New grad ED physicians opposing tPA use for strokes

[johnny_bananas]

Again, if tPA was such a great medication it would prove itself with decades of experience from satisfied clinicians

Treatments that are tried and true don't require endless trials and don't generate this much debate

I've given tPA since 2001 many, many times as a twice board-certified neurologist and been completely underwhelmed by the outcomes despite following the protocols to the letter. The overwhelming majority of my friends in the field are also underwhelmed and aren't afraid to point out that the Emperor has no clothes. They also aren't employed physicians beholden to a hospital system chasing that sweet, sweet DRG money for pushing tPA for anything possibly related to a "code stroke"

BTW, the climate denier claim is just classic. Keep up the good work!!

I provide evidence, and your retort is anecdotal experiences that you just don't 'see' patients getting better, and accusations that we are "beholden to a hospital system".

I am truly perplexed by your line of reasoning.

Due do acute stroke care mortality rates have been decreasing over time. Let me ask you a question, do you "see" less people dying?

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[DD214]

Your graph “proves” that the reported reduction in deaths is due to tPA administration? Try again

As I said, effective treatments don’t require this much effort to justify their use

You probably think donepezil and memantine are making dementia patients better too, instead of making the physician and family “feel like they’re doing something”

 

[johnny_bananas]

Your graph “proves” that the reported reduction in deaths is due to tPA administration? Try again

As I said, effective treatments don’t require this much effort to justify their use

You probably think donepezil and memantine are making dementia patients better too, instead of making the physician and family “feel like they’re doing something”

Did I say the mortality reduction was due to tPA? I specifically said 'acute stroke care'. The point was not about tPA, there is other data that shows it reduces mortality. The point was demonstrating how absurd your argument is about not 'seeing' benefit, but it seems you are having difficulty following simple arguments. I have to be honest, I am really surprised you are a neurologist, they are typically more analytical in their thinking. I engage in arguments in good faith, but it appears you have reasons to continue to be wilfully ignorant, that is your right.

Take care.

 

[DD214]

I was never debating “acute stroke care” aside from the highly questionable but according to you unassailable data regarding tPA administration and outcomes

Some of us are able to think for ourselves and see with our own eyes rather than being blinded by “data” that conflicts with our own experience and that of our colleagues

Looks like you’ve by your own admission painted yourself into a corner (low pay with oppressive call) by your choice of sub specialization and are quite sensitive when questioned about the efficacy of your available treatment

 

[johnny_bananas]

I was never debating “acute stroke care” aside from the highly questionable but according to you unassailable data regarding tPA administration and outcomes

Some of us are able to think for ourselves and see with our own eyes rather than being blinded by “data” that conflicts with our own experience and that of our colleagues

Looks like you’ve by your own admission painted yourself into a corner (low pay with oppressive call) by your choice of sub specialization and are quite sensitive when questioned about the efficacy of your available treatment

The only point you made was referencing all those 'negative trials', when I addressed that specific point with evidence and arguments, you claim I am blinded by "data" and you trust your own personal experiences. You are right, I am blinded by data, also known as evidence, and you made no attempt to argue against the data or provide counterarguments. You can continue practicing with your 'gut' and the rest of us in the 21st century will practice evidence based medicine.

And I am not "sensitive" when questioned about the efficacy of tPA, frankly I look forward to an honest and respectful discussion, as I mentioned before, the contrary arguments are largely based on misinformation that are easily addressed. I am "sensitive" to your lack of arguments that you mistake as evidence, and it is very concerning that you are allowed to treat stroke patients, they deserve better.

 

[DD214]

We should never listen to our own inner voice that questions the status quo, right?

