Editor's Note: Commentary based on Steg PG, Mehta SR, Pollack CV Jr, et al. Anticoagulation with otamixaban and ischemic events in non-ST-segment elevation acute coronary syndromes: the TAO randomized clinical trial. JAMA 2013;310:1145-55.

Background

Activation of the coagulation cascade, in addition to platelet activation, has a pivotal role in arterial thrombosis which follows plaque rupture and leads to an acute coronary syndrome (ACS).¹ Therefore, anticoagulant therapy as an adjunct to antiplatelet agents is the standard of care treatment in the acute phase of an ACS.² Several different anticoagulants have been developed, but each of these agents has limitations and no consensus on a single anticoagulant to be used across the continuum of ACS treatment has been reached.² Otamixaban is a synthetic, direct factor Xa inhibitor which is administered intravenously and inhibits thrombin generation in a dose-dependent manner, with a rapid onset and offset of action, linear kinetics, and only partial kidney clearance (25%).³ Otamixaban is therefore an attractive strategy for the treatment of ACS patients from early management to revascularization. The favorable safety profile and encouraging efficacy data from phase II investigations^4,5 have led to the design of the phase III Treatment of Acute Coronary Syndromes with Otamixaban (TAO) trial which tested otamixaban compared with unfractionated heparin (UFH) plus downstream eptifibatide in patients with Non-ST-segment elevation (NSTE) ACS with a planned invasive strategy.⁶

Methods

TAO was a randomized, double-blind, active-controlled, 2-stage, Phase III superiority trial which enrolled patients (n=13,229) with NSTE ACS planned for an early invasive strategy. During the first dose-finding stage, patients were randomized in a 1:1:1 fashion to receive either otamixaban at one of two doses, or UFH plus eptifibatide (double 180-μg/kg bolus plus 2.0 μg/kg per minute infusion). Otamixaban or UFH infusions were to be administered as soon as possible after randomization and continued until the end of percutaneous coronary intervention (PCI). Eptifibatide infusion was initiated at the start of PCI and continued for 18-24 hours after. In patients not undergoing PCI after angiography, eptifibatide was not administered and the duration of UFH or otamixaban infusion was left to the investigator's discretion. After a planned interim analysis after enrollment of approximately 35% of the patients, the higher otamixaban dose was chosen for stage 2, in which patients were randomized 1:1 to either otamixaban (0.080 mg/kg bolus and 0.140 mg/kg per hour infusion) or UFH plus eptifibatide. All randomized patients were to receive antiplatelet therapy with aspirin and a P2Y₁₂ receptor inhibitor. The primary efficacy endpoint was a composite of all-cause death or new myocardial infarction through day 7. Efficacy and bleeding analyses were performed on patients randomized to the high-dose of otamixaban (n=5,106) vs UFH plus eptifibatide (n=5,446), not on the low-dose otamixaban group.^6,7

Results

After angiography, 65.4% of patients underwent PCI and 5.2% underwent coronary artery by-pass graft (CABG). The median duration of study anticoagulation infusion was approximately four hours. At seven-day follow-up, otamixaban failed to reduce the primary endpoint (5.5% vs 5.7% with UFH plus downstream eptifibatide; adjusted relative risk: 0.99; 95% CI: 0.85-1.16; P=0.93). Similarly, the components of the primary outcome as well as thrombotic procedural complications, including stent thrombosis, were similar between groups. Results were consistent at 30 days and across multiple prespecified subgroups. Otamixaban use was associated with a 2-fold increase in thrombolysis in myocardial infarction (TIMI) major or minor bleeding (CABG and non-CABG related) compared to UFH plus eptifibatide (3.1% vs 1.5%; P<0.001), without any subgroup interaction. Discontinuation of study drug due to bleeding was significantly higher in the otamixaban group (4.7% vs 1.7%). Importantly, similar results were obtained when the low-dose otamixaban group was analyzed.⁷

Conclusion

Anticoagulation with otamixaban compared with UFH plus eptifibatide in NSTE ACS patients with planned early invasive strategy was associated with a significant increase in major bleeding without reducing the rate of ischemic events.

