class.

Methods: Responsiveness to clopidogrel was assessed by the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and aggregometry in 200 patients with coronary artery disease undergoing percutaneous coronary intervention.

Results: The platelet reactivity index (PRI) (in the VASP assay, normal range 69% to 100%) was higher in patients receiving both clopidogrel and CCBs (61%) as compared with patients receiving clopidogrel without CCBs (48%). The absolute difference was 13% (95% confidence interval: 6% to 20%; p = 0.001), and the relative difference approached 21%. A decreased platelet inhibition by clopidogrel (PRI >69%) was seen in 40% of patients with concomitant CCB treatment and in 20% of patients without concomitant treatment (chi-square test, p = 0.008). Intake of CCB remained an independent predictor of reduced platelet inhibition by clopidogrel after adjustment for cardiovascular risk factors. Adenosine diphosphate-induced platelet aggregation was 30% higher in patients on concomitant CCB treatment compared with patients without CCBs (p = 0.046). Moreover, intake of CCBs was associated with adverse clinical outcome. In vitro incubation with CCBs (nimodipine, verapamil, amlodipine, and diltiazem) did not alter the PRI or the adenosine diphosphate-induced platelet aggregation of patients taking clopidogrel. This finding indicates that the negative effect occurs in vivo, conceivably at the level of the CYP3A4 cytochrome.

Conclusions: Coadministration of CCBs is associated with decreased platelet inhibition by clopidogrel.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Angioplasty, Balloon, Coronary / methods
  • Calcium Channel Blockers / administration & dosage*
  • Case-Control Studies
  • Cell Adhesion Molecules / drug effects
  • Cell Adhesion Molecules / metabolism
  • Clopidogrel
  • Coronary Restenosis / prevention & control
  • Coronary Stenosis / blood
  • Coronary Stenosis / drug therapy*
  • Coronary Stenosis / therapy
  • Dihydropyridines / administration & dosage*
  • Drug Interactions
  • Female
  • Flow Cytometry
  • Humans
  • Logistic Models
  • Male
  • Microfilament Proteins / drug effects
  • Microfilament Proteins / metabolism
  • Middle Aged
  • Phosphoproteins / drug effects
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / administration & dosage*
  • Prospective Studies
  • Reference Values
  • Risk Assessment
  • Sensitivity and Specificity
  • Statistics, Nonparametric
  • Ticlopidine / administration & dosage
  • Ticlopidine / analogs & derivatives*
  • Treatment Outcome


  • Calcium Channel Blockers
  • Cell Adhesion Molecules
  • Dihydropyridines
  • Microfilament Proteins
  • Phosphoproteins
  • Platelet Aggregation Inhibitors
  • vasodilator-stimulated phosphoprotein
  • 1,4-dihydropyridine
  • Clopidogrel
  • Ticlopidine