Advances in Treatment of Stroke

and TIALawrence R. Wechsler, M.D.

Chair, Department of NeurologyUniversity of Pittsburgh Medical School

Cerebrovascular Disease: the Problem

800,000 new strokes each year 5th leading cause of death 4.7 million stroke survivors in US Leading cause of disability in adults $40-50 billion per year overall cost Of those who survive, 90% have

deficit Future prediction of >1 million

strokes/year

T. Kitago. ISC 2016

Stroke Treatment

Risk factor management Antiplatelet agents Anticoagulants PFO Closure Carotid revascularization Acute treatment IV tPA Endovascular therapy

Risk Factor Control

Hypertension - < 130/80 Dyslipidemia - LDL < 70-80 Diabetes - HbA1c < 7.0 Lifestyle modification Exercise Diet Weight reduction Smoking cessation

Obstructive sleep apnea Eliminate heavy alcohol

Aspirin Efficacy by Dose: Meta-Analyses in Patients With Stroke or TIA*

* Endpoint: stroke, MI, or vascular death

RRR (%) ± 95% CI

Low Dose

Medium Dose

High Dose

Algra, van GijnJohnson

50 – 10050

30075 – 300

900 – 1500650 – 1500

Dose (mg/day)

-30 -25 -15 -10 -5 0 5 10-20

CAPRIE StudyEfficacy of Clopidogrel in Primary AnalysisMI, Ischemic Stroke, or Vascular Death

Months of Follow-Up

Cum

ulat

ive

Eve

nt R

ate

(%)

0

4

8

12

16

0 3 6 9 12 15 18 21 24 27 30 33 36

5.83%

Aspirin

5.33%

Overall Risk

Reduction

8.7%*

Event Rate per Year

P = 0.045

Clopidogrel

CAPRIE Steering Committee. Lancet 1996

CHANCE Trial: Dual Antiplatelet Therapy Randomized double blind

trial of clopidogrel 300 mg then 75 mg per day for 90d + ASA for 3 wks v. ASA alone for 90d

5170 pts within 24 hrs of minor stroke or high risk TIA in 114 centers in China

3.5% absolute reduction in stroke events over 90 days (8.2% v. 11.7% p=0.001)

No increase in hemorrhages (0.3% v. 0.3%)

Wang et al. NEJM 2013

POINT Trial: Dual Antiplatelet Therapy Randomized trial of

clopidogrel 600 mg loading then 75 mg daily for 90 days + ASA v. ASA alone

4881 patients at 269 international sites

Study terminated by DSMB after 84% recruitment

Lower major ischemic events in DAP group (5.0% v. 6.5% p=0.02)

Higher hemorrhage rate in DAP group(0.9% v 0.4% p=0.02)

Johnston et al. NEJM 2018

Atrial Fibrillation

AF affects >2.7 million Americans Prevalence increases with age The leading cardiac arrhythmia in the elderly In the U.S., 70 000 cases of stroke per year are attributed to

AF Both persistent and paroxysmal AF are predictors of first as

well as recurrent stroke Of all AF patients, those with a prior stroke or TIA have the

highest relative risk of stroke (risk of 7% - 10% per year)

Kerman WH, et al. Guideline for the Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professional from the AHA/ASA. Stroke 2014;45:2160-2236

0.8%

5.5%5.5%

2.3%

7.4%

3.6%

6.3%

0.4%

3.0% 2.9%

4.5%

0.9%

4.3%

0

1

2

3

4

5

6

7

8

AFASAK

% S

trok

e/Y

ear 72%

67%

42%

86%

26% 79%

% decrease in events

Atrial Fibrillation and Stroke:Summary of Randomized Studies

Morley J, et al. Am J Card. 1996.

