Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial

Sonia Anand (1) , Jackie Bosch (2) , John Eikelboom (3) , Stuart Connolly , Rafael Diaz , Peter Widimsky , Victor Aboyans (4, 5) , Marco Alings , Ajay Kakkar , Katalin Keltai , Aldo Maggioni (6) , Basil Lewis , Stefan Störk , Jun Zhu (7) , Patricio Lopez-Jaramillo , Martin O'Donnell , Patrick Commerford , Dragos Vinereanu (8) , Nana Pogosova , Lars Ryden , Keith A.A. Fox (9) , Deepak Bhatt (10) , Frank Misselwitz , John Varigos , Thomas Vanassche , Alvaro Avezum , Edmond Chen , Kelley Branch , Darryl Leong , Shrikant Bangdiwala , Robert Hart , Salim Yusuf (11) , 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 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 Pelagagge , Leonardo Novaretto , Juan Pablo Albisu Di Gennero , Maria Ibanez Saggia , Moira Alvarez , Nestor Alejandro Vita , Stella Maris Macin , Ricardo Dario Dran , Marcelo Cardona , Luis Guzman , Rodolfo Juan Sarjanovich , Jesús Sánchez Cuadrado (12) , 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 (13) , 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 , Paul Rossi , Fabio Rossi (14) , Sergio Luiz Zimmermann , Rafael Rech , Eduardo Abib Jr , Paul Leaes , Roberto Botelho , Oscar Dutra , Weimar Souza , Maria Braile , Nilo Izukawa , Carlos Nicolau (15) , Luiz Fernando Tanajura , Carlos Serrano Junior , Cesar Minelli , Luiz Antonio Nasi , Livia Oliveira , Marcelo de Carvalho Cantarelli , Richard Tytus , Shekhar Pandey , Eva Lonn (11) , James Cha , Saul Vizel , Mohan Babapulle , André Lamy (3) , Kevin Saunders , Jose Berlingieri , Bob Kiaii , Rakesh Bhargava , Pravinsagar Mehta , Laurie Hill , David Fell , Andy y W Lam , Faisal Al-Qoofi , Craig Brown , Robert Petrella , Jose Ricci , Anthony Glanz , Nicolas Noiseux , Kevin Bainey , Fatima Merali , Anthony Della Siega , Gilles Dagenais (16) , Francois Dagenais , Steeve Brulotte , Michel Nguyen , 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 , 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 Tian , Shulin Wu , Zongqui Wu , Shao Wen Liu , Xiao Juan Bai , Yang Zheng , Yang Yang , Yang Yu , Jiwei Zhang , Junbo Ge , Ping Chen , Junxia Li , Tao Hong Hu , Ruiyan Zhang , Zhe Zheng , Xin Chen , Liang Li , Ping Jia , Weijian Jia , Guosheng Fu , Chunjian Jia , Yugang Yu , Chunsheng Wang , Xin Zhou , Ye Kong , Aristides Sotomayor , Luis Accini Mendoza , Henry Castillo , Miguel Urina , Gustavo Aroca , Maritza Perez , Dora Ines Sala , Gregorio Sanchez Vallejo , Manzur Fernando , Henry Garcia , Luis Garcia (17) , Edgar Arcos , Juan C Gómez , Francis Cuervo Millan , Alberto Trujillo Dada , Boris Vesga , Gustavo Moreno Silgado , Eva Zidkova , Jean Lubanda , Marketa Ke , Radim Kryza , Gabriel Marcinek , Marek Richter , Jindrich Spinar (18) , Jiri Matuska , Martin Tesak , Zuzana Motovska , Maria Branny , Jiri Maly , Martin Maly , Martin Wiendl , Lenka Foltynova Caisova , Jose Slaby , Petr Vojtisek , Jan Pirk , Lenka Spinar , Miroslava Benesova , Julia Li , Miroslav Homza , Jindrich Florian , Rostislav Polasek , Zdenek Coufal , Vladimira Skalnikova , Radim Brat , Miroslav Brtko , Petr Jansky , Jaroslav Li , Pavel Marcian , Zbynek Straka , Martin Tretina , Carlos Duarte , Freddy Pow Chon Long , Mayra Sanchez , Jose Lopez , Carmita Perugachi , Ricardo Marmol , Freddy Trujillo , Pablo Teran , Jaakko Tuomilehto (19) , Marja-Leena Tuominen , Henri Tuomilehto , Ilkka Kantola , Gabriel Steg (20) , Florence Leclercq (21) , Emile Ferrari (22) , Franck Boccara (23) , Emmanuel Messas (24) , Patrick Mismetti (25) , Marie Antoinette Sevestre , Guillaume Cayla (26) , Pascal Motreff (27) , Stefan Stoerk , Hans-Dirk Ge , Christoph Stellbrink , Osman Guerocak , Christoph Kadel , Ruediger Ge , Christian Tian , Hans-Friedrich Ge , Karl Appel , Bernhard Ke , Thomas Dorsel , Sigrid Nikol , Harald Darius , Jurgen Ge , Sebastian Tian , Wolfgang Jungmair , Piroze Davierwala , Marc Vorpahl , Laszlo Bajnok , Ebrahim Noori , Gabor Veress , Andras Vertes , Andras Zsary , Erno Kis , Laszlo Laszlo , Judit Bakai , Zoltán Boda (28) , Ferenc Poor , Zoltan Jarai , Vendel Ke , John Barton , Brendan Mcadam , Andre Murphy , Peter Crean , Niall Mahon , Ronan Curtin , Briain Macneill , Sean Dinneen , Majdi Halabi , David Zeltser , Yoav Ge , Eliezer Li , Amos Katz , Shaul Atar , Reuven Li , Eugenia Ge , Stefan Bosi , Monica Naldi , Pompilio Li , Debora Robba , Lucio Mos , Gianfranco Sinagra (29) , Franco Cosmi , Luigi Oltrona Visconti , de Matteis Carmine , Giuseppe Di Pasquale , Matteo Di Biase , Sara Mandorla , Marino Ge , Giovanni