Cryptogenic Stroke: Finding Light in the Darkness Scott E. Kasner, MD Professor of Neurology Director, Comprehensive Stroke Center
Disclosures WL Gore PI for Gore REDUCE Trial Medtronic DSMB for CRYSTAL AF Trial Bayer National Lead Investigator for NAVIGATE- ESUS Trial Boehringer Ingelhim Global Advisory Committee
Ischemic Stroke Subtypes Large Artery Small Vessel Cardioembolism Other Cryptogenic NINCDS Stroke Data Bank: Foulkes et al. Stroke. 1988;19:547. German Stroke Data Bank Grau A.J. et al. Stroke 2001;32:2559-2566
Large Artery Atherothromboembolism 50% stenosis of a major extraor intracranial artery
Small Vessel (Lacunar) Stroke TOAST <1.5 cm; CCS <2.0 cm diameter
High Risk Sources of Cardioembolism Mechanical prosthetic valve Atrial fibrillation Intracardiac thrombus Dilated cardiomyopathy Recent myocardial infarction (<4 weeks) Akinetic left ventricular segment Atrial myxoma or fibroelastoma Infective endocarditis
Secondary Prevention of Ischemic Stroke What is the cause of the initial cerebrovascular event? Large vessel athero Cardioembolism Small vessel dz Revascularization Antiplatelet agent Anticoagulation Antiplatelet agent Risk factor modification Statin Lifestyle modification
Other Determined Causes Drugs Cocaine Amphetamines Infections Syphilis TB VZV Genetic disorders MELAS CADASIL Vasculopathy Dissection Vasculitis Vasoconstriction Prothrombotic disorders Factor deficiencies Anti-phospholipid Ab Sickle cell disease
Secondary Prevention of Ischemic Stroke What is the cause of the initial cerebrovascular event? Other Specific therapy for specific etiology
Ischemic Stroke Subtypes 30-40% Large Artery Small Vessel Cardioembolism Other Cryptogenic NINCDS Stroke Data Bank: Foulkes et al. Stroke. 1988;19:547. German Stroke Data Bank
Cryptogenic Stroke Where do they come from?
Secondary Prevention of Ischemic Stroke What is the cause of the initial cerebrovascular event? Cryptogenic?
What is Cryptogenic Stroke? Insufficient evaluation Thorough but negative evaluation Multiple competing causes Leftovers from the known cause categories that don t quite fit
Etiology? 68-year-old man with mild left face and arm weakness and mild neglect Risk factors: hypertension, prior smoker Neuroimaging: small right cortical infarction Carotid ultrasound: no significant stenosis EKG: sinus rhythm, normal Echo (transthoracic): EF 50%, no major wall motion abnormalities, normal valves, no source Labs: LDL 95, A1c 5.0%
How Thorough is Thorough? History and examination Carotid ultrasound EKG Telemetry in hospital Echocardiogram Routine blood tests
Insufficient Evaluation vs. Thorough But Negative Evaluation How thorough is thorough? Intracranial vascular imaging Transesophageal echo Prolonged cardiac telemetry Prothrombotic testing Weird stuff?
Cryptogenic Stroke: Why should we look for intracranial stenosis?
0.4 Probability of Stroke / Vascular Death 0.3 0.2 0.1 0 0 1 2 3 4 5 Aspirin Warfarin Years after Enrollment
Beyond Medical Therapy
Intracranial Stenosis-Why Look? Prognosis High short term risk Medical Treatment (SAMMPRIS) Aspirin plus clopidogrel x 90 days Aggressive lipid and BP lowering Angioplasty/stent Definitely not first line approach
What are we really going to find on TEE? Aortic Arch Atheroma
What are we really going to find on TEE? Aortic Arch Atheroma
ARCH Trial warfarin asa/clopidogrel Recurrent event: 7.6% ASA/clop vs. 11.3% warfarin OR 0.76 (0.36-1.61), p=0.50 Inconclusive
Cryptogenic Stroke: Are We Missing Paroxysmal Atrial Fibrillation? Biological and genetic plausibility Detection of asymptomatic / occult AF Diagnostic dilemma
AF: Symptoms and Stroke 50-90% AF episodes are asymptomatic Even in patients with symptoms, ratio of asymptomatic to symptomatic is 12:1 25% of those with AFassociated stroke have no known history of AF Even in stroke patients with known PAF, 50-70% present in sinus rhythm
Mobile Cardiact Outpatient Telemetry (MCOT) in Cryptogenic Stroke (N=56) Tayal et al. Neurology 2008;71:1696 1701
AF detected day 21
Time to Detection of New Dx of AF Telemetry in hospital Holter monitor Prolonged monitoring Freedom from AT/AF 1.0 0.9 0.8 0.7 89% of NDAF patients identified beyond 1 day 78% of NDAF patients identified beyond 7 days 60% of NDAF patients identified beyond 30 days 0.6 0.5 0 3 mo. 6 mo. 9 mo. 12 mo. Number 163 127 111 106 67 at Risk: Time from Device Implant (months) Ziegler et al. Stroke 2010;41:256-260.
