Author + information
- Stephen D. Wiviott, MD* ( and )
- Jessica L. Mega, MD, MPH
- ↵*Reprint requests and correspondence:
Dr. Stephen D. Wiviott, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts
- cytochrome 2C19 polymorphism
- diphosphate receptor blocker
- percutaneous coronary intervention
- stent thrombosis
- vasodilator-stimulated phosphoprotein
Clinical guidelines recommend dual antiplatelet therapy after an acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI). The antiplatelet agent clopidogrel, a thienopyridine, has been the primary P2Y12inhibitor used over the last decade and is a key component of therapy for patients across the spectrum of coronary artery disease (1,2). Newer, more potent antiplatelet agents such as prasugrel (a third-generation thienopyridine) and ticagrelor (a nonthienopyridine P2Y12inhibitor) both achieve significantly higher levels of platelet inhibition and have demonstrated efficacy in reducing post-ACS ischemic events as compared with clopidogrel, with increased non-coronary artery bypass graft bleeding (3,4). The adoption and use of these and other new agents will be influenced by this balance of risk and benefit and likely by economic realities, as clopidogrel becomes generic. Thus, several factors suggest that the use of clopidogrel will continue to be widespread in the future.
There has been growing appreciation that not all patients respond uniformly to standard doses of clopidogrel. This variable response is linked in large part to the underlying metabolism; clopidogrel is a prodrug requiring biotransformation to form an active metabolite. Investigators have identified a number of factors that might interfere with the formation of the active metabolite, including clinical characteristics, drug–drug interactions, and polymorphisms in genes that encode metabolic enzymes and transporters, particularly CYP2C19. In response, the U.S. Food and Drug Administration (FDA) issued a boxed warning, indicating that individuals with 2 reduced-function CYP2C19alleles have a reduced response to standard doses of clopidogrel and that alternative treatment strategies should be considered in such patients.
The FDA warning was influenced by several observations: 1) individuals with particular CYP2C19genetic variants tend to form less clopidogrel active metabolite and have less platelet inhibition when receiving standard doses of clopidogrel; 2) these individuals have worse clinical outcomes, including an increased risk of recurrent myocardial infarction and stent thrombosis, particularly in the post-PCI setting; and 3) patients with high on-treatment platelet reactivity (HTPR), regardless of genotype, are at higher risk for adverse clinical outcomes. Clinicians have struggled with how to respond to these data, because there is limited information about whether changing medications or dosing of clopidogrel can overcome the response variability and, even if it can, whether it will mitigate the excess clinical risks observed. In this issue of the Journal, Bonello et al. (5) report the results of an important proof-of-concept study examining one aspect of this controversy—whether intensifying clopidogrel therapy can overcome HTPR in the short term in patients with CYP2C19reduced-function alleles.
Bonello et al. (5) tested whether serial loading doses of clopidogrel could achieve vasodilator-stimulated phosphoprotein (VASP) indexes <50% in individuals who had VASP indexes >50% (the study definition of HTPR) after an initial 600-mg loading dose; the results were evaluated among patients with 0, 1, and 2 reduced-function CYP2C19*2alleles. A total of 411 patients with non–ST-segment elevation ACS with planned PCI were enrolled. Of those, 277 patients carried no CYP2C19*2alleles, of which 154 had HTPR after a 600-mg loading dose of clopidogrel; 123 patients carried one CYP2C19*2allele, of which 97 had HTPR; and 11 patients carried two CYP2C19*2 alleles, of which 6 had HTPR. These data demonstrate that, even before consideration of the clinical intervention performed in this study, the correlations between tests are imperfect—not all CYP2C19*2carriers have HTPR and not all with HTPR are CYP2C19*2carriers. Ultimately, the study demonstrated that the intervention—serial loading of clopidogrel (up to 2,400 mg given over 4 days)—could achieve VASP indexes <50% in the vast majority of subjects, even among carriers of CYP2C19*2alleles.
Therefore, this study illustrates a key principle: HTPR in patients with genetic variants in CYP2C19can be overcome in many cases by altering the loading doses of clopidogrel. The authors acknowledge, however, that this study was not designed to test whether this strategy is practical, clinically efficacious, tolerable for many patients, or cost-effective (in some patients, as many as 3 additional days of therapy and up to 1,800 mg of additional therapy were needed). Indeed, in patients with ACS the greatest risk period is early, after presentation, so serial loading doses of a medication to achieve an effect over several days might leave a patient incompletely treated during the highest-risk period. In this era of the demonstrated benefits of early invasive therapy and concerns for hospital stay costs, such a strategy might not be widely adopted into practice.
