Extended thromboprophylaxis with betrixaban in acutely ill medical patients

Cohen A. T.; Harrington R. A.; Goldhaber S. Z.; Hull R. D.; Wiens B. L.; Gold A.; Hernandez A. F.; Gibson C. M.; Bello F.; Ferrari A. E.; Jure H.; Macin S.; Oliva M.; Parody M.; Poy C.; Baker R.; Colquhoun D.; Coughlin P.; Finfer S.; Rubinfeld A.; Huber K.; Konig J.; Mathies R.; Pilger E.; Schoenerr H.; Adzerikho I.; Koryk V.; Mikhailova E.; Mitkovskaya N.; Pimanov S.; Polonetsy L.; Soroka N.; Blockmans D.; Delforge M.; Dive A.; Lienart F.; Motte S.; Bizzacchi J.; Fiss E.; Freire A.; Manenti E.; Ramacciotti E.; Raymuno S.; Rocha A.; Saraiva J. F.; Dimov B.; Grigorov M.; Kalpachki R.; Kamenova Z.; Kostadinova M.; Milanova M.; Mincheva V.; Pencheva G.; Raev D.; Runev N.; Stoeva N.; Stoyanov M.; Syulemzova S.; Todorov G.; Tokmakova M.; Dhar A.; Douketis J.; Kahn S.; Le Gal G.; Pearce M.; Provencher S.; Verreault S.; Alarcon M.; Canon C.; Lazcano M.; Cardenas S.; Butkovic-Soldo S.; Car S.; Ciglenecki N.; Francetic I.; Jakopovic M.; Kalinic-Grgorinic H.; Knezevic A.; Malojcic B.; Marusic S.; Vagic J.; Skerk V.; Cermak O.; Chlumsky J.; Chochola J.; Cizek V.; Dunaj M.; Dusek J.; Francek L.; Havelka J.; Herold M.; Holaj R.; Horny I.; Hubac J.; Jajtner P.; Kolman P.; Lang P.; Mayer O.; Mikulova J.; Podpera I.; Reiterer P.; Spacek R.; Vejvoda J.; Vyhnanek M.; Christensen H.; Lassen M.; Storgaard M.; Tuxen C.; Urhammer S.; Lember M.; Marandi T.; Uuetoa T.; Airaksinen J.; Honkaniemi J.; Kaaja R.; Lassila R.; Saarinen J.; Tatlisumak T.; Vikman S.; Agraou B.; Aquilanti S.; Belhassane A.; Brisot D.; De Geeter G.; Debourdeau P.; Decoulx E.; El Kouri D.; Falvo N.; Grange C.; Lacroix P.; Messas E.; Mismetti P.; Montaclair K.; Mottier D.; Paleiron N.; Payot L.; Pernod G.; Pottier P.; Proust A.; Quere I.; Roy P. M.; Schmidt J.; Simoneau G.; Datikashvili-David I.; Khabeishvili G.; Khintibidze I.; Kobulia B.; Megreladze I.; Pagava Z.; Paposhvili K.; Shaburishvili T.; Amann B.; Berrouschot J.; Beyer-Westendorf J.; Blessing E.; Bott M.; Dengler T.; Dziewas R.; Genth-Zotz S.; Hamann F.; Horacek T.; Klimpe S.; Kroning R.; Lapp H.; Lawall H.; Licka M.; Rizos T.; Schellong S.; Tiefenbacher C.; Weimar C.; Zeymer U.; Alkonyi B.; Falukozy J.; Futo L.; Katona A.; Kirschner R.; Kristof P.; Lakatos F.; Laszlo Z.; Lupkovics G.; Merkely B.; Andras C.; Nemeth L.; Papp A.; Soltesz P.; Sudar Z.; Szabo G.; Szegedi N.; Timar G.; Valco J.; Vertes A.; Efrati S.; Elias M.; Gafter A.; Hayek T.; Hussein O.; Lishner M.; Lugassy G.; Zeltser D.; Ageno W.; Cerveri I.; D'Angelo A.; De Pellegrin A.; Imberti D.; Landolfi R.; Lembo G.; Lodigiani C.; Moia M.; Molteni M.; Mumoli N.; Novo S.; Orlandini F.; Parisi R.; Pizzini A.; Pomero F.; Salvi A.; Schenone A.; Visona A.; Krievins D.; Martinova V.; Pontaga N.; Rozitis V.; Stukena I.; Alekniene B.; Bagdonas A.; Basijokiene V.; Butkiene Z.; Griskeviciene V.; Naudziunas A.; Norvaisiene R.; Norviliene R.; Petrauskiene R.; Poskiene R.; Susinskiene D.; Valavicius A.; Leon R.; Pereyra R.; Karlo L.; Horna M.; Osores J.; Salas M.; Yanez L.; Fryze W.; Gaciong Z.; Gniot J.; Gorecka D.; Gruenpeter P.; Grzelakowski P.; Jastrzebski D.; Kucharski L.; Mirek-Bryniarska E.; Pulkowski G.; Sobkowicz B.; Sulik