Stroke Care within the 3 Hour IV tPA Window: Why IV tPA, or What Alternatives

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Stroke Care within the 3 Hour IV tPA WindowWhy
IV tPA, or What Alternatives?
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E. Bradshaw Bunney, MDAssociate
ProfessorDepartment of Emergency
MedicineUniversity of Illinois at
ChicagoUniversity of Illinois HospitalOur Lady
of the Resurrection Medical Center
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Disclosures

• AstraZeneca, advisory board
• Genentech, speakers bureau
• ACEP Scientific Review Committee
• Executive Board, Foundation for Education and
  Research in Neurologic Emergencies

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Objectives

• Review the evidence for the use of thrombolytics
  in ischemic stroke
• Discuss the Phase IV and re-analysis results
• Review the concerns about the use of
  thrombolytics
• Discuss other alternatives to thrombolytics.

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Case

• 19 yo female collapsed a work on Super Bowl
  Sunday 2006
• EMS found her not moving her right side, aphasic,
  eyes deviated to the left
• Onset time 20 minutes prior to EMS arrival
• BP 120/62, HR 84, RR 14

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Case

• In ED Friend confirms onset time
• Friend states no PMHx, no drug or alcohol use
• PE - R arm 0/5 strength, R leg 3/5, aphasic,
  eyes deviated to L
• No family available

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Case

• Glucose 97
• Not pregnant
• CBC, electrolytes, coagulation all normal
• CT head normal

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Case

• Is this a stroke? Seizure? Hysteria? Drugs?
• What do you do next?
• Thrombolysis?

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NINDS

• 11 years ago
• 624 subjects
• 2 arms
• 24 hour follow up no improvement
• 30 day follow up improvement

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NINDS Trial Results Percentage with favorable
outcome
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IV Thrombolysis

• 14 absolute increase for the best clinical
  outcomes as measured by an NIHSS of 0-1.
• Benefit Need to treat 8 patients with t-PA in
  order to have one additional patient with this
  best outcome.
• 6 absolute increase in the number of symptomatic
  ICH.
• Harm Will have one symptomatic ICH for every 16
  patients treated with t-PA.
• 2 patients will have a minimal or no deficit for
  everyone patient with a symptomatic ICH

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Phase IV t-PA Trials

• Can the NINDS trial results be replicated?
• What happens in the real world?
• Do protocol violations make a difference?

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Phase IV t-PA trials
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Meta-analyses
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Meta-analyses

• Wardlaw et al.
• Net benefit despite hazards
• For 1000 treated up to 6hrs, 55 improve, 20 die
• Heterogeneity and wide CI make results unreliable
• Additional trial data required

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Meta-analyses

• Graham et al., 15 published reports
• ICH rate 5.2, total death rate 13.4
• All better than NINDS
• Lysis can be used safely across wide variety of
  practice settings

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Meta-analyses

• Hacke et al.
• 6 randomized trials
• Sooner thrombolytics given the greater the
  benefit
• Particularly when given within 90 min. of onset

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CONTROVERSY Meta-analysis

• Hoffman and Cooper
• Pooled data can not replace new or confirmatory
  data
• Meta-analyses did not include streptokinase
  trials which were negative
• No reason to exclude streptokinase

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Re-analysis
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NINDS Re-analysis

• Does the protocol work?
• Do subgroup imbalances invalidate the entire
  trial?

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Baseline NIHSS Imbalance
Chi-square (4 DF) 14.8 p 0.005
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Favorable Outcome Related to Baseline NIHSS -
Modified Rankin Scale
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Baseline NIHSS - Specific Odds Ratios
Test for equal ORs Chi-square (4 DF) 1.70 p
0.79 Insufficient evidence was found to a declare
a difference in treatment effects (ORs) across
the five strata
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OTT Analysis Report

• Review Committee had concerns about analyzing OTT
  as a continuous variable
• Uncertainty about the exact time of stroke onset.
• OTT distribution was nonlinear with 25 of all
  the patients having OTT values of either 89 or 90
  minutes.

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Symptom onset vs Cumulative
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NINDS ICH Analysis

• Risk Factors for ICH
• Baseline NIHSS gt 20
• Age gt 70 years
• Ischemic changes present on initial CT
• Glucose gt 300 mg/dl (16.7 mmol/L)

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Re-analysis Conclusions

• The independent reanalysis of the NINDS t-PA
  clinical trial confirms the results from the
  initial NEJM publication
• Support the use of t-PA in stroke patients within
  three hours of symptom onset
• Number needed to treat calculation based on this
  reanalysis confirms that approximately 8-10
  patients need to be treated with t-PA in order to
  cause one extra patient to have the best clinical
  outcome.
• 2 patients will improve for every one that
  develops a symptomatic ICH

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EM Physicians and Lysis

• Brown et al.
• 1,105 of 2600 ACEP members responded
• 40 not likely to use thrombolytics
• 65 risk of ICH
• 23 perceived lack of benefit
• 12 both
• Upper limit ICH rate 3.4
• Lowest acceptable relative improvement 40

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If not t-PA, then what?

• Most therapies studied outside the 3 hour window
• Intra-arterial thrombolysis
• Mechanical clot removers
• Neuroprotectants
• Hypothermia
• Due to time needed to complete the procedure
• may not be true for neuroprotectants

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If not t-PA, then what?

• When uncertain about the diagnosis other tests
  may be needed
• CTA
• MRI
• Angiography
• This will frequently cause the 3 hour window to
  expire, but allows for other interventions
• Triple play stent, mechanical clot removal,
  intra-arterial thrombolytics

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If not t-PA, then what?

• Newer therapies have small trials compared to IV
  t-PA
• IV t-PA has been shown to be effective
• Stroke neurologists prefer IV t-PA and then a
  second look with further diagnostic tests
• MRI
• CTA
• Do not wait

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Informed Consent Documentation

• With t-PA, there is a 30 greater chance of a
  good outcome at 3 months
• With t-PA use, there is 10x greater risk of a
  symptomatic ICH (severe bleeding stroke)
• Mortality rates at 3 months are the same
  regardless of whether t-PA is used
• 2 patients will have a minimal or no deficit for
  every one patient with a symptomatic ICH

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Documentation

• Just as important
• The patient is NOT a candidate for t-PA because

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Case

• Small hospital, no neurologist interested in
  seeing the patient
• Called 2 Universities before finding one to
  accept the patient
• Family arrived, patient not improving

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Case

• Stroke neurologist Give IV t-PA
• t-PA given at 2 hours 15 minutes from onset
• R arm movement and aphasia improving prior to
  transfer

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Case

• MRI at University small infarct
• ECHO cardiogram Patent foramen ovale, likely
  embolic stroke
• Outcome normal except small vision loss.

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Conclusion

• Data supports the use of IV t-PA when the NINDS
  protocol is strictly followed
• Develop a protocol that allows patients to have
  the greatest chance of receiving therapy as
  quickly as possible
• Sooner is better
• Document well on all patients, t-PA or not

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Questions?Brad Bunneybbunney_at_uic.edu312-413-74
84www.ferne.org
Ferne_eusem_2006_bunney_3hour_100606_finalcd 8/26/
2009 418 PM