Due to the known CYP3A4 inhibition by calcium channel blockers, we hypothesized that there might be a pharmacodynamic interaction between clopidogrel and dihydropyridines in patients with coronary artery disease (CAD). Clopidogrel is activated by CYP3A4 which also metabolizes calcium channel blockers 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 (CAD) undergoing percutaneous coronary intervention (PCI). The platelet reactivity index (PRI in the VASP assay, normal range 69–100%) was higher in patients on both clopidogrel and calcium channel blockers (61%) as compared to patients on clopidogrel without calcium channel blockers (48%). The absolute difference was 13% (95%CI: 6 –20%; p = 0.001) and the relative difference approached 21%. A high post-treatment platelet reactivity (PRI > 69%) was seen in 40% of patients with concomitant calcium channel blocker treatment compared to 20% without (X2-test: p = 0.008). Intake of calcium channel blocker remained an independent predictor of high platelet reactivity after adjustment for cardiovascular risk factors. This corresponded to an increased platelet aggregation of similar magnitude (p < 0.05). In vitro incubation with calcium channel blockers (nimodipine, verapamil, amlodipine and diltiazem) did not alter the PRI or the ADP-induced platelet aggregation of patients on clopidogrel, indicating that the interaction occurs in vivo, conceivably at the level of the CYP3A4 cytochrome. Co-administration of calcium channel blockers is associated with a decreased platelet inhibition by clopidogrel.
Treatment effects of renin-angiotensin system inhibitor and calcium channel blocker in patients with coronary artery narrowing (from the Japanese Coronary Artery Disease Study)
