Diagnosis & Management Diagnosis & Management Following TIA and Stroke: Following TIA and Stroke:

Critical PathwayCritical Pathway

Diagnosis andDiagnosis and ManagementManagement

Pathophysiology of Ischemic Stroke Pathophysiology of Ischemic Stroke Emergency Room work-upEmergency Room work-up Initial managementInitial management Inpatient work-up and managementInpatient work-up and management Stroke Critical PathwayStroke Critical Pathway Discharge planningDischarge planning Rehabilitation Rehabilitation

Cerebrovascular DiseasesCerebrovascular Diseases

?

IschemicHemorrhagic

Large Artery

Embolism

LacunarCryptogenic

IntracerebralHemorrhage

SubarachnoidHemorrhage

Neuronal ProtectionNeuronal Protection

The concept of the ischemic penumbraThe concept of the ischemic penumbra

Pathogenesis of Ischemic Stroke

Penumbra

Infarction

SEVERITY OF SEVERITY OF ISCHEMIAISCHEMIA TIMETIME

EFFECTS OF REDUCED CEREBRAL BLOOD FLOW

50

25

15

8

CBFnl FXN No Sym

Infarct Cell Death

nl FXN No Sym

OEF

GEF

CMRO2 METAB nl

TIA

Penumbra Reversible

CMRO2

pH

Glut

ATP

Ca++ INFLUX

Lact

CBF Vasodilate

Loss Na/K Pump

Nitric Oxide

GABA AgonistCa+

Channel

Na+ Channel

Hyperthermia

NMDA Receptor

Ischemic Neuron(Ischemic cascade)

Hyperglycemia

Altered fibrinolysis

Dehydration

Inflammation / Infection

Pathophysiology: Ischemic Neuronal Injury

Membrane Stabilizer

Thombolytics

(ENOS vs INOS)

Anti-Oxidant

Medical Therapies for Acute Medical Therapies for Acute Stroke - OrdersStroke - Orders

IV fluids- NSIV fluids- NS Oxygen- OOxygen- O22 L NC L NC Blood pressure controlBlood pressure control Blood glucose controlBlood glucose control TemperatureTemperature HOB 30HOB 30oo vs 0 vs 0oo CT Scan HeadCT Scan Head Labs / EKG Labs / EKG

Acute Stroke Critical PathwayAcute Stroke Critical Pathway

NNMC Critical PathwayNNMC Critical Pathway Standard of CareStandard of Care Reduce Hospital StayReduce Hospital Stay Improvement in Patient OutcomeImprovement in Patient Outcome Deviation from Pathway: ID System FailureDeviation from Pathway: ID System Failure

Admission OrdersAdmission Orders

Labs and Studies:Labs and Studies:

- CBC, Platelet, Glucose, Electrolytes,- CBC, Platelet, Glucose, Electrolytes,

PT/PTT, Drug screen (if applicable)PT/PTT, Drug screen (if applicable)

- Urinalysis, CXR- Urinalysis, CXR

- 12 lead EKG rhythm monitoring- 12 lead EKG rhythm monitoring

- CT scan- CT scan

CT Scan of HeadCT Scan of Head

Ischemic StrokeIschemic Stroke Hemorrhagic Stroke (ICH)Hemorrhagic Stroke (ICH) Subarachnoid HemorrhageSubarachnoid Hemorrhage TraumaTrauma TumorTumor

BP Management Acute StrokeBP Management Acute Stroke

DBP > 140 mmHgDBP > 140 mmHg

SBP > 220, SBP > 220,

DBP >120,DBP >120,

MAP > 130 mmHgMAP > 130 mmHg

SVP < 220, DBP <120SVP < 220, DBP <120

Nipride (0.5 Nipride (0.5 µµg/kg/min)g/kg/min)Aim: 10-20% DBPAim: 10-20% DBP

Labetalol 10-20 mg IVLabetalol 10-20 mg IVRepeat or double q 10 m (300mg max d)Repeat or double q 10 m (300mg max d)Nicardipine 5mg/h IV- titrate 2.5mg/h q5m Nicardipine 5mg/h IV- titrate 2.5mg/h q5m

to max of 15mg/hto max of 15mg/h

Emergency Rx deferredEmergency Rx deferredunless acute MI, aorticunless acute MI, aorticdissection, severe CHF, HTN,Encephdissection, severe CHF, HTN,Enceph

