Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial.
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ABSTRACT: Background
Embolic strokes of undetermined source comprise up to 20% of ischemic strokes. The stroke recurrence rate is substantial with aspirin, widely used for secondary prevention. The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source international trial will compare the efficacy and safety of rivaroxaban, an oral factor Xa inhibitor, versus aspirin for secondary prevention in patients with recent embolic strokes of undetermined source.Main hypothesis
In patients with recent embolic strokes of undetermined source, rivaroxaban 15 mg once daily will reduce the risk of recurrent stroke (both ischemic and hemorrhagic) and systemic embolism (primary efficacy outcome) compared with aspirin 100 mg once daily.Design
Double-blind, randomized trial in patients with embolic strokes of undetermined source, defined as nonlacunar cryptogenic ischemic stroke, enrolled between seven days and six months from the qualifying stroke. The planned sample size of 7000 participants will be recruited from approximately 480 sites in 31 countries between 2014 and 2017 and followed for a mean of about two years until at least 450 primary efficacy outcome events have occurred. The primary safety outcome is major bleeding. Two substudies assess (1) the relative effect of treatments on MRI-determined covert brain infarcts and (2) the biological underpinnings of embolic strokes of undetermined source using genomic and biomarker approaches.Summary
The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source trial is evaluating the benefits and risks of rivaroxaban for secondary stroke prevention in embolic strokes of undetermined source patients. Main results are anticipated in 2018.
SUBMITTER: Hart RG
PROVIDER: S-EPMC6301240 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial is a randomized phase-III trial comparing rivaroxaban versus aspirin in patients with recent ESUS.AimsWe aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups.MethodsWe enrolled 7213 patients at 459 sites in 31 countries. Prespecified subgroups for primary safety and efficacy analyses included age, sex, race, global region, stroke or transient ischemic attack prior to qualifying event, time to randomization, hypertension, and diabetes mellitus.ResultsMean age was 66.9 ± 9.8 years; 24% were under 60 years. Older patients had more hypertension, coronary disease, and cancer. Strokes in older subjects were more frequently cortical and accompanied by radiographic evidence of prior infarction. Women comprised 38% of participants and were older than men. Patients from East Asia were oldest whereas those from Latin America were youngest. Patients in the Americas more frequently were on aspirin prior to the qualifying stroke. Acute cortical infarction was more common in the United States, Canada, and Western Europe, whereas prior radiographic infarctions were most common in East Asia. Approximately forty-five percent of subjects were enrolled within 30 days of the qualifying stroke, with earliest enrollments in Asia and Eastern Europe.ConclusionsNAVIGATE-ESUS is the largest randomized trial comparing antithrombotic strategies for secondary stroke prevention in patients with ESUS. The study population encompasses a broad array of patients across multiple continents and these subgroups provide ample opportunities for future research.
| S-EPMC6701183 | biostudies-literature
Project description:BACKGROUND:Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. METHODS:NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. FINDINGS:Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22-1·36), and the risk was similar for those without known PFO (1·06; 0·84-1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51-8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69-4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24-0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. INTERPRETATION:Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. FUNDING:Bayer and Janssen.
| S-EPMC6662613 | biostudies-literature
Project description:ImportanceIt 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.ObjectiveTo determine whether anticoagulation is superior to aspirin in reducing recurrent stroke in patients with ESUS and LV dysfunction.Design, setting, and participantsPost 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.InterventionsParticipants were randomized to receive either 15 mg of rivaroxaban or 100 mg of aspirin once daily.Main outcomes and measuresThe 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.ResultsLV 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 relevanceIn 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 registrationClinicalTrials.gov Identifier: NCT02313909.
