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.
Original language | English |
---|---|
Pages (from-to) | 219-229 |
Number of pages | 11 |
Journal | The Lancet |
Volume | 391 |
Issue number | 10117 |
DOIs | |
Publication status | Published - 20 Jan 2018 |
Keywords
- Peripheral arterial disease
- Cardiovascular morbidity
- Carotid artery
- Asprin
- Rivaroxaban
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Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease : an international, randomised, double-blind, placebo-controlled trial. / Anand, Sonia S.; Bosch, Jackie; Eikelboom, John W.; Connolly, Stuart J.; Diaz, Rafael; Widimsky, Peter; Aboyans, Victor; Alings, Marco; Kakkar, Ajay K.; Keltai, Katalin; Maggioni, Aldo P.; Lewis, Basil S.; Störk, Stefan; Zhu, Jun; Lopez-Jaramillo, Patricio; O'Donnell, Martin; Commerford, Patrick J.; Vinereanu, Dragos; Pogosova, Nana; Ryden, Lars; Fox, Keith A.A.; Bhatt, Deepak L.; Misselwitz, Frank; Varigos, John D.; Vanassche, Thomas; Avezum, Alvaro A.; Chen, Edmond; Branch, Kelley; Leong, Darryl P.; Bangdiwala, Shrikant I.; Hart, Robert G.; Yusuf, Salim; COMPASS Investigators; SALA, JORGELINA; CARTASEGNA, LUIS; VICO, MARISA; HOMINAL, MIGUEL ANGEL; HASBANI, EDUARDO; CACCAVO, ALBERTO; ZAIDMAN, CESAR; VOGEL, DANIEL; HRABAR, ADRIAN; SCHYGIEL, PABLO OMAR; CUNEO, CARLOS; LUQUEZ, HUGO; MACKINNON, IGNACIO J.; AHUAD GUERRERO, RODOLFO ANDRES; COSTABEL, JUAN PABLO; BARTOLACCI, INES PALMIRA; MONTANA, OSCAR; BARBIERI, MARIA; GOMEZ VILAMAJO, OSCAR; GARCIA DURAN, RUBEN OMAR; SCHIAVI, LILIA BEATRIZ; GARRIDO, MARCELO; INGARAMO, ADRIAN; BORDONAVA, ANSELMO PAULINO; PELAGAGGE, MARIA JOSE; NOVARETTO, LEONARDO; ALBISU DI GENNERO, JUAN PABLO; IBANEZ SAGGIA, LUZ MARIA; ALVAREZ, MOIRA; VITA, NESTOR ALEJANDRO; MACIN, STELLA MARIS; DRAN, RICARDO DARIO; CARDONA, MARCELO; GUZMAN, LUIS; SARJANOVICH, RODOLFO JUAN; CUADRADO, JESUS; NANI, SEBASTIAN; LITVAK BRUNO, MARCOS RAUL; CHACON, CAROLINA; MAFFEI, LAURA ELENA; GRINFELD, DIEGO; VENSENTINI, NATALIA; MAJUL, CLAUDIO RODOLFO; LUCIARDI, HECTOR LUCAS; GONZALEZ COLASO, PATRICIA DEL CARMEN; FERRE PACORA, FREDY ANTONI; VAN DEN HEUVEL, PAUL; VERHAMME, PETER; ECTOR, BAVO; DEBONNAIRE, PHILIPPE; VAN DE BORNE, PHILIPPE; LEROY, JEAN; SCHROE, HERMAN; VRANCKX, PASCAL; ELEGEERT, IVAN; HOFFER, ETIENNE; DUJARDIN, KARL; INDIO DO BRASIL, CLARISSE; PRECOMA, DALTON; ABRANTES, JOSE ANTONIO; MANENTI, EULER; REIS, GILMAR; SARAIVA, JOSE; MAIA, LILIA; HERNANDES, MAURO; ROSSI, PAULO; ROSSI DOS SANTOS, FABIO; ZIMMERMANN, SERGIO