Rivaroxaban in Peripheral Artery Disease after Revascularization
Open accessAbstract
BACKGROUND: Patients with peripheral artery disease who have undergone lower-extremity revascularization are at high risk for major adverse limb and cardiovascular events. The efficacy and safety of rivaroxaban in this context are uncertain. METHODS: In a double-blind trial, patients with peripheral artery disease who had undergone revascularization were randomly assigned to receive rivaroxaban (2.5 mg twice daily) plus aspirin or placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes. The principal safety outcome was major bleeding, defined according to the Thrombolysis in Myocardial Infarction (TIMI) classification; major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) was a secondary safety outcome. RESULTS: A total of 6564 patients underwent randomization; 3286 were assigned to the rivaroxaban group, and 3278 were assigned to the placebo group. The primary efficacy outcome occurred in 508 patients in the rivaroxaban group and in 584 in the placebo group; the Kaplan-Meier estimates of the incidence at 3 years were 17.3% and 19.9%, respectively (hazard ratio, 0.85, 95% confidence interval [CI], 0.76 to 0.96; P = 0.009). TIMI major bleeding occurred in 62 patients in the rivaroxaban group and in 44 patients in the placebo group (2.65% and 1.87%; hazard ratio, 1.43; 95% CI, 0.97 to 2.10; P = 0.07). ISTH major bleeding occurred in 140 patients in the rivaroxaban group, as compared with 100 patients in the placebo group (5.94% and 4.06%; hazard ratio, 1.42; 95% CI, 1.10 to 1.84; P = 0.007). CONCLUSIONS: In patients with peripheral artery disease who had undergone lower-extremity revascularization, rivaroxaban at a dose of 2.5 mg twice daily plus aspirin was associated with a significantly lower incidence of the composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes than aspirin alone. The incidence of TIMI major bleeding did not differ significantly between the groups. The incidence of ISTH major bleeding was significantly higher with rivaroxaban and aspirin than with aspirin alone. (Funded by Bayer and Janssen Pharmaceuticals; VOYAGER PAD ClinicalTrials.gov number, NCT02504216.).
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An increased risk of major bleeding was noted with rivaroxaban added to aspirin treatment in both COMPASS and VOYAGER PAD.
“However, an increased risk of major bleeding was noted with rivaroxaban added to aspirin treatment in both COMPASS and VOYAGER PAD.”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [207]
The Abstract and Discussion report significantly more ISTH major bleeding with rivaroxaban plus aspirin in VOYAGER PAD, but no significant difference in the trial’s principal TIMI major-bleeding outcome. The paper discusses COMPASS’s reduction in ischemic risk but does not report a COMPASS major-bleeding finding, so it supports only the VOYAGER PAD portion of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAn increased risk of major bleeding was noted with rivaroxaban added to aspirin treatment in both COMPASS and VOYAGER PAD.
“However, an increased risk of major bleeding was noted with rivaroxaban added to aspirin treatment in both COMPASS and VOYAGER PAD.”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [196]
The Abstract and Discussion report significantly more ISTH-defined major bleeding with rivaroxaban plus aspirin in VOYAGER PAD, but no significant difference in the principal TIMI-defined major-bleeding outcome. The Introduction and discussion of COMPASS describe its ischemic benefits, not an increased risk of major bleeding, so our copy does not support that part of the claim. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn the VOYAGER PAD trial, rivaroxaban 2.5 mg twice daily plus aspirin was associated with a significantly lower incidence of ischemic cardiovascular events, including major adverse limb events, compared with placebo plus aspirin.
“Rivaroxaban treatment in this group of individuals was also associated with a significantly lower incidence of ischemic cardiovascular events, including major adverse limb events.”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [207]
In the VOYAGER PAD trial, rivaroxaban 2.5 mg twice daily plus aspirin was associated with a significantly lower incidence of ischemic cardiovascular events, including major adverse limb events, compared with placebo plus aspirin.
