otamixaban and Acute-Coronary-Syndrome

As acute coronary syndrome (ACS) becomes more common nationwide and current anticoagulation regimens used in patients with ACS continue to possess their shortcomings, the need for new anticoagulants is on the rise. Although heparin and warfarin are used effectively in patients with ACS, they both have significant side effects and delivery issues. New factor Xa inhibitors offer an oral alternative that functions early in the coagulation cascade. The role of these new drugs in ACS is explored here. Electronic search strategies were used to collect reviews, randomized controlled trials, and other studies. Databases used included Medline and Cochrane Library and hand selection. Sources selected were limited to those that discussed factor Xa inhibitors in the context of ACS. Selected studies were then assessed for quality and relevance and those deemed relevant included for analysis. Some of the factor Xa inhibitors such as rivaroxaban offer anticoagulation as effective as, if not more effective, heparin and warfarin with lower risks of bleeding and other adverse effects such as heparin-induced thrombocytopenia. Many of these new agents also come in oral form, making them easy for patients to manage and use daily.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Cyclic N-Oxides; Factor Xa Inhibitors; Fondaparinux; Heparin; Humans; Morpholines; Naphthalenes; Polysaccharides; Propionates; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Treatment Outcome; Warfarin

Topics: Acute Coronary Syndrome; Anticoagulants; Antithrombins; Cyclic N-Oxides; Fondaparinux; Hirudins; Humans; Morpholines; Peptide Fragments; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiophenes

Acute coronary syndromes (ACS) are common and carry a high risk of death and serious complications. Over the past three decades, the international cardiology community has collaborated in numerous large, well-designed randomized trials evaluating promising new treatments leading to important improvements in care for patients with ACS. Industry has funded most of the ACS trials of new pharmacologic treatments, but there are many independently funded trials evaluating treatment strategies such as percutaneous coronary intervention. Improvements in ACS care have led to challenges in demonstrating the efficacy of new treatments and many current trials are comparing one active treatment against another, although new paradigms including anti-inflammatory treatments and stem cell infusions are being tested against placebo. Developing new drugs for ACS is a very expensive process with many trials not showing any benefit, and much of this expense is related to the cost of large multicenter phase 3 trials. Reducing the administrative burden and associated costs of ACS trials is an important immediate goal if the strong tradition of large collaborative trials is to continue, as well as the need for health care providers to engage more actively in the clinical research process and support large multinational independently funded trials. We discuss methodologic issues of ACS trials with recent examples and provide some perspectives for the future.

Topics: Acute Coronary Syndrome; Adenosine; Aspirin; Clinical Trials as Topic; Clopidogrel; Cyclic N-Oxides; Eptifibatide; Heart Diseases; Humans; Peptides; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Research Design; Research Support as Topic; Risk Factors; Sample Size; Thiophenes; Ticagrelor; Ticlopidine; United Kingdom

Monitoring anticoagulation with activated clotting time (ACT) has been proposed to reduce ischemic or bleeding events. However, the value of using ACT to improve outcomes is uncertain. This study sought to determine the relationship between ACT and outcomes during percutaneous coronary intervention in patients with non-ST-segment-elevation acute coronary syndrome (NSTE-ACS) treated by unfractionated heparin with GPIs (glycoprotein IIb/IIIa inhibitors).. From the randomized TAO trial (Treatment of Acute Coronary Syndromes With Otamixaban), we analyzed the value of ACT to predict ischemic and bleeding outcomes in the 3275 patients receiving unfractionated heparin plus eptifibatide. Ischemic and safety outcomes were analyzed according to ACT to determine the best threshold. Median peak ACT was 225 s. There was no correlation (. In the TAO trial, peak procedural ACT ≥250 s was associated with increased bleeding risk in non-ST-segment-elevation acute coronary syndrome patients treated with unfractionated heparin plus GPIs. This threshold was increased to 290 s when performing radial approach.. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01076764.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Blood Coagulation; Cyclic N-Oxides; Drug Dosage Calculations; Drug Monitoring; Eptifibatide; Factor Xa Inhibitors; Female; Hemorrhage; Heparin; Humans; Male; Middle Aged; Non-ST Elevated Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Predictive Value of Tests; Pyridines; Risk Factors; Time Factors; Treatment Outcome; Whole Blood Coagulation Time

