1. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial
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Sonia S Anand, Jackie Bosch, John W Eikelboom, Stuart J Connolly, Rafael Diaz, Peter Widimsky, Victor Aboyans, Marco Alings, Ajay K Kakkar, Katalin Keltai, Aldo P Maggioni, Basil S Lewis, Stefan Störk, Jun Zhu, Patricio Lopez-Jaramillo, Martin O'Donnell, Patrick J Commerford, Dragos Vinereanu, Nana Pogosova, Lars Ryden, Keith A A Fox, Deepak L Bhatt, Frank Misselwitz, John D Varigos, Thomas Vanassche, Alvaro A Avezum, Edmond Chen, Kelley Branch, Darryl P Leong, Shrikant I Bangdiwala, Robert G Hart, Salim Yusuf, JORGELINA SALA, LUIS CARTASEGNA, MARISA VICO, MIGUEL ANGEL HOMINAL, EDUARDO HASBANI, ALBERTO CACCAVO, CESAR ZAIDMAN, DANIEL VOGEL, ADRIAN HRABAR, PABLO OMAR SCHYGIEL, CARLOS CUNEO, HUGO LUQUEZ, IGNACIO J. MACKINNON, RODOLFO ANDRES AHUAD GUERRERO, JUAN PABLO COSTABEL, INES PALMIRA BARTOLACCI, OSCAR MONTANA, MARIA BARBIERI, OSCAR GOMEZ VILAMAJO, RUBEN OMAR GARCIA DURAN, LILIA BEATRIZ SCHIAVI, MARCELO GARRIDO, ADRIAN INGARAMO, ANSELMO PAULINO BORDONAVA, MARIA JOSE PELAGAGGE, LEONARDO NOVARETTO, JUAN PABLO ALBISU DI GENNERO, LUZ MARIA IBANEZ SAGGIA, MOIRA ALVAREZ, NESTOR ALEJANDRO VITA, STELLA MARIS MACIN, RICARDO DARIO DRAN, MARCELO CARDONA, LUIS GUZMAN, RODOLFO JUAN SARJANOVICH, JESUS CUADRADO, SEBASTIAN NANI, MARCOS RAUL LITVAK BRUNO, CAROLINA CHACON, LAURA ELENA MAFFEI, DIEGO GRINFELD, NATALIA VENSENTINI, CLAUDIO RODOLFO MAJUL, HECTOR LUCAS LUCIARDI, PATRICIA DEL CARMEN GONZALEZ COLASO, FREDY ANTONI FERRE PACORA, PAUL VAN DEN HEUVEL, PETER VERHAMME, BAVO ECTOR, PHILIPPE DEBONNAIRE, PHILIPPE VAN DE BORNE, JEAN LEROY, HERMAN SCHROE, PASCAL VRANCKX, IVAN ELEGEERT, ETIENNE HOFFER, KARL DUJARDIN, CLARISSE INDIO DO BRASIL, DALTON PRECOMA, JOSE ANTONIO ABRANTES, EULER MANENTI, GILMAR REIS, JOSE SARAIVA, LILIA MAIA, MAURO HERNANDES, PAULO ROSSI, FABIO ROSSI DOS SANTOS, SERGIO LUIZ ZIMMERMANN, RAFAEL RECH, EDUARDO ABIB JR, PAULO LEAES, ROBERTO BOTELHO, OSCAR DUTRA, WEIMAR SOUZA, MARIA BRAILE, NILO IZUKAWA, JOSE CARLOS NICOLAU, LUIZ FERNANDO TANAJURA, CARLOS VICENTE SERRANO JUNIOR, CESAR MINELLI, LUIZ ANTONIO NASI, LIVIA OLIVEIRA, MARCELO JOSE DE CARVALHO CANTARELLI, RICHARD TYTUS, SHEKHAR PANDEY, EVA LONN, JAMES CHA, SAUL VIZEL, MOHAN BABAPULLE, ANDRE LAMY, KEVIN SAUNDERS, JOSEPH BERLINGIERI, BOB KIAII, RAKESH BHARGAVA, PRAVINSAGAR MEHTA, LAURIE HILL, DAVID FELL, ANDY LAM, FAISAL AL-QOOFI, CRAIG BROWN, ROBERT PETRELLA, JOSEPH A RICCI, ANTHONY GLANZ, NICOLAS NOISEUX, KEVIN BAINEY, FATIMA MERALI, MICHAEL HEFFERNAN, ANTHONY DELLA SIEGA, GILLES R DAGENAIS, FRANCOIS DAGENAIS, STEEVE BRULOTTE, MICHEL