Major Adverse Limb Events and Mortality in Patients With Peripheral Artery Disease
Open accessAbstract
Background Patients with lower extremity peripheral artery disease (PAD) are at increased risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). There is limited information on the prognosis of patients who experience MALE.Objectives Among participants with lower extremity PAD, this study investigated: 1) if hospitalizations, MACE, amputations, and deaths are higher after the first episode of MALE compared with patients with PAD who do not experience MALE; and 2) the impact of treatment with low-dose rivaroxaban and aspirin compared with aspirin alone on the incidence of MALE, peripheral vascular interventions, and all peripheral vascular outcomes over a median follow-up of 21 months.Methods We analyzed outcomes in 6,391 patients with lower extremity PAD who were enrolled in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial. COMPASS was a randomized, double-blind placebo-controlled study of low-dose rivaroxaban and aspirin combination or rivaroxaban alone compared with aspirin alone. MALE was defined as severe limb ischemia leading to an intervention or major vascular amputation.Results A total of 128 patients experienced an incident of MALE. After MALE, the 1-year cumulative risk of a subsequent hospitalization was 61.5%; for vascular amputations, it was 20.5%; for death, it was 8.3%; and for MACE, it was 3.7%. The MALE index event significantly increased the risk of experiencing subsequent hospitalizations (hazard ratio [HR]: 7.21; p < 0.0001), subsequent amputations (HR: 197.5; p < 0.0001), and death (HR: 3.23; p < 0.001). Compared with aspirin alone, the combination of rivaroxaban 2.5 mg twice daily and aspirin lowered the incidence of MALE by 43% (p = 0.01), total vascular amputations by 58% (p = 0.01), peripheral vascular interventions by 24% (p = 0.03), and all peripheral vascular outcomes by 24% (p = 0.02).Conclusions Among individuals with lower extremity PAD, the development of MALE is associated with a poor prognosis, making prevention of this condition of utmost importance. The combination of rivaroxaban 2.5 mg twice daily and aspirin significantly lowered the incidence of MALE and the related complications, and this combination should be considered as an important therapy for patients with PAD. (Cardiovascular Outcomes for People Using Anticoagulation Strategies [COMPASS]; NCT01776424).
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Because rivaroxaban's ischemic benefit was consistent in the diabetes subgroup, low-dose anticoagulation added to antiplatelet therapy may be another secondary prevention option in type 2 diabetes with stable coronary disease.
“The ischemic benefits of rivaroxaban were consistent in the subgroup with diabetes mellitus, suggesting that low-dose anticoagulation added to antiplatelet therapy may be another option for secondary prevention in patients with T2DM and stable CAD.”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [59]
In COMPASS, rivaroxaban increased bleeding, though fatal bleeding was not significantly increased.
“There was an associated increased risk of bleeding with rivaroxaban, although no significant excess in fatal bleeding was noted.”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [59]
In COMPASS, major adverse cardiovascular events were significantly less frequent with rivaroxaban plus aspirin than with aspirin alone or rivaroxaban alone.
