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N Engl J Med. 2016 Aug 11;375(6):534-44. doi: 10.1056/NEJMoa1601747. Epub 2016 May 27.

Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients.

Collaborators (454)

Bello F, Ferrari AE, Jure H, Macin S, Oliva M, Parody M, Poy C, Baker R, Colquhoun D, Coughlin P, Finfer S, Rubinfeld A, Huber K, König 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 JF, 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, Cañon 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 PM, 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, Kröning R, Lapp H, Lawall H, Licka M, Rizos T, Schellong S, Tiefenbacher C, Weimar C, Zeymer U, Alkonyi B, Faluközy J, Futo L, Katona A, Kirschner R, Kristóf P, Lakatos F, Laszlo Z, Lupkovics G, Merkely B, András C, Németh L, Papp A, Soltesz P, Sudár Z, Szabo G, Szegedi N, Tímár G, Valcó 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, Visonà 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, Yañez 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 ZE, 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 RS, 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 LA, López C, Bisbe J, Guardiola A, Cepeda JM, Cereto F, Santos E, Ferrer R, Cerezo J, Gonzales-Porras JR, Grandes J, Jiménez D, Mellibovsky L, Richart C, Riera A, Trujillo J, Nunez JA, Villalta J, Akgul O, Guneri S, Kilichesmez K, Kırma 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 CK, Kazimir M, Koura F, Kung M, Lerner R, Lopez J, Macchiavelli A, Mahal S, Margolis B, McLaren G, Milling T Jr, 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.

Author information

1
From Guy's and St. Thomas' Hospitals, London (A.T.C.); the Department of Medicine, Stanford University, Stanford (R.A.H.), and Portola Pharmaceuticals, South San Francisco (B.L.W., A.G.) - both in California; the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School (S.Z.G.), and Beth Israel Deaconess Medical Center (C.M.G.) - both in Boston; the Faculty of Medicine, University of Calgary, Calgary, AB, Canada (R.D.H.); and the Division of Cardiology, Duke University and Duke Clinical Research Institute, Durham, NC (A.F.H.).

Abstract

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. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218.).

PMID:
27232649
DOI:
10.1056/NEJMoa1601747
[Indexed for MEDLINE]
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