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

Ankie M. Harmsze; Karen Robijns; Jochem W. van Werkum; Nicoline J. Breet; Christian M. Hackeng; Jurrien M. ten Berg; Hendrik J. T. Ruven; Olaf H. Klungel; Anthonius de Boer; Vera H. M. Deneer

doi:10.1160/TH09-08-0516

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2010; 103(05): 920-925
DOI: 10.1160/TH09-08-0516

Theme Issue Article

Schattauer GmbH

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

Ankie M. Harmsze

¹Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands

²Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands

,

Karen Robijns

¹Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands

,

Jochem W. van Werkum

³Department of Cardiology, St. Antonius Hospital, Nieuwegein, The Netherlands

,

Nicoline J. Breet

³Department of Cardiology, St. Antonius Hospital, Nieuwegein, The Netherlands

,

Christian M. Hackeng

⁴Department of Clinical Chemistry, St. Antonius Hospital, Nieuwegein, The Netherlands

,

Jurrien M. ten Berg

³Department of Cardiology, St. Antonius Hospital, Nieuwegein, The Netherlands

,

Hendrik J. T. Ruven

⁴Department of Clinical Chemistry, St. Antonius Hospital, Nieuwegein, The Netherlands

,

Olaf H. Klungel

²Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands

,

Anthonius de Boer

²Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands

,

Vera H. M. Deneer

¹Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands

› Institutsangaben

Abstract

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 amlodi-pine 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.

Keywords

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

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Referenzen

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