title: The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacy, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands.
authors.forename: Ankie M
authors.initials: AM
authors.lastname: Harmsze
authors.forename: Karen
authors.initials: K
authors.lastname: Robijns
authors.forename: Jochem W
authors.initials: JW
authors.lastname: van Werkum
authors.forename: Nicoline J
authors.initials: NJ
authors.lastname: Breet
authors.forename: Christian M
authors.initials: CM
authors.lastname: Hackeng
authors.forename: Jurrien M
authors.initials: JM
authors.lastname: Ten Berg
authors.forename: Hendrik J T
authors.initials: HJ
authors.lastname: Ruven
authors.forename: Olaf H
authors.initials: OH
authors.lastname: Klungel
authors.forename: Anthonius
authors.initials: A
authors.lastname: de Boer
authors.forename: Vera H M
authors.initials: VH
authors.lastname: Deneer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000368:Aged; D017311:Amlodipine / Q000494:pharmacology*; D017130:Angioplasty; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D000077144:Clopidogrel; D023903:Coronary Restenosis / Q000517:prevention & control; D003328:Coronary Thrombosis / Q000188:drug therapy / Q000209:etiology*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011183:Postoperative Complications / Q000517:prevention & control; D011446:Prospective Studies; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D010975:Platelet Aggregation Inhibitors; D017311:Amlodipine; D000077144:Clopidogrel; D013988:Ticlopidine