AF detection after stroke
Cryptogenic Stroke and Underlying Atrial Fibrillation (CRYSTAL AF) Trial 450 cryptogenic stroke patients Randomized to Reveal XT implantation vs. routine care Primary end point was time to detection of AF within 6 months after stroke
CRYSTAL AF Study More AF with longer monitoring 6 months: 8.9% vs. 1.4% 12 months: 12.4% vs. 2% 36 months: 30% vs. 3% 92% of Afib events were >6 minutes 2.4% of patients required device explantation
Implantable Monitors Implanted under skin Records up to 3 years
Look Harder for Occult AFib ~20% of cryptogenic stroke pts have occult AF Most AF episodes are asymptomatic AF yield increased with longer monitoring duration Unknown optimal duration (forever?) Short AF episodes of uncertain significance Treatment options for AFib expanding every day
How much AF increases risk of stroke?
Risk of ischaemic stroke according to pattern of atrial fibrillation: analysis of 6563 aspirin-treated patients in ACTIVE-A and AVERROES Thomas Vanassche1*, Mandy N. Lauw1, John W. Eikelboom1, Jeff S. Healey1, Robert G. Hart1, Marco Alings2, Alvaro Avezum3, Rafael Dı az4, Stefan H. Hohnloser5, Basil S. Lewis6, Olga Shestakovska1, JiaWang1, and Stuart J. Connolly1
Meta-analysis of DOAC Trials
2580 patients >65 years with recent pacemaker or AICD Subclinical atrial tachyarrhythmias (>6 minutes) were detected in 10.1% by 3 months, with more over time Subclinical atrial tachyarrhythmias independently associated with ischemic stroke or systemic embolism HR 2.5; 95% CI: 1.3-4.9; p=0.008 Atrial fibrillation vs. atrial something? Healey, JS et al. Subclinical Atrial Fibrillation and the Risk of Stroke. N Engl J Med 2012;366:120-129.
Detecting subclinical AF in pacemaker patients without history of AF Cumulative incidence 0.0 0.1 0.2 0.3 0.4 0.5 0.6 SCAF >6mins SCAF >6hours SCAF >24hours Brief AF ~5x more common than AF>24hr 0 0.5 1 1.5 2 2.5 3 3.5 No. at Risk SCAF >6mins SCAF >6hours SCAF >24hours Years of Follow-up 2455 1935 1720 1538 1265 912 637 397 2455 2161 2024 1889 1591 1197 858 554 2455 2251 2130 1993 1700 1292 940 609 Unpublished from ASSERT
Risk of ischemic stroke or systemic embolism according to duration of SCAF Cumulative event rates 0.0 0.05 0.10 0.15 0.20 No SCAF 6mins~6hrs 6hrs~24hrs >24hrs Only AF>24h associated with future stroke risk!!! 0 0.5 1 1.5 2 2.5 3 3.5 Years of Follow-up No. at Risk No SCAF 2455 1926 1708 1528 1251 900 624 390 6mins~6hrs 0 226 302 347 322 281 218 155 6hrs~24hrs 0 88 104 103 108 93 80 52 >24hrs 0 91 124 144 140 126 116 85 Unpublished from ASSERT
What is Cryptogenic Stroke? Insufficient evaluation Thorough but negative evaluation Multiple competing causes Leftovers from the known cause categories that don t quite fit
Cryptogenic Stroke: Carotids negative 40% stenosis
Are These Lacunar Strokes? TOAST <1.5 cm; CCS <2.0 cm diameter
Medium Risk Sources of Cardioembolism Mitral valve prolapse Mitral annulus calcification Mitral stenosis Atrial septal aneurysm Patent foramen ovale Congestive heart failure Atrial flutter Left atrial turbulence (smoke) Bioprosthetic cardiac valve Nonbacterial thrombotic endocarditis Hypokinetic left ventricular segment Myocardial infarction (>4 weeks, <6 months)
Patent Foramen Ovale (PFO) Congenital cardiac anomaly in ~25% people Fibrous adhesions fail to seal the atrial septum
One year follow-up 3D Echocardiogram Courtesy of John Rhodes, MD
PFO Closure Trials Meta-Analysis
Gore REDUCE Study 664 patients with cryptogenic stroke and PFO Exclude arterial stenosis, cardioembolism, lacunes, hypercoag Randomized to device closure versus antiplatelet therapy At least 2 years of clinical follow-up Primary outcome: stroke MRI confirmation of baseline stroke MRI of all suspected events MRI at 2 years (for subclinical infarctions) Multinational trial Results in Spring 2017!!!!
