ferne/emra session: treating ischemic stroke patients using a 3 to 4.5 hour tpa window
DESCRIPTION
FERNE/EMRA Session: Treating Ischemic Stroke Patients Using a 3 to 4.5 Hour tPA Window. 2009 ACEP Scientific Assembly & EMRA Semi-Annual Meetings Boston, MA October 6, 2009. - PowerPoint PPT PresentationTRANSCRIPT
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E. Bradshaw Bunney, MD
FERNE/EMRA Session: FERNE/EMRA Session:
Treating Ischemic Stroke Treating Ischemic Stroke Patients Using a Patients Using a
3 to 4.5 Hour tPA Window3 to 4.5 Hour tPA Window
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E. Bradshaw Bunney, MD
2009 ACEP Scientific Assembly & EMRA Semi-Annual Meetings
Boston, MABoston, MA
October 6, 2009October 6, 2009
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E. Bradshaw Bunney, MD
E. Bradshaw BunneyE. Bradshaw Bunney, MD Assoc. Professor
Department of Emergency MedicineUniversity of Illinois at Chicago
Chicago, Illinois
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E. Bradshaw Bunney, MD
Attending PhysicianEmergency Medicine
University of Illinois HospitalSwedish American Belvidere Hospital
Chicago, IL
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E. Bradshaw Bunney, MD
DisclosuresDisclosures• FERNE Board Member
• FERNE grants by industry
• Participation on industry-sponsored advisory boards and as lecturer in programs supported by industry
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E. Bradshaw Bunney, MD
ObjectivesObjectives
• What does the ECASS 3 study tell us?
• How does the ECASS 3 data compare to other studies?
• What other data is available regarding treatment in the 3 - 4.5 hour window?
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E. Bradshaw Bunney, MD
Time to Treatment and tPA BenefitTime to Treatment and tPA BenefitmRS 0-1 at day 90
Adjusted odds ratio with 95 % confidence interval by stroke onset to treatment time (OTT)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Ad
j us t
e d o
dd
s ra
tio
Stroke onset to treatment time (OTT) [min]
60 90 120 150 180 210 240 270 300 330 360
< 3 h 3-4 h > 4 h
Lancet 2004, 363, 368-374
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E. Bradshaw Bunney, MD
ECASS 3ECASS 3
• Prospective, randomized, placebo controlled, study
• Is tPA efficacious in the treatment of ischemic stroke in the 3 – 4.5 hour window?
• Primary outcome = mRS 0 - 1 at 90 days• Study mandated by the European
Medicines Agency (EMEA), pharmaceutical approval agency
Hacke, NEJM 2008;359:1317-29
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E. Bradshaw Bunney, MD
ECASS 3 CriteriaECASS 3 Criteria
• Inclusion– 18 – 80 years old– Symptoms > 30 min.
• Exclusion– NIHSS > 25– Prior stroke and Diabetes– Oral anticoagulation use– Seizure at onset of symptoms– BP > 185/110 not easily controlled, no IV
drips
Hacke, NEJM 2008;359:1317-29
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E. Bradshaw Bunney, MD
ECASS 3 DataECASS 3 Data
• N = 821
• 43 tPA and 48 placebo excluded– Did not treat, age, CT criteria
• Median time to treat = 3:59
Hacke, NEJM 2008;359:1317-29
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E. Bradshaw Bunney, MD
ECASS 3 DataECASS 3 Data
• Differences between tPA and placebo groups– NIHSS 10.7 v. 11.6 p=0.003
– History of stroke 7.7 v. 14.1 p=0.03
Hacke, NEJM 2008;359:1317-29
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E. Bradshaw Bunney, MD
ECASS 3 DataECASS 3 Data
• Primary out come mRS 0-1
• tPA 219/418 (52.4%)
• Placebo 182/403 (45.2%)
• P = 0.04– OR 1.34 (CI 1.02 – 1.76)
– Absolute improvement 7.2%
Hacke, NEJM 2008;359:1317-29
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E. Bradshaw Bunney, MD
ECASS 3 DataECASS 3 Data
• Secondary outcomes– mRS
– Barthel Index
– NIHSS
– Glasgow Outcome Scale
• Global odds ratio 1.28
Hacke, NEJM 2008;359:1317-29
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E. Bradshaw Bunney, MD
Types of ICHTypes of ICH
• HI 1 = small petechiae along margin of infarct
• HI 2 = more confluent petechiae without mass effect
• PH 1 = parenchymal ICH• PH 2 = clot exceeding 30% of
infarct area with mass effect
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E. Bradshaw Bunney, MD
Symptomatic ICH DefinitionsSymptomatic ICH Definitions• ECASS 3: Any hemorrhage with
neurological deterioration, increase of 4 or more NIHSS, predominant cause of deterioration.
