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? How many studies? 0

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 tPAPlacebo mRS 0-1totalmRS 0-1total ATLANTIS11181533 NINDS13331283312 ECASS II34812977 178411127422 mRS 0-143.3%30.1% p<0.00008

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