““Remember that stroke patient Remember that stroke patient you treated last night…”you treated last night…”

What to Expect following tPA Use What to Expect following tPA Use in Acute Ischemic Strokein Acute Ischemic Stroke

The INSTINCT Trial

NIH / NINDS R01 NS050372

BackgroundBackground

Stroke patients, properly treated with tPA, have Stroke patients, properly treated with tPA, have an 11% absolute greater chance of a normal an 11% absolute greater chance of a normal outcome compared to untreated patients.outcome compared to untreated patients.

Current Treatment Rates are 1-3% of all Current Treatment Rates are 1-3% of all ischemic strokesischemic strokes

Accurate expectations can enhance both Accurate expectations can enhance both physician and patient understanding of the risks physician and patient understanding of the risks of both tPA treatment and non-treatmentof both tPA treatment and non-treatment

ObjectivesObjectives

Present outcome data on tPA use in stroke from Present outcome data on tPA use in stroke from the NINDS trial and other Phase III studiesthe NINDS trial and other Phase III studies– Short-termShort-term– Long-termLong-term

Review outcome data on tPA use outside of Review outcome data on tPA use outside of investigational studies… effectivenessinvestigational studies… effectiveness

Understand the outcome feedback information Understand the outcome feedback information systems to be used locally in the INSTINCT trialsystems to be used locally in the INSTINCT trial

IV thrombolysis - backgroundIV thrombolysis - background

Small trials in late 1960s and 1970sSmall trials in late 1960s and 1970sUsed streptokinase + anticoagulation or Used streptokinase + anticoagulation or urokinaseurokinaseUsed a long treatment window (up to 36 Used a long treatment window (up to 36 hours)hours)High mortalityHigh mortalityFirst studies with tPA (dose finding) First studies with tPA (dose finding) emerged in early 1990semerged in early 1990s

IV studies overviewIV studies overview (publication date)(publication date)

NINDS rt-PA (1995)NINDS rt-PA (1995)

ECASS (1995)ECASS (1995)

MAST-I (1995)MAST-I (1995)

MAST-E (1996)MAST-E (1996)

ASK (1996)ASK (1996)

ECASS II (1998)ECASS II (1998)

ATLANTIS (1999-2001) ATLANTIS (1999-2001)

NINDS Stroke rt-PANINDS Stroke rt-PA

Two part trial Two part trial

Part 1 – (291) 4 point improvement in Part 1 – (291) 4 point improvement in NIHSS in 24 hours NIHSS in 24 hours

Part 2 – (333) 3 month clinical outcomePart 2 – (333) 3 month clinical outcome

Multi-center randomized placebo control Multi-center randomized placebo control trialtrial

““Permuted block design”Permuted block design”

NEJM 1995;333:1581

Part 1 resultsPart 1 results

NEJM 1995;333:1581

Part 1Part 1No significant difference at 24 hours based No significant difference at 24 hours based on NIHSS improvement of 4 pointson NIHSS improvement of 4 points11

However, a post hoc analysis However, a post hoc analysis demonstrated that picking any number demonstrated that picking any number other than 4 for this would have other than 4 for this would have demonstrated a benefitdemonstrated a benefit22

The study did not demonstrate a benefit at The study did not demonstrate a benefit at 24 hour by pre-specified primary endpoint24 hour by pre-specified primary endpoint

1. NEJM 1995;333:1581

2. Annals Emerg Med. 1997;30:676

Part 2Part 2

OR for favorable outcome 1.7 (1.2-2.6)OR for favorable outcome 1.7 (1.2-2.6)

Versus placebo – rt-PA treated patients Versus placebo – rt-PA treated patients about 30% more likely to have minimal or about 30% more likely to have minimal or no disabilityno disability

Put another way, 12% absolute difference Put another way, 12% absolute difference – NNT about 8– NNT about 8

NEJM 1995;333:1581

OutcomesOutcomes

NEJM 1995;333:1581

What are the risks?What are the risks?

