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Cited by 879Antiplatelet Therapy and Cardiovascular DiseasesPeripheral Artery Disease ManagementVenous Thromboembolism Diagnosis and Management

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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Anand, Sonia S, Bosch, Jackie, Eikelboom, John W, Connolly, Stuart J, Diaz, Rafael, Widimsky, Peter, Aboyans, Victor, Alings, Marco +636 more·2018·The Lancet
DOI 10.1016/s0140-6736(17)32409-1
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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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  1. [20]20. Bosch J, Eikelboom JW, Connolly SJ, et al. Rationale, design and baseline characteristics of participants in the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial. Can J Cardiol 2017; 33:1027-35.
  2. [27]27. CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996; 348: 329-39.

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Anand, S. S., Bosch, J., Eikelboom, J. W., Connolly, S. J., Diaz, R., Widimsky, P., Aboyans, V., Alings, M., Kakkar, A. K., Keltai, K., Maggioni, A. P., Lewis, B. S., Störk, S., Zhu, J., Lopez-Jaramillo, P., O'Donnell, M., Commerford, P. J., Vinereanu, D., Pogosova, N., Ryden, L., Fox, K. A. A., Bhatt, D. L., Misselwitz, F., Varigos, J. D., Vanassche, T., Avezum, A. A., Chen, E., Branch, K., Leong, D. P., Bangdiwala, S. I., Hart, R. G., Yusuf, S., SALA, J., CARTASEGNA, L., VICO, M., HOMINAL, M. A., HASBANI, E., CACCAVO, A., ZAIDMAN, C., VOGEL, D., HRABAR, A., SCHYGIEL, P. O., CUNEO, C., LUQUEZ, H., MACKINNON, I. J., AHUAD GUERRERO, R. A., COSTABEL, J. P., BARTOLACCI, I. P., MONTANA, O., BARBIERI, M., GOMEZ VILAMAJO, O., GARCIA DURAN, R. O., SCHIAVI, L. B., GARRIDO, M., INGARAMO, A., BORDONAVA, A. P., PELAGAGGE, M. J., NOVARETTO, L., ALBISU DI GENNERO, J. P., IBANEZ SAGGIA, L. M., ALVAREZ, M., VITA, N. A., MACIN, S. M., DRAN, R. D., CARDONA, M., GUZMAN, L., SARJANOVICH, R. J., CUADRADO, J., NANI, S., LITVAK BRUNO, M. R., CHACON, C., MAFFEI, L. E., GRINFELD, D., VENSENTINI, N., MAJUL, C. R., LUCIARDI, H. L., GONZALEZ COLASO, P. D. C., FERRE PACORA, F. A., 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, J. A., MANENTI, E., REIS, G., SARAIVA, J., MAIA, L., HERNANDES, M., ROSSI, P., ROSSI DOS SANTOS, F., ZIMMERMANN, S. L., RECH, R., ABIB JR, E., LEAES, P., BOTELHO, R., DUTRA, O., SOUZA, W., BRAILE, M., IZUKAWA, N., NICOLAU, J. C., TANAJURA, L. F., SERRANO JUNIOR, C. V., MINELLI, C., NASI, L. A., OLIVEIRA, L., DE CARVALHO CANTARELLI, M. J., 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, J. A., GLANZ, A., NOISEUX, N., BAINEY, K., MERALI, F., HEFFERNAN, M., DELLA SIEGA, A., DAGENAIS, G. R., 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, J. L., 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, S. W., BAI, X. J., ZHENG, Y., YANG, P., YANG, Y. M., ZHANG, J., GE, J., CHEN, X. P., LI, J., HU, T. H., ZHANG, R., ZHENG, Z., CHEN, X., TAO, L., LI, J., HUANG, W., FU, G., LI, C., DONG, Y., WANG, C., ZHOU, X., KONG, Y., SOTOMAYOR, A., ACCINI MENDOZA, J. L., CASTILLO, H., URINA, M., AROCA, G., PEREZ, M., MOLINA DE SALAZAR, D. I., SANCHEZ VALLEJO, G., FERNANDO, M. 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B., BITTNER, V., MCGUINN, W., BRANCH, K., MALHOTRA, V., MICHAELSON, S., VACANTE, M., MCCORMICK, M., ARIMIE, R., CAMP, A., DAGHER, G., KOSHY, N. M., 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, M. M., & CHIONCEL, O.