I’m sure all of the physicians handing out OxyContin in the late 90’s because “it has no addiction potential” and “pain is the 5th vital sign - pain is whatever the patient says it is!!” felt like they were practicing cutting edge medicine too

They certainly didn’t want to be labeled a bad physician and suffer the consequences of the medical board or JCAHO for their uncaring approach to treating pain

 

[CCM-MD]

Again, if tPA was such a great medication it would prove itself with decades of experience from satisfied clinicians

Treatments that are tried and true don't require endless trials and don't generate this much debate

I've given tPA since 2001 many, many times as a twice board-certified neurologist and been completely underwhelmed by the outcomes despite following the protocols to the letter. The overwhelming majority of my friends in the field are also underwhelmed and aren't afraid to point out that the Emperor has no clothes. They also aren't employed physicians beholden to a hospital system chasing that sweet, sweet DRG money for pushing tPA for anything possibly related to a "code stroke"

BTW, the climate denier claim is just classic. Keep up the good work!!

Time to stop. Your ignorance is showing.

 

[Lexdiamondz]

When you think about it, it's pretty arrogant. A ED physician, outside of their primary specialty, is reading a few articles and thinking they have the authority or knowledge to make any relevant decisions about tPA.

I don't go around reading EM journals to try and argue the cons of some resuscitation techniques.

Stay in your lane

Maybe.

The counterargument to that, however, is that in most contexts, the decision to give tPA, the administration of tPA (sometimes even the physical act of starting the infusion) and the associated liability with any complications of thrombolysis lies with the emergency physician. Certainly not arrogance to be somewhat skeptical of a drug with some risk of significant complications which you may be held liable for.

 

[johnny_bananas]

Maybe.

The counterargument to that, however, is that in most contexts, the decision to give tPA, the administration of tPA (sometimes even the physical act of starting the infusion) and the associated liability with any complications of thrombolysis lies with the emergency physician. Certainly not arrogance to be somewhat skeptical of a drug with some risk of significant complications which you may be held liable for.

There is the issue of liability and then there is the issue of what is best for your patient.

Regarding liability, the data is consistent that failure to treat with tPA or not in a timely manner leads to getting sued, and not hemorrhagic complications.
https://www.ahajournals.org/doi/10.1161/STROKEAHA.119.025352

Even in the unlikely chance that you would get sued for a hemorrhagic complication, I fail to see how they would win, given the fact that tPA is the standard of care and your decision was supported by neurology.

Now, regarding what is best for your patient, the data is clear that in appropriately selected patients the cost-benefit ratio is greatly in favour to treat with tPA. Important to remember that the modified Rankin scale considers any disability incurred from sICH, and there was a benefit with tPA in reducing disability despite any hemorrhages that resulted.

The risk of a symptomatic ICH (sICH) is 3.1% (SITS MOST definition). Importantly, that risk if not uniform and the risk is increased/decreased depending on the NIHSS (size of stroke). For strokes with NIHSS < 10 the risk is 2.4% and NIHSS <5 is 1.5%.

Risk of intracerebral haemorrhage with alteplase after acute ischaemic stroke: a secondary analysis of an individual patient data meta-analysis

Among patients given alteplase, the net outcome is predicted both by time to treatment (with faster time increasing the proportion achieving an excellent outcome) and stroke severity (with a more severe stroke increasing the absolute risk of intracerebral haemorrhage). Although, within 4·5 h of...

www.thelancet.com

The larger the stroke the greater the risk of sICH. However, that was before mechanical thrombectomy (MT), now we have patients with large strokes and vessel occlusions also undergoing MT.

So, what is the excess risk of sICH with tPA in patients with large strokes undergoing MT?

Here are the trials below:
DEVT: 1.7%
DIRECT-MT: 1.8%
SKIP: 1.9%
Mr CLEAN NO IV: -0.6%
SWIFT DIRECT: 3.4%
DIRECT SAFE: 2%

 

[Lexdiamondz]

There is the issue of liability and then there is the issue of what is best for your patient.

Regarding liability, the data is consistent that failure to treat with tPA or not in a timely manner leads to getting sued, and not hemorrhagic complications.
https://www.ahajournals.org/doi/10.1161/STROKEAHA.119.025352

Even in the unlikely chance that you would get sued for a hemorrhagic complication, I fail to see how they would win, given the fact that tPA is the standard of care and your decision was supported by neurology.