“The risk of major adverse cardiovascular events (MACEs) was significantly lower with the combination of rivaroxaban plus aspirin compared with either aspirin alone or rivaroxaban alone.”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [59]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
(1996) · The Lancet · doi:10.1016/s0140-6736(96)09457-3 · Cited by 6,503 · see citing works
Fowkes, F. G. R., Rudan, D., Rudan, I., Aboyans, V., Denenberg, J. O., McDermott, M. M., Norman, P. E., Sampson, U. K., Williams, L. J., Mensah, G. A., et al. (2013) · The Lancet · doi:10.1016/s0140-6736(13)61249-0 · Cited by 3,508 · see citing works
Self-citationClopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events
Bhatt, D. L., Fox, K. A. A., Hacke, W., Berger, P. B., Black, H. R., Boden, W. E., Cacoub, P., Cohen, E. A., Creager, M. A., Easton, J. D., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa060989 · Cited by 2,819 · see citing works
Self-citationDennis, M. S. (1996) · The Lancet · Cited by 2,724 · see citing works
Rivaroxaban with or without aspirin in stable cardiovascular disease
Eikelboom, J. W., Connolly, S. J., Bosch, J., Dagenais, G. R., Hart, R. G., Shestakovska, O., Diaz, R., Alings, M., Lonn, E. M., Anand, S. S., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1709118 · Cited by 2,438 · see citing works
Self-citationLong-term use of ticagrelor in patients with prior myocardial infarction
Bonaca, M. P., Bhatt, D. L., Cohen, M., Steg, P. G., Storey, R. F., Jensen, E. C., Magnani, G., Bansilal, S., Fish, M. P., Im, K., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1500857 · Cited by 1,999 · see citing works
Self-citationAnand, S. S., Bosch, J., Eikelboom, J. W., Connolly, S. J., Diaz, R., Widimsky, P., Aboyans, V., Alings, M., Kakkar, A. K., Keltai, K., et al. (2018) · The Lancet · doi:10.1016/s0140-6736(17)32409-1 · Cited by 879 · see citing works
Self-citationConnolly, S. J., Eikelboom, J. W., Bosch, J., Dagenais, G., Dyal, L., Lanas, F., Metsarinne, K., O'Donnell, M., Dans, A. L., Ha, J.-W., et al. (2018) · The Lancet · doi:10.1016/s0140-6736(17)32458-3 · Cited by 754 · see citing works
Self-citationTicagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease
Hiatt, W. R., Fowkes, F. G. R., Heizer, G., Berger, J. S., Baumgartner, I., Held, P., Katona, B. G., Mahaffey, K. W., Norgren, L., Jones, W. S., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1611688 · Cited by 636 · see citing works
Oral Anticoagulant and Antiplatelet Therapy and Peripheral Arterial Disease
(2007) · New England Journal of Medicine · doi:10.1056/nejmoa065959 · Cited by 442 · see citing works
Dutch Bypass Oral anti (BOA) g, Eikelboom, B., & van Urk, H. (2000) · The Lancet · doi:10.1016/s0140-6736(99)07199-8 · Cited by 391 · see citing works
Bonaca, M. P., Bhatt, D. L., Storey, R. F., Steg, P. G., Cohen, M. C., Kuder, J., Goodrich, E. L., Nicolau, J. C., Parkhomenko, A. N., Lopez-Sendon, J. L., et al. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2016.03.524 · Cited by 385 · see citing works
Self-citationVorapaxar in Patients With Peripheral Artery Disease
Bonaca, M. P., Scirica, B. M., Creager, M. A., Olin, J. W., Bounameaux, H. M., Dellborg, M., Lamp, J. M., Murphy, S. A., D, E. B. M., & Morrow, D. A. (2013) · Circulation · doi:10.1161/circulationaha.112.000679 · Cited by 303 · see citing works
Cacoub, P., Abola, M. T., Baumgartner, I., Bhatt, D. L., Creager, M., Liau, C., Goto, S., Röther, J., Steg, P., & Hirsch, A. (2009) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2008.10.023 · Cited by 261 · see citing works