Affiliations
  • Population Health Research Institute (CA)
  • Charles University (CZ)
  • Thrombosis Research Institute (GB)
  • Semmelweis University (HU)
  • Associazione Nazionale Medici Cardiologi Ospedalieri (IT)
  • University of Würzburg (DE)
  • Fu Wai Hospital (CN)
  • Ollscoil na Gaillimhe – University of Galway (IE)
  • University of Edinburgh (GB)
  • Brigham and Women's Hospital (US)
  • Bayer (Germany) (DE)
  • Monash University (AU)
  • KU Leuven (BE)
  • Bayer (United States) (US)
  • Universidad Autónoma de Madrid (ES)
  • Estudios Clínicos Latinoamérica (AR)
  • Hamilton General Hospital (CA)
  • McMaster University (CA)
  • University of Washington (US)
  • Université de Versailles Saint-Quentin-en-Yvelines (FR)
  • Centre Hospitalier Universitaire de Montpellier (FR)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • Paris Cardiovascular Research Center (FR)
  • University of Cape Town (ZA)
  • Centre Hospitalier Universitaire de Nîmes (FR)
  • Centre Hospitalier Universitaire de Clermont-Ferrand (FR)
  • Werkgroep Cardiologische centra Nederland (NL)
  • University of Debrecen (HU)
  • University of Trieste (IT)
  • Sahlgrenska University Hospital (SE)
  • Karolinska Institutet (SE)
  • Hôpital Universitaire Dupuytren (FR)
  • Istituto Cardiocentro Ticino (CH)
  • Danylo Halytsky Lviv National Medical University (UA)
  • Foscal Hospital (CO)
  • National Research Center for Preventive Medicine (RU)
  • Carol Davila University of Medicine and Pharmacy (RO)
  • Institutul de Urgenţă pentru Boli Cardiovasculare "Prof.Dr. C.C. Iliescu" (RO)
Corresponding author
Anand, Sonia S
ORCID
Venue
The Lancet
Publisher
Elsevier BV
Published
2018-01
Volume
391
Issue
10117
Pages
219-229
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(17)32409-1
OpenAlex
W4229536675
Semantic Scholar
af705d340539758c05004e20b5429bd9700e2fc2
Cited by
879
References
30
Citations by year
2026: 52 · 2025: 62 · 2024: 74 · 2023: 99 · 2022: 109 · 2021: 139 · 2020: 152 · 2019: 112 · 2018: 74 · 2017: 6
FWCI
72.81
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • The Lancet (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
  • Arrow@dit (Dublin Institute of Technology) (submittedVersion)
  • HAL (submittedVersion)
  • ARAN (University of Galway Research Repository) (Ollscoil na Gaillimhe – University of Galway) (submittedVersion, cc-by-nc-nd)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion, cc-by-sa)
  • Lirias (submittedVersion)
  • Scopus (Elsevier) (submittedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by-nc-nd)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Antiplatelet Therapy and Cardiovascular Diseases
  • Health Sciences › Medicine › Surgery › Peripheral Artery Disease Management
  • Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
Keywords
rivaroxaban, aspirin, peripheral arterial disease, carotid artery disease, coronary artery disease, major adverse limb events, major amputation, cardiovascular mortality, myocardial infarction, stroke, antiplatelet therapy, direct oral anticoagulants, ankle-brachial index, intermittent claudication, asymptomatic carotid stenosis

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