Evidence in the ED

1
Evidence in the ED

• Byron Drumheller, MD
• Penn Emergency Medicine

2
Research Question

• Does intravenous tPA (Alteplase) when given only
  within 3 hours of the onset of symptoms for acute
  ischemic stroke according to current
  inclusion/exclusion criteria result in a greater
  percentage of patients with none or minimal
  disability as defined by a modified Rankin Scale
  0-1 at 90 days?

3

• Wardlaw et al. Thrombolysis for acute ischaemic
  stroke (Review). Cochrane Database of Systematic
  Reviews 2009, Issue 4.

4
Methods

• Systematic Review and Meta-Analysis
• Searched MEDLINE, EMBASE, etc and contacted
  investigators for randomized controlled trials of
  thrombolysis vs. placebo in acute ischemic stroke
• Combined data in intention-to-treat fashion
• Multiple outcomes - death, death or dependency,
  symptomatic intracranial hemorrhage
• Calculated odds ratios for thrombolysis vs.
  placebo

5
Results

• Identified 26 trials of any thrombolytic agent
  compared with placebo
• Outcome Death or dependency at end of follow up
• Modified Rankin Scale of 3-6
• Available from 21 trials
• Thrombolytic therapy, mostly administered up to
  6 hours after ischemic stroke, significantly
  reduced the proportion of patients who were dead
  or dependent (modified Rankin 3 to 6) at three to
  six months after stroke (odds ratio (OR) 0.81,
  95 confidence interval (CI) 0.73 to 0.90).

6
Results

• Individual trial details
• 4 intra-arterial, 22 intravenous
• 4 streptokinase, 11 recombinant tPA, 6 urokinase,
  3 desmoteplase
• Dose of rtPA
• 0.9 mg/kg 6
• 1.1 mg/kg 1
• 0.7 or 0.9 mg/kg 1
• 0.85 mg/kg - 1
• 0.6 mg/kg - 1

7
Results

• Individual trial details
• Time to onset
• lt3 hrs - 2
• lt4 hrs - 1
• 3-4.5 hrs - 1
• lt6 hrs - 13
• 3-6 hrs - 1
• 3-9 hrs 3

8
Results

• Individual trial details
• Stroke type
• All 7
• Cortical/Lacunar 2
• ICA/MCA/VBA by angio 6
• Thrombotic not embolic 3

9
Research Question

• Does intravenous tpa (Alteplase) when given only
  within 3 hours of the onset of symptoms for acute
  ischemic stroke according to current
  inclusion/exclusion criteria result in a greater
  percentage of patients with none or minimal
  disability as defined by a modified Rankin Scale
  0-1 at 90 days?

0
How many studies?
10
Results

• Intravenous alteplase 11 studies
• 0.9 mg/kg rtPA (0.1 mg/kg bolus, infusion) 6
  studies
• Enrolled ANY patients within 3 hours 3
• All patients within 3 hours NINDS
• Any patients within 3 hours ATLANTIS, ECASS II

11
Results

• Current inclusion/exclusion criteria
• NINDS
• Did not exclude patients with gt1/3 cerebral
  hemisphere hypodensity on initial CT
• Did not technically excluded patients with brain
  tumor/AVM, recent neurosurgery, active bleeding
• Included patients with mild symptoms NIHSS lt 4
• ECASS II
• Excluded agegt80, coma, hctlt25
• Different cutoff for minor stroke, recent seizure
  or TBI
• Did not exclude non-compressible arterial
  puncture

12
Results

• Inclusion/exclusion criteria
• ATLANTIS
• Excluded agegt80, coma, septic embolus,
  pericarditis, hct lt25
• Different time cutoffs for recent stroke, trauma,
  biopsy, GI/GU bleeding
• Did not exclude gt1/3 cerebral hemisphere
  hypodensity

13
Research Question

• To make any evidence-based conclusion from
  current data, one must make concessions
• 1. Include only studies using intravenous
  recombinant tPA at 0.9 mg/kg with 0.1 mg/kg bolus
  and 0.8 mg/kg infusion
• 2. Include data from any patients treated within
  3 hours of symptom onset
• 3. Allow for minor differences in
  inclusion/exclusion criteria

14
Intravenous tPA only

• Is there a difference between agents/doses?
• Wardlaw et al. Cochrane Database of Systemic
  Reviews 2013. - 20 randomized/quasi trials
• rtPA 0.9 mg/kg vs. other agents 2 trials
• Haley et al. Stroke 2010 - tPA v TNK (3 doses)
• Parsons et al. NEJM 2012 - tPA v TNK (2 doses)
• rtPA 0.9 mg/kg v. other dose 0 trials
• 5 trials of rtPA at some dose v other dose

15
Inclusion/Exclusion

• IST-3. Lancet 2012
• 3035 patients treated with rtPA within 6 hours
• Used uncertainty principle in which patients
  with clear indication for IV tPA were excluded
• 53 gt 80 years ago, BP up to 220/130

16
My Meta-Analysis
tPA Placebo
mRS 0-1 total mRS 0-1 total
ATLANTIS 11 18 15 33
NINDS 133 312 83 312
ECASS II 34 81 29 77
178 411 127 422
mRS 0-1 43.3 30.1
plt0.00008
17
HUPism

• While there is no current data that exactly
  answers the question, the available data
  specifically addressing whether IV tPA given only
  within 3 hours of the onset of symptoms for acute
  ischemic stroke according to current
  inclusion/exclusion criteria suggests that a
  greater percentage of patients treated with tPA
  will achieve no or minimal disability as defined
  by a modified Rankin Scale 0-1 at 90 days