Strategies of Cerebral ProtectionStrategies of Cerebral Protection

Hydration: Hydration: IV normal saline Blood pressure regulationBlood pressure regulation

- Rx > 220/120 ischemic stroke- Rx > 220/120 ischemic stroke

- Rx on IV HEPARIN to < 200 SBP and 100 DBP- Rx on IV HEPARIN to < 200 SBP and 100 DBP

- Rx Pt. on tPA to - Rx Pt. on tPA to ≤ 185 SBP/ ≤110 DBP≤ 185 SBP/ ≤110 DBP Thrombolytic TherapyThrombolytic Therapy

Admission Orders: Target MAP 90 – 115 for 48 to 72 hrs.

Serum Glucose & Stroke OutcomeSerum Glucose & Stroke Outcome

Treatment of hyperglycemia reduces neuronal injury Treatment of hyperglycemia reduces neuronal injury (animal models & human paractice).(animal models & human paractice).

JCBFM 1994;Neurology 1998JCBFM 1994;Neurology 1998 Blood glucose levels (first 24 hrs.) >145 mg/dL Blood glucose levels (first 24 hrs.) >145 mg/dL

associated with poor outcome. (750 non-diabetic pts.) associated with poor outcome. (750 non-diabetic pts.) BMJ 1997;314:1303.BMJ 1997;314:1303.

Blood glucose levels >200 mg/dL assoc. with 25% Blood glucose levels >200 mg/dL assoc. with 25% hemorrhage (tPA tx’d pts)hemorrhage (tPA tx’d pts)

Stroke 1999;30:34-39Stroke 1999;30:34-39

Acute Hyperglycemia Reduces tPA-Acute Hyperglycemia Reduces tPA-Induced RecanalizationInduced Recanalization

44/139 (32%) recanalized in 2 hours44/139 (32%) recanalized in 2 hours Recanalization vs no recanalization admission glucose Recanalization vs no recanalization admission glucose

level 127 vs 146; p=0.039level 127 vs 146; p=0.039 Glucose >158 mg/dLGlucose >158 mg/dL Recanalization 16% vs 36%, p=.03Recanalization 16% vs 36%, p=.03 (No recanalization OR, 7.3; 95% CI 1.3-42, p<.03)(No recanalization OR, 7.3; 95% CI 1.3-42, p<.03) NIHSS at 48 hrs 14.5 vs 7, p < 0.05.NIHSS at 48 hrs 14.5 vs 7, p < 0.05.

139 Stroke pts- Intracranial thrombosis by TCD given IV tPA

Ribo, et.al., Stroke 2005

STROKE OUTCOME & STROKE OUTCOME & TEMPERATURETEMPERATURE

0102030405060708090

100

V Sev 0-14

Severe 15-29

Mod 30-44

Mild 45-58

Hypothermic

Normothermic

Hyperthermic

( % POOR OUTCOME )

Initial SSS

1 C RR poor outcome 2.2 (CI 95% 1.4-3.5)Lancet 1996;422

dea

th o

r S

SS

<30

< 36.5

36.5-37.5

>37.5

Survival curve of all patients (n=25) treated with moderate hypothermia compared with patients treated with conventional therapy.31