Now, regarding what is best for your patient, the data is clear that in appropriately selected patients the cost-benefit ratio is greatly in favour to treat with tPA. Important to remember that the modified Rankin scale considers any disability incurred from sICH, and there was a benefit with tPA in reducing disability despite any hemorrhages that resulted.

The risk of a symptomatic ICH (sICH) is 3.1% (SITS MOST definition). Importantly, that risk if not uniform and the risk is increased/decreased depending on the NIHSS (size of stroke). For strokes with NIHSS < 10 the risk is 2.4% and NIHSS <5 is 1.5%.

Risk of intracerebral haemorrhage with alteplase after acute ischaemic stroke: a secondary analysis of an individual patient data meta-analysis

Among patients given alteplase, the net outcome is predicted both by time to treatment (with faster time increasing the proportion achieving an excellent outcome) and stroke severity (with a more severe stroke increasing the absolute risk of intracerebral haemorrhage). Although, within 4·5 h of...

www.thelancet.com

The larger the stroke the greater the risk of sICH. However, that was before mechanical thrombectomy (MT), now we have patients with large strokes and vessel occlusions also undergoing MT.

So, what is the excess risk of sICH with tPA in patients with large strokes undergoing MT?

Here are the trials below:
DEVT: 1.7%
DIRECT-MT: 1.8%
SKIP: 1.9%
Mr CLEAN NO IV: -0.6%
SWIFT DIRECT: 3.4%
DIRECT SAFE: 2%

I think you misunderstand, I'm not here to argue the data on the efficacy or risks or tPA. I know tPA is standard of care and I don't fight with my neurology colleagues regarding administering tPA if the appropriate patient meeds criteria for administration.

My comment was directed at the individual unnecessarily calling us ED physicians "arrogant" and telling us to "stay in our lane", as if the attending of record from the primary team shouldn't have any opinions on the matter.

My point was that, when you're the one who is actually pulling the trigger, it's not unreasonable to have some degree of skepticism when you're being told by a voice on the phone who hasn't examined the patient themselves to administer a drug that causes symptomatic ICH in for 1 in 30 people who receive it.

 

[johnny_bananas]

I think you misunderstand, I'm not here to argue the data on the efficacy or risks or tPA. I know tPA is standard of care and I don't fight with my neurology colleagues regarding administering tPA if the appropriate patient meeds criteria for administration.

My comment was directed at the individual unnecessarily calling us ED physicians "arrogant" and telling us to "stay in our lane", as if the attending of record from the primary team shouldn't have any opinions on the matter.

My point was that, when you're the one who is actually pulling the trigger, it's not unreasonable to have some degree of skepticism when you're being told by a voice on the phone who hasn't examined the patient themselves to administer a drug that causes symptomatic ICH in for 1 in 30 people who receive it.

Thanks for the clarification, I see what you are saying.

I think it depends on what you are referring to as skepticism. I would certainly agree with you, if the ED physician is expressing concern about a certain case (i.e. stroke mimic), it would be “arrogant” for the neurologist to dismiss the concerns of the ED physician without any reasoning provided, especially if they did not examine the patient, and the optimal solution would be for both physicians to come to an agreement. Likewise, as the example provided by the poster of the original thread, it would be “arrogant” to dismiss recommendations by a consultant without any justification.

The comment you were referring to, I think the individual was referring to skepticism about the interpretation of the literature in contradiction to guidelines, and not skepticism in clinical situations. I don’t think your speciality precludes you from providing fair criticism or opinions. However, the skepticism in the EM community about tPA is largely not reasonable and driven by misinformation, and incorrect assumptions and facts. To provide one example out of many:

Tissue Plasminogen Activator (tPA) For Acute Ischemic Stroke (2021) – TheNNT

www.thennt.com

The authors of the NNT article do not practice acute stroke care, conduct no primary research on the subject of their own, and most importantly write a succinct article filled with so many inaccuracies and then build their entire argument on those inaccuracies, which only further perpetuates misinformation in the EM community. Indeed, that is arrogant!

