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.