thrombolytic therapy for acute ischemic stroke: should it be used in the community?

Thrombolytic Therapy Thrombolytic Therapy for Acute Ischemic for Acute Ischemic

Stroke:Stroke:Should it be used in the Should it be used in the

Community?Community?

Moritz Haager PGY-5Moritz Haager PGY-5

Nov 17, 2005Nov 17, 2005

CasesCases

STARS flight callSTARS flight call– Case 1:Case 1:

58yo M in Lethbridge w/ large L MCA stroke 58yo M in Lethbridge w/ large L MCA stroke onset 1.5 hrs agoonset 1.5 hrs ago

Stroke neurologist in Calgary wants tPA givenStroke neurologist in Calgary wants tPA given

– Case 2:Case 2: 65 yo M in Lethbridge w/ large R MCA stroke 65 yo M in Lethbridge w/ large R MCA stroke

onset 2 hrs agoonset 2 hrs ago Stroke neurologist in Calgary wants tPA givenStroke neurologist in Calgary wants tPA given

ObjectivesObjectives

Review Review efficacyefficacy of tPA in acute of tPA in acute ischemic stroke (AIS): what is the ischemic stroke (AIS): what is the current state of the evidence?current state of the evidence?

Review Review effectivenesseffectiveness of tPA: Can we of tPA: Can we expand thrombolytic Tx to non-expand thrombolytic Tx to non-academic centers?academic centers?

Bad Ideas Part IBad Ideas Part I

Scope of the ProblemScope of the Problem

Canadian Data:Canadian Data:– A stroke q10 minA stroke q10 min– 50,000 – 90,000 cases /yr50,000 – 90,000 cases /yr– 33rdrd leading cause of death (7% of all leading cause of death (7% of all

deaths)deaths) overall mortality rate is 47.8 per 100 000 overall mortality rate is 47.8 per 100 000

populationpopulation

– #1 cause of permanent disability#1 cause of permanent disability– $2.7 billion / yr = 2.1% of all health care $2.7 billion / yr = 2.1% of all health care

costcost

Thrombolysis in Acute Thrombolysis in Acute Ischemic Stroke: is it Ischemic Stroke: is it

efficaciousefficacious??

How well does it work in How well does it work in RCT’s?RCT’s?

RCT’s of IV Thrombolytics in RCT’s of IV Thrombolytics in AISAIS

TRIAL InterventionTimewindow

(n)Primary outcome

result

MAST-E 19961) Placebo2) SK

6 hrs 310 NEGATIVE

MAST-I 19951) Placebo 2) ASA 300 mg

3) SK 4) ASA + SK6 hrs 622 NEGATIVE

ASK 1996 1) Placebo2) SK

4 hrs 340 NEGATIVE

ECASS 19951) Placebo2) IV tPA (1.1 mg/kg)

6 hrs 620 NEGATIVE

ECASS II 1998

1) Placebo2) IV tPA (0.9 mg/kg)

6 hrs 800 NEGATIVE

ATLANTIS 1999


3-5 hrs 547 NEGATIVE

ATLANTIS 2000


0-6 hrs 142 NEGATIVE

ATLANTIS 2002


3 hrs 61 POSITVE

NINDS 19951) Placebo2) IV tPA (0.9 mg/kg)

3 hrs 624 POSITIVE

NINDS:NINDS: Tissue Plasminogen Activator For Tissue Plasminogen Activator For Acute Ischemic Stroke N Engl J Med Acute Ischemic Stroke N Engl J Med

1995;333:1581-71995;333:1581-7 2 part DBRCT of IV tPA vs placebo of 2 part DBRCT of IV tPA vs placebo of

624 pts w/in 3 hrs of stroke onset624 pts w/in 3 hrs of stroke onset– Part I:Part I:

? improvement in neuro deficits w/ tPA at 24 ? improvement in neuro deficits w/ tPA at 24 hrshrs

– Part II:Part II: ? improvement in neuro deficits w/ tPA at 3 ? improvement in neuro deficits w/ tPA at 3

momo

– Inclusion / Exclusion criteriaInclusion / Exclusion criteria

NB: early ischemic changes on CT were NOT part of exclusion criteria


1995;333:1581-71995;333:1581-7 Efficacy Results:Efficacy Results:

– tPA pts did better at 90d on all neuro tPA pts did better at 90d on all neuro scoresscores Better global outcome score at 90d: Better global outcome score at 90d:

– RR 1.9 (1.3–2.9) , p=0.002, ARR 12%, NNT = 8 RR 1.9 (1.3–2.9) , p=0.002, ARR 12%, NNT = 8

NIHSSSNIHSSS ≤1 at 90d:≤1 at 90d:– 18.5% vs. 12%; p=0.033, NNT = 1518.5% vs. 12%; p=0.033, NNT = 15

mRSmRS ≤1 at 90d: ≤1 at 90d:– 23.2% vs 15.8%; p=0.019, NNT = 13.523.2% vs 15.8%; p=0.019, NNT = 13.5

– Good outcomes Good outcomes held up at 1 yr f/uheld up at 1 yr f/u as well as well Wiatkowski et al. N Engl J Med 1999;340:1781-7 Wiatkowski et al. N Engl J Med 1999;340:1781-7

