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Initiating prevention after acute stroke in NVAF and beyond

This article discusses the timing and strategies for anticoagulation therapy after AF-related stroke, as well as the management of embolic strokes of undetermined source (ESUS). It also explores diagnostic criteria, potential causes, and diagnostic algorithms for ESUS. The CRYSTAL-AF and EMBRACE studies are presented as examples of the benefits of extended cardiac monitoring in detecting atrial fibrillation.

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Initiating prevention after acute stroke in NVAF and beyond

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  1. Initiating prevention after acute stroke in NVAF and beyond George Ntaios University of Thessaly, Larissa/Greece

  2. Disclosures • Scholarships: European Stroke Organization; Hellenic Society of Atherosclerosis • Honoraria: Medtronic; Quintiles; Boehringer-Ingelheim • Speaker fees: Sanofi; Boehringer-Ingelheim; Galenica; Elpen; Bayer; Winmedica; BMS/Pfizer • Research support: European Union (Horizon 2020); BMS/Pfizer (ERISTA) • Support to attend conferences: Bayer; Sanofi-Aventis; Pfizer; Lundbeck; Boehringer-Ingelheim; Galenica;Elpen; BMS/Pfizer

  3. Anticoagulation after AF-related stroke: How soon (or late)?

  4. Anticoagulation after AF-related stroke: How soon (or late)? Recurrence risk (%) 0.2 0.4 0.6 0.8 1.0 0 20 15 10 0 5 Days after index stroke Ntaios & Michel. CerebrovascDis. 2011;32:246–253.

  5. Anticoagulation after AF-related stroke: How soon (or late)? Anticoagulants for acute ischaemic stroke (review) Recurrent ischaemic or unknown stroke during treatment period Sandercock PAG, Counsell C, Kamal AK 1.0 Favours treatment Favours control Symptomatic intracranial haemorrhage during treatment period 1.0 Favours control Favours treatment Treatment: unfractionatedheparin (s.c. or i.v.), lowmolecularweightheparin, heparinoid (s.c. or i.v.), VKA, thrombininhibitor or direct thrombininhibitor (s.c.; for ICH outcomeonly) Sandercock, et al. Cochrane Database Syst Rev. 2015;3:CD000024.

  6. Anticoagulation after AF-related stroke: How soon (or late)? • Reasons to start early • Low NIHSS • Small/no brain infarction on MRI • High recurrence riske.g. thrombus on echo • No haemorrhagic transformation • Patient is clinically stable • Young patient • Blood pressure is controlled • Reasons to wait • High NIHSS • Large/moderate brain infarction • Haemorrhagic transformation • Neurologically unstable • Elderly patient • Uncontrolled hypertension Heidbuchel, et al. Europace. 2015;17:1467–1507.

  7. The 1–3–6–12 rule • TIA 1 day • Small infarct  3 days • Moderate infarct 6 days • Large infarct  12 days Heidbuchel,et al. Europace. 2015;17:1467–1507.

  8. Our non-AF patient • 81 years old • Fully dependent at 3 months • Hypertensive, non-smoker, non-diabetic • LDL: 104 mg/dL • LA diameter: 42 mm • 30% LICA stenosis • 24 hrs ECG: - • Echocardiography: -

  9. ESUS: Embolic Strokes of Undetermined Source Hart, et al. Lancet Neurol. 2014;13:429–438.

  10. ESUS: Diagnostic criteria • Stroke detected by CT or MRI that is not lacunar. • Absence of extracranial or intracranial atherosclerosis causing>50% luminal stenosis in arteries supplying the area of ischaemia. • No major-risk cardioembolic source of embolism.(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 endocarditis) • No other specific cause of stroke identified. Hart, et al. Lancet Neurol. 2014;13:429–438.

  11. ESUS: Potential causes Covert Atrial Fibrillation Cancer associated • Covert non-bacterial thrombotic endocarditis • Tumour 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 • Pulmonary arteriovenous fistula Minor-risk potential cardioembolic sources Mitral valve • Myomatous valvulopathy with prolapse • Mitral annular calcification Aortic valve • Aortic valve stenosis • Calcific aortic valve Non-AF 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 Hart, et al. Lancet Neurol. 2014;13:429–438.

  12. ESUS: Diagnostic algorithm • Brain CT or MRI • 12-lead ECG • Precordial echocardiography • Imaging of both extra- and intracranial arteriessupplying the area of brain ischaemia • Cardiac monitoring for ≥24 hours withautomated rhythm detection Hart, et al. Lancet Neurol. 2014;13:429–438.

  13. CRYSTAL-AF Sanna, et al. N Engl J Med. 2014;370:2478–2486.

  14. CRYSTAL-AF: The more you look, the more you find Hazard ratio 8.8 (95% CI 3.5, 22.2)p<0.001 by log-rank test ICM Patients with AF detected (%) Control 10 30 20 0 36 30 24 18 12 6 0 Months since randomisation Sanna. et al. N Engl J Med. 2014;370:2478–86.

