Left Ventricular Dysfunction Among Patients With Embolic Stroke of Undetermined Source and the Effect of Rivaroxaban vs Aspirin: A Subgroup Analysis of the NAVIGATE ESUS Randomized Clinical Trial

Abstract

Importance: It is uncertain whether anticoagulation is superior to aspirin at reducing recurrent stroke in patients with recent embolic strokes of undetermined source (ESUS) and left ventricular (LV) dysfunction.

Objective: To determine whether anticoagulation is superior to aspirin in reducing recurrent stroke in patients with ESUS and LV dysfunction.

Design, setting, and participants: Post hoc exploratory analysis of data from the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) trial, a randomized, phase 3 clinical trial with enrollment from December 2014 to September 2017. The study setting included 459 stroke recruitment centers in 31 countries. Patients 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of the 7213 NAVIGATE ESUS participants, 7107 (98.5%) had a documented assessment of LV function at study entry and were included in the present analysis. Data were analyzed in January 2021.

Interventions: Participants were randomized to receive either 15 mg of rivaroxaban or 100 mg of aspirin once daily.

Main outcomes and measures: The study examined whether rivaroxaban was superior to aspirin at reducing the risk of (1) the trial primary outcome of recurrent stroke or systemic embolism and (2) the trial secondary outcome of recurrent stroke, systemic embolism, myocardial infarction, or cardiovascular mortality during a median follow-up of 10.4 months. LV dysfunction was identified locally through echocardiography and defined as moderate to severe global impairment in LV contractility and/or a regional wall motion abnormality. A Cox proportional hazards model was used to assess for treatment interaction and to estimate the hazard ratios for those randomized to rivaroxaban vs aspirin by LV dysfunction status.

Results: LV dysfunction was present in 502 participants (7.1%). Of participants with LV dysfunction, the mean (SD) age was 67 (10) years, and 130 (26%) were women. Among participants with LV dysfunction, annualized primary event rates were 2.4% (95% CI, 1.1-5.4) in those assigned to rivaroxaban vs 6.5% (95% CI, 4.0-11.0) in those assigned aspirin. Among the 6605 participants without LV dysfunction, rates were similar between those assigned to rivaroxaban (5.3%; 95% CI, 4.5-6.2) vs aspirin (4.5%; 95% CI, 3.8-5.3). Participants with LV dysfunction assigned to rivaroxaban vs aspirin had a lower risk of the primary outcome (hazard ratio, 0.36; 95% CI, 0.14-0.93), unlike those without LV dysfunction (hazard ratio, 1.16; 95% CI, 0.93-1.46) (P for treatment interaction = .03). Results were similar for the secondary outcome.

Conclusions and relevance: In this post hoc exploratory analysis, rivaroxaban was superior to aspirin in reducing the risk of recurrent stroke or systemic embolism among NAVIGATE ESUS participants with LV dysfunction.

Trial registration: ClinicalTrials.gov Identifier: NCT02313909.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Merkler reports grants from the American Heart Association during the conduct of the study and has served as an expert witness regarding neurological disorders outside the submitted work. Dr Kasner reports grant support from Bayer during the conduct of the study and grant support from W.L. Gore & Associates, Medtronic, Genentech, and Bristol-Myers Squibb; consulting fees from Medtronic, Bristol-Myers Squibb, and Abbott; and royalties from UpToDate outside the submitted work. Dr Shoamanesh reports grant support from Bayer during the conduct of the study and grant support from Bayer, Daiichi Sankyo Company, Bristol-Myers Squibb, Servier Canada, Portola Pharmaceuticals, and Octapharma and consulting fees from Bayer, Daiichi Sankyo Company, and Servier Canada outside the submitted work. Dr Kamel serves as co–principal investigator for the National Institutes of Health–funded ARCADIA trial, which receives in-kind study drugs from the Bristol-Myers Squibb–Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics; serves as Deputy Editor for JAMA Neurology; as a steering committee member of Medtronic’s Stroke AF trial (uncompensated); serves on an end point adjudication committee for a trial of empagliflozin for Boehringer-Ingelheim; and has served on an advisory board for Roivant Sciences related to Factor XI inhibition outside the submitted work. Dr Sheth reports grants from Hyperfine Research Inc, Bard, Biogen, and Novartis; personal fees from Zoll for service as chair of the data and safety monitoring board; personal fees from Ceribell and NControl; and other support from Alva outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flow Diagram

Figure 2.. Kaplan-Meier Curves for Time to Primary Outcome Event by Left Ventricular Dysfunction and Assigned Treatment

The primary outcome of this study was the primary efficacy outcome of the trial: the composite end point of recurrent stroke or systemic embolism.