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Original Investigation
April 24, 2019

Association of Rivaroxaban With Thromboembolic Events in Patients With Heart Failure, Coronary Disease, and Sinus Rhythm: A Post Hoc Analysis of the COMMANDER HF Trial

Author Affiliations
  • 1Cardiology Division, Department of Medicine, University of California, San Diego, La Jolla
  • 2Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis
  • 3Berlin–Brandenburg Center for Regenerative Therapies, Berlin, Germany
  • 4Department of Cardiology, German Center for Cardiovascular Research partner site Berlin, Charite Universitatsmedizin Berlin, Berlin, Germany
  • 5Janssen Research and Development, Raritan, New Jersey
  • 6Robertson Centre for Biostatistics and Clinical Trials, University of Glasgow, Glasgow, Scotland
  • 7National Heart and Lung Institute, Imperial College London, London, England
  • 8Janssen Research and Development, Spring House, Pennsylvania
  • 9National Heart Centre Singapore, Singapore
  • 10Duke-National University of Singapore, Singapore
  • 11Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  • 12Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 13Research and Development, Pharmaceuticals, Thrombosis and Hematology Therapeutic Area, Bayer US, Whippany, New Jersey
  • 14Universite de Lorraine, INSERM Unite 1116, Vandoeuvre les Nancy, France
  • 15Clinical Investigation Center 1433, French Clinical Research Infrastructure Network, Investigation Network Initiative–Cardiovascular and Renal Clinical Trialists, Centre Hospitalier Regional et Universitaire de Nancy, Vandoeuvre les Nancy, France
JAMA Cardiol. 2019;4(6):515-523. doi:10.1001/jamacardio.2019.1049
Key Points

Question  Did the addition of low-dose rivaroxaban to background antiplatelet therapy reduce risk for thromboembolic events in patients with chronic heart failure and reduced ejection fraction, coronary artery disease, and sinus rhythm?

Findings  In this post hoc analysis of a randomized clinical trial of 5022 patients, although thromboembolic events were not the major driver of the primary efficacy outcome, they occurred frequently. Rivaroxaban was associated with reduced risk of thromboembolic events compared with placebo from 15.5% to 13.1% with inclusion of sudden/unwitnessed deaths as part of the outcome and from 7.6% to 6.1% when sudden/unwitnessed deaths where not considered as part of the thromboembolic composite outcome.

Meaning  Thromboembolic events are common in patients with heart failure, coronary artery disease, and sinus rhythm, and rivaroxaban may reduce risk of their occurrence.

Abstract

Importance  Whether anticoagulation benefits patients with heart failure (HF) in sinus rhythm is uncertain. The COMMANDER HF randomized clinical trial evaluated the effects of adding low-dose rivaroxaban to antiplatelet therapy in patients with recent worsening of chronic HF with reduced ejection fraction, coronary artery disease (CAD), and sinus rhythm. Although the primary end point of all-cause mortality, myocardial infarction, or stroke did not differ between rivaroxaban and placebo, there were numerical advantages favoring rivaroxaban for myocardial infarction and stroke.

Objective  To examine whether low-dose rivaroxaban was associated with reduced thromboembolic events in patients enrolled in the COMMANDER HF trial.

Design, Setting, and Participants  Post hoc analysis of the COMMANDER HF multicenter, randomized, double-blind, placebo-controlled trial in patients with CAD and worsening HF. The trial randomized 5022 patients postdischarge from a hospital or outpatient clinic after treatment for worsening HF between September 2013 and October 2017. Patients were required to be receiving standard care for HF and CAD and were excluded for a medical condition requiring anticoagulation or a bleeding history. Patients were randomized in a 1:1 ratio. Analysis was conducted from June 2018 and January 2019.

Intervention  Patients were randomly assigned to receive 2.5 mg of rivaroxaban given orally twice daily or placebo in addition to their standard therapy.

Main Outcomes and Measures  For this post hoc analysis, a thromboembolic composite was defined as either (1) myocardial infarction, ischemic stroke, sudden/unwitnessed death, symptomatic pulmonary embolism, or symptomatic deep venous thrombosis or (2) all of the previous components except sudden/unwitnessed deaths because not all of these are caused by thromboembolic events.

Results  Of 5022 patients, 3872 (77.1%) were men, and the overall mean (SD) age was 66.4 (10.2) years. Over a median (interquartile range) follow-up of 19.6 (11.7-30.8) months, fewer patients assigned to rivaroxaban compared with placebo had a thromboembolic event including sudden/unwitnessed deaths: 328 (13.1%) vs 390 (15.5%) (hazard ratio, 0.83; 95% CI, 0.72-0.96; P = .01). When sudden/unwitnessed deaths were excluded, the results analyzing thromboembolic events were similar: 153 (6.1%) vs 190 patients (7.6%) with an event (hazard ratio, 0.80; 95% CI, 0.64-0.98; P = .04).

Conclusions and Relevance  In this study, thromboembolic events occurred frequently in patients with HF, CAD, and sinus rhythm. Rivaroxaban may reduce the risk of thromboembolic events in this population, but these events are not the major cause of morbidity and mortality in patients with recent worsening of HF for which rivaroxaban had no effect. While consistent with other studies, these results require confirmation in prospective randomized clinical trials.

Trial Registration  ClinicalTrials.gov identifier: NCT01877915

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