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Curzen N.,University of Southampton | Gurbel P.A.,Sinai Center for Thrombosis Research | Myat A.,Kings College London | Bhatt D.L.,Harvard University | Redwood S.R.,Kings College London
The Lancet | Year: 2013

Acute ST-segment elevation myocardial infarction (STEMI) is a dynamic, thrombus-driven event. As understanding of its pathophysiology has improved, the central role of platelets in initiation and orchestration of this process has become clear. Key components of STEMI include formation of occlusive thrombus, mediation and ultimately amplification of the local vascular inflammatory response resulting in increased vasoreactivity, oedema formation, and microvascular obstruction. Activation, degranulation, and aggregation of platelets are the platforms from which these components develop. Therefore, prompt, potent, and predictable antithrombotic therapy is needed to optimise clinical outcomes after primary percutaneous coronary intervention. We review present pharmacological and mechanical adjunctive therapies for reperfusion and ask what is the optimum combination when primary percutaneous coronary intervention is used as the mode of revascularisation in patients with STEMI. Source

The platelet P2Y12 receptor is involved in all aspects of arterial thrombosis, including adhesion, activation, aggregation, secretion and development of a stable aggregate on which coagulation proteins can assemble and fibrin strands can mesh. Inhibition of the P2Y12 receptor has been shown convincingly to reduce cardiovascular events among patients with acute coronary syndromes (ACS) and in patients undergoing percutaneous intervention (PCI). Current studies are exploring whether there is a threshold of platelet aggregation below which only more bleeding occurs, without a concomitant reduction in clinical events. The following review considers the potential relevance of reversible and irreversible mechanisms of P2Y12 inhibition to bleeding risk, posing the question, "Is it not only how much but how a platelet P2Y12 receptor is inhibited that determines the attributable safety profile?" © Schattauer 2010. Source

Kandzari D.E.,Piedmont Heart Institute | Mauri L.,Harvard University | Popma J.J.,Beth Israel Deaconess Medical Center | Turco M.A.,Center for Cardiac and Vascular Research | And 3 more authors.
JACC: Cardiovascular Interventions | Year: 2011

Objectives: This study sought to compare late safety and efficacy outcomes following percutaneous coronary revascularization with zotarolimus-eluting stents (ZES) and sirolimus-eluting stents (SES). Background: Despite higher late lumen loss and binary restenosis with ZES compared with SES, it is uncertain whether differences in early angiographic measures translate into more disparate late clinical events. Methods: Clinical outcomes were prospectively evaluated through 5 years in the ENDEAVOR III (A Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions) that randomized 436 patients of relatively low anatomic and clinical risk to treatment with ZES (n = 323) or SES (n = 113) and evaluated a primary endpoint of 8-month angiographic late lumen loss. Results: At 5 years (completeness of follow-up: 95.2%), pre-specified endpoints of all-cause mortality (5.2% vs. 13.0%, p = 0.02), myocardial infarction (1.0% vs. 4.6%, p = 0.03), and the composite event rates of cardiac death/myocardial infarction (1.3% vs. 6.5%, p = 0.009) and major adverse cardiac events (14.0% vs. 22.2%, p = 0.05) were significantly lower among patients treated with ZES. Rates of target lesion (8.1% ZES vs. 6.5% SES, p = 0.68) and target vessel revascularization were similar between treatment groups. Stent thrombosis was infrequent and similar in both groups (0.7% ZES vs. 0.9% SES, p = 1.0). Between 9 months and 5 years, progression of major adverse cardiac events was significantly more common with SES than with ZES (16.7% vs. 7.8%, p = 0.015). Conclusions: Despite initially higher angiographic late lumen loss, rates of clinical restenosis beyond the protocol-specified angiographic follow-up period remain stable with ZES compared with the rates for SES, resulting in similar late-term efficacy. Over 5 years, significant differences in death, myocardial infarction, and composite endpoints favored treatment with ZES. (The Medtronic Endeavor III Drug Eluting Coronary Stent System Clinical Trial [ENDEAVOR III]; NCT00217256). © 2011 American College of Cardiology Foundation. Source

Gurbel P.A.,Sinai Center for Thrombosis Research | Mahla E.,Medical University of Graz | Tantry U.S.,Sinai Center for Thrombosis Research
Thrombosis and Haemostasis | Year: 2011

The pivotal role of platelet activation and reactivity during atherothrombotic event occurrence associated with acute coronary syndromes (ACS) or percutaneous coronary interventions (PCI) is well established. Numerous translational research studies have established a threshold level of platelet reactivity during dual antiplatelet therapy above which a higher risk for ischaemic event occurrence has been observed. The clinical validity of these threshold values in reducing ischemic event occurrence with modified P2Y 12 receptor therapy is currently under investigation in large-scale clinical trials. The association between on-treatment platelet reactivity measured by an ex vivo assay and the occurrence of bleeding events is less established. Currently, there is limited evidence of an association between platelet inhibition and coronary artery bypass grafting (CABG)- related bleeding in patients on clopidogrel therapy indicating that preoperative platelet function monitoring may guide both the timing of elective CABG and the administration of blood products in patients needing surgery. However, in the absence of a large-scale prospective clinical trial, routine platelet function monitoring and modification of timing of surgery based on platelet function monitoring are currently not recommended. © Schattauer 2011. Source

Gurbel P.A.,Sinai Center for Thrombosis Research | Tantry U.S.,Sinai Center for Thrombosis Research | Shuldiner A.R.,University of Maryland Baltimore County | Kereiakes D.J.,Vascular Center
Journal of the American College of Cardiology | Year: 2010

The loss-of-function hepatic cytochrome P450 (CYP) 2C19*2 allele has been associated with reduced clopidogrel active metabolite generation and higher ex vivo platelet reactivity to adenosine diphosphate. Independently, in post hoc analyses, CYP2C19*2 has been associated with worse clinical outcomes during clopidogrel therapy. The controversy surrounding the diminished effectiveness of clopidogrel in poor metabolizers, those having 2 loss-of-function alleles, has been recently highlighted in the "boxed warning" issued by the U.S. Food and Drug Administration. However, much of the variation in clopidogrel response is not explained by the CYP2C19*2 allele (the most frequent loss-of-function allele), and other factors, both genetic and nongenetic, are likely to be important contributors. High on-treatment platelet reactivity to adenosine diphosphate during clopidogrel therapy is a well-documented predictor of recurrent ischemic events in the percutaneous coronary intervention population. While platelet function is dynamic in individual patients because of the influence of variable external factors, the influence of the CYP2C19*2 allele is intrinsically constant. Thus, it may be reasonable to consider both genotyping and platelet function measurement to assess ischemic risk and to guide antiplatelet therapy. Prospective clinical trials to test new algorithms for optimal personalized antiplatelet therapy are needed to provide the evidence base required for the routine adoption of genotyping into clinical practice. © 2010 American College of Cardiology Foundation. Source

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