Why have studies of tailored anti-platelet therapy failed so far?

 

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Summary

Published data linking clopidogrel non-responsiveness to adverse ischaemic events lead to the suggestion that the magnitude of platelet inhibition by clopidogrel can be monitored and individually adjusted. This has been tested in randomised clinical trials (ARCTIC, GRAVITAS and TRIGGER-PCI), but despite reducing platelet reactivity, a strategy of therapy adjustment based on platelet function monitoring did not reduce the incidence of cardiac ischaemic events. Several critical issues regarding the design of these trials, which might in part have led to negative results, are discussed in this article.

• References

• 1 Siller-Matula JM, Delle-Karth G, Lang IM. et al. Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study. J Thromb Haemost 2012; 10: 529-542.
  CrossrefPubMedGoogle Scholar
• 2 Trenk D, Kristensen SD, Hochholzer W. et al. High on-treatment platelet reactivity and P2Y12 antagonists in clinical trials. Thromb Haemost 2012; 109: 834-845.
  Article in Thieme ConnectPubMedGoogle Scholar
• 3 Siller-Matula JM, Delle-Karth G, Christ G. et al. Dual non-responsiveness to antiplatelet treatment is a stronger predictor of cardiac adverse events than isolated non-responsiveness to clopidogrel or aspirin. Int J Cardiol. 2013. Epub ahead of print.
  CrossrefGoogle Scholar
• 4 von Beckerath N, Kastrati A, Wieczorek A. et al. A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days. Eur Heart J 2007; 28: 1814-1819.
  CrossrefPubMedGoogle Scholar
• 5 Angiolillo DJ, Bernardo E, Sabate M. et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 2007; 50: 1541-1547.
  CrossrefPubMedGoogle Scholar
• 6 Angiolillo DJ, Bernardo E, Palazuelos J. et al. Functional impact of high clopidogrel maintenance dosing in patients undergoing elective percutaneous coronary interventions. Results of a randomized study. Thromb Haemost 2008; 99: 161-168.
  Article in Thieme ConnectPubMedGoogle Scholar
• 7 Bonello L, Camoin-Jau L, Armero S. et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol 2009; 103: 5-10.
  CrossrefPubMedGoogle Scholar
• 8 Bonello L, Camoin-Jau L, Arques S. et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol 2008; 51: 1404-1411.
  CrossrefPubMedGoogle Scholar
• 9 Collet JP, Cuisset T, Range G. et al. Bedside Monitoring to Adjust Antiplatelet Therapy for Coronary Stenting. N Engl J Med. 2012. Epub ahead of print.
  CrossrefGoogle Scholar
• 10 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. J Am Med Assoc 2011; 305: 1097-1105.
  CrossrefPubMedGoogle Scholar
• 11 Trenk D, Stone GW, Gawaz M. et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 2012; 59: 2159-2164.
  CrossrefPubMedGoogle Scholar
• 12 Carlquist JF, Knight S, Horne BD. et al. Cardiovascular risk among patients on clopidogrel anti-platelet therapy after placement of drug-eluting stents is modified by genetic variants in both the CYP2C19 and ABCB1 genes. Thromb Haemost 2013; 109: 744-754.
  Article in Thieme ConnectPubMedGoogle Scholar
• 13 Mega JL, Hochholzer W, Frelinger 3rd AL. et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. J Am Med Assoc 2011; 306: 2221-2228.
  PubMedGoogle Scholar
• 14 Saucedo JF, Angiolillo DJ, Deraad R. et al. Decrease in high on-treatment platelet reactivity (HPR) prevalence on switching from clopidogrel to prasugrel: Insights from the switching anti-platelet (SWAP) study. Thromb Haemost 2013; 109: 347-355.
  Article in Thieme ConnectPubMedGoogle Scholar
• 15 Siller-Matula JM, Francesconi M, Dechant C. et al. Personalized antiplatelet treatment after percutaneous coronary intervention: The MADONNA study. Int J Cardiol. 2012
  Google Scholar
• 16 Thygesen K, Alpert JS, Jaffe AS. et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012; 60: 1581-1598.
  CrossrefPubMedGoogle Scholar
• 17 De Caterina R, Marchioli R, Andreotti F. Bedside monitoring of antiplatelet therapy for coronary stenting. N Engl J Med 2013; 368: 871.
  PubMedGoogle Scholar
• 18 Stone G. A large-scale, prospective, multicenter registry examining the relationship between platelet responsiveness and stent thrombosis after des implantation. Results from the ADAPT-DES study. J Am Coll Cardiol. 2011. 58 (Suppl) B: Abstract LBCT
  Google Scholar
• 19 Bonello L, Tantry US, Marcucci R. et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919-933.
  CrossrefPubMedGoogle Scholar
• 20 Valgimigli M, Campo G, de Cesare N. et al. Intensifying platelet inhibition with tirofiban in poor responders to aspirin, clopidogrel, or both agents undergoing elective coronary intervention: results from the double-blind, prospective, randomized Tailoring Treatment with Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel study. Circulation 2009; 119: 3215-3222.
  CrossrefPubMedGoogle Scholar
• 21 Cuisset T, Frere C, Quilici J. et al. Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel nonresponders: a prospective, randomized study. JACC Cardiovasc Interv 2008; 1: 649-653.
  CrossrefPubMedGoogle Scholar