Extended Thromboprophylaxis With Betrixaban
Is an extended-duration venous thromboembolism (VTE) prophylaxis with betrixaban superior to standard use of subcutaneous enoxaparin in patients with acute medical illnesses?
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.
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).
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.
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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