NNT for tPA in MI is26; mortality 1%


1995;333:1581-71995;333:1581-7 Safety ResultsSafety Results

– Mortality at 90dMortality at 90d 17% vs. 21% in placebo, p=0.3017% vs. 21% in placebo, p=0.30

– Intracerebral HemorrhageIntracerebral Hemorrhage Overall: 10.9% vs. 3.5%, P<0.001, NNH = 14Overall: 10.9% vs. 3.5%, P<0.001, NNH = 14 Symptomatic: 6.4% vs. 0.6%, P<0.001 NNH Symptomatic: 6.4% vs. 0.6%, P<0.001 NNH

= 17= 17

Questions regarding NINDSQuestions regarding NINDS

Are the results valid?Are the results valid?– Placebo pts had slightly more severe AISPlacebo pts had slightly more severe AIS– No mortality benefitNo mortality benefit– Only trial to show benefit Only trial to show benefit

Most would point to the <3 hr Tx windowMost would point to the <3 hr Tx window

– Benefit is small & limited to select ptsBenefit is small & limited to select pts– How generalizable are these findings?How generalizable are these findings?

Association of outcome with early stroke treatment: Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDSpooled analysis of ATLANTIS, ECASS, and NINDS rt- rt-PA stroke trials. Lancet 2004; 363: 768–74PA stroke trials. Lancet 2004; 363: 768–74

Meta-analysis of pooled data from Meta-analysis of pooled data from 2775 pts treated w/ IV-tPA w/in 6 hrs2775 pts treated w/ IV-tPA w/in 6 hrs

Main question was Main question was relationship relationship between favorable neuro outcome* & between favorable neuro outcome* & onset to treatment time (OTT)onset to treatment time (OTT)– Used multiple regression model in an ITT Used multiple regression model in an ITT

fashionfashion

*Defined good neuro outcomes as NIHSSS ≤1, mRS ≤1, or BI >95 at 90d


Mortality:Mortality:

Intracranial Hemorrhage:Intracranial Hemorrhage:– Risk of a type II PH was 5.9% of the rt-PA patients Risk of a type II PH was 5.9% of the rt-PA patients

compared with 1.1% of placebo patients (p<0.0001)compared with 1.1% of placebo patients (p<0.0001) sICH rate not providedsICH rate not provided

– The risk of ICH did not appear to increase w/ timeThe risk of ICH did not appear to increase w/ time

Wardlaw et al. Cochrane Database Wardlaw et al. Cochrane Database of Sytematic Reviews, Volume (3) of Sytematic Reviews, Volume (3) 20052005 Looked at pooled data for 5675 pts from Looked at pooled data for 5675 pts from

all RCT’s all RCT’s Significant heterogeneitySignificant heterogeneity

– any type of thrombolytic (tPA, SK, UK etc)any type of thrombolytic (tPA, SK, UK etc)– included both IA & IV administrationincluded both IA & IV administration– Different stroke types & severityDifferent stroke types & severity– Different dosing regimensDifferent dosing regimens– Different use of antithrombotics / Different use of antithrombotics /

anticoagulantsanticoagulants– Variable inclusion / exclusion criteriaVariable inclusion / exclusion criteria

Wardlaw et al. Cochrane Database Wardlaw et al. Cochrane Database of Sytematic Reviews, Volume (3) of Sytematic Reviews, Volume (3)

20052005 Overall results: all lytics vs. placeboOverall results: all lytics vs. placebo

– Death or dependancyDeath or dependancy ( (mRSmRS >2)* at any >2)* at any timetime 53.3% vs. 58% of controls (OR 0.84 [0.75-53.3% vs. 58% of controls (OR 0.84 [0.75-

0.95] p=0.004); 0.95] p=0.004); NNT = 21NNT = 21

– All cause All cause mortalitymortality at any time at any time 18.2% vs 15.2% in controls (OR 1.33 [1.15-18.2% vs 15.2% in controls (OR 1.33 [1.15-

1.53], p=0.0002); 1.53], p=0.0002); NNH = 33NNH = 33

– Symptomatic ICHSymptomatic ICH at any time at any time 8.7% vs. 2.5% in controls (OR 3.37 [2.68-8.7% vs. 2.5% in controls (OR 3.37 [2.68-

4.22] p<0.00001); 4.22] p<0.00001); NNH = 16NNH = 16*Benefit maintained when defined as *Benefit maintained when defined as mRS >1 (OR 0.79, 95% CI 0.69 to >1 (OR 0.79, 95% CI 0.69 to 0.90)0.90)

BottomlineBottomline

ASA in Acute Coronary Syndromes

Thrombolysis in AIS

Bad Ideas Part IIBad Ideas Part II

Thrombolysis in AIS: Thrombolysis in AIS: is it is it effectiveeffective??

Does t-PA work in the Does t-PA work in the realreal world?world?