| S-EPMC8546621 | biostudies-literature
Project description:Background and purposeOne-fifth of ischemic strokes are embolic strokes of undetermined source (ESUS). Their theoretical causes can be classified as cardioembolic versus noncardioembolic. This distinction has important implications, but the categories' proportions are unknown.MethodsUsing data from the Cornell Acute Stroke Academic Registry, we trained a machine-learning algorithm to distinguish cardioembolic versus non-cardioembolic strokes, then applied the algorithm to ESUS cases to determine the predicted proportion with an occult cardioembolic source. A panel of neurologists adjudicated stroke etiologies using standard criteria. We trained a machine learning classifier using data on demographics, comorbidities, vitals, laboratory results, and echocardiograms. An ensemble predictive method including L1 regularization, gradient-boosted decision tree ensemble (XGBoost), random forests, and multivariate adaptive splines was used. Random search and cross-validation were used to tune hyperparameters. Model performance was assessed using cross-validation among cases of known etiology. We applied the final algorithm to an independent set of ESUS cases to determine the predicted mechanism (cardioembolic or not). To assess our classifier's validity, we correlated the predicted probability of a cardioembolic source with the eventual post-ESUS diagnosis of atrial fibrillation.ResultsAmong 1083 strokes with known etiologies, our classifier distinguished cardioembolic versus noncardioembolic cases with excellent accuracy (area under the curve, 0.85). Applied to 580 ESUS cases, the classifier predicted that 44% (95% credibility interval, 39%-49%) resulted from cardiac embolism. Individual ESUS patients' predicted likelihood of cardiac embolism was associated with eventual atrial fibrillation detection (OR per 10% increase, 1.27 [95% CI, 1.03-1.57]; c-statistic, 0.68 [95% CI, 0.58-0.78]). ESUS patients with high predicted probability of cardiac embolism were older and had more coronary and peripheral vascular disease, lower ejection fractions, larger left atria, lower blood pressures, and higher creatinine levels.ConclusionsA machine learning estimator that distinguished known cardioembolic versus noncardioembolic strokes indirectly estimated that 44% of ESUS cases were cardioembolic.
| S-EPMC8034802 | biostudies-literature
Project description:Background We sought to determine recurrent stroke predictors among patients with embolic strokes of undetermined source (ESUS). Methods and Results We applied Cox proportional hazards models to identify clinical features associated with recurrent stroke among participants enrolled in RE-SPECT ESUS (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) trial, an international clinical trial evaluating dabigatran versus aspirin for patients with ESUS. During a median follow-up of 19 months, 384 of 5390 participants had recurrent stroke (annual rate, 4.5%). Multivariable models revealed that stroke or transient ischemic attack before the index event (hazard ratio [HR], 2.27 [95% CI, 1.83-2.82]), creatinine clearance <50 mL/min (HR, 1.69 [95% CI, 1.23-2.32]), male sex (HR, 1.60 [95% CI, 1.27-2.02]), and CHA2DS2-VASc ≥4 (HR, 1.55 [95% CI, 1.15-2.08] and HR, 1.66 [95% CI, 1.21-2.26] for scores of 4 and ≥5, respectively) versus CHA2DS2-VASc of 2 to 3, were independent predictors for recurrent stroke. Conclusions In RE-SPECT ESUS trial, expected risk factors previously linked to other common stroke causes were associated with stroke recurrence. These data help define high-risk groups for subsequent stroke that may be useful for clinicians and for researchers designing trials among patients with ESUS. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.
| S-EPMC9238731 | biostudies-literature
Project description:ImportanceThe 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.ObjectiveTo 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 participantsSubgroup 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.InterventionsRivaroxaban, 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.ResultsMicrobleeds 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 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 outcomes.Trial registrationClinicalTrials.gov Identifier: NCT02313909.
| S-EPMC7573796 | biostudies-literature
Project description:Background and Purpose- The RE-SPECT ESUS trial (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) tested the hypothesis that dabigatran would be superior to aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. This exploratory subgroup analysis investigates the impact of age, renal function (both predefined), and dabigatran dose (post hoc) on the rates of recurrent stroke and major bleeding. Methods- RE-SPECT ESUS was a multicenter, randomized, double-blind trial of dabigatran 150 or 110 mg (for patients aged ≥75 years and/or with creatinine clearance 30 to <50 mL/minute) twice daily compared with aspirin 100 mg once daily. The primary outcome was recurrent stroke. Results- The trial, which enrolled 5390 patients from December 2014 to January 2018, did not demonstrate superiority of dabigatran versus aspirin for prevention of recurrent stroke in patients with embolic stroke of undetermined source. However, among the population qualifying for the lower dabigatran dose, the rate of recurrent stroke was reduced with dabigatran versus aspirin (7.4% versus 13.0%; hazard ratio, 0.57 [95% CI, 0.39-0.82]; interaction P=0.01). This was driven mainly by the subgroup aged ≥75 years (7.8% versus 12.4%; hazard ratio, 0.63 [95% CI, 0.43-0.94]; interaction P=0.10). Stroke rates tended to be lower with dabigatran versus aspirin with declining renal function. Risks for major bleeding were similar between treatments, irrespective of renal function, but with a trend for lower bleeding rates with dabigatran versus aspirin in older patients. Conclusions- In subgroup analyses of RE-SPECT ESUS, dabigatran reduced the rate of recurrent stroke compared with aspirin in patients qualifying for the lower dose of dabigatran. These results are hypothesis-generating. Aspirin remains the standard antithrombotic treatment for patients with embolic stroke of undetermined source. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.
