Evidence in the ED

Byron Drumheller, MDPenn Emergency Medicine

Research QuestionDoes 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?

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

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).”

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

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

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

Research QuestionDoes 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

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

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

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

Research Question• To make any evidence-based conclusion from

current data, one must make concessions1. Include only studies using intravenous recombinant tPA at 0.9 mg/kg with 0.1 mg/kg bolus and 0.8 mg/kg infusion2. Include data from any patients treated within 3 hours of symptom onset3. Allow for “minor” differences in inclusion/exclusion criteria

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

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

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%p<0.00008

HUPismWhile 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