Limitations of Phase IV Limitations of Phase IV trials:trials:

Heterogenous settingsHeterogenous settings– Some community only, some mix of Some community only, some mix of

academic & community hospitals, some academic & community hospitals, some academic onlyacademic only

– Some in Europe, some in NA Some in Europe, some in NA Heterogenous tPA protocolsHeterogenous tPA protocols

– AHA, Canadian, original NINDS AHA, Canadian, original NINDS Small numbers individuallySmall numbers individually Different outcome measures usedDifferent outcome measures used No control arms – often c/w NINDS dataNo control arms – often c/w NINDS data

Trials (n) Design Symp ICH Mortality Nero Outcomes

NINDS1995

624 DBRCT1) placebo2) IV tPA

1) 0.6% 2) 6.4% P<0.001

1) 21%2) 17% p=0.30

good

CASES 2005 1135 Prospective cohort 4.6% (3.4%–6.0%)

22.3% (20.0%–25.0%)

good

STARS 2000 389 Prospective Cohort 3% 13% good

Houston 2001 269 Prospective cohort 6% 15% NDC

Calgary, 2000 78 Prospective 9% 16% good

London, 2002 82 Prospective cohort 2% 13% good

Vancouver, 2000 46 Prospective /retrospective 2.2% 22% Excellent

OSF 2000 57 Prospective cohort 5% 9% Excellent

Cologne 1998 100 Prospective cohort 5% 12% Excellent

Houston 1998 30 Prospective cohort 7% 23% fair

Helsinki, 2003 75 Prospective cohort 8% parenchymal 5% good

Phoenix 2005 1) 53 rural 2) 73 local

Prospective cohort 1) 2% 2) 0%

1) 6% 2) 1% P=0.08

good

Bethesda, 2003 44 Prospective cohort 7% NR good

Cleveland 2000 1) 70 tPA2) control

Retrospective case control 1)16%2) NR

1) 16% 2) 7% (p=0.01)

NDCBetter in controls

Inndianapolis 2001 50 Retrospective chart review 10% 10% Excellent

Reed 2001 362 Retrospective chart review NR 9.9% NR

Tanne 1999 189 Retrospective survey 6% 10% good

Connecticut 2002 63 Retrospective Chart Review 6% 25% NR

Katzan et al. Use of t-PA for Acute Ischemic Katzan et al. Use of t-PA for Acute Ischemic Stroke: The Stroke: The ClevelandCleveland Area Experience. Area Experience. JAMA 2000; 283: 1151- 1158JAMA 2000; 283: 1151- 1158

Retrospective chart review of 70 pts Retrospective chart review of 70 pts treated w/ IV t-PA over 1 yr treated w/ IV t-PA over 1 yr – AHA guidelines 1996AHA guidelines 1996

29 hospitals – 10 were teaching sites29 hospitals – 10 were teaching sites– Ranged from 10 – 389 admissions for AISRanged from 10 – 389 admissions for AIS

Median Median NIHSSSNIHSSS ~12 ~12 Compared their results to “matched Compared their results to “matched

controls” who had not gotten t-PAcontrols” who had not gotten t-PA

Katzan et al. Use of t-PA for Acute Ischemic Katzan et al. Use of t-PA for Acute Ischemic Stroke: The Stroke: The ClevelandCleveland Area Experience. Area Experience. JAMA 2000; 283: 1151- 1158JAMA 2000; 283: 1151- 1158

Cleveland Cleveland

t-PAt-PAMatched Matched ControlsControls

NINDS NINDS

t-PAt-PA

Protocol Protocol violationviolation 50%50% NRNR NRNR

sICHsICH15.7%15.7%*no sig association *no sig association w/ AIS volumew/ AIS volume

NRNR 6.4%6.4%

MortalityMortality 15.7%15.7%7.2%*7.2%*

P=0.01P=0.0117%17%

Neuro Neuro outcomesoutcomes

Home: Home:

28.6% 28.6% Home: 46.6%* Home: 46.6%*

P=0.004P=0.004NRNR

Katzan et al. Use of t-PA for Acute Ischemic Katzan et al. Use of t-PA for Acute Ischemic Stroke: The Stroke: The ClevelandCleveland Area Experience. Area Experience. JAMA 2000; 283: 1151- 1158JAMA 2000; 283: 1151- 1158 CommentsComments

– ““matched” controls from same cohortmatched” controls from same cohort Must be a reason why they did not get tPAMust be a reason why they did not get tPA

– What is a community hospital?What is a community hospital? Neurologists involved in 95.5% of cases & present in 82%Neurologists involved in 95.5% of cases & present in 82% 10/29 were teaching hospitals10/29 were teaching hospitals

– State no significant association b/w AIS admission State no significant association b/w AIS admission volume and rate of tPA use BUT:volume and rate of tPA use BUT: 4/14 hospitals w/ AIS volume <100 admissions gave tPA 4/14 hospitals w/ AIS volume <100 admissions gave tPA 11/13 hospitals w/ AIS volume >100 admissions gave tPA11/13 hospitals w/ AIS volume >100 admissions gave tPA Hospitals w/ <100 admissions accounted for 8/70 (11%) pts Hospitals w/ <100 admissions accounted for 8/70 (11%) pts

treated w/ tPAtreated w/ tPA– Hard to compare larger centers & small hospitals Hard to compare larger centers & small hospitals

Don’t directly compare complications b/w sitesDon’t directly compare complications b/w sites

CONNECTICUTCONNECTICUT: Bravata et al. Thrombolysis : Bravata et al. Thrombolysis for Acute Stroke in Routine Clinical Practice. for Acute Stroke in Routine Clinical Practice. Arch Intern Med 2002; 162: 1994 – 2001Arch Intern Med 2002; 162: 1994 – 2001

