Sonia S Anand1,2, Will Hiatt3,4, Leanne Dyal2, Rupert Bauersachs5,6, Scott D Berkowitz7,8, Kelley R H Branch9, Sebastian Debus10, Keith A A Fox11, Yan Liang12, Eva Muehlhofer13, Mark Nehler3,14, Lloyd P Haskell15, Manesh Patel16, Michael Szarek4,7,17, Salim Yusuf1,2, John Eikelboom1,2, Marc P Bonaca3,4,18. 1. Department of Medicine, McMaster University, 1280 Main St West, Hamilton, ON L8S 4L8, Canada. 2. Population Health Research Institute, Hamilton Health Sciences, 237 Barton St East, Hamilton, ON L8L 2X2, Canada. 3. Department of Cardiology, University of Colorado School of Medicine, 13001 E 17th Pl, Boulder, Colorado 80045, USA. 4. Colorado Prevention Center (CPC) Clinical Research, 2115 N Scranton St., Suite 2040, Aurora, Colorado 80045, USA. 5. AGAPLESION Bethanien Krankenhaus Im Prüfling 23 D-60389, Frankfurt, Germany. 6. Center for Thrombosis and Hemostasis, University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. 7. University of Colorado School of Medicine, 13001 E 17th Pl, Boulder, Colorado 80045, USA. 8. Colorado Prevention Center (CPC) Clinical Research, 2115 N Scranton St. , Suite 2040, Aurora, Colorado 80045, USA. 9. Division of Cardiology, University of Washington Medical Center, 1959 N.E. Pacific St., Seattle, WA 98195, USA. 10. Department of Vascular Medicine, University of Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany. 11. Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. 12. Department of Emergency, National Center for Cardiovascular Disease and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Xicheng District, Beijing 100037, People's Republic of China. 13. Research and Development, Pharmaceuticals, Bayer AG, Friedrich-Ebert-Straße 217/333, 42117 Wuppertal, Germany. 14. Department of Vascular Surgery, University Of Colorado School Of Medicine, 13100 E Colfax Ave, Suite 70, Aurora, CO 80011, USA. 15. JANSSEN Research & Development, LLC, 920 US-202, Raritan, NJ 08869, USA. 16. Department of Cardiology and Clinical Pharmacology, Duke University School Of Medicine, 2301 Erwin Road, Hafs Building, Room 8695, Durham, NC 27710, USA. 17. SUNY Downstate Health Sciences University, Brooklyn, New York, USA. 18. Division of Cardiovascular Medicine, University of Colorado Anschutz School of Medicine, 13001 East 17th Place, Aurora, CO 80045, USA.
Abstract
AIMS: Peripheral artery disease (PAD) patients suffer a high risk of major cardiovascular (CV) events, with athero-thrombo-embolism as the underlying pathophysiologic mechanism. Recently, two large randomized clinical trials evaluated the efficacy and safety of low-dose rivaroxaban twice daily plus aspirin in stable PAD outpatients and those immediately after peripheral revascularization. We sought to determine if the effects of low-dose rivaroxaban and aspirin compared to aspirin alone are consistent across this broad spectrum of PAD patients. METHODS AND RESULTS: We conducted a random-effects meta-analysis of the COMPASS and VOYAGER randomized trials among 11 560 PAD patients (4996 from COMPASS and 6564 from VOYAGER) in the primary analysis and 9332 (2768 from COMPASS and 6564 from VOYAGER) with lower extremity (LE)-PAD in the secondary analysis. The hazard ratio (HR) for the composite of CV death, myocardial infarction, ischaemic stroke, acute limb ischaemia, or major vascular amputation was 0.79 (95% confidence interval, CI: 0.65-0.95) comparing low-dose rivaroxaban plus aspirin to aspirin alone. While the risk of major bleeding was increased with low-dose rivaroxaban plus aspirin compared to aspirin alone [HR: 1.51 (95% CI: 1.22-1.87)], there was no significant increase in severe bleeding [HR: 1.18 (95% CI: 0.79-1.76)]. Similar effects were observed in the subset with symptomatic LE-PAD. CONCLUSIONS: Among PAD patients, low-dose rivaroxaban plus aspirin is superior to aspirin alone in reducing CV and limb outcomes including acute limb ischaemia and major vascular amputation. This reduction is offset by a relative increase in major bleeding, but not by an excess of fatal or critical organ bleeding. The consistency of findings of these trials supports the use of combination low-dose rivaroxaban plus aspirin in PAD patients across a broad spectrum of disease.
AIMS: Peripheral artery disease (PAD) patients suffer a high risk of major cardiovascular (CV) events, with athero-thrombo-embolism as the underlying pathophysiologic mechanism. Recently, two large randomized clinical trials evaluated the efficacy and safety of low-dose rivaroxaban twice daily plus aspirin in stable PAD outpatients and those immediately after peripheral revascularization. We sought to determine if the effects of low-dose rivaroxaban and aspirin compared to aspirin alone are consistent across this broad spectrum of PAD patients. METHODS AND RESULTS: We conducted a random-effects meta-analysis of the COMPASS and VOYAGER randomized trials among 11 560 PAD patients (4996 from COMPASS and 6564 from VOYAGER) in the primary analysis and 9332 (2768 from COMPASS and 6564 from VOYAGER) with lower extremity (LE)-PAD in the secondary analysis. The hazard ratio (HR) for the composite of CV death, myocardial infarction, ischaemic stroke, acute limb ischaemia, or major vascular amputation was 0.79 (95% confidence interval, CI: 0.65-0.95) comparing low-dose rivaroxaban plus aspirin to aspirin alone. While the risk of major bleeding was increased with low-dose rivaroxaban plus aspirin compared to aspirin alone [HR: 1.51 (95% CI: 1.22-1.87)], there was no significant increase in severe bleeding [HR: 1.18 (95% CI: 0.79-1.76)]. Similar effects were observed in the subset with symptomatic LE-PAD. CONCLUSIONS: Among PAD patients, low-dose rivaroxaban plus aspirin is superior to aspirin alone in reducing CV and limb outcomes including acute limb ischaemia and major vascular amputation. This reduction is offset by a relative increase in major bleeding, but not by an excess of fatal or critical organ bleeding. The consistency of findings of these trials supports the use of combination low-dose rivaroxaban plus aspirin in PAD patients across a broad spectrum of disease.
Authors: Scott D Berkowitz; Rupert M Bauersachs; Michael Szarek; Mark R Nehler; E Sebastian Debus; Manesh R Patel; Sonia S Anand; Warren H Capell; Connie N Hess; Judy Hsia; Nicholas J Leeper; David Brasil; Lajos Mátyás; Rafael Diaz; Marianne Brodmann; Eva Muehlhofer; Lloyd P Haskell; Marc P Bonaca Journal: J Thromb Haemost Date: 2022-03-07 Impact factor: 16.036