Clinical InvestigationThe safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial
Section snippets
Methods
The APEX (Clinicaltrials.gov number, NCT01583218) trial was a randomized, double-blind, double-dummy, active-controlled, multinational clinical trial.4 A detailed description of the study design has been published elsewhere.5 In brief, hospitalized medically ill subjects at elevated risk for VTE were randomized to either subcutaneous enoxaparin (40 mg once daily) for a duration of 10 ± 4 days plus oral betrixaban placebo once daily for 35 to 42 days, or subcutaneous enoxaparin placebo once daily
Baseline characteristics
A total of 3,759 subjects were randomized to betrixaban and 3,754 to enoxaparin. Of those randomized, 3,721 in the betrixaban arm and 3,720 in the enoxaparin arm were included in the mITT population, and 3,112 in the betrixaban arm and 3,174 in the enoxaparin arm were included in the PEOP. Of the 3,721 subjects randomized to the betrixaban group and in the mITT population, 2,986 were administered the full 80-mg dose of betrixaban, 730 were administered the reduced dose of 40 mg, 4 were not
Discussion
This analysis of APEX demonstrates that the full 80-mg dose of betrixaban was associated with a reduction in VTE compared with standard-of-care enoxaparin across all 3 predefined cohorts, including cohort 1. The dosing criteria for full versus reduced dose of betrixaban were prespecified, and subjects were stratified at randomization based on these criteria. Betrixaban is a factor Xa inhibitor with an oral bioavailability of 34% and a renal clearance of 7% of the administered and 17% of the
Limitations
There were fewer subjects in the 40-mg dose group, and the analysis may have been underpowered to ascertain a difference from enoxaparin. There was also insufficient statistical power to evaluate the relationship between the plasma concentration of betrixaban and clinical outcomes. No pharmacodynamic data were collected, although a strong relationship between pharmacokinetic and pharmacodynamics data has been established for betrixaban.8., 10. In addition, the reported betrixaban concentrations
Conclusion
The full 80-mg dose of extended-duration betrixaban is associated with improved efficacy across all cohorts relative to standard-dose enoxaparin without an excess risk of major bleeding in the management of medically ill subjects. In contrast, the reduced dose of 40 mg achieves approximately half the concentration and was not associated with improved outcomes.
The following are the supplementary data related to this article.
Acknowledgements
Purva Jain, MPH, and Daniel Flynn, MPH, are greatly acknowledged for their statistical and proofreading contributions. This research was funded by Portola Pharmaceuticals, Inc.
References (10)
- et al.
Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines
Chest
(2012) - et al.
The design and rationale for the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study
Am Heart J
(2014) - et al.
Recognition of biomarker identified high-risk patients in the acute medically ill venous thromboembolism prevention with extended duration betrixaban study resulting in a protocol amendment
Am Heart J
(2015) - et al.
Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenz amide, a highly potent, selective, and orally efficacious factor Xa inhibitor
Bioorg Med Chem Lett
(2009) - et al.
Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality
Thromb Haemost
(2007)
Cited by (0)
J. Michael DiMaio, MD served as guest editor for this article.