Symptomatic ICH Symptomatic ICH 6.4% with rt-PA6.4% with rt-PA

Only 0.6% with Only 0.6% with placeboplacebo

Mortality is not Mortality is not significantly different significantly different at 3 monthsat 3 months

NEJM 1995;333:1581

NINDS rt-PA 10 years laterNINDS rt-PA 10 years later

Still controversial Still controversial Many patients treated in less than 90 minutes – Many patients treated in less than 90 minutes – which does not reflect usual realitywhich does not reflect usual realityDespite limitations – did show a benefit versus Despite limitations – did show a benefit versus placebo (no we are not just “curing” a bunch of placebo (no we are not just “curing” a bunch of TIA’s)TIA’s)Is the only FDA approved pharmacologic Is the only FDA approved pharmacologic therapy currentlytherapy currentlyIs recommended by the ASA / AHAIs recommended by the ASA / AHA

European Cooperative Acute European Cooperative Acute Stroke Study (ECASS)Stroke Study (ECASS)

Randomized, prospective, double-blind placebo Randomized, prospective, double-blind placebo controlledcontrolled

75 hospitals in 14 European countries75 hospitals in 14 European countries

620 patients620 patients

1.1 mg/kg rt-PA or placebo within 6 hours1.1 mg/kg rt-PA or placebo within 6 hours

Age 18-80Age 18-80

Exclusions Exclusions

CT showing > 33% MCA infarction - excluded CT showing > 33% MCA infarction - excluded

JAMA. 1995;274:1017

ECASS - exclusionsECASS - exclusions

JAMA. 1995;274:1017

ECASS DemographicsECASS Demographics

JAMA. 1995;274:1017

ECASS - resultsECASS - results

33 (0.035) 2

JAMA. 1995;274:1017

ECASS – more on resultsECASS – more on results

JAMA. 1995;274:1017

Protocol violations - deadlyProtocol violations - deadly

JAMA. 1995;274:1017

HemorrhagesHemorrhages

No difference in overall hemorrhagesNo difference in overall hemorrhages

More parenchymal hematomas in rt-PA More parenchymal hematomas in rt-PA groupgroup

JAMA. 1995;274:1017

ECASS – summary pointsECASS – summary points

Higher doseHigher doseLong treatment windowLong treatment windowHigh number of protocol violations (almost 20%)High number of protocol violations (almost 20%)Extremely high mortality in patients with PVExtremely high mortality in patients with PVSuggestion of some improvement in protocol rt-Suggestion of some improvement in protocol rt-PA treated patientsPA treated patientsIncreased mortality in rt-PA treated patients Increased mortality in rt-PA treated patients overalloverall

Multi-centre Acute Stroke Trial - Multi-centre Acute Stroke Trial - ItalyItaly

Randomized “open” trialRandomized “open” trial

622 patients622 patients

4 groups4 groups– Streptokinase aloneStreptokinase alone– Aspirin aloneAspirin alone– BothBoth– NeitherNeither

Lancet. 1995;346:1509

MAST-I resultsMAST-I results

Aspirin + streptokinase increased 10 day Aspirin + streptokinase increased 10 day mortality (to 34% from 13% for neither)mortality (to 34% from 13% for neither)Trend (NS) towards increased mortality Trend (NS) towards increased mortality with streptokinase alonewith streptokinase alone9% ARR for streptokinase versus aspirin 9% ARR for streptokinase versus aspirin (death and disability at 6 months)(death and disability at 6 months)Major lesson : probably should not mix Major lesson : probably should not mix lytics and aspirinlytics and aspirin

Lancet. 1995;346:1509

MAST – E (Europe)MAST – E (Europe)

Multicenter, double blind, controlled trial of Multicenter, double blind, controlled trial of streptokinase vs. placebostreptokinase vs. placebo310 patients (enrollment stopped early) up to 6 310 patients (enrollment stopped early) up to 6 hourshoursCould use heparin (and they did about 2/3Could use heparin (and they did about 2/3 rdrd of of the time)the time)Hypotension only 0.6% !Hypotension only 0.6% !No difference in efficacy (disability) at 6 monthsNo difference in efficacy (disability) at 6 monthsIncrease in 10 day mortality (34% vs 18%)Increase in 10 day mortality (34% vs 18%)6 month mortality not significantly different 6 month mortality not significantly different

NEJM 1995;335:145

Australian Streptokinase Trial Australian Streptokinase Trial (ASK)(ASK)

340 patients within 4 hours340 patients within 4 hours

Streptokinase or placeboStreptokinase or placebo

Only 3 patients treated in less than 90 minutes!Only 3 patients treated in less than 90 minutes!

