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Otamixaban: A Novel Agent Being Tested in Non-ST-Elevation ACS
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The use of anticoagulant agents — along with antiplatelet therapy — has become the mainstay for the management of non-ST-segment elevation ACS. However, there is currently no single accepted superior anticoagulant strategy in this indication.
Treatment regimens vary across regions of the world according to local habits, preferences and management strategies. The main current choices include unfractionated heparin (UFH), enoxaparin (Lovenox, Sanofi-Aventis), fondaparinux (Arixtra, GlaxoSmithKline) and bivalirudin (Angiomax, The Medicines Company). Although these drugs have been proven to be effective for non-ST segment elevation ACS (NSTEACS), there is uncertainty as to which is the best regimen. While guidelines provide clinicians with a choice between these drugs according to patient profile and the performance and timing of an invasive strategy, there is at present no consensus on a single optimal agent that could be used across the continuum of care for NSTEACS from the pre-hospital or emergency department setting through to the coronary care unit, cath lab or operating room, and post-intervention settings.
Amir-Ali Fassa
P. Gabriel Steg
UFH, which is both effective and inexpensive, is the most commonly used drug. However, it suffers from a potentially unpredictable pharmocodynamic activity, a narrow therapeutic window requiring monitoring, platelet activation proprieties and the rare but serious risk of heparin-induced thrombocytopenia. The latter may also occur with the use of enoxaparin.
Although enoxaparin was shown to be superior to UFH in early trials of patients with NSTEACS receiving medical therapy as a primary treatment strategy, it failed to demonstrate superior efficacy in the more recent SYNERGY trial, which included high-risk patients to be treated with an intended early invasive strategy. The OASIS-5 trial showed that fondaparinux reduced bleeding and cardiac mortality in comparison to enoxaparin. However, because of an increased risk of catheter thrombosis during interventional procedures, an adjunctive dose of UFH must be administered if PCI is performed.
Finally, the ACUITY trial showed that a strategy using bivalirudin alone was associated with a reduction of bleeding (but not of ischemic events) when compared with UFH or enoxaparin with glycoprotein IIb/IIIa inhibitors in NSTEACS.
The Role of Otamixaban
Otamixaban (Sanofi-Aventis) is a novel parenteral inhibitor of factor Xa that inhibits free and clot-bound factor Xa, and is administered according to a weight-based regimen. Furthermore, it is immediately effective upon administration and has a short half-life (~30 min), with a rapid decrease of anti-Xa activity upon drug discontinuation, resulting in quick onset and offset. The pharmacodynamic effect of otamixaban is strongly correlated with its blood concentration, with modest variability between patients for a specific dose. In addition, otamixaban is mainly cleared unchanged via the biliary system, with less than 25% renal excretion, suggesting that there is no need for dose modification in case of mild or moderate renal insufficiency.
Figure 1. Proportion of patients with the primary efficacy endpoint of all-cause death, MI, severe recurrent myocardial ischemia requiring urgent revascularization or bailout use of a glycoprotein IIb/IIIa inhibitor for recurrent ischemia or for a thrombotic complication PCI. P=0.34 for trend across the otamixaban dose group. RRs and 95% CIs compared with the control group of UFH plus eptifibatide are displayed below the corresponding bars in the graph. The RR for otamixaban doses 0.105 and 0.14 mg/kg/h combined vs. UFH plus eptifibatide was 0.6 (95% CI, 0.38-0.94).
Figures: Sabatine MS. Lancet. 2009; 374:787-795; printed with permission.
Figure 2. Proportion of patients with all-cause death or MI. The RR for otamixaban doses 0.105 and 0.14 mg/kg/h combined vs. UFH plus eptifibatide was 0.54 (95% CI, 0.32-0.91).
