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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Greenberg reports personal fees from Janssen Research & Development LLC as a member of the steering committee of the COMMANDER HF trial and consulting fees from Bayer during the conduct of the study; consulting fees from Janssen Research & Development LLC, Bayer, Novartis, Mesoblast, Ionis Pharmaceuticals, Zensun USA, and Cellular Dynamics outside the submitted work; speaker fees from Novartis and Otsuka Pharmaceutical outside the submitted work; and personal fees from AstraZeneca, Actelion, Amgen, EBR Systems, Impulse Dynamics, MyoKardia, Rocket Pharma, Sanofi, and Viking Therapeutics outside the submitted work. Dr Neaton reports personal fees (honoraria) from Johnson & Johnson during the conduct of the study; fees from Janssen Research & Development LLC as a member of the steering committee of the COMMANDER HF trial; and fees from Bristol-Myers Squibb and EBR Systems for serving on data and safety monitoring boards for heart failure trials. Dr Anker reports personal fees from Janssen Research & Development LLC as a member of the steering committee of the COMMANDER HF trial during the conduct of the study; personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Laboratoires Servier, Thermo Fisher Scientific, Vifor Pharma, V-Wave, CVRx, and Impulse Dynamics outside the submitted work; and grants from Vifor Pharma and Abbott Vascular outside the submitted work. Dr Byra reports other support from Janssen Research & Development LLC during the conduct of the study and is employed by and is a shareholder of Johnson & Johnson. Dr Cleland reports personal fees from Janssen Research & Development LLC as a member of the steering committee of the COMMANDER HF trial and research grants and honoraria for speaking, committees, and advisory boards from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Medtronic, MyoKardia, Novartis, Philips Healthcare, Pharmacosmos, Pharma Nord, Sanofi, Laboratoires Servier, Stealth BioTherapeutics, Torrent Pharmaceuticals, and Vifor Pharma. Dr Deng reports other support from Janssen Research & Development LLC during the conduct of the study and outside the submitted work and is employed by and a shareholder of Johnson & Johnson. Dr Fu reports other support from Janssen Research & Development LLC during the conduct of the study and is employed by and a shareholder of Johnson & Johnson. Mr La Police reports other support from Janssen Research & Development LLC during the conduct of the study and is employed by and a shareholder of Johnson & Johnson. Dr Lam reports personal fees from Janssen Research & Development LLC during the conduct of the study; research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; personal fees from serving on the advisory board/steering committee/executive committee/clinical end points committee for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia Medical, Stealth BioTherapeutics, Jana Care, Biofourmis, Applied Therapeutics Inc, WebMD Global LLC, Radcliffe Group Ltd, Takeda Pharmaceutical Company, and Darma Laboratories outside the submitted work; and support from a Clinician Scientist Award from the National Medical Research Council of Singapore. Dr Mehra reports personal fees from Janssen Research & Development LLC as a member of the steering committee of the COMMANDER HF trial and consulting fees during the conduct of the study and personal fees from Abbott, Medtronic, Portola Pharmaceuticals, Bayer, Mesoblast, Baim Institute for Clinical Research, Xogenex, NupulseCV, and FineHeart outside the submitted work. Dr Nessel reports other support from Janssen Research & Development LLC during the conduct of the study and is employed by and a shareholder of Johnson & Johnson. Dr Spiro is employed by and is a shareholder of Bayer. Dr van Veldhuisen reports personal fees from Johnson & Johnson and Bayer during the conduct of the study and reports receiving board membership fees from Janssen Research & Development LLC as a member of the steering committee of the COMMANDER HF trial. Ms Vanden Boom reports other support from Janssen Research & Development LLC during the conduct of the study and is employed by and a shareholder of Johnson & Johnson. Dr Zannad reports personal fees from Janssen Research & Development LLC and Bayer during the conduct of the study; personal fees from AstraZeneca, Boehringer Ingelheim, LivaNova, GE Healthcare, Amgen, Novartis, Quantum Genomics, Cardior Pharmaceuticals, CardioRenal, CVCT, Merck, CVRx, Vifor Fresenius Medical Care Renal Pharma, NovoNordisk, and MundiPharma outside the submitted work; fees for serving on a steering committee or a safety and data monitoring board from Actelion, Amgen, Bayer, Boehringer Ingelheim, Boston Scientific, CVRx, GE Healthcare, Janssen Research & Development LLC, Novartis, and ResMed; and consulting fees from AstraZeneca, Cardior Pharmaceuticals, CardioRenal, Quantum Genomics, and Vifor Fresenius Medical Care Renal Pharma.

Figures

Figure.. Time to First Occurrence of Thromboembolic Events

A, The composite of thromboembolic events includes myocardial infarction, ischemic stroke, sudden/unwitnessed death, symptomatic pulmonary embolism, or symptomatic deep vein thrombosis. The cumulative percentage of patients with a thromboembolic event were 7%, 14%, and 18% after approximately 12, 24, and 36 months, respectively, among those assigned to rivaroxaban and 10%, 16%, and 22%, respectively, among those assigned to placebo. B, The composite of thromboembolic events includes myocardial infarction, ischemic stroke, symptomatic pulmonary embolism, or symptomatic deep vein thrombosis. The cumulative percentage of patients with a thromboembolic event excluding sudden/unwitnessed deaths was 4%, 7%, and 9% after 12, 24, and 36 months, respectively, for those patients assigned to rivaroxaban, and 5%, 8%, and 11%, respectively, for those assigned to placebo. HR indicates hazard ratio.