Interesting read, this has long been a debate on the EM blogs. Not only has the decision to give tPA or not prompted tons of lawsuits, even a delay in giving tPA has gotten doctors sued: https://expertwitness.substack.com/p/expert-witness-case-15
I recall these initial studies but stunned to see that they go back 30 years. 30 years of technological and therapeutic advancements yet we are still using therapy based on old and possibly outdated and now questionable studies? Realizing the low likelihood of seeing another placebo controlled randomized thrombolytic study and considering the legal environment, the public will soon learn that another SOC treatment is not so beneficial and maybe should not be so standard.
Thanks to the author for having the courage to write and investigate this but why am I reading it on Substack instead of some " prestigious peer reviewed high impact" journal?
1. Whether one says there are valid watchful waiting situations, or that there is striaght-up broad equipose, it seems this would be a good place to do head to head trials against oral fibrolynitics like nattokinse and lumbrokinase. They are more gradual and certainly safer and I have heard anecdotes of them saving people's lives.
2. What is the significance of old lacunar infarcts on a CT scan? I have heard it said they are not strokes. Also heard they are gradations of white matter hyperintensities. Both of those answers seem wrong.
It's important to look at the totality of the evidence. NINDS was published in 1995 and despite being the first trial, much more evidence in favor of thrombolysis has been accumulated over the years.
Next do stents! Stents are another sacred cow of cardiology and in actual studies don’t really offer lower all cause mortality for most people (possibly exception acute myocardial infarction…possibly.)
"What do we do??? Watchful waiting would be tough on pt and doc" This question started bouncing around in my mind just after reading the first part of the article. Of course TIME is of the essence but all the possibilities of assessment, and the time needed starts breaking the race horses leg at the starting gate. I notice the continued correlation to alcohol and wonder why thats even a question. Its easy to establish blood alcohol level and that should change the dynamics of the 'search' for a solution shouldnt it? So as with many studies, we dont have consensus. This article is an eye opener but then again the cynical part of me asks 'so whats new? Why be surprised?, most studies are tainted with the need for profit---the need to insulate from lawsuit, the need for far more depth then probably funding allowed,or just flat incompetency. So WHAT DOES ONE DO based on anything said here? By the way, Im a real estate contract law guy--no medical training at all. I just wish I had gone into medicine because it has some of the greatest puzzles of all and to me it seems the ultimate satisfaction of finding that one clue to save a human life.
The edifice of institutionalized acute stroke care is now deeply entrenched in hospital culture. The bean counters are all ways a quick protected text away from correcting the wayward clinician who deviates from protocol. The patients with vague neurologic complaints all get funneled into the stroke alert pathway and the money churning begins. This is, plain and simple, poor value healthcare. Thanks to folks like Hoffman and Mandrola for shedding light on the flimsy evidence supporting this practice.
Very interesting to read the comments of ER physicians that have to make immediate decisions. "Standards of Care" are almost oxymoronic in medical practice and should be eliminated from the discourse. Medicine is an extremely individualistic discipline and doctors should not be placed in legalistic jeopardy for not following established "guidelines" in every case.
As an Intern we participated in the MI trials. The study envelopes were in a safe. They were thick if a real drug and thin if placebo. The residents pulled the thick packets if the MI was large and or patient unstable. You get the picture. No shock here. I was examining a patient in the ER with unstable angina when he said, my pain is coming back and the ST segments elevated in front of me. Time to Tpa was 10 minutes. Worked great. ( before the days of stents-i am older).
My 95 year old dad went to stroke center with a left arm paralysis due to embolic stroke with afib. His arm was improving with only minimal weakness. Neurologist said no "ARM no foul" it was less than 6o minutes- he will change to apixaban for his afib.. No TPA and he now has zero residual.
It is always about risk vs benefit.
No one thinks they have any risk ( that will happen to the other guy), and they will get maximal benefit.
Remember the first rule= " Always do as much nothing as possible"
To be honest, I find this utterly confusing. Not entirely sure what you proved. Never look at RRR or HR which is what all studies show. Only look at ARR. There is always the specter of selection bias.
80% of all studies are flawed or useless. Jerome Hoffman and others have stated this after meticulous evaluation.
