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Active metabolite concentration of clopidogrel in patients taking different doses of aspirin: results of the interaction trial
Author(s) -
Liang Y.,
Hirsh J.,
Weitz J. I.,
Sloane D.,
Gao P.,
Pare G.,
Zhu J.,
Eikelboom J. W.
Publication year - 2015
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12829
Subject(s) - clopidogrel , aspirin , medicine , metabolite , pharmacokinetics , randomized controlled trial , ticlopidine , active metabolite , geometric mean , pharmacology , anesthesia , statistics , mathematics
Summary Background The CURRENT ‐ OASIS ‐7 and PLATO trials suggest that the benefit of clopidogrel is influenced by the dose of aspirin. Objective To explore a potential pharmacokinetic interaction between aspirin and clopidogrel, and determinants of clopidogrel active metabolite ( AM ) levels. Methods In part 1, using a 2 × 2 factorial design, we randomized patients to clopidogrel 600 mg loading dose ( LD ) followed by 150 mg day −1 for 6 days and 75 mg day −1 thereafter, or clopidogrel 300 mg LD followed by 75 mg day −1 thereafter, and compared aspirin at 325 mg or 81 mg day −1 . In part 2, patients were given a 600‐mg clopidogrel LD , and were randomly allocated to aspirin 325 mg or 81 mg day −1 . We combine the data from the two parts. Blood samples were collected 1 h after administration of the study drug. Results 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 −1 ; 95% CI , 10.96–14.72 ng mL −1 ; and geometric mean, 12.55 ng mL −1 ; 95% CI , 10.80–14.58 ng mL −1 ; P = 0.91). Blood levels of clopidogrel were lower in CYP 2C19*2 loss‐of‐function ( LOF ) carriers compared with non‐carriers (10.72 ng mL −1 ; 95% CI , 8.83–13.01 ng mL −1 ; and 15.21 ng mL −1 ; 95% CI , 13.30–17.40 ng mL −1 , respectively; P = 0.003) whereas levels in gain of function carriers and non‐carriers were similar (13.31 ng mL −1 ; 95% CI , 11.53–15.35 ng mL −1 ; and 14.07 ng mL −1 ; 95% CI , 11.74–16.87 ng mL −1 , respectively; P = 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. Conclusion 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 CYP 2C19 metabolizer status.