SEPIA-ACS1 TIMI 42: Mixed Results for Otamixaban in ACS

August 30, 2009

(Updated August 30, 2009) (Barcelona, Spain) — Intermediate doses of the new intravenous direct factor Xa inhibitor otamixaban (Sanofi-Aventis) showed the most promising results in the phase 2 SEPIA-ACS1 TIMI 42 trial in high-risk non-ST-elevation-ACS patients [1]. These doses showed a trend toward lower ischemic end points with a similar rate of bleeding complications compared with unfractionated heparin plus eptifibatide.

The trial was presented here at the European Society of Cardiology (ESC) 2009 Congress and simultaneously published online in the Lancet.

The authors, led by Dr Marc Sabatine (Brigham and Women's Hospital, Boston, MA), say that further testing of one of these intermediate doses in a phase 3 trial is warranted. But the authors of an accompanying Comment question whether another IV agent for this indication is needed [2].

In the paper, Sabatine et al explain that otamixaban has the advantage of being reversible, with near-immediate onset of action after a bolus and a short half-life, offering rapid on–off anticoagulant activity, which is a desirable feature in the setting of invasive management of ACS. It is also mainly cleared unchanged via the biliary system, suggesting no need for dose modification in case of renal insufficiency. A previous phase 2 study (SEPIA-PCI) showed that intermediate doses of otamixaban (0.12 and 0.16 mg/kg/h) showed lower ischemic end points and similar bleeding rates compared with heparin in patients undergoing nonurgent PCI. The current study was therefore conducted to investigate which dose looked best in patients with high-risk non-ST-elevation ACS.

The SEPIA-ACS1 TIMI 42 trial involved 3241 patients randomized to one of five maintenance doses of otamixaban (all given with a 0.08-mg/kg bolus) or to a control of unfractionated heparin plus eptifibatide. Of the patients, 63% underwent PCI and 4% underwent CABG. The median duration of treatment with otamixaban or heparin was five hours and with eptifibatide or placebo was 21 hours. Enrollment into the lowest-dose group was stopped early because of clinical evidence of a lack of anticoagulation.

Results were consistent with the SEPIA PCI study, with the intermediate doses (bolus of 0.08 mg/kg followed by an infusion of 0.10 to 0.14 mg/kg/h) seeming to provide the best balance of safety and efficacy, with a 40% reduction in death or ischemic complications (nonsignificant) compared with heparin plus eptifibatide and a similar rate of bleeding. "The reduction in the primary efficacy end point was driven by reductions in death and MI, the hardest end points," Sabatine noted at an ESC press conference. Lower doses were associated with increased thrombotic complications, and higher doses showed significantly greater bleeding than heparin plus eptifibatide. "Thus, otamixaban given with a bolus of 0.080 mg/kg followed by an infusion of 0.100 to 0.140 mg/kg/h seems to be the most reasonable choice for future study," Sabatine et al conclude.

SEPIA-ACS1 TIMI 42: Major Results

End point Heparin+eptifibatide Otamixaban 0.035 mg/kg/h Otamixaban 0.070 mg/kg/h Otamixaban 0.105 mg/kg/h Otamixaban 0.140 mg/kg/h Otamixaban 0.175 mg/kg/h
Primary efficacy end point* (%) 6.2 7.2 4.6 3.8 3.6 4.3
TIMI major or minor bleeding not related to CABG (%) 2.7 1.6 1.6 3.1 3.4 5.4
*Primary efficacy end point=death/MI/urgent revascularization/ bailout GP IIb/IIIa-inhibitor use up to 7 days

Is Another IV Agent Needed?

But otamixaban will have to compete in a crowded market, as there are now many alternative anticoagulants that have been studied in non-ST-elevation-ACS patients, including enoxaparin, bivalirudin, and another factor Xa inhibitor, fondaparinux, although Sabatine et al note that neither bivalirudin nor fondaparinux has yet been approved in the US for the treatment of this indication. They say that enoxaparin seems "fairly similar" to heparin in the setting of an early invasive strategy in ACS patients, and bivalirudin showed similar rates of ischemic events and lower rates of bleeding compared with heparin plus a GP IIb/IIIa inhibitor, the opposite of that seen with otamixaban in this study.