Carlo Piccinni , Michel Li , Marc Galvani , Flavio Venturi , Giorgio Morocutti , Maria Baldin , Carlo Li , Gian Piero Perna , Vincenzo Cirrincione , Takayasu Kanno , Hiroyuki Roy , Yukio Yu , Naomasa Miyamoto , Shinichi Higashiue , Hiroshi Domae , Shinobu Hosokawa , Hiroo Kobayashi , Takehiko Ke , Kenshi Ke , Kazuaki Mizutomi , Keijiro Ke , Kazuo Kimura , Yoshiharu Higuchi , Mitsunori Abe , Haruhito Okuda , Toshiyuki Yu , Teruaki Mita , Atsushi Hirayama , Haruhiko Onaka , Moriaki Inoko , Mitsugu Hirokami , Munenori Okubo , Mizuho Imamaki , Haruo Kamiya , Mamoru Manita , Toshiharu Himi , Hideki Ueno , Yuji Yu , Junya Ako , Yasuhiro Nishino , Hideo Kawakami , Yutaka Yu , Yukihiro Yu , Takahisa Yamada , Tetsuro Yoshida , Hideki Shimomura , Noriyuki Yu , Akihiko Takahashi , Khalid Yu , Wan Azman Wan Ahmad , Muhammad Radzi Abu Hassan , Sazzli Li , Aizai Azan Abdul Rahim , Dimon Mohd Zamrin , Masaharu Machida , Yorihiko Higashino , Noriaki Utsu , Akihiko Nakano (30) , Shigeru Ge , Tetsuo Hashimoto , Kenji Ke , Tomohiro Sakamoto , F.J. Prins , Dirk Lok , Jan Ge , Eric Ge , Frank Willems , Henk Swart , Marc Li , Rob Breedveld , Jan Ke , Roger Ge , Fanny Oei , Stieneke Ke , Hans Kragten , Paul Herrman , Paul Ge , Marc Gosselin , Eduard Hoekstra , Erwin Ge , Eelko Ronner , Frank den Hartog (31) , Gerard Ge , Peter Nierop , Coen van Der Zwaan , Jacob van Eck , Edwin van Gorselen , Bjorn Groenemeijer , Pieter Hoogslag , Robert de Groot , Aldrin Loyola , Jose Li , Nannette Rey , Maria Abola , Dante Morales , Ellen Palomares , Eva Abat , Gregorio Ge , Philip Li , Jose del Pilar , Dennis Alcaraz , Geraldine Ge , Louie Tirador , Jose Cruz , John Anonuevo , Arthur Hu , Maria Janion , Tomasz Guzik , Grzegorz Gajos , Maciej Zabowka , Andrzej Rynkiewicz , Marlena Broncel , Andrzej Szuba (32) , Danuta Czarnecka , Pawel Maga , Zhe Strazhesko , Zhanna Sizova , Yury Yu , Olga Barbarash , Mikhail Voevoda , Tatiana Tian , Alexey Repin , Irina Osipova , Anna Efremushkina , Nina Novikova , Oleg Averkov , Dmitry Zateyshchikov , Arkadiy Vertkin , Eva Ausheva , Saadiya Seedat , Louis van Zyl , Jan Rech , Ellen Li , Catharina Elizabeth Li , Zaid Mohamed , Adrian Horak , Thomas Mabin , Eric Klug , Jan Bae , Cheolho Kim , Chong-Jin Kim , Dong-Soo Dong , Yong Jin Kim , Seungjae Joo , Jong-Won Ha , Chul Soo Hu , Jan Kim , Young-Kwon Kim , Christina Jarnert , Thomas Mooe , Mikael Dellborg (33) , Ingemar Ge , Per Albertsson , Hans Ha , Faris Li , Henri Almroth , Tommy Andersson , Emil Pantev , Bengt-Olov Tengmark , Bo Liu , Gundars Rasmanis , Carl-Magnus Wahlgren , Tiziano Moccetti (34) , Alexander Park , Vira Tseluyko , Volodymyr Volkov , Olena Koval , Lyudmyla Yu , Oleksandr Prokhorov , Henk Chen , Andriy Bazylevych (35) , Leonid Rudenko , Vadym Vizir , Oleksandr Karpenko , Yaroslav Maly , Valentyna Koval , Bo Hu , James Cotton , Asok Atar , Andre Moriarty , Derek Connolly (36) , Patrick Davey , Roxy Senior , Paul Birdi , John Calvert , Patrick Donnelly , Per Trevelyan , Justin Carter , Aaron Peace , David Austin , Neville Kukreja , Thomas Hilton , Sunny Srivastava , Ronald Walsh , Ronald Fields , Jose Ha , Edward Portnay , Harinder Ha , Abraham Sala , John Hu , Nicolas Ha , Damodhar Ha , Ricky Schneider , Paul Gurbel , Subhash Ha , Paul Grena , Noel Bedwell , Stephen Sloan , Steven Lupovitch , Anand Soni , Kathleen Gibson , Renee Li , Rajendra Mehta , Peter I-Hsuan Tsai , Gilles Gillespie , Stephen Dempsey , Glenn Ha , Robert Black , Ellis Li , John Kostis , Vera Bittner , Kelley Ke , Vinay Malhotra , Matthew Mccormick , Raluca Arimie , Alan Camp , George Ge , N. Mathew Koshy , Stephen Thew , Eric Costello , Mark Heiman , Robert Hilton , Michael Cha , Fredric Adler , Anthony Comerota , Andre Seiwert , William Li , Harvey Ha , Robert Ha , Faisal Bakaeen , Shuab Hu , Lokesh Cha , Alan Whelan , Andre Boyle , Robert Li , James Ge , Patrick Carroll (37) , David Colquhoun , James Ha , Peter Blombery , John Amerena , Chris Hii , Alistair Roy , Bhuwan Hu , Jose Selvanayagam , Jan Jansen , Wingchi Lo , Christoph Ha , Rohan Ha , Ye Ha , Henri Ge , Henri Nielsen , Gunnar Gislason , Lars Køber (38) , Kim Li , Bo Ke , Ulrik Dixen , Jens Refsgaard , Elisabeth Li , Peter Soegaard , Maria Hranai , Ludovit Gaspar , Daniel Pella , Katarina Atar , Erika Ako , Ioan Coman , Doina Dimulescu , Mircea Cinteza , Crina Sinescu (39) , Catalina Li , Imre Benedek (40) , Bob Bobescu , Dan Dobreanu , Dan Gaita , Adrian Iancu , Adrian Li , Daniel Li , Petr Petrescu , Octavian Pirvu , Iulia Li , Dan Lo , Marc Marcian , Ovidiu Chioncel (41)

