Elsevier

American Heart Journal

Volume 185, March 2017, Pages 93-100
American Heart Journal

Clinical Investigation
The safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial

https://doi.org/10.1016/j.ahj.2016.12.004Get rights and content

Background

The APEX trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among hospitalized, acutely ill medical patients. The 80-mg betrixaban dose was halved to 40 mg among subjects with severe renal insufficiency and those receiving a concomitant strong P-glycoprotein inhibitor.

Methods

This analysis assessed the pharmacokinetics, efficacy, and safety of full- (80 mg) and reduced-dose (40 mg) betrixaban relative to enoxaparin in the APEX trial.

Results

The median concentration of betrixaban among subjects administered the 80-mg dose was higher than that of the 40-mg dose (19 ng/mL vs 11 ng/mL, P < .001). In the primary analysis cohort 1 (d-dimer ≥2× upper limit of normal), the primary efficacy outcome (asymptomatic proximal deep vein thrombosis, symptomatic proximal or distal deep vein thrombosis, symptomatic nonfatal pulmonary embolism, or venous thromboembolism–related death) was significantly reduced among subjects treated with 80 mg of extended-duration betrixaban versus enoxaparin (6.27% [95/1516] vs 8.39% [130/1549], relative risk reduction = 0.26 [0.04-0.42], P = .023), and similarly in the entire primary efficacy outcome population (4.87% [122/2506] vs 7.06% [181/2562], relative risk reduction = 0.30 [0.13-0.44], P = .001). There was no difference in the primary outcome for subjects treated with 40 mg betrixaban vs enoxaparin across cohorts. In addition, there was no excess of major bleeding associated with either betrixaban dose compared with enoxaparin.

Conclusions

The 80-mg betrixaban dose achieves higher plasma concentrations than the 40-mg dose and, in contrast to the 40-mg dose, 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.

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.

. Betrixaban concentrations in selected time windows

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.

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J. Michael DiMaio, MD served as guest editor for this article.

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