Stroke 1998;29:2461

Induced Hypothermia 33oC x 4-72 hours

Alsius Fortius Catheter

Indications For Hypothermic Indications For Hypothermic CoolingCooling

Cardiac ArrestCardiac Arrest

? Stroke? Stroke

? Head Trauma ? Head Trauma

6 Month Outcome6 Month Outcome

OutcomeOutcome NormoNormo.. HypoHypo.. RRRR pp

Good Good Recovery-Recovery-

HACAHACA

39%39%BernardBernard

21%21%

HACAHACA

55%55%BernardBernard

35%35%

1.401.40 0.0090.009

Moderate Moderate Disability Disability DeathDeath

HACAHACA

55%55%BernardBernard

68%68%

HACAHACA

41%41%BernardBernard

51%51%

0.740.74 0.020.02

Zeiner, et.al. HACA. Stroke Jan 2000Holzer, et.al. Crit Care Med, Jun 2005

Hypothermia After Cardiac ArrestHypothermia After Cardiac Arrest

Now recommended after successful Now recommended after successful resuscitation in all OOH CA patientsresuscitation in all OOH CA patients

cooled to 32°C–34°C for 12–24 hours cooled to 32°C–34°C for 12–24 hours Proof of concept that neuroprotection is Proof of concept that neuroprotection is

possible after ischemia in humanspossible after ischemia in humans ? Faster cooling with catheters, etc? Faster cooling with catheters, etc

Oct 2002 - Advanced Life Support Task Force of the International Liaison Committee on Resuscitation recommended:

Bernard. Med J Aust 2004; 181:468-9

ASPIRIN IN ACUTE STROKEASPIRIN IN ACUTE STROKEIST & CastIST & Cast

N=>33,000 Patients EnrolledN=>33,000 Patients Enrolled

ASAASA PLACPLAC Events/1000Events/1000

DeathDeath 11021102 11871187 5/10005/1000

StrokeStroke 396396 473473 5/10005/1000

OverallOverall 9.1%9.1% 10.1%10.1% 10/1000 p<.00110/1000 p<.001

AAN CONCLUSIONS AND RECOMMENDATIONSAAN CONCLUSIONS AND RECOMMENDATIONSEMERGENT ANTICOAGULATION AFTER STROKEEMERGENT ANTICOAGULATION AFTER STROKE

Causes a modest increase of symptomatic intracranial or Causes a modest increase of symptomatic intracranial or systemic bleeding (2.5%)systemic bleeding (2.5%)

No evidence of lowering risk of early recurrent strokeNo evidence of lowering risk of early recurrent strokeIncluding among patients with cardioembolismIncluding among patients with cardioembolism

No evidence of halting neurological worseningNo evidence of halting neurological worsening No evidence of improving neurological outcomesNo evidence of improving neurological outcomes So, no data to recommend emergent anticoagulation for So, no data to recommend emergent anticoagulation for

most patients with acute ischemic strokemost patients with acute ischemic stroke

Possible situations for acute Possible situations for acute anticoagulation anticoagulation (weight adjusted) (weight adjusted)

{{my opinionmy opinion}}

Acute extracranial carotid or vertebral occlusion Acute extracranial carotid or vertebral occlusion or dissection -- to prevent distal embolizationor dissection -- to prevent distal embolization

Venous thrombosisVenous thrombosis Highly “embologenic” cardiac conditionHighly “embologenic” cardiac condition

– Acute MI with mural thrombusAcute MI with mural thrombus– Mechanical valve with thrombusMechanical valve with thrombus

Heparin in Stroke?Heparin in Stroke?

Progressive Vertebral Basilar ThrombosisProgressive Vertebral Basilar Thrombosis Critical Carotid Stenosis – String Sign (> Critical Carotid Stenosis – String Sign (>

95%) occlusion 95%) occlusion

FAST-MAG Pilot TrialFAST-MAG Pilot TrialTreatment RegimenTreatment Regimen

In the fieldIn the field– 2.5 gram Mg (prefilled syringe) over 10 min2.5 gram Mg (prefilled syringe) over 10 min

In hospitalIn hospital– Additional 1.5 gm Mg over 5 min (total 4 gm load)Additional 1.5 gm Mg over 5 min (total 4 gm load)– Maintenance infusion 16 gm Mg over 24 hrMaintenance infusion 16 gm Mg over 24 hr