The mRNA shots and the fibrous clots which, afaik are not amenable to antithrombotic therapy, should move us farther away from the latter.
“Thrombectomy patients generally had better outcomes: Trial of Thrombectomy for Stroke with a Large Infarct of Unrestricted Size”
N Engl J Med 2024;390:1677-1689
DOI: 10.1056/NEJMoa2314063
VOL. 390 NO. 18
That said (for those of us who have not taken the shots, and have no coagulopathy), if faced with a large hemispheric stroke, especially dominant, I would get myself to the hospital post haste and opt for the treatment. The outcomes of conservative therapy are dismal, and time is brain.
It is important to note there's a big difference between thrombolytic therapy and thrombectomy. Huge difference. Thrombectomy for LVO has better data and acceptance by the EM community.
Interesting read, this has long been a debate on the EM blogs. Not only has the decision to give tPA or not prompted tons of lawsuits, even a delay in giving tPA has gotten doctors sued: https://expertwitness.substack.com/p/expert-witness-case-15
I was very surprised by the early enthousiasm of neurologists giving TPAse for ischaemic stroke : "we see the deficit regressing before our eyes"
But NINDS 1 and 2 said (didn't convincingly prove IMHO) the improvement was significant at 3 months, not at H24.
I recall these initial studies but stunned to see that they go back 30 years. 30 years of technological and therapeutic advancements yet we are still using therapy based on old and possibly outdated and now questionable studies? Realizing the low likelihood of seeing another placebo controlled randomized thrombolytic study and considering the legal environment, the public will soon learn that another SOC treatment is not so beneficial and maybe should not be so standard.
Thanks to the author for having the courage to write and investigate this but why am I reading it on Substack instead of some " prestigious peer reviewed high impact" journal?
Thank you for this - the horse had bolted and lytics are the rage. It seems spin rules over sense. Keep up the good work.
1. Whether one says there are valid watchful waiting situations, or that there is striaght-up broad equipose, it seems this would be a good place to do head to head trials against oral fibrolynitics like nattokinse and lumbrokinase. They are more gradual and certainly safer and I have heard anecdotes of them saving people's lives.
2. What is the significance of old lacunar infarcts on a CT scan? I have heard it said they are not strokes. Also heard they are gradations of white matter hyperintensities. Both of those answers seem wrong.
“Randomization error”? What might those be?
Through 90% of this post, I was thinking it was an RCT, and if baseline characteristics appeared to differ, that’s a chance finding.
But if there was an issue with randomization itself, then it’s important to know what happened there.
It's important to look at the totality of the evidence. NINDS was published in 1995 and despite being the first trial, much more evidence in favor of thrombolysis has been accumulated over the years.
For example, this 2014 meta-analysis of 6756 patients from 9 trials (incl. NINDS A & B) is a good read of the alteplase vs. placebo literature: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)60584-5/fulltext
Alteplase showed benefit: OR for a good functional outcome (mRS 0-1) at 3-6 months
- when alteplase given within 3 h from symptom onset: 1.75, 95%CI 1.35–2.27
- when given within 3-4.5 h 1.2 [1.05-1.51].
This was independent of stroke severity at baseline, as indicated by subgroup analyses by baseline NIHSS.
Beyond that newer data show
- better functional outcome for bridging thrombectomy with thrombolysis (w/ tecenteplase) when appropriate vs. thrombectomy alone: https://www.nejm.org/doi/full/10.1056/NEJMoa2503867
- better functional outcome of thrombolysis in an extended window of 4.5 to 9 h when there is salvageable tissue in imaging: https://www.nejm.org/doi/full/10.1056/NEJMoa1813046
- better functional outcome of thrombolysis in stroke of unknown onset when there is salvageable tissue in imaging: https://www.nejm.org/doi/full/10.1056/NEJMoa1804355
- better functional outcome with mobile stroke units that reduce time to thrombolysis when compared to standard ED care: https://www.nejm.org/doi/full/10.1056/NEJMoa2103879
Yes, thrombolysis increases risk of symptomatic intracranial hemorrhage. But improved disability outcomes at 3 months clearly support its use.
Acute stroke care has evolved since 1995. It has become very nuanced and individualized.
Critiques against current standards shouldn't rely solely on re-analyses of a 30-y old trial ignoring all subsequent evidence.
