Swaminathan Murugappan, MD, PhD, and Michael Linenberger, MD
Drs. Murugappan and Linenberger indicated no relevant conflicts of interest.
Price MJ, Berger PB, Teirstein PS, et al. Standard- vs. high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention. The GRAVITAS Randomized Trial. JAMA. 2011;305:1097-1105.
Clopidogrel suppresses adenosine diphosphate (ADP)-mediated platelet activation by inhibiting the platelet ADP P2Y12 receptor. Clopidogrel and aspirin are recommended for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) and drug-eluting stent (DES) implantation to prevent subsequent ischemic events. The platelet response to clopidogrel may vary, however; this variability can relate to both nongenetic factors and polymorphisms in the cytochrome P450 gene CYP2C19. High platelet reactivity on clopidogrel and loss-of-function alleles of CYP2C19 have been linked to adverse cardiovascular outcomes after PCI, particularly stent thrombosis.1 By comparison, CYP2C19 polymorphisms may not reduce the benefit of clopidogrel for ACS and atrial fibrillation.2 Thus, the relevance of platelet reactivity while on clopidogrel, the relative contributions of acquired and genetic co-factors to platelet function, and the potential benefit of intensifying clopidogrel dosing to “personalize” treatment for poorly responding patients remain undefined.
The Gauging Responsiveness With A VerifyNow Assay-Impact on Thrombosis and Safety (GRAVITAS) study, reported by Dr. Matthew Price from Scripps Translational Science Institute in San Diego, was designed to address whether higher-dose clopidogrel could enhance outcomes for patients with high on-treatment platelet reactivity after PCI and DES placement. This multicenter, randomized, doubleblind, active-control trial enrolled 5,429 patients, 2,214 of whom had high platelet reactivity after clopidogrel initiation, as determined by a commercially available P2Y12 assay known as VerifyNow, which measures ADP-induced platelet agglutination. Patients were defined as poor responders if the assay showed P2Y12 reaction unit (PRU) values of 230 or higher. These patients were then randomized to receive either high-dose clopidogrel (600 mg loading followed by 150 mg daily) or standard dose (no additional loading followed by 75 mg daily) for six months. Primary efficacy endpoints included death from cardiovascular causes, nonfatal myocardial infarction (MI), or stent thrombosis. Pharmacodynamic assessments involved PRU determinations at 30 days and six months. CYP2C19 genotype data were not reported. The rates of death at 30 days and six months from cardiovascular causes and all-cause mortality were not different among the high-dose and standard-dose clopidogrel cohorts. Similarly, there were no differences in nonfatal MI or stent thrombosis. High-dose clopidogrel resulted in significantly lower platelet reactivity at 30 days and six months compared with standard dosing, without increased bleeding events. In a secondary comparison, patients with high on-treatment platelet reactivity receiving standard-dose therapy had greater composite primary event rates than 586 observational cohort patients who did not have high on-treatment reactivity at study entry; but these differences were not statistically significant.
The results of the GRAVITAS trial highlight the challenges of using population-based studies to define key targets and optimal goals for personalized therapeutic interventions. Despite GRAVITAS being the largest randomized trial to date of individualized antiplatelet dosing, it did not discern a significant effect of clopidogrel dose intensification. This may relate to the use of fixed drug dosing, genetic heterogeneity, nongenetic factors, variable pharmacodynamic responses, and unexpectedly low event rates among relatively modest sample sizes. Ongoing trials are investigating more potent ADP inhibitors that are not significantly affected by CYP2C19 polymorphisms. Additional study data are also needed to better define at-risk populations, the most reliable biological and/or genetic markers, and optimal on-target endpoints. Until further high-grade evidence is available, platelet inhibition strategies and pharmacogenetic testing for patients with ACS and PCI must remain “impersonal.”
- Mega JL, Simon T, Collet J-P, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI. A meta-analysis. JAMA. 2010;304:1821-1830.
- Paré G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med. 2010;363:1704-1714.
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