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The Worry About Clopidogrel "Nonresponsiveness"

Identification and Treatment in the Post-Percutaneous Coronary Intervention Patient^_*

Paul A. Gurbel, MD^,_*, Udaya S. Tantry, PhD, Alan R. Shuldiner, MD

Sinai Center for Thrombosis Research, Baltimore, Maryland
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland

Key Words: platelet • clopidogrel • nonresponsiveness • gene polymorphism

Clopidogrel is a prodrug that is activated by hepatic cytochrome (CYP) P450 isoenzymes including CYP2C19, CYP3A, CYP1A2, and CYP2B6 in a 2-step process. Multiple lines of evidence strongly indicate that variable and suboptimal active metabolite generation are the primary explanation for clopidogrel response variability and nonresponsiveness (5). Recent studies have identified the common loss-of-function cytochrome P450 (CYP P450) 2C19*2 allele as a major determinant of the response to conventional dose clopidogrel and as a risk factor for post-stenting ischemic events (5–7). This allele is created by a guanine adenine mutation in exon 5 of CYP2C19 present in chromosome 10q24 that produces an aberrant splice site leading to an altered reading frame at amino acid 215 and a premature stop codon 20 amino acids downstream. A nonfunctional protein and/or and lack of translation results. This single nucleotide polymorphism (SNP) has a high prevalence in Caucasians (24%), African Americans (33%), and Asian populations (51%) (6). Nongenetic factors, including drug-drug interactions at the CYP level involving lipophilic statins and calcium antagonists with CYP3A4, and proton pump inhibitors (PPIs) with CYP2C19 have also been reported to attenuate clopidogrel responsiveness. However, the clinical significance of these associations remains debated (5).

Gladding et al. (4) explore a critical question toward more individualized and effective dosing of clopidogrel: can an increased dose of clopidogrel overcome genetically determined decreased-responsiveness to clopidogrel? They studied the antiplatelet effect of increasing the standard "one-size-fits-all" 75 mg/day clopidogrel maintenance dose to 150 mg/day for 1 week in 39 patients, 88% of whom had undergone PCI. The VerifyNow P2Y12 assay was used, and measurements were taken before and after the dose increase. The investigators genotyped for the reduced/loss-of-function SNPs, CYP2C19*2, *3, *4 and CYP2C9*2 and *3, and the increased function, CYP2C19*17 SNP. The primary hypothesis was that treatment with the 150-mg dose for 1 week would increase the antiplatelet response in CYP2C19*2 carriers. On standard-dose clopidogrel therapy, carriers of the CYP2C19*2 allele had lower platelet inhibition compared with noncarriers. The effect of the other CYP2C variants on clopidogrel-induced inhibition of platelet reactivity was less certain, perhaps due to the limited sample size. Overall, they found a modest effect of the increased maintenance dose; an 8.6 ± 13.5% increase in platelet inhibition in CYP2C19*2 and *3 carriers suggesting that genotype-directed dosing of clopidogrel may play a role in determining who will respond to high-dose clopidogrel. However, the large standard deviation is strong evidence of the variable response even to the 150-mg dose; indeed some carriers of the CYP2C19*2 variant had little or no response to the higher dose. Furthermore, although it is stated that those with the CYP2C19*2 allele had a greater change in platelet aggregation in response to the higher dose of clopidogrel than noncarriers, it is unclear based on an investigation of this size to determine the actual frequency of CYP2C19*2 carriers who will achieve the same level of platelet inhibition on higher-dose clopidogrel as noncarriers on standard dose therapy. Similarly, in a limited number of patients on PPIs (n = 12), the higher maintenance dose was associated with a 9 ± 10% increase in platelet inhibition. However, it is again unclear from this study how effective the increased dose in patients on PPIs will be in achieving the same level of inhibition as those on standard-dose clopidogrel not on PPIs (4).

These data are concordant with prior studies (5–7). Although conclusive association between the CYP2C19*2 polymorphism (pharmacogenetic measurement), suboptimal active metabolite generation (pharmacokinetic measurement), decreased clopidogrel responsiveness as measured by a platelet function assay (pharmacodynamic measurement), and poorer clinical outcomes have not yet been confirmed in a single study, the effect of CYP2C19 genotype on clopidogrel response appears well established (6). A more thorough analysis of these relationships will enhance our understanding of the mechanisms responsible for high post-PCI risk associated with specific SNPs that have been previously reported.

