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

              E. Bradshaw Bunney, MD
E. Bradshaw Bunney, MD
          Associate Professor

    Department of Emergency Medicine
      University of Illinois at Chicago

       University of Illinois Hospital
Our Lady of the Resurrection Medical Center
                         E. Bradshaw Bunney, MD
             Disclosures
• AstraZeneca, advisory board
• Genentech, speakers bureau

• ACEP Scientific Review Committee
• Executive Board, Foundation for Education and
  Research in Neurologic Emergencies



                            E. Bradshaw Bunney, MD
             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.



                          E. Bradshaw Bunney, MD
                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

                        E. Bradshaw Bunney, MD
                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


                        E. Bradshaw Bunney, MD
                Case
• Glucose = 97
• Not pregnant
• CBC, electrolytes, coagulation all
  normal
• CT head = normal



                        E. Bradshaw Bunney, MD
                Case
• Is this a stroke? Seizure? Hysteria?
  Drugs?
• What do you do next?
• Thrombolysis?




                        E. Bradshaw Bunney, MD
                 NINDS
• 11 years ago
• 624 subjects
• 2 arms
 – 24 hour follow up = no improvement
 – 30 day follow up = improvement



                        E. Bradshaw Bunney, MD
     NINDS Trial Results
  Percentage with favorable outcome
                          t-PA Placebo
No. of patients: 312       157         145
Modified Rankin Scale     40%         28%
Glasgow Outcome Scale     43%         32%
NIHSS                     34%         20%
Symptomatic ICH (within   6.4%        0.6%
36 hr)
Death (by 90 days)        17%          21%
                      E. Bradshaw Bunney, MD
          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

                               E. Bradshaw Bunney, MD
    Phase IV t-PA Trials
• Can the NINDS trial results be
  replicated?
• What happens in “the real world”?
• Do protocol violations make a
  difference?



                       E. Bradshaw Bunney, MD
                  Phase IV t-PA trials
 Author   Eligible    Patients    Mean     Median   Favorable   % ICH         %          %
          patients   receiving   time to   NIHSS    outcome               Symptom     Protocol
                       tPA(%)      Rx      score                           atic ICH   deviation
 NINDS                 312                   14      31-54%     10.9%         6.4%
 Chiu      1035      30(2.9%)    2’37”       14       63%        10%          6.6%
 Tanne                 189        >2’      11-15                  9%          5.8%      30%
 Wang       900      57(6.3%)    2’28”       15      44-54%       9%           5%        9%
Buchan     1540      68(4.4%)                15       95%        31%           9%       16%
 Albers                389       2’44”       13      35-43%     11.5%         3.3%      33%
Katzan     3948      70(1.8%)                12                  22%          15.7%     50%
Chapman    2556      46(1.8%)    2’45”       14      30-48%       9%          2.2%      17%
 Grotta    1689      269(16%)    2’17”       14       33%                     4.5%      13%
Bravata                 63                   15                  17%           6%       67%
 Total    12,282     928(5.8%)   2’25”     10-15     33-95%      9.6%         5.2%    13-67%

                                                     E. Bradshaw Bunney, MD
Meta-analyses

        E. Bradshaw Bunney, MD
         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
                        E. Bradshaw Bunney, MD
           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



                          E. Bradshaw Bunney, MD
         Meta-analyses
• Hacke et al.
• 6 randomized trials
• Sooner thrombolytics given the greater
  the benefit
• Particularly when given within 90 min.
  of onset


                       E. Bradshaw Bunney, MD
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
                       E. Bradshaw Bunney, MD
Re-analysis

       E. Bradshaw Bunney, MD
        NINDS Re-analysis
• Does the protocol work?
• Do subgroup imbalances invalidate the
  entire trial?




                      E. Bradshaw Bunney, MD
       Baseline NIHSS Imbalance

NIHSS Score         0-5    6-10 11-15 16-20               > 20
        Placebo     16      83        66            70    77
No. of  (n=312)
patients t-Pa       42      67        65            73    63
         (n=310)

         Chi-square (4 DF) = 14.8; p = 0.005

                                 E. Bradshaw Bunney, MD
Favorable Outcome Related to Baseline
   NIHSS - Modified Rankin Scale
           100

            80

    Percent 60
                                                  t-PA
   Favorable
                                                  Placebo
   Outcome 40

            20

             0
                 0-5   6-10 11-15 16-20   >20
                       Baseline NIHSS


                                     E. Bradshaw Bunney, MD
Baseline NIHSS - Specific Odds Ratios
                 10
    Odds Ratio




                                  2.6                   2.1         2.5         2.1
                                              1.9
                  1      1.2




                 0.1
                       0-5     6-10       11-15     16-20        > 20        All
                                                                           Patients
                                        Baseline NIHSS Score

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
                                                      E. Bradshaw Bunney, MD
  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.
                   E. Bradshaw Bunney, MD
                        Symptom onset vs Cumulative %
Cumulative percentage




                              Time from symptom onset to treatment (minutes)
                                                             E. Bradshaw Bunney, MD
            NINDS ICH Analysis
           Risk Factors for ICH:
           • Baseline NIHSS > 20
           • Age > 70 years
           • Ischemic changes present on initial CT
           • Glucose > 300 mg/dl (16.7 mmol/L)

# of Risk # of patients treated    # Symptomatic ICHs             Percentage
Factors         with t-PA         (# of placebo patients              (%)
                 (n=310)                 with ICH)
   0               114                     2 (1)                     1.8
   1               144                     7 (1)                     4.9
  >1               52                        11                      21.2

                                         E. Bradshaw Bunney, MD
 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
                               E. Bradshaw Bunney, MD
 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%                       E. Bradshaw Bunney, MD
      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


                                E. Bradshaw Bunney, MD
   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


                              E. Bradshaw Bunney, MD
   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

                           E. Bradshaw Bunney, MD
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

                               E. Bradshaw Bunney, MD
         Documentation
• Just as important

• “The patient is NOT a candidate for t-PA
  because…”




                         E. Bradshaw Bunney, MD
                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



                        E. Bradshaw Bunney, MD
                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



                       E. Bradshaw Bunney, MD
               Case
• MRI at University = small infarct
• ECHO cardiogram = Patent foramen
  ovale, likely embolic stroke
• Outcome = normal except small vision
  loss.



                      E. Bradshaw Bunney, MD
            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


                           E. Bradshaw Bunney, MD
                           Questions?
                                 Brad Bunney
                               bbunney@uic.edu
                                 312-413-7484
                                www.ferne.org
Ferne_eusem_2006_bunney_3hour_100606_finalcd
9/13/2012 7:11 PM
                                               E. Bradshaw Bunney, MD

				
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