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CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY

Cytochrome P450 2C19 681G>A Polymorphism and High On-Clopidogrel Platelet Reactivity Associated With Adverse 1-Year Clinical Outcome of Elective Percutaneous Coronary Intervention With Drug-Eluting or Bare-Metal Stents

Dietmar Trenk, PhD^_*,_*, Willibald Hochholzer, MD^_*, Martin F. Fromm, MD, Ligia-Emilia Chialda, MD, Andreas Pahl, PhD, Christian M. Valina, MD^_*, Christian Stratz, MD^_*, Peter Schmiebusch, MD^_*, Hans-Peter Bestehorn, MD^_*, Heinz Joachim Büttner, MD^_* and Franz-Josef Neumann, MD^_*

^_* Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany.

Manuscript received September 10, 2007; revised manuscript received November 30, 2007, accepted December 10, 2007.

^_* Reprint requests and correspondence: Dr. Dietmar Trenk, Herz-Zentrum Bad Krozingen, Suedring 15, D-79189 Bad Krozingen, Germany. (Email: dietmar.trenk{at}herzzentrum.de).

Objectives: We investigated whether the loss of function CYP2C19 681G>A *2 polymorphism is associated with high (>14%) residual platelet aggregation (RPA) on clopidogrel and whether high on-clopidogrel RPA impacts clinical outcome after elective coronary stent placement.

Background: The cytochrome P450 (CYP)–dependent conversion of clopidogrel to its active metabolite may contribute to the variability in antiplatelet effect of clopidogrel.

Methods: The study included 797 consecutive patients undergoing percutaneous coronary intervention, who were followed-up for 1 year. Adenosine-diphosphate–induced (5 µmol/l) RPA was assessed after a 600-mg loading dose and after the first 75-mg maintenance dose of clopidogrel before discharge. CYP2C19 genotype was analyzed by real-time polymerase chain reaction.

Results: Of the patients included, 552 (69.3%) were CYP2C19 wild-type homozygotes (*1/*1) and 245 (30.7%) carried at least one *2 allele. Residual platelet aggregation at baseline did not differ significantly between genotypes. On clopidogrel, RPA was significantly (p < 0.001) higher in *2 carriers than in wild-type homozygotes (23.0% [interquartile range (IQR) 8.0% to 38.0%] vs. 11.0% [IQR 3.0% to 28.0%] after loading; 11.0% [IQR 5.0% to 22.0%] vs. 7.0% [IQR 3.0% to 14.0%] at pre-discharge). Between *2 carriers and wild-type homozygotes, we found significant (p < 0.001) differences in the proportion of patients with RPA >14%, both after loading (62.4% vs. 43.4%) and at pre-discharge (41.3% vs. 22.5%). Residual platelet aggregation >14% at pre-discharge incurred a 3.0-fold increase (95% confidence interval 1.4 to 6.8; p = 0.004) in the 1-year incidence of death and myocardial infarction.

Conclusions: Patients carrying at least one CYP2C19*2 allele are more prone to high-on clopidogrel platelet reactivity, which is associated with poor clinical outcome after coronary stent placement (Effect of Clopidogrel Loading and Risk of PCI [EXCELSIOR]; NCT00457236 [ClinicalTrials.gov] ).

Abbreviations and Acronyms   ADP = adenosine diphosphate   CI = confidence interval   CYP = cytochrome P450   GP = glycoprotein   MI = myocardial infarction   PCI = percutaneous coronary intervention   PCR = polymerase chain reaction   RPA = residual platelet aggregation

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