STROKE UPDATE Carlos S. Kase, M.D. Department of Neurology Boston Medical Center Medicine Grand Rounds New England Baptist Hospital March 17, 2011

STROKE UPDATESTROKE UPDATE

Carlos S. Kase, M.D.Carlos S. Kase, M.D.

Department of NeurologyDepartment of Neurology

Boston Medical CenterBoston Medical Center

Medicine Grand Rounds New England Baptist Hospital

March 17, 2011

Albers GW, et al. Chest. 2001;119:300S-320S.Albers GW. Personal communication. February 27, 2003.Rosamond WD, et al. Stroke. 1999;30:736-743.

Hemorrhagic Stroke (15%)

Subarachnoid Hemorrhage (5%)

IntracerebralHemorrhage (10%)

Cardioembolic (25%)

Lacunar (15%)

Ischemic Stroke (85%)

Cryptogenic (15%)

Large Vessel (30%)

STROKE STROKE MECHANISMSMECHANISMS

?

ADVANCES IN CEREBROVASCULAR ADVANCES IN CEREBROVASCULAR DISEASEDISEASE

I.I. Treatment of Acute Ischemic Treatment of Acute Ischemic StrokeStroke

II.II. Secondary Stroke PreventionSecondary Stroke Prevention



• IV ThrombolysisIV Thrombolysis

• IA ThrombolysisIA Thrombolysis

• EmbolectomyEmbolectomy






First proven effective therapy for acute

stroke

Double-blind, randomized, 624 pts.

t-PA 0.9 mg/kg (max. 90 mg) IV over 1 hour

Treatment started < 3 hrs. from stroke onset

CT documenting absence of hemorrhage

No anticoagulants/antiplatelets for 24 hrs.

NINDS t-PA StudyNINDS t-PA StudyNEJM 1995;333:1581-7NEJM 1995;333:1581-7

IV tPA IV tPA Declining Benefit over TimeDeclining Benefit over Time

Hacke W, et al. Lancet 2004;363:768-74

IV tPA IV tPA Declining Benefit over TimeDeclining Benefit over Time

Hacke W, et al. Lancet 2004;363:768-74

4½ h.

NEJM 2008;359;1317-29

Stroke 2009;40:2945-8

The eligibility criteria for treatment in this time period are similar to those for persons treated at earlier time

periods, with any one of the following additional exclusion criteria: Patients older than 80 years, those taking oral

anticoagulants, those with a baseline National Institutes of Health Stroke Scale score >25, or those with both a

history of stroke and diabetes.






(Prolyse in Acute Cerebral Thromboembolism)

PROACT IIPROACT II

180 patients180 patients

6-hour window6-hour window

MCA stem or division occlusionMCA stem or division occlusion

121 proUK (9 mg) IA; 59 control121 proUK (9 mg) IA; 59 control

EfficacyEfficacy: Rankin 0-2 at 90 days: Rankin 0-2 at 90 days

SafetySafety: Rate of symptomatic ICH, mortality: Rate of symptomatic ICH, mortality

PROACT II TRIAL

Furlan A, Higashida R, Wechsler L, et al. - JAMA

1999;282:2003-11

Randomized trial of IA pro-Urokinase+heparin v. heparin in

angiographically-documented MCA occlusion

RESULTS

Rankin < 2 at 3 months in 40% r-proUK, 25% control

(p=.04)

Symptomatic ICH in 10% r-proUK, 2% control (p=.06)

Recanalization 66% r-proUK, 18% control (p<.001)

Mortality 25% r-proUK, 27% control

Diagnostic Imaging EvaluationDiagnostic Imaging Evaluation

• Head CT without contrast: r/o ICH

• CTA: Evaluation for large artery occlusion

• CTP: Evaluation of perfusion mismatch

• MRI: Extent of infarct on DWI

• MRA: Large artery occlusion

• MRP: Evaluation of perfusion mismatch

CBVCerebral Blood Volume

MTTMean Transit Time

Perfusion MismatchPerfusion MismatchPenumbra =Penumbra =Tissue at RiskTissue at Risk