Retrospective chart review of 63 t-PA Retrospective chart review of 63 t-PA treated pts in 16 hospitals over 18 treated pts in 16 hospitals over 18 momo– Followed AHA guidelines 1996Followed AHA guidelines 1996– Only 1 center had 24/7 radiology & Only 1 center had 24/7 radiology &

neurologyneurology Compared outcomes w/ NINDS dataCompared outcomes w/ NINDS data Baseline Mean Baseline Mean NIHSSSNIHSSS 15 15

CONNECTICUTCONNECTICUT: Bravata et al. Thrombolysis : Bravata et al. Thrombolysis for Acute Stroke in Routine Clinical Practice. for Acute Stroke in Routine Clinical Practice. Arch Intern Med 2002; 162: 1994 – 2001Arch Intern Med 2002; 162: 1994 – 2001

ConnecticConnecticutut

NINDS t-NINDS t-PAPA P-valueP-value

Protocol Protocol violationsviolations

97%97%67% had 67% had at least 1 at least 1 majormajor

NRNR

sICHsICH 6%6% 6%6% 0.990.99

In-hospital In-hospital mortalitymortality 25%25% 13%13% 0.010.01

CONNECTICUTCONNECTICUT: Bravata et al. Thrombolysis : Bravata et al. Thrombolysis for Acute Stroke in Routine Clinical Practice. for Acute Stroke in Routine Clinical Practice. Arch Intern Med 2002; 162: 1994 – 2001Arch Intern Med 2002; 162: 1994 – 2001 CommentsComments

– Hospitals more reflective of Canadian Hospitals more reflective of Canadian community centerscommunity centers

– Huge protocol violation rateHuge protocol violation rate– RetrospectiveRetrospective

No data on number of pts w/ incomplete No data on number of pts w/ incomplete data and how they dealt with thisdata and how they dealt with this

– No data on neuro outcomes, or mortality No data on neuro outcomes, or mortality at 30d, 90dat 30d, 90d Mortality in NINDS tPA group at 90d was Mortality in NINDS tPA group at 90d was

17%17%

PHOENIXPHOENIX. Frey et al. tPA by telephone: . Frey et al. tPA by telephone: Extending the benefits of a comprehensive Extending the benefits of a comprehensive stroke center. Neurology 2005;64:154–156stroke center. Neurology 2005;64:154–156 Prospective comparison of 53 pts given Prospective comparison of 53 pts given

tPA in community (telephone consults for tPA in community (telephone consults for “drip & ship”) vs. 73 at stroke center“drip & ship”) vs. 73 at stroke center

CommunityCommunity Stroke CenterStroke Center P valueP value

MortalityMortality 4/53 (6%)4/53 (6%) 1/73 (1%)1/73 (1%) P=0.08P=0.08

sICHsICH 1/53 (2%)1/53 (2%) 0/73 (0%) 0/73 (0%) NRNR

DispositionDispositionHome: 30%Home: 30%

Rehab: 42%Rehab: 42%

SNF: 21%SNF: 21%

Home: 56%Home: 56%

Rehab: 38%Rehab: 38%

SNF: 4%SNF: 4%

p=0.004p=0.004

p=0.72p=0.72

P=0.003 P=0.003

PHOENIXPHOENIX. Frey et al. tPA by telephone: . Frey et al. tPA by telephone: Extending the benefits of a comprehensive Extending the benefits of a comprehensive stroke center. Neurology 2005;64:154–156stroke center. Neurology 2005;64:154–156

CommentsComments– Results suggest pts do better when Results suggest pts do better when

treated in Stroke Center, buttreated in Stroke Center, but Community-treated pts were described as Community-treated pts were described as

older, w/ more severe strokes older, w/ more severe strokes Poor methods description – hard to assessPoor methods description – hard to assess The protocol violation rate is not providedThe protocol violation rate is not provided Not sure if the difference in sICH is Not sure if the difference in sICH is

significantsignificant

Reed et al. Treatment With Tissue Plasminogen Reed et al. Treatment With Tissue Plasminogen Activator and Inpatient Mortality Rates for Patients Activator and Inpatient Mortality Rates for Patients With Ischemic Stroke Treated in Community With Ischemic Stroke Treated in Community Hospitals. Stroke. 2001; 32:1832-1840Hospitals. Stroke. 2001; 32:1832-1840 Retrospective review of 362 pts treated w/ Retrospective review of 362 pts treated w/

IV tPA at 137 hospitalsIV tPA at 137 hospitals– 34% teaching centers, 78% had Neurosurgery34% teaching centers, 78% had Neurosurgery

ResultsResults– In-hospital mortality 9.9% (6.9 – 13%) In-hospital mortality 9.9% (6.9 – 13%) – Final Disposition was home in 36%Final Disposition was home in 36%– Multivariate analysisMultivariate analysis

No significant interaction w/ teaching vs non-No significant interaction w/ teaching vs non-teaching hospital, or urban vs rural & likelihood teaching hospital, or urban vs rural & likelihood of deathof death

