Maximizing IV Thrombolytic Therapy in Acute Ischemic Stroke

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Maximizing IV Thrombolytic Therapy in Acute
Ischemic Stroke

• Kamakshi Lakshminarayan, MD PhD
• Assistant Professor
• Neurology Epidemiology
• University of Minnesota
• Great Lakes Regional Stroke Network October 8,
  2009

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Disclosures

• K Lakshminarayan receives research grant
  support from the NIH and CDC
• No off-label or investigational drugs/devices
  will be discussed

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Classes of Recommendations

• Class I Evidence for and/or general agreement
  that the treatment is useful and effective 
•    
• Class II Conflicting evidence and/or a
  divergence of opinion about usefulness/efficacy
  of a treatment        
• IIa Weight of evidence or opinion is in favor of
  the treatment.       
•  IIb Usefulness is less well established by
  evidence or opinion.   
•  Class III Evidence and/or general agreement
  that the treatment is not useful and in some
  cases may be harmful

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Levels of Evidence

• Level A Data derived from multiple RCT  
• Level B Data derived from single RCT or
  nonrandomized studies    
• Level C Consensus opinion of experts

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Maximizing Opportunities for rtPA delivery

• Expanded time window for treatment
• Management of rapidly improving or mild strokes
• IV thrombolysis in the elderly

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An Expanded Time Window is Needed
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Intravenous Thrombolytic Therapy The Minnesota
Stroke Registry Quarter 2, 2008 to Quarter 2,
2009
Time and date last well known documented
Came within 2 hours of symptom onset
Received IV tPA
Documented contraindications
The thrombolytic therapy performance measure
calculation is the numerator, indicated by the
box labeled Numerator, divided by the
denominator, the sum of the boxes indicated by
the ().
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An Expanded Time Window is Needed!

• Minnesota Stroke Registry Less than 1/3 of
  patients with documented times come within 2
  hours of symptom onset

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ECASS-3 Trial

• Multi-center prospective randomized controlled
  trial
• rtPA n418
• Placebo n403
• Treat within 3-4.5 hours of symptom onset
• Median time to treatment 4 hours
• rtPA dosing regimen the same

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Similarities to NINDS tPA Trial

• Similar inclusion and exclusion criteria But
  additional exclusions
• Age over 80 years
• NIHSS gt 25
• Any oral anticoagulant use
• Previous stroke DM

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Ancillary Care Post Thrombolysis

• Similar to NINDS trial except
• DVT prophylaxis with parenteral anticoagulants
  allowed

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Outcomes of ECASS-3 NINDS Trials - Disability

• mRS of 0,1 at 3 months
• ECASS-3
• 52 (rtPA) vs. 45 (control)
• OR 1.34 (1.02-1.74) P 0.04
• NINDS
• 39 (rtPA) vs. 26 (control)
• OR 1.7 (1.1-2.6) P 0.019

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Outcomes of ECASS-3 versus NINDS Trials - ICH

• Symptomatic ICH (NINDS definition)
• ECASS-3
• 7.9 vs. 3.5 (placebo) P 0.006
• NINDS
• 6.4 vs. 0.6 (placebo) P lt 0.001

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Outcomes of ECASS-3 versus NINDS Trials -
Mortality

• Death at 3 months
• ECASS-3
• 32 vs. 34 (placebo) P 0.68
• NINDS
• 17 vs. 24 (placebo) P 0.3

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AHA Guideline Recommendations

• IV rtPA is recommended for selected patients
  who may be treated within 3 hours of symptom
  onset of ischemic stroke
• Class I, Level A

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AHA Guideline Recommendations

• IV rtPA should be administered for those who
  can be treated 3-4.5 hours after symptom onset
  with similar exclusionary criteria as for within
  3 hour window age gt 80, oral anticoagulant use,
  NIHSS gt 25, history of stroke DM
• Class I, Level B
• In those with above additional exclusionary
  criteria utility is not well established, needs
  further study
• Class IIb, Level C

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Diffusion of Trial Evidence into Practice
Minnesota Stroke Registry

• September 25, 2008 ECASS-3 published NEJM
• May 28, 2009 AHA guideline recommendations on
  the expanded window online

refers to all IV tPA cases as denominator
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Rapidly Improving or Mild Strokes
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Exclusions to IV rtPA

• NINDS Trial
• Patients excluded if rapidly improving or minor
  symptoms (RIMS)
• AHA Guidelines
• Neurological signs should not be clearing
  spontaneously
• Neurological signs should not be minor isolated

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How Often Does This Occur?

