Which platelet function test is suitable to monitor clopidogrel responsiveness? A pharmacokinetic analysis on the active metabolite of clopidogrel


Jochem W. van Werkum, Department of Cardiology, St. Antonius Hospital, PO Box 2500, 3435 CM Nieuwegein, the Netherlands.
Tel.: +31 306099111; fax: +31 306034420.
E-mail: w.van.werkum@gmail.com


Summary. Background: Multiple platelet function tests claim to be P2Y12-pathway specific and capable of capturing the biological activity of clopidogrel. Objectives: The aim of the present study was to determine which platelet function test provides the best reflection of the in vivo plasma levels of the active metabolite of clopidogrel (AMC). Patients/methods: Clopidogrel-naive patients scheduled for elective percutaneous coronary intervention (PCI) received a 600 mg loading dose of clopidogrel and 100 mg of aspirin. For pharmacokinetic analysis, blood was drawn at 0, 20, 40, 60, 90, 120, 180, 240 and 360 min after clopidogrel loading and peak plasma concentrations (Cmax) of the AMC were quantified with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Platelet function testing was performed at baseline and 360 min after the clopidogrel loading. Results: The VASP-assay, the VerifyNow P2Y12-assay and 20 μmol L−1 adenosine diphosphate (ADP)-induced light transmittance aggregometry (LTA) showed strong correlations with Cmax of the AMC (VASP: R2 = 0.56, P < 0.001; VerifyNow platelet reactivity units (PRU): R2 = 0.48, P < 0.001; VerifyNow %inhibition: R2 = 0.59, P < 0.001; 20 μmol L−1 ADP-induced LTA: R2 = 0.47, P < 0.001). Agreement with Cmax of the AMC was less evident for 5 μmol L−1 ADP-induced LTA or whole blood aggregometry (WBA), whereas the IMPACT-R ADP test did not show any correlation with plasmalevels of the AMC. Conclusion: The flow cytometric VASP-assay, the VerifyNow P2Y12 assay and, although to a lesser extent, 20 μmol L−1 ADP-induced LTA correlate best with the maximal plasma level of the AMC, suggesting these may be the preferred platelet function tests for monitoring the responsiveness to clopidogrel.