LUIZ; RECH, RAFAEL; ABIB, EDUARDO; LEAES, PAULO; BOTELHO, ROBERTO; DUTRA, OSCAR; SOUZA, WEIMAR; BRAILE, MARIA; IZUKAWA, NILO; NICOLAU, JOSE CARLOS; TANAJURA, LUIZ FERNANDO; SERRANO JUNIOR, CARLOS VICENTE; MINELLI, CESAR; NASI, LUIZ ANTONIO; OLIVEIRA, LIVIA; DE CARVALHO CANTARELLI, MARCELO JOSE; TYTUS, RICHARD; PANDEY, SHEKHAR; LONN, EVA; CHA, JAMES; VIZEL, SAUL; BABAPULLE, MOHAN; LAMY, ANDRE; SAUNDERS, KEVIN; BERLINGIERI, JOSEPH; KIAII, BOB B.; BHARGAVA, RAKESH; MEHTA, PRAVINSAGAR; HILL, LAURIE; FELL, DAVID; LAM, ANDY; AL-QOOFI, FAISAL; BROWN, CRAIG; PETRELLA, ROBERT; RICCI, JOSEPH A.; GLANZ, ANTHONY; NOISEUX, NICOLAS; BAINEY, KEVIN; MERALI, FATIMA; HEFFERNAN, MICHAEL; DELLA SIEGA, ANTHONY; DAGENAIS, GILLES R.; DAGENAIS, FRANCOIS; BRULOTTE, STEEVE; NGUYEN, MICHEL; HARTLEIB, MICHAEL; GUZMAN, RANDOLPH; BOURGEOIS, RONALD; RUPKA, DENNIS; KHAYKIN, YAARIV; GOSSELIN, GILBERT; HUYNH, THAO; PILON, CLAUDE; CAMPEAU, JEAN; PICHETTE, FRANCIS; DIAZ, ARIEL; JOHNSTON, JAMES; SHUKLE, PRAVIN; HIRSCH, GREGORY; RHEAULT, PAUL; CZARNECKI, WLODZIMIERZ; ROY, ANNIE; NAWAZ, SHAH; FREMES, STEPHEN; SHUKLA, DINKAR; JANO, GABRIEL; COBOS, JORGE LEONARDO; CORBALAN, RAMON; MEDINA, MARCELO; NAHUELPAN, LEONARDO; RAFFO, CARLOS; PEREZ, LUIS; POTTHOFF, SERGIO; STOCKINS, BENJAMIN; SEPULVEDA, PABLO; PINCETTI, CHRISTIAN; VEJAR, MARGARITA; TIAN, HONGYAN; WU, XUESI; KE, YUANNAN; JIA, KAIYING; YIN, PENGFEI; WANG, ZHAOHUI; YU, LITIAN; WU, SHULIN; WU, ZONGQUI; LIU, SHAO WEN; BAI, XIAO JUAN; ZHENG, YANG; YANG, PING; YANG, YUN MEI; ZHANG, JIWEI; GE, JUNBO; CHEN, XIAO PING; LI, JUNXIA; HU, TAO HONG; ZHANG, RUIYAN; ZHENG, ZHE; CHEN, XIN; TAO, LIANG; LI, JIANPING; HUANG, WEIJIAN; FU, GUOSHENG; LI, CHUNJIAN; DONG, YUGANG; WANG, CHUNSHENG; ZHOU, XINMIN; KONG, YE; SOTOMAYOR, ARISTIDES; ACCINI MENDOZA, JOSE LUIS; CASTILLO, HENRY; URINA, MIGUEL; AROCA, GUSTAVO; PEREZ, MARITZA; MOLINA DE SALAZAR, DORA INES; SANCHEZ VALLEJO, GREGORIO; FERNANDO, MANZUR J.; GARCIA, HENRY; GARCIA, LUIS HERNANDO; ARCOS, EDGAR; GOMEZ, JUAN; CUERVO MILLAN, FRANCISCO; TRUJILLO DADA, FREDY ALBERTO; VESGA, BORIS; MORENO SILGADO, GUSTAVO ADOLFO; ZIDKOVA, EVA; LUBANDA, JEAN CLAUDE; KALETOVA, MARKETA; KRYZA, RADIM; MARCINEK, GABRIEL; RICHTER, MAREK; SPINAR, JINDRICH; MATUSKA, JIRI; TESAK, MARTIN; MOTOVSKA, ZUZANA; BRANNY, MARIAN; MALY, JIRI; MALY, MARTIN; WIENDL, MARTIN; FOLTYNOVA CAISOVA, LENKA; SLABY, JOSEF; VOJTISEK, PETR; PIRK, JAN; SPINAROVA, LENKA; MURPHY, ANDREW W.; WAN AHMAD, WAN AZMAN; ANDERSSON, TOMMY ; AUSTIN, DAVID; BLACK, ROBERT; ROBERTS-THOMSON, PHILIP; SELVANAYAGAM, JOSEPH.
