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 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 21 healthy probands and 244 patients with coronary artery disease (CAD). Results: At 5 mol/L ADP, the imprecision of the assay was 11%. Mean (SD) impedance of the healthy cohort was 12.2 (2.2) ⍀. The mean ؊ 3 SD was used to define the cutoff for clopidogrel responsiveness: responders and nonresponders exhibited a 6-min impedance <5 ⍀ and >5 ⍀, 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 ‫؍‬ 0.0353, MannWhitney U-test) was given to responders (median, 450

Background: Insufficient platelet inhibition is associated with an increased cardiovascular risk in up to 30% of patients taking regular doses of aspirin. We describe an assay to study aspirin responsiveness. Methods: We performed impedance aggregometry on diluted whole blood with 1 mg/L collagen and 0.5 mmol/L arachidonic acid (AA). We measured thromboxane B 2 (TXB 2 ) by RIA. We examined 66 healthy control individuals, 144 aspirin users with stable coronary artery disease (CAD), and 245 CAD patients treated with aspirin and clopidogrel. Nonresponsive samples were incubated with excess DL-lysinmonoacetylsalicylic acid. Results: Assay imprecision (CV) was 9.8% and 8.2% at mean (SD) 6-min impedance of 13.7 (2.8) ⍀ and 13.6 (2.3) ⍀ for collagen and AA, respectively. Collagen induced stronger aggregation (P ‫؍‬ 0.0199) in women [n ‫؍‬ 28, 14.6 (2.4) ⍀] than in men [n ‫؍‬ 38, 13.1 (2.9) ⍀], even after sample incubation with 0.1 mmol/L acetylsalicylic acid (ASA) or 1 mol/L terbogrel, a combined inhibitor of thromboxane synthase and receptors. The sex association persisted in aspirin users, but not if clopidogrel was also taken. A 6-min impedance >8 ⍀ with collagen (mean ؊ 2 SD of the controls) was taken as evidence of nonresponsiveness, particularly if incubation with ASA did not inhibit aggregation further (>2 ⍀). Compared with AA, collagen identified more nonresponsive samples among aspirin users (15%) and CAD patients who also received clopidogrel (10%). Incubation with ASA improved inhibition of aggregation in 70% of samples and consistently reduced TXB 2 formation during aggregation.