Sinai Center for Thrombosis Research

Baltimore, MD, United States

Sinai Center for Thrombosis Research

Baltimore, MD, United States
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Tantry U.S.,Sinai Center for Thrombosis Research | Gurbel P.A.,Sinai Center for Thrombosis Research
Current Pharmaceutical Design | Year: 2013

Dual antiplatelet therapy of clopidogrel added aspirin is an established treatment strategy to prevent recurrent ischemic event occurrence in coronary artery disease patients. Generally, a one size fits all nonselective strategy is used without an assessment of pharmacodynamic efficacy of clopidogrel therapy. However, pharmacodynamic studies revealed various limitations of clopidogrel metabolism and numerous factors such as genetic and, drug-drug interactions influence the antiplatelet response to clopidogrel therapy. Translational platelet function investigations performed in the percutaneous coronary intervention (PCI)-treated population receiving clopidogrel have identified high platelet reactivity (HPR) to adenosine diphosphate as a major risk factor for both acute as well as long-term ischemic event occurrence, including stent thrombosis. Recent studies have highlighted the relation of single nucleotide polymorphisms of genes involved in clopidogrel absorption and metabolism to reduced pharmacokinetic and pharmacodynamic responses to clopidogrel. Cytochrome (CYP) 2C19 loss-of-function (LoF) allele carriage has been associated with increased thrombotic risk in the PCI population. However, clopidogrel is pharmacodynamically effective in about two thirds of patients undergoing PCI; these patients do not have HPR. Therefore, selectively treating two thirds of patients with generic clopidogrel may provide significant cost savings. Unselected therapy with the new P2Y12 receptor blockers is associated with increased bleeding. The introduction of generic clopidogrel holds the strong possibility of inducing a change in practice whereby genetic and platelet function testing are performed more frequently in patients receiving a stent. © 2013 Bentham Science Publishers.

Tantry U.S.,Sinai Hospital of Baltimore | Kereiakes D.J.,Christ Hospital | Gurbel P.A.,Sinai Hospital of Baltimore | Gurbel P.A.,Sinai Center for Thrombosis Research
JACC: Cardiovascular Interventions | Year: 2011

Dual antiplatelet therapy with aspirin and clopidogrel is associated with a significant reduction in vascular ischemic events; however, gastrointestinal bleeding events are a major concern in high-risk and older patients. Clinical practice guidelines recommend combination therapy with proton pump inhibitors (PPI) and dual antiplatelet therapy to attenuate gastrointestinal bleeding risk. In addition, high on-treatment platelet reactivity has been associated with recurrent ischemic events. Whether or not the pharmacological interaction between clopidogrel and PPI, which results in diminished antiplatelet effect, adversely influences clinical efficacy is highly controversial and the subject of debate. Based on largely anecdotal post-hoc analyses, the U.S. Federal Drug Administration's and European Medicines Agency's recommendations discourage PPI use (particularly omeprazole) in patients treated with clopidogrel. However, many American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions experts do not support change in clinical practice guidelines recommendations without adequately powered, prospective, randomized clinical trial data. © 2011 American College of Cardiology Foundation.

Gouya G.,Medical University of Vienna | Arrich J.,Medical University of Vienna | Wolzt M.,Medical University of Vienna | Huber K.,Wilhelminen Hospital | And 4 more authors.
Stroke | Year: 2014