In: The Lancet, Vol. 391, No. 10117, 20.01.2018, p. 219-229.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease
T2 - an international, randomised, double-blind, placebo-controlled trial
AU - Anand, Sonia S.
AU - Bosch, Jackie
AU - Eikelboom, John W.
AU - Connolly, Stuart J.
AU - Diaz, Rafael
AU - Widimsky, Peter
AU - Aboyans, Victor
AU - Alings, Marco
AU - Kakkar, Ajay K.
AU - Keltai, Katalin
AU - Maggioni, Aldo P.
AU - Lewis, Basil S.
AU - Störk, Stefan
AU - Zhu, Jun
AU - Lopez-Jaramillo, Patricio
AU - O'Donnell, Martin
AU - Commerford, Patrick J.
AU - Vinereanu, Dragos
AU - Pogosova, Nana
AU - Ryden, Lars
AU - Fox, Keith A.A.
AU - Bhatt, Deepak L.
AU - Misselwitz, Frank
AU - Varigos, John D.
AU - Vanassche, Thomas
AU - Avezum, Alvaro A.
AU - Chen, Edmond
AU - Branch, Kelley
AU - Leong, Darryl P.
AU - Bangdiwala, Shrikant I.
AU - Hart, Robert G.
AU - Yusuf, Salim
AU - COMPASS Investigators
AU - SALA, JORGELINA
AU - CARTASEGNA, LUIS
AU - VICO, MARISA
AU - HOMINAL, MIGUEL ANGEL
AU - HASBANI, EDUARDO
AU - CACCAVO, ALBERTO
AU - ZAIDMAN, CESAR
AU - VOGEL, DANIEL
AU - HRABAR, ADRIAN
AU - SCHYGIEL, PABLO OMAR
AU - CUNEO, CARLOS
AU - LUQUEZ, HUGO
AU - MACKINNON, IGNACIO J.
AU - AHUAD GUERRERO, RODOLFO ANDRES
AU - COSTABEL, JUAN PABLO
AU - BARTOLACCI, INES PALMIRA
AU - MONTANA, OSCAR
AU - BARBIERI, MARIA
AU - GOMEZ VILAMAJO, OSCAR
AU - GARCIA DURAN, RUBEN OMAR
AU - SCHIAVI, LILIA BEATRIZ
AU - GARRIDO, MARCELO
AU - INGARAMO, ADRIAN
AU - BORDONAVA, ANSELMO PAULINO
AU - PELAGAGGE, MARIA JOSE
AU - NOVARETTO, LEONARDO
AU - ALBISU DI GENNERO, JUAN PABLO
AU - IBANEZ SAGGIA, LUZ MARIA
AU - ALVAREZ, MOIRA
AU - VITA, NESTOR ALEJANDRO
AU - MACIN, STELLA MARIS
AU - DRAN, RICARDO DARIO
AU - CARDONA, MARCELO
