Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source.

BACKGROUND: Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin. METHODS: We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding. RESULTS: A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001). CONCLUSIONS: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).

Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial.

BACKGROUND: The 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. AIMS: We aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups. METHODS: We 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. RESULTS: Mean 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. CONCLUSIONS: NAVIGATE-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.

Global Survey of the Frequency of Atrial Fibrillation-Associated Stroke: Embolic Stroke of Undetermined Source Global Registry.

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) is increasingly recognized as the single most important cause of disabling ischemic stroke in the elderly. We undertook an international survey to characterize the frequency of AF-associated stroke, methods of AF detection, and patient features. METHODS: Consecutive patients hospitalized for ischemic stroke in 2013 to 2014 were surveyed from 19 stroke research centers in 19 different countries. Data were analyzed by global regions and World Bank income levels. RESULTS: Of 2144 patients with ischemic stroke, 590 (28%; 95% confidence interval, 25.6-29.5) had AF-associated stroke, with highest frequencies in North America (35%) and Europe (33%) and lowest in Latin America (17%). Most had a history of AF before stroke (15%) or newly detected AF on electrocardiography (10%); only 2% of patients with ischemic stroke had unsuspected AF detected by poststroke cardiac rhythm monitoring. The mean age and 30-day mortality rate of patients with AF-associated stroke (75 years; SD, 11.5 years; 10%; 95% confidence interval, 7.6-12.6, respectively) were substantially higher than those of patients without AF (64 years; SD, 15.58 years; 4%; 95% confidence interval, 3.3-5.4; P<0.001 for both comparisons). There was a strong positive correlation between the mean age and the frequency of AF (r=0.76; P=0.0002). CONCLUSIONS: This cross-sectional global sample of patients with recent ischemic stroke shows a substantial frequency of AF-associated stroke throughout the world in proportion to the mean age of the stroke population. Most AF is identified by history or electrocardiography; the yield of conventional short-duration cardiac rhythm monitoring is relatively low. Patients with AF-associated stroke were typically elderly (>75 years old) and more often women.

Intravenous Thrombolysis for Stroke Recurring Within 3 Months From the Previous Event.

BACKGROUND AND PURPOSE: According to the European license, alteplase can be given no sooner than 3 months after previous stroke. However, it is not known whether past history of stroke influences the effect of treatment. Our aim was to evaluate safety and functional outcome after intravenous thrombolysis administered in everyday practice to patients with previous stroke≤3 months compared with those with first-ever stroke. METHODS: We analyzed consecutive cases treated with alteplase between October 2003 and July 2014 contributed to the Safe Implementation of Thrombolysis for Stroke-Eastern Europe registry from 12 countries. Odds ratios were calculated using unadjusted and adjusted logistic regression. RESULTS: Of 13,007 patients, 11,221 (86%) had no history of stroke and 249 (2%) experienced previous stroke≤3 months before admission. Patients with previous stroke≤3 months had a higher proportion of hypertension and hyperlipidemia. There were no significant differences in outcome, including symptomatic intracerebral hemorrhage according to European Cooperative Acute Stroke Study (unadjusted odds ratio 1.27, 95% confidence interval: 0.74-2.15), and being alive and independent at 3 months (odds ratio 0.81, 95% confidence interval: 0.61-1.09). CONCLUSIONS: Patients currently treated with alteplase, despite a history of previous stroke≤3 months, do not seem to achieve worse outcome than those with first-ever stroke. Although careful patient selection was probably of major importance, our findings provide reassurance that this group of patients may safely benefit from thrombolysis and should not be arbitrarily excluded as a whole. Further studies are needed to identify the shortest safe time lapse from the previous event to treatment with alteplase.

A Pilot Study of Application of the Stroke Riskometer Mobile App for Assessment of the Course and Clinical Outcomes of COVID-19 among Hospitalized Patients.

