Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease

an international, randomised, double-blind, placebo-controlled trial

Sonia S Anand, Jackie Bosch, John W Eikelboom, Stuart J Connolly, Rafael Diaz, Peter Widimsky, Victor Aboyans, Marco Alings, Ajay K Kakkar, Katalin Keltai, Aldo P Maggioni, Basil S Lewis, Stefan Störk, Jun Zhu, Patricio Lopez-Jaramillo, Martin O'Donnell, Patrick J Commerford, Dragos Vinereanu, Nana Pogosova, Lars Ryden & 14 others Keith A A Fox, Deepak L Bhatt, Frank Misselwitz, John D Varigos, Thomas Vanassche, Alvaro A Avezum, Edmond Chen, Kelley Branch, Darryl P Leong, Shrikant I Bangdiwala, Robert G Hart, Salim Yusuf, COMPASS Investigators, Kim Christian Houlind

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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.

Original languageEnglish
JournalLancet
Volume391
Issue number10117
Pages (from-to)219-229
ISSN0140-6736
DOIs
Publication statusPublished - 20. Jan 2018

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Placebos
Rivaroxaban
Ankle Brachial Index
Intermittent Claudication
Carotid Stenosis
Platelet Aggregation Inhibitors
Random Allocation
Coronary Artery Disease
Randomized Controlled Trials
Research Personnel

Keywords

  • Aged
  • Amputation/statistics & numerical data
  • Aspirin/administration & dosage
  • Cardiovascular Diseases/mortality
  • Carotid Artery Diseases/complications
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Factor Xa Inhibitors/administration & dosage
  • Female
  • Hemorrhage/chemically induced
  • Humans
  • Incidence
  • Lower Extremity/blood supply
  • Male
  • Middle Aged
  • Morbidity
  • Myocardial Infarction/epidemiology
  • Peripheral Arterial Disease/complications
  • Platelet Aggregation Inhibitors/administration & dosage
  • Rivaroxaban/administration & dosage
  • Stroke/epidemiology

Cite this

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 ; Houlind, Kim Christian. / Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease : an international, randomised, double-blind, placebo-controlled trial. In: Lancet. 2018 ; Vol. 391, No. 10117. pp. 219-229.
@article{5ff3a405b9c2464bb7d6b9b235cf1f53,
title = "Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial",
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.",
keywords = "Aged, Amputation/statistics & numerical data, Aspirin/administration & dosage, Cardiovascular Diseases/mortality, Carotid Artery Diseases/complications, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Drug Therapy, Combination, Factor Xa Inhibitors/administration & dosage, Female, Hemorrhage/chemically induced, Humans, Incidence, Lower Extremity/blood supply, Male, Middle Aged, Morbidity, Myocardial Infarction/epidemiology, Peripheral Arterial Disease/complications, Platelet Aggregation Inhibitors/administration & dosage, Rivaroxaban/administration & dosage, Stroke/epidemiology",
author = "Anand, {Sonia S} and Jackie Bosch and Eikelboom, {John W} and Connolly, {Stuart J} and Rafael Diaz and Peter Widimsky and Victor Aboyans and Marco Alings and Kakkar, {Ajay K} and Katalin Keltai and Maggioni, {Aldo P} and Lewis, {Basil S} and Stefan St{\"o}rk and Jun Zhu and Patricio Lopez-Jaramillo and Martin O'Donnell and Commerford, {Patrick J} and Dragos Vinereanu and Nana Pogosova and Lars Ryden and Fox, {Keith A A} and Bhatt, {Deepak L} and Frank Misselwitz and Varigos, {John D} and Thomas Vanassche and Avezum, {Alvaro A} and Edmond Chen and Kelley Branch and Leong, {Darryl P} and Bangdiwala, {Shrikant I} and Hart, {Robert G} and Salim Yusuf and {COMPASS Investigators} and Houlind, {Kim Christian}",
note = "Copyright {\circledC} 2017 Elsevier Ltd. All rights reserved.",
year = "2018",
month = "1",
day = "20",
doi = "10.1016/S0140-6736(17)32409-1",
language = "English",
volume = "391",
pages = "219--229",
journal = "Lancet",
issn = "0140-6736",
publisher = "TheLancet Publishing Group",
number = "10117",

}

Anand, SS, Bosch, J, Eikelboom, JW, Connolly, SJ, Diaz, R, Widimsky, P, Aboyans, V, Alings, M, Kakkar, AK, Keltai, K, Maggioni, AP, Lewis, BS, Störk, S, Zhu, J, Lopez-Jaramillo, P, O'Donnell, M, Commerford, PJ, Vinereanu, D, Pogosova, N, Ryden, L, Fox, KAA, Bhatt, DL, Misselwitz, F, Varigos, JD, Vanassche, T, Avezum, AA, Chen, E, Branch, K, Leong, DP, Bangdiwala, SI, Hart, RG, Yusuf, S, COMPASS Investigators & Houlind, KC 2018, 'Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial', Lancet, vol. 391, no. 10117, pp. 219-229. https://doi.org/10.1016/S0140-6736(17)32409-1

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 ; Houlind, Kim Christian (Member of author group).

In: Lancet, Vol. 391, No. 10117, 20.01.2018, p. 219-229.

Research output: Contribution to journalJournal articleResearchpeer-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

A2 - Houlind, Kim Christian

N1 - Copyright © 2017 Elsevier Ltd. All rights reserved.

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 - Aged

KW - Amputation/statistics & numerical data

KW - Aspirin/administration & dosage

KW - Cardiovascular Diseases/mortality

KW - Carotid Artery Diseases/complications

KW - Dose-Response Relationship, Drug

KW - Double-Blind Method

KW - Drug Administration Schedule

KW - Drug Therapy, Combination

KW - Factor Xa Inhibitors/administration & dosage

KW - Female

KW - Hemorrhage/chemically induced

KW - Humans

KW - Incidence

KW - Lower Extremity/blood supply

KW - Male

KW - Middle Aged

KW - Morbidity

KW - Myocardial Infarction/epidemiology

KW - Peripheral Arterial Disease/complications

KW - Platelet Aggregation Inhibitors/administration & dosage

KW - Rivaroxaban/administration & dosage

KW - Stroke/epidemiology

U2 - 10.1016/S0140-6736(17)32409-1

DO - 10.1016/S0140-6736(17)32409-1

M3 - Journal article

VL - 391

SP - 219

EP - 229

JO - Lancet

JF - Lancet

SN - 0140-6736

IS - 10117

ER -