FAST-MAG Pilot Trial ResultsFAST-MAG Pilot Trial ResultsSafety of Field Initiation EndpointsSafety of Field Initiation Endpoints

Serious Adverse EventsSerious Adverse Events 0 (0%) 0 (0%)HypotensionHypotension 00

Cardiac dysrhythmia/arrestCardiac dysrhythmia/arrest 00

Respiratory compromise/arrestRespiratory compromise/arrest 00

Neuromuscular blockadeNeuromuscular blockade 00

Minor AEsMinor AEs 2 (10%) 2 (10%)Skin flushingSkin flushing 11

Nausea/vomitingNausea/vomiting 11

Dramatic Early RecoveryDramatic Early Recovery Improved Completely or Improved Completely or >> 10 NIHSS Points at 24 hours 10 NIHSS Points at 24 hours

12

27 25

0

5

10

15

20

25

30

35

Percent

NINDS Placebo NINDS TPA FAST-MAG <2h

Field Administration of Stroke Treatment – Field Administration of Stroke Treatment – Magnesium (FAST-MAG) Phase 3 TrialMagnesium (FAST-MAG) Phase 3 Trial

Placebo-controlled, double-blind, randomizedPlacebo-controlled, double-blind, randomized Multicenter, single regionMulticenter, single region

– 69 hospitals, Los Angeles County69 hospitals, Los Angeles County 4 gm Mg field, 16 gm Mg maintenance x 24h4 gm Mg field, 16 gm Mg maintenance x 24h 1270 patients1270 patients All patients enrolled within 2 hours of last known wellAll patients enrolled within 2 hours of last known well

– One-half within 1 hourOne-half within 1 hour MRI substudy in 180 patientsMRI substudy in 180 patients 4 years4 years Primary endpoint: Rankin ScalePrimary endpoint: Rankin Scale

NINDS rt-PA Stroke TrialNINDS rt-PA Stroke TrialRandomized Double-blind Placebo Randomized Double-blind Placebo

Controlled Trial: 630 Pts.Controlled Trial: 630 Pts.

0 to 90 minutes0 to 90 minutes

91 to 180 minutes91 to 180 minutes

Dose: rt-PA 0.9 MG/Kg IVDose: rt-PA 0.9 MG/Kg IV

10% Bolus, rest infused over 60 min.10% Bolus, rest infused over 60 min.

Part 1: 24 hour NIHSSPart 1: 24 hour NIHSS

Part 2: 90 day functional outcomePart 2: 90 day functional outcome

NINDS t-PA Stroke TrialNINDS t-PA Stroke TrialInclusion CriteriaInclusion Criteria

≥ ≥ 18 years of age18 years of age Clinical diagnosis ischemic strokeClinical diagnosis ischemic stroke Measurable neurologic deficitMeasurable neurologic deficit Clearly defined time of stroke onsetClearly defined time of stroke onset

(≤ 91 min or 91-180 min before treatment)(≤ 91 min or 91-180 min before treatment) Baseline CT scan with no evidence ICHBaseline CT scan with no evidence ICH

NINDS t-PA Stroke TrialNINDS t-PA Stroke TrialExclusion CriteriaExclusion Criteria

Rapidly improving or Rapidly improving or minor symptomsminor symptoms

CT scan showing ICHCT scan showing ICH History of ICHHistory of ICH Seizure at stroke onsetSeizure at stroke onset Stroke or serious head Stroke or serious head

trauma trauma ≤ 3 months≤ 3 months Major surgery or other Major surgery or other

serious injury ≤ 2 wksserious injury ≤ 2 wks GI or UT bleed ≤ 3 wksGI or UT bleed ≤ 3 wks

SBP >185, DBP >110 mmHGSBP >185, DBP >110 mmHG Glucose < 50 or > 400 mg/dLGlucose < 50 or > 400 mg/dL Arterial puncture non-Arterial puncture non-

compressible or LP < 7dcompressible or LP < 7d Platelet count < 100,000Platelet count < 100,000 Heparin or Coumadin need nl Heparin or Coumadin need nl

