Grace Y. Kuo, MD, MS, BA

Diener H-C, Sacco RL, Easton JD, Granger CB, Bernstein RA, Uchiyama S, et al. Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source. N Engl J Med. 2019; 380:1906-1917.

In the age of novel oral anti-coagulants (NOACs), secondary stroke prevention is arriving at a crossroads of innovation versus tradition. Many cryptogenic strokes, which make up 20-30% of ischemic strokes, are suspected to be embolic strokes of undetermined source (ESUS). In this population, do NOACs have a role in secondary stroke prevention?

Sponsored by Boehringer Ingelheim, the RE-SPECT ESUS study investigated the efficacy of dabigatran in preventing recurrent strokes in an international multi-center, randomized, double-blind, parallel group trial against aspirin. 5390 patients from 564 sites were randomly assigned to either dabigatran or aspirin, and followed for average of 19 months (6-36 months) for the primary outcome of recurrent strokes. ESUS was defined as a non-lacunar ischemic stroke in a patient with no extracranial or intracranial atherosclerosis causing 50% or greater stenosis in arteries supplying the area of the stroke, no A-fib greater than 6 minutes, and no intra-cardiac thrombus. Study subjects received 2 pills – either dabigatran and an aspirin placebo, or a dabigatran placebo and aspirin. In patients older than 75 years old or with impaired renal function, an adjusted dose of dabigatran was given. Primary efficacy outcome was recurrent ischemic, hemorrhagic or unspecified type stroke, assessed in a time-to-event analysis.

The study was aggressively designed to detect a 30% lower risk of recurrent stroke, with 92% power with enrollment of 6000 patients. Due to slow enrollment, only 5830 patients were screened, with 5390 actually randomized. 177 (6.6%) patients of the dabigatran group had a recurrent stroke (4.1% per year). In the aspirin arm, 207 (7.7%) patients had recurrent stroke (rate of 4.7% per year). The dabigatran group did not have a significant improvement in the primary outcome. There was no significant difference between risk of major bleeding between the two arms (dabigatran at 1.7% per year vs aspirin at 1.4% per year; within the subgroup of intracranial hemorrhages, the dabigatran group again was not significantly more at risk). However, when looking at the composite outcome of major bleeding plus clinically relevant non-major bleeding, the dabigatran group did have significantly more occurrences.

Although RE-SPECT ESUS was unable to show a significant benefit of dabigatran over aspirin in ESUS in the studied population, there were some interesting observations from secondary analyses. Amongst the subgroup analyses of primary outcome, subjects older than 75 years old receiving dabigatran appeared to have a slight benefit over the aspirin comparison. (HR 0.63, 95% CI 0.43–0.94). Secondary outcome analysis also showed that the dabigatran group suffered less events when looking only at disabling strokes. (0.6% per year in dabigatran group vs 1.6% in aspirin group, HR 0.59, 95% CI 0.36 – 0.96). Post-hoc analysis also showed that dabigatran may have had an effect at reducing strokes up to the 1 year. Perhaps a study aimed to measure the effects of NOACs on decreasing disability would provide more positive evidence towards its use in ESUS. Despite the lack of significance found in the primary outcome of this study, its secondary observations certainly keep the question open of whether or not NOACs have a role in these likely embolic cryptogenic strokes.