Reed et al. Treatment With Tissue Plasminogen Reed et al. Treatment With Tissue Plasminogen Activator and Inpatient Mortality Rates for Patients Activator and Inpatient Mortality Rates for Patients With Ischemic Stroke Treated in Community With Ischemic Stroke Treated in Community Hospitals. Stroke. 2001; 32:1832-1840Hospitals. Stroke. 2001; 32:1832-1840

Comments:Comments:– Heterogenous collection of “community” Heterogenous collection of “community”

hospitalshospitals– No baseline No baseline NIHSSSNIHSSS scores scores– No data on protocol violations No data on protocol violations – No data on symptomatic ICHNo data on symptomatic ICH– No neuro outcome dataNo neuro outcome data– Retrospective w/ poorly defined Retrospective w/ poorly defined

methodsmethods

CALGARYCALGARY: Buchan et al. Effectiveness of t-PA : Buchan et al. Effectiveness of t-PA in acute ischemic stroke: Outcome relates to in acute ischemic stroke: Outcome relates to appropriateness. Neurology 2000; 54(3): appropriateness. Neurology 2000; 54(3): 679679 Prospective cohort of 68 consecutive Prospective cohort of 68 consecutive

pts treated w/ IV t-PA at FMC using pts treated w/ IV t-PA at FMC using NINDS protocol over 30 mo periodNINDS protocol over 30 mo period

Baseline Mean Baseline Mean NIHSSNIHSS 15 15 Compared outcomes to NINDSCompared outcomes to NINDS

CALGARYCALGARY: Buchan et al. Effectiveness of t-PA : Buchan et al. Effectiveness of t-PA in acute ischemic stroke: Outcome relates to in acute ischemic stroke: Outcome relates to appropriateness. Neurology 2000; 54(3): appropriateness. Neurology 2000; 54(3): 679679

CalgaryCalgary NINDS t-PANINDS t-PA

Protocol Protocol violation rateviolation rate 16%16% NANA

sICHsICH 9%9%5% excl protocol violations5% excl protocol violations

6.4%6.4%

90d Mortality90d Mortality16%16%

10% excl protocol 10% excl protocol violationsviolations

17%17%

mRSmRS ≤ 2≤ 2 at 90d at 90d 57%57% 43%43%

NIHSSSNIHSSS ≤1 at ≤1 at 90d90d 38%38% 31%31%

CALGARYCALGARY: Buchan et al. Effectiveness of t-PA : Buchan et al. Effectiveness of t-PA in acute ischemic stroke: Outcome relates to in acute ischemic stroke: Outcome relates to appropriateness. Neurology 2000; 54(3): appropriateness. Neurology 2000; 54(3): 679679 CommentComment

– Protocol violation associated w/ Protocol violation associated w/ significantly higher risk of sICH, significantly higher risk of sICH, mortality, & worse neuro outcomemortality, & worse neuro outcome 6/57 (10%) deaths in protocol pts vs 5/11 6/57 (10%) deaths in protocol pts vs 5/11

(46%) in violators (p < 0.01)(46%) in violators (p < 0.01)

– Calculated NNT relative to the NINDS Calculated NNT relative to the NINDS study placebo groupstudy placebo group NNT = 6 for good outcome (NNT = 6 for good outcome (NIHSSNIHSS score 0 to score 0 to

1) 1) NNT = 3 for independence (NNT = 3 for independence (mRSmRS 0-20-2) )

CASES:CASES: Hill et al. Thrombolysis for acute Hill et al. Thrombolysis for acute ischemic stroke: results of the Canadian ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study Alteplase for Stroke Effectiveness Study CMAJ 2005;172(10):1307-12CMAJ 2005;172(10):1307-12 Prospective registry of 1135* t-PA Prospective registry of 1135* t-PA

treated AIS pts at 60 Canadian treated AIS pts at 60 Canadian hospitals in 2.5 yrshospitals in 2.5 yrs– 33 community, 27 academic33 community, 27 academic

10 “high volume” centers = >1 pt 10 “high volume” centers = >1 pt treated/motreated/mo

– Treated 61% of all ptsTreated 61% of all pts

Median Median NIHSSSNIHSSS 14 at baseline 14 at baseline Looked at outcomes at 90dLooked at outcomes at 90d

* Estimate this accounts for 84% of all AIS pts treated w/ tPA in Canada during study periodEstimate this accounts for 84% of all AIS pts treated w/ tPA in Canada during study period

CASES:CASES: Hill et al. Thrombolysis for acute Hill et al. Thrombolysis for acute ischemic stroke: results of the Canadian ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study Alteplase for Stroke Effectiveness Study CMAJ 2005;172(10):1307-12CMAJ 2005;172(10):1307-12

CASESCASES NINDS tPANINDS tPA NINDS placeboNINDS placebo

Protocol Protocol violationviolation 13.6%13.6%

sICHsICH44.6% .6%

(3.4%-6.0%)(3.4%-6.0%)6.4%6.4% 0.6%0.6%

MortalityMortality22.3% 22.3%

(20.0%–25.0%)(20.0%–25.0%)17%17% 21%21%

mRSmRS ≤1* ≤1* 31.8%31.8% 39% 39% 26%26%

NIHSSSNIHSSS ≤1 ≤1 25.3%25.3% 31% 31% 20%20%

*mRS adjusted for baseline was 36.8%, which was not significantly different (p = 0.15) from the expected rate of 39.9% based on NINDS data