I think EM physicians are an integral part of the stroke community, that is why I find it frustrating and sad, that so many are swayed by self-appointed "experts".

 

[DrSatan]

Again, if tPA was such a great medication it would prove itself with decades of experience from satisfied clinicians

Treatments that are tried and true don't require endless trials and don't generate this much debate

I've given tPA since 2001 many, many times as a twice board-certified neurologist and been completely underwhelmed by the outcomes despite following the protocols to the letter. The overwhelming majority of my friends in the field are also underwhelmed and aren't afraid to point out that the Emperor has no clothes. They also aren't employed physicians beholden to a hospital system chasing that sweet, sweet DRG money for pushing tPA for anything possibly related to a "code stroke"

BTW, the climate denier claim is just classic. Keep up the good work!!

How are you underwhelmed? The evidence shows that it improves **long-term** outcomes (3 months plus). You are not seeing these patients in the hospital or at follow up clinics. You are potentially not seeing much of them ever again after receiving tPA if they are immediately shipped the the neuro ICU for close monitoring afterwards.

I agree that tPA feels underwhelming. No one here spouts it as a "miracle" cure, but we can appreciate that it may lyse some clots that may not have otherwise lysed (hard to prove this certainly) & otherwise put someone at higher risk for significantly improved neurologic function at 3 months. It's thrombectomy that is the "miracle" in a lot of situations, but we still see it "fail" with regular frequency.

 

[DD214]

How are you underwhelmed? The evidence shows that it improves **long-term** outcomes (3 months plus). You are not seeing these patients in the hospital or at follow up clinics. You are potentially not seeing much of them ever again after receiving tPA

You haven't been paying attention

I, along with the ED physician, gave the tPA, followed them in their inpatient stay and then saw them in follow up in my NEUROLOGY clinic.

BTW, I'm not the only neurologist who is less than impressed by the "standard of care" so stated by the gods of EBM and the infallible AAN

Here are some quotes from Sermo:

"I was very pro t-PA. I trained in one of the centers of the original NINDS stroke trials. As soon as the drug was released in 1995. Within a month of it's release, I modified protocols for 5 large hospitals (in which I provided consults) in the City I live in.
Within the first few years, we had infused 60-70 pts (as direct Neurologist in charge ordering the drug, as the ER docs were very reluctant to do have anything to do with the drug). About 6 Hemorrhages (only a couple died due to bleed). A couple of "Lazarus" effects. The rest really didn't see much happen (as expected).
Interest dwindled away. After a couple of years, it was very rare that t-PA was administered. The protocols I had modified were in place, but no-one really used it.
It wasn't until re-imbursement changes occurred for "Stroke Centers" that the interest in t-PA, rekindled. Now every dog and cat hospital wanted to be a "Stroke Center" !!! LOL."

"I was one of the clinical investigators for the original study. . I was not impressed."

"The only ones that are impressed are the "strokologists", and of course JACHO and all the business peoples that can advertise that their hospital is a "stroke center"; the rest of us "have" to go along because of the guidelines/protocols put forth."

 

[Thama]

Anyone using anecdote to make clinical decisions regarding a medication with an OR for good outcome less than 2 and a noisy enough natural history that signal is only visible in the context of a large clinical trial is either too dumb to practice medicine or has an astonishing level of hubris.

 

[johnny_bananas]

You haven't been paying attention

I, along with the ED physician, gave the tPA, followed them in their inpatient stay and then saw them in follow up in my NEUROLOGY clinic.

