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CLINICAL RESEARCH: ANTIPLATELET THERAPY

Calcium-Channel Blockers Reduce the Antiplatelet Effect of Clopidogrel

Jolanta M. Siller-Matula, MD^_*, Irene Lang, MD, Guenter Christ, MD and Bernd Jilma, MD^_*,_*

^_* Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
Department of Cardiology, Medical University of Vienna, Vienna, Austria

Manuscript received March 17, 2008; revised manuscript received June 16, 2008, accepted July 2, 2008.

^_* Reprint requests and correspondence: Dr. Bernd Jilma, Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna A-1090, Austria (Email: bernd.jilma{at}meduniwien.ac.at).

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.

Key Words: calcium-channel blockers • clopidogrel • drug–drug interaction • platelets • pharmacology

Abbreviations and Acronyms   ADP = adenosine diphosphate   CABG = coronary artery bypass graft   CAD = coronary artery disease   CCB = calcium-channel blocker   HR = hazard ratio   MFI = mean fluorescence intensity   PCI = percutaneous coronary intervention   PG = prostaglandin   PRI = platelet reactivity index   VASP = vasodilator-stimulated phosphoprotein

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