Background and Purpose - The efficacy and safety of different antiplatelet regimes for prevention of stroke in patients at high risk were investigated in a systematic review and meta-analysis. Methods - We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and Web of Science. Twenty-two studies comprising 173 371 patients were included. Results - In the overall population, dual antiplatelet therapy (DAPT) with aspirin and clopidogrel in comparison to aspirin monotherapy reduced the relative risk of total stroke by 20% (risk ratio [RR], 0.80; 95% confidence interval [CI], 0.73-0.88; P<0.0001; I 2=28%) and of ischemic stroke or transient ischemic attack by 23% (RR, 0.77; 95% CI, 0.69-0.85; P<0.0001; I2=18%) without increasing the risk of intracranial hemorrhage. In the secondary prevention cohort, DAPT with aspirin and clopidogrel also reduced the relative risk of total stroke by 24% as compared with aspirin alone (RR, 0.76; 95% CI, 0.68-0.86; P<0.0001; I2=0%). DAPT with prasugrel or ticagrelor and aspirin versus DAPT with clopidogrel and aspirin was not associated with a risk reduction of stroke. Conclusions - DAPT with clopidogrel and aspirin compared with aspirin effectively reduces the risk of total and ischemic stroke in the overall cohort consisting of patients with cardiovascular disease without increase in intracranial hemorrhage, as well as decreases the risk of a recurrent total stroke in patients with a previous stroke/transient ischemic attack. Our meta-analysis suggests that DAPT including low-dose aspirin (75-100 mg) and clopidogrel (75 mg) should be further investigated as a strategy to reduce recurrent strokes. © 2013 American Heart Association, Inc.

Angiolillo D.J.,Florida College | Saucedo J.F.,The University of Oklahoma Health Sciences Center | Deraad R.,Black Hills Clinical Research Center | Frelinger A.L.,University of Massachusetts Medical School | And 6 more authors.
Journal of the American College of Cardiology | Year: 2010

Objectives The objective was to evaluate the pharmacodynamic response of switching patients on maintenance phase clopidogrel therapy after an acute coronary syndrome (ACS) to prasugrel. Background Prasugrel P2Y12 receptor blockade is associated with greater pharmacodynamic platelet inhibition and reduction of ischemic complications compared with that of clopidogrel in ACS patients undergoing percutaneous coronary intervention. The pharmacodynamic effects of switching patients during maintenance phase clopidogrel therapy after an ACS event to prasugrel are unknown. Methods The SWAP (SWitching Anti Platelet) study was a phase 2, multicenter, randomized, double-blind, double-dummy, active-control trial. After a run-in of daily open-label clopidogrel 75 mg with aspirin therapy for 10 to 14 days, patients were randomly assigned to 1 of the following 3 treatments: placebo loading dose (LD)/clopidogrel 75 mg maintenance dose (MD), placebo LD/prasugrel 10 mg MD, or prasugrel 60 mg LD/10 mg MD. Platelet function was evaluated at 2 h, 24 h, 7 days, and 14 days using light transmittance aggregometry, VerifyNow P2Y 12 assay, and vasodilator-stimulated phosphoprotein phosphorylation. Results A total of 139 patients were randomized, of whom 100 were eligible for analysis. Maximum adenosine diphosphate-induced platelet aggregation (20 μM) by light transmittance aggregometry at 1 week (primary end point) was lower after prasugrel MD compared with clopidogrel MD (41.1% vs. 55.0%, p < 0.0001), and was also lower in the prasugrel LD+MD group compared with clopidogrel MD (41.0% vs. 55.0%, p < 0.0001). At 2 h, a prasugrel LD resulted in higher platelet inhibition compared with the other regimens. Similar results were found using light transmittance aggregometry with 5 μM adenosine diphosphate, VerifyNow P2Y12, and vasodilator-stimulated phosphoprotein phosphorylation assays. Conclusions For patients receiving maintenance clopidogrel therapy after an ACS event, switching from clopidogrel to prasugrel is associated with a further reduction in platelet function by 1 week using prasugrel MD or within 2 h with the administration of a prasugrel LD. (A Pharmacodynamic Comparison of Prasugrel [LY640315] Versus Clopidogrel in Subjects With Acute Coronary Syndrome Who Are Receiving Clopidogrel [SWAP]; NCT00356135) © 2010 American College of Cardiology Foundation.

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.

