title: Clopidogrel response variability and the advent of personalised antiplatelet therapy. A bench to bedside journey.
abstract: Platelet-mediated thrombosis is a dreaded clinical event and is the primary cause of acute coronary syndromes and post-percutaneous intervention (PCI) ischaemic events. There has been a long standing interest in the ex vivo quantification of platelet reactivity to assess the risk of thrombosis. Early studies demonstrated platelet activation and heightened platelet reactivity in acute coronary syndromes and after PCI. However, a demonstration that heightened reactivity actually precipitated the ischaemic event was lacking. Our knowledge of platelet receptor physiology and the advent of novel inhibitors have significantly advanced the field. The P2Y12 receptor has been shown to play a pivotal role in the amplification of platelet activation by multiple agonists and its inhibition has resulted in improved clinical outcomes. The most widely used drug to block P2Y12 receptor, clopidogrel is associated with resistance in selected patients and these patients have been shown to be at increased risk for post-PCI ischaemic event occurrence in multiple studies. Importantly, a threshold of high platelet reactivity has been demonstrated, and beyond this threshold ischaemic events occur precipitously. Based on the current evidence, it is rational to quantify the intensity of the ADP-P2Y12 interaction in the patient at the greatest risk for thrombosis-the PCI patient. However, there is only evidence from small clinical trials demonstrating the clinical efficacy of changing an antiplatelet regimen based on an ex vivo platelet function measurement. Moreover, there are numerous patients with vulnerable coronary anatomy that have not yet experienced plaque rupture; the prognostic role of a measurement of platelet reactivity in the latter group has never been studied. Large-scale trials are ongoing that will investigate the role of personalised antiplatelet therapy in the PCI patient.
authors.affiliation: Sinai Center for Thrombosis Research, Cardiac Catheterization Laboratory, 2401 W. Belvedere Ave, Baltimore, MD 21215, USA. pgurbel@lifebridgehealth.org
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gurbel
authors.forename: Udaya S
authors.initials: US
authors.lastname: Tantry
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000188:drug therapy; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects; D002986:Clinical Trials as Topic; D000077144:Clopidogrel; D006801:Humans; D066298:In Vitro Techniques; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine; D011446:Prospective Studies; D058925:Receptors, Purinergic P2Y12 / Q000097:blood; D012307:Risk Factors; D015398:Signal Transduction; D015607:Stents / Q000009:adverse effects; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D057170:Translational Research, Biomedical
chemical_list: C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D013988:Ticlopidine