1. N Engl J Med. 2018 Sep 20;379(12):1118-1127. doi: 10.1056/NEJMoa1805090. Epub
2018 Aug 26.

Rivaroxaban for Thromboprophylaxis after Hospitalization for Medical Illness.

Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard
GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER
Investigators.

Collaborators: Douketis J, Turpie AG, Schulman S, Kearon C, Linkins LA, Schellong
S, Bauer K, Geerts W, Roberts R, Casais P, Gallus A, Karrasch J,
Eichinger-Hasenauer S, Krivenchuk V, Hadzovic-Dzuvo A, Trbojevic S, Lopes R,
Mincheva V, Carrier M, Dennis R, Tudoric N, Spinar J, Nielsen H, Marandi T,
Shaburishvili T, Beyer-Westendorf J, Vardas P, Boda Z, Brenner B, Piovella F,
Krievins D, Petrauskiene B, Dejanova-Ilijevska V, Virgen Carrillo LR, Middeldorp 
S, Castillo Leon RP, Torbicki A, Saraiva de Sousa M, Dorobantu M, Militaru C,
Yavelov I, Vuckovic B, Reuter H, Basson M, Monreal M, Kucukoglu S, Parkhomenko A,
Alikhan R, Rosenberg D, Yusen R, Khorana A, Tapson V, Pollack C, Hazelrigg M,
Jure H, Alvarisqueta A, Cartasegna L, Hominal M, Cursack G, Alzogaray M, Maillo
M, Parody M, Caccavo A, Dran RD, Muntaner JA, Casas M, Schmidberg J, Sarjanovich 
R, Gabito A, Garrido M, Amuchastegui M, Fernandez A, Loureyro J, Giumelli C,
Heazlewood V, Colquhoun D, White H, Sabet A, Bowler S, Carroll P, Khalafallah A, 
Baker R, Hedger S, Simpson FG, Jackson D, Chong B, Siostrzonek P, Gary T, Hoppe
U, Dosta N, Prystrom A, Gorokhovsky S, Yanushko V, Skrahin A, Kulik A, Maslianski
B, Yakubtsevich R, Timkin I, Moguchaya O, Tanaskovic N, Miljkovic S, Stojkovic S,
Kovacevic-Preradovic T, Jovic D, Basagic E, Radjen M, Mutapcic M,
Rizvanovic-Vojic E, Galic K, Terzic I, Pojskic B, Stevanovic D, Cehajic M, Rech
R, Annichino-Bizzacchi J, Stelmach R, Blanco D, Castro I, Backes LM, Saraiva JF, 
Ramacciotti E, de Barros e Silva PGM, Reis G, Moreira Vieira E, Leães P,
Zimmermann S, Van Bellen B, Precoma D, Luiz Silvestrini T, Hernandes ME, Kyoleyan
M, Kalinova T, Tiholov R, Petrov I, Mihov A, Chompalova B, Velikov C, Pencheva G,
Atanasov P, Raev D, Kinova E, Peltegov V, Marchev S, Siulemezova S, Ayryanova ID,
Grigorov M, Naydenova I, Koteva N, Dimov B, Runev N, Getov D, Metev H, Donchev K,
Taseva M, Hadzhieva A, Benov H, Stoyanov M, Tisheva-Gospodinova S, Mihaylova N,
Abadzhiev S, Atzev B, Georgiev R, Mollov M, Stoikov A, Mazhdrakov G, Karastanev
K, Dube F, Roth S, Mansour S, Wu C, Dolan S, Pesant Y, Pietrangelo M, Dresser G, 
Kahn S, Kruisselbrink R, Cadena Bonfanti A, Botero R, Quintero Ossa A, Poveda CM,
Cedano J, Gómez Isaza L, Villaquiran Torres C, Gomez Mesa J, Vargas Alonso R,
Espinosa D, Rodriguez JM, Sanchez G, Accini Mendoza JL, Gómez Flórez CC, Cuervo
Millan F, Pesek K, Horvat D, Fuckar K, Ruzic A, Ostricki B, Knezevic A,
Breitenfeld T, Laganovic M, Samodol A, Sikic J, Starcevic B, Babic Z, Samarzija
