By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved an oral factor Xa inhibitor for the prophylaxis of venous thromboembolism in hospitalized patients suffering from an acute illness. Betrixaban was granted a priority review and fast-track designation, and is the fourth oral factor Xa inhibitor to be approved and the first with this specific indication. Currently marketed oral factor Xa inhibitors are rivaroxaban, apixaban, and edoxaban. Betrixaban is marketed as Bevyxxa.
Betrixaban is indicated for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications because of moderate or severe restricted mobility and other risk factors for VTE.1
Clinicians should administer an initial dose of 160 mg, followed by 80 mg once daily for 35 to 42 days.1 In patients with severe renal impairment (CrCl ≥ 15 to < 30 mL/min) or taking a P-glycoprotein (P-gp) inhibitor (e.g., amiodarone, verapamil), the dose should be 80 mg initially, followed by 40 mg daily. Betrixaban should be taken at the same time each day with food. Betrixaban is available as 40 mg and 80 mg capsules.
Extended duration betrixaban has been shown to be more effective than short duration enoxaparin, with comparable rates of major bleeding.1,2 Betrixaban is the only member of the class to be approved for VTE prophylaxis in the hospitalized, acutely ill patient. In contrast, extended treatment with apixaban and rivaroxaban has been associated with increased risk of major bleeding.3-5
Treatment discontinuation because of bleeding was more likely with betrixaban compared to enoxaparin (2.4% vs. 1.2%).1 Betrixaban carries the black box warning for epidural or spinal hematoma in patients receiving neuraxial anesthesia or undergoing spinal puncture.
The approval of betrixaban was based on reanalysis of data from a randomized, double-blind, double-dummy trial that compared extended-duration betrixaban to short-duration enoxaparin in acutely medically ill hospitalized subjects at risk for VTE.1 Subjects were ≥ 40 years of age and had been hospitalized for < 96 hours for specified acute medical illnesses (heart failure, respiratory failure, infectious disease, rheumatic disease, or ischemic stroke) and reduced mobility.2 Subjects (n = 7,513) were randomized to betrixaban (80 mg daily for 35 to 42 days following a 160 mg loading dose) along with placebo injection for six to 14 days or subcutaneous enoxaparin (40 mg once daily) for six to 14 days and placebo for 35 to 42 days. Subjects with renal impairment or with concomitant use of a P-gp inhibitor received a reduced dose (80 mg followed by 40 mg daily). The primary efficacy outcome was a composite of asymptomatic proximal deep vein thrombosis between day 32 and day 47, symptomatic proximal or distal deep vein thrombosis, symptomatic nonfatal pulmonary embolism, or death from VTE between day one and 42. The primary safety outcome was the occurrence of major bleeding at any point until seven days after the discontinuation of all study medications. This was based on the criteria of the International Society on Thrombosis and Haemostasis.
A total of 7,441 subjects met the criteria of efficacy analyses (3,721 for betrixaban, and 3,720 for enoxaparin).1 The primary outcome occurred in 165 subjects who received betrixaban (4.4%) and 223 (6.0%) in the enoxaparin arm (25% risk reduction). Subjects randomized to the reduced dose showed no difference in efficacy outcome (6.9% vs. 6.7%, respectively) and corresponding 42% lower median drug plasma levels.6 Results from a retrospective substudy suggest betrixaban also reduced all-cause stroke and ischemic stroke compared to enoxaparin through 77 days of follow-up.7 Major bleeding occurred in 0.67% of the betrixaban subjects compared to 0.57% for enoxaparin (P = 0.55). However, clinically relevant non-major (CRNM) bleeding was significantly higher with betrixaban (2.45% vs. 1.02 %; P < 0.001). CRNM bleeding was defined as overt bleeding not meeting criteria for major bleeding (e.g., ≥ 2 g/dL drop in hemoglobin, need for transfusion ≥ 2 units) but associated with medical intervention, unscheduled contact with a physician, temporary or permanent cessation of study treatment, or associated with discomfort (e.g., pain or impairment of activities of daily life).
VTE is a common cause of morbidity and mortality in patients hospitalized with acute medical illness. The American College of Chest Physicians recommends that nonsurgical acutely ill hospitalized medical patients at increased risk of thrombosis should receive thromboprophylaxis with low-molecular weight heparin, low-dose unfractionated heparin, or fondaparinux, and suggests against extending the duration of prophylaxis beyond the period of patient immobilization or hospital stay.8 However, most VTE episodes occur after discharge, with 67% reported to occur within one month after discharge.9 This suggests extended-duration thromboprophylaxis as a potential unmet need.10 A systematic review and meta-analysis suggest that extended treatment with apixaban, rivaroxaban, and enoxaparin reduces the risk of VTE but was associated with increased risk of major bleeding.6 Betrixaban, the first anticoagulant to be approved for extended duration use, was more effective than short duration enoxaparin but was not associated with increased risk of major bleeding. However, it was associated with increased risk of CRNM bleeding. The cost for betrixaban was not available at the time of this review. The drug is expected to launch between August and November 2018.
- Bevyxxa Prescribing Information. Portola Pharmaceuticals, Inc. June 2017.
- Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med 2016;375:534-544.
- Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011 365;2167-2177.
- Cohen AT, Spiro TE, Büller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013;368:513-523.
- Liew AY, Piran S, Eikelboom JW, Douketis JD. Extended-duration versus short-duration pharmacological thromboprophylaxis in acutely Ill hospitalized medical patients: A systematic review and meta-analysis of randomized controlled trials. J Thromb Thrombolysis 2017;43:291-301.
- Gibson CM, Halaby R, Korjian S, et al. 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. Am Heart J 2017;185:93-100.
- Gibson CM, Chi G, Halaby R, et al. Extended-duration betrixaban reduces the risk of stroke versus standard-dose enoxaparin among hospitalized medically ill patients: An APEX trial substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban). Circulation 2017;135:648-655.
- Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest 2012;141 (Suppl):e195S-e226s.
- Spencer FA, Lessard D, Emery C, et al. Venous thromboembolism in the outpatient setting. Arch Intern Med 2007;167:1471-1475.
- Korjian S, Daaboul Y, Halaby R, et al. Extended-duration thromboprophylaxis among acute medically ill patients: An unmet need. J Cardiovasc Pharmacol Ther 2016;21:227-232.