Response variability to P2Y12 receptor inhibitors: expectations and reality

JACC Cardiovasc Interv. 2013 Nov;6(11):1111-28. doi: 10.1016/j.jcin.2013.06.011.


P2Y12 inhibitors are widely used in patients with acute coronary syndromes and in the secondary prevention of thrombotic events in vascular diseases. Within the past few years, several pharmacological, genetic, and clinical limitations of the second-generation thienopyridine clopidogrel have raised major concerns. High on-treatment platelet reactivity, which is common in clopidogrel-treated patients, and its clinical implications led to the development of the more effective platelet P2Y12 inhibitors prasugrel (a third-generation thienopyridine) and ticagrelor (a cyclopentyl-triazolo-pyrimidine). The pharmacokinetics and pharmacodynamics of prasugrel and ticagrelor indicate that they provide more consistent, more rapid, and more potent platelet inhibition than clopidogrel, which translates into improved ischemic outcomes. Nevertheless, higher efficacy, which is reflected by low on-treatment platelet reactivity, increases the risk of major bleeding events. Therefore, cardiologists might be facing a new challenge in the future: to individualize the level of platelet inhibition in order to decrease thrombotic events without increasing bleeding. The current review focuses on the use of platelet function testing and pharmacogenomic testing in order to identify patients who either do not respond to or are at risk of not responding sufficiently to P2Y12 inhibitors. Moreover, this paper discusses randomized trials, which so far have failed to show that tailored antiplatelet therapy improves clinical outcome, and treatment options for patients with high on-treatment platelet reactivity.

Keywords: ADP; AUC; CADP; CYP; GP; HTPR; MACE; MEA; OR; PCI; PGE(1); ROC; TEG; VASP; adenosine diphosphate; area under the curve; clopidogrel; collagen/adenosine diphosphate; cytochrome P450; glycoprotein; high on-treatment platelet reactivity; major adverse cardiac events; multiple electrode aggregometry; odds ratio; percutaneous coronary intervention; personalized treatment; platelet reactivity; prasugrel; prostaglandin E(1); receiver-operating characteristic; thrombelastography; ticagrelor; vasodilator-stimulated phosphoprotein.

Publication types

  • Review

MeSH terms

  • Animals
  • Biotransformation / genetics
  • Blood Platelets / drug effects*
  • Blood Platelets / metabolism
  • Drug Resistance
  • Fibrinolytic Agents / adverse effects
  • Fibrinolytic Agents / pharmacokinetics
  • Fibrinolytic Agents / therapeutic use*
  • Genotype
  • Hemorrhage / chemically induced
  • Humans
  • Patient Selection
  • Pharmacogenetics
  • Phenotype
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation Inhibitors / adverse effects
  • Platelet Aggregation Inhibitors / pharmacokinetics
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Platelet Function Tests
  • Precision Medicine
  • Predictive Value of Tests
  • Purinergic P2Y Receptor Antagonists / adverse effects
  • Purinergic P2Y Receptor Antagonists / pharmacokinetics
  • Purinergic P2Y Receptor Antagonists / therapeutic use*
  • Receptors, Purinergic P2Y12 / blood
  • Receptors, Purinergic P2Y12 / drug effects*
  • Risk Factors
  • Thrombosis / blood
  • Thrombosis / drug therapy*
  • Thrombosis / genetics
  • Thrombosis / metabolism
  • Thrombosis / prevention & control
  • Treatment Outcome


  • Fibrinolytic Agents
  • P2RY12 protein, human
  • Platelet Aggregation Inhibitors
  • Purinergic P2Y Receptor Antagonists
  • Receptors, Purinergic P2Y12