NGUYEN, MICHAEL HARTLEIB, RANDOLPH GUZMAN, RONALD BOURGEOIS, DENNIS RUPKA, YAARIV KHAYKIN, GILBERT GOSSELIN, THAO HUYNH, CLAUDE PILON, JEAN CAMPEAU, FRANCIS PICHETTE, ARIEL DIAZ, JAMES JOHNSTON, PRAVIN SHUKLE, GREGORY HIRSCH, PAUL RHEAULT, WLODZIMIERZ CZARNECKI, ANNIE ROY, SHAH NAWAZ, STEPHEN FREMES, DINKAR SHUKLA, GABRIEL JANO, JORGE LEONARDO COBOS, RAMON CORBALAN, MARCELO MEDINA, LEONARDO NAHUELPAN, CARLOS RAFFO, LUIS PEREZ, SERGIO POTTHOFF, BENJAMIN STOCKINS, PABLO SEPULVEDA, CHRISTIAN PINCETTI, MARGARITA VEJAR, HONGYAN TIAN, XUESI WU, YUANNAN KE, KAIYING JIA, PENGFEI YIN, ZHAOHUI WANG, LITIAN YU, SHULIN WU, ZONGQUI WU, SHAO WEN LIU, XIAO JUAN BAI, YANG ZHENG, PING YANG, YUN MEI YANG, JIWEI ZHANG, JUNBO GE, XIAO PING CHEN, JUNXIA LI, TAO HONG HU, RUIYAN ZHANG, ZHE ZHENG, XIN CHEN, LIANG TAO, JIANPING LI, WEIJIAN HUANG, GUOSHENG FU, CHUNJIAN LI, YUGANG DONG, CHUNSHENG WANG, XINMIN ZHOU, YE KONG, ARISTIDES SOTOMAYOR, JOSE LUIS ACCINI MENDOZA, HENRY CASTILLO, MIGUEL URINA, GUSTAVO AROCA, MARITZA PEREZ, DORA INES MOLINA DE SALAZAR, GREGORIO SANCHEZ VALLEJO, MANZUR J FERNANDO, HENRY GARCIA, LUIS HERNANDO GARCIA, EDGAR ARCOS, JUAN GOMEZ, FRANCISCO CUERVO MILLAN, FREDY ALBERTO TRUJILLO DADA, BORIS VESGA, GUSTAVO ADOLFO MORENO SILGADO, EVA ZIDKOVA, JEAN-CLAUDE LUBANDA, MARKETA KALETOVA, RADIM KRYZA, GABRIEL MARCINEK, MAREK RICHTER, JINDRICH SPINAR, JIRI MATUSKA, MARTIN TESAK, ZUZANA MOTOVSKA, MARIAN BRANNY, JIRI MALY, MARTIN MALY, MARTIN WIENDL, LENKA FOLTYNOVA CAISOVA, JOSEF SLABY, PETR VOJTISEK, JAN PIRK, LENKA SPINAROVA, MIROSLAVA BENESOVA, JULIA CANADYOVA, MIROSLAV HOMZA, JINDRICH FLORIAN, ROSTISLAV POLASEK, ZDENEK COUFAL, VLADIMIRA SKALNIKOVA, RADIM BRAT, MIROSLAV BRTKO, PETR JANSKY, JAROSLAV LINDNER, PAVEL MARCIAN, ZBYNEK STRAKA, MARTIN TRETINA, YAN CARLOS DUARTE, FREDDY POW CHON LONG, MAYRA SANCHEZ, JOSE LOPEZ, CARMITA PERUGACHI, RICARDO MARMOL, FREDDY TRUJILLO, PABLO TERAN, JAAKKO TUOMILEHTO, HENRI TUOMILEHTO, MARJA-LEENA TUOMINEN, ILKKA KANTOLA, GABRIEL STEG, VICTOR ABOYANS, FLORENCE LECLERCQ, EMILE FERRARI, FRANCK BOCCARA, EMMANUEL MESSAS, PATRICK MISMETTI, MARIE ANTOINETTE SEVESTRE, GUILLAUME CAYLA, PASCAL MOTREFF, STEFAN STOERK, HANS-DIRK DUENGEN, CHRISTOPH STELLBRINK, OSMAN GUEROCAK, CHRISTOPH KADEL, RUEDIGER BRAUN-DULLAEUS, MICHAEL JESERICH, CHRISTIAN OPITZ, HANS-FRIEDRICH VOEHRINGER, KARL-FRIEDRICH APPEL, BERNHARD WINKELMANN, THOMAS DORSEL, SIGRID NIKOL, HARALD DARIUS, JURGEN RANFT, SEBASTIAN SCHELLONG, WOLFGANG JUNGMAIR, PIROZE DAVIERWALA, MARC VORPAHL, LASZLO BAJNOK, ZOLTAN LASZLO, EBRAHIM NOORI, GABOR VERESS, ANDRAS VERTES, ANDRAS ZSARY, ERNO KIS, LASZLO KORANYI, JUDIT BAKAI, ZOLTAN BODA, FERENC