Stroke Update. Claire J. Creutzfeldt, MD January 12, 2018

Stroke Update Claire J. Creutzfeldt, MD January 12, 2018

Disclosures None relevant to this presentation I receive funding from the NINDS

What s new in stroke? A new model for cardioembolic stroke: atrial cardiopathy Expanding indications for NOACs? Thrombectomy update Expanding the time window

What s new in stroke? A new model for cardioembolic stroke: atrial cardiopathy Expanding indications for NOACs? Thrombectomy update Expanding the time window

What we know.

How are Afib and Stroke related? ASSERT study. Circulation 2014; 129: 2094-2099.

Ischemic stroke in North American and European Studies Ischemic stroke subtypes Other, known Other, unknown (cryptogenic) Large Artery Cardioembolic Small artery (lacunes) Lancet Neurology 2014; 13: 429-

A new model for stroke & atrial fibrillation? Stroke 2016; 47: 895-900.

Afib as a marker for atrial cardiopathy Often cohabitates with other atrial abnormalities Fibrosis Endothelial dysfunction Impaired myocyte function Chamber dilatation Mechanical dysfunction Stroke 2016; 47: 895-900.

Abnormal atria and stroke Stroke 2016; 47: 895-900. Stroke 2014; 45: 2787.

Abnormal atria and stroke Stroke 2016; 47: 895-900.

Other atrial factors and stroke: LAA Windsock 4% Chicken Wing Cactus 12% J Am Coll Cardiol 2012; 60: 531-8. Cauliflower

A new model for stroke & atrial fibrillation? Other arrhythmias Enlarged L atrium PTFV1 Lab biomarkers (NT-proBNP) CT/MR/Echo LAA morphology Stroke 2016; 47: 895-900.

A new model for stroke & atrial fibrillation? Stroke 2016; 47: 895-900.

Elevated NT-proBNP Relative Risk Reduction of 70% on warfarin! Stroke 2013; 44: 714-19.

What s new in stroke? A new model for cardioembolic stroke: atrial cardiopathy Expanding indications for NOACs? Thrombectomy update Expanding the time window

Brief reminder NOAC efficacy Lancet 2014; 383: 955-62.

Brief reminder NOAC safety Lancet 2014; 383: 955-62.

A new model for stroke & atrial fibrillation? Apixaban Dabigatran Edoxaban Rivaroxaban Other arrhythmias Enlarged L atrium PTFV1 Lab biomarkers (NT-proBNP) CT/MR/Echo LAA morphology Stroke 2016; 47: 895-900.

NAVIGATE ESUS Rivaroxaban vs ASA for secondary stroke prevention ESUS Halted Primary outcome: Early Stroke or systemic embolization; major bleed Industry sponsored RE-SPECT ESUS Dabigatran vs ASA ESUS Primary outcome: Recurrent stroke (ischemic or hemorrhagic) Industry sponsored ATTICUS Apixaban vs ASA ESUS + suggestion of cardiac risk* Primary outcome: imaging evidence of new ischemia (FLAIR, DWI) at 12mo University Hospital Tuebingen (Germany) ARCADIA Apixaban vs ASA ESUS + atrial cardiopathy Primary outcome: Recurrent stroke; symptomatic intracranial hemorrhage or major bleed NINDS *LA size >45mm, spontaneous echo contrast in LAA, LAA flow velocity <=0.2m/s, atrial high rate episodes, CHAD2VASC score >=4, PFO. Severe LA enlargement on echo, PTFV1, NT-proBNP

What s new in stroke? A new model for cardioembolic stroke: atrial cardiopathy Expanding indications for NOACs? Thrombectomy update Expanding the time window

Endovascular Thrombectomy

26.5% 46.0% Lancet 2016; 387: 1723-31.

HERMES collaboration: efficacy of endovascular thrombectomy NNT to reduce disability by at least one level = 2.6 Lancet 2016; 387: 1723-31.

HERMES: What about timing? Lancet 2016; 387: 1723-31.

Who and how late can we go?

Can we extend the intervention time window? DAWN Prospective, randomized looking at intervention vs medical management in patients presenting w/in 6-24h Imaging: MR-DWI or CTPrCBF DEFUSE 3 Prospective, randomized looking at intervention vs medical management in patients presenting w/in 6-16h of stroke onset Imaging: CT perfusion/cta or MR DWI/PWI/MRA

DAWN Study Methods: Workflow 6-24h - Age 18 - NIHSS 10 - Pre-mRS 0-1 - TLSW to Randomization: 6-24h NCCT/DWI: <1/3 MCA Territory CTA/MRA: ICA-T and/or MCA-M1 (Tandem Occlusions Allowed) RAPID CTP/DWI CIM: Informed Consent A. 80 y/o: 1. NIHSS 10 + core <21cc B. <80 y/o: 2. NIHSS 10 + core <31cc 3. NIHSS 20 + core <51cc Slide courtesy of Dr. Tudor Jovin 1:1 Randomization: - CIM subgroup - ICA-T vs M1-6-12 vs 12-24h Control Thrombectomy 90-day mrs