In patients with non-ST-segment-elevation myocardial infarction (NSTEMI) and GRACE (Global Registry of Acute Coronary Events) score >140, coronary angiography (CAG) is recommended by European and American guidelines within 24 hours. We sought to study the association of very early (ie, ≤12 hours), early (12-24 hours), and delayed (>24 hours) CAG in patients with NSTEMI with GRACE score >140 with ischemic outcomes.. The TAO trial (Treatment of Acute Coronary Syndrome With Otamixaban) randomized patients with NSTEMI and CAG scheduled within 72 hours to heparin plus eptifibatide versus otamixaban. In this post hoc analysis, patients with a GRACE score >140 were categorized into 3 groups according to timing of CAG from admission (<12, ≥12-<24, and ≥24 hours). The primary ischemic outcome was the composite of all-cause death and myocardial infarction within 180 days of randomization.. CAG was performed in 4071 patients (<12 hours, n=1648 [40.5%]; 12-24 hours, n=1420 [34.9%]; ≥24 hours, n=1003 [24.6%]). With CAG ≥24 hours as a reference, CAG from 12 to 24 hours was not associated with a lower risk of primary ischemic outcome at 180 days (odds ratio, 0.96; 95% confidence interval, 0.75-1.23), whereas CAG <12 hours was associated with a lower risk of death and myocardial infarction (odds ratio, 0.71; 95% confidence interval, 0.55-0.91). Performing CAG <12 hours was also associated with a lower risk of death and myocardial infarction (odds ratio, 0.76; 95% confidence interval, 0.61-0.94;. In patients with high-risk NSTEMI, undergoing CAG within the initial 12 hours after admission (as opposed to later, either 12-24 or ≥24 hours) was associated with lower risk of ischemic outcomes at 180 days.

Topics: Acute Coronary Syndrome; Aged; Cohort Studies; Coronary Angiography; Cyclic N-Oxides; Disease Management; Factor Xa Inhibitors; Female; Humans; Internationality; Male; Middle Aged; Non-ST Elevated Myocardial Infarction; Pyridines; Risk Factors; Time Factors; Treatment Outcome

The optimal anticoagulant for patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) managed with an invasive strategy remains controversial.. To compare the clinical efficacy and safety of otamixaban, a novel intravenous direct factor Xa inhibitor, with that of unfractionated heparin plus downstream eptifibatide in patients with NSTE-ACS undergoing a planned early invasive strategy.. Randomized, double-blind, active-controlled superiority trial that enrolled 13,229 patients with NSTE-ACS and a planned early invasive strategy, at 568 active sites in 55 countries and conducted between April 2010 and February 2013. A planned interim analysis was conducted for otamixaban dose selection.. Eligible participants were randomized to otamixaban (bolus and infusion, at 1 of 2 doses) or unfractionated heparin plus, at the time of percutaneous coronary intervention, eptifibatide. The otamixaban dose selected at interim analysis was an intravenous bolus of 0.080 mg/kg followed by an infusion of 0.140 mg/kg per hour.. The primary efficacy outcome was the composite of all-cause death or new myocardial infarction through day 7.. Rates of the primary efficacy outcome were 5.5% (279 of 5105 patients) randomized to receive otamixaban and 5.7% (310 of 5466 patients) randomized to receive unfractionated heparin plus eptifibatide (adjusted relative risk, 0.99 [95% CI, 0.85-1.16]; P = .93). There were no differences for the secondary end points, including procedural thrombotic complications. The primary safety outcome of Thrombosis in Myocardial Infarction major or minor bleeding through day 7 was increased by otamixaban (3.1% vs 1.5%; relative risk, 2.13 [95% CI, 1.63-2.78]; P < .001). Results were consistent across prespecified subgroups.. Otamixaban did not reduce the rate of ischemic events relative to unfractionated heparin plus eptifibatide but did increase bleeding. These findings do not support the use of otamixaban for patients with NSTE-ACS undergoing planned early percutaneous coronary intervention.. clinicaltrials.gov Identifier: NCT01076764.

Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Anticoagulants; Cause of Death; Cyclic N-Oxides; Double-Blind Method; Eptifibatide; Factor Xa Inhibitors; Female; Hemorrhage; Heparin; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Myocardial Infarction; Peptides; Percutaneous Coronary Intervention; Platelet Glycoprotein GPIIb-IIIa Complex; Pyridines; Risk; Survival Analysis; Treatment Outcome

Otamixaban is a synthetic intravenous direct factor Xa inhibitor, with rapid onset/offset, linear kinetics, and no significant renal elimination. A phase II trial in acute coronary syndromes (ACS) showed a marked reduction in the combined end point of death or myocardial infarction (MI) and similar bleeding rates with otamixaban at midrange doses, compared with unfractionated heparin (UFH) and eptifibatide.. The TAO trial is a phase III, randomized, double-blind, triple-dummy controlled trial testing the efficacy of otamixaban over UFH plus eptifibatide in patients with non-ST-segment elevation ACS to be treated with dual oral antiplatelet therapy and an invasive strategy. Approximately 13,220 patients in 55 countries will be randomized (1:1:1 ratio) to receive UFH plus downstream eptifibatide (started pre-percutaneous coronary intervention and continued per label) or otamixaban (0.08 mg/kg intravenous bolus at randomization then 0.100 or 0.140 mg/kg per hour intravenous infusion). An interim analysis was performed after ≥1,969 patients per arm completed 7 days of follow-up and the Data Monitoring Committee selected 1 otamixaban dose (blinded to investigators) to be carried forward using a prespecified algorithm. The primary efficacy outcome is the composite of all-cause mortality or new MI through day 7. The primary safety outcome is thrombolysis in MI major or minor bleeding through day 7. Secondary outcomes include all-cause mortality, recurrent ischemia/infarction resulting in prolonged/recurrent hospitalization, periprocedural angiographic complications, and pharmacokinetic data in 6,000 patients.. The TAO trial will assess the clinical efficacy and safety of otamixaban in non-ST-segment elevation ACS with planned invasive strategy.

Topics: Acute Coronary Syndrome; Adolescent; Adult; Cyclic N-Oxides; Double-Blind Method; Drug Therapy, Combination; Eptifibatide; Factor Xa Inhibitors; Hemorrhage; Heparin; Humans; Myocardial Infarction; Peptides; Platelet Aggregation Inhibitors; Pyridines; Research Design; Treatment Outcome; Young Adult

Otamixaban is an intravenous direct factor Xa inhibitor. We aimed to assess its efficacy and safety in non-ST-elevation acute coronary syndromes and to identify the optimum dose range for further assessment in a phase 3 study.. In this double-blind, phase 2 trial undertaken in 196 sites in 36 countries, 3241 patients with non-ST-elevation acute coronary syndromes were randomly assigned via a central, telephone-based interactive voice response system to one of five doses of otamixaban (0.08 mg/kg bolus followed by infusions of 0.035 [n=125], 0.070 [676], 0.105 [662], 0.140 [658], or 0.175 [671] mg/kg/h) or to a control of unfractionated heparin (60 IU/kg intravenous bolus followed by an infusion of 12 IU/kg/h) plus eptifibatide (180 microg/kg intravenous bolus followed by an infusion of 1.0-2.0 microg/kg/min [n=449]). Both investigators and patients were unaware of treatment allocation. Enrolment into the lowest dose group was stopped early at the recommendation of the Data Monitoring Committee. The primary efficacy endpoint was a composite of death, myocardial infarction, urgent revascularisation, or bailout glycoprotein IIb/IIIa inhibitor use up to 7 days. The primary safety endpoint was TIMI major or minor bleeding not related to coronary-artery bypass grafting. Efficacy analyses were by intention to treat; safety analyses were in treated patients. This study is registered with ClinicalTrials.gov, number NCT00317395.. Rates of the primary efficacy endpoint in the five otamixaban doses were 7.2% (nine of 125) with 0.035 mg/kg/h, 4.6% (31/676) with 0.070 mg/kg/h, 3.8% (25/662) with 0.105 mg/kg/h, 3.6% (24/658) with 0.140 mg/kg/h, and 4.3% (29/671) with 0.175 mg/kg/h (p=0.34 for trend). In the control group, the rate was 6.2% (28/449), yielding relative risks for the five otamixaban doses of 1.16 (95% CI 0.56-2.38), 0.74 (0.45-1.21), 0.61 (0.36-1.02), 0.58 (0.34-1.00), and 0.69 (0.42-1.15), respectively. Rates of the primary safety endpoint in the five otamixaban doses were 1.6% (two of 122), 1.6% (11/669), 3.1% (20/651), 3.4% (22/651), and 5.4% (36/664), respectively (p=0.0001 for trend); the rate in the control group was 2.7% (12/448).. In patients with non-ST-elevation acute coronary syndromes, otamixaban infusions of 0.100-0.140 mg/kg/h might reduce ischaemic events and have a safety profile similar to unfractionated heparin plus eptifibatide. Further testing in a phase 3 trial is warranted.. Sanofi-Aventis.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Coronary Angiography; Cyclic N-Oxides; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Eptifibatide; Female; Follow-Up Studies; Hemorrhage; Heparin; Humans; Infusions, Intravenous; Injections, Intravenous; Kaplan-Meier Estimate; Male; Middle Aged; Peptides; Platelet Aggregation Inhibitors; Pyridines; Safety; Treatment Outcome

