Entertainingly enough, as tPA proponents continue their push for longer time windows and less-stringent inclusion criteria, Stroke recently published a sort of head-to-head debate regarding tPA within the 3 – 4.5h window.
Despite the breathless madness typically exhibited by stroke neurologists and the current Level B recommendations from the AHA, Lawrence Wechsler from the University of Pittsburgh writes a very reasonable critique of ECASS III, incorporating data from ATLANTIS and IST-3. His general point, overall, is the theoretical effect size, if any, is small beyond 3 hours. Therefore, he proposes patients should be carefully selected – perhaps by penumbral perfusion imaging.
His opponents, from Germany, in their response, offer a critique featuring this well-written, professional, academic segment:
Is advanced imaging necessary to make this decision? Why, No?! Would a lacunar versus nonlacunar syndrome make a difference here? No!! It would not make a difference within 3 hours, would it? And what about an MRI without perfusion imaging/diffusion weighted imaging mismatch or with proof of a lacunar stroke, would this make a difference? Hell, no!!! There is no evidence at all for this conclusion. And is there any reason to believe that rt-PA does not work in the 3- to 4.5-hour time window or that it does work only in “a carefully selected set of patients”? What the h…, No, No No!!!!
In keeping with Patrick Lyden’s lovely ad hominem attacks on Anand Swaminathan (“young”, “naive”), it is yet again abundantly clear some proponents of tPA have no response in reasonable, scientific debate other than nonsensical, authoritative bluster.
“The 4.5-Hour Time Window for Intravenous Thrombolysis With Intravenous Tissue-Type Plasminogen Activator Is Not Firmly Established”
http://www.ncbi.nlm.nih.gov/pubmed/24526061
“4.5-Hour Time Window for Intravenous Thrombolysis With Recombinant Tissue-Type Plasminogen Activator Is Established Firmly”
http://www.ncbi.nlm.nih.gov/pubmed/24526060
Wasn't there already a study on desmoteplase with MRI/CTA for stroke showing no benefit?
Yes – but remember, alteplase is "special". That's a desmoteplase trial – nothing about its failure reflects on the remaining body of stroke literature (so says the party line).
ECASS IV basically re-does DIAS-2:
http://controlled-trials.com/ISRCTN71616222/
And, as everyone knows, in pharma, you just keep redoing trials until you find a favorable result, and then find a way to explain away the negatives.
Just debated Swami on this topic: I was the "pro" tpa side. Lots of flaws in arguments attacking NINDS and ECASS3. But even w my Devils Advocate hat on, we agreed that IST3 was a neg. trial, that the time theory is alive and well, and that while we debate 0-3hrs, the inc. to 4.5 is dependent on interpretation of the risks. And 4.5-6 is just kinda crazy.
It was a good discussion. I'm not sure I'm convinced that the time window matters that much and I definitely don't think the agent matters. In STEMI, alteplase had a slightly higher bleed rate than urokinase or streptokinase. It's a class effect.
The real danger in not analyzing these studies and forgetting that a single study should not trump all the other ones. Just watch, when a positive study comes out on clot retrieval in stroke, we're going to be told to ignore all the past studies. We need to be vigilant and be healthy skeptics.
Come on !
They all do like Karl said (Popper).
Write down a hypothesis you believe reasonable.
Then try and disprove it.
I you can't disprove it (and really try) the hypothesis is likely valid.
That is how everybody does.
Incredible commentary. I'm shocked that this was printed in Stroke. Here's what's not surprising:
"Drs Schellinger and Köhrmann received honoraria, travel grants,
and consulting fees from Boehringer Ingelheim and Cerevast, and
both are members of the steering committee for ECASS 4 EXTEND"