Additionally, the study by Bonello et al. (5) tested achieved platelet function and not clinical outcomes, and as such it was not designed to comment on the relative merits of platelet function testing versus genotyping. It would be circular logic to conclude that platelet function testing is better than genotyping at identifying poor response to clopidogrel when poor response status is being defined with platelet function testing. Furthermore, only one-half of the small number of individuals in the study who carried 2 reduced-function CYP2C19*2alleles were found to have HTPR, an unexpected finding compared with previous studies. Other unanswered questions include: what would have been observed if additional platelet function tests were performed? And, how would these individuals with 1 or 2 reduced-function CYP2C19*2alleles fare with long-term therapy? Additional studies will be instrumental in determining whether higher maintenance doses of clopidogrel in the secondary prevention setting lead to an optimal antiplatelet response among carriers of a reduced-function CYP2C19allele.
To date, both HTPR and the CYP2C19genotype have been associated with an increased risk of cardiovascular events, including stent thrombosis, in the setting of treatment with standard doses of clopidogrel (6–11). Importantly, these 2 metrics seem to offer independent information (12). Platelet function testing is attractive because it integrates many factors at a specific time, including the clinical presentation (e.g., acute vs. chronic coronary artery disease) and the comorbidities of the patient (e.g., diabetes). Genotyping, performed once, identifies a lifelong predisposition but might not account for all factors influencing the response to clopidogrel. Yet, not everyone with a CYP2C19reduced-function genetic variant (a complex rather than a Mendelian genetic trait) or abnormal platelet function testing will experience an adverse cardiovascular event in the setting of standard doses of clopidogrel. It seems that in this situation it is a matter of shifting probabilities, with the totality of the data suggesting that both the CYP2C19genotype and HTPR are associated with an increased risk of adverse cardiovascular outcomes with standard doses of clopidogrel.
Thus, it is an exciting time for the cardiology community; we are at a clinical crossroad and in the process of determining the future of how to best tailor therapy for our patients. Prospective randomized clinical trials will be instrumental in determining the ultimate utility of personalized antiplatelet therapy. Because these data are not currently available, the cardiology and regulatory communities are grappling with how to best integrate platelet function and genetic data. There is precedent to use information, such as body weight or creatinine clearance that provides information about anticipated drug levels and clearance, to adjust the dose of medications in the absence of dedicated randomized trials. In a similar vein, the FDA has now highlighted that diagnostic testing can identify a cohort of individuals who, on the whole, are less likely to respond optimally to standard doses of clopidogrel. Bonello et al. (5) have provided interesting information about altering the loading dose of clopidogrel in patients with CYP2C19*2genetic variants and HTPR, and thus the study takes another step on the path to a tailored and effective antiplatelet therapy strategy.
Dr. Wiviott has received research funding from Eli Lilly, Daiichi Sankyo, and Schering-Plough; consulting fees from Bristol-Myers Squibb, Sanofi-Aventis, AstraZeneca, ARENA, and Medco; and independent CME speaking fees from Eli Lilly, Daiichi Sankyo, and Schering-Plough. Dr. Mega has received research funding from Eli Lilly, Daiichi Sankyo, Bristol-Myers Squibb, Sanofi-Aventis, Johnson & Johnson, and Bayer; and consulting fees from Bristol-Myers Squibb, Sanofi-Aventis, and AstraZeneca.
↵* Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
- American College of Cardiology Foundation
- Kushner F.G.,
- Hand M.,
- Smith S.C. Jr..,
- et al.
- Anderson J.L.,
- Adams C.D.,
- Antman E.M.,
- et al.
- Bonello L.,
- Armero S.,
- Mokhtar O.A.,
- et al.
- Matetzky S.,
- Shenkman B.,
- Guetta V.,
- et al.
- Gurbel P.A.,
- Bliden K.P.,
- Samara W.,
- et al.
- Hochholzer W.,
- Trenk D.,
- Bestehorn H.P.,
- et al.