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Lancet Neurol. 2018 Dec;17(12):1053-1060. doi: 10.1016/S1474-4422(18)30319-3. Epub 2018 Sep 28.

Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.

Collaborators (1337)

Abdelhamid N, Abdul Rahman D, Abdul-Saheb M, Abreu P, Abroskina M, Abu Ahmad F, Accassat S, Acciaresi M, Adami A, Ahmad N, Ahmed F, Alberto Hawkes M, Alemseged F, Ali A, Altavilla R, Alwis L, Amarenco P, Amaro S, Amaya Sanchez LE, Amelia Pinto A, Ameriso SF, Amin H, Amino T, Amjad AK, Anagnostou E, Andersen G, Anderson C, Anderson DC, Andrea Falco M, Andres Mackinnon F, Andreu D, Androulakis M, Angel Gamero M, Angel Saredo G, Angeles Diaz R, Angels Font M, Anticoli S, Arauz A, Arauz Gongora AA, Araya P, Arenillas Lara JF, Arias Rivas S, Arnold M, Augustin S, Avelar W, Azevedo E, Babikian V, Bacellar A, Badalyan K, Bae HJ, Baez Martinez EM, Bagelmann H, Bailey P, Bak Z, Baker M, Balazs A, Baldaranov D, Balogun I, Balueva T, Bankuti Z, Bar M, Baranowska A, Bardutzky J, Barker Trejo S, Barlinn J, Baronnet F, Barroso C, Barteys M, Bartolottiova T, Barulin A, Bas M, Bashir S, Basile V, Bathe-Peters R, Bathula R, Batista C, Batur Caglayan H, Baumgartner P, Bazan R, Bazhenova O, Beaudry M, Beer J, Behnam Y, Beilei C, Beinlich A, Bejot Y, Belkin A, Benavente OR, Benjamin A, Berardi V, Bereczki D, Berkowitz SD, Berlingieri J, Berrios W, Berrouschot J, Bhandari M, Bhargavah M, Bicker H, Bicsak T, Bilik M, Bindila D, Birchenall J, Birnbaum L, Black T, Blacker D, Blacquiere D, Blanc-Labarre C, Blank C, Blazejewska-Hyzorek B, Bloch S, Bodiguel E, Bogdanov E, Boos L, Borcsik L, Bornstein N, Bouly S, Braga G, Bragado I, Bravi MC, Brokalaki C, Brola W, Brouns R, Bruce D, Brzoska-Mizgalska J, Buck B, Buksinska-Lisik M, Burke J, Burn M, Bustamante G, Cabrejo L, Cai K, Cajaraville S, Calejo M, Calvet D, Campillo J, Campos Costa E, Camps P, Can Alaydin H, Candeloro E, Canepa C, Cantu Brito CG, Cappellari M, Carcel C, Cardona Portela P, Cardoso F, Carek M, Carletti M, Carlos Portilla J, Caruso P, Casado-Naranjo I, Castellini P, Castro D, Castro Meira F, Cavallini A, Cayuela Caudevilla N, Cenciarelli S, Cereda C, Cerrone P, Chakrabarti A, Chaloulos-Iakovidis P, Chamorro A, Chandrasena D, Chang DI, Che C, Chembala J, Chen J, Chen Z, Chen T, Chen H, Chen X, Chen H, Chen G, Chen J, Chen J, Chen L, Chen S, Cheripelli B, Chin M, Chiquete Anaya E, Chorazy M, Christensen H, Christensen T, Christian L, Chu F, Chung CS, Clark W, Clarke R, Claverie S, Clemente Agostoni E, Clissold B, Coelho J, Cohen D, Colakoglu S, Collas D, Condurso R, Connolly SJ, Consoli D, Constantin C, Constantino Silva AB, Contardo L, Corlobe A, Correia M, Correia C, Cortijo Garcia E, Coull B, Coutts S, Coveney S, Cras