tPA in Stroke Whats All the Fuss

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					                            tPA in Stroke: What's All the Fuss?
                                  Joseph R. Lex, MD, FACEP, FAAEM
                                Associate Professor of Emergency medicine
                                   Department of Emergency Medicine
                                  Temple University School of Medicine
                                          Philadelphia, PA USA
 Review the results of the NINDS clinical trials
 Discuss Phase Four clinical data on clinical use of tPA for stroke
 Describe an appropriate informed consent for use of tPA in stroke

1995: ECASS I
    620 patients
    Interval from onset window: 6 hours
    tPA dose: 1.1 mg/kg
    No difference between placebo and treated
 Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne
 MH, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric
 stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995 Oct 4;274(13):1017-25.

1998: ECASS II
    800 patients
    Interval from onset window: 6 hours
    tPA dose: 0.9 mg/kg
    Mortality: no change
    2 – 5 x rate of ICH
 Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G,
 Schneider D, Diez-Tejedor E, Trouillas P. Randomised double-blind placebo-controlled trial of thrombolytic
 therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute
 Stroke Study Investigators. Lancet. 1998 Oct 17;352(9136):1245-51.

1999: ATLANTIS (post-NINDS)
    547 patients
    Interval from onset window: 3 – 5 hours
    tPA dose: 0.9 mg/kg
    No difference between placebo and treated
 Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type
 plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study:
 a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke.
 JAMA. 1999 Dec 1;282(21):2019-26.

1995: NINDS
    312 patients
    Interval from onset window: 3 hours
    tPA dose: 0.9 mg/kg

  Joe Lex, MD, FACEP, FAAEM                        Temple University School of Medicine, Philadelphia, PA
IV Thrombolysis: Up Side
Rankin:         12% absolute benefit
Glasgow:        11% absolute benefit
NIHSS:          14% absolute benefit
Conclusion: treat 7 – 8 patients with t-PA to have one additional patient with better outcome

IV Thrombolysis: Down Side
6% absolute increase in number of symptomatic intracranial hemorrhages
Conclusion: treat 16 patients with tPA to have one additional symptomatic intracranial hemorrhage

IV Thrombolysis: Summary
So if you treat 100 patients who meet t-PA criteria…
…12 will have an absolute benefit, but…
…6 will have symptomatic intracranial hemorrhage
Two patients will have minimal or no deficit for every one patient with symptomatic intracranial

NINDS: Design Issues
Patients were excluded if…
…blood pressure > 185/110 mm Hg
…required “aggressive treatment” of blood pressure
…anti-coagulated within 48 hours
…anti-platelet treatment within 24 hours

 [No authors listed] Tissue plasminogen activator for acute ischemic stroke. The National Institute of
 Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995 Dec 14;333(24):1581-7.

       August 2000: American Heart Association upgraded recommendation of tPA for stroke from
        optional (Class IIB) to definitely recommended (Class IA)
       2005: Joint Commission on Accreditation of Healthcare Organizations began certifying primary
        stroke centers
       Medicare created DRG 559: “acute ischemic stroke with use of thrombolytic agent” – pays
        US$6000 more than DRG 014

NINDS Baseline Imbalance
Larger number of people with lowest NIHSS triaged to treatment group, larger number with highest
NIHSS triaged to placebo group.
So if you treat 100 patients who meet t-PA criteria…
…8 will have an absolute benefit, but…
…6 will have symptomatic intracranial hemorrhage
 Wardlaw JM, Lindley RI, Lewis S. Thrombolysis for acute ischemic stroke: still a treatment for the few by the
 few. West J Med. 2002 May;176(3):198-9.

NINDS in Clinical Practice
    Must consider tPA, but patient selection                       Need adequate severity, but not too
      very difficult                                                 severe
    Must maximize risk/benefit ratio                               <2% of stroke patients meet criteria
    Must avoid hemorrhage, if possible

  Joe Lex, MD, FACEP, FAAEM                         Temple University School of Medicine, Philadelphia, PA
SITS MOST: Lancet 2007
    Observational study                                           trials
    6500 patients                                                “Systematically excluded everyone with
    NIHSS 24 or less (bad EXCLUDED)                               protocol violation”
    Prior stroke EXCLUDED                                        Conclusion: “community-based tPA as
    NIHSS score in one week in 80%                                safe and effective as controlled trials”
    Mortality same as randomized trials
    Morbidity comparable to randomized

 Wahlgren N, Ahmed N, Dávalos A, Ford GA, Grond M, Hacke W, Hennerici MG, Kaste M, Kuelkens S, Larrue
 V, Lees KR, Roine RO, Soinne L, Toni D, Vanhooren G; SITS-MOST investigators. Thrombolysis with
 alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study
 (SITS-MOST): an observational study. Lancet. 2007 Jan 27;369(9558):275-82.

   821
     acute     Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig
     ische     T, Schneider D, von Kummer R, Wahlgren N, Toni D; ECASS Investigators. Thrombolysis with alteplase 3 to
     mic       4.5 hours after acute ischemic stroke. N Engl J Med. 2008 Sep 25;359(13):1317-29.
     strok                                                      NINDS never duplicated: “unethical to
     e                                                            do so”
   NIHSS 24 or less                                            NINDS better than earlier studies
   Window extended to 4.5 hours                                  because of 3 hour window
   Treated group younger, lower stroke                         Post-NINDS ATLANTIS: 3-5 hours,
     score, fewer prior strokes                                   stopped  increased mortality
   Modified Rankin 7% better                                   ECASS-III 2nd (of 10) to be positive
   Symptomatic ICH: 2.5% vs. 0.2%
   All ICH: 27.0% vs 17.6%
   90 day mortality: same