Commentary/Perspective

Thrombin is pivotal in platelet activation processes leading to pathological thrombosis, and thrombin levels are known to be elevated in ACS.^1,8 Despite the key role of factor X in the coagulation process leading to thrombin generation and the promising results of the dose finding phase II trials^5,6, the large-scale phase III TAO trial demonstrated that early and potent inhibition of factor X in patients with NSTE ACS did not provide any additional benefit over UFH plus eptifibatide. Moreover, in routine clinical practice many patients do not receive a combination of UFH plus a glycoprotein IIb/IIIa inhibitor since others strategies, such as heparin alone or the direct thrombin inhibitor bivalirudin, have shown to cause less bleeding without an adverse overall tradeoff in thrombotic complications.^9,10 Therefore, it may be hypothesized that otamixaban would have probably resulted in an even further increase in bleeding risk compared with one of these strategies.

The potential role of factor X inhibition in ACS was explored in two prior large clinical trials with the subcutaneous indirect factor X inhibitor fondaparinux. Fondaparinux had a favorable bleeding profile but with an increase in guidewire or catheter thrombosis during PCI.^11,12 The TAO trial showed us that sufficient direct factor X inhibition was able to avoid thrombotic complications, but was achieved at the expenses of increasing hemorrhagic complications. This suggests a narrow therapeutic window for otamixaban. Therefore, these data suggest that in the era of potent antiplatelet therapies and more expedited access to cardiac catheterization, an early potent anticoagulant agent may not be required in patients with NSTE ACS with a planned invasive strategy.

References

1. Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013;368:2004-13.
2. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e179-347.
3. Chu V, Brown K, Colussi D, at al. Pharmacological characterization of a novel factor Xa inhibitor, FXV673. Thromb Res 2001; 103:309-24.
4. Sabatine MS, Antman EM, Widimsky P, et al. Otamixaban for the treatment of patients with non-ST-elevation acute coronary syndromes (SEPIA-ACS1 TIMI 42): a randomised, double-blind, active-controlled, phase 2 trial. Lancet 2009;374:787-95.
5. Cohen M, Bhatt DL, Alexander JH, et al. Randomized, double-blind, dose-ranging study of otamixaban, a novel, parenteral, short-acting direct factor Xa inhibitor, in percutaneous coronary intervention: the SEPIA-PCI trial. Circulation 2007;115:2642-51.
6. Steg PG, Mehta SR, Pollack CV Jr, et al. Design and rationale of the treatment of acute coronary syndromes with otamixaban trial: a double-blind triple-dummy 2-stage randomized trial comparing otamixaban to unfractionated heparin and eptifibatide in non-ST-segment elevation acute coronary syndromes with a planned early invasive strategy. Am Heart J 2012;164:817-24.e13.
7. Steg PG, Mehta SR, Pollack CV Jr, et al. Anticoagulation with otamixaban and ischemic events in non-ST-segment elevation acute coronary syndromes: the TAO randomized clinical trial. JAMA 2013;310:1145-55.
8. Brummel-Ziedins K, Undas A, Orfeo T, et al. Thrombin generation in acute coronary syndrome and stable coronary artery disease: dependence on plasma factor composition. J Thromb Haemost 2008;6:104-10.
9. Petersen JL, Mahaffey KW, Hasselblad V, et al. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-Segment elevation acute coronary syndromes: a systematic overview. JAMA 2004;292:89-96.
10. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203-16.
11. Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 2006;295:1519-30.
12. Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006;354:1464-76.

Keywords: Acute Coronary Syndrome, Angiography, Anticoagulants, Aspirin, Factor Xa Inhibitors, Hemorrhage, Heparin, Kinetics, Myocardial Infarction, Peptides, Percutaneous Coronary Intervention, Platelet Activation, Platelet Aggregation Inhibitors, Pyridines, Standard of Care, Thrombin, Thrombosis, Troleandomycin

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