Predictors of Recurrent Ischemic Stroke in Patients with Embolic Strokes of Undetermined Source and Effects of Rivaroxaban Versus Aspirin According to Risk Status: The NAVIGATE ESUS Trial

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Abstract

Background: Embolic stroke of undetermined source (ESUS) identifies patients with cryptogenic ischemic stroke presumed due to embolism from several unidentified sources. Among patients with recent ESUS, we sought to determine independent predictors of recurrent ischemic stroke during treatment with aspirin or rivaroxaban and to assess the relative effects of these treatments according to risk. Methods: Exploratory analyses of 7213 participants in the NAVIGATE ESUS international trial who were randomized to aspirin 100 mg/day or rivaroxaban 15 mg/day and followed for a median of 11 months, during which time there were 309 first recurrent ischemic strokes (4.6% per year). Baseline features were correlated with recurrent stroke by multivariate analysis. Results: The 7 independent predictors of recurrent stroke were stroke or transient ischemic attack (TIA) prior to the qualifying stroke (hazard ratio [HR] 2.03 95% confidence internal [CI] 1.58-2.60), current tobacco user (HR 1.62, 95% CI 1.24-2.12), age (HR 1.02 per year increase, 95%CI 1.01-1.03), diabetes (HR 1.28, 95% CI 1.01-1.64), multiple acute infarcts on neuroimaging (HR 1.49, 95% CI 1.09-2.02), aspirin use prior to qualifying stroke (HR 1.34, 95% CI 1.02-1.70), and time from qualifying stroke to randomization (HR .98, 95% CI .97-.99). The rate of recurrent stroke rate was 2.6% per year for participants without any of these risk factors, and increased by an average of 45% for each independent predictor (P < .001). There were no significant interactions between treatment effects and independent stroke predictors or stroke risk status. Conclusions: In this large cohort of ESUS patients, several features including prior stroke or TIA, advanced age, current tobacco user, multiple acute infarcts on neuroimaging, and diabetes independently identified those with an increased risk of ischemic stroke recurrence. The relative effects of rivaroxaban and aspirin were similar across the spectrum of independent stroke predictors and recurrent stroke risk status.

Introduction

Ischemic strokes of uncertain cause (ie, cryptogenic strokes) remain frequent despite diagnostic advances aimed at determining stroke etiology.1, 2 Most nonlacunar cryptogenic ischemic strokes are likely due to emboli originating from one of several potential cardiac and arterial sources and occasionally from venous thromboembolism (ie, via paradoxical embolism),3 and the construct of embolic strokes of undetermined source (ESUS) has been proposed.1 ESUS criteria identify patients with a rate of recurrent ischemic stroke that averages about 5% per year.4, 5, 6

In the New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source (NAVIGATE ESUS) randomized trial, we compared rivaroxaban (an anticoagulant), a selective direct factor Xa inhibitor, with aspirin (an antiplatelet drug) for prevention of recurrent stroke in ESUS patients.7 Rates of recurrent ischemic stroke were similar in both treatment arms.5 Here, we analyze independent predictors of recurrent ischemic stroke and the relative effects of rivaroxaban versus aspirin among high-risk ESUS patients.8 Because the presumed underlying potential embolic sources were heterogeneous, treatment interactions with individual risk factors for recurrent stroke were explored in order to potentially shed light on the overall neutral trial results. Seeking pathomechanistic insights, we additionally assessed differences in independent predictors between antithrombotic treatment arms and on recurrent strokes classified as recurrent ESUS.

Section snippets

Methods

NAVIGATE ESUS (ClinicalTrials.gov number NCT02313909) was an international, double-blinded, randomized phase III trial conducted at 459 centers in 31 countries and involved 7213 participants. The study rationale, design, participant features, and main results have been previously published.1, 5, 7, 9 Patients with recent (7 days to 6 months) ischemic stroke visualized by neuroimaging were eligible if they met criteria for ESUS as proposed by the Cryptogenic Stroke/ESUS International Working

Results

The 7213 participants were recruited from Europe (59%), East Asia (19%), North America (13%), and Latin America (10%). The mean participant age was 67 years, 62% were men, and history of hypertension, diabetes, and prior stroke or TIA was present in 77%, 25%, and 17%, respectively. Participants were randomized, on average, 37 days after the qualifying ESUS. During a median follow-up of 11 months, first recurrent ischemic strokes occurred in 309 participants (annualized rate 4.6% per year), with

Discussion

In undertaking these exploratory analyses, we sought to identify a distinctive pattern of recurrent stroke predictors that would be relatively specific to ESUS patients and that would offer pathomechanistic insights into the heterogeneous underlying embolic sources and to their responses to antiplatelet versus anticoagulant therapy. Prior stroke or TIA was the strongest and most consistent predictor of recurrent ischemic stroke (and also of recurrent ESUS), but this feature does not offer clues

Conflict of Interest

All authors received payments for participating in the NAVIGATE ESUS randomized trial except for HM, SDB and GP who were employed by the trial sponsors (Bayer AG, Janssen Research and Development LLC).

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