POOR, ZOLTAN JARAI, VENDEL KEMENY, JOHN BARTON, BRENDAN MCADAM, ANDREW MURPHY, PETER CREAN, NIALL MAHON, RONAN CURTIN, BRIAIN MACNEILL, SEAN DINNEEN, MAJDI HALABI, REUVEN ZIMLICHMAN, DAVID ZELTSER, YOAV TURGEMAN, ELIEZER KLAINMAN, BASIL LEWIS, AMOS KATZ, SHAUL ATAR, EUGENIA NIKOLSKY, STEFANO BOSI, MONICA NALDI, POMPILIO FAGGIANO, DEBORA ROBBA, LUCIO MOS, GIANFRANCO SINAGRA, FRANCO COSMI, LUIGI OLTRONA VISCONTI, DE MATTEIS CARMINE, GIUSEPPE DI PASQUALE, MATTEO DI BIASE, SARA MANDORLA, MARINO BERNARDINANGELI, GIOVANNI CARLO PICCINNI, MICHELE MASSIMO GULIZIA, MARCELLO GALVANI, FLAVIO VENTURI, GIORGIO MOROCUTTI, MARIA GRAZIA BALDIN, CARLO OLIVIERI, GIAN PIERO PERNA, VINCENZO CIRRINCIONE, TAKAYASU KANNO, HIROYUKI DAIDA, YUKIO OZAKI, NAOMASA MIYAMOTO, SHINICHI HIGASHIUE, HIROSHI DOMAE, SHINOBU HOSOKAWA, HIROO KOBAYASHI, TAKEHIKO KURAMOCHI, KENSHI FUJII, KAZUAKI MIZUTOMI, KEIJIRO SAKU, KAZUO KIMURA, YOSHIHARU HIGUCHI, MITSUNORI ABE, HARUHITO OKUDA, TOSHIYUKI NODA, TERUAKI MITA, ATSUSHI HIRAYAMA, HARUHIKO ONAKA, MORIAKI INOKO, MITSUGU HIROKAMI, MUNENORI OKUBO, YUTAKA AKATSUKA, MIZUHO IMAMAKI, HARUO KAMIYA, MAMORU MANITA, TOSHIHARU HIMI, HIDEKI UENO, YUJI HISAMATSU, JUNYA AKO, YASUHIRO NISHINO, HIDEO KAWAKAMI, YUTAKA YAMADA, YUKIHIRO KORETSUNE, TAKAHISA YAMADA, TETSURO YOSHIDA, HIDEKI SHIMOMURA, NORIYUKI KINOSHITA, AKIHIKO TAKAHASHI, KHALID YUSOFF, WAN AZMAN WAN AHMAD, MUHAMMAD RADZI ABU HASSAN, SAZZLI KASIM, AIZAI AZAN ABDUL RAHIM, DIMON MOHD ZAMRIN, MASAHARU MACHIDA, YORIHIKO HIGASHINO, NORIAKI UTSU, AKIHIKO NAKANO, SHIGERU NAKAMURA, TETSUO HASHIMOTO, KENJI ANDO, TOMOHIRO SAKAMOTO, F.J. PRINS, DIRK LOK, JOHANNES GERT-JAN MILHOUS, ERIC VIERGEVER, FRANK WILLEMS, HENK SWART, MARCO ALINGS, ROB BREEDVELD, KEES-JAN DE VRIES, ROGER VAN DER BORGH, FANNY OEI, STIENEKE ZOET-NUGTEREN, HANS KRAGTEN, JEAN PAUL HERRMAN, PAUL VAN BERGEN, MARCEL GOSSELINK, EDUARD HOEKSTRA, ERWIN ZEGERS, EELKO RONNER, FRANK DEN HARTOG, GERARD BARTELS, PETER NIEROP, COEN VAN DER ZWAAN, JACOB VAN ECK, EDWIN VAN GORSELEN, BJORN GROENEMEIJER, PIETER HOOGSLAG, MARC ROBERT DE GROOT, ALDRIN LOYOLA, DENNIS JOSE SULIT, NANNETTE REY, MARIA TERESA ABOLA, DANTE MORALES, ELLEN PALOMARES, MARC EVANS ABAT, GREGORIO ROGELIO, PHILIP CHUA, JOSE CARLO DEL PILAR, JOHN DENNIS ALCARAZ, GERALDINE EBO, LOUIE TIRADOR, JOSEFINA CRUZ, JOHN ANONUEVO, ARTHUR PITARGUE, MARIANNA JANION, TOMASZ GUZIK, GRZEGORZ GAJOS, MACIEJ ZABOWKA, ANDRZEJ RYNKIEWICZ, MARLENA BRONCEL, ANDRZEJ SZUBA, DANUTA CZARNECKA, PAWEL MAGA, IRINA STRAZHESKO, YURY VASYUK, ZHANNA SIZOVA, YURY POZDNYAKOV, OLGA BARBARASH, MIKHAIL VOEVODA, TATIANA POPONINA, ALEXEY REPIN, IRINA OSIPOVA, ANNA EFREMUSHKINA, NINA