Price M.J.,Scripps Research Institute | Tantry U.S.,Sinai Center for Thrombosis Research | Gurbel P.A.,Sinai Center for Thrombosis Research
Reviews in Cardiovascular Medicine | Year: 2011

P2Y12 antagonists, in combination with aspirin, significantly reduce thrombotic and ischemic events in patients presenting with an acute coronary syndrome and in patients undergoing percutaneous coronary intervention. The thienopyridine clopidogrel is a prodrug that requires bioactivation by the cytochrome P450 (CYP) system in order to exert its antiplatelet effect. Common genetic polymorphisms that reduce the catalytic activity of the CYP2C19 isoenzyme decrease circulating levels of active metabolite, reduce levels of platelet inhibition, and increase the risk of ischemic events in clopidogrel-treated patients. Herein, we review the impact of the CYP2C19 genotype on the pharmacokinetics and pharmacodynamics of clopidogrel, the association between CYP2C19 genotype and clinical outcome, and present the rationale for the implementation of CYP2C19 genotyping to individualize antiplatelet therapy in clinical practice. © 2011 MedReviews®, LLC.

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.

Gurbel P.A.,Sinai Center for Thrombosis Research | Jeong Y.-H.,Sinai Center for Thrombosis Research | Tantry U.S.,Sinai Center for Thrombosis Research
Expert Opinion on Investigational Drugs | Year: 2011

Introduction: Platelet activation and reactivity are pivotal for both acute and chronic atherothrombotic event occurrences. Areas covered: Only 20% relative risk (∼ 2% absolute risk) reduction associated with newer P2Y12 receptor blocker therapy such as prasugrel and ticagrelor compared with clopidogrel indicates that dual antiplatelet therapy may be associated with a ceiling effect in attenuating platelet-mediated ischemic event occurrence and that residual ischemic event occurrences are mediated by other pathways that are unblocked by current antiplatelet therapy. Therefore, inhibition of the thrombinprotease-activated receptor (PAR)-1 interaction may provide additional benefits in attenuating ischemic event occurrence in selected patients. There are two major PAR-1 blockers are under investigations vorapaxar and atopaxar. In preclinical and Phase I II studies, inhibition of thrombin-mediated platelet activation by a PAR-1 inhibitor, in general, has added to the antithrombotic efficacy of aspirin and clopidogrel without increasing bleeding. However, intracranial hemorrhage in patients with a history of stroke associated with vorapaxar and hepatic toxicity associated with atopaxar are important concerns. Expert opinion: At this time, the specific role of PAR-1 inhibitor in the settings of percutaneous coronary intervention and acute coronary syndrome, both during the acute setting and as a long-term therapeutic agent, is not clear. Although the PAR-1 inhibitors are associated with less bleeding, its effectiveness as an antithrombotic agent and also side effects are major concerns. Future large-scale trials with goals addressing these concerns are needed to define the specific role of PAR-1 receptor inhibitor. © 2011 Informa UK, Ltd. All rights reserved.

Gurbel P.A.,Sinai Center for Thrombosis Research | Tantry U.S.,Sinai Center for Thrombosis Research
JACC: Heart Failure | Year: 2014

There has been a 3-fold increase in hospital discharges for heart failure (HF) and also significantly increased mortality rate in HF patients in recent years. A major focus of HF research has been in the area of neurohormonal control and resynchronization therapy. There is a great urgency in better understanding the pathophysiology underlying the exceedingly high mortality and a need for exploration of therapeutic strategies beyond those that influence neurohormonal pathways. The decision to treat patients with HF with antiplatelet therapy remains largely influenced by the presence or absence of concomitant arterial disease. Antithrombotic therapy has been shown to be effective in many forms of cardiac disease, including patients with HF and atrial fibrillation. Although it is clear that platelet activation and hypercoagulability are present in HF, and there is evidence that stroke is reduced by warfarin therapy in the HF patient, the available data suggest that the risk of major bleeding overshadows the antithromboembolic benefit in HF patients in sinus rhythm. The utility of oral anticoagulant and/or antiplatelet therapy has never been evaluated in an adequately powered dedicated clinical trial of HF patients in sinus rhythm. Inthis state-of-the art paper we explore the evidence for targeting the inhibition of platelet function and coagulation to improve outcomes in the HF patient. © 2014 American College of Cardiology Foundation.

Gurbel P.A.,Sinai Center for Thrombosis Research | Tantry U.S.,Sinai Center for Thrombosis Research
Thrombosis and Haemostasis | Year: 2011

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 P2Y 12 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 P2Y 12 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-P2Y 12 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. © Schattauer.

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