BTW, I'm not the only neurologist who is less than impressed by the "standard of care" so stated by the gods of EBM and the infallible AAN

Here are some quotes from Sermo:

"I was very pro t-PA. I trained in one of the centers of the original NINDS stroke trials. As soon as the drug was released in 1995. Within a month of it's release, I modified protocols for 5 large hospitals (in which I provided consults) in the City I live in.
Within the first few years, we had infused 60-70 pts (as direct Neurologist in charge ordering the drug, as the ER docs were very reluctant to do have anything to do with the drug). About 6 Hemorrhages (only a couple died due to bleed). A couple of "Lazarus" effects. The rest really didn't see much happen (as expected).
Interest dwindled away. After a couple of years, it was very rare that t-PA was administered. The protocols I had modified were in place, but no-one really used it.
It wasn't until re-imbursement changes occurred for "Stroke Centers" that the interest in t-PA, rekindled. Now every dog and cat hospital wanted to be a "Stroke Center" !!! LOL."

"I was one of the clinical investigators for the original study. . I was not impressed."

"The only ones that are impressed are the "strokologists", and of course JACHO and all the business peoples that can advertise that their hospital is a "stroke center"; the rest of us "have" to go along because of the guidelines/protocols put forth."

I don't know what is more idiotic, your argument, or me for continuously responding to you. I feel like I am trying to teach a child how to count, and getting no where.

Below is the number of patients out of 100 that were improved and harmed with tPA compared to placebo in NINDS. But ignore that. Pretend this is the distribution of patients that improved in your centre where you give tPA to everyone. How would you know that the patients that got better would have without tPA?

Answer: You don't, it is impossible. This is why placebo trials are required. Your experience or "Sermo's" is utterly meaningless.

Curing 13 more patients, and helping 32 more patients out of 100 with tPA is not insignificant, especially for those individuals and on a population level. We have multiple registry data that also demonstrates it reduces mortality in the longterm.

Your point is what about the 68 patients that I more commonly see not improve. Due to NINDS, this led to the development of acute stroke units around the world, practice guidelines, and paved the way to the development of mechanical thrombectomy. Is there more work to be done? Of course, but having a defeatist attitude like yourself is certainly not going to get us there.

 

[DD214]

I feel like I am trying to teach a child how to count, and getting no where.

So only your experience counts. You can't deal with dissenting opinions that dare blaspheme your EBM god. I get it

I provided you with statements from the people who participated in the original trials who were quite unimpressed, used their own eyes to see that tPA is at best weak sauce in even the most carefully selected patients AFTER follow up and you still can't understand that.

Having a "defeatist attitude" is again laughable. You don't see many neurologists arguing the merits of actual effective treatments for migraine, PD, MS, neuropathy and a host of others where the clinical experience speaks for itself.

 

[VA Hopeful Dr]

So only your experience counts. You can't deal with dissenting opinions that dare blaspheme your EBM god. I get it

I provided you with statements from the people who participated in the original trials who were quite unimpressed, used their own eyes to see that tPA is at best weak sauce in even the most carefully selected patients AFTER follow up and you still can't understand that.

Having a "defeatist attitude" is again laughable. You don't see many neurologists arguing the merits of actual effective treatments for migraine, PD, MS, neuropathy and a host of others where the clinical experience speaks for itself.

As an outpatient FP I have absolutely no dog in this fight, but I would suggest taking anything from Sermo with a HUGE grain of salt.

 

[DD214]

I have absolutely no dog in this fight, but I would suggest taking anything from Sermo with a HUGE grain of salt.

Sermo up until a few years ago was an excellent resource for clinical discussion, depending on who you associated with.....

It really went downhill after the website redesign

The people I quoted had an extensive post history over a decade and I have no reason to doubt their statements

If you did have a dog in this, it would be named "Alteplase" and pee on your leg frequently while a consortium of neighbors told you it was raining inside.

 

[VA Hopeful Dr]

Sermo up until a few years ago was an excellent resource for clinical discussion, depending on who you associated with.....

It really went downhill after the website redesign

The people I quoted had an extensive post history over a decade and I have no reason to doubt their statements

If you did have a dog in this, it would be named "Alteplase" and pee on your leg frequently while a consortium of neighbors told you it was raining inside.

