Treatment of Acute Coronary Syndromes With Otamixaban - TAO

Sep 01, 2013
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Sanofi
Date Presented:
01/01/2013
Date Published:
01/01/2013
Date Updated:
09/01/2013
Original Posted Date:
09/01/2013
References

Description:

The optimal anticoagulation strategy in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) is unclear. The current trial sought to compare the safety and efficacy of otamixaban, a novel intravenous factor Xa inhibitor, as compared with unfractionated heparin (UFH) + eptifibatide in these patients.

Hypothesis:

Otamixaban would be superior to UFH + eptifibatide in patients with ACS undergoing PCI in reducing recurrent ischemic events.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Presentation with non–ST-segment elevation (NSTE)-ACS
  • Early invasive angiography (within 36 hours of randomization or day 3 of presentation)

    Number of enrollees: 13,524
    Number of enrollees: 13,229
    Duration of follow-up: 30 days
    Mean patient age: 62 years
    Percentage female: 30%

Exclusions:

  • Revascularization already performed for index procedure
  • Acute STEMI
  • Receipt of a therapeutic dose of injectable anticoagulant for more than 24 hours before randomization
  • Treatment with abciximab
  • If received in the 24 hours before randomization, treatment with UFH or bivalirudin must have been discontinued at least 90 minutes, but no longer than 150 minutes before starting otamixaban, and the last dose of LMWH or fondaparinux must have been received at least 8 hours before starting otamixaban

Primary Endpoints:

  • Primary efficacy outcome: Death/MI at 7 days
  • Primary safety outcome: TIMI major or minor bleeding at 7 days

Secondary Endpoints:

  • Death/MI at 30 days
  • Composite of all-cause death, new MI, or any stroke from randomization to day 7
  • Rehospitalization or prolongation of hospitalization due to a new episode of myocardial ischemia or MI from randomization to day 30
  • All-cause death from randomization to day 30
  • Periprocedural and postprocedural thrombotic complications during the index PCI (including
    postprocedural stent thrombosis)

Drug/Procedures Used:

Randomization occurred in two stages. In the first stage, patients were randomized in a 1:1 fashion to either otamixaban (received intravenous bolus of 0.08 mg/kg followed by an infusion of either 0.1 mg/kg/hr or 0.14 mg/kg/hr) or UFH + eptifibatide. In the second stage (after the interim analysis), patients only received the 0.14 mg/kg/hr infusion of otamixaban. In the UFH-plus-eptifibatide group, throughout both study stages, patients received UFH (60-IU/kg intravenous bolus [maximum, 4000 IU], followed by an infusion of 12 IU/kg/hr [maximum, 1000 IU/h] to maintain an activated partial thromboplastin time at 1.5-2.0 times the control group) as soon as possible after randomization and continued until the end of PCI.

At the time of PCI, additional UFH boluses could be administered if the activated clotting time was not in the 200- to 250-second range. Eptifibatide was administered as a double bolus (180 mcg/kg each), followed by infusion at 2 mcg/kg/min (1 mg/kg/min if chronic kidney disease).

Concomitant Medications:

Aspirin (97%), clopidogrel (86%), prasugrel (2%), ticagrelor (3%), UFH (30.5%), low molecular weight heparin (LMWH) (33%), and fondaparinux (3.5%)

Principal Findings:

A total of 13,229 patients were randomized: 2,657 to otamixaban 0.1 mg/kg/hr infusion, 5,106 to otamixaban 0.14 mg/kg/hr, and 5,466 to UFH + eptifibatide. Baseline characteristics were fairly similar among the three arms. Nearly 88% of patients had evidence of elevated biomarkers at enrollment. Approximately 28% had a history of diabetes, 5% had prior cerebrovascular accident, and 19% had prior myocardial infarction (MI). TIMI risk score was ≥3 in nearly 70% of all patients. Radial access was utilized in 54% of patients. Median time between randomization and angiography was 240 minutes.

The primary endpoint of death/MI at 7 days was similar among the otamixaban 0.1 mg/kg/hr, otamixaban 0.14 mg/kg/hr, and UFH + eptifibatide arms (6.3% vs. 5.5% vs. 5.7%, p = 0.63 for high-dose otamixaban vs. UFH/eptifibatide). Other outcomes including stroke (0.4% vs. 0.3%) and stent thrombosis (1.3% vs. 1.6%) were similar between the high-dose otamixaban and UFH/eptifibatide arms. At 30 days, the primary endpoint was similar between the high-dose otamixaban and UFH/eptifibatide arms (6.9% vs. 7.0%). The primary safety endpoint of TIMI major or minor bleeding at day 7 was significantly higher in the high-dose otamixaban arm (3.1% vs. 1.5%, hazard ratio 2.13, 95% confidence interval 1.63-2.78). All forms of bleeding, including TIMI major, non–coronary artery bypass grafting (CABG)-related major, and CABG-related and TIMI minor bleeding were higher in the otamixaban arm.

Interpretation:

The results of the large phase III TAO study indicate that otamixaban is not superior to UFH/eptifibatide in the management of patients with ACS undergoing PCI and results in higher bleeding. These findings are contrary to the results from the phase II SEPIA-TIMI 42 trial with otamixaban, in which reductions in ischemic endpoints had been noted. This again highlights the importance of adequately powered phase III randomized clinical trials for making meaningful inferences regarding medications and devices.

Current guidelines list UFH with or without glycoprotein IIb/IIIa inhibitors, bivalirudin, LMWH, and fondaparinux as acceptable options for patients with ACS undergoing PCI. Otamixaban is an anti-Xa inhibitor (similar to fondaparinux). However, the current trial does not support its use in the management of these patients. Unlike fondaparinux, no increase in catheter-associated thrombosis was noted.

References:

Steg PG, Mehta SR, Pollack CV Jr, et al., on behalf of the TAO Investigators. Anticoagulation with otamixaban and ischemic events in non–ST-segment elevation acute coronary syndromes: the TAO randomized clinical trial. JAMA 2013;Sep 1:[Epub ahead of print].

Presented by Dr. P.G. Steg at the European Society of Cardiology Congress, Amsterdam, Holland, September 1, 2013.

Keywords: Polysaccharides, Acute Coronary Syndrome, Myocardial Infarction, Stroke, Follow-Up Studies, Cyclic N-Oxides, Heparin, Low-Molecular-Weight, Pyridines, Hirudins, Percutaneous Coronary Intervention, Stents, Biomarkers, Thrombosis, Partial Thromboplastin Time, Peptide Fragments, Recombinant Proteins, Confidence Intervals, Factor Xa, Coronary Artery Bypass, Renal Insufficiency, Chronic, Diabetes Mellitus, Platelet Glycoprotein GPIIb-IIIa Complex


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