• Minnesota Stroke Registry 2008 data
• 315 IS patients came within 2 hours
• 76 (24) did not receive IV tPA due to RIMS
• Case series
• 876 IS patients with 24 hours
• 162 (19) did not receive IV rtPA due to RIMS
  (Nedeltchev et al. Stroke 2007)
• Calgary study
• 314 IS patients came within 3 hours
• 98 (31) did not receive IV rtPA due to RIMS
  Barber et al. Neurology 2001

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What happens to them when they are not treated
with IV rtPA?
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Discharge Outcomes

• Minnesota Stroke Registry
• 76 patients no rtPA due to RIMS
• Prior to this stroke 69 (91) ambulated
  independently
• At d/c 38 (50) ambulated independently!
• Case Series
• 41 patients not treated due to RIMS
• 11/41 (27) died or not discharged home due to
  worsening (6) or persistent mild deficit (5)
  Smith et al. Stroke 2005

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Discharge Outcomes

• Calgary Study
• 98 patients did not receive IV rtPA due to RIMS
• 32 of these remained dependent at discharge or
  died during hospitalization Barber et al.
  Neurology 2001

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Outcomes at 3 Months

• Case series 162 patients with RIMS
• Favorable 75 (122 patients, mRS 0,1)
• Unfavorable 25 (40 patients, mRS gt 1)
• mRS 2 16
• mRS 3, 4 7
• Dead 1
• 2 recurrent strokes
• No difference in outcomes between mild and
  rapidly improving Nedeltchev Stroke 2007

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What if they are treated with IV rtPA?
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Treated with IV rtPA

• Case Series
• 19 patients with rapid improvement were treated
  at mean NIHSS of 5 range 1-6
• 3 month outcomes
• one patient died due to recurrent stroke from AF
• NIHSS at 3 months in remaining was 0, mRS range
  0-1 Baumann et al. Stroke 2006

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What should we do about them?
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Management of Rapidly Improving or Minor Strokes

• RIMS that have poor outcomes are a
  heterogeneous group
• TIA subsequently have strokes during
  hospitalization
• Mild strokes worsen during hospitalization
• Seemingly mild strokes with low NIHSS but have
  gait ataxia or cognitive deficit not captured on
  the NIHSS Smith et al. Stroke 2005

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Management

• TIA
• If clear resolution of symptoms restart the clock
  if symptoms recur unless there are imaging
  correlates of tissue damage (DWI)
• Neuro-checks every 30-60 minutes for 1st 12 hours
• Mild strokes do not restart clock
• Need clinical trials to guide treatment decisions
  since this population were not included in the
  original trials

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Elderly Patients

• Limited data on thrombolysis in the elderly
• NINDS trial included a few patients over 80 years
• ECASS-3 did not
• IST-3 does and is still recruiting till 2011
• Cochrane meta-analysis 42 patients gt 80 years in
  thrombolysis RCT (not including IST-3)
• Anecdotal reports on nonagenarians and
  centenarians being treated

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Thrombolysis in the Elderly

• Main worry is the risk of ICH
• Systematic review of 6 cohort studies found
  similar likelihood of symptomatic ICH OR 1.22
  (95 CI 0.77-1.94)
• Three times higher odds of dying after
  thrombolysis for those gt 80
• Similar in those without thrombolysis three
  times higher odds of dying

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The Minnesota Experience

• Minnesota Stroke Registry Year 2008
• 33 patients 90 or older came within 2 hours of
  symptom onset
• 7 received IV rtPA, 2 died soon after
• 26 did not receive IV rtPA, 4 died soon after

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Summary

• ECASS-3 extends the thrombolysis time window
  beyond 3 hours with restrictions class I Level
  A
• Clinical trials are needed to evaluate
  thrombolysis in those with mild deficits or
  rapidly improving strokes
• Paucity of data on elderly await IST-3.
  Community practice is to discuss with family and
  treat

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Questions?

• Thank you!