Microbleeds and the Effect of Anticoagulation in Patients With Embolic Stroke of Undetermined Source

Abstract

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 MEASURESThe 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,, 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 RELEVANCEMicrobleeds 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 out...

Cerebral microbleeds: from depiction to interpretation

“…With regard to anticoagulation, there were no interactions identified between baseline presence, location or severity of CMBs and rivaroxaban 15 mg daily compared with aspirin for the outcomes of IS, ICH or mortality over 11 months of follow-up in NAVIGATE ESUS participants (n=3699, 11% with CMBs). 111 In particular, there was no suggestion of a treatment effect for the outcome of sICH (participants with CMBs: HR 3.1, 95% CI 0.3 to 30.0; without CMBs: HR 3.0, 95% CI 0.6 to 14.7; interaction p=0.97).…”

Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke

“… 3 On the other hand, an exploratory analysis of 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) trial that compared the direct oral anticoagulant rivaroxaban to the platelet inhibitor aspirin recently showed that CMBs in patients with ischemic stroke may well be a marker of worse clinical outcome in general without implying annulment of a beneficial effect of an intervention. 9 …”

Atrial cardiopathy is associated with cerebral microbleeds in ischemic stroke patients

“…However, anti-coagulation use is known to not only increase the risk of symptomatic intracranial hemorrhage ( 33 ), but some data suggests that the number of CMB in patients with AF increase when patients are placed on oral anti-coagulation ( 2 , 34 ). However, subgroup analyses of the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. Aspirin to Prevent Embolism in Embolic Strokes of Undetermined Sources (NAVIGATE ESUS) trial found that while CMB are a marker of increased risk of recurrent stroke and mortality, they do not increase the risk of poor outcomes for patients on rivaroxaban vs. aspirin, which is encouraging ( 35 ).…”