SPAF1 SPAF2 BAATAF CAFS SPINAF

WarfarinAspirinPlacebo

WARFARIN VS. ASPIRIN FOR RECURRENT STROKE STUDY (WARSS)

2206 patients over 2 years Randomized, double blinded study Non-cardioembolic stroke, non-

operable atherosclerotic disease within 30 days of event

Warfarin INR 1.4-2.8 v. ASA 325 mg

Primary endpoint – recurrent ischemic stroke or death

Secondary endpoints – TIA, MI No difference in ischemic events

or hemorrhage rate over 2 yrfollowup

0 90 180 270 360 450 540 630 720

Days after Randomization

Aspirin

Warfarin

Prob

abili

ty o

f Ev

ent

(%)

Mohr J, et al, NEJM 2001

New Anticoagulants

Dabigatran Rivaroxaban Apixaban Edoxaban

Mechanism Direct thrombin inh

Factor Xainhibitor

Factor Xainhibitor

Factor Xainhibitor

Frequency Twice daily Once daily Twice daily Once daily

Onset 2-3 hrs 3 hrs 3 hrs 1-3 hrs

Half life 12-17 hrs 7-11 hrs 9-14 hrs 10-14 hrs

Clearance Renal Renal GI/Renal GI/Renal

New Anticoagulants Advantages No monitoring Rapid onset of action Once or twice daily Lower stroke risk Reduced overall bleeding

risk Reduced ICH Fewer interactions

Disadvantages No reversal agent (except

dabigatran) Increased GI bleeds Compliance important Expense Renal adjustment

Cardiac Monitoring for AfibCRYSTAL AF

Sanna et al. NEJM 2014

EMBRACE

Gladstone et al. NEJM 2014

• RCT 441 pts with cryptogenic stroke and no Afib by 24 hr monitoring

• Randomized to insertable cardiac monitoring or conventional follow-up

• Afib within 36 mo in 30% v. 3% of patients

• RCT 572 pts with cryptogenic stroke and no Afib by 24 hr monitoring

• Randomized to 30 day cardiac event monitoring or one additional 24 hr monitor

• Afib within 90 days in 16.1% v. 3.2% of patients

ESUS Trials – Cryptogenic StrokeNAVIGATE ESUS - Rivaroxaban

Hart et al. NEJM 2018 Diener et al. NEJM 2019

RE-SPECT ESUS - Dabigatran

ARCADIA: Atrial Cardiopathy Afib may be a marker for atrial

cardiopathy Randomized trial of Apixiban v. ASA

in patients with ESUS (no Afib) up to 120d from event

Atrial cardiopathy >1 of following: P wave Terminal Force in V1 >4,000 μV*ms on 12-lead ECG (ECG criteria).

Left atrial size >42 mm for women or >46 mm for men on echocardiogram (Echo criteria).

Serum NT-proBNP >185 pg/mL (BNP criteria).

Planned enrollment 1100 patients

What We Know About PFOs

Present in ~ 10 -12% of population Found in up to 26% on autopsy Greater frequency in patients with stroke Even greater frequency (45-55%) in young

patients with cryptogenic stroke Causative or innocent bystander? Does endovascular closure prevent recurrent

stroke?

PFO Device RCTs - 2012

CLOSURE RESPECT PC TRIALPts 909 980 414

Design Superiority Endpoint Superiority

Inclusion Stroke and TIA Stroke Stroke,TIA*, Emb

Endpoint Stroke,TIA, Dth Stroke, Dth Str, TIA, Dth, Emb

Follow-up 2 yrs 25 endpoints 4 yrs

Device event rate 3.1% (1.5% yr) 2.2% (0.44%/yr) 3.4% (0.85%/yr)

Medical event rate 3.4% (1.7% yr) 6.5% (1.3%/yr) 5.2% (1.3%/yr)

* Documented MRI lesion

RESPECT Trial: 10 yr results

HR (95% CI) RRP

value

Ischemic stroke 0.55 (0.30-0.99) 45% 0.046

Stroke of unknown mechanism

0.38 (0.18-0.79) 62% 0.007

Age < 60 yrs0.42 (0.21-0.83) 58% 0.010

PFO closure effective over longer term Prevents cryptogenic stroke, not other types

Saver et al. Stroke 2017

PFO Device RCTs - 2017

RESPECT 10 CLOSE REDUCEPts 909 663 664

Design Device v. BMT Device v. AP Device v. AP

Inclusion Stroke Stroke, High risk PFO

Stroke81% mod, lg PFO

Endpoint Stroke Stroke Stroke 2yrs

Follow-up 5.9 yrs 5.3 yrs 3.4 yrs

Device event rate 0.58* 0 1.4%

Medical event rate 1.07* 14 5.4%

* Events per 100 pt yrs

PFO Meta-analysis

Ntaios et al. Stroke. 2018;49:412-418

Closure v. Medical Therapy – Stroke Recurrence Closure v. Medical Therapy – Atrial Fibrillation

Symptomatic Carotid Stenosis:Pooled RCT Data CEA v. Medical Therapy

% Stenosis n ARR (%) P

< 30 1746 -2.2 .05

30 – 49 1429 3.2 .6

50 – 69 1549 4.6 .04

> 70 Without near-occlusion

1095 16.0 <.001

Rothwell PM, et al. Lancet. 2003; 361:107-116.

