Extended-duration betrixaban versus shorter-duration enoxaparin for venous thromboembolism prophylaxis in critically ill medical patients: an APEX trial substudy
- 421 Downloads
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.
- 5.Fraisse F, Holzapfel L, Couland JM, Simonneau G, Bedock B, Feissel M, Herbecq P, Pordes R, Poussel JF, Roux L, The Association of Non-University Affiliated Intensive Care Specialist Physicians of France (2000) Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. Am J Respir Crit Care Med 161:1109–1114CrossRefGoogle Scholar
- 8.Goldhaber S, Kett D, Cusumano C, Kuroki C (2000) Low molecular weight heparin versus minidose unfractionated heparin for prophylaxis against venous thromboembolism in medical intensive care unit patients: a randomized controlled trial. J Am Coll Cardiol 35(2 suppl A):325A2000Google Scholar
- 9.PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group, Cook D, Meade M, Guyatt G, Walter S, Heels-Ansdell D, Warkentin TE, Zytaruk N, Crowther M, Geerts W, Cooper DJ, Vallance S, Qushmaq I, Rocha M, Berwanger O, Vlahakis NE (2011) Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med 364:1305–1314CrossRefGoogle Scholar
- 13.Chi G, Gibson CM, Hernandez AF, Hull RD, Cohen AT, Harrington RA, Alkhalfan F, Kalayci A, Kerneis M, Nafee T, Goldhaber SZ, APEX Investigators (2018) Betrixaban versus enoxaparin for venous thromboembolism prophylaxis in critically ill patients: findings from the APEX trial. Eur Heart J 39:Ehy563.4321–Ehy4563.4321Google Scholar
- 14.Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (2005) Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 3:692–694CrossRefGoogle Scholar
- 15.Kaatz S, Ahmad D, Spyropoulos AC, Schulman S, Subcommittee on Control of Anticoagulation (2015) Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 13:2119–2126CrossRefGoogle Scholar
- 16.Sr Kahn, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, Cook DJ, Balekian AA, Klein RC, LE H, Schulman S, Murad MH (2012) 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 141:E195s–E226sCrossRefGoogle Scholar
- 17.Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, de Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, Mcintyre LA, Mclean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van Der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP (2017) Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 43:304–377CrossRefGoogle Scholar
- 19.Raskob GE, Spyropoulos AC, Zrubek J, Ageno W, Albers G, Elliott CG, Halperin J, Haskell L, Hiatt WR, Maynard GA, Peters G, Spiro T, Steg PG, Suh EY, Weitz JI (2016) The mariner trial of rivaroxaban after hospital discharge for medical patients at high risk of VTE. Design, rationale, and clinical implications. Thromb Haemost 115:1240–1248CrossRefGoogle Scholar
- 20.Gibson CM, Spyropoulos AC, Cohen AT, Hull RD, Goldhaber SZ, Yusen Rd, Hernandez AF, Korjian S, Daaboul Y, Gold A, Harrington RA, Chi G (2017) The IMPROVEDD VTE risk score: incorporation of d-dimer into the IMPROVE score to improve venous thromboembolism risk stratification. Th Open 1:E56–E65CrossRefGoogle Scholar
- 24.Guyatt GH, Eikelboom JW, Gould MK, Garcia DA, Crowther M, Murad MH, Kahn SR, Falck-Ytter Y, Francis CW, Lansberg MG, Akl EA, Hirsh J (2012) Approach to outcome measurement in the prevention of thrombosis in surgical and medical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141:E185s–E194sCrossRefGoogle Scholar
- 25.European Medicines Agency (2016) Guideline on clinical investigation of medicinal products for prevention of venous thromboembolism (VTE) in non-surgical patients (Formerly CPMP/EWP/6235/04). EMA, LondonGoogle Scholar
- 26.Kearon C (2003) Natural history of venous thromboembolism. Circulation 107:I22–I30Google Scholar
- 27.Markel A (2005) Origin and natural history of deep vein thrombosis of the legs. Semin Vasc Med 5(1):65–74.Google Scholar
- 29.Hull RD, Pineo GF, Stein PD, Mah AF, Macisaac SM, Dahl OE, Butcher M, Brant RF, Ghali WA, Bergqvist D, Raskob GE (2001) Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med 135:858–869CrossRefGoogle Scholar
- 32.Kalayci A, Gibson CM, Chi G, Mk Yee, Korjian S, Datta S, Nafee T, Gurin M, Haroian N, Qamar I, Hull RD, Hernandez AF, Cohen AT, Harrington RA, Goldhaber SZ (2018) Asymptomatic deep vein thrombosis is associated with an increased risk of death: insights from the APEX trial. Thromb Haemost 118:2046–2052CrossRefGoogle Scholar
- 33.Chi G, Goldhaber SZ, Kittelson JM, Turpie AGG, Hernandez AF, Hull RD, Gold A, Curnutte JT, Cohen AT, Harrington RA, Gibson CM (2017) Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis. J Thromb Haemost 15:1913–1922CrossRefGoogle Scholar
- 35.Eriksson BI, Lassen MR, PENTasaccharide in HIp-FRActure Surgery Plus Investigators (2003) Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study. Arch Intern Med 163:1337–1342CrossRefGoogle Scholar
- 36.Chi G, Goldhaber SZ, Hull RD, Hernandez AF, Kerneis M, Al Khalfan F, Cohen AT, Harrington RA, Gibson CM (2017) Thrombus burden of deep vein thrombosis and its association with thromboprophylaxis and d-dimer measurement: insights from the APEX trial. Thromb Haemost 117:2389–2395CrossRefGoogle Scholar
- 37.Chan NC, Bhagirath V, Eikelboom JW (2015) Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vasc Health Risk Manag 11:343–351Google Scholar
- 39.Hutchaleelaha A, Ye C, Song Y, Lorenz T, Gretler D, Lambing JL (2012) Metabolism and disposition of betrixaban and its lack of interaction with major CYP enzymes. Blood 120:2266Google Scholar
- 40.Cook DJ, Griffith LE, Walter SD, Guyatt GH, Meade MO, Heyland DK, Kirby A, Tryba M, Canadian Critical Care Trials Group (2001) The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients. Crit Care 5:368–375CrossRefGoogle Scholar
- 41.Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM (2014) Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383:955–962CrossRefGoogle Scholar