Extended-duration betrixaban versus shorter-duration enoxaparin for venous thromboembolism prophylaxis in critically ill medical patients: an APEX trial substudy
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To assess the efficacy and safety of betrixaban for venous thromboembolism (VTE) prophylaxis among critically ill patients.
The APEX trial randomized 7513 acutely ill hospitalized patients to betrixaban for 35–42 days or enoxaparin for 10 ± 4 days. Among those, 703 critically ill patients admitted to the intensive care unit were included in the analysis, and 547 patients who had no severe renal insufficiency or P-glycoprotein inhibitor use were included in the full-dose stratum. The risk of VTE, bleeding, net clinical benefit (composite of VTE and major bleeding), and mortality was compared at 35–42 days and at 77 days.
At 35–42 days, extended betrixaban reduced the risk of VTE (4.27% vs 7.95%, P = 0.042) without causing excess major bleeding (1.14% vs 3.13%, P = 0.07). Both VTE (3.32% vs 8.33%, P = 0.013) and major bleeding (0.00% vs 3.26%, P = 0.003) were decreased in the full-dose stratum. Patients who received betrixaban had more non-major bleeding than enoxaparin (overall population: 2.56% vs 0.28%, P = 0.011; full-dose stratum: 3.32% vs 0.36%, P = 0.010). Mortality was similar at the end of study (overall population: 13.39% vs 16.19%, P = 0.30; full-dose stratum: 13.65% vs 16.30%, P = 0.39).
Compared with shorter-duration enoxaparin, critically ill medical patients who received extended-duration betrixaban had fewer VTE without more major bleeding events. The benefit of betrixaban was driven by preventing asymptomatic thrombosis and offset by an elevated risk of non-major bleeding. The APEX trial did not stratify by intensive care unit admission and the present study included a highly selected population of critically ill patients. These hypothesis-generating findings need to be validated in future studies.
Clinical trial registration
http://www.clinicaltrials.gov. Unique identifier: NCT01583218.
KeywordsVenous thrombosis Anticoagulants Betrixaban Enoxaparin Critical care
Deep vein thrombosis
Intensive care unit
Upper limit of normal
Compliance with ethical standards
Conflicts of interest
The study was sponsored by Portola Pharmaceuticals, Inc. The funding source had no role in (1) design and conduct of the study; (2) collection, management, analysis, and interpretation of the data; (3) preparation, review, or approval of the manuscript; and (4) decision to submit and disseminate the results for publication. Dr. Chi receives modest research grant support paid to the Beth Israel Deaconess Medical Center, Harvard Medical School from Portola Pharmaceuticals, Bayer, and Janssen Scientific Affairs. Dr. Gibson receives consultant fees from Portola Pharmaceuticals and reports grants from Angel Medical Corporation and CSL Behring; grants and other support from Bayer Corporation; grants and personal fees from Janssen, Johnson & Johnson, and Portola Pharmaceuticals; and personal fees from The Medicines Company, Boston Clinical Research Institute, Cardiovascular Research Foundation, Eli Lilly, Gilead Sciences Inc, Novo Nordisk, Pfizer, Web MD, UpToDate in Cardiovascular Medicine, Amarin Pharma, Amgen, Arena Pharmaceuticals, Bayer Corporation, Boehringer Ingelheim, Chiesi, Merck & Co, PharmaMar, Sanofi, Somahlution, St Francis Hospital, and Verreseon Corporation. Dr. Cohen reports grant support, personal fees, and non-financial support from Portola Pharmaceuticals during the conduct of the study; grant support, personal fees, and non-financial support from Daiichi–Sankyo, Bristol–Myers Squibb, Pfizer, Janssen, and Bayer Pharmaceuticals, personal fees from Boehringer Ingelheim and Sanofi, and personal fees and non-financial support from Johnson & Johnson and Aspen Pharmaceuticals outside the submitted work. Dr. Hernandez reports receipt of grant support from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Luitpold, Merck, and Novartis; and personal fees from Amgen, AstraZeneca, Bayer, Bristol–Myers Squibb, Boston Scientific, Luitpold, and Novartis outside the submitted work. Dr. Hull reports grant support from Portola Pharmaceuticals during the conduct of the study, and grant support and personal fees from Leo Pharma outside the submitted work. Dr. Harrington reports grant support from Portola Pharma during the conduct of the study; grant support from CSL Behring, AstraZeneca, GlaxoSmithKline, Regado, and Sanofi Aventis, grant support and personal fees from Merck and The Medicines Company, personal fees from Amgen, Gilead Sciences, MyoKardia, and WebMD, and other support from Scanadu, SignalPath, Element Science, Vida Health, and Adverse Events outside the submitted work. Dr. Goldhaber has provided consulting for Boehringer Ingelheim, Bayer, Portola, Daiichi–Sankyo, Janssen, BiO2 Medical, EKOS/BTG, BMS, and Zafgen. All remaining authors declare no conflicts of interest.
All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments.
Informed consent was obtained from all individual participants included in the study.
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