Asymptomatic Stenosis RCTs:CEA v. Medical Therapy

Years Pts F/UStr-Dth/Yr

MedStr-Dth/Yr

Surg ARR / Yr

VACS 1983-1987 444 4 yrs 2.4%* 1.2%* 1.2%*

ACAS 1987-1993 1659 5 yrs 2.2% 1% 1.2%

ACST 1993-2003 3120 5 yrs 2.4% 1.3 1.1%

* ipsilateral nonfatal and fatal stroke

Hobson et al. NEJM 1993, ACAS JAMA 1995, ACST Lancet 2004

Carotid Stenting: an Emerging Option

PRE POST POSTPRER CAROTID L CAROTID

CREST ResultsCEA v. CAS for Carotid Stenosis

CAS CEA HR 95% CI P Value

Primary Endpoint < 4 yrs* 7.2% 6.8% 1.11 0.81-1.51 0.51

Periprocedural Stroke 4.1% 2.3% 1.79 1.14-2.82 0.01

Periprocedural MI 1.1% 2.3% 0.50 0.26-0.94 0.03

Major Stroke 0.9% 0.6% 1.35 0.54-3.36 0.52

Ipsilateral Stroke up to 4 yrs 2.0% 2.4% 0.94 0.50-1.76 0.85

* Any periprocedural stroke, MI, death plus ipsilateral stroke thereafter

Brott et al. NEJM 2010

Oxford Vascular StudyStroke Risk with > 50% Carotid Stenosis

Event Number % / yr

Ipsilateral minor stroke

1 0.34%

Ipsilateral major stroke

0 0%

TIA 5 1.78%

• Population based study of 1153 pts with stroke or TIA recruited between 2002 – 2009• All pts treated with intensive medical therapy – AP, statins, BP reduction, lifestyle changes• 101 (8.8%) with > 50% asymptomatic stenosis• Mean followup 3 years

Marquardt et al. Stroke 2010

CREST-2 Parallel Study Design

(n = 1,240 in each trial)

S = ScreenedR = Randomized

Intensive Medical TherapyRisk Factor Goal Measurement

Primary Risk Factors

LDL < 70 mg/dL Local lab

Systolic BP < 130 mm Hg Measured each visit

Secondary Risk Factors

Non-HDL < 100 mg/dL Local lab

HgA1c < 7.0% Local lab

Smoking Cessation Self

Weight management BMI <25 kg/mm2 or 10% Weight at each visit

Exercise > 30 min 3 X per week Self

Limitations of IV tPA

3-4.5 hour time window Less effective for large artery

occlusion – less than 50% recanalization

Early reocclusion in 20 – 30% Early IV tPA v. IV/IA therapy

failed to show benefit Stent retrievers more

effective and rapid recanalization

MR CLEAN Trial: EVT v. Usual CareEffect of Intervention on Primary Outcome

Common adjusted odds ratio: 1.67 (95% CI:1.21 to 2.30)