PTT or INR <PTT or INR < 1.7 1.7 Pregnant or lactating femalesPregnant or lactating females

Outcome at 3 monthsOutcome at 3 monthsPart 2: 0 to 180 minutesPart 2: 0 to 180 minutes

tPAtPA PlaceboPlacebo pp OROR RRRR

Global OutcomeGlobal Outcome .008.008 1.71.7

Barthel Barthel ≥ 95≥ 95 50%50% 38%38% .026.026 1.61.6 1.31.3

Modified Rankin Modified Rankin ≤ 1≤ 1 39%39% 26%26% .019.019 1.71.7 1.51.5

Glascow Outcome =1Glascow Outcome =1 44%44% 32%32% .025.025 1.61.6 1.41.4

NIHSS NIHSS ≤ 1≤ 1 31%31% 20%20% .035.035 1.71.7 1.51.5

Barthel Index at 3 MonthsPart 2

50

38

16

23

17

21

Death0-5050-9095-100

Placebo

t-PA

Barthel Index

Outcome and Stroke SubtypeOutcome and Stroke Subtype

Percent Favorable OutcomePercent Favorable OutcomeSmall VesselSmall Vessel Large VesselLarge Vessel EmbolicEmbolic

t-PAt-PA

5151

PlaceboPlacebo

3030

t-PAt-PA

117117

PlaceboPlacebo

135135

t-PAt-PA

136136

PlaceboPlacebo

137137

Barthel Barthel ≥95≥95 75%75% 50%50% 49%49% 36%36% 46%46% 37%37%

Rankin Rankin ≤1≤1 63%63% 40%40% 40%40% 22%22% 38%38% 28%28%

Glascow =1Glascow =1 63%63% 43%43% 45%45% 28%28% 39%39% 31%31%

NIHSS NIHSS ≤1≤1 47%47% 33%33% 33%33% 18%18% 29%29% 20%20%

HEMORRHAGEHEMORRHAGE

t-PAt-PA PlaceboPlacebo

SymptomaticSymptomatic 20 (6.4%)20 (6.4%) 2 (.6%)2 (.6%)

AsymptomaticAsymptomatic 14 (4.5%)14 (4.5%) 9 (2.8%)9 (2.8%)

Post-marketing open-label studies Meta-analysis: ~5.2% hemorrhage

Graham, Stroke 2003

Hemorrhagic Complications:Hemorrhagic Complications:MortalityMortality

t-PAt-PA PlaceboPlacebo

9/312 9/312 (2.9%)(2.9%) 1/312 1/312 (0.3%)(0.3%)

ECASS II: Outcome & CT ECASS II: Outcome & CT HypoattenuationHypoattenuation

HypodensityHypodensity Rankin 0,1Rankin 0,1 ICH @ d 1ICH @ d 1

NormalNormal PlaceboPlacebo

rtPArtPA

45%45%

49%49%

1%1%

7%7%

< 1/3 MCA< 1/3 MCA PlaceboPlacebo

rtPArtPA

31%31%

34%34%

3%3%

13%13%

> 1/3 MCA> 1/3 MCA PlaceboPlacebo

rtPArtPA

18%18%

20%20%

0%0%

20%20%

Blood Pressure Monitoring Blood Pressure Monitoring Guidelines Following tPAGuidelines Following tPA

Monitor Blood Pressure for First 24 HoursMonitor Blood Pressure for First 24 Hours

Every 15 minutes for 2 hours after starting RxEvery 15 minutes for 2 hours after starting Rx Every 30 minutes for 6 hours, thenEvery 30 minutes for 6 hours, then Every hour for 18 hoursEvery hour for 18 hours

Blood Pressure Management Blood Pressure Management Guidelines Following tPAGuidelines Following tPA

DBP > 140 mmHG, IV Nipride (.5-1.0 DBP > 140 mmHG, IV Nipride (.5-1.0 μg/kg/min)μg/kg/min)

