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Lancet. 2018 Jan 20;391(10117):219-229. doi: 10.1016/S0140-6736(17)32409-1. Epub 2017 Nov 10.

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

Collaborators (612)

Sala J, Cartasegna L, Vico M, Hominal MA, Hasbani E, Caccavo A, Zaidman C, Vogel D, Hrabar A, Schygiel PO, Cuneo C, Luquez H, Mackinnon IJ, Ahuad Guerrero RA, Costabel JP, Bartolacci IP, Montana O, Barbieri M, Gomez Vilamajo O, Garcia Duran RO, Schiavi LB, Garrido M, Ingaramo A, Bordonava AP, Pelagagge MJ, Novaretto L, Albisu DI Gennero JP, Ibanez Saggia LM, Alvarez M, Vita NA, Macin SM, Dran RD, Cardona M, Guzman L, Sarjanovich RJ, Cuadrado J, Nani S, Litvak Bruno MR, Chacon C, Maffei LE, Grinfeld D, Vensentini N, Majul CR, Luciardi HL, Gonzalez Colaso PDC, Ferre Pacora FA, VAN DEN Heuvel P, Verhamme P, Ector B, Debonnaire P, VAN DE Borne P, Leroy J, Schroe H, Vranckx P, Elegeert I, Hoffer E, Dujardin K, Indio DO Brasil C, Precoma D, Abrantes JA, Manenti E, Reis G, Saraiva J, Maia L, Hernandes M, Rossi P, Rossi Dos Santos F, Zimmermann SL, Rech R, Abib E Jr, Leaes P, Botelho R, Dutra O, Souza W, Braile M, Izukawa N, Nicolau JC, Tanajura LF, Serrano Junior CV, Minelli C, Nasi LA, Oliveira L, DE Carvalho Cantarelli MJ, Tytus R, Pandey S, Lonn E, Cha J, Vizel S, Babapulle M, Lamy A, Saunders K, Berlingieri J, Kiaii B, Bhargava R, Mehta P, Hill L, Fell D, Lam A, Al-Qoofi F, Brown C, Petrella R, Ricci JA, Glanz A, Noiseux N, Bainey K, Merali F, Heffernan M, Della Siega A, Dagenais GR, Dagenais F, Brulotte S, Nguyen M, Hartleib M, Guzman R, Bourgeois R, Rupka D, Khaykin Y, Gosselin G, Huynh T, Pilon C, Campeau J, Pichette F, Diaz A, Johnston J, Shukle P, Hirsch G, Rheault P, Czarnecki W, Roy A, Nawaz S, Fremes S, Shukla D, Jano G, Cobos JL, Corbalan R, Medina M, Nahuelpan L, Raffo C, Perez L, Potthoff S, Stockins B, Sepulveda P, Pincetti C, Vejar M, Tian H, Wu X, Ke Y, Jia K, Yin P, Wang Z, Yu L, Wu S, Wu Z, Liu SW, Bai XJ, Zheng Y, Yang P, Yang YM, Zhang J, Ge J, Chen XP, Li J, Hu TH, Zhang R, Zheng Z, Chen X, Tao L, Li J, Huang W, Fu G, Li C, Dong Y, Wang C, Zhou X, Kong YE, Sotomayor A, Accini Mendoza JL, Castillo H, Urina M, Aroca G, Perez M, Molina DE Salazar DI, Sanchez Vallejo G, Fernando MJ, Garcia H, Garcia LH, Arcos E, Gomez J, Cuervo Millan F, Trujillo Dada FA, Vesga B, Moreno Silgado GA, Zidkova E, Lubanda JC, Kaletova M, Kryza R, Marcinek G, Richter M, Spinar J, Matuska J, Tesak M, Motovska Z, Branny M, Maly J, Maly M, Wiendl M, Foltynova Caisova L, Slaby J, Vojtisek P, Pirk J, Spinarova L, Benesova M, Canadyova J, Homza M, Florian J, Polasek R, Coufal Z, Skalnikova V, Brat R, Brtko M, Jansky P, Lindner J, Marcian P, Straka Z, Tretina M, Duarte YC, Pow Chon Long F, Sanchez M, Lopez J, Perugachi C, Marmol R, Trujillo F, Teran P, Tuomilehto J, Tuomilehto H, Tuominen ML, Tuomilehto H, Kantola I, Steg G, Aboyans V, Leclercq F, Ferrari E, Boccara F, Messas E, Mismetti P, Sevestre MA, Cayla G, Motreff P, Stoerk S, Duengen HD, Stellbrink C, Guerocak O, Kadel C, Braun-Dullaeus R, Jeserich M, Opitz C, Voehringer HF, Appel KF, Winkelmann B, Dorsel T, Nikol S, Darius H, Ranft J, Schellong S, Jungmair W, Davierwala P, Vorpahl M, Bajnok L, Laszlo Z, Noori E, Veress G, Vertes A, Zsary A, Kis E, Koranyi L, Bakai J, Boda Z, Poor F, Jarai Z, Kemeny V, Barton J, McAdam B, Murphy A, Crean P, Mahon N, Curtin R, Macneill B, Dinneen S, Halabi M, Zimlichman R, Zeltser D, Turgeman Y, Klainman E, Lewis B, Katz A, Atar S, Zimlichman R, Nikolsky E, Bosi S, Naldi M, Faggiano P, Robba D, Mos L, Sinagra G, Cosmi F, Oltrona Visconti