otamixaban and Hemorrhage

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

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

The optimal anticoagulant regimen for percutaneous coronary intervention (PCI) remains to be determined. Otamixaban, a selective and direct inhibitor of factor Xa, was investigated in patients undergoing nonurgent percutaneous coronary intervention.. In this double-blind, double-dummy, parallel-group, dose-ranging trial, 947 patients were randomly assigned to either 1 of 5 weight-adjusted otamixaban regimens or weight-adjusted unfractionated heparin (UFH) before percutaneous coronary intervention. The primary end points were change in prothrombin fragments 1+2 (F1+2), and anti-factor Xa activity. The main secondary end points were Thrombolysis In Myocardial Infarction (TIMI) bleeding at day 3 or hospital discharge (whichever came first) and 30-day ischemic events. The median change in F1+2 from baseline to the end of infusion was greater with the highest otamixaban dose compared with UFH (-0.3 versus -0.2 ng/mL, P=0.008). Anti-factor Xa levels were 65, 155, 393, 571, and 691 ng/mL with otamixaban doses 1 to 5, respectively. Significant TIMI bleeding (major or minor) occurred in 2.0%, 1.9%, 3.8%, 3.9%, and 2.6% of patients receiving otamixaban doses 1 to 5, respectively, and in 3.8% of patients receiving UFH. Four TIMI major bleeds were observed. Ischemic events occurred in 5.8%, 7.1%, 3.8%, 2.5%, and 5.1% of patients receiving otamixaban doses 1 to 5, respectively, and in 5.6% of patients receiving UFH.. Otamixaban reduced F1+2 significantly more than UFH at the highest dose regimen, whereas no significant difference in the incidence of TIMI bleeding was observed between the otamixaban and UFH groups. These results set the stage for adequately powered clinical outcome trials of selective direct factor Xa inhibition in patients with acute coronary syndromes.

Topics: Aged; Angioplasty, Balloon, Coronary; Antithrombin III; Coronary Disease; Cyclic N-Oxides; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Partial Thromboplastin Time; Peptide Fragments; Protein Precursors; Prothrombin; Pyridines

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