Self-citationMahoney, E. M., Wang, K., Keo, H. H., Duval, S., Smolderen, K. G. E., Cohen, D. J., Steg, P. G., Bhatt, D. L., Hirsch, A. T., & on behalf of the Reduction of Atherothrombosis for Continued Health (REACH) Registry Investigators* (2010) · Circulation Cardiovascular Quality and Outcomes · doi:10.1161/circoutcomes.109.930735 · Cited by 257 · see citing works
Self-citationAcute Limb Ischemia and Outcomes With Vorapaxar in Patients With Peripheral Artery Disease
Bonaca, M. P., Gutierrez, J. A., Creager, M. A., Scirica, B. M., Olin, J. W., Murphy, S. A., D, E. B. M., & Morrow, D. A. (2016) · Circulation · doi:10.1161/circulationaha.115.019355 · Cited by 190 · see citing works
Bosch, J., Eikelboom, J. W., Connolly, S. J., Bruns, N. C., Lanius, V., Yuan, F., Misselwitz, F., Chen, E., Díaz, R., Alings, M., et al. (2017) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2017.06.001 · Cited by 168 · see citing works
Self-citationHess, C. N., Norgren, L., Ansel, G. M., Capell, W. H., Fletcher, J., Fowkes, F. G. R., Gottsäter, A., Hitos, K., Jaff, M. R., Nordanstig, J., et al. (2017) · Circulation · doi:10.1161/circulationaha.117.024469 · Cited by 165 · see citing works
Jones, W. S., Baumgärtner, I., Hiatt, W. R., Heizer, G., Conte, M. S., White, C. J., Berger, J. S., Held, P., Katona, B. G., Mahaffey, K. W., et al. (2016) · Circulation · doi:10.1161/circulationaha.116.025880 · Cited by 135 · see citing works
Readmissions After Revascularization Procedures for Peripheral Arterial Disease
Secemsky, E., Schermerhorn, M., Carroll, B. J., Kennedy, K., Shen, C.-Y., Valsdottir, L. R., Landon, B., & Yeh, R. (2018) · Annals of Internal Medicine · doi:10.7326/m17-1058 · Cited by 61 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- 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.
- Hiatt WR, Fowkes FG, Heizer G, et al. Tica- grelor versus clopidogrel in symptomatic periph- eral artery disease. N Engl J Med 2017;376:32-40.
Cited by
Sorted by citations
Heart Disease and Stroke Statistics—2020 Update: A Report From the American Heart Association
Virani, S. S., Alonso, A., Benjamin, E. J., Bittencourt, M. S., Callaway, C. W., Carson, A. P., Chamberlain, A. M., Chang, A. R., Cheng, S., Delling, F. N., et al. (2020) · Circulation · doi:10.1161/cir.0000000000000757 · Cited by 9,175 · see citing works
2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes
Knuuti, J., Wijns, W., Saraste, A., Capodanno, D., Barbato, E., Funck-Brentano, C., Prescott, E., Storey, R. F., Deaton, C., Cuisset, T., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz425 · Cited by 7,166 · see citing works
Self-citationHeart Disease and Stroke Statistics—2023 Update: A Report From the American Heart Association
Tsao, C. W., Aday, A. W., Almarzooq, Z. I., Anderson, C. A. M., Arora, P., Avery, C. L., Baker-Smith, C. M., Beaton, A. Z., Boehme, A. K., Buxton, A. E., et al. (2023) · Circulation · doi:10.1161/cir.0000000000001123 · Cited by 8,300 · see citing works
Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association
Tsao, C. W., Aday, A. W., Almarzooq, Z. I., Alonso, A., Beaton, A. Z., Bittencourt, M. S., Boehme, A. K., Buxton, A. E., Carson, A. P., Commodore-Mensah, Y., et al. (2022) · Circulation · doi:10.1161/cir.0000000000001052 · Cited by 5,987 · see citing works
Global Vascular Guidelines on the management of chronic limb-threatening ischemia.
Conte, M. S., Bradbury, A. W., Kolh, P., White, J. V., Dick, F., Fitridge, R., Mills, J. L., Ricco, J.-B., Suresh, K. R., Murad, M. H., et al. (2019) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2019.02.016 · Cited by 2,015 · see citing works
2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes.
