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

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
Topic:

Hot topics in Cardiovascular Cell and Pharmacotherapy (Part 2)

DOI: http://dx.doi.org/10.1160/TH09-08-0516
Issue: 2010: 103/5 (May) pp. 875–1108
Pages: 920-925

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

A. M. Harmsze (1, 2), K. Robijns (1), J. W. van Werkum (3), N. J. Breet (3), C. M. Hackeng (4), J. M. ten Berg (3), H. J. T. Ruven (4), O. H. Klungel (2), A. de Boer (2), V. H. M. Deneer (1)

(1) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands; (2) Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands; (3) Department of Cardiology, St. Antonius Hospital, Nieuwegein, The Netherlands; (4) Department of Clinical Chemistry, St. Antonius Hospital, Nieuwegein, The Netherlands

Keywords

clopidogrel, percutaneous coronary intervention, platelet reactivity, drug-drug interaction, calcium channel blockers, P-glycoprotein, CYP3A4

Summary

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 μM adenosine diphospate (ADP) and clopidogrel poor-response (defined as > 70% platelet aggregation to 20 μM 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.

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