I was active there from 2013-2016 and I would disagree with your assessment

 

[DD214]

I was active there from 2013-2016 and I would disagree with your assessment

yes, I'm sure most of the neurologists I discussed cases with on Sermo were bored teenagers who happened to bypass the medical licensing requirement for membership and had fun discussing risks of PML with natalizumab etc

 

[VA Hopeful Dr]

yes, I'm sure most of the neurologists I discussed cases with on Sermo were bored teenagers who happened to bypass the medical licensing requirement for membership and had fun discussing risks of PML with natalizumab etc

I didn't say they weren't doctors (where did you pull that nonsense from?), I just disagreed in your assertion that it was "an excellent resource for clinical discussion" as I did not find it so.

 

[DD214]

I didn't say they weren't doctors (where did you pull that nonsense from?), I just disagreed in your assertion that it was "an excellent resource for clinical discussion" as I did not find it so.

Actually, there was a time when nonphysicians were found to have joined which compromised the integrity of the site

Sorry you didn't find any value discussing cases with colleagues

 

[deathmerchant]

Why are we entertaining this trolling! I think you got very good replies/evidence from posters above which we all agree with.
You are not the only one who looks at studies with skepticism. When Adulhelm was approved most neurologists stood against it. Myself and most other neurologists have looked into these studies/guidelines in detail for years and also have personal experience with hundreds of tpa patients and know it is beneficial when chosen for the right patient. We also know it has limitations and is not a miracle drug.

Also BTW we are starting to use tenecteplase at our institution.

 

[DD214]

Just wait until they move the goalposts with Aduhelm and despite multiple disappointing trials they do a meta analysis and the AAN and a consortium of experts decides that Aduhelm is now the standard of care

Now neurologists, primary care physicians and anyone who sees patients with a nonspecific complaint of memory loss will have to document extensively why they didn't prescribe Aduhelm to prevent the ravages of AD

Physicians negative experiences with the hassle and medicolegal risks will be shouted down by experts who tout weak data supporting Aduhelm use at their Comprehensive Memory Centers which of course benefit handsomely from the DRG money.

Of course, just like many gov't programs promising savings by raising taxes and spending, the real benefits will only ever be seen "two towns over"

 

[Thama]

Of course, just like many gov't programs promising savings by raising taxes and spending, the real benefits will only ever be seen "two towns over"

And now we get the real punchline.

G'night everyone

 

[Jabbed]

I'm an EM doc married to a neurologist. We have this conversation at least once a month.

1. Are there any randomized trials supporting the phenomenon of "tPA-aborted stroke"? The only thing that I am familiar with is the phase I NINDS trial which showed no difference at 24 hours.

2. A commonly cited refrain is that after re-analysis of NINDs and ECASS-3 to adjust for baseline indifference, the statistical significance of the outcomes was lost. This leads to the often-quoted "no RCTs support the administration of tPA" and was what primarily led to the change in theNNT.com.

3. The literature on primary EVT without tPA (SKIP, DIRECT-MT) seem somewhat mixed, possibly because of the non-inferiority trial design. Are there any current or upcoming trials that are expected to provide clinical equipoise on the topic?

 

[johnny_bananas]

I'm an EM doc married to a neurologist. We have this conversation at least once a month.

1. Are there any randomized trials supporting the phenomenon of "tPA-aborted stroke"? The only thing that I am familiar with is the phase I NINDS trial which showed no difference at 24 hours.

2. A commonly cited refrain is that after re-analysis of NINDs and ECASS-3 to adjust for baseline indifference, the statistical significance of the outcomes was lost. This leads to the often-quoted "no RCTs support the administration of tPA" and was what primarily led to the change in theNNT.com.

3. The literature on primary EVT without tPA (SKIP, DIRECT-MT) seem somewhat mixed, possibly because of the non-inferiority trial design. Are there any current or upcoming trials that are expected to provide clinical equipoise on the topic?

"1. Are there any randomized trials supporting the phenomenon of "tPA-aborted stroke"? The only thing that I am familiar with is the phase I NINDS trial which showed no difference at 24 hours."

It depends on what you mean by “tPA aborted stroke”. Since you are referencing NINDS part 1, it seems you mean early neurological improvement (ENI).

