Predictors of Atrial Fibrillation Development in Patients With Embolic Stroke of Undetermined Source: An Analysis of the RE-SPECT ESUS Trial.

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 CHA2DS2-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.

Dabigatran or Aspirin After Embolic Stroke of Undetermined Source in Patients With Patent Foramen Ovale: Results From RE-SPECT ESUS.

BACKGROUND AND PURPOSE: Patent foramen ovale (PFO) may increase the risk of embolic stroke of undetermined source (ESUS). Guidelines suggest anticoagulation may be more effective than antiplatelets in preventing stroke in patients with ESUS and PFO when interventional closure is not performed. METHODS: Patients with ESUS randomized to dabigatran (150/110 mg BID) or aspirin (100 mg QD) from the RE-SPECT ESUS study (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) were included. The rate of recurrent stroke (primary end point) and ischemic stroke was reported for patients with and without baseline PFO. A meta-analysis comparing the effects of anticoagulant and antiplatelet therapy on ischemic stroke in patients with PFO was updated to include RE-SPECT ESUS. RESULTS: PFO was present in 680 of 5388 (12.6%) patients with documented PFO status. The risk of recurrent stroke with dabigatran versus aspirin was similar in patients with and without PFO (P for interaction, 0.8290). In patients with PFO, the meta-analysis found no statistically significant difference between anticoagulant and antiplatelet therapy (odds ratio, 0.70 [95% CI, 0.43-1.14]) for ischemic stroke. CONCLUSIONS: There is insufficient evidence to recommend anticoagulation over antiplatelet therapy for patients with ESUS and a PFO. More data are needed to guide antithrombotic therapy in this population. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02239120.

Antithrombotic Treatment of Embolic Stroke of Undetermined Source: RE-SPECT ESUS Elderly and Renally Impaired Subgroups.

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.

Patients' Perceptions of Atrial Fibrillation, Stroke Risk, and Oral Anticoagulation Treatment: An International Survey.

Background Global differences exist in the management of atrial fibrillation (AF), and cultural differences may influence patients' expectations and perceptions of healthcare. This survey investigated whether country-specific differences in patients' perceptions of AF and oral anticoagulation (OAC) exist and if recent stroke influences these perceptions. Methods Cross-sectional survey of 937 adults with nonvalvular AF receiving OAC for stroke prevention was conducted across United States, Canada, Germany, France, and Japan. Thirty-minute online interviews conducted between April and November 2015 included AF patients with recent stroke, and newly diagnosed AF and established AF, both without recent stroke. Results U.S. patients and those with recent stroke perceived AF as more serious (54.0 and 55.2%, respectively) and were more concerned about stroke (50.0 and 68.0%, respectively). Japanese patients were more likely to perceive AF as not serious (41.0%), but 50.4% were frequently concerned about stroke. Patients in the United States, Canada, and Germany and those without recent stroke preferred to be involved in OAC treatment decisions (either shared decision making or patient's choice), while French and Japanese patients and those with recent stroke preferred their doctor to choose. For all country groups, stroke prevention was the most important factor when choosing OAC. Conclusion In this international cohort of AF patients, country-specific differences exist in patients' perceptions of AF, concerns about stroke, and preference for involvement in OAC treatment decisions; recent experience of stroke significantly influenced patients' values and preferences regarding AF and treatment. Stroke prevention was rated as the most important factor when choosing OAC treatment.

Atrial fibrillation patient preferences for oral anticoagulation and stroke knowledge: Results of a conjoint analysis.

BACKGROUND: Guidelines recommend that patients with atrial fibrillation (AF) are involved in oral anticoagulant (OAC) treatment decisions. Understanding which OAC attributes AF patients value most could help optimize treatment. OBJECTIVE: To assess the relationship between patient's stroke knowledge and their preferences for specific OAC attributes. METHODS: A cross-sectional online survey was conducted in patients with nonvalvular AF taking an OAC for stroke prevention in the United States, Canada, Germany, France, and Japan. Patients were asked about their stroke knowledge, perception of the seriousness of AF and concern about stroke, and to rank 7 OAC attributes in order of importance. A conjoint analysis was performed to determine the inherent value of 4 attributes. RESULTS: In total, 937 patients (mean age [standard deviation] 54.3 [16.6] years; 37.1% female) participated. Of these, 19.5%, 27.9%, and 29.8% had good, moderate, and low stroke knowledge, respectively; 22.8% had no stroke knowledge. Overall, 39.4% of patients (47.5% with good stroke knowledge) perceived AF as very/extremely serious. The OAC attribute ranked as most important was stroke prevention followed by major bleeding risk, other side effects, dosing frequency, antidote availability, dietary restrictions, and use with/without food. In the conjoint analysis, stroke risk reduction was the most valued property, followed by reduction in major bleeding risk, less frequent administration, and administration with/without food. Preferences did not differ with level of stroke knowledge, perception of seriousness of AF, concern of stroke, or medication burden. CONCLUSIONS: Most AF patients consider efficacy and safety to be the most important OAC attributes, whereas dosing frequency was deemed as less important.