• ECASS 2: Same as ECASS 3 without causal requirement
• NINDS: Suspicion of hemorrhage or neuro deterioration, and finding hemorrhage not previously there on a subsequent CT.
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E. Bradshaw Bunney, MD
NINDS sICH Definition NINDS sICH Definition
Hacke, NEJM 2008;359:1317-29
tPA Placebo
NINDS 6.4% 0.6%
ECASS 3 7.9% 3.5%
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E. Bradshaw Bunney, MD
ECASS3 sICH Definition ECASS3 sICH Definition
Hacke, NEJM 2008;359:1317-29
tPA Placebo
NINDS N/A N/A
ECASS 3 2.4% 0.2%
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E. Bradshaw Bunney, MD
ECASS 3 ConclusionsECASS 3 Conclusions
• tPA significantly improved clinical outcomes in patients with acute ischemic stroke presenting between 3 – 4.5 hours.
• tPA is associated with increased sICH compared to placebo.
Hacke, NEJM 2008;359:1317-29
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E. Bradshaw Bunney, MD
ECASS 3 CriticismsECASS 3 Criticisms
• Fewer diabetics compared to NINDS– tPA 14.8% v. 22%, placebo 16.6% v.
20%
• Much lower mean NIHSS– tPA 10.7 v. 14, placebo 11.6 v. 14
• No history of prior stroke and diabetes allowed
Lyden, NEJM 2008;395:1393-95
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E. Bradshaw Bunney, MD
Meta-analysisMeta-analysis
• ECASS 1, ECASS 2, ECASS 3, ATLANTIS
• Patients in 3 – 4.5 hour window• Mean age 65• Mean NIHSS 2 – 3 points less in
ECASS 3• Mean onset to drug 4 hours• Diabetes similar among ECASS’s
16%, ATLANTIS 21%
Lansberg, Stroke 2009;40:2438-41
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E. Bradshaw Bunney, MD
Meta-analysisMeta-analysis
• mRS 0 – 1, OR 1.31• Global outcome
– mRS– NIHSS– Barthel Index– OR 1.31
• Mortality same, OR 1.04
Lansberg, Stroke 2009;40:2438-41
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E. Bradshaw Bunney, MD
SITS-ISTR 3 – 4.5 hourSITS-ISTR 3 – 4.5 hour
• European data base
• Observational study
• Not randomized controlled trial
• Compare 664 treated 3 – 4.5 h with 11865 treated within 3 h.
Wahlgren, Lancet 2008;372:1303-09
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E. Bradshaw Bunney, MD
SITS-ISTR 3 – 4.5 hourSITS-ISTR 3 – 4.5 hour
• Median 55 min. later 195 min. v. 140 min.– 60% before 200 min.
• 3 years younger 65 v. 68
• NIHSS lower 11 v. 12
Wahlgren, Lancet 2008;372:1303-09
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E. Bradshaw Bunney, MD
SITS-ISTR 3 – 4.5 hourSITS-ISTR 3 – 4.5 hour
• Independence 58% 3-4.5 v. 56%
• sICH 2.2% v. 1.6%
• Mortality 12.7% v. 12.2%
Wahlgren, Lancet 2008;372:1303-09
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E. Bradshaw Bunney, MD
Number Needed to TreatNumber Needed to Treat
• Benefit: To improve by 1 or more mRS– 0 – 3 hours 32.3/100 treated– 3 - 4.5 hours 16.4/100 treated
• Harm: To worsen by 1 or more mRS– 0 – 3 hours 3.3/100 treated– 3 – 4.5 hours 2.7/100 treated
Saver, Stroke 2009;40:2433-37
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E. Bradshaw Bunney, MD
Number Needed to TreatNumber Needed to Treat
• NNT to benefit by 1 or more mRS is 6
• NNT to harm by 1 or more mRS is 37
• From ECASS 3 NNT to benefit to mRS of 0 – 1 (best outcome) is 14
Saver, Stroke 2009;40:2433-37
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E. Bradshaw Bunney, MD
Who should be treated in 3 – 4.5 h?Who should be treated in 3 – 4.5 h?
• Relatively young, 65 +/- 10years old
• Less severe strokes, NIHSS < 11 +/- 6, median in tPA group of ECASS 3 was 9
• Diabetes??
• No one with diabetes and prior stroke
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E. Bradshaw Bunney, MD
ConclusionsConclusions
• Meta-analysis and observational studies appear to support the use of tPA beyond the 3 hour window
• Extension of the treatment window to 4.5 hours is being endorsed by many
• Institutions must modify their protocols to adjust for the population treated in the ECASS 3 trial in the 3 – 4.5 hour window