Berkhemer et al. NEJM 2015

mRS 0-2 33%

mRS 0-2 19%

Endovascular Trials: Stent Retrievers

Pts Control Window Selection Endpoint Diff NNT OR

MR CLEAN 500 Best Med < 6 hrsNIHSS > 2Grey area principle

mRs 0-2 14% 7 1.7**

ESCAPE 314 Best Med < 12 hrsNIHSS > 5; ASPECT > 5P2P < 60 min; P2R < 90 min

mRS 0-2 or NIHSS 0-2

24% 4 2.6**

EXTEND-IA 70 IV tPA < 6 hrsCore < 70 ccPenumbra > 10 cc

Reperfusion 24 hrs

31% 3 3.8

SWIFT-PRIME 196 IV tPA < 6 hrs ASPECT > 6NIHSS > 7 mRS 0-2* 25% 4 2.8

REVASCAT 195 IV tPA < 8 hrs NIHSS > 5ASPECT > 6 mRS 0-2 16% 6 2.1

* SWIFT-PRIME primary Rankin shift, mrs0-2 secondary

NR – Not reported** Rankin shift

Pooled Analysis of Endovascular Trials

7.3 hrs

2.3 2.52.9

3.44.2

5.58.6

NNTs

Saver et al. JAMA 2016

Number Needed to Treat

NNT

PCI to prevent MI 30

IV tPA – additional good outcome 8

EVT – additional good outcome 3-4

AND

Substantially morepatients eligible

Tissue Clock v. Time Clock

Thrombectomy 6-24 hr Window

NEJM Jan 2018

NEJM Feb 2018

DAWN Trial

Study Design

Study Objective

Study design Global, multi-center, adaptive, population enrichment, prospective, randomized, open, blinded endpoint (PROBE), controlled FDA IDE trial

Patientpopulation

• Acute ischemic stroke (AIS) with large vessel occlusion• Able to be randomized between six to 24 hours after time last known well• Clinical imaging mismatch (CIM) defined by age, core, and NIHSS

Target vessel Intracranial ICA, M1 segment of the MCA

Randomization 1:1 Trevo + medical management vs. medical management alone

Sites Up to 50 sites worldwide (30 US and 20 international)

Sample size 500 maximum subjects: 250 in the treatment arm and 250 in the control arm. Minimum sample size is 150 subjects.

Follow-up 24 hours (-6/+24), day 5-7/discharge, day 30 (± 14), and day 90 (± 14)

To demonstrate superior functional outcomes at 90 days with Trevo plus medical management compared to medical management alone in appropriately selected patients treated six to 24 hours after last seen well

Noguiera et al. NEJM 2017

DAWN: Primary Endpoint

OutcomeTreatment

arm N=107

Control arm

N=99

AbsoluteDifference(95% CI)

AdustedDifference(95% CI)

NNTPosterior

Probability of Superiority

Utility weighted mRS90 days

5.5 + 3.8 3.4 + 3.1 2.1 (1.2-3.1) 2.0 (1.1-3.0) 2.0 >0.999

Functional Independence(mRS 0-2)

52 (49%) 13 (13%) 36 (24-47) 33 (21-44) 2.8 >0.999

Nogueira et al. NEJM 2017

4%

9%

5%

22%

4%

17%

16%

13%

34%

13%

36%

26%

CONTROL

TREVO

mRS 0/uW mRS 10 mRS 1/uW mRS 9.1 mRS 2/ uW mRS 7.6mRS 3/ uW mRS 6.5 mRS 4/ uW mRS 3.3 mRS 5-6/ uW mRS 0

Probability of superiority >0.9999

mRS 0-2 - 49%

mRS 0-2 - 13%

Odds ratio: 2.8 (1.6 - 4.7) P<0.0001 Adjusted odds ratio: 3.4 (2.0 - 5.8) P=0.0004Number needed to treat: 2

Results: Primary Outcome

mRS 0-2 44%

mRS 0-2 16%

DAWN - 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

Trevo MM

Noguiera et al. NEJM 2017

Impact of the 24 hour Acute Stroke Window

< 4.5 hours IV tPA window NIHSS, CT

< 6 hour thrombectomy window NIHSS, CT, CTA

6-24 hour patient selection for thrombectomy NIHSS, CT, CTA RAPID, perfusion, DWI, collaterals

Endovascular Therapy Summary

Treatment window for EVT extended to 24 hours for highly selected patients

Selection in late time window based on tissue clock not time clock – Clinical/core mismatch

For every 100 patients treated with endovascular therapy, 49 will have a less disabled outcome as a result of treatment, including 36 who will be functionally independent.

Acute Stroke Therapy

“Get the right patient to the right hospital for the right treatment”

CSCPSC

IV tPA 0-4.5 hrsIV tPA 0-4.5 hrsEVT 0-6 hrs, 6-24 hrs

Transfer

Prehospital Triage: Mobile Stroke Unit

Ambulance Portable CT POC lab Telemedicine Teleradiology

IV tPA in the field Identify LVO and

transfer direct to CSC

Rajan et al.JAMA Neurol 2014

Summary

Stroke is a leading cause of death and disability in US and worldwide

Many recent advances in stroke diagnosis and treatment Mechanical thrombectomy is highly effective in

appropriate patients and should be standard of care Transport and triage of acute stroke must be

reorganized to deliver the right patient to the right hospital for the right therapy at the earliest time.

THANK YOU!

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