CASES:CASES: Hill et al. Thrombolysis for acute Hill et al. Thrombolysis for acute ischemic stroke: results of the Canadian ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study Alteplase for Stroke Effectiveness Study CMAJ 2005;172(10):1307-12CMAJ 2005;172(10):1307-12 Multivariate AnalysisMultivariate Analysis

– Found no significant difference in rate of Found no significant difference in rate of neuro outcomes or sICH b/w pts treated neuro outcomes or sICH b/w pts treated at:at: High volume vs. low volume centerHigh volume vs. low volume center Community vs. academic centerCommunity vs. academic center

– Found significant relationship b/w protocol Found significant relationship b/w protocol violation & risk of sICHviolation & risk of sICH 7.8% v. 3.9%; RR 2.0, 95%CI 1.1–3.87.8% v. 3.9%; RR 2.0, 95%CI 1.1–3.8

– Predictors of sICH:Predictors of sICH:– Elevated glucoseElevated glucose

(OR 1.6, (OR 1.6, 95% CI 1.2–2.3 per 5-mmol/L increase95% CI 1.2–2.3 per 5-mmol/L increase))– Increased time from stroke onset to TxIncreased time from stroke onset to Tx

(OR 1.2, 95% CI 1.0–1.5 per 30-minute increase)(OR 1.2, 95% CI 1.0–1.5 per 30-minute increase)

ConclusionsConclusions

IV t-PA IV t-PA improves neuro outcomesimproves neuro outcomes in select in select AIS pts in RCTsAIS pts in RCTs– Benefit diminishes rapidly with timeBenefit diminishes rapidly with time

IV t-PA has a IV t-PA has a narrow therapeutic indexnarrow therapeutic index– Need to select pts carefully & stick to protocolNeed to select pts carefully & stick to protocol

Multiple case series report Multiple case series report results similar results similar to NINDS in routine clinical useto NINDS in routine clinical use

The data to The data to support or refutesupport or refute use of t-PA use of t-PA in community centers isin community centers is limited limited & difficult & difficult to interpretto interpret

ConclusionsConclusions

So should we give t-PA in Lethbridge?So should we give t-PA in Lethbridge? Currently noCurrently no Tomorrow maybe yes, provided:Tomorrow maybe yes, provided:

– Establishment of detailed protocolEstablishment of detailed protocol– Telephone consult to stroke team at FMCTelephone consult to stroke team at FMC– Transmission of CT images to FMCTransmission of CT images to FMC– Transfer for all t-PA pts to FMCTransfer for all t-PA pts to FMC– Rigorous QI/QA process to track & addressRigorous QI/QA process to track & address

Protocol violation rateProtocol violation rate Outcomes of pts treated in periphery vs. at stroke Outcomes of pts treated in periphery vs. at stroke

centercenter

Questions?Questions?

Bad Ideas Part III

Are we just increasing the number of Are we just increasing the number of disabled survivors?disabled survivors?

Lancet 2004; 363: 768–74

Barriers to t-PA Tx in CVABarriers to t-PA Tx in CVA Systematic review:Systematic review:

– failure to recognise symptoms of stroke or seek failure to recognise symptoms of stroke or seek urgent helpurgent help

– Failure to call for and ambulance first Failure to call for and ambulance first – Incorrect triage as non-urgent by paramedics Incorrect triage as non-urgent by paramedics

or ED staffor ED staff– delays in neuroimaging,delays in neuroimaging,– Inefficient stroke care pathwaysInefficient stroke care pathways– Obtaining informed consent Obtaining informed consent – Physician inexperience & uncertainty w/ giving Physician inexperience & uncertainty w/ giving

thrombolytics in CVAthrombolytics in CVA Kwan et al. Age and Ageing 2004; 33: 116–121Kwan et al. Age and Ageing 2004; 33: 116–121

Kwan et al. Age and Ageing 2004; 33: 116–121Kwan et al. Age and Ageing 2004; 33: 116–121

Albers et al. ATLANTIS trial: results for patients Albers et al. ATLANTIS trial: results for patients treated within 3 hours of stroke onset. Stroke treated within 3 hours of stroke onset. Stroke

2002;33: 493-5.2002;33: 493-5.

Analysis of 61 pts treated w/ IV-tPA Analysis of 61 pts treated w/ IV-tPA w/in 3 hrs in a DBRCTw/in 3 hrs in a DBRCT– ResultsResults

NIHSSS ≤1 at 90dNIHSSS ≤1 at 90d– 60.9% vs. 26.3% in placebo; p=0.01, NNT = 360.9% vs. 26.3% in placebo; p=0.01, NNT = 3

Mortality at 90dMortality at 90d– 17.4% vs. 5.3% in placebo; p=0.12, NNH = 817.4% vs. 5.3% in placebo; p=0.12, NNH = 8

sICH at 10dsICH at 10d– 13% vs 0% in placebo; p=0.05, NNH = 33 13% vs 0% in placebo; p=0.05, NNH = 33

ASPECTSASPECTS

The ASPECTS value is calculated from two standard axial CT cuts:-one at the level of the thalamus and basal ganglia-one just rostral to the ganglionic structures.