M, Milas K, Votocek S, Kvapil M, Kolman P, Bindas P, Simon V, Adamek T, Svobodova
J, Gergely L, Lastuvka J, Macel I, Navratil K, Gregor P, Lacnak B, Janousek J,
Kellnerova I, Hulinsky V, Matusek Z, Prucek L, Dunaj M, Pirchala M, Vencour D,
Pavolko M, Gorican K, Fiksa J, Tuxen C, Meyer C, Suppli Ulrik C, Uuetoa T,
Otarishvili N, Khintibidze I, Emukhvari N, Kipiani Z, Gochitashvili D,
Mamatsashvili M, Megreladze I, Paposhvili K, Agladze R, Eradze Z, Chelidze K,
Lominadze S, Chukhrukidze A, Chumburidze V, Metreveli S, Danelia V, Orjonikidze
S, Kobulia B, Nikolaishvili G, Gvenetadze R, Melia A, Tsinamdzgvrishvili B,
Sekhniashvili M, Sikharulidze I, Meuser M, Licka M, Rauch-Kroehnert U, Graf K,
Brachmann J, Akin I, Toumbis M, Vassilikos V, Konstantinides S, Steiropoulos P,
Gogos C, Andrikopoulos G, Parthenakis F, Karydi P, Tsivgoulis G, Mertzanos G,
Olympios C, Karapanayiotides T, Paraskevopoulou E, Kifnidis K, Hahalis G,
Skoutelis A, Vadikolias K, Nyirati G, Nagy L, Matoltsy A, Komoly S, Lippai J,
Kiss K, Tóth K, Pozsegovits K, Király C, Bereczki D, Zolyomi S, Boda Z, Szakal I,
Pall D, Fűtő L, Forster T, Lovasz O, Papp A, Kiraly Z, Pozsonyi Z, Hajkó E,
Kristóf P, Lakatos F, Plés Z, Kirschner R, Lupkovics G, Tímár G, Pintér I,
Kristof T, Kis E, Kovacs A, Jakab G, Palinkas A, Müller G, Túri T, Horváth C,
Kondakor I, Csanyi A, Frankfurter Z, Gurzo M, Gafter-Gvili A, Kuchuk M, Azzam Z, 
Elis A, Halabi M, Hussein O, Blum A, Tsoran-Rosenthal I, Lishner M,
Hochberg-Klein S, Caraco Y, Atar S, Elias N, Gavish D, Butnaru A, Cosmi F,
Garbelotto R, Giorgi Pierfranceschi M, Simioni L, Gronda E, Pesci A, D'Angelo A, 
Fedele F, Ghirarduzzi A, Piovaccari G, Lembo G, Ria L, Monaco GL, Brunelli C,
Tosetto A, Capucci A, Zanatta N, Pistolesi M, Mazzi V, Testa S, Scherillo M, Di
Biase M, Antonicelli R, Lodigiani C, Nassiacos D, Viksne I, Lapkovska Z, Rancane 
G, Sime I, Pontaga N, Eglite R, Puzule S, Smolova R, Butkiene Z, Bagdonas A,
Raugaliene R, Norkiene S, Norviliene R, Basijokiene V, Stonkus S, Griskeviciene
V, Miskiniene A, Norvaisiene R, Skripkauskiene I, Jovkovska-Kaeva B,
Kochovska-Kamchevska N, Antovski A, Nechevska L, Celeska V, Ilievska-Poposka B,
Kostojchinoska M, Donchovska S, Kedev S, Kuzmanovski I, Bushletikj O, Stojchev S,
Bakrachevski N, Kuzmanovska B, Angusheva T, Llamas Esperón G, Valdez López H,
Medina Pech C, Cortés Hernandez M, Virgen Carrillo L, Gans S, Smulders S, Swart
H, Boersma W, Goosens M, Hovens M, Semplonius G, Söhne M, Lema Osores J, Salas
Pérez MD, Rodriguez A, Rios Oliva C, Cotrina R, Berrospi Argandoña P, Toce Yañez 
L, Chavez Ayala C, Mirek-Bryniarska E, Goch A, Skucha W, Skorski M, Miekus P,
Szyszka A, Piotrowski G, Gniot J, Czerski T, Debich P, Zaluska R, Bebenek W,
Wozakowska-Kaplon B, Sciborski R, Ilkowski J, Wojnowski P, Uscinska E, Gaciong Z,
Bonek R, Sobkowicz B, Berkowski P, Bejgier K, Polonski L, Kosior D, Lata S,
