Embolinen aivoinfarkti vailla syytä (ESUS) Neurologipäivät 2.11.2017 Jukka Putaala, vsel HYKS 1
Disclosures Research grant Helsinki and Uusimaa Hospital District, Academy of Finland, Finnish Funding Agency for Innovation, St. Jude Medical (Abbott) Research collaboration Nokia Technologies, Bittium, BcB Medical, Bayer, Vital Signum Speaker s honorary Boehringer Ingelheim, BMS Pfizer, Bayer, St. Jude Medical (Abbott) Advisory board BMS Pfizer, Boehringer Ingelheim, Bayer Guideline committee European Stroke Organisation: Post stroke hyperglycemia Secondary prevention in patients with AF Finnish Duodecim Society and Stroke Society: Ischemic stroke and TIA
OXVASC Study (n=2555; 63% IS, 37% TIA): Incidence of cryptogenic stroke 0.36/1000/year Unknown (incomplete workup) 13 % Large artery atherosclerosis 11 % Cryptogenic 32 % Cardioembolism 26 % Mean age 70.4 y In patients <55 y: 48% cryptogenic More than one cause 4 % Other, rare 2 % Small vessel disease 12 % Li et al. Lancet Neurol 2015
ESUS: The first serious attempt to create diagnostic criteria for cryptogenic strokes Hart et al. Lancet Neurol 2014
Cardioembolic sources of ischemic stroke Definite sources AF, sustained atrial flutter Left atrial or LAA thrombus Left ventricular thrombus Dilated cardiomyopathy (LVEF <30%) Recent myocardial infarction (<4 weeks) Bioprosthetic or mechanical heart valve Rheumatic valvular disease (mitral stenosis) Endocarditis (infective, non infective) Atrial myxoma/other cardiac tumors Uncertain sources (ESUS) PFO Atrial septal aneurysm Mitral valve disease (valve prolapse, annular calcification, valve strands) Aortic valve disease (sclerosis, stenosis, regurgitation) Left atrial smoke Left ventricular aneurysm without thrombus Yang et al. Eur Heart J 2016
Textbook examples of embolic infarctions
Hart et al. Lancet Neurol 2014
Frequency of ESUS patients 7 25% (avg. 17%) Among pts <50 yrs: 23 42% Antithrombotic tx Recurrent stroke Mortality 86% on APT 4.5%/y 3.9%/y Hart et al. Stroke 2017; Putaala et al. Ann Med 2015; Ladeira et al. Int J Stroke 2015
Recurrence after ESUS: AthensRegistry ESUS 29% CE 27% Ntaios et al. Stroke 2015
Survival after ESUS: Athens Registry Lacunar Misc. Large-artery atherosclerosis ESUS 66% Non-ESUS undetermined Cardioembolic 39% Ntaios et al. Stroke 2015
Clinical characteristics of ESUS Younger than most non cryptogenic cases OXVASC 70 vs. LAA 73 vs. non LAA 75 yrs ESUS Global: mean age 62 vs. 68 yrs Slight male preponderance in ESUS cases Athens: 64% ESUS Global: 57% Milder symptoms compared to cardioembolism from a known source Athens: median NIHSS 5 vs. 13 ESUS Global: median NIHSS 4 Ntaios et al. Stroke 2015; Li et al. Lancet Neurol 2015; Perera et al. Int J Stroke 2016
CHADS 2 CHA 2 DS 2 -VASc Recurrence Mortality Ntaios et al. Stroke 2016
Minor risk tromboembolic sources or comorbid findings in the ESUS Global Registry % Cervical artery nonstenotic plaques 79 Aortic arch atherosclerotic plaques 28 Patent foramen ovale (in TEE investigated patients) 25 Aortic stenosis and/or calcification 7 Dilatation of left atrium (moderate to severe) 6 Mitral valve annular calcification and/or thickening 5 Hypokinetic/akinetic left ventricle 4 Any minor risk thromboembolic source 74 Any minor risk thromboembolic source excluding carotid artery plaques 35 Two or more minor risk thromboembolic sources 24 Perera et al. Int J Stroke 2016
EMBRACE: 30 day ECG event recorder (electrode belt) in cryptogenic stroke/tia, n=287 vs. 24 h Holter, n=285 Gladstone et al. NEJM 2014
CRYSTAL AF: n=221 Reveal XT vs. n=220 24 Holter in cryptogenic stroke/tia 30% 3% Sanna et al. NEJM 2014 15
ESUS: Potilasvalinta laiterekisteröintiin? Tutkittu eteisvärinän ennustekijä Julkaisu kryptogeenisen aivoinfarktin saaneilla Korkeampi ikä (>60 v.) Favilla et al. Stroke 2015; Thijs et al. Neurology 2016; Sudacevschi et al. J Stroke Cerebrovasc Dis 2016 Naissukupuoli Miller et al. 2013 Diabetes Tayal et al. 2008 Runsas kammiolisälyöntisyys Holterissa Bhatt et al. 2011 Runsas eteislisälyöntisyys/ eteisjuoksutukset Gaillar et al. 2010; Miller et al. 2013; Poli et al. Eur J Neurol 2015, Gladstone et al. 2015; Sudacevschi et al. J Stroke Cerebrovasc Dis 2016 Pidentynyt PR väli Thijs et al. Neurology 2016 Alentunut ejektiofraktio Miller et al. 2013 Vasemman eteisen koko (>45 mm) Poli et al. Eur J Neurol 2015 BNP/ProBNP Wachter et al. PlosOne 2012; Rodríguez Yáñez et al. Neurology 2013; Fonseca et al. Int J Stroke 2014