SBP > 230 or DBP 121-140 mmHG, IV Labetalol 20 SBP > 230 or DBP 121-140 mmHG, IV Labetalol 20 mg over 1-2 minutes. May repeat or double q 10 mg over 1-2 minutes. May repeat or double q 10 minutes, max 150 mg (if not effective: Nipride)minutes, max 150 mg (if not effective: Nipride)

SBP 180-230 or DBP 105-120 two readings 5 minutes SBP 180-230 or DBP 105-120 two readings 5 minutes apart, IV Labetalol 10 mg over 1-2 minutes. May apart, IV Labetalol 10 mg over 1-2 minutes. May repeat or double q 10-20 minutes, max 150 mgrepeat or double q 10-20 minutes, max 150 mg

SYMPTOMATIC ICH FOLLOWING tPASYMPTOMATIC ICH FOLLOWING tPA

0

2

4

6

8

10

12

14

16

18

0 to 5 6 to 10 11 to 15 16 to 20 > 206 to 10 16 to 20

% S

ymp

tom

atic

IC

H

Baseline NIHSS ScoreNINDS t-PA Stroke Study

OR = 1.8 95% CL 1.2-2.8

Aspirin and Heparin after tPA: Aspirin and Heparin after tPA: The First 24 HoursThe First 24 Hours

No direct safety data from NINDSNo direct safety data from NINDS 90 day new ischemic event rate:90 day new ischemic event rate:

tPAtPA 18/312 18/312 (5.8%)(5.8%)PlaceboPlacebo 17/312 17/312 (5.4%)(5.4%)

MAST-1 (SK MAST-1 (SK ± ASA) 10 d fatality:± ASA) 10 d fatality:SK (n=157)SK (n=157) 19%19%SK + ASA 325 mg X 10d (n=156)SK + ASA 325 mg X 10d (n=156) 34%34%

p<.001p<.001

Symptomatic ICH First 36 Hours: Symptomatic ICH First 36 Hours: AgeAge

AgeAge PlaceboPlacebo tPAtPA

< 60< 60 0/85 0/85 (0.0%)(0.0%) 3/71 3/71 (4.2%)(4.2%)

60-7560-75 1/153 1/153 (0.7%)(0.7%) 9/149 9/149 (6.0%)(6.0%)

> 75> 75 1/74 1/74 (1.4%)(1.4%) 8/92 8/92 (8.7%)(8.7%)

An Approach to Suspected ICHAn Approach to Suspected ICHNeuro Deterioration, Headache, Acute HTN, Nausea/VomitingNeuro Deterioration, Headache, Acute HTN, Nausea/Vomiting

Discontinue t-PA Discontinue t-PA infusioninfusion

Immediate CTImmediate CT Draw PT/PTT, Platelet Draw PT/PTT, Platelet

Count, FibrinogenCount, Fibrinogen

Fibrinogen 6 to 8 units Fibrinogen 6 to 8 units and Cryoprecipitateand Cryoprecipitate

Platelet 6 to 8 unitsPlatelet 6 to 8 units Neurosurgical and Neurosurgical and

Hematological Hematological ConsultationsConsultations

Surgical Requirement in tPA UseSurgical Requirement in tPA Use

Neurosurgical back-up within 2 hoursNeurosurgical back-up within 2 hours Capability of transferring patient to a hospital with Capability of transferring patient to a hospital with

Neurosurgical Service (2 hours)Neurosurgical Service (2 hours) Medical management of hematological changes as Medical management of hematological changes as

statedstated Cerebellar hemorrhage; surgical considerationCerebellar hemorrhage; surgical consideration