Hypotension noted in 33%Hypotension noted in 33%

12.6% sICH (treated) versus 2.4% untreated12.6% sICH (treated) versus 2.4% untreated

Significantly increased death rate in those Significantly increased death rate in those treated over 3 hourstreated over 3 hours

JAMA 1996;276:961

If you allow 4 hours you will get If you allow 4 hours you will get four hoursfour hours

JAMA 1996;276:961

ECASS 2 trialECASS 2 trial

0.9 mg/kg rt-PA within 6 hours0.9 mg/kg rt-PA within 6 hours

800 patients800 patients

Only 81 rt-PA treated patients within 3 hours Only 81 rt-PA treated patients within 3 hours (placebo 75 in 3 hr)(placebo 75 in 3 hr)

No significant difference in mortalityNo significant difference in mortality

No difference in primary endpoints (disability)No difference in primary endpoints (disability)

Conclusion of investigators – its safe! (but it Conclusion of investigators – its safe! (but it doesn’t work…)doesn’t work…)

Lancet. 1998;352:1245

ATLANTIS ATLANTIS (Alteplase Thrombolysis for Acute (Alteplase Thrombolysis for Acute

Noninterventional Therapy in Acute Ischemic Stroke)Noninterventional Therapy in Acute Ischemic Stroke)

Main study – did not Main study – did not show a benefit of rt-show a benefit of rt-PA within 6 hours (or PA within 6 hours (or from 3-5 hours)from 3-5 hours)Did a sub-group Did a sub-group analysis of < 3 hranalysis of < 3 hrOnly accepted up to Only accepted up to age 79age 79

Stroke. 2002;33:493; JAMA 1999;282:2019

ATLANTIS 0-3hrATLANTIS 0-3hr

Stroke. 2002;33:493

ATLANTIS bottom lineATLANTIS bottom line

Another study which suggests treating Another study which suggests treating after 3 hours is badafter 3 hours is bad

Subgroup analysis agrees with NINDS Subgroup analysis agrees with NINDS study findingsstudy findings

StudyStudy LocatioLocationn

DrugDrug DoseDose TimeTime Exclusion Exclusion criteriacriteria

Atlantis Atlantis A (1991-A (1991-93)93)

USUS rt-PArt-PA 0.9 mg/kg 0.9 mg/kg (max: 90 (max: 90 mg)mg)

0-60-6 Blood pressure Blood pressure (BP)(BP)

NINDS NINDS (1991-94)(1991-94)

USUS rt-PArt-PA 0.9 mg/kg 0.9 mg/kg (max: 90 (max: 90 mg)mg)

0-3 0-3 (1:59)*(1:59)*

Blood pressure Blood pressure

MAST-I MAST-I (1991-95)(1991-95)

Italy, UK, Italy, UK, PortugalPortugal

streptokinasestreptokinase 1.5 million 1.5 million uu

0-6 hours0-6 hours

ECASS 1 ECASS 1 (1992-94)(1992-94)

EuropeEurope rt-PArt-PA 1.1mg/kg 1.1mg/kg (max: (max: 100mg)100mg)

0-6 0-6 (4:24)*(4:24)*

CT evidence of CT evidence of early infarct; ageearly infarct; age

MAST-E MAST-E (1992-94)(1992-94)

France, France, UKUK

streptokinasestreptokinase 1.5 million 1.5 million uu

0-6 h 0-6 h (4:36)**(4:36)**

Mild strokeMild stroke

ASK Trial ASK Trial (1992-94)(1992-94)

AustraliaAustralia streptokinasestreptokinase 1.5 million 1.5 million uu

0-4 (3:28)0-4 (3:28) Age; minor strokeAge; minor stroke

Atlantis Atlantis B (1993-B (1993-98)98)

USUS rt-PArt-PA 0.9 mg/kg 0.9 mg/kg (max: 90 (max: 90 mg)mg)

3-5 3-5 (4:36)**(4:36)**

Blood pressure; Blood pressure; ageage

ECASS 2 ECASS 2 (1996-98)(1996-98)

Europe Europe ANZ*ANZ*

rt-PArt-PA 0.9 mg/kg 0.9 mg/kg (max: 90 (max: 90 mg)mg)

0-6 0-6 BP; CT evidence BP; CT evidence of early infarct; of early infarct; ageage

* mean; ** median time onset-to-treatment;

tPA Safety Meta AnalysistPA Safety Meta Analysis

15 published, open-label studies in non-15 published, open-label studies in non-selective patient populationsselective patient populations

2,639 treated patients2,639 treated patients

Symptomatic ICH rate 5.2% [95% CI 4.3 to Symptomatic ICH rate 5.2% [95% CI 4.3 to 6.0]6.0]

Total death rate 13.4%Total death rate 13.4%

Very favorable outcome 37.1%Very favorable outcome 37.1%

Protocol deviations 19.8%Protocol deviations 19.8%Graham, G. D. Stroke 2003;34:2847-2850

““But what about outcomes in the But what about outcomes in the community setting…”community setting…”

““Community physicians cannot Community physicians cannot duplicate the results of specialized duplicate the results of specialized stroke teams in an academic setting”stroke teams in an academic setting”– can’t diagnose a strokecan’t diagnose a stroke– can’t tell the time of onsetcan’t tell the time of onset– can’t get a CT interpretationcan’t get a CT interpretation– can’t follow a checklist of can’t follow a checklist of

inclusions/exclusionsinclusions/exclusions

29 Cleveland area hospitals29 Cleveland area hospitals

70 patients treated with tPA70 patients treated with tPA

50% protocol deviations50% protocol deviations

16% symptomatic ICH16% symptomatic ICH

96% with neurologist involved96% with neurologist involved

Katzan IL et al: JAMA. 2000 Mar 1;283(9):1151-8.

“Ad hoc” Delivery Systems 1997-98 Cleveland, OH

Graham, G. D. Stroke 2003;34:2847-2850

Mortality rate vs Percentage of Protocol Deviations in each of 12 studies reporting

death rates

With support: CCHS Stroke QI PlanWith support: CCHS Stroke QI Plan

Protocol, stroke Protocol, stroke paging system, CME paging system, CME and performance and performance reportsreports

June 2000 – June June 2000 – June 2001 results:2001 results:– 47 patients treated47 patients treated– Protocol deviations Protocol deviations

17%17%– Symptomatic ICH 6%Symptomatic ICH 6%

Katzan IL et al: Stroke. 2003 Mar;34(3):799-800

INSTINCT Preliminary DataINSTINCT Preliminary DataSafety of Community Use of tPA Safety of Community Use of tPA

(SCUT)(SCUT)

Retrospective, observational study of tPA Retrospective, observational study of tPA use at 4 Michigan hospitals without use at 4 Michigan hospitals without dedicated tPA-stroke teamsdedicated tPA-stroke teams

1/1/96 to 1/1/20051/1/96 to 1/1/2005

Comparisons to NINDS trialComparisons to NINDS trial

Sites not from selected INSTINCT Sites not from selected INSTINCT populationpopulation

Scott PA, Frederiksen SM, Caveney AF, … Sandretto AM, Barsan WG, Silbergleit R. Safety of Community Use of tPA. Presented 2007 ASA ISC; San Francisco, CA; Feb 7, 2007.

Outcome MeasuresOutcome Measures

Primary Outcome MeasurePrimary Outcome Measure– Mortality rate at one year as measured by Mortality rate at one year as measured by

the National Death Indexthe National Death Index

Secondary Outcome MeasuresSecondary Outcome Measures– Rate of symptomatic ICH within 10 days Rate of symptomatic ICH within 10 days

of treatmentof treatment– Rate of total intracerebral hemorrhageRate of total intracerebral hemorrhage– rt-PA treatment guideline violationsrt-PA treatment guideline violations– Temporal performance measuresTemporal performance measures

Results: EP ExperienceResults: EP Experience

273273 patients treated by patients treated by 9595 individual individual EPsEPs

Median number of treatments per Median number of treatments per physician was 2, the mode was 1physician was 2, the mode was 1

Results: Patient CharacteristicsResults: Patient Characteristics

Similar to NINDSSimilar to NINDS– Mean age 68Mean age 68– 45% female45% female– DM, HTN, strokeDM, HTN, stroke

Higher proportion of Higher proportion of patients with disability patients with disability prior to strokeprior to stroke

Median and mean Median and mean initial NIHSS = 13initial NIHSS = 13

Distribution of NIHSS

-10% -5% 0% 5% 10%

1

5

9

13

17

21

25

29

33

37

NIHS

S Sc

ore

Percent of patients

NINDS SCUT

Results: Treatment TimesResults: Treatment Times

Mean onset-to-tx time Mean onset-to-tx time = 154 min= 154 min

Median = 160 minMedian = 160 min

Very similar to NINDS Very similar to NINDS 90 – 180 min group90 – 180 min group

Distribution of time from stroke onset to treatment

-20% -10% 0% 10% 20%

0

90

180

270

time

to tr

eatm

ent (

ten

min

ute

epoc

hs)

Percent of patients

NINDS SCUT

This 90 minute bar extends to 41.5%

Results: ICHResults: ICH

Rate of ANY ICH Rate of ANY ICH within 36h of tx: 9.9% within 36h of tx: 9.9% – RR 0.94, 95% CI 0.58 – 1.51 RR 0.94, 95% CI 0.58 – 1.51

to NINDS tPAto NINDS tPA

Rate of Symptomatic Rate of Symptomatic ICH by CT criteria (PH-ICH by CT criteria (PH-2): 6.6% 2): 6.6% – RR 1.03, 95% CI 0.56 -1.9 to RR 1.03, 95% CI 0.56 -1.9 to

