The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response

• Published in: Thrombosis and haemostasis Vol. 103; no. 5; p. 920
• Main Authors: Harmsze, Ankie M, Robijns, Karen, van Werkum, Jochem W, Breet, Nicoline J, Hackeng, Christian M, Ten Berg, Jurrien M, Ruven, Hendrik J T, Klungel, Olaf H, de Boer, Anthonius, Deneer, Vera H M
• Format: Journal Article
• Language: English
• Published: Germany 01.05.2010
• Subjects: Aged; Amlodipine - pharmacology; Angioplasty; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; Blood Platelets - drug effects; Blood Platelets - metabolism; Blood Platelets - pathology; Calcium Channel Blockers - pharmacology; Coronary Restenosis - prevention & control; Coronary Thrombosis - drug therapy; Coronary Thrombosis - etiology; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Platelet Activation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Platelet Aggregation Inhibitors - therapeutic use; Postoperative Complications - prevention & control; Prospective Studies; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacology; Ticlopidine - therapeutic use
• ISSN: 0340-6245
• DOI: 10.1160/TH09-08-0516

Clopidogrel is a prodrug that has to be converted in vivo to its active metabolite by cytochrome (CYP)P450 iso-enzymes. As calcium channel blockers (CCBs) are inhibitors of CYP3A4, concomitant use of these drugs might play a role in the wide inter-individual variability in the response to clopidogrel. However, some CCBs also have strong inhibitory effects on the drug transporter P-glycoprotein (Pgp), which mediates clopidogrel's intestinal absorption. It was the aim of this study to evaluate the effect of co-administration of Pgp-inhibiting and non-Pgp-inhibiting CCBs on on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective percutaneous coronary intervention (PCI). In a total of 623 consecutive patients undergoing elective PCI treated with clopidogrel and aspirin, platelet reactivity to 5 and 20 muM adenosine diphospate (ADP) and clopidogrel poor-response (defined as > 70% platelet aggregation to 20 muM ADP) were evaluated by light transmittance aggregometry. A total of 222 patients (35.6%) were on CCB treatment, of which 98 used Pgp-inhibiting CCBs (verapamil, nifedipine, diltiazem, barnidipine) and 124 patients used the non-Pgp-inhibiting CCB amlodipine. Adjusted mean ADP-induced on-clopidogrel platelet reactivity was significantly higher in both users of Pgp-inhibiting CCBs and amlodipine as compared to CCB non-users (all p<0.05). However, only the use of amlodipine was significantly associated with a 2.3-fold increased risk of clopidogrel poor-response. This study demonstrates that concomitant use of Pgp-inhibiting CCBs and amlodipine increases on-clopidogrel platelet reactivity. Only amlodipine was associated with clopidogrel poor-response. The drug-drug interaction between clopidogrel and amlodipine might be more clinically relevant as compared to P-glycoprotein-inhibiting CCBs.