That said, I do agree with the statement that reading the seminal trials is an enlightening learning experience!
This is awesome work, Dr. John.
Next do stents! Stents are another sacred cow of cardiology and in actual studies don’t really offer lower all cause mortality for most people (possibly exception acute myocardial infarction…possibly.)
https://www.nejm.org/doi/full/10.1056/NEJMoa070829
"What do we do??? Watchful waiting would be tough on pt and doc" This question started bouncing around in my mind just after reading the first part of the article. Of course TIME is of the essence but all the possibilities of assessment, and the time needed starts breaking the race horses leg at the starting gate. I notice the continued correlation to alcohol and wonder why thats even a question. Its easy to establish blood alcohol level and that should change the dynamics of the 'search' for a solution shouldnt it? So as with many studies, we dont have consensus. This article is an eye opener but then again the cynical part of me asks 'so whats new? Why be surprised?, most studies are tainted with the need for profit---the need to insulate from lawsuit, the need for far more depth then probably funding allowed,or just flat incompetency. So WHAT DOES ONE DO based on anything said here? By the way, Im a real estate contract law guy--no medical training at all. I just wish I had gone into medicine because it has some of the greatest puzzles of all and to me it seems the ultimate satisfaction of finding that one clue to save a human life.
The edifice of institutionalized acute stroke care is now deeply entrenched in hospital culture. The bean counters are all ways a quick protected text away from correcting the wayward clinician who deviates from protocol. The patients with vague neurologic complaints all get funneled into the stroke alert pathway and the money churning begins. This is, plain and simple, poor value healthcare. Thanks to folks like Hoffman and Mandrola for shedding light on the flimsy evidence supporting this practice.
Very interesting to read the comments of ER physicians that have to make immediate decisions. "Standards of Care" are almost oxymoronic in medical practice and should be eliminated from the discourse. Medicine is an extremely individualistic discipline and doctors should not be placed in legalistic jeopardy for not following established "guidelines" in every case.
As an Intern we participated in the MI trials. The study envelopes were in a safe. They were thick if a real drug and thin if placebo. The residents pulled the thick packets if the MI was large and or patient unstable. You get the picture. No shock here. I was examining a patient in the ER with unstable angina when he said, my pain is coming back and the ST segments elevated in front of me. Time to Tpa was 10 minutes. Worked great. ( before the days of stents-i am older).
My 95 year old dad went to stroke center with a left arm paralysis due to embolic stroke with afib. His arm was improving with only minimal weakness. Neurologist said no "ARM no foul" it was less than 6o minutes- he will change to apixaban for his afib.. No TPA and he now has zero residual.
It is always about risk vs benefit.
No one thinks they have any risk ( that will happen to the other guy), and they will get maximal benefit.
Remember the first rule= " Always do as much nothing as possible"
Wonderful piece, good start. Looking forward to more. For a similar effort over a decade ago, see:
https://thennt.com/nnt/thrombolytics-for-stroke/
To be honest, I find this utterly confusing. Not entirely sure what you proved. Never look at RRR or HR which is what all studies show. Only look at ARR. There is always the specter of selection bias.
80% of all studies are flawed or useless. Jerome Hoffman and others have stated this after meticulous evaluation.
Is there any medical research that is not compromised?
Fair point. It was the “research” on the “dangers of IVM” that opened my eyes. Journal editors have opined about ⅓.
The mRNA shots and the fibrous clots which, afaik are not amenable to antithrombotic therapy, should move us farther away from the latter.
“Thrombectomy patients generally had better outcomes: Trial of Thrombectomy for Stroke with a Large Infarct of Unrestricted Size”
N Engl J Med 2024;390:1677-1689
DOI: 10.1056/NEJMoa2314063
VOL. 390 NO. 18
That said (for those of us who have not taken the shots, and have no coagulopathy), if faced with a large hemispheric stroke, especially dominant, I would get myself to the hospital post haste and opt for the treatment. The outcomes of conservative therapy are dismal, and time is brain.
It is important to note there's a big difference between thrombolytic therapy and thrombectomy. Huge difference. Thrombectomy for LVO has better data and acceptance by the EM community.
Agree. The mRNA shots have permanently altered the decision making process. (LVO means large vessel occlusion.)