Cochrane Database
     Randomized trials of any thrombolytic agent compared with control in patients with definite
        ischemic stroke
     18 trials including 5727 patients
     Not all trials looked at each outcome
     Sixteen trials were double-blind
Lytic administered up to 6 hours after ischemic stroke significantly reduced proportion of patients
who were dead or dependent (modified Rankin 3 to 6) at 3 to 6 month follow-up (OR 0.84, 95% CI
0.75 to 0.95)
     Net benefit despite real hazards
     Heterogeneity and wide CI make results unreliable
     Additional trial data required

Standard of Care??
    <2% of community hospitals use tPA                           Lawsuits filed for failure to offer
       for acute stroke                                           Lawsuits filed for misdiagnosis
    Lawsuits filed for failure to use

  Joe Lex, MD, FACEP, FAAEM                       Temple University School of Medicine, Philadelphia, PA
       Lawsuits filed for complications of                      therapy / failure of informed consent

Inclusion Criteria
     Clinical diagnosis of ischemic stroke causing measurable neurological deficit.
     Administration of TPA can be initiated within 3 hours of onset of symptoms (or within 3 hours
        from the time patient was last seen normal).
     Age 18 years or older.
     A patient or family members who under-stand the potential risks and benefits.
Exclusion Criteria
     Stroke or head trauma in past 3 months.
     Symptoms suggestive of subarachnoid hemorrhage (even in the presence of a normal noncontrast
        CT brain).
     Any prior history of intracranial hemorrhage.
     Major surgery in past 14 days.
     Gastrointestinal or urinary tract hemorrhage in past 21 days.
     Myocardial infarction in past 3 months.
     Arterial puncture at a noncompressible site in past 7 days.
     Rapid improvement of stroke symptoms.
     Minor or isolated neurological signs.
     Seizure (if residual impairments are thought possibly to be the result of the post-ictal state).
     Presentation consistent with acute myocardial infarction or post-myocardial infarction
     Persistent hypertension (SBP>185 or DBP>110) or requiring aggressive therapy to control blood
     Pregnancy
     Active bleeding or acute trauma.
     Platelet count < 100,000.
     Glucose < 50 or > 400.
     If patient is taking anticoagulation medications, INR > 1.7 or a PTT > normal range.
     CT evidence of hemorrhage.

Informed Consent
Why should we? IV tPA for acute ischemic stroke is a Class 1 recommendation by the American Heart
       What Do We Tell the Patient?
        “If we do nothing, there is a 40% chance you’ll have good recovery.”
        “If we give you tPA, there is a 52% chance you will have good recovery after 3 months.”
        “That means there is a one in eight chance that the drug will help.”
        “There is no evidence that tPA will make any difference before 3 months, so we won’t know
            right away if it’s working.”
        “If we use tPA, there is a one in sixteen chance that you will develop bleeding in your brain.”
        Explain to Patient / Family
        “Despite this increase in brain bleeding, your risk of being dead at 3 months is about the same
            with or without tPA.”

  Joe Lex, MD, FACEP, FAAEM                       Temple University School of Medicine, Philadelphia, PA
What Do We Chart??
Diagnosing Stroke: “The patient has symptoms that are fixed and are consistent with an acute ischemic
Neurological Exam: Document a systematic neurologic exam, one that could be used to develop an
approximate NIHSS, i.e. “The approximate NIHSS was 12-18, in the range that suggests that IV tPA may
be of benefit as was the case in the NINDS clinical trial.”
Onset Time: “The ischemic stroke onset time has been confirmed (in the following way), suggesting the
three hour window for IV tPA has not expired.”
CT Interpretation: “The CT has been reviewed and has been cleared by the radiologist who is aware of the
potential use of IV tPA.”
Blood Pressure: “The blood pressure was stabilized without extraordinary intervention and was
consistently less than 185/110 mmHg, allowing for safe IV tPA use.”
Informed Consent: “The following were discussed with the patient and family:”
     With tPA, there is a 30% greater chance of good outcome at 3 months
     With tPA use, there is a 10 time greater risk of symptomatic intracranial hemorrhage (brain bleed)
     Mortality rates at 3 months are the same regardless of tPA use, because stroke is a bad disease
     About two patients will improve for every one that develops a symptomatic ICH
     “The individuals who were part of and consented to the decision to use IV tPA were _________”
IV tPA Risk / Benefit: “The potential risks and benefits of the use of IV tPA were discussed with the
patient and/or family and these discussions lead to the decision to treat / not to treat) with IV tPA.”
     “The patient was not a candidate for IV tPA because the time of stroke onset was not
         conclusively determined.”
     “IV tPA was not indicated because of the presence of atrial fibrillation and an approximate
         NIHSS above 20.”
NINDS Protocol Followed: “I am aware of the specifics of the NINDS protocol regarding IV tPA use and
followed the protocol in order to maximize the likelihood of a good outcome for this patient.”
tPA Not Clinically Indicated: “IV tPA was not clinically indicated in this ischemic stroke patient
     Risk/benefit profile does not suggest improved outcome with IV tPA use
     Stroke onset time unclear
     Patient / family decline use
     Systems in place do not favor its use

       Patient selection difficult
       Histories unreliable: must have exact time of onset
       Old habits: tendency not to intervene
       First do no harm
       Data supports use of IV tPA when NINDS protocol strictly followed
       Outcomes similar to NINDS can be achieved
       Sooner may be better
       Narrow therapeutic window
       In practice, relatively few patients receive tPA treatment
       Thoroughly document decision-making well on all patients, tPA or not

  Joe Lex, MD, FACEP, FAAEM                      Temple University School of Medicine, Philadelphia, PA

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