Post on 05-Oct-2020
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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