Marx, N., Federici, M., Schütt, K., Müller-Wieland, D., Ajjan, R. A., Antunes, M. J., Christodorescu, R. M., Crawford, C., Di Angelantonio, E., Eliasson, B., et al. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehad192 · Cited by 1,642 · see citing works
Self-citationGlobal vascular guidelines on the management of chronic limb-threatening ischemia
Conte, M. S., Bradbury, A. W., Kolh, P., White, J. V., Dick, F., Fitridge, R., Mills, J. L., Ricco, J.-B., Suresh, K. R., Murad, M. H., et al. (2019) · European Journal of Vascular and Endovascular Surgery · doi:10.1016/j.ejvs.2019.05.006 · Cited by 1,582 · see citing works
Self-citationPathology of Peripheral Artery Disease in Patients With Critical Limb Ischemia
Narula, N., Dannenberg, A. J., Olin, J. W., Bhatt, D. L., Johnson, K. W., Nadkarni, G., Min, J., Torii, S., Poojary, P., Anand, S. S., et al. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.08.002 · Cited by 326 · see citing works
Self-citationArnold, S. V., Bhatt, D. L., Barsness, G. W., Beatty, A. L., Deedwania, P. C., Inzucchi, S. E., Kosiborod, M., Leiter, L. A., Lipska, K. J., Newman, J. D., et al. (2020) · Circulation · doi:10.1161/cir.0000000000000766 · Cited by 304 · see citing works
Self-citationGornik, H. L., Aronow, H. D., Goodney, P. P., Arya, S., Brewster, L. P., Byrd, L., Chandra, V., Drachman, D. E., Eaves, J. M., Ehrman, J. K., et al. (2024) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2024.02.013 · Cited by 294 · see citing works
Verma, S., Al‐Omran, M., Leiter, L. A., Mazer, C. D., Rasmussen, S., Saevereid, H. A., Sejersten Ripa, M., & Bonaca, M. P. (2022) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.14700 · Cited by 61 · see citing works
Smolderen, K. G., Ameli, O., Chaisson, C. E., Heath, K., & Mena-Hurtado, C. (2022) · AJPM Focus · doi:10.1016/j.focus.2022.100016 · Cited by 11 · see citing works
Kumbhani, D. J., Armbruster, A. L., Cheng, R. K., Chrispin, J., Fischer, U., Holbrook, A. M., Joglar, J., & Sevestre, M.-A. (2026) · JACC · doi:10.1016/j.jacc.2026.05.033 · Cited by 2 · see citing works
- Authors
- Anand, S. S., Caron, F., Eikelboom, J. W., Bosch, J., Dyal, L., Aboyans, V., Abola, M. T., Branch, K. R. H., Keltai, K., Bhatt, D. L., Verhamme, P., Fox, K. A. A., Cook-Bruns, N., Lanius, V., Connolly, S. J., & Yusuf, S.
- Affiliations
- Population Health Research Institute (CA)
- Hôpital Universitaire Dupuytren (FR)
- Philippine Heart Center (PH)
- University of Washington (US)
- Semmelweis University (HU)
- Brigham and Women's Hospital (US)
- KU Leuven (BE)
- University of Edinburgh (GB)
- Bayer (Germany) (DE)
- Corresponding author
- Anand, Sonia S.
- ORCID
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 71
- Issue
- 20
- Pages
- 2306-2315
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W2793659838
- Cited by
- 466
- References
- 20
- Citations by year
- 2026: 42 · 2025: 61 · 2024: 55 · 2023: 49 · 2022: 57 · 2021: 75 · 2020: 61 · 2019: 45 · 2018: 20 · 2017: 1
- FWCI
- 52.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Bayer
- Heart and Stroke Foundation of Canada
- Topics
- Health Sciences › Medicine › Surgery › Peripheral Artery Disease Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Antiplatelet Therapy and Cardiovascular Diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Vascular Procedures and Complications
- Keywords
- peripheral arterial disease, major adverse limb events, amputation, rivaroxaban, aspirin, low-dose rivaroxaban, major adverse cardiovascular events, limb ischemia, hospitalization, mortality, peripheral vascular intervention, COMPASS trial, anticoagulation, bleeding risk, cardiovascular risk stratification
- MeSH terms
- Rivaroxaban, Aged, Aspirin, Double-Blind Method, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Male, Middle Aged, Mortality, Platelet Aggregation Inhibitors, Lower Extremity, Peripheral Arterial Disease, Factor Xa Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