Though NINDS part 1 was not statistically significant for ENI, there was a trend. For the combined group OR 1.2 (1-1.4 CI, p=0.06) and for the 0-90 min it was significant OR 1.3 (1-1.7 CI, p=0.02).

In post hoc analysis, the median NIHSS was significantly different between the groups, and interestingly any other definition of ENI (i.e. NIHSS>5, NIHSS >6 and so on) would have also been significant.

Another post-hoc analysis showed that if they used % change in NINDS it would have also been significant.

https://www.ahajournals.org/doi/epub/10.1161/STROKEAHA.119.027476

At 24 hours tPA patients also had smaller infarcts compared to placebo.
Effect of intravenous recombinant tissue plasminogen activator on ischemic stroke lesion size measured by computed tomography. NINDS; The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Group - PubMed

Clearly, the tPA groups had lower (better) NIHSS scores and had more improvement than the placebo group at 24 hours.

Many tPA studies do not measure ENI, but the ones that do as a secondary outcome have demonstrated that ENI is statistically greater with tPA: ECASS 1, ATLANTIS A (the trial was cut short though), EXTEND-TPA, BEST-MSU study

Also improved recanalization rates at 24 hours of intracranial occlusions occur substantially more with tPA.

Therefore, looking at all the evidence ENI does occur with tPA.

"2. A commonly cited refrain is that after re-analysis of NINDs and ECASS-3 to adjust for baseline indifference, the statistical significance of the outcomes was lost. This leads to the often-quoted "no RCTs support the administration of tPA" and was what primarily led to the change in theNNT.com."

Regarding NINDS re-analysis:
Important to keep in mind that the NIHSS imbalance occurred in part 2 in the 90-180 min group. There was no imbalance in NINDS part 1, which was an independent study, and it was statistically significant for the 90 day outcome. Also in part 2, the 0-90 minute subgroup was statistically significant, and no imbalance in baseline NIHSS. If the imbalance can explain the treatment effect, how do we explain part 1 and the 0-90 minute subgroup?

There was a special independent committee composed of emergency medicine physicians and statisticians that adjusted for the baseline differences in NINDS and determined that it would not account for the treatment effect. There have been around 5 re-analyses of the data adjusting for the imbalance and all observed the treatment effect persisted.

https://www.ahajournals.org/doi/full/10.1161/01.STR.0000140891.70547.56

Did that satisfy the skeptics? No, in 2009 Hoffman et al. performed a “graphical re-analysis” using the NIHSS at 90 days, keep in mind that NIHSS is not the primary outcome at 90 days and it is not a measure of disability. Hoffman performed zero statistics and left it up to the reader to decide on the interpretation. Importantly, he did not take into account the ordinal, non-interval nature of the NIHSS, and his graphical charts utilized improper scales and therefore hid the treatment effect. Saver et al. 2010 wrote an entire paper refuting the claims of Hoffman, it has been 10 years and Hoffman has yet to respond to Saver’s points. When graphed by Saver the 90-day NIHSS shows: “tPA patients on average recover two thirds of the way toward normal versus half-way toward normal for placebo patients, with a particular increase in the rate of complete recovery with tPA.”

https://www.ahajournals.org/doi/full/10.1161/STROKEAHA.110.583807

What do skeptics do, they cite Hoffman’s paper without even mentioning everything else! Gives the reader a skewed perception of reality. This is not scholarship or fair criticism.
See this article by the same NNT author that illustrates my point:
After Re-Analysis, No Trials Show Efficacy of tPA in Acute Ischemic Stroke - ACEP Now

Regarding ECASS3 re-analysis:
Alper et al. 2020 did find statistical significance adjusting for the baseline differences in ECASS3, however he required to organize the data according to the original paper. A fair criticism by Alper is that according to him these conditions were not prespecified but post-hoc. There is a previous study adjusting for baseline difference in ECASS3 and they observed the treatment effect persisted.

Importantly, 2812 patients from a pooled meta-analysis support that time window.

