Despite great progress in the diagnosis and treatment of unstable coronary syndromes, it is estimated that 785,000 Americans will have new acute cardiac events and 470,000 will have recurrent events this year.¹ Central to the pathogenesis of acute coronary syndromes is the adhesion and activation of platelets leading to aggregation, thrombus formation, and vessel occlusion. Unfortunately, the absolute risk of recurrent vascular events among patients taking platelet inhibitors remains relatively high.¹

The observation that platelet-dependent thrombosis occurs despite treatment with platelet inhibitors has led to a large number of studies assessing the cause of these treatment failures. Often termed "resistance," treatment failure in patients taking aspirin or clopidogrel has been ascribed to myriad causes, including nonadherence to drug regimens, inadequate doses of drugs, and coexisting medical conditions. Such a lack of response to therapy may affect 5 to 45% of patients.² It has also become apparent that heritable factors play a major role in determining endogenous platelet function³ and that the platelet-activation response varies widely among patients. However, genetic variants in platelet receptors have not been consistently shown to influence platelet function, alter drug response, or be associated with cardiovascular disease.⁴

For clopidogrel, an inhibitor of platelet P2Y₁₂ receptor, there are data suggesting that genetics may affect drug responsiveness and efficacy. The responsible genetic variant appears to occur not in the expected P2Y₁₂ receptor but, rather, in an enzyme responsible for the metabolism of the drug. Clopidogrel is a prodrug that requires activation by specific hepatic cytochrome P-450 (CYP) enzymes. The genes encoding the CYP-dependent oxidative steps are polymorphic, and previous studies have shown that carriers of the specific alleles of CYP2C19 and CYP3A4 have a diminished response to the antiplatelet effects of clopidogrel.^5,6,7,8 A reduced response to clopidogrel has been specifically associated with the CYP2C19*2 allele, which causes loss of function, in patients after coronary-stent placement⁹ and after myocardial infarction without ST elevation.¹⁰ It is consistent with these pharmacodynamic findings that prasugrel, another P2Y₁₂ inhibitor, appears to be unaffected by variability in CYP2C19 isoenzymes.¹¹ (At the time of this writing, prasugrel was not approved by the Food and Drug Administration.) It is also consistent with the importance of hepatic enzymes that the coadministration of omeprazole, which is metabolized by CYP2C19, has been shown to decrease the platelet-inhibitory effect of clopidogrel.¹²

Two articles in this issue of the Journal contribute to our understanding of the genetic variation in these enzymes in regulating the actions and efficacy of clopidogrel. In a study conducted by the French Registry of Acute ST-Elevation or Non–ST-Elevation Myocardial Infarction (FAST-MI) investigators (ClinicalTrials.gov number, NCT00673036), Simon et al.¹³ report on a cohort of more than 2200 clopidogrel-treated patients who presented with acute myocardial infarction. The investigators, who looked at the relationship between genetic variants that are potentially relevant to platelet function and clinical outcome during a 1-year period, found that patients carrying any two CYP2C19 loss-of-function alleles (*2, *3, *4, or *5) had a higher event rate. Carriers of the ABCB1 variant that modulates clopidogrel absorption also had a modestly increased rate of events. However, they found no association with polymorphisms of P2Y₁₂ or glycoprotein IIb/IIIa or with coadministration of omeprazole.

In another study, Mega et al.¹⁴ investigated the association between genetic variants in CYP genes, the plasma concentration of active metabolite, and platelet function in healthy subjects. In a subsequent analysis, they examined the association between CYP genetic variants and cardiovascular outcomes in nearly 1500 patients who presented with an acute coronary syndrome and who were treated with clopidogrel during the earlier Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38 (NCT00097591). They found that in healthy subjects, carriers of at least one CYP2C19 loss-of-function allele had decreased levels of the active clopidogrel metabolite and less reduction in platelet aggregation, as compared with noncarriers. In clopidogrel-treated subjects from TRITON–TIMI 38, carriers of the loss-of-function alleles had an increased risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers.

In addition, subjects in TRITON–TIMI 38 who carried the CYP2C19*2 allele had a risk of stent thrombosis that was three times that of noncarriers. In this study, the event curves diverged soon after treatment with clopidogrel, a finding that was consistent with the potential immediate loss of a platelet-inhibitory effect. Inconsistent with these observations is the fact that no trend was found for increased bleeding among noncarriers of the CYP2C19 variant; however, the numbers of patients were small and the definition of hemorrhage was potentially too stringent to discern a difference.

Several of the findings in these studies are inconsistent with those of past reports. Previously, carriers of CYP3A4 were also noted to have a reduced response to clopidogrel.⁸ Although there were some differences in the populations studied, the clinical end points in the current studies^13,14 should supersede surrogates for thrombosis. Also, as described by Simon et al., the use of proton-pump inhibitors had no effect on the clinical response to clopidogrel. The causes of the discrepancy in this finding between the study by Simon et al. and the previous reports are unclear. However, until this question can be answered in a larger set of patients with clear clinical outcomes, the use of clinical outcomes, as opposed to platelet-function testing, provides some reassurance.

These two studies raise many pivotal questions. Could the loss of effect that was seen with the genetic variant be overcome by increasing the dose of clopidogrel? The mean dose in the French study was 300 mg per day; in TRITON–TIMI 38, a standard dose of 300 mg per day was given, with a discharge dose of 75 mg per day in both studies. Would patients with a loss-of-function CYP variant have improved platelet function and clinical outcomes (thrombosis and hemorrhage) with an alternative platelet inhibitor (such as prasugrel) that does not require similar hepatic transformation? Would genetic testing and adjustments in the dose or type of therapy enhance efficacy? The data currently available cannot answer these questions. Until a prospective study is completed demonstrating how best to treat patients, particularly those who have poor metabolism of clopidogrel, it is not clear that routine genetic testing will be clinically or fiscally advantageous.

In summary, these studies demonstrate that patients with loss-of-function genetic variants have altered pharmacokinetic and pharmacodynamic responses to clopidogrel and an increased cardiac risk that persists after adjustment for other known potential risk factors. What is striking about these two studies is their concordance despite distinct differences in populations of patients. The fundamental observations are similar: that loss-of-function CYP2C19 alleles are associated with an increased risk of acute cardiovascular events, particularly among patients undergoing percutaneous coronary intervention. Since these genetic variants are common in the general population, this observation is not trivial. To optimally guide the selection of therapy, we must await further information concerning genetic testing, the role of extended genotypic classification, dose adjustment, and the effect of tailored therapeutic selection on thrombotic and hemorrhagic outcomes across a wide spectrum of patients in clinical practice.

Dr. Freedman reports receiving grant support from Boehringer Ingelheim; and Dr. Hylek, receiving grant support from AstraZeneca, serving as an advisor to Boehringer Ingelheim, Bristol-Myers Squibb, Sanofi-Aventis, and the Medicines Company, and participating in clinical symposia sponsored by Bayer and Bristol-Myers Squibb. No other potential conflict of interest relevant to this article was reported.

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