Active metabolite concentration of clopidogrel in patients taking different doses of aspirin: results of the interaction trial. (4th February 2015)

• Record Type: Journal Article
• Authors: Liang, Y.; Hirsh, J.; Weitz, J. I.; Sloane, D.; Gao, P.; Pare, G.; Zhu, J.; Eikelboom, J. W.
• Is Part Of: Journal of thrombosis and haemostasis. Volume 13:Number 3(2015:Mar.)
• Page Start: 347
• Page End: 352
• Publication Date: 2015-02-04
• Subjects: Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.12829
• Languages: English
• ISSNs: 1538-7933

Abstract

<abstract abstract-type="main" id="jth12829-abs-0001"> <title>Summary</title> <sec id="jth12829-sec-0001" sec-type="section"> <title>Background</title> <p>The CURRENT‐OASIS‐7 and PLATO trials suggest that the benefit of clopidogrel is influenced by the dose of aspirin.</p> </sec> <sec id="jth12829-sec-0002" sec-type="section"> <title>Objective</title> <p>To explore a potential pharmacokinetic interaction between aspirin and clopidogrel, and determinants of clopidogrel active metabolite (AM) levels.</p> </sec> <sec id="jth12829-sec-0003" sec-type="section"> <title>Methods</title> <p>In part 1, using a 2 × 2 factorial design, we randomized patients to clopidogrel 600 mg loading dose (LD) followed by 150 mg day<sup>−1</sup> for 6 days and 75 mg day<sup>−1</sup> thereafter, or clopidogrel 300 mg LD followed by 75 mg day<sup>−1</sup> thereafter, and compared aspirin at 325 mg or 81 mg day<sup>−1</sup>. In part 2, patients were given a 600‐mg clopidogrel LD, and were randomly allocated to aspirin 325 mg or 81 mg day<sup>−1</sup>. We combine the data from the two parts. Blood samples were collected 1 h after administration of the study drug.</p> </sec> <sec id="jth12829-sec-0004" sec-type="section"> <title>Results</title> <p>We randomized 302 patients (mean age 60.4 ± 9.9 years). Clopidogrel AM levels were similar in patients randomized to aspirin 325 or 81 mg (geometric mean, 12.70 ng mL<sup>−1</sup>; 95% CI, 10.96–14.72 ng mL<sup>−1</sup>; and geometric mean, 12.55 ng mL<sup>−1</sup>; 95% CI, 10.80–14.58 ng mL<sup>−1</sup>; <italic>P</italic> = 0.91). Blood levels of clopidogrel were lower in CYP2C19*2 loss‐of‐function (LOF) carriers compared with non‐carriers (10.72 ng mL<sup>−1</sup>; 95% CI, 8.83–13.01 ng mL<sup>−1</sup>; and 15.21 ng mL<sup>−1</sup>; 95% CI, 13.30–17.40 ng mL<sup>−1</sup>, respectively; <italic>P</italic> = 0.003) whereas levels in gain of function carriers and non‐carriers were similar (13.31 ng mL<sup>−1</sup>; 95% CI, 11.53–15.35 ng mL<sup>−1</sup>; and 14.07 ng mL<sup>−1</sup>; 95% CI, 11.74–16.87 ng mL<sup>−1</sup>, respectively; <italic>P</italic> = 0.4). Independent baseline predictors of clopidogrel AM levels were LOF genotype, body mass index, diabetes, proton pump inhibitor use and creatinine clearance, but accounted for only 20% of the variability in levels.</p> </sec> <sec id="jth12829-sec-0005" sec-type="section"> <title>Conclusion</title> <p>Aspirin dose does not predict clopidogrel AM levels 1 h post‐LD. Most of the variability in clopidogrel AM levels is not explained by patient characteristics or CYP2C19 metabolizer status.</p> </sec> </abstract>