Few data are available on procedural complications of percutaneous coronary intervention (PCI) in the setting of acute coronary syndrome in the contemporary era.. We sought to describe the prevalence of procedural complications of PCI in a non-ST-segment elevation acute coronary syndrome (NSTE ACS) cohort, and to identify their clinical characteristics and association with clinical outcomes.. Patients randomized in TAO (Treatment of Acute coronary syndrome with Otamixaban), an international randomized controlled trial (ClinicalTrials.gov Identifier: NCT01076764) that compared otamixaban with unfractionated heparin plus eptifibatide in patients with NSTE ACS who underwent PCI, were included in the analysis. Procedural complications were collected prospectively, categorized and adjudicated by a blinded Clinical Events Committee, with review of angiograms. A multivariable model was constructed to identify independent clinical characteristics associated with procedural complications.. A total of 8656 patients with NSTE ACS who were enrolled in the TAO trial underwent PCI, and 451 (5.2%) experienced at least one complication. The most frequent complications were no/slow reflow (1.5%) and dissection with decreased flow (1.2%). Procedural complications were associated with the 7-day ischaemic outcome of death, myocardial infarction or stroke (24.2% vs. 6.0%, odds ratio 5.01, 95% confidence interval 3.96-6.33; P<0.0001) and with Thrombolysis In Myocardial Infarction major and minor bleeding (6.2% vs. 2.3%, odds ratio 2.79, 95% confidence interval 1.86-4.2; P<0.0001). Except for previous coronary artery bypass grafting, multivariable analysis did not identify preprocedural clinical predictors of complications.. In a contemporary NSTE ACS population, procedural complications with PCI remain frequent, are difficult to predict based on clinical characteristics, and are associated with worse ischaemic and haemorrhagic outcomes.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Cyclic N-Oxides; Databases, Factual; Eptifibatide; Factor Xa Inhibitors; Female; Hemorrhage; Heparin; Humans; Incidence; Male; Middle Aged; No-Reflow Phenomenon; Non-ST Elevated Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prevalence; Pyridines; Randomized Controlled Trials as Topic; Recurrence; Risk Assessment; Risk Factors; Stroke; Time Factors; Treatment Outcome

Antithrombotic therapy is the cornerstone of management of patients with acute coronary syndromes. Its role has become increasingly important with the widespread use of percutaneous revascularization, particularly after stent implantation. In this context, use of dual antiplatelet therapy is mandatory, combining aspirin with thienopyridines, mostly clopidogrel. As well as antiplatelets, anticoagulants are also required in patients with acute myocardial infarction up to the time of percutaneous intervention and stent implantation. Following the tremendous success of clopidogrel and enoxaparin over the last decade, new antithrombotic agents have been introduced, of which fondaparinux and prasugrel are examples, with both advantages and disadvantages compared to older drugs. The last European Congress in Barcelona in 2009 was particularly rich in this area as the results of three major clinical trials were presented, all with significant implications for clinical practice: the PLATO study testing the first reversible antiplatelet drug acting via the P2Y12 platelet receptor; the CURRENT-OASIS 7 study testing higher doses of aspirin and clopidogrel; and the SEPIA-ACS1 TIMI 42 trial launching the new parenteral anticoagulant otamixaban, a factor Xa inhibitor. These three trials are briefly reviewed in the current paper, highlighting the characteristics that may lead to new recommendations and the implications for daily clinical practice.

Topics: Acute Coronary Syndrome; Adenosine; Biomedical Research; Clopidogrel; Cyclic N-Oxides; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Pyridines; Ticagrelor; Ticlopidine

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Anticoagulants; Clinical Trials, Phase II as Topic; Cyclic N-Oxides; Drug Monitoring; Heparin; Hirudins; Humans; Metabolic Clearance Rate; Patient Selection; Peptide Fragments; Pyridines; Recombinant Proteins