P.; Tomkowski W.; Walasek L.; Waldemar K.; Wrzesinski K.; Balogh Z. E.; Bojinca M.; Marin I.; Mot S.; Musetescu R.; Podoleanu C.; Popescu M.; Stamate S.; Stanciulescu G.; Vida-Simiti L.; Abashev A.; Andreev D.; Apartsin K.; Arkhipov M.; Averkov O.; Barbarash O.; Belskaya G.; Bogdanov E.; Boldueva S.; Chefranova Z.; Dovgalevskiy Y.; Ershova O.; Goloshchekin B.; Khachatryan N.; Klein G.; Kobalava Z.; Kosmacheva E.; Kostenko V.; Malygin A.; Martynenko T.; Martynenko V.; Maslova N.; Mordovin V.; Nikolaev K.; Nilk R.; Panchenko E.; Popov D.; Privalova E.; Reshetko O.; Sergeeva E.; Shapovalova Y.; Shpagina L.; Shvarts Y.; Simanenkov V.; Solovyov O.; Vishneva E.; Vishnevskiy A.; Apostolovic S.; Celic V.; Ilic S.; Kovacevic-Kuzmanovic A.; Miloradovic V.; Tan R. S.; Bodikova S.; Cervenakova A.; Dvorak M.; Gaspar L.; Herman O.; Hrubon A.; Kokles M.; Krastev G.; Payer J.; Prokop D.; Spisakova M.; Adler D.; Basson M.; Breedt J.; Engelbrecht J.; Jacobson B.; Mitha I.; Van Dyk C.; Sala L. A.; Lopez C.; Bisbe J.; Guardiola A.; Cepeda J. M.; Cereto F.; Santos E.; Ferrer R.; Cerezo J.; Gonzales-Porras J. R.; Grandes J.; Jimenez D.; Mellibovsky L.; Richart C.; Riera A.; Trujillo J.; Nunez J. A.; Villalta J.; Akgul O.; Guneri S.; Kilichesmez K.; Kirma C.; Kutluk H.; Nazliel B.; Okumus G.; Ongen G.; Tigen K.; Topcuoglu M.; Tuncay E.; Abrahamovych O.; Batushkin V.; Brozhyk J.; Burmak I.; Godlevska O.; Goloborodko A.; Goloborodko B.; Goncharova Y.; Gryb V.; Karpenko O.; Kopytsya M.; Koshlia V.; Krakhmalova O.; Kyrychenko I.; Legkonogov O.; Malynovsky Y.; Maslovaskyi V.; Nikonov V.; Parkhomenko O.; Perepeliuk M.; Reshotko D.; Rudenko L.; Ryabichenko T.; Svyridova I.; Svyshchenko Y.; Tseluyko V.; Ursol G.; Vakaliuk I.; Vishnivestsky I.; Voronkov L.; Yagensky A.; Body R.; Davis M.; MacCallum P.; McCollum C.; Natarajan I.; Almasri E.; Amin M.; Anderson C.; Baker S.; Barney J.; Bastani A.; Bercz P.; Bidair M.; Carman T.; Chang H.; Clark C.; Concha M.; Cornell J.; Dhingra R.; Doshi A.; Farley B.; Fermann G.; Fraiz J.; Fulmer J.; Gaggin H.; Goytia-Leos D.; Hahn B.; Haidar A.; Hamad A.; Hazelrigg M.; Ioachimescu O.; Kabler H.; Kao C. K.; Kazimir M.; Koura F.; Kung M.; Lerner R.; Lopez J.; Macchiavelli A.; Mahal S.; Margolis B.; McLaren G.; Milling T.; Mittal M.; Nadar V.; Ohaju V.; Ortel T.; Overcash J.; Parthiban K.; Pearl R.; Pineda L.; Pratt R.; Pullman J.; Quintana O.; Rajan R.; Rastogi P.; Rees C.; Rodriguez W.; Saba F.; Shammas N.; Sharma S.; Sokol S.; Stoltz S.; Tuck M.; Updegrove J.; Warner A.; Welch M.; Welker J.; Whitman B.; Wichman T.; Yousef K.; Yusen R.; Zakai N.

doi:10.1056/NEJMoa1601747

BACKGROUND: Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. METHODS: Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated D-dimer level (cohort 1), patients with an elevated D-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. RESULTS: A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P = 0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P = 0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P = 0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P = 0.55). CONCLUSIONS: Among acutely ill medical patients with an elevated D-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts.