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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
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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
?
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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
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ADVANCES IN CEREBROVASCULAR ADVANCES IN CEREBROVASCULAR DISEASEDISEASE
I.I. Treatment of Acute Ischemic Treatment of Acute Ischemic StrokeStroke
• IV ThrombolysisIV Thrombolysis
• IA ThrombolysisIA Thrombolysis
• EmbolectomyEmbolectomy
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ADVANCES IN CEREBROVASCULAR ADVANCES IN CEREBROVASCULAR DISEASEDISEASE
I.I. Treatment of Acute Ischemic Treatment of Acute Ischemic StrokeStroke
• IV ThrombolysisIV Thrombolysis
• IA ThrombolysisIA Thrombolysis
• EmbolectomyEmbolectomy
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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
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IV tPA IV tPA Declining Benefit over TimeDeclining Benefit over Time
Hacke W, et al. Lancet 2004;363:768-74
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IV tPA IV tPA Declining Benefit over TimeDeclining Benefit over Time
Hacke W, et al. Lancet 2004;363:768-74
4½ h.
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NEJM 2008;359;1317-29
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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.
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ADVANCES IN CEREBROVASCULAR ADVANCES IN CEREBROVASCULAR DISEASEDISEASE
I.I. Treatment of Acute Ischemic Treatment of Acute Ischemic StrokeStroke
• IV ThrombolysisIV Thrombolysis
• IA ThrombolysisIA Thrombolysis
• EmbolectomyEmbolectomy
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(Prolyse in Acute Cerebral Thromboembolism)
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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
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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
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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
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CBVCerebral Blood Volume
MTTMean Transit Time
Perfusion MismatchPerfusion MismatchPenumbra =Penumbra =Tissue at RiskTissue at Risk
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CBVCerebral Blood Volume
MTTMean Transit Time
Perfusion MatchPerfusion MatchNo PenumbraNo Penumbra
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Diagnostic Evaluation: MRIDiagnostic Evaluation: MRI
DWI PWI
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Diagnostic EvaluationDiagnostic Evaluation
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ADVANCES IN CEREBROVASCULAR ADVANCES IN CEREBROVASCULAR DISEASEDISEASE
I.I. Treatment of Acute Ischemic Treatment of Acute Ischemic StrokeStroke
• IV ThrombolysisIV Thrombolysis
• IA ThrombolysisIA Thrombolysis
• EmbolectomyEmbolectomy
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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
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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
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ADVANCES IN CEREBROVASCULAR ADVANCES IN CEREBROVASCULAR DISEASEDISEASE
II. Secondary Stroke PreventionII. Secondary Stroke Prevention
• Risk factor controlRisk factor control
• Anti-platelet agentsAnti-platelet agents
• AnticoagulantsAnticoagulants
• Interventional proceduresInterventional procedures
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ADVANCES IN CEREBROVASCULAR ADVANCES IN CEREBROVASCULAR DISEASEDISEASE
II. Secondary Stroke PreventionII. Secondary Stroke Prevention
• Risk factor controlRisk factor control
• Anti-platelet agentsAnti-platelet agents
• AnticoagulantsAnticoagulants
• Interventional proceduresInterventional procedures
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(Perindopril Protection Against Recurrent Stroke Study)
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Stroke 2008;39:1647-52
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Stroke 2008;39:1647-52
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ATRIAL FIBRILLATIONATRIAL FIBRILLATION
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Fibrin Clot
IIaIIa Inhibitors InhibitorsXII
VIIVIII
IX
XI
II
V
X
I
Direct Thrombin Inhibitors
Tested: Ximelagatran
New: DabigatranDabigatran
Direct thrombin inhibitors
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Fibrin Clot
IIaIIa Inhibitors InhibitorsXII
VIIVIII
IX
XI
II
V
X
I
Direct Thrombin Inhibitors
Tested: Ximelagatran
New: DabigatranDabigatran
Direct thrombin inhibitors
XimelagatranXimelagatranAs effective as warfarinHepatotoxic
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Fibrin Clot
IIaIIa Inhibitors InhibitorsXII
VIIVIII
IX
XI
II
V
X
I
Direct Thrombin Inhibitors
Tested: Ximelagatran
New: DabigatranDabigatran
Direct thrombin inhibitors
XimelagatranXimelagatranAs effective as warfarinHepatotoxic
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pp. 1139-1151
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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
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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
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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
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Net clinical benefit and Net clinical benefit and componentscomponents
CharacteristicCharacteristicDD
110 110 mgmg
DD150 150 mgmg
WarfarWarfarinin
P-valueP-value110 vs. 110 vs.
WW
P-valueP-value150 vs. 150 vs.
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
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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
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ADVANCES IN CEREBROVASCULAR ADVANCES IN CEREBROVASCULAR DISEASEDISEASE
II. Secondary Stroke PreventionII. Secondary Stroke Prevention
• Risk factor controlRisk factor control
• Anti-platelet agentsAnti-platelet agents
• AnticoagulantsAnticoagulants
• Interventional proceduresInterventional procedures
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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)
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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
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ADVANCES IN CEREBROVASCULAR ADVANCES IN CEREBROVASCULAR DISEASEDISEASE
II. Secondary Stroke PreventionII. Secondary Stroke Prevention
• Risk factor controlRisk factor control
• Anti-platelet agentsAnti-platelet agents
• AnticoagulantsAnticoagulants
• Interventional proceduresInterventional procedures
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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
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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
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ADVANCES IN CEREBROVASCULAR ADVANCES IN CEREBROVASCULAR DISEASEDISEASE
II. Secondary Stroke PreventionII. Secondary Stroke Prevention
• Risk factor controlRisk factor control
• Anti-platelet agentsAnti-platelet agents
• AnticoagulantsAnticoagulants
• Interventional proceduresInterventional procedures
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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)
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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
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CAROTID ARTERY STENOSISCAROTID ARTERY STENOSISEndarterectomy or Endarterectomy or
Angioplasty/Stenting?Angioplasty/Stenting?
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SAPPHIRE trialSAPPHIRE trial
NEJM 2006;351;1493-501
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SAPPHIRE trialSAPPHIRE trialCriteria for High-Risk for Criteria for High-Risk for
CEACEA
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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
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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
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EVA-3S trialEVA-3S trial
NEJM 2006;355:1660-71
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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%
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CREST trialCREST trial
NEJM 2010;363:11-23
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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
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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
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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
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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
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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
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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
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