NOVIKOVA, OLEG AVERKOV, DMITRY ZATEYSHCHIKOV, ARKADIY VERTKIN, AZA AUSHEVA, PATRICK COMMERFORD, SAADIYA SEEDAT, LOUIS VAN ZYL, JAN ENGELBRECHT, ELLEN MAKONLI MAKOTOKO, CATHARINA ELIZABETH PRETORIUS, ZAID MOHAMED, ADRIAN HORAK, THOMAS MABIN, ERIC KLUG, JANG-HO BAE, CHEOLHO KIM, CHONG-JIN KIM, DONG-SOO KIM, YONG JIN KIM, SEUNGJAE JOO, JONG-WON HA, CHUL SOO PARK, JANG YOUNG KIM, YOUNG-KWON KIM, CHRISTINA JARNERT, THOMAS MOOE, MIKAEL DELLBORG, INGEMAR TORSTENSSON, PER ALBERTSSON, LARS JOHANSSON, FARIS AL-KHALILI, HENRIK ALMROTH, TOMMY ANDERSSON, EMIL PANTEV, BENGT-OLOV TENGMARK, BO LIU, GUNDARS RASMANIS, CARL-MAGNUS WAHLGREN, TIZIANO MOCCETTI, ALEXANDER PARKHOMENKO, VIRA TSELUYKO, VOLODYMYR VOLKOV, OLENA KOVAL, LYUDMYLA KONONENKO, OLEKSANDR PROKHOROV, VALERIY VDOVYCHENKO, ANDRIY BAZYLEVYCH, LEONID RUDENKO, VADYM VIZIR, OLEKSANDR KARPENKO, YAROSLAV MALYNOVSKY, VALENTYNA KOVAL, BORYS STOROZHUK, JAMES COTTON, ASOK VENKATARAMAN, ANDREW MORIARTY, DEREK CONNOLLY, PATRICK DAVEY, ROXY SENIOR, INDERPAUL BIRDI, JOHN CALVERT, PATRICK DONNELLY, JASPER TREVELYAN, JUSTIN CARTER, AARON PEACE, DAVID AUSTIN, NEVILLE KUKREJA, THOMAS HILTON, SUNNY SRIVASTAVA, RONALD WALSH, RONALD FIELDS, JOSEPH HAKAS, EDWARD PORTNAY, HARINDER GOGIA, ABRAHAM SALACATA, JOHN J. HUNTER, J MICHAEL BACHARACH, NICOLAS SHAMMAS, DAMODHAR SURESH, RICKY SCHNEIDER, PAUL GURBEL, SUBHASH BANERJEE, PAUL GRENA, NOEL BEDWELL, STEPHEN SLOAN, STEVEN LUPOVITCH, ANAND SONI, KATHLEEN GIBSON, RENEE SANGRIGOLI, RAJENDRA MEHTA, PETER I-HSUAN TSAI, EVE GILLESPIE, STEPHEN DEMPSEY, GLENN HAMROFF, ROBERT BLACK, ELLIS LADER, JOHN B. KOSTIS, VERA BITTNER, WILLIAM MCGUINN, KELLEY BRANCH, VINAY MALHOTRA, STEPHEN MICHAELSON, MICHAEL VACANTE, MATTHEW MCCORMICK, RALUCA ARIMIE, ALAN CAMP, GEORGE DAGHER, N. MATHEW KOSHY, STEPHEN THEW, FREDERICK COSTELLO, MARK HEIMAN, ROBERT CHILTON, MICHAEL MORAN, FREDRIC ADLER, ANTHONY COMEROTA, ANDREW SEIWERT, WILLIAM FRENCH, HARVEY SEROTA, ROBERT HARRISON, FAISAL BAKAEEN, SHUAB OMER, LOKESH CHANDRA, ALAN WHELAN, ANDREW BOYLE, PHILIP ROBERTS-THOMSON, JAMES ROGERS, PATRICK CARROLL, DAVID COLQUHOUN, JAMES SHAW, PETER BLOMBERY, JOHN AMERENA, CHRIS HII, ALISTAIR ROYSE, BHUWAN SINGH, JOSEPH SELVANAYAGAM, SHIRLEY JANSEN, WINGCHI LO, CHRISTOPHER HAMMETT, ROHAN POULTER, SESHASAYEE NARASIMHAN, HENRIK WIGGERS, HENRIK NIELSEN, GUNNAR GISLASON, LARS KOBER, KIM HOULIND, VIBEKE BOENELYKKE SOERENSEN, ULRIK DIXEN, JENS REFSGAARD, ELISABETH ZEUTHEN, PETER SOEGAARD, MARIAN HRANAI, LUDOVIT GASPAR, DANIEL PELLA, KATARINA HATALOVA, ERIKA DROZDAKOVA, IOAN COMAN, DOINA DIMULESCU, DRAGOS VINEREANU, MIRCEA CINTEZA, CRINA SINESCU, CATALINA ARSENESCU, IMRE BENEDEK, ELENA