No reduction of recurrent stroke with DOAC after embolic stroke of undetermined source

Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source

Literature - Diener H-C, Sacco RL, Easton JD, et al. - N Engl J Med 2019;380:1906-17. DOI: 10.1056/NEJMoa1813959

Introduction and methods

Ischemic infarctions are categorized by their cause: large-artery extracranial or intracranial atherosclerosis, embolism from a cardiac source, small-artery occlusion, and other causes [1]. 20-30% Of ischemic strokes are classified as cryptogenic [2,3] and within this category some are defined as embolic strokes of undetermined source. For patients who have suffered from cryptogenic stroke, guidelines recommend use of antiplatelet agents, such as aspirin, combination of dipyridamole and aspirin, or clopidogrel and aspirin [4], to prevent secondary stroke. It was hypothesized that the direct thrombin inhibitor dabigatran can reduce recurrent stroke in those with embolic stroke of undetermined source compared to aspirin use.

The RE-SPECT ESUS (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) trial evaluated the efficacy and safety of dabigatran vs. aspirin for the prevention of recurrent stroke. Patients ≥60 years were eligible if they had an embolic stroke of undetermined source within the previous 3 months or if they had ≥1 vascular risk factor within the previous 6 months and patients 18-59 years were eligible if they had a qualifying stroke within the previous 3 months and ≥1 vascular risk factor.

Embolic stroke of undetermined source was defined as a nonlacunar ischemic stroke without detection of extracranial or intracranial atherosclerosis causing ≥50% stenosis in arteries supplying the area of the stroke, no AF >6 min, no intracardiac thrombus, and no other specific cause of stroke [5].

Patients were randomized to receive dabigatran and placebo (n=2695) or aspirin and placebo (n=2695). The primary efficacy outcome was recurrent stroke of ischemic, hemorrhagic, or unspecified type. The primary safety outcome was major bleeding according to International Society on Thrombosis and Hemostasis (ISTH) criteria. Median follow- up duration was 19 months (IQR 13-27).

Main results

  • Primary outcome was not different between groups: in 6.6% of patients in the dabigatran group and 7.7% in the aspirin group (HR: 0.85, 95%CI: 0.69-1.03, P=0.10).
  • Ischemic strokes occurred in 6.4% in the dabigatran group compared to 7.5% in the aspirin group (HR: 0.84, 95%CI:0.68-1.03).
  • Composite outcome of nonfatal stroke, nonfatal MI, or CV death was not different between groups (7.7% in those who received dabigatran and 8.6% in the aspirin group – HR: 0.88, 95%CI: 0.73-1.06).
  • Hemorrhagic stroke occurred in 0.2% in the dabigatran group and 0.3% in the aspirin group (HR: 0.86, 95%CI: 0.29 to 2.55). Disabling strokes occurred in 0.9% in the dabigatran group and 1.6% in the aspirin group (HR: 0.59, 95%CI 0.36 to 0.96).
  • No difference in major bleeding was observed between the 2 groups (2.9% in the dabigatran group and 2.4% in the aspirin group – HR: 1.19, 95%CI: 0.85-1.66).
  • Composite outcome of major or clinically relevant nonmajor bleeding was more frequent in dabigatran group vs. the aspirin group (HR: 1.44, 95% CI: 1.12-1.85). Incidence of clinically relevant nonmajor bleeding episodes were higher with dabigatran vs. aspirin (HR: 1.73, 95%CI 1.17-2.54).
  • Incidence of intracranial hemorrhage and life-threatening bleeding were not different between the 2 groups.


In the RE-SPECT ESUS trial, no difference in outcome of recurrent stroke was detected between treatment with dabigatran vs. aspirin in patients who had suffered from embolic stroke of undetermined source. The risk of major bleeding was not different between the two treatment groups, but incidence of clinically relevant nonmajor bleeding was higher in patients on dabigatran.


1. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial: TOAST: Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24: 35-41.

2. Fonseca AC, Ferro JM. Cryptogenic stroke. Eur J Neurol 2015; 22: 618-23.

3. Ntaios G, Papavasileiou V, Milionis H, et al. Embolic strokes of undetermined source in the Athens Stroke Registry: a descriptive analysis. Stroke 2015; 46: 176-81.

4. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45: 2160-236.

5. Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13: 429-38.

Find this article online at N Engl J Med

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