Author + information
- Received March 2, 2018
- Revision received March 2, 2018
- Accepted March 2, 2018
- Published online May 14, 2018.
- Sonia S. Anand, MD, PhDa,∗ (, )
- Francois Caron, MDa,b,
- John W. Eikelboom, MBBS, MSca,
- Jackie Bosch, MSc, PhDc,d,
- Leanne Dyal, MScd,
- Victor Aboyans, MD, PhDe,
- Maria Teresa Abola, MDf,
- Kelley R.H. Branch, MD, MScg,
- Katalin Keltai, MD, PhDh,
- Deepak L. Bhatt, MD, MPHi,
- Peter Verhamme, MDj,
- Keith A.A. Fox, MBChB, BSck,
- Nancy Cook-Bruns, MDl,
- Vivian Lanius, PhDl,
- Stuart J. Connolly, MDa and
- Salim Yusuf, DPhila
- aDepartment of Medicine, Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada
- bCISSS du Bas-St-Laurent, Quebec, Canada
- cSchool of Rehabilitation Science, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada
- dPopulation Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada
- eDepartment of Cardiology, Dupuytren University Hospital, Limoges, France
- fDepartment of Medicine, University of Philippines/Philippine Heart Centre, Manila, Philippines
- gDepartment of Medicine, University of Washington, Seattle, Washington
- hDepartment of Medicine, Semmelweis University, Budapest, Hungary
- iDepartment of Medicine, Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts
- jDepartment of Medicine, University of Leuven, Leuven, Belgium
- kUniversity of Edinburgh, Edinburgh, United Kingdom
- lBayer AG, Wuppertal, Germany
- ↵∗Address for correspondence:
Dr. Sonia S. Anand, Population Health Research Institute, McMaster University, 30 Birge Street, Hamilton, Ontario L8L 0A6, Canada.
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)
This study was funded by Bayer AG. Dr. Anand is supported by a Tier 1 Canada Research Chair in Ethnicity and Cardiovascular Disease and the Michael G. DeGroote Heart and Stroke Foundation Chair in Population Health. Dr. Eikelboom is supported by the Jack Hirsh Population Health Research Institute Chair in Thrombosis Research. Dr. Yusuf is supported by the Heart & Stroke Foundation/Marion W. Burke Chair in Cardiovascular Disease. Dr. Anand has received honoraria and consulting fees from Bayer and Novartis. Dr. Eikelboom has received grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Janssen, AstraZeneca, Eli Lilly, GlaxoSmithKline, and Sanofi-Aventis. Dr. Aboyans has received honoraria from Bayer, Bristol-Myers Squibb, Pfizer, Novartis, Pfizer/Bristol-Myers Squibb alliance, and Merck Sharp and Dohme. Dr. Abola has received speaker fees from AstraZeneca, Bayer, and Pfizer. Dr. Branch has received grants from Bayer, Astellas, and Janssen. Dr. Bhatt is a member of the advisory board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; on the board of directors for Boston VA Research Institute and the Society of Cardiovascular Patient Care; is chair of the American Heart Association Quality Oversight Committee; a member of data monitoring committees for the Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, and the Population Health Research Institute; has received honoraria from the American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; vice-chair, ACC Accreditation Committee), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), Population Health Research Institute (clinical trial steering committee, including for his roles in the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] trial as the U.S. national lead investigator, steering committee member, and operations committee member), Slack Publications (chief medical editor, Cardiology Today’s Intervention), the Society of Cardiovascular Patient Care (secretary/treasurer), and WebMD (CME steering committees); other involvement, including Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), and the VA CART Research and Publications Committee (chair); has received research funding from Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi-Aventis, and The Medicines Company; has received royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as site co-investigator for Biotronik, Boston Scientific, and St. Jude Medical (now Abbott); is a Trustee for the American College of Cardiology; and has performed unfunded research for FlowCo, Merck, PLx Pharma, and Takeda. Dr. Verhamme has received grants and honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Pfizer, Sanofi, and LEO Pharma. Dr. Fox has received grants and personal fees from AstraZeneca and Bayer/Janssen; and personal fees from Lilly and Sanofi/Regeneron. Drs. Cook-Bruns and Lanius are employed by Bayer AG. Dr. Connolly has received grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Janssen, AstraZeneca, Portola, and Sanofi-Aventis. Dr. Yusuf has received research grants and honoraria and travel reimbursement for speaking from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, AstraZeneca, and Sanofi-Aventis; and research grants from Cadila. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received March 2, 2018.
- Revision received March 2, 2018.
- Accepted March 2, 2018.
- 2018 American College of Cardiology Foundation