Determination of clopidogrel resistance by whole blood platelet aggregometry and inhibitors of the P2Y12 receptor

Background: Inhibition Of platelet aggregation by clopidogrel may be insufficient in up to 30% of users. These nonresponders carry an increased risk of cardiovascular. events. We reported here a simple assay to study clopidogrel responsiveness. Methods: Electrical impedance aggregometry was performed in diluted whole blood in the, presence of 5 and 20 mu mol/L ADP. Some samples were incubated with 0.1 mmol/L methyl-S-adenosine monophosphate (Me-SAMP), a P2Y(12) receptor blocker, to maximize inhibition of aggregation before aggregometry. To validate the assay, we analyzed 6-min impedance in 1 healthy probands and 244 patients with coronary artery disease (CAD). Results: At 5 mu mol/L ADP, the imprecision of the assay Was 11%. Mean (SD) impedance of the healthy cohort was 12.2 (2.2) Omega. The mean - 3 SD was used to define the cutoff for clopidogrel responsiveness: responders and nonresponders exhibited a 6-min impedance <= 5 Omega and >5 Omega, respectively. Samples from nonresponders were incubated with MeSAMP and Analyzed again to distinguish pharmacokinetic and. pharmacodynamic types of. resistance. Sixteen percent of CAD patients were classified as nonresponders (38 and 2 cases of pharmacokinetic and pharmacodynamic resistance, respectively). Female sex was, strongly Associated with clopidogrel resistance (P = 0.0002, Fisher exact test). A higher clopidogrel loading dose (P = 0.035, Mann-Whitney U-test) was given to responders (median, 450 mg) than nonrespohders (median 300 mg). Age and cardiovascular diagnosis showed no significant associations. Conclusions: Impedance Aggregometry using 5 mu mol/L ADP is a useful. tool for studying clopidogrel responsiveness. MeSAMP allows characterization. of responsiveness "on treatment" and may be useful for optimizing clopidogrel dosing. (C) 2006 American Association for Clinical Chemistry.