EMBRACE: AF todennäköisyys <9% jos <100 AES/24h 40% jos >1500 AES/24h Gladstone et al. Stroke 2015
Atrial dysfuntion/cardiopathy: A proposed cause for ischemic stroke independent of AF Definition: Elevated serum NT probnp level (>250 pg/ml) Severe left atrial enlargement (LAE) on echocardiogram (criteria: Yaghi et al. Stroke 2015) P wave terminal force velocity in lead V1 on ECG greater than 5000 µvms Kamel et al. Future Cardiol 2015; Stroke 2016
Atrial dysfuntion/cardiopathy as a proposed cause for ischemic stroke independent of AF Atherosclerosis Risk in Communities, n=14,542 aged 45 64, free of AF PTF associated with incident ischemic non lacunar stroke, independent of incident AF, ahr 1.49 (95% CI 1.07 2.07) Northern Manhattan Study, case control, ischemic stroke n=241, stroke free controls n=798 PTF associated with ischemic stroke, ahr 1.20 (95% CI 1.03 1.39) and composite of cryptogenic or cardioembolic stroke, ahr 1.31 (95% CI 1.08 1.58) independent of AF; trend for cryptogenic, ahr 1.29 (95% 0.96 1.72) Cross sectional pilot case control study, n=40 elderly patients with cryptogenic stroke 63% with at least 1 biomarker of atrial cardiopathy 49% with elevated NT probnp 20% with PTF 5% with severe left atrial enlargement Kamel et al. Ann Neurol 2015; Kamel et al. Stroke 2016; Yaghi et al. J Stroke Cerebrocvasc Dis 2016
Back to Overview NAVIGATE ESUS Embolic Stroke of Undetermined Source Study Official study title: Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source (ESUS) Objective: Efficacy of rivaroxaban in reducing the risk of recurrent stroke and systemic embolism in patients with a recent Embolic Stroke of Undetermined Source (ESUS) Rivaroxaban 15 mg od N~7,000 Population: Patients with recent embolic stroke of undetermined source R Event-driven study 30 days Safety Follow-up 1:1 Day 1 ASA 100 mg od Efficacy Cut-off Date Study End Total study duration: ~3 years Mean treatment duration per patient: ~2 years Short design: Multicentre, randomized, double-blind, double-dummy, active-comparator, event-driven, superiority study Indication: Secondary stroke prevention in ESUS Start: Q4 2014 LPLV: Q4 2017 www.clinicaltrials.gov/ct2/show/nct02313909
RE-SPECT ESUS : design Primary endpoint: any stroke Index ischaemic stroke (ESUS)* Assess with MRI/CT to rule out lacunae; vascular imaging and 24-hr rhythm monitoring to rule out AF Dabigatran (150 or 110 mg BID) Placebo (matching ASA) ASA (100 mg OD) Placebo (matching dabigatran) 0 days 3 months 0.5 3 years End of treatment n=3000 n=3000 30-day follow-up An estimated 6000 patients and observation period of ~3 years will be necessary to achieve sufficient observed events for required statistical power (actual number and duration will be adjusted as needed) *mrs 3, age 60, or 18 59 years with additional risk factors; All patients receive dabigatran 150 mg BID, unless 75 years or creatinine clearance 30 50 ml/min. These patients receive dabigatran 110 mg BID; 0 days 6 months in patients aged >60 years with additional risk factors. ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source; mrs, modified Rankin score 1. Boehringer Ingelheim Clinical Trial Protocol, Trial No. 1160.189; 2. Diener HC et al. Int J Stroke 2015 21 Mar 2016
ATTICUS
Other ongoing (or not yet recruiting) studies enrolling ESUS patients (ClinicalTrials.gov) Study Patients Intervention Antic. compl. MOBILE AF ESUS Smartphone ECG vs. 7 2019 day Holter Young ESUS Patient ESUS N/A; observational 2018 Registry (Y ESUS) Prediction of AF in ESUS N/A; observational 2018 ESUS (AF ESUS) EDUCATE ESUS ESUS N/A; observational, 2019 7 day Holter ECG ETO ESUS N/A; observational, TEE 2020 SPACE ESUS Shuxuetong vs. placebo 2018 ARCADIA SECRETO ESUS with atrial cardiopathy ESUS and other cryptogenic Apixaban vs. aspirin 2021 N/A; observational 2019
Wachter et al. Lancet 2017