Dabigatran no better than aspirin for preventing a stroke after initial embolic cryptogenic stroke

Reference

Diener HC, Sacco RL, Easton JD, et al, for the RE-SPECT ESUS Steering Committee and Investigators. Dabigatran for prevention of stroke after embolic stroke of undetermined source. N Engl J Med 2019;380(20):1906-1917.

Synopsis

Approximately 25% of ischemic strokes are classified as embolic cryptogenic strokes because the MRI pattern resembles that of an embolism but there is no clear source for it, such as atrial fibrillation or carotid disease. This trial identified patients 60 years or older who had experienced such a stroke within the past 3 months (or in the past 6 months if they also had at least one vascular risk factor), and patients aged 18 to 59 years if they had experienced an embolic cryptogenic stroke in the past 3 months and had at least one vascular risk factor. Patients underwent a standard evaluation, and were allowed to have no more than 6 minutes of atrial fibrillation during 20 hours or more of monitoring. The 5390 patients were randomized to receive aspirin 100 mg once daily or dabigatran150 mg twice daily in a double-blind, double-dummy manner (patients older than 75 years or with creatinine clearance between 30 mL and 50 mL per minute received a 110-mg dose of dabigatran). Groups were balanced at the start of the study and analysis was by intention to treat. The mean age of the patients was 64 years, 37% were women, 13% had patent foramen ovale, 23% were Asian, and only 2% were black. Although only a few patients were completely lost to follow-up, more than one quarter in each group (790 in the dabigatran group and 720 in the aspirin group) discontinued the study drug. There was no significant difference between groups with regard to the primary efficacy outcome of recurrent stroke (4.1% per year with dabigatran vs 4.8% per year with aspirin; hazard ratio [HR] 0.85; 95% CI 0.69 - 1.03). The only individual outcome for which there was a statistically significant difference was disabling stroke (0.6% per year with dabigatran vs 0.9% per year with aspirin; HR 0.59; 0.36 - 0.96; number needed to treat = 333 per year). A subgroup analysis by age found a trend toward greater benefit with increasing age with dabigatran that became statistically significant after age 75 years. There was no difference in major bleeding between groups, but more clinically relevant nonmajor bleeds were seen with dabigatran (1.6% vs 0.9%; HR 1.73; 1.17 - 2.54; number needed to treat to harm = 143). Inspection of survival curves showed what may be increasing benefit to dabigatran after 1 year of treatment, but this was a post hoc finding that requires confirmation. For this study, data acquisition, analysis, and manuscript writing were all done by the industry sponsor.