ESUS:

Embolic Strokes of Undetermined Source

Not so cryptogenic anymore?

George Ntaios University of Thessaly, Larissa, Greece Ragusa 10/09/2015

Disclosures • • • • • Scholarships: European Stroke Organization; Hellenic Society of Atherosclerosis.

Honoraria: Medtronic; Quintiles; CHUV; Belgian Stroke Council; Boehringer-Ingelheim.

Speaker fees: Sanofi; Boehringer-Ingelheim; Galenica; Elpen; Bayer Support to attend conferences: Bayer; Sanofi-Aventis; Pfizer; Lundbeck; Boehringer Ingelheim; Galenica; Elpen; Bristol Myers Squibb.

Participation in trials: – NAVIGATE-ESUS / National Coordinator (Greece) – GLORIA-AF / Sub-investigator (Larissa).

– FOURIER / Principal investigator (Larissa).

– ENOS / National Coordinator (Greece).

– EBBINGHAUS / Principal Investigator (Larissa).

– – PRECIOUS / National Coordinator (Greece).

BIOSIGNAL / Principal Investigator (Larissa).

– PREVISE / Principal investigator (Larissa).

TOAST classification Adams. Stroke 1993

TOAST classification

?

Cryptogenic stroke: not rare

Cryptogenic stroke: not innocent Ntaios. Eur J Neurol. 2014; 21:1108-14

Cryptogenic stroke: what actually do you mean?

Cryptogenic Not investigated Multiple causes Really cryptogenic

ESUS: E mbolic S trokes of U ndetermined S ource Hart. Lancet Neurol 2014; 13: 429–38

ESUS: potential causes Hart. Lancet Neurol 2014; 13: 429–38

ESUS: diagnostic criteria  Stroke detected by CT or MRI that is not lacunar .

 Absence of extracranial or intracranial atherosclerosis causing in arteries supplying the area of ischemia.

>50% luminal stenosis  No major-risk cardioembolic source of embolism

endocarditis

).

(

permanent or paroxysmal AF, sustained atrial flutter, intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or other cardiac tumours, mitral stenosis, recent (<4 weeks) MI, LVEF<30%, valvular vegetations, or infective

 No other specific cause of stroke identified.

Hart. Lancet Neurol 2014; 13: 429–38

ESUS: diagnostic algorithm  Brain CT or MRI  12-lead ECG  Precordial echocardiography  Imaging of both extra- and intracranial arteries supplying the area of brain ischemia  Cardiac monitoring for ≥24hours with automated rhythm detection Hart. Lancet Neurol 2014; 13: 429–38

CRYSTAL-AF Sanna. N Engl J Med 2014;370:2478-86

CRYSTAL-AF : the more you look, the more you find

12.4% vs. 2.0% 30.0% vs. 3.0%

Sanna. N Engl J Med 2014;370:2478-86

EMBRACE : the more you look, the more you find Gladstone. N Engl J Med 2014;370:2467-77

EMBRACE : the more you look, the more you find Gladstone. N Engl J Med 2014;370:2467-77

EMBRACE : the more you look, the more you find Gladstone. N Engl J Med 2014;370:2467-77

ESUS in the Athens Stroke Registry Ntaios. Stroke 2015; 46:176-81

Ntaios. Stroke 2015; 46:176-81

Mitral valve Myxomatous valvulopathy with prolapse Mitral annular calcification Aortic valve Aortic valve stenosis Calcific aortic valve Non-atrial fibrillation atrial dysrhythmias and stasis Atrial asystole and sick-sinus syndrome Atrial high-rate episodes Atrial appendage stasis with reduced flow velocities or spontaneous echodensities Atrial structural abnormalities Atrial septal aneurysm Chiari network Left ventricle Moderate systolic or diastolic dysfunction (global or regional) Ventricular non-compaction Endomyocardial fibrosis Covert paroxysmal atrial fibrillation (detected during follow-up) Atrial fibrillation detected on stroke recurrence Atrial fibrillation detected on monitoring during follow-up Atrial fibrillation not confirmed but strongly suspected Cancer-associated Covert non-bacterial thrombotic endocarditis Tumor emboli from occult cancer Arteriogenic emboli Aortic arch atherosclerotic plaques Cerebral artery non-stenotic plaques with ulceration Paradoxical embolism Patent foramen ovale Atrial septal defect

5 (1.8%) 8 (2.9%) 3 (1.1%) 12 (4.4%) 3 (1.1%) 7 (2.6%) 6 (2.2%) 10 (3.6%) 0 42 (15.4%) 12 (4.4%) 1 (0.4%) 30 (11.0%) 50 (18.3%) 38 (13.9%) 1 (0.4%) 2 (0.8%) 9 (3.3%) 29 (10.6%) 11 (4.0%) 3 (1.1%)

ESUS: 5-yrs stroke recurrence Ntaios. Stroke 2015; 46:2087-93

ESUS & AF at follow-up: how much causality is there ?

AF-related strokes are more severe

Patient characteristics NIHSS on admission Large-artery atherosclerotic stroke Cardioembolic stroke n=496 n=993 Lacunar stroke Stroke of undetermined origin Stroke of miscellaneous causes n=647 n=533 n=61

8.6

12.8

3.4

9.7

7.6

Ntaios. Eur J Neurol. 2014; 21:1108-14

ESUS & AF : how much of a causality?

NIHSS score AF ESUS (n=80) Non-AF ESUS (n=195) p-value

5 (2-13) 5 (2-14) 0.998

Ntaios, under review

Statins for AF-related stroke?

Ntaios. Int J Cardiol 2014

So, how to treat my ESUS patient?

Approach 1 Furie. Stroke 2010

So, how to treat my ESUS patient?

Approach 2

So, how to treat my ESUS patient?

Approach 3

NAVIGATE- ESUS

R

Rivaroxaban 15mg 1x1 Aspirin 100mg 1x1

RESPECT - ESUS

R

Dabigatran 110/150 1x2 Aspirin 100mg 1x1

- Everybody gets happy!

- Almost half stroke patients get an anticoagulant!

Take-home messages  Cryptogenic  ESUS  ~10% of all stroke patients  ESUS needs a complete (?) diagnostic work-up  Covert AF is frequently detected in ESUS  Perhaps AF is over-estimated as a stroke cause  High recurrence rate  NOACs to replace antiplatelets?