“Rivaroxaban treatment in this group of individuals was also associated with a significantly lower incidence of ischemic cardiovascular events, including major adverse limb events.”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [196]
In COMPASS and VOYAGER PAD, adding rivaroxaban to aspirin increased risk of major bleeding.
“However, an increased risk of major bleeding was noted with rivaroxaban added to aspirin treatment in both COMPASS and VOYAGER PAD.”
From 10. Cardiovascular Disease and Risk Management: <i>Standards of Care in Diabetes—2023</i> (2023) · cites this paper as [170]
In VOYAGER PAD, rivaroxaban plus aspirin was associated with significantly lower incidence of ischemic cardiovascular events including major adverse limb events.
“Rivaroxaban treatment in this group of patients was also associated with a signi fi cantly lower incidence of ischemic cardiovascular events, including major adverse limb events.”
From 10. Cardiovascular Disease and Risk Management: <i>Standards of Care in Diabetes—2023</i> (2023) · cites this paper as [170]
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- Authors
- Bonaca, M. P., Bauersachs, R. M., Anand, S. S., Debus, E. S., Nehler, M. R., Patel, M. R., Fanelli, F., Capell, W. H., Diao, L., Jaeger, N., Hess, C. N., Pap, A. F., Kittelson, J. M., Gudz, I., Mátyás, L., Krievins, D. K., Diaz, R., Brodmann, M., Muehlhofer, E., Haskell, L. P., Berkowitz, S. D., & Hiatt, W. R.
- Affiliations
- Colorado School of Public Health (US)
- From Colorado Prevention Center (CPC) Clinical Research (M.P.B., M.R.N., W.H.C., L.D., N.J., C.N.H., W.R.H.), the Department of Medicine, Division of Cardiovascular Medicine (M.P.B., C.N.H., W.R.H.), the Department of Surgery, Division of Vascular Surgery (M.R.N.), and the Department of Medicine, Division of Endocrinology (W.H.C.), University of Colorado Anschutz Medical Campus, and the Department of Biostatistics and Informatics, Colorado School of Public Health (J.M.K.) — all in Aurora; the...
- ORCID
- Bonaca, Marc P.
- Bauersachs, Rupert M.
- Anand, Sonia S.
- Debus, E. Sebastian
- Nehler, Mark R.
- Patel, Manesh R.
- Fanelli, Fabrizio
- Capell, Warren H.
- Diao, Lihong
- Hess, Connie N.
- Pap, Akos F.
- Gudz, Ivan
- Mátyás, Lajos
- Krievins, Dainis K.
- Brodmann, Marianne
- Muehlhofer, Eva
- Haskell, Lloyd P.
- Berkowitz, Scott D.
- Hiatt, William R.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2020-05-21
- Volume
- 382
- Issue
- 21
- Pages
- 1994-2004
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W3013428853
- Cited by
- 1,045
- References
- 9
- Citations by year
- 2026: 134 · 2025: 173 · 2024: 168 · 2023: 150 · 2022: 163 · 2021: 183 · 2020: 73
- FWCI
- 130.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Janssen Research and Development
- Bayer
- Topics
- Health Sciences › Medicine › Surgery › Peripheral Artery Disease Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Antiplatelet Therapy and Cardiovascular Diseases
- Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
- Keywords
- rivaroxaban, peripheral arterial disease, lower extremity revascularization, acute limb ischemia, major amputation, major bleeding, aspirin, oral anticoagulation, thromboprophylaxis, bleeding risk stratification, cardiovascular mortality, myocardial infarction
- MeSH terms
- Rivaroxaban, Aged, Aspirin, Cardiovascular Diseases, Combined Modality Therapy, Double-Blind Method, Drug Therapy, Combination, Female, Hemorrhage, Humans, Ischemia, Male, Middle Aged, Platelet Aggregation Inhibitors, Incidence, Lower Extremity, Kaplan-Meier Estimate, Endovascular Procedures, Peripheral Arterial Disease, Factor Xa Inhibitors
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