Author + information
- Received March 2, 2018
- Revision received March 2, 2018
- Accepted March 2, 2018
- Published online March 11, 2018.
- Sonia S. Anand, MD, PhDa,∗ (, )
- Francois Caron, MDb,
- John W. Eikelboom, MBBS, MSca,
- Jackie Bosch, MSc, PhDa,
- Leanne Dyal, MSca,
- Victor Aboyans, MD, PhDc,
- Maria Teresa Abola, MDd,
- Kelley R.H. Branch, MD, MSce,
- Katalin Keltai, MD, PhDf,
- Deepak L. Bhatt, MD, MPHg,
- Peter Verhamme, MDh,
- Keith A.A. Fox, MDChB, BSci,
- Nancy Cook-Bruns, MDj,
- Vivian Lanius, PhDj,
- Stuart J. Connolly, MDa,
- Salim Yusuf, DPhil, FRSCa,
- for the COMPASS trial Investigators
- aDepartment of Medicine, Population Health Research Institute, McMaster University, Hamilton Health Sciences
- bDepartment of Medicine, Population Health Research Institute, McMaster University, Hamilton Health Sciences, CISSS d Bas-St-Laurent
- cDepartment of Cardiology, Dupuytren University Hospital, Limoges, France
- dDepartment of Medicine, University of Philippines College of Medicine
- eDepartment of Medicine, University of Washington
- fDepartment of Medicine, Semmelweis University, Budapest, Hungary
- gDepartment of Medicine, Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts, USA
- hDepartment of Medicine, University of Leuven
- iProfessor of Cardiology, University of Edinburgh, Edinburgh, UK
- jBayer Healthcare, Wuppertal, Germany
- ↵∗Corresponding Author: Sonia S. Anand, MD, PhD Population Health Research Institute 30 Birge Street Hamilton, Ontario, Canada, L8L 0A6 Telephone: 905-525-9140 ext. 21523 Fax: 905-528-2814.
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 suffer MALE.
Objectives Among participants with lower extremity PAD, we investigated: 1) if hospitalizations, MACE, amputations, and deaths are higher after first episode of MALE compared with PAD patients who do not experience MALE and 2) the impact of treatment with low dose rivaroxaban and aspirin compared to 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 trial - a randomized double blind placebo controlled trial of low dose rivaroxaban and aspirin combination, rivaroxaban alone, as compared to aspirin alone. MALE was defined as severe limb ischemia leading to an intervention or major vascular amputation.
Results A total of 128 patients suffered an incident MALE. After MALE, the one year cumulative risk of a subsequent hospitalization was 95.4%, for vascular amputations it was 22.9%, for death it was 8.7%, and for MACE it was 3.8%. The MALE index event significantly increased the risk to experience subsequent hospitalizations (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).
Summary Among individuals with lower extremity PAD, the development of MALE is associated with a poor prognosis, making its prevention of utmost importance. The combination of rivaroxaban 2.5 mg bid and aspirin significantly lowers the incidence of MALE and its related complications and should be considered as an important therapy for patients with PAD.
Clinical trial This is a subgroup analysis of a clinical trial called COMPASS registered on clinical trials.gov.
Funder: Bayer AG
Disclosures: Anand has received honoraria and consulting fees from Bayer and Novartis. Eikelboom reports grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, during the conduct of the study; grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Janssen, Astra Zeneca, Eli Lilly, Glaxo Smith Kline, and Sanofi Aventis, outside the submitted work. Aboyans has received honoraria from Bayer, BMS, Pfizer, and Novartis, Pfizer/BMS alliance, MSD, outside the submitted work. Branch reports grants from Bayer, Astellas, and Janseen during the conducted of the study outside of the submitted work. Bhatt discloses the following relationships - Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Population Health Research Institute; Honoraria: 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 COMPASS: US National Lead Investigator, Steering Committee, and Operations Committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott); Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, PLx Pharma, Takeda. Verhamme has received grants and honoraria from Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Pfizer, Sanofi, and LEO Pharma. Fox reports grants and personal fees from Bayer/ Janssen, during the conduct of the study; grants and personal fees from AstraZeneca, personal fees from Sanofi/ Regeneron, personal fees from Lilly, outside the submitted work. Cook-Bruns and Lanius are employed by Bayer AG. Connolly reports grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, during the conduct of the study; grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Janssen, Astra Zeneca, Portola and Sanofi Aventis, outside the submitted work. Yusuf has received research grants and honoraria and travel reimbursement for speaking from Bayer, Boehringer Ingelheim, BMS, Astra Zeneca and Sanofi Aventis and research grants from Cadila. Bosch, Keltai, Caron, Dyal, and Abola have nothing to disclose.
- Received March 2, 2018.
- Revision received March 2, 2018.
- Accepted March 2, 2018.
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