acute stroke therapy

Acute Stroke TherapyAcute Stroke Therapy

Andrew Slivka, MD

Associate Professor of Neurology

Cerebrovascular Diseases and Stroke

The Ohio State University Medical Center

General Early Supportive CareGeneral Early Supportive Care

1. Early mobilization and measures to prevent aspiration

*2. Heparin for DVT prophylaxis in immobilized patients, pneumatic compression devices in patients who cannot receive heparin

Treatment of Cerebral EdemaTreatment of Cerebral Edema

*1. Steroids not recommended2.Osmotherapy, hyperventilation for patients

deteriorating due to increased intracranial pressure or with herniation syndromes

3.Surgical decompression, ventricular shunt for large cerebellar infarcts compressing brain stem

4.Surgical decompression for large hemispheric infarct may be life-saving, but may have severe residual neurological deficits

Acute Treatment Antithrombotic TherapyAcute Treatment Antithrombotic Therapy

1. Heparin or LMW heparin when used within 48 hours of acute ischemic stroke do not reduce morbidity, mortality, or rate of stroke reoccurrence, but do increase systemic and CNS bleeding risk independent of stroke subtype

2.Aspirin (160-325mg) within 48 hours

Early Anticoagulation afterEarly Anticoagulation afterCardioembolic StrokeCardioembolic Stroke

Trial Agent NDuration of Treatment

Recurrent Stroke ICH

Heparin 24 14d 0% 0%No Heparin 21 10.0% 10.0%

Heparin 1557 14d 2.8% 2.5%No Heparin 1612 4.5% 0.3%Danaparoid 143 7d 0% 2.9%

Placebo 123 1.6% 0.9%Dalteparin 224 10d 8.5% 2.7%

ASA 225 7.5% 1.8%

CESG (1983)

IST (1997)

TOAST (1998)cardioembolicHAEST (2000)

Acute Stroke Treatment StrategiesAcute Stroke Treatment Strategies

Recanalization Neuroprotection

Recanalization StrategiesRecanalization Strategies

Delivery (iv, ia, iv-ia) Drugs (UK, t-PA, Pro-UK, retaplase, desmoteplase) Mechanical (wire, balloon, snare, angiojet, MERCI)

Thrombolytic Therapy - iv t-PAThrombolytic Therapy - iv t-PA

NINDS t-PA Stroke Trial

Inclusion Criteria Age > 18 years Clearly defined time of onset < 3 hours Clinical diagnosis of ischemic stroke


Exclusion Criteria Suspicion of SAH Recent intracranial surgery, serious head trauma, recent

previous stroke (within 3 months) History of ICH Uncontrolled HPT (> 185 mmHg systolic, > 110 mgHg

diastolic Seizure at onset active internal bleeding Intracranial neoplasm, AVM, or aneurysm


Exclusion Criteria - continued Bleeding diathesis: PT > 15 sec (or INR > 1.7 ) -

heparin treatment with elevated PTT, platelet <100,000/mm3

Major surgery, serious trauma < 2 weeks GI or GU hemorrhage < 3 weeks

Arterial puncture at noncompressable site or LP < 1 week


Exclusion Criteria - continued Pregnant Rapidly improving neurological signs Isolated mild neurological deficits Glucose < 50 mg/dl or > 400 mg/dl

NINDS t-PA Stroke Trial: DesignNINDS t-PA Stroke Trial: Design

Part I (n=291): half treated within 90 minutes Primary outcome – complete resolution or > 4 point

improvement in NIHSS at 24 hours. Secondary outcome – minimal or no disability at 3 months

Part II (n= 333): half treated within 90 minutes Primary outcome – minimal or no disability at 3 months

Dose: 0.9 mg/kg (maximum 90 mg); 10% bolus, remainder infused over 1 hour

Outcome of Patients Outcome of Patients Treated With t-PATreated With t-PA

Modified Rankin 0 to 1 2 to 3 4 to 5 Death

t-PA 39% 21% 23% 17%Placebo 26% 25% 27% 21%

STARS Study(1 month) 35% 21% 31% 13%

NIHSS Score 0 to 1 2 to 8 > 8 Deatht-PA 31% 30% 22% 17%Placebo 20% 32% 27% 21%

CASES Study(3 months) 31% 32% 11% 22%

NINDS Study(3 months)

NINDS Study(3 months)

NIH iv t-PA TrialNIH iv t-PA Trial

Baseline NIHSSRX 91-180 minutes

t-PA Placebo t-PA Placebo0 to 5 24/39 (83%) 6/7 (86%) 0/29 0/76 to 10 23/37 (62%) 23/46 (50%) 2/37 (5%) 1/46 (2%)

11 to 15 10/26 (38%) 5/35 (14%) 2/26 (8%) 0/3516 to 20 9/33 (27%) 6/33 (18%) 2/33 (6%) 1/33 (3%)