Fondaparinux, which is not short-acting, has shown good results in this indication, with similar short-term rates of ischemic events, less bleeding, and lower 30-day mortality compared with enoxaparin, but it is recommended to supplement another anticoagulant in PCI patients to avoid catheter-related thromboses. Sabatine et al point out that no catheter-related thromboses with either the 0.105- or the 0.140-mg/kg/h otamixaban doses were seen in this study but note that careful tracking of these events will be needed in a phase 3 trial.

In the accompanying Comment, Drs John Eikelboom and Jeffrey Weitz (McMaster University, Hamilton, ON) say that the SEPIA findings suggest that "like bivalirudin, otamixaban might be a useful alternative to heparin for patients with ACS who are undergoing PCI." But they question whether another parenteral agent for this indication is needed, given that it would have to show efficacy superior not only to heparin but also to bivalirudin before being adopted for clinical use, adding, "To our knowledge, there are no ongoing phase 3 trials to explore these possibilities, nor is otamixaban under development for other clinical indications."

They note that most of the attention in ACS has moved away from parenteral anticoagulants, such as otamixaban, and is focused on new oral agents, such as apixaban and rivaroxaban, new oral factor Xa inhibitors that can be given in fixed doses without routine coagulation monitoring, which are being evaluated in phase 3 trials for the long-term management of ACS patients.

But at an ESC press conference, Sabatine disputed these points. "While the oral agents are exciting for long-term use, we still need good IV anticoagulants for use in the acute situation," he said. "All the agents we have available have their pros and cons, but for patients managed invasively, none have shown a reduction in ischemic events compared with heparin. This is the unique selling point of this new drug."

Sabatine added that further development of otamixaban is being planned, with a phase 3 trial "under active consideration."

Lower Dose May Be Better

White also suggested that the lower 0.070-mg/kg/h dose of otamixaban should be considered for further trials rather than the 0.105- or 0.140-mg/kg/h doses. He pointed out that the lower dose had shown a comparable effect to the two slightly higher doses on the hard end point of death and MI. In addition, the 0.070-mg/kg/h dose did not increase major bleeding compared with the heparin/eptifibatide arm, whereas the 0.105- and 0.140--mg/kg/h doses showed trends toward increased major bleeding, which White said was a more appropriate safety end point than major and minor bleeding combined.

SEPIA-ACS1 TIMI 42: Effect on Death/MI And Major Bleeding

Outcome Heparin+eptifibatide Otamixaban 0.070 mg/kg/h Otamixaban 0.105 mg/kg/h Otamixaban 0.140 mg/kg/h
Death/MI (%) 4.9 2.8 2.6 2.7
TIMI major bleeding (%) 1.8 1.8 3.4 2.6

"I think when selecting the dose for phase 3, we should focus on the ceiling for unacceptable bleeding, which in my view is major bleeding, not major and minor bleeding combined. Why would you take forward a dose that increases major bleeding compared with the control arm, when you have a lower dose that produces a similar effect on death/MI without increasing major bleeding?" White challenged.

This study was funded by Sanofi-Aventis. The TIMI Study Group receives research grant support from Sanofi-Aventis, Johnson & Johnson, Bayer, and Daiichi Sankyo. Sabatine reports receiving honoraria/consultant fees from Sanofi-Aventis and Bristol-Myers Squibb. Other coauthors receive research grants/consultant fees from Sanofi-Aventis, Daiichi-Sankyo, Bayer, and Johnson & Johnson. Eikelboom has received honoraria/research support from companies that are developing or marketing drugs mentioned in this comment, including: Bayer (aspirin), Bristol-Myers Squibb (clopidogrel), Eli Lilly (prasugrel), GlaxoSmithKline (fondaparinux, low-molecular-weight heparin), Regado Biosciences (RB006/007), and Sanofi-Aventis (clopidogrel, low-molecular-weight heparin). Weitz has received honoraria/research support from Bristol-Myers Squibb, Sanofi-Aventis, and the Medicines Company (bivalirudin).

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