Kolodziej P, Gessek J, Kachel T, Talalaj M, Musial J, Lewczuk J, Krysiak W,
Kucharski L, Wysokinski A, Minc P, Martinez J, Gregório T, Almeida F, Monteiro P,
Stanciulescu G, Mercea CD, Iosipescu LC, Ciobotaru V, Crisu D, Burca M, Tudoran
M, Savu A, Negrean V, Cojocaru C, Minescu B, Popa V, Blajan D, Nastase-Melicovici
D, Fruntelata A, Barbulescu S, Lukinyh L, Akhunova S, Vishneva E, Semenova I,
Nikolaev K, Shaydyuk O, Nilk R, Shalnev V, Apartsin K, Goloshchekin BM, Shpagina 
L, Khlevchuk T, Arkhipov M, Malygin A, Shvarts Y, Khaisheva L, Popov D, Kobalava 
Z, Lipchenko A, Shapovalova Y, Zrazhevsky K, Greshnova I, Maslova N, Karabenenko 
A, Shogenov Z, Budankova E, Barbarash O, Uspenskiy Y, Kosmacheva E, Berns S,
Kostenko V, Zateyshchikov D, Vishnevsky A, Boldueva S, Podzolkov V, Sergeeva E,
Grinshtein Y, Khrustalev O, Bugrova O, Repin A, Andreev D, Petrovic P, Boskovic
Matic T, Apostolovic S, Lazic Z, Stankovic D, Stankovic A, Mitov V, Sofronic D,
Kopitovic I, Zdravkovic V, Joksimovic Z, Lazovic N, Petrovic-Stanojevic N, Ilic
A, Vujadinovic O, Pencic-Popovic B, Andjelkovic N, Sekularac N, Hinic S, Radjen
G, Zivkovic A, Putnikovic B, Ivanov I, Babic R, Van Zyl L, Hobson B, Engelbrecht 
J, Mitha I, Siebert H, Jacobson B, Breedt J, Prozesky H, Ntsekhe M, Bayat J,
Ellis G, Tarr G, Adler D, Van Dyk C, Ismail SM, Spargo CE, Abdool-Gaffar M,
Saaiman J, Venter K, Lorente Aroca ML, Fernández Portales F, Pedrajas Navas J,
Rodríguez Botaro A, Santa Cruz Siminiani A, López Reyes R, Bisbe i Company J,
Piedecausa Selfa M, Velasco Garrido J, Sobrino-Martinez J, Muñoz Delgado G, Sala 
Llinas E, Blanco Coronado J, Almenar Bonet L, Vida Gutiérrez M, Sánchez Lora F,
Sánchez Martínez R, Calderón EJ, Villalta Blanch J, De la Hera Galarza JM,
Bustamante Ruiz A, García-Fuster MJ, Ripoll Vera T, Álvarez-Sala Walter L, Todolí
Parra JA, Díaz Fernández J, Bosa Ojeda F, Pellicer-Ciscar C, Jara Palomares L,
Quiles Granado J, Trigo Bautista A, Ruiz Bustillo S, Ordi Ros J, Tolosa-Vilella
C, Marín Ortuño F, García Sánchez F, Barba Martín R, Segovia Cubero J,
Cuervas-Mons Martínez V, Galán Montejano M, López Meseguer M, Sener Comert S,
Koksal N, Tertemiz K, Ernam D, Dursun AB, Yildiz O, Rudenko L, Abrahamovych O,
Goloborodko A, Holovchenko N, Kulyk A, Yagensky A, Batushkin V, Zolotaikina V,
Kozyolkin O, Faynyk A, Maslovskyy V, Petrovskyy R, Koshlia V, Chopey I, Burmak I,
Malynovsky Y, Voronkov L, Karpenko O, Dziublyk O, Godlevska O, Borovyk V,
Bezrodna L, Serik S, Ovsyannikova N, Vynnychenko L, Kopytsya M, Rudkovskiy V,
Grishyna O, Vyshnyvetskyy I, Prystupa L, Tseluyko V, Perepeliuk M, Koval O,
Sychov O, Church A, Goudie A, Elliott M, Ferguson C, Welker J, Kao CK, Bhagwat R,
Serota H, Bozorgchami H, Nambiar R, Spilseth S, Bhagwath G, Syed F, Morrow L,
Updegrove J, Bercz P, Kambo V, Henderson D, Wright P, Dang N, Nadar V, Jaffrani
