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Evidence in the ED

Evidence in the ED. Byron Drumheller, MD Penn Emergency Medicine. Research Question.

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Evidence in the ED

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  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 • <3 hrs - 2 • <4 hrs - 1 • 3-4.5 hrs - 1 • <6 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 >1/3 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 < 4 • ECASS II • Excluded age>80, coma, hct<25 • Different cutoff for minor stroke, recent seizure or TBI • Did not exclude non-compressible arterial puncture

  12. Results • Inclusion/exclusion criteria • ATLANTIS • Excluded age>80, coma, septic embolus, pericarditis, hct <25 • Different time cutoffs for recent stroke, trauma, biopsy, GI/GU bleeding • Did not exclude >1/3 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% > 80 years ago, BP up to 220/130

  16. My Meta-Analysis

  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

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