Calcium-channel blockers reduce the antiplatelet effect of clopidogrel.
OBJECTIVE
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.
Siller-Matula
Jolanta M
JM
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Lang
Irene
I
Christ
Guenter
G
Jilma
Bernd
B
D000368:Aged; D015906:Angioplasty, Balloon, Coronary / Q000379:methods; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000378:metabolism; D000077144:Clopidogrel; D023903:Coronary Restenosis / Q000517:prevention & control; D023921:Coronary Stenosis / Q000097:blood / Q000188:drug therapy* / Q000628:therapy; D004095:Dihydropyridines / Q000008:administration & dosage*; D004347:Drug Interactions; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016015:Logistic Models; D008297:Male; D008840:Microfilament Proteins / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D011446:Prospective Studies; D012016:Reference Values; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016896:Treatment Outcome; D000098662:Vasodilator-Stimulated Phosphoprotein
D002121:Calcium Channel Blockers; D015815:Cell Adhesion Molecules; D004095:Dihydropyridines; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D000098662:Vasodilator-Stimulated Phosphoprotein; C038806:1,4-dihydropyridine; D000077144:Clopidogrel; D013988:Ticlopidine