This section details key aspects of ESUS management, including current treatment recommendations, and the potential for NOAC use in such patients

In this section:


Currently, limited data are available to guide treatment decisions in patients with ESUS; no therapies have been specifically tested in randomized trials in patients with ESUS to prevent ischaemic stroke recurrence. The standard treatment for secondary prevention of stroke is antiplatelet therapy; however, emerging evidence suggests that anticoagulation may reduce the risk of recurrent stroke in ESUS patients, even those patients who do not have NVAF.

Current treatment recommendations for ESUS

There are currently no established guidelines on the long-term treatment of ESUS; based on the studies summarized below, guidelines from the American Heart Association/American Stroke Association and the American College of Chest Physicians, recommend antiplatelet therapy (in the absence of sufficient data on NOACs – as detailed below – coupled with lifestyle modification and control of other risk factors such as hypertension, diabetes and dyslipidaemia.

Studies supporting antithrombotic therapies in ESUS: incidence of events and bleeding rates
Approach Incidence of adverse events Bleeding rates
ASA (30–325 mg od)
vs placebo
Not reported
ASA (30–325 mg od)
vs ASA (30–325 mg od) plus dipyridamole (200 mg bid)
ASA: 3.85% ASA +
ASA (325 mg od) vs
clopidogrel (75 mg od)
ASA: 1.55%b Clopidogrel:
ASA (325 mg od) vs
warfarin (INR 1.4–2.8)
ASA: 1.5% Warfarin: 2.2%

aEvent rate per year; bany severe bleeding disorder.
bid, twice daily; INR, international normalized ratio; od, once daily.

Current treatment guidelines related to ESUS
Guidance Class Level of evidence Grade
American Heart Association/American Stroke Association 2014 guidelines: Antithrombotic therapy for non-cardioembolic stroke (including ESUS)
Antiplatelet agents recommended rather than oral anticoagulation
Indicated as initial therapy after TIA or ischaemic stroke for prevention of future stroke:
  • ASA
    (50–325 mg/day) monotherapy
  • Combination of ASA 25 mg and extended-release dipyridamole
    200 mg twice daily
Clopidogrel (75 mg) monotherapy: reasonable option for secondary prevention of stroke in place of ASA or combination ASA/dipyridamole (also applies to patients who are allergic to ASA) IIa B
American Heart Association/American Stroke Association 2014 guidelines: Secondary stroke prevention in patients with PFO
Insufficient data to establish whether anticoagulation is equivalent or superior to ASA IIb B
For patients with an ischaemic stroke or TIA and a PFO who are not undergoing anticoagulation therapy, antiplatelet therapy recommended I B
For patients with an ischaemic stroke or TIA and both a PFO and a venous source of embolism, anticoagulation is indicated, depending on stroke characteristics I A
When anticoagulation is contraindicated, an inferior vena cava filter is reasonable IIa C
For patients with a cryptogenic ischaemic stroke or TIA and a PFO without evidence for DVT, available data do not support a benefit for PFO closure III A
In the setting of PFO and DVT, PFO closure by a transcatheter device might be considered, depending on the risk of recurrent DVT IIb C
American College of Chest Physicians 2012 guidelines: Patients with PFO and stroke or TIA
Initial ASA therapy IB
Substitute VKA for ASA if recurrence 2C
In patients with cryptogenic stroke and DVT and a PFO:
  • VKA therapy for 3 months
  • Consider PFO closure

The recurrence rate of ischaemic stroke, however, remains substantial despite antiplatelet therapy (at approximately 8% with ASA use), and adverse events associated with antiplatelet use may lead to discontinuation and potentially increased risk of a further stroke.

Potential for anticoagulants in patients after ESUS

A recent study showed that a high proportion of older patients (≥55 years) who have an ESUS have underlying paroxysmal AF. This is an important observation because, when AF is present, anticoagulation with a VKA (e.g. warfarin) has been shown to be more effective than antiplatelet therapy (by approximately 40%) to prevent recurrent stroke.

A subgroup analysis of a large study comparing warfarin and ASA for the prevention of recurrent ischaemic stroke (the WARRS study) has suggested greater benefits with anticoagulation versus antiplatelet therapy in ESUS patients enrolled in this study (26% [576 of 2206] were classified as “cryptogenic’’):

  • 2-year rate of recurrent stroke or death in:
    • ESUS patients (cryptogenic stroke with embolic features; n=338): 12% with warfarin versus 18% ASA
    • ESUS patients with PFO (n=260): 9% of warfarin versus 17% of ASA users

To date, no randomized trials have compared NOACs with antiplatelet therapy to prevent recurrent stroke among patients with non-cardioembolic stroke or TIA.

The potential for NOAC usage in ESUS

Ongoing trials with NOACs in patients with an ESUS (details summarized in the Table below) will further elucidate the benefit–risk profile for these agents to prevent recurrent stroke versus antiplatelet therapy in this setting.

Ongoing trials with NOACs in patients with ESUS
Intervention comparison Trial name and design details Estimated enrolment and NOAC dosing Source(s) for further information
Apixaban vs ASA ATTICUS
Open-label, phase III RCT in Germany
500 patients

Apixaban 5 mg bid NCT02427126
Dabigatran vs ASA RE-SPECT ESUS
Double-blind, phase III, international RCT
6000 patients

Dabigatran 110 mg or 150 mg bid NCT02239120
Diener HC et al. 2015
Rivaroxaban vs ASA NAVIGATE ESUS
Double-blind, double-dummy, phase III, international RCT
7000 patients

Rivaroxaban 15 mg od NCT02313909

bid, twice daily; od, once daily; RCT, randomized controlled trial

Next section: Venous Thromboembolism

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