DAWN: Randomization and follow-up Randomized (n=206) Trevo + MM N=107 Stratification by clinical core mismatch, time, and occlusion location MM N=99 Final FU available 106 90-day complete 1 withdrew after 30 day visit* ITT cohort * 30 day mrs carried forward in 4 pts 100% follow-up to 30 days Slide courtesy of Dr. Tudor Jovin Final FU available 96 90-day complete 2 LTFU after 30 days* 1 withdrew after 30 day visit*

DAWN: Demographics Treatment arm N=107 Control arm N=99 P-value Age (years) (median, [IQR]) 72.0 [60.0-79.0] 73.0 [61.0-82.0] 0.51 NIHSS, baseline (median, [IQR]) 17 [13-21] 17 [14-21] 0.64 Sex, male (%) 39.3% 51.5% 0.09 Race White/Caucasian 66.0% 63.6% 0.77 Black or African American 21.7% 15.2% 0.28 Other* 12.3% 21.2% 0.09 IV-tPA administered 4.7% 13.1% 0.05 Slide courtesy of Dr. Tudor Jovin

DAWN: Medical history Treatment arm N=107 Control arm N=99 P-value Hypertension 79.0% 75.8% 0.62 Heart failure 18.8% 15.5% 0.58 Coronary artery disease 31.4% 24.0% 0.27 Atrial fibrillation 41.3% 25.0% 0.02 Diabetes mellitus 25.2% 31.6% 0.35 Dyslipidemia 58.8% 59.4% 1.00 Current smoker (within last year) 20.4% 23.5% 0.61 Previous ischemic stroke 12.1% 11.1% 1.00 Slide courtesy of Dr. Tudor Jovin

DAWN: Patient presentation Treatment arm N=107 Time since time last seen well to randomization (hrs) Mean ± SD Median (Q1, Q3) Range (min, max) 13.4 ± 4.1 12.2 (10.2, 16.0) (6.1, 23.5) Control arm N=99 13.0 ± 4.5 13.2 (9.4, 15.8) (6.4, 23.9) P- value 0.53 Stroke sub-population Wake up stroke 64.5% 47.5% 0.01 Witnessed stroke 10.3% 14.1% 0.52 Un-witnessed stroke 25.2% 38.4% 0.05 Slide courtesy of Dr. Tudor Jovin

DAWN: Adjudicated safety outcomes P=0.3 P<0.01 22.1% P=0.6 18.0% 10.5% 13.0% 4.8% 3.2% sich rate Neurological deterioration Stroke related mortality Trevo MM

DAWN: Primary outcome mrs 0/uW mrs 10 mrs 1/uW mrs 9.1 mrs 2/ uw mrs 7.6 mrs 3/ uw mrs 6.5 mrs 4/ uw mrs 3.3 mrs 5-6/ uw mrs 0 48% TREVO 9% 22% 17% 13% 13% 26% Probability of superiority >0.9999 CONTRO L 4% 5% 4% 16% 34% 36% 13% 73% relative risk reduction of dependency in ADL s NNT for any lower disability 2.0 Slide courtesy of Dr. Tudor Jovin

90 Day mrs 0-2 by TLSW to Randomization Trevo MM P-value 6-12h 55.1% 20.0% <0.001 12-24h 43.1% 7.4% <0.001 Slide courtesy of Dr. Tudor Jovin Trevo MM

DAWN: Conclusions Appropriately selected patients in the 6-24h time window can benefit from thrombectomy Treatment in this late window is effective NNT 2.0 for any lower disability NNT 2.8 to increase those achieving functional independence Treatment in the later window appears safe

Can we extend the intervention time window? DAWN Prospective, randomized looking at intervention vs medical management in patients presenting w/in 6-24h Imaging: MR-DWI or CTPrCBF DEFUSE 3 Prospective, randomized looking at intervention vs medical management in patients presenting w/in 6-16h of stroke onset Imaging: CT perfusion/cta or MR DWI/PWI/MRA

DEFUSE 3 Study Methods: Workflow 6-16h NCCT/DWI: ASPECTS 6; DWI core <25ml CTA/MRA: ICA-C or T and/or MCA-M1 (Tandem Occlusions Allowed) Control 90-day mrs Informed Consent 1:1 Randomization - Age 18-90 - NIHSS 6 - Pre-mRS 2 - TLSW to puncture: 6-16h Target Mismatch Profile On CT perfusion or MRI: -ischemic core volume <70ml -mismatch ratio 1.8 AND -mismatch volume 15ml Thrombectomy

Summary Atrial cardiopathy is an emerging risk factor for both stroke and Afib NOACs are effective and safe for stroke prevention after Afib can we extrapolate this to secondary prevention in the setting of atrial cardiopathy? Thrombectomy is coming/already here at a hospital near you in a later time window 6-24h