Microbleeds and the Effect of Anticoagulation in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Randomized Clinical Trial

Abstract

Importance: The reported associations of cerebral microbleeds with recurrent stroke and intracerebral hemorrhage have raised concerns regarding antithrombotic treatment in patients with a history of stroke and microbleeds on magnetic resonance imaging.

Objective: To characterize microbleeds in embolic strokes of undetermined source (ESUS) and report interactions between microbleeds and the effects of random assignment to anticoagulant vs antiplatelet therapy.

Design, setting, and participants: Subgroup analyses of the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) international, double-blind, randomized, event-driven phase 3 clinical trial. Participants were enrolled between December 2014 and September 2017 and followed up for a median of 11 months. The study setting included 459 stroke recruitment centers in 31 countries. Patients aged 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of these 7213 NAVIGATE ESUS participants, 3699 (51%) had information on cerebral microbleeds reported on their baseline clinical magnetic resonance imaging and were eligible for these analyses. Patients with a prior history of symptomatic intracerebral hemorrhage were excluded from the NAVIGATE ESUS trial.

Interventions: Rivaroxaban, 15 mg, compared with aspirin, 100 mg, daily.

Main outcomes and measures: The primary outcome was recurrent stroke. Secondary outcomes were ischemic stroke, intracerebral hemorrhage, and all-cause mortality.

Results: Microbleeds were present in 395 of 3699 participants (11%). Of patients with cerebral microbleeds, mean (SD) age was 69.5 (9.4) years, 241 were men (61%), and 201 were White (51%). Advancing age (odds ratio [OR] per year, 1.03; 95% CI, 1.01-1.04), East Asian race/ethnicity (OR, 1.57; 95% CI, 1.04-2.37), hypertension (OR, 2.20; 95% CI, 1.54-3.15), multiterritorial infarcts (OR, 1.95; 95% CI, 1.42-2.67), chronic infarcts (OR, 1.78; 95% CI, 1.42-2.23), and occult intracerebral hemorrhage (OR, 5.23; 95% CI, 2.76-9.90) were independently associated with microbleeds. The presence of microbleeds was associated with a 1.5-fold increased risk of recurrent stroke (hazard ratio [HR], 1.5; 95% CI, 1.0-2.3), a 4-fold risk of intracerebral hemorrhage (HR, 4.2; 95% CI, 1.3-13.9), a 2-fold risk of all-cause mortality (HR, 2.1; 95% CI, 1.1-4.3), and strictly lobar microbleeds with an approximately 2.5-fold risk of ischemic stroke (HR, 2.3; 95% CI, 1.3-4.3). There were no interactions between microbleeds and treatment assignments for recurrent stroke, ischemic stroke, or all-cause mortality. The HR of intracerebral hemorrhage on rivaroxaban was similar between persons with microbleeds (HR, 3.1; 95% CI, 0.3-30.0) and persons without microbleeds (HR, 3.0; 95% CI, 0.6-14.7; interaction P = .97).

Conclusions and relevance: Microbleeds mark an increased risk of recurrent stroke, ischemic stroke, intracerebral hemorrhage, and mortality in ESUS but do not appear to influence effects of rivaroxaban on clinical outcomes.

Trial registration: ClinicalTrials.gov Identifier: NCT02313909.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Shoamanesh reported receiving grants and personal fees from Bayer AG, Bristol Myers Squibb, Daiichi-Sankyo, Servier Canada Inc, Janssen, and Bayer Canada and personal lecture and advisory board fees from Bayer AG, Bristol Myers Squibb, Boehringer Ingelheim, Servier Canada Inc, and Bayer Canada during the conduct of the study. Dr Hart reported receiving a research contract and personal fees from Bayer AG during the conduct of the study. Dr Connolly reported receiving grants from Janssen and Boston Scientific; grants and personal fees from Bayer, BMS, Daiichi-Sankyo, Portola, Boehringer Ingelheim, and Sanofi outside of the submitted work; and an institutional research grant from Bayer. Dr Kasner reported receiving grants from WL Gore; grants and personal fees from Bayer and Janssen; and personal fees from Bristol Myers Squibb, Boehringer Ingelheim, Medtronic, and AbbVie outside of the submitted work. Dr Smith reported receiving a grant from McMaster University during the conduct of the study. Dr Martí-Fàbregas reported receiving grants and personal fees from Bayer, Janssen, Daichii-Sankyo, Pfizer, and Boehringer Ingelheim during the conduct of the study. Dr Uchiyama reported receiving personal fees from Bayer, Boehringer Ingelheim, Daiichi-Sankyo, AstraZeneca, Takeda, and Bristol Myers Squibb during the conduct of the study. Dr Mikulik reported receiving grants from the National Program of Sustainability II, the Ministry of Education Youth and Sports Czech Republic, and the International Clinical Research Center of St. Anne's University Hospital Brno outside the submitted work. Dr Veltkamp reported receiving grants and personal fees from Bayer, BMS, and Janssen and personal fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, and Daiichi-Sankyo outside of the submitted work. Dr O’Donnell reported receiving grants from Bayer and Janssen during the conduct of the study. Dr Ntaios reported receiving research support and personal fees from Bayer, Bristol Myers Squibb, Pfizer, and Boehringer Ingelheim during the conduct of the study. Dr Muir reported receiving grants from Bayer and Janssen; advisory board fees from Bayer, Daiichi-Sankyo, and Boehringer Ingelheim; and personal fees from ReNeuron during the conduct of the study. Dr Field reported receiving personal fees and research support from Bayer, Janssen, and Bristol Myers Squibb during the conduct of the study. Dr Santo reported receiving personal fees from Bayer and Janssen during the conduct of the study. Dr Olavarria reported receiving grants from Bayer, Janssen, Clínica Alemana de Santiago, Boehringer Ingelheim, and Comision Nacional de Investigacion Cientifica y Tecnologica outside the submitted work. Dr Mundl reported being employed by Bayer and receiving personal fees from Bayer during the conduct of the study. Dr Lutsep reported receiving grants from Bayer and Janssen and personal fees from Medscape Neurology, National Institute of Neurological Disorders and Stroke/Mayo CREST2 trial, BMS Axiomatic-SSP trial, and Coherex Medical outside the submitted work. Dr Berkowitz reported being employed as a clinical research physician by Bayer and receiving personal fees from Bayer during the conduct of the study. Dr Sharma reported receiving grants and personal fees from Bayer, BMS, and Janssen during the conduct of the study and personal fees from Bristol Myers Squibb, Boehringer Ingelheim, Portola, and Daiichi-Sankyo outside of the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flow Diagram

Figure 2.. Kaplan-Meier Curves for Outcomes Stratified by Cerebral Microbleed (CMB) Status

From a total of 7213 randomized participants, 395 CMBs were reported. CMB status included 190 recurrent stroke (A), 179 ischemic stroke (B), 12 intracerebral hemorrhage (C), and 49 all-cause mortality (D). HR indicates hazard ratio.