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
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