the MCA territory is allotted 10 points -1 point is subtracted for each area of early ischemic change, such as

-focal swelling-parenchymal hypoattenuation,

A normal CT scan has an ASPECTS value of 10 points Barber et al. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. Lancet 2000;

355: 1670–74

ASPECTSASPECTS

In logistic regression analysis, baseline ASPECTS value In logistic regression analysis, baseline ASPECTS value ≤7 was a significant predictor of both ≤7 was a significant predictor of both – Poor functional outcome (OR82 [95% CI 23–290], p<0·001) Poor functional outcome (OR82 [95% CI 23–290], p<0·001) – Increased risk of symptomatic ICH (OR 14 [2–117], p=0·012)Increased risk of symptomatic ICH (OR 14 [2–117], p=0·012)

Kappa was 0.71 – 0.89 depending on trainingKappa was 0.71 – 0.89 depending on training

IV t-PA >3 hrsIV t-PA >3 hrs

Meta-analyses suggest modest benefit Meta-analyses suggest modest benefit after 3 hrs – rapidly diminishes w/ timeafter 3 hrs – rapidly diminishes w/ time

New strategies to select pts w/ New strategies to select pts w/ potentially reversible ischemiapotentially reversible ischemia– DWI/PWI MRI DWI/PWI MRI

Clinical – MRI mismatchClinical – MRI mismatch

– CT perfusion imaging (CTP) CT perfusion imaging (CTP) Estimates blood volume as ml /100 g brain Estimates blood volume as ml /100 g brain

tissuetissue– Both need further study & validationBoth need further study & validation

How does t-PA cause ICH?How does t-PA cause ICH?

Proposed mechanismsProposed mechanisms– interaction with NMDA receptors, promoting calcium influx interaction with NMDA receptors, promoting calcium influx

into ischemic cells into ischemic cells excitotoxicity excitotoxicity– enhances degradative enzymatic activity in the intercellular enhances degradative enzymatic activity in the intercellular

matrix by up-regulating MMP-9, which leads to disruption of matrix by up-regulating MMP-9, which leads to disruption of tissue integrity and may predispose to hemorrhagetissue integrity and may predispose to hemorrhage

giving inhibitors of these effects may minimize the giving inhibitors of these effects may minimize the side effects & this is under investigation:side effects & this is under investigation:– caffeine & EtOH in combocaffeine & EtOH in combo– albuminalbumin– MagnesiumMagnesium– HypothermiaHypothermia– OxygenOxygen– SteroidsSteroids

Frey. Recombinant Tissue Plasminogen Activator (rtPA) for Stroke: The perspective at 8 years. Neurologist 2005;11: 123–133

EP’s Role in AISEP’s Role in AIS Emergency CareEmergency Care

– Fast recognition of potential CVA & appropriate Fast recognition of potential CVA & appropriate triage/assessmenttriage/assessment

– Initial TxInitial Tx OxygenOxygen IV rehydrationIV rehydration ECGECG Bedside C/SBedside C/S Pharmacologic control of hyperglycemia & hyperpyrexiaPharmacologic control of hyperglycemia & hyperpyrexia ASA 160 – 235 ASA 160 – 235 if no tpAif no tpA NPO until swallowing assessedNPO until swallowing assessed

– Fast CT to r/o ICH or other causesFast CT to r/o ICH or other causes– Determination of eligibility for tPADetermination of eligibility for tPA– Dedicated stroke teams & stroke unitsDedicated stroke teams & stroke units

– Wilson et al. Creating a Canadian stroke system. CMAJ 2001; Wilson et al. Creating a Canadian stroke system. CMAJ 2001; 164: 1853-1855164: 1853-1855

U/S Enhanced thrombolysis?U/S Enhanced thrombolysis?

DBRCT of 126 pts give IV tPA for AIS & randomized to TCD U/S or placebo

Results:– Complete recanalization or dramatic

clinical recovery w/in 2 hrs 49% of TCD U/S pts vs 30% placebo; p

=0.03

– No other significant benefit long-term N Engl J Med 2004;351:2170-8.Early clinical recovery was defined as a reduction of 10 or more points on the

NIHSS, and dramatic recovery as a total NIHSS score of 3 or less within two hours after administrationof the t-PA bolus

Evidence for ASAEvidence for ASA Cochrane Review of antiplatelet agents in Cochrane Review of antiplatelet agents in 41,399

AIS pts in 9 trials– 98% were ASA trials (PO or PR)– Sig decrease in death or dependancy at 6mo

OR = 0.94; 95% CI 0.91 to 0.98OR = 0.94; 95% CI 0.91 to 0.98 NNT =100

– Small decrease in mortality OR = 0.92; 95% CI 0.85 to 1.00; p=0.05 NNT = 125

– Small increase in risk of sICH OR = 1.23; 95% CI 1.00 to 1.50; p=0.05 NNH = 500

– Sandercock et al. Antiplatelet therapy for acute ischaemic Sandercock et al. Antiplatelet therapy for acute ischaemic Stroke. Cochrane Collaboration Volume (3), 2005Stroke. Cochrane Collaboration Volume (3), 2005

Heparin or ASA?Heparin or ASA?

