Rivaroxaban Plus Aspirin in Obese and Overweight Patients With Vascular Disease in the COMPASS Trial

Abstract

Background: Direct oral anticoagulants are administered in fixed doses irrespective of body weight, but guidelines recommend against their use in patients with extremes of body weight.

Objectives: This study determined the effects of dual-pathway inhibition antithrombotic regimen (rivaroxaban 2.5 mg twice daily plus aspirin 100 mg/day) compared with aspirin Halone across a range of patient body mass indexes (BMIs) and body weights.

Methods: This was a secondary analysis of the COMPASS (Cardiovascular OutcoMes for People using Anticoagulation StrategieS) trial, which included patients with chronic coronary artery disease or peripheral artery disease. Efficacy and safety outcomes were studied in relation to BMI: (normal 18.5 ≤BMI <25 kg/m2, overweight 25 ≤BMI <30 kg/m2, obese ≥30 kg/m2) and body weight (≤70 kg, 70 < weight ≤90 kg, and >90 kg; as well as ≤120 kg vs. >120 kg).

Results: Among 27,395 randomized patients, 6,459 (24%) had normal BMI, 12,047 (44%) were overweight, and 8,701 (32%) were obese. The combination of rivaroxaban and aspirin compared with aspirin produced a consistent reduction in the primary outcome of cardiovascular death, stroke, or myocardial infarction, irrespective of BMI or body weight. For 18.5 ≤BMI <25 kg/m2: 3.5% vs. 5.0%; hazard ratio (HR): 0.73 (95% credible interval [CrI]: 0.58 to 0.90); 25 ≤ BMI <30 kg/m2: 4.3% vs. 5.1%; HR: 0.80 (95% CrI: 0.66 to 0.96); BMI ≥30 kg/m2: 4.2% vs. 6.1%; HR: 0.71 (95% CrI: 0.57 to 0.86). For body weight ≤70 kg: 4.1% vs. 5.3%; HR: 0.75 (95% CrI: 0.62 to 0.91); 70 < weight ≤90 kg: 4.1% vs. 5.3%; HR: 0.76 (95% CrI: 0.65 to 0.89); >90 kg: 4.2% vs. 5.7%; HR: 0.74 (95% CrI: 0.61 to 0.90). Effects on bleeding, mortality, and net clinical benefit were consistent irrespective of BMI or bodyweight.

Conclusions: The effects of dual-pathway antithrombotic therapy are consistent irrespective of BMI or body weight, suggesting no need for dose adjustments in the ranges of weights and BMI of patients enrolled in the COMPASS trial. Further studies need to address this problem in relation to greater extremes of body weight. (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease [COMPASS]; NCT01776424).

Keywords: DOAC; cardiovascular risk; prevention; rivaroxaban.

Conflict of interest statement

Funding Support and Author Disclosures Bayer AG funded the COMPASS trial and had nonvoting members on the Steering Committee. The COMPASS trial data was collected and managed by the Population Health Research Institute. The data analysis for this paper was conducted by PHRI. Bayer coauthors (Drs. Berkowitz and Muehlhofer) reviewed and provided comments on this paper. Drs. Guzik, Pogosova, and Lopez-Jaramillo have received grants and speaking/consulting fees from Bayer during the conduct of the study. Dr. Guzik has received funding from the European Research Council (Project Identifier: InflammaTENSION–726318). Dr. Berkowitz is employed as a clinical research physician by Bayer US, LLC. Dr. Bhatt has served on the advisory board of Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, MyoKardia, PhaseBio, PLx Pharma, and Regado Biosciences; has served on the Board of Directors of Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; has served as chair of the American Heart Association Quality Oversight Committee, NCDR-ACTION Registry Steering Committee, and VA CART Research and Publications Committee; has served on Data Monitoring Committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), and 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), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Cochair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national coleader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); has served as Deputy Editor for Clinical Cardiology; has received research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, MyoKardia, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, 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, CSI, St. Jude Medical (now Abbott), and Svelte; has served as a Trustee of the American College of Cardiology; and has performed unfunded research for FlowCo, Merck, Novo Nordisk, and Takeda. Dr. Fox has received grants and personal fees from AstraZeneca and Bayer/Janssen, as well as personal fees from Lilly and Sanofi/Regeneron. Dr. Muehlhofer is employed as Global Clinical Leader Thrombosis by Bayer A.G. Dr. Yusuf is supported by the Heart & Stroke Foundation/Marion W. Burke Chair in Cardiovascular Disease; has received research grants and honoraria and travel reimbursement for speaking from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, AstraZeneca, and Sanofi; and has received research grants from Cadila. Dr. Eikelboom is supported by the Jack Hirsh Population Health Research Institute Chair in Thrombosis Research; has received grants and personal fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, and Daiichi-Sankyo during the conduct of the study; and has received grants and personal fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi-Sankyo, Janssen, AstraZeneca, Eli Lilly, GlaxoSmithKline, and Sanofi, outside of the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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