Dr. Jean-Philippe Collet ,
Much attention has recently been focused on patient response to clopidogrel with a strong relationship between high on-clopidogrel platelet reactivity (HOPR) and the occurrence of stent thrombosis despite stringent adherence to DAPT1. However, the randomized GRAVITAS trial failed to show any benefit of high maintenance dose of clopidogrel (150mg) versus the standard of care (75mg) to reduce further cardiovascular events in patients who underwent PCI while having HOPR defined as ≥230 P2Y12 reaction units according to the VerifyNow P2Y12 platelet function test2. Of interest, reanalyzing HOPR as a time-varying covariate, Dr Price reports an OTR <208 P2Y12 reaction units to be an independent predictor of the primary end point at 60 days (HR 0.23; 95% CI 0.05 to 0.98; P=0.047) suggesting that achievement of <208 P2Y12 reaction units at 12 to 24 hours after PCI or during follow-up could be the ideal threshold to further evaluate the efficacy of an individualized strategy. The case-control ONASSIST study reported by Dr Cayla suggests that combining the genotypes of three genes related to clopidogrel metabolism and platelet function (CYP2C19, ABCB1, ITGB3) with clinical risk factors, significantly improves the ability to identify patients at-risk of early ST. The only two modifiable factors of early ST are related to clopidogrel metabolism, namely clopidogrel loading dose and clopidogrel interaction with proton pump inhibitors suggesting that ST is an inefficient clopidogrel disease and that rapid genetic testing might be a useful implementation in addition to the clinical risk assessment to predict more accurately ST. The role of a new player in the pharmacogenetics of clopidogrel namely paraoxonase-1 (PON1), recently reported as a major determinant of the bioactivation and clinical efficacy of clopidogrel, has been challenged again3. Indeed, the group of Trenk et al. reported neither effect of the PON1 Q192R on platelet reactivity or on clinical outcome variants, further suggesting that early identification of PON1 may be a spurious finding. Finally, Young-Hoon Jeong from the ACCEL Registry Investigators reported for the first time the influence of CYP2C19*3 allele on both platelet reactivity and clinical outcomes in clopidogrel-treated AMI patients. This loss of function allele for clopidogrel bioactivation with a very low allele frequency in Caucasian was never shown to be related to clinical outcome further highlighting the key effect of ethnicity in genetic investigation. Dr Sabatine concluded that certain clinical factors may identify subsets of patients in whom more potent antiplatelet therapy seems particularly efficacious (eg, PCI, STEMI, diabetics) or harmful (eg, prior stroke, elderly). Platelet function data predicts clinical outcome and tailoring therapy to platelet function pre-PCI reduces MACE as opposed to platelet function obtained post-PCI. With respect to genotyping, the CYP2C19 variants predicts clinical outcomes in patients treated with clopidogrel undergoing PCI and the benefit of prasugrel & ticagrelor relative to clopidogrel tends to be greater in CYP2C19 reduced-function variant carriers. However, there is so far no prospective evaluation showing that tailoring antiplatelet therapy based on platelet function or genotyping improve patient outcome.
1. Bonello L, Tantry U, Marcucci R, et al. Consensus and Future Directions on the Definition of High On-Treatment Platelet Reactivity to ADP. J Am Coll Cardiol. 2010;56(2):112-116. 2. 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(11):1097-1105. 3. Bouman HJ, Schömig E, van Werkum JW, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med. 2010;(1):110-116. 4. Collet JP, Hulot JS, Montalescot G. Cytochrome P450 2C19 polymorphism and clopidogrel after MI. Lancet. 2009;373:1172-1173. 5. Hulot JS, Collet JP, Silvain J, et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-funtion allele or proton pump inhibitor co-administration: A systematic meta-analysis. J Am Coll Cardiol 2010;56(2):134-143. 6. Mega JL, Simon T, Collet JP, 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(16):1821-1830. 7. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic Determinants of Response to Clopidogrel and Cardiovascular Events. N Engl J Med. 2009;360:363-375. 8. Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2009;38(1):92-99. 9. Mega JL, Close SL, Wiviott SD, et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010;376(9749):1312-1319. 10. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. Jama. Oct 23-30 2002;288(16):2023-2031. 11. Satra M, Samara M, Wosniak G, et al. Sequence variations in the FII, FV, F13A1, FGB and PAI-1 genes are associated with differences in myocardial perfusion. Pharmacogenomics. Feb 2011;12(2):195-203.12. Wang Y, Zhang W, Zhang Y, et al. VKORC1 haplotypes are associated with arterial vascular diseases (stroke, coronary heart disease, and aortic dissection). Circulation. Mar 28 2006;113(12):1615-1621.
State of the Art - Antiplatelet therapy: clinical, genetic and platelet determinants of risk
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