P, Crols R, Crozier S, Csanyi A, Csiba L, Csontos K, Csuha R, Cui L, Cunha L, Curtze S, Czerska M, Czlonkowska A, Czurko M, Czuryszkiewicz M, Dagnino M, Dai C, Daineko A, Dalek G, Damgaard D, Danese A, Dani K, Danku V, Dario Toledo W, Dávalos A, De Havenon A, De Keyser J, De Klippel N, De La Torre J, De Pauw A, De Smedt A, De Torres R, De Vries Basson MM, Dearborn J, Deganutto R, Degeorgia M, Deguchi I, Del Giudice A, Delcourt C, Delgado-Mederos R, Della Marca G, Delpont B, Deltour S, Demets DL, Dennis M, Desai J, Devine J, Dhollander I, Di Mascio MT, Diaconu M, Diaz Otero F, Dietzel J, Diez-Tejedor E, Ding N, Ding J, Ding J, Diomedi M, Dioszeghy P, Distefano M, Domigo V, Dorodnicov E, Dossi D, Doubal F, Druzenko I, Du P, Du J, Duman T, Duodu Y, Dutta D, Dylewicz L, Eckstein J, Ehrensperger E, Ehrlich S, Einer Allende G, Elena Halac B, Elyas S, Endres M, Engelbrecht JM, Engelter S, Epinat M, Eren F, Esbjornsson M, Escribano B, Escudero I, Esisi B, Essa B, Esterbauer M, Evans N, Eveson D, Fabio S, Fang L, Fanta S, Fares M, Fatar M, Faust K, Favate A, Fazekas F, Federica Denaro M, Fedin A, Felipe Amaya P, Feng J, Ferencova K, Fernanda Gilli M, Fernandez MD, Fernandez Pirrone PN, Fernandez Vera J, Ferrari J, Ferreira A, Ferreira Junior G, Fidler M, Field D, Field T, Figueroa C, Fiksa J, Filipov A, Firstenfeld A, Fisch L, Fischer U, Fisselier M, Fiszer U, Fluri F, Fortea G, Fotherby K, Fraczek A, France E, Freitas G, Frey S, Frick M, Friedman A, Friedrich M, Frisullo G, Fryze W, Fuentes Gimeno B, Fujigasaki H, Fukuyama K, Furlan A, Furlanis G, Furnace J, Gabriel M, Gabriel Reich E, Gagliardi RJ, Galati F, Galli Giqueauk E, Gallina A, Gallinella E, Gallo J, Gangadharan S, Gao Y, Garcia Lopez R, Garcia Pastor A, Garcia Sanchez SM, Garnauf M, Garnier P, Gasecki D, Gasic K, Gasiorek K, Gasser S, Gaugg M, Gebreyohanns M, Gebura K, Geng J, Geniz Clavijo M, Georg Haeusler K, Geran R, Geremek M, Gerocs Z, Ghia D, Giannandrea D, Giatsidis F, Gien Lopez JA, Gil Nunez A, Gimenez L, Giralt E, Glabinski A, Gladstone D, Gliem M, Gluszkiewicz M, Goddeau R, Gogoleva E, Gokce M, Goldemund D, Golikov K, Gomes Neto A, Gomez Schneider M, Gomez-Choco M, Gomis M, Gongora-Rivera JF, Gonysheva Y, Gonzalez L, Gonzalez Toledo ME, Gottschal M, Gozdzik I, Grabowski S, Graf S, Green D, Greer D, Gregorio T, Greisenegger S, Greshnova I, Griebe M, Grzesik M, Guan J, Guarda S, Gueguen A, Guidoux C, Guillermo Povedano P, Guillon B, Guiraudg V, Gunathilagan G, Guryanova N, Gusev V, Gustavo Persi G, Gutiérrez R, Guyler P, Gyuker N, Hachinski V, Hajas A, Hallevi H, Hankey G, Hankey GJ, Hanouskova L, Hao L, Haraguchi K, Haralur Sreekantaiah Y, Haratz S, Hargroves D, Harkness K, Harmel P, Harrasser M, Hart RG, Harvey M, Hasan