CBVCerebral Blood Volume

MTTMean Transit Time

Perfusion MatchPerfusion MatchNo PenumbraNo Penumbra

Diagnostic Evaluation: MRIDiagnostic Evaluation: MRI

DWI PWI

Diagnostic EvaluationDiagnostic Evaluation






Mechanical removal of thrombus:MERCI trial

• Embolectomy device (Merci Retriever) to open occluded intracranial large vessels within 8 hours of symptom onset

• All patients ineligible for intravenous tPA

• Outcomes- Recanalization and safety - Neurological outcome at 90 days in recanalized vs. non-recanalized patients

Intra-arterial thrombectomyIntra-arterial thrombectomy

Smith WS, et al. Stroke 2005;36:1432-8

ACUTE ISCHEMIC STROKE TREATMENT ACUTE ISCHEMIC STROKE TREATMENT OPTIONSOPTIONS

TIME (HOURS)TIME (HOURS)

IV t-PAIntra-arterial Thombolysis/

Thrombectomy

MERCIMR Rescue trial

0 - 3 4½ 6 - 8

0 - 8

IV tPA extended window


II. Secondary Stroke PreventionII. Secondary Stroke Prevention

• Risk factor controlRisk factor control

• Anti-platelet agentsAnti-platelet agents

• AnticoagulantsAnticoagulants

• Interventional proceduresInterventional procedures







(Perindopril Protection Against Recurrent Stroke Study)

Stroke 2008;39:1647-52

Stroke 2008;39:1647-52

ATRIAL FIBRILLATIONATRIAL FIBRILLATION

Fibrin Clot

IIaIIa Inhibitors InhibitorsXII

VIIVIII

IX

XI

II

V

X

I

Direct Thrombin Inhibitors

Tested: Ximelagatran

New: DabigatranDabigatran

Direct thrombin inhibitors

Fibrin Clot


VIIVIII

IX

XI

II

V

X

I





XimelagatranXimelagatranAs effective as warfarinHepatotoxic

Fibrin Clot


VIIVIII

IX

XI

II

V

X

I





XimelagatranXimelagatranAs effective as warfarinHepatotoxic

pp. 1139-1151

18,113 patients randomizedDesign: Open-label, Non-Inferiority trial

Median treatment duration: 2 years951 centers in 44 countries

December 2005 to March 2009

pp. 1139-1151

Stroke / Systemic Embolism – RE-LY StudyStroke / Systemic Embolism – RE-LY Study

0

0.5

1

1.5

2

110 mg BID 150 mg BID Warfarin

% p

er

year 1.53

1.11

P < 0.001 (NI)

P < 0.001 (SUP)

RRR: 45%

182/6,025 134/6,076 199/6,022

1.69

Major bleeding and componentsMajor bleeding and components

CharacteristicCharacteristicDD

110 110 mgmg

DD150 150 mgmg

WarfaWarfarinrin

P-P-valuevalue

110 vs. 110 vs. WW

P-valueP-value150 vs. 150 vs.

WW

Number of patientsNumber of patients 60156015 60766076 60226022

Major bleedingMajor bleeding 2.712.71 3.113.11 3.363.36 0.0030.003 0.310.31

- Life threatening- Life threatening- Non-life - Non-life threatening threatening - Gastrointestinal - Gastrointestinal

1.221.221.661.661.121.12

1.451.451.881.881.511.51

1.801.801.761.761.021.02

<0.001<0.0010.560.560.430.43

0.0370.0370.470.47

<0.001<0.001

Data represent %/year

Net clinical benefit and Net clinical benefit and componentscomponents

CharacteristicCharacteristicDD

110 110 mgmg

DD150 150 mgmg

WarfarWarfarinin


WW


WW

Number of Number of patients (n)patients (n) 60156015 60766076 60226022

Net Clinical Net Clinical BenefitBenefit 7.097.09 6.916.91 7.647.64 0.100.10 0.040.04