INTRODUCTION: Early determination of COVID-19 severity and health outcomes could facilitate better treatment of patients. Different methods and tools have been developed for predicting outcomes of COVID-19, but they are difficult to use in routine clinical practice. METHODS: We conducted a prospective cohort study of inpatients aged 20-92 years, diagnosed with COVID-19 to determine whether their individual 5-year absolute risk of stroke at the time of hospital admission predicts the course of COVID-19 severity and mortality. The risk of stroke was determined by the Stroke Riskometer mobile application. RESULTS: We examined 385 patients hospitalized with COVID-19 (median age 61 years). The participants were categorized based on COVID-19 severity: 271 (70.4%) to the "not severe" and 114 (29.6%) to the "severe" groups. The median risk of stroke the next day after hospitalization was significantly higher among patients in the severe group (2.83, 95% CI: 2.35-4.68) versus the not severe group (1.11, 95% CI: 1.00-1.29). The median risk of stroke and median systolic blood pressure (SBP) were significantly higher among non-survivors (12.04, 95% CI: 2.73-21.19) and (150, 95% CI: 140-170) versus survivors (1.31, 95% CI: 1.14-1.52) and (134, 95% CI: 130-135), respectively. Those who spent more than 2.5 h a week on physical activity were 3.1 times more likely to survive from COVID-19. Those who consumed more than one standard alcohol drink a day, or suffered with atrial fibrillation, or had poor memory were 2.5, 2.3, and 2.6 times more likely not to survive from COVID-19, respectively. CONCLUSIONS: High risk of stroke, physical inactivity, alcohol intake, high SBP, and atrial fibrillation are associated with severity and mortality of COVID-19. Our findings suggest that the Stroke Riskometer app could be used as a simple predictive tool of COVID-19 severity and mortality.

Rivaroxaban versus aspirin for prevention of covert brain infarcts in patients with embolic stroke of undetermined source: NAVIGATE ESUS MRI substudy.

BACKGROUND: Covert brain infarcts are associated with important neurological morbidity. Their incidence in patients with embolic stroke of undetermined source (ESUS) is unknown. AIMS: To assess the incidence of covert brain infarcts and cerebral microbleeds using MRI in a prospective substudy of the NAVIGATE ESUS randomized trial and to evaluate the effects of antithrombotic therapies. METHODS: At 87 sites in 15 countries, substudy participants were randomly assigned to receive rivaroxaban 15 mg daily or aspirin 100 mg daily and underwent brain MRI near randomization and after study termination. The primary outcome was incident brain infarct (clinical ischemic stroke or covert brain infarct). Brain infarcts and microbleeds were ascertained centrally by readers unaware of treatment. Treatment effects were estimated using logistic regression. RESULTS: Among the 718 substudy participants with interpretable, paired MRIs, the mean age was 67 years and 61% were men with a median of 52 days between the qualifying ischemic stroke and randomization and a median of seven days between randomization and baseline MRI. During the median (IQR) 11 (12) month interval between scans, clinical ischemic strokes occurred in 27 (4%) participants, while 60 (9%) of the remaining participants had an incident covert brain infarct detected by MRI. Assignment to rivaroxaban was not associated with reduction in the incidence of brain infarct (OR 0.77, 95% CI 0.49, 1.2) or of covert brain infarct among those without clinical stroke (OR 0.85, 95% CI 0.50, 1.4). New microbleeds were observed in 7% and did not differ among those assigned rivaroxaban vs. aspirin (HR 0.95, 95% CI 0.52-1.7). CONCLUSIONS: Incident covert brain infarcts occurred in twice as many ESUS patients as a clinical ischemic stroke. Treatment with rivaroxaban compared with aspirin did not significantly reduce the incidence of covert brain infarcts or increase the incidence of microbleeds, but the confidence intervals for treatment effects were wide.Registration: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Non-immunogenic recombinant staphylokinase versus alteplase for patients with acute ischaemic stroke 4·5 h after symptom onset in Russia (FRIDA): a randomised, open label, multicentre, parallel-group, non-inferiority trial.