Meta-analysis of 16,558 pts in trials Meta-analysis of 16,558 pts in trials of ASA vs. heparin, heparin has:of ASA vs. heparin, heparin has:– NS Reduction of death or dependancyNS Reduction of death or dependancy

OR 1.07 (0.98 – 1.15)OR 1.07 (0.98 – 1.15)

– Small increase in MortalitySmall increase in Mortality OR 1.10 (1.01 – 1.29); NNH = 50OR 1.10 (1.01 – 1.29); NNH = 50

– Significantly higher risk of sICHSignificantly higher risk of sICH OR 2.35 (1.49 – 3.46)OR 2.35 (1.49 – 3.46)

Berge & Sandercock. Stroke. 2003;34:1571-1572

NINDS Exclusion / InclusionNINDS Exclusion / Inclusion Inclusion Criteria:Inclusion Criteria:

– Ischemic stroke with a clearly defined time of onset <180 min oldIschemic stroke with a clearly defined time of onset <180 min old– a deficit measurable on the NIHSSa deficit measurable on the NIHSS– base-line CT head that showed no evidence of intracranial hemorrhage.base-line CT head that showed no evidence of intracranial hemorrhage.

Exclusion Criteria:Exclusion Criteria:– prior stroke or serious head trauma within the preceding 3 monthsprior stroke or serious head trauma within the preceding 3 months– major surgery within 14 daysmajor surgery within 14 days– history of intracranial hemorrhage;history of intracranial hemorrhage;– systolic blood pressure > 185 mm Hg or diastolic blood pressure > 110 mm Hgsystolic blood pressure > 185 mm Hg or diastolic blood pressure > 110 mm Hg– rapidly improving or minor symptoms;rapidly improving or minor symptoms;– symptoms suggestive of subarachnoid hemorrhagesymptoms suggestive of subarachnoid hemorrhage– GI hemorrhage or urinary tract hemorrhage within the previous 21 daysGI hemorrhage or urinary tract hemorrhage within the previous 21 days– arterial puncture at a noncompressible site within the previous 7 daysarterial puncture at a noncompressible site within the previous 7 days– had a seizure at the onset of strokehad a seizure at the onset of stroke– on anticoagulants or who had received heparin within the 48 hours preceding on anticoagulants or who had received heparin within the 48 hours preceding

the onset of stroke and had an elevated partial-thromboplastin time, or those the onset of stroke and had an elevated partial-thromboplastin time, or those with prothrombin times greater than 15 seconds, platelet counts below 100,000 with prothrombin times greater than 15 seconds, platelet counts below 100,000 per cubic millimeterper cubic millimeter

– glucose concentrations below 2.7 mmol per liter or >22.2 mmol/L Patients glucose concentrations below 2.7 mmol per liter or >22.2 mmol/L Patients – if aggressive treatment was required to reduce their BP to the specified limitsif aggressive treatment was required to reduce their BP to the specified limits

Back to previous slide

BP MangementBP Mangement No great evidenceNo great evidence

– Used to aggressively control all; now some data to Used to aggressively control all; now some data to suggest worse outcomes w/ aggessive BP mgmt suggest worse outcomes w/ aggessive BP mgmt

Guidelines for BP mgmt in acute stroke:Guidelines for BP mgmt in acute stroke:– only patients pressures repeatedly >220/120 mm Hg

should be treated labetalol or sodium nitroprusside

– Other indications are: Getting tPA for AIS congestive heart failure, myocardial infarction aortic dissection Other acute end-organ failure attributable to HTN

– BP target during the acute phase should be: 180/105 mm Hg ifpreviously hypertensive 160–180/90–100 mm Hg if previously normotensive

Lancet Neurol 2003;2(11):698-701

Wang et al. Treating Acute Stroke Patients Wang et al. Treating Acute Stroke Patients With Intravenous tPA: The With Intravenous tPA: The OSF Stroke OSF Stroke NetworkNetwork Experience. Stroke. 2000;31:77-81 Experience. Stroke. 2000;31:77-81

Prospective cohort study of 57 pts Prospective cohort study of 57 pts treated w/ IV t-PA in a stroke networktreated w/ IV t-PA in a stroke network– 34 treated in community w/ telephone 34 treated in community w/ telephone

consultconsult 35% treated by EP’s35% treated by EP’s

– 23 treated at stroke center (SC)23 treated at stroke center (SC) Baseline mean NIHSSS 14Baseline mean NIHSSS 14

Wang et al. Treating Acute Stroke Patients Wang et al. Treating Acute Stroke Patients With Intravenous tPA: The With Intravenous tPA: The OSF Stroke OSF Stroke NetworkNetwork Experience. Stroke. 2000;31:77-81 Experience. Stroke. 2000;31:77-81 ResultsResults

– Symp ICH: 5%Symp ICH: 5%– Mortality: 9%Mortality: 9%– Neuro outcomes:Neuro outcomes:

mRS≤1: 47%mRS≤1: 47% NIHSSS≤1: 44%NIHSSS≤1: 44%

– Tx beyond 3 hrs: Tx beyond 3 hrs: 9%9%

CommentsComments– No data on protocol No data on protocol

violationsviolations– No breakdown of No breakdown of

outcomes b/w outcomes b/w community vs. community vs. Stroke centerStroke center

thrombolytic therapy for acute ischemic stroke: should it be used in the community?

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