By Dean J Kereiakes
Patient-related factors which have been identified as independent risk predictors for the occurrence of stent thrombosis include acuity of the clinical syndrome, intrinsic platelet reactivity, diabetes mellitus and clopidogrel resistance, early discontinuance or non-compliance. Clopidogrel non-responders are almost invariably responsive to either prasugrel or ticagrelor. In the large scale, randomised controlled trials PLATO (Platelet inhibition and patient outcomes) and TRITON-TIMI 38 (Trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel–thrombolysis in myocardial infarction), patients with acute coronary syndromes were randomly assigned to treatment with either ticagrelor (PLATO) or prasugrel (TRITON-TIMI 38) in comparison to clopidogrel.
In TRITON-TIMI 38, stent thrombosis was significantly reduced by prasugrel (vs. clopidogrel) both early (≤30 days) as well as late (>30 days–15 months) regardless of stent type (drug-eluting stent or bare metal stent). The relative benefit of prasugrel for reduction in stent thrombosis was evident across multiple subgroup analyses. In PLATO, ticagrelor (vs. clopidogrel) reduced stent thrombosis regardless of acute coronary syndrome type, stent type (drug-eluting vs. bare metal stent), or diabetic status. The relative benefit of ticagrelor for reduction in stent thrombosis was not evident for patients treated in North America. In addition, both lower aspirin dose at randomisation (600mg/day) appeared to enhance the relative benefit of ticagrelor versus clopidogrel for stent thrombosis reduction.
The CYP2C19 loss of function of the allele appears to be associated with a gene-dose response for platelet inhibition, the prevalence of high platelet reactivity (HPR) and clinical outcomes. Both HPR and stent thrombosis are increased in a step-wise fashion from heterozygote to homozygote carriers of the CYP2C19 loss of function allele versus non-carriers. Presence of the CYP2C19 loss of function allele genotype did not affect the efficacy of either prasugrel or ticagrelor in comparison to clopidogrel. Both prasugrel and ticagrelor provide a significantly greater level of platelet inhibition when compared with double-dose clopidogrel in patients who are clopidogrel-poor responders. The prevalence of residual HPR is significantly reduced by either prasugrel or ticagrelor compared with double dose clopidogrel.
HPR on clopidogrel is influenced by genomic, phenotypic and drug-drug interactions and is associated with adverse ischaemic events post-percutaneous coronary intervention. The optimal threshold and timecourse for measuring HPR has not been defined. Whether or not HPR is a modifiable risk remains to be determined. Both prasugrel and ticagrelor provide more rapid, intense and less variable platelet inhibition (versus clopidogrel) and significantly reduce stent thrombosis independent of stent type. Although prasugrel appears to provide relatively greater reduction in stent thrombosis (versus clopidogrel), this observation may be confounded by relative differences in respective trial designs, study population demographics and/or timing of study drug administration relative to the performance of percutaneous coronary intervention. Novel P2Y12 receptor inhibitors (prasugrel or ticagrelor) should be administered to patients at clinical high risk for stent thrombosis (ST-segment elevation myocardial infarction [STEMI] / non-STEMI), diabetes, etc) and/or demonstrated HPR on clopidogrel therapy who have no specific contraindications. The relative benefit of prasugrel (versus ticagrelor) for reducing stent thrombosis awaits definition by an adequately powered, randomised controlled clinical trial.
Dean J Kereiakes is medical director, The Christ Hospital Heart and Vascular Center, and The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, and professor of Clinical Medicine, Ohio State University, USA.