N, El-Shahawy M, Grossman CH, Pearle J, Weinstein D, Galanis TP, Gazmuri R,
Kastelic R, Martinez R, Laman D Jr, Macchiavelli A, Kmetzo J, Thurm C, Kayembe T,
Chandrashekhar Y, Bassetti D, Jaoude P, Williams H, Dewhurst R, Naqvi S, Burr J, 
Rodriguez-Cintron W, Jeanfreau R, Kosinski E, Ndukwu IM, Sotolongo C, Daboul N,
Wilmer C, Simon P, Tak T, Rees C, Gupta N, Lerner R, Graffagnino C, Reed RM,
Alford CM, Mody F, Wellmon B, Hamroff G, Rajan R, Kaatz S.

Comment in
    N Engl J Med. 2018 Dec 06;379(23):2279.
    MMW Fortschr Med. 2019 Apr;161(7):34.

BACKGROUND: Patients who are hospitalized for medical illness remain at risk for 
venous thromboembolism after discharge, but the role of extended
thromboprophylaxis in the treatment of such patients is a subject of controversy.
METHODS: In this randomized, double-blind trial, medically ill patients who were 
at increased risk for venous thromboembolism on the basis of a modified
International Medical Prevention Registry on Venous Thromboembolism (IMPROVE)
score of 4 or higher (scores range from 0 to 10, with higher scores indicating a 
higher risk of venous thromboembolism) or a score of 2 or 3 plus a plasma d-dimer
level of more than twice the upper limit of the normal range (defined according
to local laboratory criteria) were assigned at hospital discharge to either
once-daily rivaroxaban at a dose of 10 mg (with the dose adjusted for renal
insufficiency) or placebo for 45 days. The primary efficacy outcome was a
composite of symptomatic venous thromboembolism or death due to venous
thromboembolism. The principal safety outcome was major bleeding.
RESULTS: Of the 12,024 patients who underwent randomization, 12,019 were included
in the intention-to-treat analysis. The primary efficacy outcome occurred in 50
of 6007 patients (0.83%) who were given rivaroxaban and in 66 of 6012 patients
(1.10%) who were given placebo (hazard ratio, 0.76; 95% confidence interval [CI],
0.52 to 1.09; P=0.14). The prespecified secondary outcome of symptomatic nonfatal
venous thromboembolism occurred in 0.18% of patients in the rivaroxaban group and
0.42% of patients in the placebo group (hazard ratio, 0.44; 95% CI, 0.22 to
0.89). Major bleeding occurred in 17 of 5982 patients (0.28%) in the rivaroxaban 
group and in 9 of 5980 patients (0.15%) in the placebo group (hazard ratio, 1.88;
95% CI, 0.84 to 4.23).
CONCLUSIONS: Rivaroxaban, given to medical patients for 45 days after hospital
discharge, was not associated with a significantly lower risk of symptomatic
venous thromboembolism and death due to venous thromboembolism than placebo. The 
incidence of major bleeding was low. (Funded by Janssen Research and Development;
MARINER ClinicalTrials.gov number, NCT02111564 .).

DOI: 10.1056/NEJMoa1805090 
PMID: 30145946  [Indexed for MEDLINE]