  15. EMBRACE: The more you look, the more you find Gladstone, et al. N Engl J Med. 2014;370:2467–2477.

  16. EMBRACE: The more you look, the more you find Patients with AF detected (%) 14.8 12.3 11.6 7.4 2.2 15 20 10 5 0 24 hours 1 week 2 weeks 3 weeks 4 weeks Duration of ECG monitoring Gladstone. et al. N Engl J Med. 2014;370:2467–77.

  17. ESUS: Embolic Strokes of Undetermined Source Hart, et al. Lancet Neurol. 2014;13:429–438.

  18. ESUS in the Athens Stroke Registry Ntaios,et al. Stroke. 2015;46:176–181. (Athens Stroke Registry)

  19. Patients with acute first-ever ischaemic stroke (n=2,735) Patients with missing data (n=4) n=2,731 Patients with lacunar stroke detected by CT or MRI (n=622) n=2,109 Presence of extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis inarteries supplying the area of ischaemia (n=497) n=1,612 Major-risk cardioembolic source of embolism (n=869) n=743 Other/rare specific causes (n=102) n=641 Incomplete diagnostic work-up (or ≥2 causes identified) or non-visualised infarct (n=366) ESUS (n=275) Ntaios,et al. Stroke. 2015;46:176–181. (Athens Stroke Registry)

  20. ESUS: Patient characteristics Ntaios, et al. Stroke. 2015;46:176–181. (Athens Stroke Registry)

  21. ESUS: Stroke severity Ntaios, et al. Stroke. 2015;46:176–181. (Athens Stroke Registry)

  22. ESUS: Potential causes Ntaios, et al. Stroke. 2015;46:176–181. (Athens Stroke Registry)

  23. ESUS & AF at follow-up: How much causality is there? Ntaios,et al. Manuscriptsubmitted.

  24. ESUS & AF at follow-up: How much causality is there? Ntaios, et al. Manuscriptsubmitted.

  25. ESUS: 5-year functional outcome ESUS Cardioembolic Large-arteryatherosclerotic Lacunar Undeterminedother than ESUS Miscellaneous mRS = 0-1 mRS = >1 Ntaios,et al. Stroke. 2015;46:2087–2093. (Athens Stroke Registry)

  26. ESUS: 5-year stroke recurrence ESUS Cardioembolic Risk of stroke recurrence (%) Large-artery atherosclerotic Lacunar Undetermined other than ESUS Miscellaneous 0.3 0.1 0.4 0.2 0 24 36 48 60 12 0 Months Ntaios,et al. Stroke. 2015;46:2087–2093. (Athens Stroke Registry)

  27. So, how to treat my ESUS patient? Approach 1 Furie, et al. Stroke 2011;42:227–276.

  28. So, how to treat my ESUS patient? Approach 2

  29. So, how to treat my ESUS patient? Approach 3

  30. NAVIGATE – ESUS Primary endpoints Time from randomisation to first occurrence of: • Stroke (ischaemic, haemorrhagic or undefined) or TIA with positive neuroimaging or SE • Major bleeding (ISTH criteria) ~36 months Rivaroxaban 15 mg once daily Patients with recent ESUS (7 days to 6 months before randomisation) R Aspirin 100 mg once daily N=7,060 Study number NCT02313909: https://clinicaltrials.gov/show/NCT02313909

  31. RE-SPECT ESUS Primary endpoints Time to first recurrent stroke (ischaemic, haemorrhagic or unspecified) Up to 36 months Dabigatran 150 mg* twice daily Patients with recent ESUS (up to 3 months before randomisation) R Aspirin 100 mg once daily N=6,000 *Dabigatran 110 mg twice daily in selected patients Study number NCT02239120: https://clinicaltrials.gov/show/NCT02239120

  32. ATTICUS Primary endpoint Occurrence of ≥1 new ischaemic lesion identified by MRI at 12 months when compared withbaseline FLAIR/DWI MRI obtained at time of study drug initiation 12 months Apixaban5 mg* twice daily Patients with ESUS and ≥1 suggestive risk factor for cardiac embolism R Aspirin 100 mg once daily N=500 *Apixaban 2.5 mg twice daily in selected patients Study number NCT02427126: https://clinicaltrials.gov/show/NCT02427126

  33. ESUS: Risk stratification for recurrence and mortality Absolute number (n) Percent (%) 50 40 Absolute number (n) 0 1 2 3 4 5 & 6 40 Percent (%) 30 30 20 20 10 10 0 0 0 1 2 3 4 5 6 7 8 150 200 250 250 350 300 150 100 200 50 0 0 50 100 Ntaios. et al. Manuscriptsubmitted.

  34. Prediction of Atrial Fibrillation in patients with Embolic Stroke of Undetermined Source (AF-ESUS) • Multicenter investigator-initiated study • ESUS • AF predictors • Prognostic score Lausanne Larissa Athens Ntaios, Michel & Vemmos. Ongoing.

  35. Take-home messages • 1–3–6–12 rule • Cryptogenic  ESUS • ~10% of all stroke patients • ESUS needs a complete (?) diagnostic work-up • Covert AF is frequently detected in ESUS • High recurrence rate • Ongoing studies are evaluating the use of NOACs in ESUS

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