- Stroke / SE- Stroke / SE

- Death- Death- MBE* - MBE* - PE - PE - MI - MI

1.531.53

3.753.752.71 2.71 0.120.120.720.72

1.111.11

3.643.643.11 3.11 0.150.150.740.74

1.691.69

4.134.133.363.360.090.090.530.53

<0.001 <0.001 (NI)(NI)0.34 0.34 (sup)(sup)0.130.13

0.003 0.003 0.560.560.070.07

<0.001 <0.001 (NI)(NI)

<0.001 <0.001 (sup)(sup)0.0510.0510.31 0.31 0.210.210.0480.048

Data represent %/year* Major Bleeding Events

Dabigatran for Stroke Prevention in AF:Dabigatran for Stroke Prevention in AF:Pros and Cons Pros and Cons

Cons

Open-label design

Short f/u period (2 years)

Small absolute risk reduction

Increase in rate of MI

Increase rate GI bleeding

Lack of antidote

More expensive than warfarin

Pros

NI/superior to warfarin

Fixed-dose

Rapid onset of action

No need x monitoring

No drug/food interactions

Lower rates of ICH

No hepatotoxicity







Aspirin Efficacy by Dose: Meta-Aspirin Efficacy by Dose: Meta-Analyses in Patients with Stroke or Analyses in Patients with Stroke or

TIATIA

Endpoint: Stroke, MI, or Vascular Death

-10 -5 0 5 10 15 20 25 30

RRR (%) ± 95% CI

Low Dose

Medium Dose

High Dose

Algra, van GijnJohnsonTijssen

50 - 100

50

50 - 75

300

75 - 300

300

900 - 1500

650 - 1500

900 - 1500

Dose (mg/day)

ACCP Guidelines - Antiplatelet ACCP Guidelines - Antiplatelet AgentsAgents

““For long-term stroke prevention in patients with noncardioembolic stroke or transient ischemic attack (TIA) [ie, atherothrombotic, lacunar, or cryptogenic], we recommend treatment with an antiplatelet agent (Grade 1A), including aspirin (recommended dose, 50–100 mg/d), the combination of aspirin and extended-release dipyridamole (25 mg/200 mg bid), or clopidogrel (75 mg qd). In these patients, we recommend use of the combination of aspirin and extended-release dipyridamole (25/200 mg bid) over aspirin (Grade 1A) and suggest clopidogrel over aspirin (Grade 2B), and recommend avoiding long-term use of the combination of aspirin and clopidogrel (Grade 1B). For patients who are allergic to aspirin, we recommend clopidogrel (Grade 1A)””

Albers et al., Chest 2008;133;630S-669S







NEJM 2001;345:1444-1451

Secondary stroke prevention trial

Design: multicenter, double-blind, randomized

Non-cardioembolic, non-operable carotid stroke in prior 3

months

Agents: warfarin (INR=1.4-2.8) vs. ASA (325 mg qd)

N = 1,103 warfarin – 1,103 ASA

Duration of treatment: 2 years

Primary end-point: recurrent ischemic stroke/death in 2 yrs.

Adverse experience: hemorrhage

Analysis: intention-to-treat

WARSSWARSS

Warfarin

Aspirin

70

80

90

100

WarfarinAspirin

1103 972 8851103 984 900

Hazard rate ratio=1.13 95% CI 0.92-1.38 two-sided p-value=0.25

Kaplan-Meier: Recurrent Kaplan-Meier: Recurrent Ischemic Stroke or DeathIschemic Stroke or Death

Perc

en

t fr

ee o

f even

t

Number at risk

0 90 180 270 360 450 540 630 720

Days after randomization







CEA for Stroke Prevention: CEA for Stroke Prevention: Symptomatic v. Asymptomatic Symptomatic v. Asymptomatic

Carotid StenosisCarotid Stenosis

Symptomatic Asymptomatic

Medical Rx

CEA

Str

oke

Rate

(%

/year)