BOBESCU, DAN DOBREANU, DAN GAITA, ADRIAN IANCU, ADRIANA ILIESIU, DANIEL LIGHEZAN, LUCIAN PETRESCU, OCTAVIAN PIRVU, IULIA TEODORESCU, DAN TESLOIANU, MARIUS MARCIAN VINTILA, OVIDIU CHIONCEL, Divisions of Cardiology and Thromboembolism McMaster University Hamiton, Population Health Research Institute, McMaster University [Hamilton, Ontario], Service de Chirurgie Thoracique et Vasculaire - Médecine vasculaire [CHU Limoges], CHU Limoges, Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Research Center [Associazione Nazionale Medici Cardiologi Ospedalieri] (ANMCO Research Center), Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), Department of Statistics, University of Haifa [Haifa], Cardiology, University and Emergency Hospital, University of Edinburgh, VA Boston Healthcare System, Hamilton General Hospital, Universidad Autonoma de Madrid (UAM), Cardiology Department, Dipartimento di Bioscienze, University of Parma, University of Barcelona, Hospital Clinic Barcelona, Laval University and Hospital Heart and Lung Institute, UVSQ - UFR des sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), University Hospital Brno, Masaryk University, Department of Public Health, Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Pasteur [Nice] (CHU), Service de Cardiologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe de recherche sur la thrombose (GRT (EA 3065)), Université Jean Monnet [Saint-Étienne] (UJM), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), CHU Gabriel Montpied (CHU), CHU Clermont-Ferrand, Department of Medicine (DEBRECEN - Dpt Medicine), University of Debrecen, University of Trieste, Lab Dev Cell Biol,Bunkyo Ku, The University of Tokyo, The Netherlands Organisation for Applied Scientific Research (TNO), Regional Specialist Hospital in Wroclaw, Research and Development Centre, Kamienskiego, Division of Angiology, Wroclaw Medical University, Sahlgrenska University Hospital/Östra, Cardiocentro Ticino [Lugano], University of Zürich [Zürich] (UZH), Danylo Halytskyi Lviv National Medical University, Department of Cardiology, Sandwell General Hospital, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Rigshospitalet [Copenhagen], Université de Médecine Carol Davila, Cardiology Department [Târgu Mureș], University of Medicine and Pharmacy of Târgu Mureș, Institute for Cardiovascular Diseases C.C. Iliescu, Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Associazione Nazionale Medici Cardiologi Ospedalieri [Firenze] (ANMCO), University of Parma = Università degli studi di Parma [Parme, Italie], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHU Gabriel Montpied [Clermont-Ferrand], The University of Tokyo (UTokyo), Universität Zürich [Zürich] = University of Zurich (UZH), and Copenhagen University Hospital