>20 4/28 (14%) 2/46 (4%) 4/28 (14%) 0/46All patients 70/153 (46%) 42/167 (25%) 10/153 (7%) 2/167 (1%)

mRS 0 to 1 Symptomatic ICH

Predictors of Outcome with t-PAPredictors of Outcome with t-PA

Age, deficit severity, diabetes, admission blood pressure, early CT changes, influence outcome, but do not alter likelihood of responding favorably to t-PA

NIHSS > 20: Rankin 0-1(at 3 months) 10% with t-PA, 4% placebo; Rankin 4,5 or 6 is 70%, independent of treatment

Brain edema/mass effect on CT: Rankin 0-1 (at 3 months) 25% with t-PA, 16% placebo; Rankin 4,5 or 6 is 55%, independent of treatment

Time to treatment correlates with outcome

Symptomatic Intracerebral Symptomatic Intracerebral Hemorrhage with t-PA TreatmentHemorrhage with t-PA Treatment

NINDS Trial (n=312) 6% STARS Study (n=389) 3% CASES Study (n=450) 4% Average Phase IV Studies 5% (16%)

n=>1400

Risks for Symptomatic Risks for Symptomatic Intracerebral HemorrhageIntracerebral Hemorrhage

Hospital size (experience) Protocol violations Severity of neurological deficit Brain edema or mass effect on CT

IV t-PA Use After 3 HoursIV t-PA Use After 3 Hours

Atlantis: 613 patients, 3-5 hours after stroke, NIH > 3

ECASS II: 800 patients < 6 hours after stroke 90 day Outcome: Placebo t-PA

Atlantis ECASS II Atlantis ECASS II

Favorable ClinicalOutcome

32% 37% 34% 40%

Mortality 7% 10% 11% 10%Symptomatic ICH 1% 3% 7% 9%

Intra-arterial ThrombolysisIntra-arterial Thrombolysis

Series with t-PA, UK Pro-urokinase (PROACT II)

180 patients with proximal MCA occlusion within 6 hours

Recanalization: 66% treated group, 19% control Good outcome: 40% treated group, 25% control Symptomatic ICH: 10% treated group, 2% control Mortality: 25% treated group, 27% control

Intra-arterial Thrombolysis at OSUIntra-arterial Thrombolysis at OSU

81 patients treated from May 1995 to July 2003 52% male, 16% African American, 1% Asian

American, Mean age 72 years 26% with good clinical outcome (mRS < 2) 70% with recanalization (33% complete) 7% with symptomatic ICH

Predictors of Clinical OutcomePredictors of Clinical Outcome

No occlusion 38% with good outcome vs. 26% with occlusion, Rx

Age > 80 years 0/14 with good outcomes (57% recanalize, 29% complete)

Admission NIHSS Good outcome 11/16 (69%) 4-10

9/48 (19%) 11-20

1/18 (6%) >20


Time to Treat < 5 hours – good outcome 15/47 (32%)

Recanalization 77% (41% complete) > 5 hours – good outcome 6/34 (18%)

Recanalization 62% (24% complete)


Recanalization Complete recanalization-13/27 (48%) good outcome Partial recanalization 7/30 (23%) good outcome No recanalization 1/24 (4%) good outcome

Predictors of OutcomePredictors of Outcome

Collateral Circulation When complete recanalization – linear

relationship between clinical outcome and infarct size and collateral grade

When partial/no recanalization – no correlation with clinical outcome, excellent collateral have smaller infarcts than other collateral grades

Intravenous – Intra arterialIntravenous – Intra arterial

IMS (Stroke, 2004) 80 Patients within 3 hours 6 mg/kg (max 60 mg) t-PA iv over 30 minutes up

to 22 mg t-PA ia over 2 hours if occlusion seen by angiography

Good outcome 30% (32% iv t-PA, 18% control Symptomatic ICH 6.3% (6.6% iv t-PA, 1% control Mortality 16% (21% iv t-PA, 24% control)

Mechanical DisruptionMechanical Disruption

Anecdotal: snare, balloon, angio jet MERCI (Stroke, 2005)

141 patients with intracranial large vessel occlusion treated within 8 hours

Recanalization: 48% (19% PROACT control) Complications: 7% (emboli, dissection, SAH) Good outcome: 28% (46% recanalized, 10% occluded) Mortality: 43% (32 recanalized, 54% occluded)

Detection of Preservable BrainDetection of Preservable Brain

MR DWI PI MRA

CT CTP CTA

DesmoteplaseDesmoteplase

45-60 patients within 9 hours, DWI/PI mismatch DIAS – Europe, DEDAS – USA, Germany Dose response found Reperfusion: 50-70% (vs 20-37% control) Good outcome: 66% (vs 22-25% control) No symptomatic ICH

Treatment AlgorithmsTreatment Algorithms

Less than 3 hours NIHSS <10 iv t-PA NIHSS 10 or greater iv/ia t-PA

3-6 hours DIAS-II NIHSS < 10 or lacunar infarct: MR then ia t-PA (? Iv t-PA)

Greater than 6 hours NIHSS 10 or greater: MR then MERCI

Treatment: Special PopulationsTreatment: Special Populations

Post catheterization Post operative Children/adolescents

acute stroke therapy

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