Platelet reactivity in patients with coronary artery disease on treatment with ivabradine and clopidogrel: The PLATIVA study

Abstract

The combination of aspirin and clopidogrel remains the most frequent dual antiplatelet therapy in patients with acute coronary syndrome or undergoing percutaneous coronary intervention. Clopidogrel, a P2Y12 adenosine diphosphate (ADP) platelet receptor inhibitor requires transformation by cytochrome P450 (CYP) in the liver to produce an active metabolite. On the other hand, ivabradine is an effective antianginal drug that is also metabolized by the CYP enzyme, acting as a weak inhibitor. Our aim is to evaluate the impact of ivabradine on platelet reactivity in patients receiving clopidogrel and to evaluate the possible pharmacodynamic interactions between them. This is a prospective, observational, post-authorization pharmacodynamic study including patients treated with aspirin and clopidogrel and initiating ivabradine. Patients with platelet abnormalities and those treated with anticoagulants or other CYP inhibitors were excluded. A platelet aggregation test was performed at baseline before the first dose of ivabradine and repeated after 4 weeks of treatment. The primary endpoint was inhibition of platelet aggregation (IPA) after 20 mM ADP stimulation. A total of 34 patients were initially recruited; eight patients were excluded, leaving 25 patients for final analysis. All patients had chronic ischemic heart disease. The maximum ivabradine dosage of 7.5 mg twice daily was achieved in seven patients (28%). After 4 weeks of treatment with ivabradine, no significant differences were found in maximal platelet aggregation from baseline, as assessed with 20 μM ADP stimulation. In addition, no significant difference in IPA from baseline was detected after stimulation with ADP 5 μM, arachidonic acid, thrombin receptor-activated peptide 25 μM, and platelet reactivity index. Ivabradine did not alter antiplatelet response to clopidogrel in patients treated concomitantly with both drugs.