Author: Dr.Gerrit. M Grosse brain under magnifying glass

Dept. of Neurology, Hannover Medical School

Twitter: @gerritgrosse

Assuming that a relevant proportion of patients with cryptogenic stroke actually have a concealed cardioembolic mechanism, three large randomised controlled trials (RCT) have so far been conducted comparing non-vitamin K-dependent oral anticoagulants (NOACs) with aspirin: RESPECT-ESUS (1), NAVIGATE-ESUS (2) and the yet unpublished ARCADIA trial (3). All of these studies in the end remained neutral and did not demonstrate superiority of NOACs over aspirin in a general ESUS population.

Recently the fourth ESUS RCT, the ATTICUS trial, was published in NEJM evidence (5). ATTICUS was initiated by the Tübingen colleagues, lead by Prof. Sven Poli and Prof. Tobias Geisler. In ATTICUS, patients were selected who had suffered ESUS 3 to 28 days previously and also had one of the following risk factors for cardioembolism: A CHA2DS2VASc ≥ 4, short episodes of supraventricular tachycardia, or supraventricular extrasystoles, a left atrial diameter > 45mm, spontaneous echo contrast, or flow velocity less than or equal to 0.2 m/s in the left atrial appendage in echocardiography or presence of a patent foramen ovale (PFO). All patients received a cardiac monitoring device within 28 days of the index event. Patients were randomised 1:1 to an apixaban or aspirin treatment arm. The duration of treatment was 12 months. Participants underwent MRI examinations at baseline, after 12 months and in case of detection of atrial fibrillation (AF) within 14 days of such a diagnosis.

The primary endpoint in ATTICUS was imaging-based and defined as any new ischaemic lesion identifiable during follow-up. Secondary endpoints were cerebrovascular, cardiovascular and bleeding events, as well as cognitive outcomes and quality of life as reported by patients via questionnaires. The study was conducted at 16 sites in Germany and was planned with a sample size of n=600. After 353 patients had been randomised, the study was terminated early due to futility. The baseline characteristics were well balanced between the groups. The median NIHSS was 1 and the time from index event to randomisation was 8 days. The primary outcome was observed in 13.6% of apixaban-treated patients and in 16.0% of ASA-treated patients, which corresponds to an adjusted odds ratio (OR) of 0.79 (95% confidence interval: 0.42-1.48). The secondary clinical outcomes were also not significantly different. No cerebral haemorrhage occurred in both groups. Atrial fibrillation was detected less frequently in the apixaban group (22.5%) than in the ASA group (28.2%). 45 of the ASA-treated patients diagnosed with AF subsequently switched to the apixaban group. In the prespecified subgroup analysis, no significant differences were found between the groups, with the exception of a strong trend in favour of apixaban in patients aged 75 years or older, but with low precision of the estimate (OR: 0.38; 95% confidence interval: 0.13-1.05).

In conclusion, Apixaban was not superior to aspirin in secondary prevention in patients who have suffered an ESUS with risk factors for a cardioembolic mechanism. A possible trend in favour of apixaban, however, was found in patients who were at least 75 years old. Despite the more rigorous selection of patient, ATTICUS is thus the fourth ESUS trial that remained neutral. Possible reasons for this are the relatively small sample size, the possibly too short follow-up period of 12 months, the group switch from 45 patients to the apixaban group as well as a selection effect: as in the previous ESUS studies, the patients in ATTICUS were relatively young. The majority (almost two thirds) of the patients also had a single risk factor for cardioembolism, only a third had multiple risk factors. Importantly, only 7.9% in the apixaban group and 9.2% in the aspirin group had a left atrial diameter >45mm. This may have led to a relative underrepresentation of patients who may actually benefit from NOAC treatment due to atrial cardiomyopathy. In ARCADIA, risk factors of atrial cardiomyopathy were also considered as inclusion criteria. However, in ARCADIA a large proportion of patients were recruited on the basis of a relatively low nt-proBNP cut-off. It may therefore be necessary to stratify ESUS patients who are likely to benefit from anticoagulation even more rigorously. ATTICUS supports the hypothesis that may apply in particular to older ESUS patients. A sub-analysis from RE-SPECT ESUS already came to the same conclusion (6). The PIs of ATTICUS are therefore already planning a larger follow-up study in this population, the ATTICUS75+ study. Moreover, it is also possible that a larger proportion of ESUS than previously thought is due to non-stenosing plaques and other sources of embolism, which benefit less from general anticoagulant treatment (7). In any case, further risk stratification and more personalised strategies for secondary prevention in ESUS are urgently needed since ATTICUS has also shown that recurrence rates are not negligible and affect a vulnerable patient population.


  1. Diener HC, Sacco RL, Easton JD, et al. Dabigatran for prevention of stroke after embolic stroke of undetermined source. N Engl J Med 2019;380:1906-1917.
  2. Hart RG, Sharma M, Mundl H, et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med 2018;378:2191-2201.
  3. Kamel H, Longstreth WT Jr, Tirschwell DL, et al. The AtRial Cardiopathy and Antithrombotic Drugs In prevention After cryptogenic stroke randomized trial: rationale and methods. Int J Stroke 2019; 14:207-214.
  4. Healey JS, Gladstone DJ, Swaminathan B, et al. Recurrent Stroke With Rivaroxaban Compared With Aspirin According to Predictors of Atrial Fibrillation: Secondary Analysis of the NAVIGATE ESUS Randomized Clinical Trial. JAMA Neurol. 2019 Jul 1;76(7):764-773.
  5. Geisler T, Keller T, Martus P et al., Apixaban versus Aspirin for Embolic Stroke of Undetermined Source. NEJM Evid 2024;3(1)
  6. Diener HC, Sacco RL, Easton JD, et al. Antithrombotic Treatment of Embolic Stroke of Undetermined Source: RE-SPECT ESUS Elderly and Renally Impaired Subgroups. Stroke. 2020 Jun;51(6):1758-1765.
  7. Diener HC, Easton JD, Hart RG, et al. Review and update of the concept of embolic stroke of undetermined source. Nat Rev Neurol. 2022 Aug;18(8):455-465.

ESOC is Europe’s leading forum for advances in research and clinical care of patients with cerebrovascular diseases. ESOC 2024 will live up to its expectation, and present to you a packed, high quality scientific programme including major clinical trials, state-of-the-art seminars, educational workshops, scientific communications of the latest research, and debates about current controversies. Learn more.