There are additional study design and methodological caveats worthy of comment. First, there is no mention of concomitant aspirin therapy or dose, and aspirin has a dose-dependent effect on platelet reactivity to ADP. Second, the time of platelet function testing in relation to the time of the last clopidogrel dose (both 75 mg and 150 mg) is uncertain. Third, a true baseline platelet function measurement in the absence of clopidogrel therapy was not made. Instead the authors refer to platelet "inhibition" based on platelet function stimulated by iso-thrombin receptor activating peptide in the VerifyNow assay. Finally, as recognized by the investigators, there was no determination of compliance. All of these limitations may influence the results, particularly in light of the relatively small sample size (4).

Despite these limitations, we agree with the primary conclusion of the authors; higher clopidogrel dosing does lower platelet reactivity in selected patients. The largest clinical study that addressed the clinical effect of 75 mg versus 150 mg clopidogrel maintenance therapy was the CURRENT–OASIS 7 (Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs–Organization to Assess Strategies in Ischemic Syndromes 7) acute coronary syndrome trial recently reported at the European Society of Cardiology Congress (8). In this trial, patients treated with the higher clopidogrel maintenance dose also received a 600-mg load as compared with a 300-mg load administered to patients treated with the conventional maintenance dose. In the PCI population, the higher dose of clopidogrel was associated with a lower incidence of the 30-day primary ischemic end point but an increased incidence of the CURRENT–OASIS 7 study defined major bleeding (8). It is uncertain from this study whether high-dose clopidogrel has the same effects in the nonacute coronary syndrome population or whether the higher dose affects CYP2C19*2 carriers differentially.

A major unresolved question is how to predict who will achieve sufficient inhibition from the higher dose and/or who will need an alternative P2Y₁₂ inhibitor. Are CYP2C genotypes the predictive tool to address this question? Based on the Gladding et al. (4) data, CYP2C genotyping alone would likely not provide the level of predictive value required for clinically effective decision making in this patient population. As the investigators acknowledge, the small overall improvement observed may also not be clinically relevant, and many CYP2C19*2 carriers had persistent low platelet inhibition. Since platelet function critically influences the occurrence of thrombotic events in stented patients, a diagnostic tool with higher sensitivity and specificity to predict whether a sufficient antiplatelet effect will occur is needed.

Based upon our current knowledge of clopidogrel pharmacogenetics and pharmacodynamics, we conclude that genotyping alone cannot be regarded as a surrogate for platelet function testing in identifying clopidogrel nonresponders. Prospective large-scale studies are required to determine the clinical utility of CYP2C genotyping to guide personalized antiplatelet therapy. These trials need to be adequately powered to assess clinical efficacy as well as adverse bleeding events that may be associated with increased clopidogrel dosing, especially in certain patient subgroups identified in the TRITON–TIMI 38 (TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel–Thrombolysis In Myocardial Infarction 38) trial who were at increased bleeding risk with the more potent antiplatelet agent prasugrel (i.e., age >75 years, weight <60 kg, and patients undergoing coronary artery bypass graft) (9). The rapid genotyping methodology reported in the current study will likely facilitate these investigations and potential future translation into clinical practice. Finally, multiple factors, both genetic and nongenetic, determine clopidogrel metabolism and its pharmacodynamic response, and subsequent cardiovascular events. Algorithms that incorporate CYP2C genotypes, point-of-care platelet aggregation testing, concurrent medication use, and other relevant factors may be more clinically useful predictive tools to direct individualized dosing and/or choice of antiplatelet agent. Furthermore, variants in other genes that influence clopidogrel response are likely to exist (6). Once discovered, genetic testing may improve predictive algorithms to guide more individualized and effective antiplatelet regimens.

	Footnotes

 
Dr. Gurbel receives grant support from Schering-Plough, AstraZeneca, Bayer Healthcare, Sanofi-Aventis, Portola Pharmaceuticals, Daiichi-Sankyo, and Lilly; and receives honoraria/consulting income from Schering-Plough, AstraZeneca, Bayer Healthcare, Sanofi-Aventis, Portola Pharmaceuticals, Daiichi-Sankyo, Lilly, and Pozen.

^_* Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.

^_* Reprint requests and correspondence: Dr. Paul A. Gurbel, Sinai Center for Thrombosis Research, Cardiac Catheterization Laboratories, Sinai Hospital of Baltimore, 2401 West Belvedere Avenue, Baltimore, Maryland 21215 (Email: pgurbel{at}lifebridgehealth.org).

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