1 Divisions of Cardiology and Thromboembolism McMaster University Hamiton
2 Population Health Research Institute
3 McMaster University [Hamilton, Ontario]
4 Service de Chirurgie Thoracique et Vasculaire - Médecine vasculaire [CHU Limoges]
5 NET - Neuroépidémiologie Tropicale
6 ANMCO Research Center - Research Center [Associazione Nazionale Medici Cardiologi Ospedalieri]
7 Department of Statistics
8 Cardiology
9 Edin. - University of Edinburgh
10 VA Boston Healthcare System
11 Hamilton General Hospital
12 UAM - Universidad Autónoma de Madrid
13 Cardiology Department
14 Dipartimento di Bioscienze
15 UB - Universitat de Barcelona
16 Laval University and Hospital Heart and Lung Institute
17 UVSQ Santé - Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil
18 University Hospital Brno
19 Department of Public Health
20 LBPC (U698) - Hémostase, bio-ingénierie et remodelage cardiovasculaires
21 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
22 CHU - Hôpital Pasteur [Nice]
23 CHU Saint-Antoine [AP-HP]
24 PARCC - UMR-S U970 - Paris-Centre de Recherche Cardiovasculaire
25 GRT - Groupe de recherche sur la thrombose, pharmacologie des antithrombotiques et situations à risque
26 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
27 CHU Gabriel Montpied [Clermont-Ferrand]
28 DEBRECEN - Dpt Medicine - Department of Medicine
29 Università degli studi di Trieste = University of Trieste
30 Lab Dev Cell Biol,Bunkyo Ku
31 TNO - The Netherlands Organisation for Applied Scientific Research
32 Regional Specialist Hospital in Wroclaw, Research and Development Centre, Kamienskiego, Division of Angiology
33 Sahlgrenska University Hospital/Östra
34 Cardiocentro Ticino [Lugano]
35 Danylo Halytskyi Lviv National Medical University
36 Department of Cardiology
37 Physiopathologie et thérapie des déficits sensoriels et moteurs
38 Rigshospitalet [Copenhagen]
39 Université de Médecine Carol Davila
40 Cardiology Department [Târgu Mureș]
41 Institute for Cardiovascular Diseases C.C. Iliescu

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.

Domaines: Santé publique et épidémiologie

Sonia Anand, Jackie Bosch, John Eikelboom, Stuart Connolly, Rafael Diaz, et al.. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. The Lancet, 2018, 391 (10117), pp.219-229. ⟨10.1016/S0140-6736(17)32409-1⟩. ⟨hal-02043696⟩