Table 2

Studies of anticoagulation in embolic stroke of undetermined source

Design and sample sizeSelection criteriaComparison groupsPrimary outcomeResults
NAVIGATE-ESUSRandomised prospective; 7213 participants at 459 sites.Aspirin 100 mg vs rivaroxaban 15 mg daily.
  • Composite endpoint of stroke (ischaemic, haemorrhagic and undefined stroke, TIA with positive neuroimaging) and systemic embolism.

  • Incidence rate of a major bleeding event according to ISTH criteria.

No reduction in recurrent stroke with rivaroxaban.
Increased risk of bleeding with rivaroxaban.
RESPECT-ESUSRandomised prospective; 5390 participants from 564 sites.Aspirin 100 mg vs dabigatran etexilate 110 mg or 150 mg two times per day.
  • Adjudicated recurrent stroke (ischaemic, haemorrhagic or unspecified).

  • First major bleed defined according to ISTH.

No reduction in recurrent stroke with rivaroxaban.
ATTICUSRandomised prospective; 500 participants.At least one of the following non-major but suggestive risk factors for cardiac embolism:
  • LA size >45 mm (parasternal axis).

  • Spontaneous echo contrast in LAA.

  • LAA flow velocity ≤0.2 m/s.

  • Atrial high rate episodes.

  • CHA2DS2VASc score ≥4.

  • Persistent foramen ovale.

Aspirin 100 mg vs apixaban 5 mg two times per day.
  • Occurrence of at least one new ischaemic lesion at 12 months after study drug initiation when compared with baseline MRI before study drug initiation by MRI (axial T2-weighted fluid attenuated inversion recovery MRI and/or axial diffusion-weighted MRI).

Secondary outcomes:
  • Combination of recurrent ischaemic stroke, haemorrhagic stroke and systemic embolism.

  • Combination of major adverse cardiovascular events, including recurrent stroke, myocardial infarction and cardiovascular death.

  • Combination of major and clinically relevant non-major bleeding defined according to ISTH criteria.

  • Change of cognitive function (MOCA).

  • Life quality (EQ-5D).

ARCADIARandomised prospective; 1100 participants.
  • Atrial cardiopathy defined by either P wave terminal force in V1, atrial enlargement by echocardiography or elevated NT-pro-BNP.

Aspirin 81 mg vs apixaban 5 mg two times per day.
  • Recurrent stroke.

  • ARCADIA, Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke; ATTICUS, Apixaban for Treatment of Embolic Stroke of Undetermined Source; ISTH, International Society on Thrombosis and Haemostasis; LA, left atrium; LAA, left atrium appendage; NAVIGATE-ESUS, Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source trial; NT-pro-BNP, amino terminal pro B-type natriuretic peptide; RESPECT-ESUS, Dabigatran for Stroke Prevention after Embolic Stroke of Undetermined Source.