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Background: A proportion of patients with embolic stroke of undetermined source have silent atrial fibrillation (AF) or develop AF after the initial evaluation. Better understanding of the risk for development of AF is critical to implement optimal monitoring strategies with the goal of preventing recurrent stroke attributable to underlying AF. 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) provides an opportunity to assess predictors for developing AF and associated recurrent stroke., Methods: RE-SPECT ESUS was a randomized, controlled trial (564 sites, 42 countries) assessing dabigatran versus aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. Of 5390 patients enrolled and followed for a median of 19 months, 403 (7.5%) were found to develop AF reported as an adverse event or using cardiac monitoring per standard clinical care. Univariable and multivariable regression analyses were performed to define predictors of AF., Results: In the multivariable model, older age (odds ratio for 10-year increase, 1.99 [95% CI, 1.78-2.23]; P <0.001), hypertension (odds ratio, 1.36 [95% CI, 1.03-1.79]; P =0.0304), diabetes (odds ratio, 0.74 [95% CI, 0.56-0.96]; P =0.022), and body mass index (odds ratio for 5-U increase, 1.29 [95% CI, 1.16-1.43]; P <0.001) were independent predictors of AF during the study. In a sensitivity analysis restricted to 1117 patients with baseline NT-proBNP (N-terminal prohormone of brain natriuretic peptide) measurements, only older age and higher NT-proBNP were significant independent predictors of AF. Performance of several published predictive models was assessed, including HAVOC (AF risk score based on hypertension, age ≥75 years, valvular heart disease, peripheral vascular disease, obesity, congestive heart failure, and coronary artery disease) and CHA 2 DS 2 -VASc (stroke risk score based on congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, previous stroke, transient ischemic attack or thromboembolism [doubled], vascular disease, age 65 to 74 years, and sex category [female]) scores, and higher scores were associated with higher rates of developing AF., Conclusions: Besides age, the most important variable, several other factors, including hypertension, higher body mass index, and lack of diabetes, are independent predictors of AF after embolic stroke of undetermined source. When baseline NT-proBNP was available, only older age and elevation of this biomarker were predictive of subsequent AF. Understanding who is at higher risk of developing AF will assist in identifying patients who may benefit from more intense, long-term cardiac monitoring. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.

Background: The international 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 (RE-SPECT ESUS) trial did not demonstrate superiority of dabigatran over aspirin for reduction of recurrent strokes in patients with embolic strokes of undetermined source (ESUS). Based on pre-defined subanalyses, the safety and efficacy of dabigatran vs. aspirin in Japanese patients was assessed., Methods and results: ESUS patients were randomized to receive either dabigatran (150 or 110 mg twice daily) or aspirin (100 mg once daily). Of 5,390 patients randomized, 594 were Japanese. Most Japanese patients (99.8%) underwent brain magnetic resonance imaging for trial screening, compared to 76.8% of non-Japanese (P<0.0001). In the Japanese cohort, over a 19.4-month median follow-up period, recurrent stroke as the primary outcome occurred in 20/294 patients (4.3%/year) in the dabigatran group and 38/300 (8.3%/year) in the aspirin group (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.32-0.94). Major bleeding occurred in 12 patients (2.5%/year) and 17 patients (3.5%/year), respectively (HR, 0.72; 95% CI, 0.34-1.52). In contrast, in the non-Japanese cohort, recurrent stroke occurred in 4.1%/year and 4.3%/year, respectively, showing no apparent difference in recurrent stroke for dabigatran vs. aspirin (HR, 0.91; 95% CI, 0.74-1.14). The P-interaction for treatment and region did not reach statistical significance (P=0.09)., Conclusions: Dabigatran was putatively associated with a lower relative risk of recurrent stroke compared with aspirin in Japanese ESUS patients.

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.

Background: Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear., Methods: We conducted a multicenter, randomized, double-blind trial of dabigatran at a dose of 150 mg or 110 mg twice daily as compared with aspirin at a dose of 100 mg once daily in patients who had had an embolic stroke of undetermined source. The primary outcome was recurrent stroke. The primary safety outcome was major bleeding., Results: A total of 5390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2695 patients) or aspirin (2695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P = 0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively., Conclusions: In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group. (Funded by Boehringer Ingelheim; RE-SPECT ESUS ClinicalTrials.gov number, NCT02239120.)., (Copyright © 2019 Massachusetts Medical Society.)

Venous thromboembolism (VTE) incidence is increasing among children owing to many factors, including improved diagnosis of VTE. There is a need for alternative treatment options. Our objective was to investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran etexilate in adolescents with VTE. Adolescents aged 12 to <18 years (n = 9) who successfully completed planned treatment for primary VTE were administered dabigatran etexilate twice daily for three days; initially 1.71 (± 10 %) mg/kg (80 % of a 150 mg/70 kg twice daily adult dose), followed by 2.14 (± 10 %) mg/kg (target adult dose adjusted for patient's weight), if there were no safety concerns. No bleeding events, deaths or drug-related serious adverse events (AEs) were reported; three treatment-emergent AEs, all gastrointestinal-related, occurred in two patients. In these adolescent patients with normal renal function, presumed steady-state trough plasma concentrations of dabigatran were low (geometric mean dose-normalised total dabigatran plasma concentration: 0.493 ng/ml/mg at 72 hours). Total dabigatran concentrations were well predicted by the RE-LY® population PK model (94 % of trough concentrations were within the 80 % prediction interval). The relationship between total dabigatran plasma concentration, diluted thrombin time and ecarin clotting time (ECT) was linear; the relationship with activated partial thromboplastin time (aPTT) was non-linear. Adult population PK/PD models predicted the adolescent concentration-ECT and -aPTT relationships well. In conclusion, dabigatran etexilate was generally well tolerated, except for occurrence of dyspepsia in two patients, over the three-day treatment period. The dabigatran PK/PD relationship observed in adolescent patients was similar to that in adult patients.

Rationale: Cryptogenic ischemic strokes constitute 20-30% of ischemic strokes, the majority of which are embolic strokes of undetermined source. The standard preventive treatment in these patients is usually acetylsalicylic acid., Aim: The Randomized, double-blind, Evaluation in secondary Stroke Prevention comparing the EfficaCy and safety of the oral Thrombin inhibitor dabigatran etexilate vs. acetylsalicylic acid in patients with Embolic Stroke of Undetermined Source (RE-SPECT ESUS) is designed to determine whether the oral thrombin inhibitor dabigatran, taken within three-months after embolic stroke of undetermined source, is superior to acetylsalicylic acid for prevention of recurrent stroke and to characterize the safety of dabigatran in this setting., Design: Prospective, randomized, double-blind, multicenter trial in approximately 6000 patients and 550 centers with embolic stroke of undetermined source. Subjects are randomized to dabigatran or acetylsalicylic acid and treated for an expected minimum of six-months and up to approximately three-years. It is an event-driven trial aiming for 353 adjudicated primary outcome events., Study Outcomes: The primary efficacy outcome is time to first recurrent stroke (ischemic, hemorrhagic, or unspecified). Key secondary outcomes are time to first ischemic stroke and time to first occurrence in the composite outcome of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death. The primary safety outcome is major hemorrhage, including symptomatic intracranial hemorrhage., Discussion: Acetylsalicylic acid is the most common antithrombotic given to patients with embolic strokes of undetermined source to reduce recurrence risk. This trial will determine whether anticoagulation with dabigatran is more effective than acetylsalicylic acid, and acceptably safe., (© 2015 World Stroke Organization.)