| S-EPMC7379165 | biostudies-literature
Project description:Embolic stroke of undetermined source (ESUS) recurrence and functional outcome from long-term follow-up is not well delineated. The purpose of this study is to compare these functional variables between ESUS vs. cardioembolic stroke (CS) patients.We analyzed data of consecutive ESUS and CS patients from our institutional database, from January 2003 until April 2015. The endpoints were stroke recurrence, mortality and poor clinical outcome (Modified Rankin Score 3-6), at discharge, 6 months and final follow-up. Adjusted multivariate Cox analysis and Kaplan-Meier curves were used to estimate the probability of recurrence and death.149 ESUS (median age 44 years) and 235 CS (median age 66 years) consecutive patients were included in the study. Median follow-up period for the entire sample was 19 months (interquartile range 6.0-45.0 months). Stroke recurrence was similar between ESUS and CS patients (5.4% vs. 9.8% respectively, p = 0.12). Death occurred in 30 CS cases (12.8%), with a cumulative probability of survival of 77%. Poor functional outcome was present in 58.3%, 54.0% and 54.9% at discharge, 6 months and final follow-up respectively in CS patients, significantly worst compared to ESUS cases (HR 3.1; CI 95% 1.96-4.68). Oral anticoagulation presents with a HR 8.01 for recurrence, and antiplatelet therapy had the highest risk for recurrence for both groups (HR 24.3).ESUS patients are substantially younger than CS patients but have a stroke recurrence rate similar to CS patients, with a lower mortality rate, and better functional outcome on long-term follow-up.
| S-EPMC5104315 | biostudies-other
Project description:PurposeThe etiology of an ischemic stroke remains undetermined in 20-35% of cases and many patients do not have any of the conventional risk factors. Increased visceral adipose tissue (VAT) is a suggested new risk factor for both carotid artery atherosclerosis (CAA) and atrial fibrillation (AF), but its role in the remaining stroke population is unknown. We assessed the amount of VAT in patients with embolic stroke of undetermined source (ESUS) after excluding major-risk cardioembolic sources, occlusive atherosclerosis, and lacunar stroke.MethodsAltogether 58 patients (mean age 57.7 ± 10.2 years, 44 men) with ischemic stroke of unknown etiology but without CAA, known AF or small vessel disease underwent computed tomography angiography and assessment of VAT. For comparison VAT values from three different reference populations were used. Conventional risk factors (smoking, hypertension, diabetes, increased total and LDL-cholesterol, decreased HDL-cholesterol) were also registered.ResultsMean VAT area was significantly higher in stroke patients (205 ± 103 cm2 for men and 168 ± 99 cm2 for women) compared to all reference populations (P < 0.01). 50% of male and 57% of female patients had an increased VAT area. In male patients, VAT was significantly higher despite similar body mass index (BMI). Increased VAT was more common than any of the conventional risk factors.ConclusionIncreased VAT was found in over half of our patients with ESUS suggesting it may have a role in the pathogenesis of thromboembolism in this selected group of patients.
| S-EPMC4354901 | biostudies-literature
Project description:ObjectiveOur aim was to evaluate the diagnostic yield of transesophageal echocardiography (TEE) in consecutive patients with ischemic stroke (IS) fulfilling the diagnostic criteria of embolic strokes of undetermined source (ESUS).MethodsWe prospectively evaluated consecutive patients with acute IS satisfying ESUS criteria who underwent in-hospital TEE examination in 3 tertiary care stroke centers during a 12-month period. We also performed a systematic review and meta-analysis estimating the cumulative effect of TEE findings on therapeutic management for secondary stroke prevention among different IS subgroups.ResultsWe identified 61 patients with ESUS who underwent investigation with TEE (mean age 44 ± 12 years, 49% men, median NIH Stroke Scale score = 5 points [interquartile range: 3-8]). TEE revealed additional findings in 52% (95% confidence interval [CI]: 40%-65%) of the study population. TEE findings changed management (initiation of anticoagulation therapy, administration of IV antibiotic therapy, and patent foramen ovale closure) in 10 (16% [95% CI: 9%-28%]) patients. The pooled rate of reported anticoagulation therapy attributed to abnormal TEE findings among 3,562 acute IS patients included in the meta-analysis (12 studies) was 8.7% (95% CI: 7.3%-10.4%). In subgroup analysis, the rates of initiation of anticoagulation therapy on the basis of TEE investigation did not differ (p = 0.315) among patients with cryptogenic stroke (6.9% [95% CI: 4.9%-9.6%]), ESUS (8.1% [95% CI: 3.4%-18.1%]), and IS (9.4% [95% CI: 7.5%-11.8%]).ConclusionsAbnormal TEE findings may decisively affect the selection of appropriate therapeutic strategy in approximately 1 of 7 patients with ESUS.
| S-EPMC5027807 | biostudies-literature