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Carotid Artery Diseases ,Male ,Myocardial Infarction ,MESH: Lower Extremity ,030204 cardiovascular system & hematology ,THERAPY ,Stroke/epidemiology ,MESH: Dose-Response Relationship, Drug ,0302 clinical medicine ,Rivaroxaban ,prevention ,Hemorrhage/chemically induced ,MESH: Peripheral Arterial Disease ,MESH: Double-Blind Method ,guidelines ,MESH: Incidence ,030212 general & internal medicine ,Cardiovascular Diseases/mortality ,risk ,RISK ,MESH: Aged ,MESH: Middle Aged ,Incidence ,General Medicine ,Middle Aged ,3. Good health ,Stroke ,MESH: Myocardial Infarction ,Lower Extremity ,Cardiovascular Diseases ,MESH: Platelet Aggregation Inhibitors ,Factor Xa Inhibitors/administration & dosage ,Drug Therapy, Combination ,Female ,MESH: Factor Xa Inhibitors ,OUTPATIENTS ,MESH: Rivaroxaban ,management ,MESH: Hemorrhage ,metaanalysis ,Lower Extremity/blood supply ,Rivaroxaban/administration & dosage ,Hemorrhage ,MESH: Drug Administration Schedule ,Amputation, Surgical ,Drug Administration Schedule ,MESH: Stroke ,Peripheral Arterial Disease ,03 medical and health sciences ,Double-Blind Method ,atherothrombosis ,Myocardial Infarction/epidemiology ,MANAGEMENT ,Humans ,MESH: Amputation ,MESH: Aspirin ,Aspirin/administration & dosage ,Platelet Aggregation Inhibitors/administration & dosage ,METAANALYSIS ,Aged ,MESH: Humans ,Aspirin ,Dose-Response Relationship, Drug ,MESH: Carotid Artery Diseases ,MORTALITY ,MESH: Cardiovascular Diseases ,cardiovascular event rates ,PREVENTION ,CARDIOVASCULAR EVENT RATES ,MESH: Male ,outpatients ,atrial-fibrillation ,MESH: Drug Therapy, Combination ,MESH: Morbidity ,Carotid Artery Diseases/complications ,lower-extremity amputation ,Peripheral Arterial Disease/complications ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Morbidity ,MESH: Female ,Platelet Aggregation Inhibitors ,Amputation/statistics & numerical data ,Factor Xa Inhibitors - Abstract
BACKGROUND: Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications.METHODS: This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS: Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57-0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35-0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69-1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043).INTERPRETATION: Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding.FUNDING: Bayer AG.
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- 2018
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