AU - GUZMAN, LUIS
AU - SARJANOVICH, RODOLFO JUAN
AU - CUADRADO, JESUS
AU - NANI, SEBASTIAN
AU - LITVAK BRUNO, MARCOS RAUL
AU - CHACON, CAROLINA
AU - MAFFEI, LAURA ELENA
AU - GRINFELD, DIEGO
AU - VENSENTINI, NATALIA
AU - MAJUL, CLAUDIO RODOLFO
AU - LUCIARDI, HECTOR LUCAS
AU - GONZALEZ COLASO, PATRICIA DEL CARMEN
AU - FERRE PACORA, FREDY ANTONI
AU - VAN DEN HEUVEL, PAUL
AU - VERHAMME, PETER
AU - ECTOR, BAVO
AU - DEBONNAIRE, PHILIPPE
AU - VAN DE BORNE, PHILIPPE
AU - LEROY, JEAN
AU - SCHROE, HERMAN
AU - VRANCKX, PASCAL
AU - ELEGEERT, IVAN
AU - HOFFER, ETIENNE
AU - DUJARDIN, KARL
AU - INDIO DO BRASIL, CLARISSE
AU - PRECOMA, DALTON
AU - ABRANTES, JOSE ANTONIO
AU - MANENTI, EULER
AU - REIS, GILMAR
AU - SARAIVA, JOSE
AU - MAIA, LILIA
AU - HERNANDES, MAURO
AU - ROSSI, PAULO
AU - ROSSI DOS SANTOS, FABIO
AU - ZIMMERMANN, SERGIO LUIZ
AU - RECH, RAFAEL
AU - ABIB, EDUARDO
AU - LEAES, PAULO
AU - BOTELHO, ROBERTO
AU - DUTRA, OSCAR
AU - SOUZA, WEIMAR
AU - BRAILE, MARIA
AU - IZUKAWA, NILO
AU - NICOLAU, JOSE CARLOS
AU - TANAJURA, LUIZ FERNANDO
AU - SERRANO JUNIOR, CARLOS VICENTE
AU - MINELLI, CESAR
AU - NASI, LUIZ ANTONIO
AU - OLIVEIRA, LIVIA
AU - DE CARVALHO CANTARELLI, MARCELO JOSE
AU - TYTUS, RICHARD
AU - PANDEY, SHEKHAR
AU - LONN, EVA
AU - CHA, JAMES
AU - VIZEL, SAUL
AU - BABAPULLE, MOHAN
AU - LAMY, ANDRE
AU - SAUNDERS, KEVIN
AU - BERLINGIERI, JOSEPH
AU - KIAII, BOB B.
AU - BHARGAVA, RAKESH
AU - MEHTA, PRAVINSAGAR
AU - HILL, LAURIE
AU - FELL, DAVID
AU - LAM, ANDY
AU - AL-QOOFI, FAISAL
AU - BROWN, CRAIG
AU - PETRELLA, ROBERT
AU - RICCI, JOSEPH A.
AU - GLANZ, ANTHONY
AU - NOISEUX, NICOLAS
AU - BAINEY, KEVIN
AU - MERALI, FATIMA
AU - HEFFERNAN, MICHAEL
AU - DELLA SIEGA, ANTHONY
AU - DAGENAIS, GILLES R.