Clinical Evaluation
Otamixaban has been tested in the context of ACS in the randomized phase 2 dose-ranging trial SEPIA-ACS1 TIMI 42, which compared five dose regimens of otamixaban to a control arm of UFH plus eptifibatide (Integrilin, Millennium/Schering-Plough) in 3,241 patients with NSTEACS treated according to an early invasive strategy. The study showed that intermediate doses of otamixaban (bolus of 0.080 mg/kg followed by an infusion of 0.105 mg/kg/h or 0.140 mg/kg/h) resulted in a significant reduction (40%) of the primary efficacy endpoint — a composite of all-cause death, new MI, severe recurrent ischemia requiring urgent revascularization and in-hospital bailout use of glycoprotein IIb/IIIa inhibitor within 7 days following randomization — when compared with the control arm (Figure 1). These differences were driven by marked reductions (46%) of death or MI (Figure 2).
Furthermore, there was no significant difference in the incidence of the primary safety endpoint, defined as TIMI major and minor bleeding, in patients treated with intermediate doses compared with patients treated with UFH plus eptifibatide. These results, along with its pharmacologic characteristics, suggest that otamixaban may one day provide an attractive option for anticoagulation in NSTEACS patients, particularly those undergoing PCI.
TAO Trial
In order to explore otamixaban’s potential role in NSTEACS, the ongoing Treatment of Acute Coronary Syndromes with Otamixaban, or TAO, trial (ClinicalTrial.gov ID. NCT01076764) is testing the hypothesis that otamixaban provides superior efficacy, as measured by the composite endpoint of all-cause death and MI, compared with combination UFH/eptifibatide in patients with moderate-to-high-risk NSTEACS with a planned early invasive strategy. This is a prospective, randomized, multinational, multicenter, double blind, phase 3 study, with an expected enrollment of more than 13,000 patients.
The study has a two-stage design. During the first stage of the study, patients are randomly assigned to either the control arm (UFH plus eptifibatide) or to one of two arms with different doses of otamixaban arms (bolus of 0.080 mg/kg followed by either 0.100 mg/kg/h or 0.140 mg/kg/h). An interim analysis was planned in order to select the most appropriate dose of otamixaban, and the second phase of the study continues with the selected dose of otamixaban vs. UFH plus eptifibatide.
Conclusion
Given the uncertainty regarding the optimal anticoagulant strategy in NSTEACS, otamixaban is a potentially attractive option. With its quick onset and offset, it would be applicable to the emergency setting, and might be practical to minimize peri- or post-procedural bleeding, addressing an increasing concern of clinicians. It has the potential to emerge as a single agent used across the continuum of care, from diagnosis through to the cath lab, with the possibility of rapid withdrawal if a patient requires surgery or experiences bleeding. In addition, its linear characteristics and modest renal elimination also suggest a potential for improved safety in the increasingly older ACS patient population in whom the prevalence of chronic kidney dysfunction increases steadily.
Furthermore, if the results from the SEPIA-ACS1 TIMI 42 trial were to be confirmed by the TAO trial, otamixaban would emerge as one of the most potent anticoagulants in terms of reduction of ischemic events. An important consideration will be the safety outcome of the trial and whether use of otamixaban is associated with higher, similar or even lower rates of bleeding than the conventional control strategy. As the current practice of PCI is moving toward a bleeding-avoidance strategy with the increasing use of the transradial approach, a combined use of otamixaban and transradial PCI could possibly result in the safest and most efficient strategy for management of moderate- to high-risk NSTEACS.
Finally, otamixaban may link to continued oral anti-Xa therapy in secondary prevention, which, at least at low doses, may provide genuine clinical benefits. Obviously, the balance of benefit and risk of otamixaban in TAO, which is expected to report in 2013, will determine its future in the management of ACS.
Disclosure: Fassa reports no relevant financial disclosures. Steg reports being a speaker or consultant for Ablynx, Amarin, Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo/Eli Lilly, GlaxoSmithKline, Medtronic, Merck, Novartis, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier and The Medicines Company.