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Extended Thromboprophylaxis With Betrixaban
Study Questions:
Is an extended-duration venous thromboembolism (VTE) prophylaxis with betrixaban superior to standard use of subcutaneous enoxaparin in patients with acute medical illnesses?
Methods:
Hospitalized medical patients were randomly assigned to enoxaparin 40 mg daily for 10 ± 4 days or betrixaban 80 mg daily for 35-42 days in a randomized, placebo-controlled, double-blind, multinational trial. Three sequential (and progressively larger) analyses were pre-planned: 1) patients with elevated D-dimer levels (cohort 1), 2) patients with an elevated D-dimer level or age ≥75 years (cohort 2), and all enrolled patients (cohort 3). Primary efficacy was a composite of asymptomatic proximal deep-vein thrombosis plus symptomatic VTE. The principal safety outcome was major bleeding.
Results:
Between March 2012 and November 2015, 7,513 patients were randomized (3,870 in cohort 1, 5,735 in cohort 2). In cohort 1, the primary efficacy outcome occurred in 6.9% of betrixaban-treated patients and 8.5% of enoxaparin-treated patients (relative risk [RR], 0.81; 95% confidence interval [CI], 0.65-1.00; p = 0.054). In cohort 2, the rates were 5.6% vs. 7.1%, respectively (RR, 0.80; 95% CI, 0.66-0.98; p = 0.03), while in cohort 3, the rates were 5.3% vs. 7.0%, respectively (RR, 0.76; 95% CI, 0.63-0.92; p = 0.006). In cohort 3, major bleeding occurred in 0.7% of betrixaban-treated patients and 0.6% of enoxaparin-treated patients (RR, 1.19; 95% CI, 0.67-2.12; p = 0.55).
Conclusions:
The authors concluded that among acute medically ill patients with an elevated D-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin. They also concluded that exploratory analyses in a broader medical population suggest potential benefit for betrixaban over enoxaparin for VTE prophylaxis.
Perspective:
Appropriate prevention of VTE among hospitalized medical patients is an ongoing challenge. Betrixaban, a direct oral anti-Xa inhibitor, was compared to enoxaparin injections for VTE prevention. Of note, this study used an extended duration (35 ± 4 days) of betrixaban in comparison to a more standard regimen of enoxaparin (10 ± 4 days). Based on data from the MAGELLAN trial of rivaroxaban versus enoxaparin (Cohen AT, et al., N Engl J Med 2013;368:513-23), a ‘high-risk’ cohort with an elevated D-dimer was analyzed first. While the RR did not reach the threshold of statistical significance (p = 0.054 and a 95% CI that barely included 1.00), it raises the question of dichotomizing statistical significance based on a somewhat arbitrary threshold of p = 0.05 (Greenland S, et al., Eur J Epidemiol 2016;31:337-50). It also challenges the paradigm that an inpatient physician would be willing to prescribe a medication beyond the inpatient stay. Food and Drug Administration documentation is likely to be submitted in 2016, and clinicians will eagerly await their interpretation of the data.
Keywords: Acute Disease, Anticoagulants, Enoxaparin, Fibrin Fibrinogen Degradation Products, Hemorrhage, Inpatients, Primary Prevention, Risk, Vascular Diseases, Venous Thromboembolism, Venous Thrombosis
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