L, Carmine M, DI Pasquale G, DI Biase M, Mandorla S, Bernardinangeli M, Piccinni GC, Gulizia MM, Galvani M, Venturi F, Morocutti G, Baldin MG, Olivieri C, Perna GP, Cirrincione V, Kanno T, Daida H, Ozaki Y, Miyamoto N, Higashiue S, Domae H, Hosokawa S, Kobayashi H, Kuramochi T, Fujii K, Mizutomi K, Saku K, Kimura K, Higuchi Y, Abe M, Okuda H, Noda T, Mita T, Hirayama A, Onaka H, Inoko M, Hirokami M, Okubo M, Akatsuka Y, Imamaki M, Kamiya H, Manita M, Himi T, Ueno H, Hisamatsu Y, Ako J, Nishino Y, Kawakami H, Yamada Y, Koretsune Y, Yamada T, Yoshida T, Shimomura H, Kinoshita N, Takahashi A, Yusoff K, Wan Ahmad WA, Abu Hassan MR, Kasim S, Abdul Rahim AA, Mohd Zamrin D, Machida M, Higashino Y, Utsu N, Nakano A, Nakamura S, Hashimoto T, Ando K, Sakamoto T, Prins FJ, Lok D, Milhous JG, Viergever E, Willems F, Swart H, Alings M, Breedveld R, DE Vries KJ, VAN DER Borgh R, Oei F, Zoet-Nugteren S, Kragten H, Herrman JP, VAN Bergen P, Gosselink M, Hoekstra E, Zegers E, Ronner E, DEN Hartog F, Bartels G, Nierop P, VAN DER Zwaan C, VAN Eck J, VAN Gorselen E, Groenemeijer B, Hoogslag P, DE Groot MR, Loyola A, Sulit DJ, Rey N, Abola MT, Morales D, Palomares E, Abat ME, Rogelio G, Chua P, Del Pilar JC, Alcaraz JD, Ebo G, Tirador L, Cruz J, Anonuevo J, Pitargue A, Janion M, Guzik T, Gajos G, Zabowka M, Rynkiewicz A, Broncel M, Szuba A, Czarnecka D, Maga P, Strazhesko I, Vasyuk Y, Sizova Z, Pozdnyakov Y, Barbarash O, Voevoda M, Poponina T, Repin A, Osipova I, Efremushkina A, Novikova N, Averkov O, Zateyshchikov D, Vertkin A, Ausheva A, Commerford P, Seedat S, VAN Zyl L, Engelbrecht J, Makotoko EM, Pretorius CE, Mohamed Z, Horak A, Mabin T, Klug E, Bae JH, Kim C, Kim CJ, Kim DS, Kim YJ, Joo S, Ha JW, Park CS, Kim JY, Kim YK, Jarnert C, Mooe T, Dellborg M, Torstensson I, Albertsson P, Johansson L, Al-Khalili F, Almroth H, Andersson T, Pantev E, Tengmark BO, Liu BO, Rasmanis G, Wahlgren CM, Moccetti T, Parkhomenko A, Tseluyko V, Volkov V, Koval O, Kononenko L, Prokhorov O, Vdovychenko V, Bazylevych A, Rudenko L, Vizir V, Karpenko O, Malynovsky Y, Koval V, Storozhuk B, Cotton J, Venkataraman A, Moriarty A, Connolly D, Davey P, Senior R, Birdi I, Calvert J, Donnelly P, Trevelyan J, Carter J, Peace A, Austin D, Kukreja N, Hilton T, Srivastava S, Walsh R, Fields R, Hakas J, Portnay E, Gogia H, Salacata A, Hunter JJ, Bacharach JM, Shammas N, Suresh D, Schneider R, Gurbel P, Banerjee S, Grena P, Bedwell N, Sloan S, Lupovitch S, Soni A, Gibson K, Sangrigoli R, Mehta R, I-Hsuan Tsai P, Gillespie E, Dempsey S, Hamroff G, Black R, Lader E, Kostis JB, Bittner V, McGuinn W, Branch K, Malhotra V, Michaelson S, Vacante M, McCormick M, Arimie R, Camp A, Dagher G, Koshy NM, Thew S, Costello F, Heiman M, Chilton R, Moran M, Adler F, Comerota A, Seiwert A, French W, Serota H, Harrison R, Bakaeen F, Omer S, Chandra L, Whelan A, Boyle A, Roberts-Thomson P, Rogers J, Carroll P, Colquhoun D, Shaw J, Blombery P, Amerena J, Hii C, Royse A, Singh B, Selvanayagam J, Jansen S, Lo W, Hammett C, Poulter R, Narasimhan S, Wiggers H, Nielsen H, Gislason G, Kober L, Houlind K, Boenelykke Soerensen V, Dixen U, Refsgaard J, Zeuthen E, Soegaard P, Hranai M, Gaspar L, Pella D, Hatalova K, Drozdakova E, Coman I, Dimulescu D, Vinereanu D, Cinteza M, Sinescu C, Arsenescu C, Benedek I, Bobescu E, Dobreanu D, Gaita D, Iancu A, Iliesiu A, Lighezan D, Petrescu L, Pirvu O, Teodorescu I, Tesloianu D, Vintila MM, Chioncel O.

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.

PMID:
29132880
DOI:
10.1016/S0140-6736(17)32409-1
[Indexed for MEDLINE]
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