BACKGROUND: Non-immunogenic staphylokinase is modified recombinant staphylokinase with low immunogenicity, high thrombolytic activity, and selectivity to fibrin. We aimed to assess the safety and efficacy of a single intravenous bolus of non-immunogenic staphylokinase compared with alteplase in patients with acute ischaemic stroke within 4·5 h after symptom onset. METHODS: We did a randomised, open-label, multicentre, parallel-group, non-inferiority trial in 18 clinical sites in Russia. We included patients aged 18 years and older with a diagnosis of acute ischaemic stroke (up to 25 points on the National Institutes of Health Stroke Scale). The study drug had to be administered within 4·5 h after the onset of symptoms. Patients were randomly assigned to receive either non-immunogenic staphylokinase (10 mg) or alteplase (0·9 mg/kg, maximum 90 mg), both administered intravenously. The randomisation sequence was created by an independent biostatistician using computer-generated random numbers. 84 blocks (block size of four) of opaque sealed envelopes were numbered sequentially from 1 to 336 and were opened in numerical order. Patients were unaware of their assigned treatment and were assessed by the study investigators who were also unaware of the treatment assignment on all trial days. Emergency department staff, who administered the assigned drug and opened the envelopes, were not masked to treatment. The primary efficacy endpoint was a favourable outcome, defined as a modified Rankin scale (mRS) score of 0-1 on day 90. The margin of non-inferiority was established as 16% for the difference in mRS score of 0-1 on day 90. Non-inferiority was tested using Welch's t-test for the primary outcome only. Endpoints were analysed in the per-protocol population, which comprised all randomly assigned patients who completed treatment without any protocol violations; this population was identical to the intention-to-treat population. This trial is completed and registered at ClinicalTrials.gov, NCT03151993. FINDINGS: Of 385 patients recruited from March 18, 2017, to March 23, 2019, 336 (87%) were included in the trial. 168 (50%) patients were randomly assigned to receive non-immunogenic staphylokinase and 168 (50%) to receive alteplase. The median duration of follow-up was 89 days (IQR 89-89). 84 (50%) of 168 patients in the non-immunogenic staphylokinase group had a favourable outcome at day 90 compared with 68 (40%) of 168 patients in the alteplase group (odds ratio [OR] 1·47, 95% CI 0·93 to 2·32; p=0·10). The difference in the rate of favourable outcome at day 90 was 9·5% (95% CI -1·7 to 20·7) and the lower limit did not cross the margin of non-inferiority (pnon-inferiority <0·0001). Symptomatic intracranial haemorrhage occurred in five (3%) patients in the non-immunogenic staphylokinase group and in 13 (8%) patients in the alteplase group (p=0·087). On day 90, 17 (10%) patients in the non-immunogenic staphylokinase group and 24 (14%) patients in the alteplase group had died (p=0·32). 22 (13%) patients in the non-immunogenic staphylokinase group had serious adverse events, compared with 37 (22%) patients in the alteplase group (p=0·044). INTERPRETATION: Non-immunogenic staphylokinase was non-inferior to alteplase for patients with acute ischaemic stroke. Mortality, symptomatic intracranial haemorrhage, and serious adverse events did not differ significantly between groups. Future studies are needed to continue to assess the safety and efficacy of non-immunogenic staphylokinase in patients with acute ischaemic stroke within the 4·5 h time window, and to assess the drug in patients with acute ischaemic stroke outside this time window with reperfusion CT or magnetic resonance angiography followed by thrombectomy if necessary. FUNDING: The Russian Academy of Sciences.

Embolic strokes of undetermined source: Prevalence and patient features in the ESUS Global Registry.

BACKGROUND: Recent evidence supports that most non-lacunar cryptogenic strokes are embolic. Accordingly, these strokes have been designated as embolic strokes of undetermined source (ESUS). AIMS: We undertook an international survey to characterize the frequency and clinical features of ESUS patients across global regions. METHODS: Consecutive patients hospitalized for ischemic stroke were retrospectively surveyed from 19 stroke research centers in 19 different countries to collect patients meeting criteria for ESUS. RESULTS: Of 2144 patients with recent ischemic stroke, 351 (16%, 95% CI 15% to 18%) met ESUS criteria, similar across global regions (range 16% to 21%), and an additional 308 (14%) patients had incomplete evaluation required for ESUS diagnosis. The mean age of ESUS patients (62 years; SD = 15) was significantly lower than the 1793 non-ESUS ischemic stroke patients (68 years, p ≤ 0.001). Excluding patients with atrial fibrillation (n = 590, mean age = 75 years), the mean age of the remaining 1203 non-ESUS ischemic stroke patients was 64 years (p = 0.02 vs. ESUS patients). Among ESUS patients, hypertension, diabetes, and prior stroke were present in 64%, 25%, and 17%, respectively. Median NIHSS score was 4 (interquartile range 2-8). At discharge, 90% of ESUS patients received antiplatelet therapy and 7% received anticoagulation. CONCLUSIONS: This cross-sectional global sample of patients with recent ischemic stroke shows that one-sixth met criteria for ESUS, with additional ESUS patients likely among those with incomplete diagnostic investigation. ESUS patients were relatively young with mild strokes. Antiplatelet therapy was the standard antithrombotic therapy for secondary stroke prevention in all global regions.

Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial.

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.