Medical Management of ESUS – what have we learnt so far?

Author: Dr Nicolas Martinez-Majander
Affiliation: Clinical Neurosciences, Department of Neurology, University of Helsinki and Department of Neurology, Helsinki University Hospital, Finland

Medical Management of ESUS

In 2014, a subset of cryptogenic stroke was presented, embolic stroke of undetermined source (ESUS).1 Exclusion criteria include >50% stenosis in a large proximal artery in the territory of ischemia, major-risk cardioembolism such as atrial fibrillation, lacunar disease, or any other identified uncommon cause. Potential causes of ESUS may include minor-risk cardioembolic sources (e.g. mitral annular calcification, calcific aortic valve, atrial septal aneurysm), cancer-associated strokes, arteriogenic emboli (e.g. aortic arch atherosclerotic paques) and paradoxical embolism involving patent foramen ovale or pulmonary arteriovenous fistula. It was also suggested that ESUS patient might benefit from anticoagulation compared to antiplatelets in secondary prevention.

Now after four years we have received much anticipated results from the two largest international randomized phase III trials comparing novel oral anticoagulants (NOACs) with aspirin in patients with a recent ESUS.

Evidence of medical treatment so far?

Results from NAVIGATE ESUS trial (NCT02313909) were first presented in European Stroke Organisation Conference. Gothenburg and published simultaneously in New England Journal of Medicine.2 The trial enrolled 7213 individuals and the baseline characteristics were already presented in March, 2018.3 NAVIGATE ESUS was stopped early, since perhaps quite surprisingly it showed that with a median of 11 months follow-up, rivaroxaban 15 mg was not superior to aspirin 100mg regarding any recurrent stroke or systemic. This was also true for secondary efficacy outcomes, such as any recurrent ischemic stroke alone. In fact, rivaroxaban treatment arm had higher rate of major bleeding and it was discussed that perhaps these patients with ESUS were too heterogeneous after all, harboring several underlying potential embolic sources and having a wide spectrum of risk factor profiles.

In September, the first prespecified subgroup analysis was published in Lancet Neurology, focusing on NAVIGATE ESUS patients with patent foramen ovale.4 It also concluded that there was no difference in the risk of recurrent ischemic stroke between treatment arms with PFO patients. Also the risk of major bleeding was similar compared to overall NAVIGATE ESUS population.

However, results from another subgroup analysis were just recently presented in World Stroke Congress in Montreal. It showed that up to 10% of patient in NAVIGATE ESUS had a left atrial enlargement (diameter larger than 4.6 cm) and that rivaroxaban might reduce the risk of recurrent stroke after ESUS in these patients compared to aspirin alone. This supports the hypothesis of atrial myopathy as a significant source of embolism even in the absence of atrial fibrillation, although results have be interpreted with caution and confirmed in future studies.

In the same congress we heard the first results from RE-SPECT ESUS (NCT02239120), comparing dabigatran 110-150 mg twice daily with aspiring 100mg once daily. With 5390 enrolled patients, it also showed that the rate of recurrent stroke was similar in both treatment arms (4.1% with dabigatran vs 4.8%. Median follow-up was slightly longer than in NAVIGATE ESUS (19 months) and Kaplan Meier curves showed a trend of separation between groups in favor of dabigatran with progressing follow-up. In contrast to NAVIGATE ESUS, the rate of major bleedings was actually similar in both arms and all of the fatal bleeds (three of them) occurred in the aspirin arm. These results have not yet been published in any journal.

What’s next?

Finally, a third ESUS trial (multicenter German ATTICUS, NCT02427126) comparing apixaban 5mg twice daily with aspirin 100mg is still enrolling patients and the target of 500 participants should be completed in December 2019. It will be interesting to hear if patients in apixaban have better outcomes, regarding both recurrent stroke and major bleedings.



  1. Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell MJ, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014;13:429-438.
  2. Hart RG, Sharma M, Mundl H, Kasner SE, Bangdiwala SI, Berkowitz SD, et al. Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source. N Engl J Med 2018;378:2191-2201.
  3. Kasner SE, Lavados P, Sharma M, Wang Y, Wang Y, Davalos A, et al. Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial. J Stroke Cerebrovasc Dis 2018;27:1673-1682.
  4. Kasner SE, Swaminathan B, Lavados P, Sharma M, Muir K, Veltkamp R, et al. Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial. Lancet Neurol 2018 Sep 28.


Outcome Rivaroxaban Group (N=3609), n (%/year) Aspirin Group (N=3604), n (%/year) Hazard Ratio          (95% CI)
Any recurrent stroke 171 (5.1) 158 (4.7) 1.08 (0.87–1.34)
     Ischemic stroke 158 (4.7) 156 (4.7) 1.01 (0.81–1.26)
ISTH major bleeding 62 (1.8) 23 (0.7) 2.72 (1.68–4.39)
Intracerebral hemorrhage 12 (0.3) 3 (0.1) 4.01 (1.13–14.2)
Life-threatening or      fatal bleeding 35 (1.0) 15 (0.4) 2.34 (1.28–4.29)
     All-cause mortality 65 (1.9) 52 (1.5) 1.26 (0.87–1.81)
Outcome Dabigatran Group N=2695,  n (%/year) Aspirin Group,  N=2695,  n (%/year) Hazard Ratio          (95% CI)
Any recurrent stroke 177 (4.1) 207 (4.8) 0.85 (0.69-1.03)
     Ischemic stroke 172 (4.0) 203 (4.7) 0.84 (0.68-1.03)
ISTH major bleeding 77 (1.7) 64 (1.4) 1.19 (0.85-1.66)
Intracerebral hemorrhage 32 (0.7) 32 (0.7) 0.98 (0.60-1.60)
Life-threatening or      fatal bleeding 38 (0.8) 48 (1.1) 0.83 (0.54-1.28)
     All-cause mortality 56 (1.2) 58 (1.3) 0.96 (0.66-1.38)