AU - DAGENAIS, FRANCOIS
AU - BRULOTTE, STEEVE
AU - NGUYEN, MICHEL
AU - HARTLEIB, MICHAEL
AU - GUZMAN, RANDOLPH
AU - BOURGEOIS, RONALD
AU - RUPKA, DENNIS
AU - KHAYKIN, YAARIV
AU - GOSSELIN, GILBERT
AU - HUYNH, THAO
AU - PILON, CLAUDE
AU - CAMPEAU, JEAN
AU - PICHETTE, FRANCIS
AU - DIAZ, ARIEL
AU - JOHNSTON, JAMES
AU - SHUKLE, PRAVIN
AU - HIRSCH, GREGORY
AU - RHEAULT, PAUL
AU - CZARNECKI, WLODZIMIERZ
AU - ROY, ANNIE
AU - NAWAZ, SHAH
AU - FREMES, STEPHEN
AU - SHUKLA, DINKAR
AU - JANO, GABRIEL
AU - COBOS, JORGE LEONARDO
AU - CORBALAN, RAMON
AU - MEDINA, MARCELO
AU - NAHUELPAN, LEONARDO
AU - RAFFO, CARLOS
AU - PEREZ, LUIS
AU - POTTHOFF, SERGIO
AU - STOCKINS, BENJAMIN
AU - SEPULVEDA, PABLO
AU - PINCETTI, CHRISTIAN
AU - VEJAR, MARGARITA
AU - TIAN, HONGYAN
AU - WU, XUESI
AU - KE, YUANNAN
AU - JIA, KAIYING
AU - YIN, PENGFEI
AU - WANG, ZHAOHUI
AU - YU, LITIAN
AU - WU, SHULIN
AU - WU, ZONGQUI
AU - LIU, SHAO WEN
AU - BAI, XIAO JUAN
AU - ZHENG, YANG
AU - YANG, PING
AU - YANG, YUN MEI
AU - ZHANG, JIWEI
AU - GE, JUNBO
AU - CHEN, XIAO PING
AU - LI, JUNXIA
AU - HU, TAO HONG
AU - ZHANG, RUIYAN
AU - ZHENG, ZHE
AU - CHEN, XIN
AU - TAO, LIANG
AU - LI, JIANPING
AU - HUANG, WEIJIAN
AU - FU, GUOSHENG
AU - LI, CHUNJIAN
AU - DONG, YUGANG
AU - WANG, CHUNSHENG
AU - ZHOU, XINMIN
AU - KONG, YE
AU - SOTOMAYOR, ARISTIDES
AU - ACCINI MENDOZA, JOSE LUIS
AU - CASTILLO, HENRY
AU - URINA, MIGUEL
AU - AROCA, GUSTAVO
AU - PEREZ, MARITZA
AU - MOLINA DE SALAZAR, DORA INES
AU - SANCHEZ VALLEJO, GREGORIO
AU - FERNANDO, MANZUR J.
AU - GARCIA, HENRY
AU - GARCIA, LUIS HERNANDO
AU - ARCOS, EDGAR
AU - GOMEZ, JUAN
AU - CUERVO MILLAN, FRANCISCO
AU - TRUJILLO DADA, FREDY ALBERTO
AU - VESGA, BORIS
AU - MORENO SILGADO, GUSTAVO ADOLFO
AU - ZIDKOVA, EVA
AU - LUBANDA, JEAN CLAUDE
AU - KALETOVA, MARKETA
AU - KRYZA, RADIM
AU - MARCINEK, GABRIEL
AU - RICHTER, MAREK
AU - SPINAR, JINDRICH
AU - MATUSKA, JIRI
AU - TESAK, MARTIN
AU - MOTOVSKA, ZUZANA
AU - BRANNY, MARIAN
AU - MALY, JIRI
AU - MALY, MARTIN
AU - WIENDL, MARTIN
AU - FOLTYNOVA CAISOVA, LENKA
AU - SLABY, JOSEF
AU - VOJTISEK, PETR
AU - PIRK, JAN
AU - SPINAROVA, LENKA
AU - MURPHY, ANDREW W.
AU - WAN AHMAD, WAN AZMAN
AU - ANDERSSON, TOMMY
AU - AUSTIN, DAVID
AU - BLACK, ROBERT
AU - ROBERTS-THOMSON, PHILIP
AU - SELVANAYAGAM, JOSEPH
PY - 2018/1/20
Y1 - 2018/1/20
N2 - 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.
AB - 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.
KW - Peripheral arterial disease
KW - Cardiovascular morbidity
KW - Carotid artery
KW - Asprin
KW - Rivaroxaban
UR - http://www.scopus.com/inward/record.url?scp=85033579790&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(17)32409-1
DO - 10.1016/S0140-6736(17)32409-1
M3 - Article
C2 - 29132880
VL - 391
SP - 219
EP - 229
JO - Lancet
JF - Lancet
SN - 0140-6736
IS - 10117
ER -