What is Cryptogenic Stroke? Insufficient evaluation Look harder! Thorough but negative evaluation Are you sure it is negative? Leftovers from the known cause categories that don t quite fit Should we make them fit? Multiple competing causes Are these really cryptogenic?
Ischemic Stroke Subtypes 30-40% Large Artery Small Vessel Cardioembolism Other Cryptogenic
Ischemic Stroke Subtypes Improved Diagnosis and Definition <10% Large Artery Small Vessel Cardioembolism Other Cryptogenic
Embolic Stroke of Uncertain Source (ESUS) Stroke detected by CT or MRI that is not lacunar Subcortical infarct 1.5 cm ( 2.0 cm on DWI) in largest dimension, and in the distribution of the small, penetrating cerebral arteries. Absence of extracranial or intracranial atherosclerosis Causing a 50% luminal stenosis in arteries supplying the area of ischemia No major-risk cardioembolic source of embolism AF, intracardiac thrombus, prosthetic valve, myxoma/tumors, mitral stenosis, recent MI, EF<30%, vegetations No other specific cause of stroke identified (e.g., arteritis, dissection, migraine/vasospasm, drug misuse) Lancet 2014
ESUS Components Truly unexplained ischemic stroke Stroke with undetected/occult AF or atrial something Stroke due to low-to-medium risk cardiac sources Stroke due to arch atheroma Stroke due to <50% extra- or intracranial atherosclerosis And many others yet to be determined
Secondary Prevention of Ischemic Stroke What is the cause of the initial cerebrovascular event? Cryptogenic/ ESUS?
Cryptogenic Stroke Maybe we should just shoot first and ask questions later!
Anticoagulation For ESUS? Post hoc subgroups from WARSS Sacco, 2006
Anticoagulation For ESUS? Intracranial stenosis (WASID) Aortic arch atheroma (ARCH)
Anticoagulation for ESUS? PFO (RESPECT)
AVERROES: Apixaban Better than Aspirin for AF Stroke or Systemic Embolism Cumulative Risk 0.0 0.01 0.03 0.05 RR= 0.46 95%CI= 0.33-0.64 p<0.001 ASA Apixaban 0 3 6 9 12 18 21 Months No. at Risk ASA 2791 2720 2541 2124 1541 626 329 Apix 2809 2761 2567 2127 1523 617 353
Apixaban: Similar Risk of Major Bleeding as Aspirin 5 Major bleeding (%) 4 3 2 1 1.2 1.4 0 Aspirin Apixaban Compared to aspirin: Apixaban: 1.14 (0.74-1.75); p=0.56
Anticoagulation vs. Aspirin? Trials underway: NAVIGATE-ESUS Rivaroxaban vs. aspirin for allesus RESPECT-ESUS Dabigatran vs. aspirin for all ESUS ARCADIA (soon) Apixaban vs. aspirin for ESUS with atrial cardiopathy
Cardiac monitors TEE Xa inhibitors Vascular imaging DTIs