R, Hasegawa Y, Hassan A, Hattori M, Hatzitolios A, Hauk M, Hayashi T, Hayhoe H, Hedna VS, Heine M, Held V, Hellwig S, Henkner J, Henninger N, Hermans S, Hernandez J, Herrero D, Hervieu-Begue M, Herzig R, Hicken L, Hieber M, Hill M, Hirose M, Hobeanu MC, Hobson B, Hochstetter M, Hoe Heo J, Hoffmann M, Holmstedt C, Hon P, Hong KS, Honma Y, Horev A, Horgan G, Horvath L, Horvath M, Hoyer C, Huang D, Huang H, Huber B, Huhtakangas J, Hussain M, Igarashi S, Iglesias Mohedano AM, Ignacio Tembl J, Impellizzeri M, Inanc Y, Ioli P, Irina Aniculaesei A, Ishida K, Itabashi R, Iversen H, Jagolino A, Jakab K, Jander S, Janka H, Jankovych J, Jansen J, Jasek L, Javier Alet M, Javor L, Jin X, Jing P, Joachim B, Joan Macleod M, Johnson M, Jose Martin J, Joyner C, Judit Szabo K, Jun-Oconnell A, Jura R, Kaczorowska B, Kadlcikova J, Kahles T, Kakaletsis N, Kakuk I, Kalinowska K, Kaminska K, Kaneko C, Kanellos I, Kapeller P, Kapica-Topczewska K, Karasz O, Karlinski M, Karlsson JE, Kasa K, Kashaeva E, Kasner SE, Kaste M, Kasza J, Katalin Iljicsov A, Katsurayama M, Kaur S, Kawanishi M, Kaygorodtseva S, Ke K, Kei A, Keilitz J, Kellner J, Kelly P, Kelly S, Kemlink D, Kerekgyarto M, Keskinarkaus I, Khairutdinova D, Khanna A, Khaw A, Kholopov M, Khoumri C, Kirpicheva S, Kirshner H, Kitagawa K, Kittner S, Kivioja R, Klein F, Kleindorfer D, Kleinig T, Klivenyi P, Knecht S, Kobayashi Y, Kobayashi A, Koch M, Koehler L, Koivu M, Kolianov V, Koltsov I, Kondo T, Konkov I, Kopecky S, Korompoki E, Korpela J, Kosarz-Lanczek K, Koutroubi A, Kovacs K, Kovacs T, Kovacs H, Kowalczyk K, Kowalska M, Krajickova D, Kral M, Krarup Hansen C, Kraska J, Krebs S, Krejci V, Kremer C, Kreuzpointer R, Krzyzanowska M, Kucken D, Kulakowska A, Kunzmann J, Kurenkova N, Kuris A, Kurkowska-Jastrzebska I, Kurtenkova N, Kurushina O, Kusnick G, Kustova M, Kuwashiro T, Kwan Cha J, Lago A, Lagutenko M, Lajos B, Lambeck J, Lamy C, Landolfi A, Lanfranconi S, Lang W, Lara Lezama LB, Lara Rodriguez B, Largo T, Lasek-Bal A, Latte L, Lauer V, Lavados P, Le Bouc R, Leal Cantu R, Lechner H, Lecouturier K, Leder S, Lee J, Lee BC, Leger A, Leira E, Leisse I, Leker R, Lembo G, Lenskaya L, Leyden J, Li G, Li M, Li S, Li J, Liamis G, Liang H, Liang Z, Ligot N, Lin H, Lindert R, Lindgren A, Linna M, Litwin T, Liu K, Liu X, Llull L, Lohninger B, Longoni M, Loomis C, Lopes D, Lopez Fernandez M, Lopez Garza N, Lord A, Louw S, Lovasz R, Lowenkopf T, Lu Z, Lubke-Detring SC, Luder R, Lujan S, Luo B, Lupinogina L, Luschin G, Lutsep H, Lvova A, Ly J, Grosse GM, Ma H, Ma C, Machado M, Machado C, Macher S, Machetanz J, Macian-Montoro F, Mackey E, Mackey A, Maclean G, Maestre-Moreno J, Magadan A, Magyar T, Mahagney A, Majid A, Majjhoo A, Makaritsis K, Mandzia J, Mangas Guijarro