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State of the Art - Antiplatelet therapy: clinical, genetic and platelet determinants of risk

  • Platelet reactivity on clopidogrel therapy and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent pharmacodynamic analysis of the GRAVITAS trial, presented by M Price (La Jolla, US) - Abstract
  • Paraoxonase-1 Q192R polymorphism and antiplatelet effects of clopidogrel in patients undergoing elective coronary stent placement, presented by D Trenk (Bad Krozingen, DE) - Abstract
  • Impact of the cytochrome P450 2C19*3 polymorphism on platelet reactivity and adverse clinical events in patients with acute myocardial infarction, presented by YH Jeong (Baltimore, US) - Abstract
  • Clinical and genetic determinants of coronary stent thrombosis in patients on dual antiplatelet therapy G Cayla, presented by (Nimes, FR) - Abstract
  • State of the Art - Antiplatelet therapy: clinical, genetic and platelet determinants of risk, presented by M Sabatine (Boston, US)
Cardiovascular Pharmacology and Pharmacotherapy

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.


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State of the Art - Antiplatelet therapy: clinical, genetic and platelet determinants of risk

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.