In this 2 part EM Cases Journal Jam podcast Justin Morgenstern, Rory Spiegel and Anton Helman do a deep dive into the world’s literature on systemic thrombolysis for ischemic stroke followed by an analysis of endovascular therapy for stroke. We elucidate the important issues related to p-values, ordinal analysis, fragility index, heterogeneity of studies, stopping trials early and conflicts of interest related to this body of evidence. While “calling a code stroke” is now considered standard for most stroke patients and tPA for stroke is considered a class 1A drug, a close look at the literature tells us that the evidence is not as strong as our stroke protocols suggest…
Podcast produced by Anton Helman, Justin Morgenstern and Rory Spiegel; sound design and editing by Anton Helman; EBM bomb by Anton Nikoline.
Written Summary and blog post by Anton Helman July, 2016
The systemic thrombolysis for stroke RCTs
Two out of 12 systemic thrombolysis studies suggest a benefit: NINDS-2 and ECASS-3.
NINDS-1 tested neurologic improvement at 24 hours and found no benefit.
NINDS-2 subjects in the thrombolytic arm experienced milder strokes than those in the placebo arm.
Outcome measure = “chance of a good outcome” 12% better (even though goal was to show 20%)
Overall: Benefit = NNT of 8 for post-hoc “favorable outcome” measure
MAST-I 1995 – <6hrs, increased death (OR 2.7), slight decrease disability (OR 0.5)
ECASS 1 1995 – <6hrs, no difference in disability or death (included big bad strokes)
ECASS-3 Three to 4.5hrs window; more favorable outcomes with tPA, no mortality difference
NNT=15 for “favorable outcome” – again, milder strokes in lytic arm
MAST-Europe 1996 – <6hrs increased mortality and ICH stopped early
ASK 1996 <4-5hrs window, slight decrease disability but increased mortality at 3 months; stopped early
ECASS-ll 1998 – <6hrs (20% <3hrs) no difference in favorable outcome (modified Rankin) at 3 months
ATLANTIS-B 1999 3-5hrs window, favourable outcome at 3 months, increased ICH, slight increase mortality, stopped early
ATLANTIS A 2000 <6hrs improved NIHSS at 24hrs but 1 month favored placebo, increased ICH and increased mortality at 3 months stopped early
DIAS-2 2008 – 3-9hrs window, notable inclusion is reversible ischemic penumbra on MR or CT; no difference in favorable outcome
IST-3 2012 0-6hrs window, short term 1wk increased mortality, no difference in primary outcome (% alive and independent at 6 months)
Secondary ordinal analysis showing a “shift” in outcomes favoring thrombolytics
Overall harm (symptomatic ICH) NNH: 1 in 20
Issues with the thrombolysis for stroke literature
The modified Rankin Scale used to measure outcomes in most stroke trials is subjective. Even among trained neurologists there is variability in categorizing patients into the scale. The modified Rankin Scale has been shown in a systematic review to be unreliable.
There is no consistency in the definition of intracranial hemorrhage between trials.
Ordinal analysis used in many stroke trials makes the outcomes difficult to interpret.
P-values in the studies have been misinterpreted. P-values don’t convey the truth, they simply alter the post-test probability. A decent p-value only tells us that a trial should be replicated. However NINDS-2 never was replicated, so we don’t know the truth.
The Fragility index of the two positive trials (NINDS and ECASS-3) are only 3 and 1 respectively. The Fragility index indicates how easily random chance could have changed the results of a trial. This means that in the ECASS-3 trial, if a single patient had a different outcome, the trial would have been reported as negative instead of positive.
Fragility index for NINDS is discussed in Pulmcrit by Josh Farkas
Suggested shared decision making script for thrombolysis in stroke management
Care of Justin Morgenstern @First10EM
“There is a treatment we sometimes use for stroke that is supposed to break down the clot causing the stroke. The treatment is controversial, and you will probably hear different things from different doctors. The issue is that out of 12 major trials, only 2 have shown benefit, and both of those trials have some problems, and they were both paid for by the people who make the drug. There are some risks that we’re certain about: about 1 in 12 patients will have severe bleeding resulting in worse neurologic outcome. Despite that risk, in the best case scenario, about 1 in 10 people given this drug early will have a noticeable improvement in their function after 3 months. Unfortunately, it isn’t clear how reliable the science has been, and we don’t know which patients have the greatest chance at benefit or harm. The choice to receive this medication remains up to each individual patient.”
Drs. Helman, Morgenstern and Spiegel have no conflicts of interest to declare
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FOAMed Resources on thrombolytics for stroke
The SGEM on Thrombolysis for Acute Stroke