M, Mangion D, Manios E, Mann S, Manning L, Manno C, Manuel Garcia J, Maqueda V, Mar Castellanos M, Mar Freijo M, Marando C, Marcela Lepera S, Marcos Couto J, Maria Bruera G, Maria Greco L, Maria Lorenzo A, Maria Obmann S, Maria Roa A, Marini C, Marinkovic I, Mario Sumay G, Mario Torres C, Marko M, Markova S, Markus H, Marsh R, Marsili E, Marta Esnaola M, Marta Moreno J, Marti-Fabregas J, Martina Angelocola S, Martínez Sánchez P, Martinez-Majander N, Martins S, Marzelik O, Mastrocola S, Matamala G, Matoltsy A, Matosevic B, Matsumoto S, Maud A, Mauri Cabdevila G, May Z, Mayasi Y, Mayr A, Mazzoli T, Mcarthur K, Mccullough L, Medina Pech CE, Medlin F, Mehdiratta M, Mehta S, Mehta D, Mehta B, Melis M, Melnikova E, Mendez B, Mendonca T, Mengual Chirifie JJ, Menon N, Mensch A, Meseguer E, Messe S, Metcalf K, Meyer N, Michas F, Micheletti N, Mikulik R, Milionis H, Miller B, Milling T, Minelli C, Minhas J, Minns M, Mircea D, Mishra S, Mismas A, Mistri A, Mitrovic N, Miyake H, Modrau B, Moey A, Molina C, Molina J, Molis A, Moller J, Molnar S, Moniche F, Monosi C, Monzani V, Moonis M, Morais R, Morales L, Morales A, Morar-Precup D, Moreton F, Moro C, Morozova E, Morton M, Morvan T, Morvan E, Motko T, Mowla A, Mozhejko E, Muddegowda G, Mudhar O, Mueller T, Muhl C, Muir KW, Mundl H, Munoz S, Murphy C, Murphy S, Murtuzova A, Musuka T, Mutzenbach J, Myint M, Mysliwy W, Naccarato M, Naeije G, Nagakane Y, Natarajan I, Navaratnam D, Nave A, Nazliel B, Nedeltchev K, Nel J, Nell H, Nemeth R, Nemeth L, Neto O, Ng K, Ngeh J, Nicolas Chialvo L, Nieminen T, Nikkanen M, Nikl J, Nikoforova M, Nishino S, Nishiyama Y, Njovane X, Nogawa S, Nombela F, Norrving B, Nosek K, Nowak B, Nowakowska-Sledz E, Ntaios G, Numminen H, Nunez F, Obadia M, Oberndorfer S, Obrezan A, Ochiai J, Oczkowski W, O'Donnell MJ, Odyniec A, Oh K, Ohira M, Okamoto Y, Okpala M, Okubo S, Olah L, Olavarria V, Oleszek J, Onat Demirci N, Ondar V, Ongun G, Ooyama K, Orosz V, Ortiz R, Osseby G, Österlund-Tauriala E, Ovesen C, Ozcekic 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Abstract

BACKGROUND:

Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial.

METHODS:

NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy.

FINDINGS:

Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22-1·36), and the risk was similar for those without known PFO (1·06; 0·84-1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51-8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69-4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24-0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity.

INTERPRETATION:

Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted.

FUNDING:

Bayer and Janssen.

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