NINDS tPANINDS tPA

Symptomatic ICH within 36 hours of treatment

0%

1%

2%

3%

4%

5%

6%

7%

0 5 10 15 20 25 30 35 40

time from treatment (hours)

perc

ent o

f pat

ient

s

SCUT

NINDS tPA

NINDS placebo

Results: 1-Year MortalityResults: 1-Year Mortality

27.8%; consistent 27.8%; consistent with NINDS tx and with NINDS tx and placeboplacebo

One year survival

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 28 56 84 112 140 168 196 224 252 280 308 336 364

days after treatment

% s

urvi

val

SCUT

NINDS tPA

NINDS placebo

Results: Treatment Guideline ViolationsResults: Treatment Guideline Violations

ED violations: 71 / 273 (26%)ED violations: 71 / 273 (26%)– 61% time (median 15 min over 180 min)61% time (median 15 min over 180 min)– 11% hypertension11% hypertension

Post-admission violations (24h): 25%Post-admission violations (24h): 25%– 36% hypertension36% hypertension– 39% anti-platelet agents early39% anti-platelet agents early– 25% anticoagulant use early25% anticoagulant use early

modified Rankin scoren

020

015

026

127

127

131

215

230

230

314

323

329

438

453

490

531

524

582

69

620

624

0% 20% 40% 60% 80% 100%

NINDS tPA*

SCUT tPA

NINDS placebo

Results: Neurologic Recovery (at discharge; mean 8 days)

Importance to INSTINCTImportance to INSTINCT

Extensive evidence regarding safety Extensive evidence regarding safety of tPA use outside acute stroke teamsof tPA use outside acute stroke teams

Educational methods in INSTINCT Educational methods in INSTINCT originated and enhanced from those originated and enhanced from those at preliminary sitesat preliminary sites

Reinforces probability of success of Reinforces probability of success of studystudy

Results from local treatmentResults from local treatment

Customize case study for local siteCustomize case study for local site

The ImpactThe Impact

(T.E. Dec 2003, 37 yo female RN)

INSTINCT HospitalsINSTINCT Hospitals

Trial SpecificsTrial Specifics

Multi-center, randomized, controlled trial Multi-center, randomized, controlled trial testing a multi-level, systems-based, testing a multi-level, systems-based, educational intervention educational intervention Intervention based on adult education Intervention based on adult education and behavior change theoryand behavior change theoryTailored to local needs by identifying Tailored to local needs by identifying local barrierslocal barriersBased on clinical pilot dataBased on clinical pilot data

Feedback MechanismsFeedback Mechanisms

Targeted messagingTargeted messaging– ContentContent– ProcessProcess

Critical Incident DefusingCritical Incident Defusing

On-site visitsOn-site visits– Mock codesMock codes

Telephone access to Brain Injury GroupTelephone access to Brain Injury Group

Lessons LearnedLessons Learned

Protocol, Protocol, ProtocolProtocol, Protocol, ProtocolMultiple stakeholder “buy-in”Multiple stakeholder “buy-in”Backup for tough casesBackup for tough casesMonitor treatments and outcomes Monitor treatments and outcomes FeedbackFeedbackAddress system barriersAddress system barriers

Okay, I have lectured for 3 Okay, I have lectured for 3 hourshours

Here is a clinical scenarioHere is a clinical scenario

And - all of a sudden you And - all of a sudden you awaken!awaken!

You have a dense left You have a dense left hemiparesishemiparesis

Your NIHSS is 11Your NIHSS is 11

You don’t get complicated You don’t get complicated migraines and you are well migraines and you are well adjusted!adjusted!

WHAT ARE WE GOING TO WHAT ARE WE GOING TO DO?DO?

Summary PointsSummary Points

NINDS rt-PA trial only trial to show NINDS rt-PA trial only trial to show improvement and is only FDA approved improvement and is only FDA approved pharmacotherapypharmacotherapy

Other acute IV trials are heterogeneousOther acute IV trials are heterogeneous

Community use of tPA with protocols is safeCommunity use of tPA with protocols is safe

Feedback mechanisms designed to Feedback mechanisms designed to enhance proper use of tPA in strokeenhance proper use of tPA in stroke

The Current National Stroke RealityThe Current National Stroke Reality

A Vision of the Future…A Vision of the Future…