13%

4%

2%1%

(>70% stenosis) (>60% stenosis)

Carotid Endarterectomy for Carotid Endarterectomy for Stroke Prevention: SummaryStroke Prevention: Summary

Benefit is established for high-grade Benefit is established for high-grade ((>> 70%) symptomatic carotid 70%) symptomatic carotid

stenosisstenosis Value in moderate (50-69%) Value in moderate (50-69%) symptomatic symptomatic stenosis established, but stenosis established, but of smaller of smaller magnitudemagnitude No value for symptomatic carotid No value for symptomatic carotid stenosis stenosis << 50% 50% Role of carotid angioplasty/stenting Role of carotid angioplasty/stenting undergoing evaluation in clinical trialsundergoing evaluation in clinical trials

CAROTID ARTERY STENOSISCAROTID ARTERY STENOSISEndarterectomy or Endarterectomy or

Angioplasty/Stenting?Angioplasty/Stenting?

SAPPHIRE trialSAPPHIRE trial

NEJM 2006;351;1493-501

SAPPHIRE trialSAPPHIRE trialCriteria for High-Risk for Criteria for High-Risk for

CEACEA

SAPPHIRESAPPHIREStenting and Angioplasty with Protection in Patients at High Risk for EndarterectomyStenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy

747

167 167

NEJM 2004;351:1493-1501

SAPPHIRE results – 30 daysSAPPHIRE results – 30 daysIntention-to-Treat AnalysisIntention-to-Treat Analysis

0

2

4

6

8

10

Death Stroke MI D/Str/MI

Stent

CEA

Perc

en

tag

e o

f p

ati

en

ts (

%) 9.8%

4.8%

p value 0.08 0.60 0.07 0.08

EVA-3S trialEVA-3S trial

NEJM 2006;355:1660-71

EVA-3S results – 30 daysEVA-3S results – 30 daysIntention-to-Treat AnalysisIntention-to-Treat Analysis

0

2

4

6

8

10

Death Stroke MI

Stent

CEA

Perc

en

tag

e o

f p

ati

en

ts (

%)

p value 0.68 0.004 0.62

8.8%

2.7%

CREST trialCREST trial

NEJM 2010;363:11-23

Patient Patient CharacteristicsCharacteristics

CAS(n=1262)

CEA(n=1240)

Age 69 69Female - % 36 34Asymptomatic - %

47 47

Hypertension - % 86 86Diabetes - % 30 30Dyslipidemia - % 82 85Current smoker - %

26 26

Primary Endpoint ≤ 4 years(any stroke, MI, or death within peri-procedural period

plus ipsilateral stroke thereafter)

CAS vs. CEACAS vs. CEA Hazard Ratio, 95% CIHazard Ratio, 95% CI P-P-ValueValue

7.2 vs. 6.8% HR=1.11; 95% CI: 0.81-1.51 0.51




7.2 vs. 6.8% HR=1.11; 95% CI: 0.81-1.51 0.51




7.2 vs. 6.8% HR=1.11; 95% CI: 0.81-1.51 0.51

CREST TrialCREST TrialPeri-procedural Stroke and MIPeri-procedural Stroke and MI

Stroke MI

CEA

CAS

Even

t R

ate

(%

)

2.3%

4.1%

2.3%

1.1%

P=0.01

P=0.03

ConclusionsConclusions

CEA and CAS have similar net outcomes CEA and CAS have similar net outcomes though the individual risks vary, lower stroke though the individual risks vary, lower stroke with CEA and lower MI with CASwith CEA and lower MI with CAS

Younger patients may have improved efficacy Younger patients may have improved efficacy with CAS and older patients with CEAwith CAS and older patients with CEA

For the future, both CEA and CAS appear For the future, both CEA and CAS appear to be useful tools for preventing stroketo be useful tools for preventing stroke

Documents

STROKE UPDATE Carlos S. Kase, M.D. Department of Neurology Boston Medical Center Medicine Grand Rounds New England Baptist Hospital March 17, 2011