Number Needed to Treat (NNT) to Benefit from IV Number Needed to Treat (NNT) to Benefit from IV TPATPA

mRankin ScalemRankin Scale NNTNNT

Dichotomized 0,1 vs 2-6 Dichotomized 0,1 vs 2-6 6 6

Full scale, 7 strata Full scale, 7 strata 3 3

Saver, AHA 2003

Number Needed to Treat (NNT) to Harm from IV TPA

Full scale, 7 strata 34

NNT

Linking Linking NeuroprotectionNeuroprotection to to ThrombolysisThrombolysis

Combined NINDS, ECASS, ATLANTIS data: 2776 pts

NXY-059 (free radical trapping agent) NXY-059 (free radical trapping agent) protection in Acute Stroke: SAINT I trialprotection in Acute Stroke: SAINT I trial

1722 pt randomized to NXY-059 vs placebo <6 h 1722 pt randomized to NXY-059 vs placebo <6 h following stroke. following stroke.

NXY-059 vs PlaceboNXY-059 vs Placebo mRS OR 1.20 (95% CI 1.01-1.42) p=0.04mRS OR 1.20 (95% CI 1.01-1.42) p=0.04

ICH 2.5% 6.4% p< .05ICH 2.5% 6.4% p< .05On tPAOn tPA

Lee, et al. Stroke 2006; 37(2)page 708

Complication: Orolingual angioedemaComplication: Orolingual angioedema

Uncommon and generally mild < 5%Uncommon and generally mild < 5% More common in patients on ACE inhibitor, though More common in patients on ACE inhibitor, though

ACE-inh use is not a contra-indication to tPA ACE-inh use is not a contra-indication to tPA therapytherapy

Symptomatic Treatment: intubation (airway Symptomatic Treatment: intubation (airway support),epinephrine, steroids and anti-histamines.support),epinephrine, steroids and anti-histamines.

CCombinedombined LLysisysis OOff TThrombushrombus inin BBrain ischemia using rain ischemia using

2 MHz transcranial2 MHz transcranial UUltrasound andltrasound and SSystemicystemic TTPAPA

A Phase II Multi-center Randomized Clinical TrialA Phase II Multi-center Randomized Clinical Trial

Sponsors: NIH 1 K23 NS 02229-01Sponsors: NIH 1 K23 NS 02229-01

Study A2207s, Investigator-Sponsored Trial, Genentech, Inc.Study A2207s, Investigator-Sponsored Trial, Genentech, Inc.

PI: Andrei V. Alexandrov, MDPI: Andrei V. Alexandrov, MD

Study sites: Houston, Baltimore, New Orleans, Study sites: Houston, Baltimore, New Orleans,

Calgary, Edmonton, BarcelonaCalgary, Edmonton, Barcelona

CLOTBUSTCLOTBUST

M2M1

How Does US Enhance Thrombolysis?How Does US Enhance Thrombolysis?

3 mm3 mm

1.1. Reversible changes in fibrin structureReversible changes in fibrin structure2.2. Streaming of plasma through thrombusStreaming of plasma through thrombus3.3. More TPA is delivered to binding sitesMore TPA is delivered to binding sites

M2M1

3 mm3 mm

Recanalization and Dramatic RecoveryRecanalization and Dramatic Recovery

09:55 10:05 10:15 10:5009:55 10:05 10:15 10:50

22 22 16 022 22 16 0 NIH Stroke Scale Scores NIH Stroke Scale Scores

TPA bolus at 09:55 end of TPA infusionTPA bolus at 09:55 end of TPA infusion

Alexandrov et al. J Neuroimaging 2000;10:27-32Alexandrov et al. J Neuroimaging 2000;10:27-32

0

10

20

30

40

50

Combined End-point during 2 hrsCombined End-point during 2 hrs

Control n=63Target n=63

NNT 5 (3-50)NNT 5 (3-50)

RR 1.6 (1.03-2.6)RR 1.6 (1.03-2.6)

p p << 0.02 0.02 Mantel-Haenszel Chi-SquareMantel-Haenszel Chi-Square

Primary End-Point: Complete Recanalization ORPrimary End-Point: Complete Recanalization OR total NIHSS total NIHSS << 3 OR Recovery by 3 OR Recovery by >>10 NIHSS points 10 NIHSS points

30% 49%30% 49%

Alexandrov, NEJM 2004

Microbubbles Accelerate Clot Lysis with Microbubbles Accelerate Clot Lysis with 2-MHz Ultrasound with IV tPA2-MHz Ultrasound with IV tPA

2.5g galactose-based MBs at 2, 20 & 40 minutes 2.5g galactose-based MBs at 2, 20 & 40 minutes p tPA with continuous 2-MHz TCD.p tPA with continuous 2-MHz TCD.

tPA tPA+US tPA+US+MBtPA tPA+US tPA+US+MB

(n=36) (n=37) (n=38)(n=36) (n=37) (n=38)

Complete 24% 40.8% 54.5% p=.03Complete 24% 40.8% 54.5% p=.03

Recanal 2hRecanal 2h

Symp ICH 2(5.5%) 1(2.7%) 1(2.6%)Symp ICH 2(5.5%) 1(2.7%) 1(2.6%)

Molina,et al. Stroke 2006:37;425

Mechanical Embolus Removal in Mechanical Embolus Removal in Cerebral Ischemia (MERCI)Cerebral Ischemia (MERCI)

Approved by FDA for intra-cerebral clot removal Approved by FDA for intra-cerebral clot removal in pts ineligible or failed IV-tPA in pts ineligible or failed IV-tPA

140 pts Rx’d: ave time to groin puncture 4.3 hrs 140 pts Rx’d: ave time to groin puncture 4.3 hrs and ave time to completion 2.1 hours.and ave time to completion 2.1 hours.

48 % recanalization vs 18% in PROACT controls48 % recanalization vs 18% in PROACT controls 12% complication rate.12% complication rate.

Liebeskind. Stroke Clincal Update Jun 2005

Approach to TIAApproach to TIA

1707 TIA patients:1707 TIA patients:

180 (10.5%) Returned to ED with a Stroke-90 d180 (10.5%) Returned to ED with a Stroke-90 d

91 (5.3%) Returned to ED with a Stroke- 2 d 91 (5.3%) Returned to ED with a Stroke- 2 d Total 90 Day Events Rate: 25.1 %Total 90 Day Events Rate: 25.1 %

Stroke (10.5%), TIA (12.7%), MI (2.6Stroke (10.5%), TIA (12.7%), MI (2.6%), %), Death (2.6%)Death (2.6%)

Johnston, etal. JAMA 2000:284(22):2901-2906

Factors for Recurrent Events: TIAsFactors for Recurrent Events: TIAs

High grade stenosis (27% recurrent stroke rate at 10 High grade stenosis (27% recurrent stroke rate at 10 days post-admission)days post-admission)

TCD measured MCA emboli: TCD measured MCA emboli:

44 patients TIA or Stroke: 25 pts with recurrent 44 patients TIA or Stroke: 25 pts with recurrent emboli following anti-platelet Rx- 24% stroke/30 demboli following anti-platelet Rx- 24% stroke/30 d

Goertler, etal. JNNP 2002;72:338-342

Stroke 2002

Mortality Following StrokeMortality Following Stroke

27.0%

10.1%

0

5

10

15

20

25

30

Per

cen

tag

e

Stroke Deaths MI Deaths

Deaths from stroke or MI among patients with a first cerebral infarction (n = 764)

Petty GW, et al. Neurology 1998;50:208-216.

In data acquired over an 18-year observation period, for those In data acquired over an 18-year observation period, for those with an initial stroke, the risk of death from stroke is more than with an initial stroke, the risk of death from stroke is more than 2.5 times the risk of death from MI2.5 times the risk of death from MI

Impact of Protect: Discharge Treatment Rates Post-Stroke

Protect : Incidence of Recurrent Stroke .

SummarySummary

Acute Stroke Management: MedicalAcute Stroke Management: Medical Standard of Care / Critical PathwayStandard of Care / Critical Pathway Interventional OptionsInterventional Options Rapid Implementation Stroke Rapid Implementation Stroke

PreventionPrevention