Lastly, post hoc data cannot change the conclusion of a RCT, that would be a gross over interpretation. If that would be the case, then I would claim after re-analysis ALL tPA studies are now positive, after all for all the tPA studies there is post hoc data demonstrating benefit.

"3. The literature on primary EVT without tPA (SKIP, DIRECT-MT) seem somewhat mixed, possibly because of the non-inferiority trial design. Are there any current or upcoming trials that are expected to provide clinical equipoise on the topic?"

There are 6 trials in total, some still not published. 4 out of 6 trials failed to demonstrate non-inferiority. The 2 European/north American trials failed to demonstrate non-inferiority.

A pooled meta-analysis is on its way. IMO, thrombolysis (TNK or tPA) prior to thrombectomy is here to stay, but will probably be skipped in individual cases where the bleeding risk is high.

DEVT: positive
DIRECT-MT: positive
SKIP: failed to demonstrate non-inferiority
Mr CLEAN NO IV: failed to demonstrate non-inferiority
SWIFT DIRECT: failed to demonstrate non-inferiority
DIRECT SAFE: failed to demonstrate non-inferiority

 

[johnny_bananas]

I tried to attach two graphics to the original post but I was unable to, so I attached them here.

Figure below demonstrating early neurological improvement (NIHSS at 24hr) in tPA vs placebo, the x-axis is different definitions of ENI based on cut-offs of NIHSS. The only one that was not significant was NIHSS >4 (the primary outcome in the study), all other definitions were significant (i.e. NIHSS >5 and so on).

Figure below from Saver et al. 2010 - demonstrating percent change of NIHSS at 90 days between tPA and placebo group. Addressing the concern raised by Hoffman.

 

[johnny_bananas]

I'm an EM doc married to a neurologist. We have this conversation at least once a month.

1. Are there any randomized trials supporting the phenomenon of "tPA-aborted stroke"? The only thing that I am familiar with is the phase I NINDS trial which showed no difference at 24 hours.

2. A commonly cited refrain is that after re-analysis of NINDs and ECASS-3 to adjust for baseline indifference, the statistical significance of the outcomes was lost. This leads to the often-quoted "no RCTs support the administration of tPA" and was what primarily led to the change in theNNT.com.

3. The literature on primary EVT without tPA (SKIP, DIRECT-MT) seem somewhat mixed, possibly because of the non-inferiority trial design. Are there any current or upcoming trials that are expected to provide clinical equipoise on the topic?

I am curious, in your opinion how common is the skepticism about tPA in the EM community, and how much of an influence do EM blogs, podcasts, NNT website have? It seems like those sources are quoted often.

 

[xenotype]

Maybe.

The counterargument to that, however, is that in most contexts, the decision to give tPA, the administration of tPA (sometimes even the physical act of starting the infusion) and the associated liability with any complications of thrombolysis lies with the emergency physician. Certainly not arrogance to be somewhat skeptical of a drug with some risk of significant complications which you may be held liable for.

Telestroke gets rid of all these problems for you. Neurologist examines patient, directly takes history, orders the tPA in the EMR themselves, and is virtually present when tPA is administered and managing blood pressure directly. Sure, you carry liability as well but no longer the largest amount of liability as you did not order it. Telestroke is also now available pretty much anywhere including many very remote, 'podunk' ERs along with free standing EDs.

As for the guy with nothing but anecdotal personal experience that tPA doesn't work along with the same tired arguments about the irrelevant trials conducted outside of the 4.5 hour window- absolutely ridiculous. Hope you are prepared to get sued/peer reviewed and defend your substandard care- as others point out the legal risk is appropriately almost all on the side of not offering when it should have been offered.

 

[johnny_bananas]

Telestroke gets rid of all these problems for you. Neurologist examines patient, directly takes history, orders the tPA in the EMR themselves, and is virtually present when tPA is administered and managing blood pressure directly. Sure, you carry liability as well but no longer the largest amount of liability as you did not order it. Telestroke is also now available pretty much anywhere including many very remote, 'podunk' ERs along with free standing EDs.

As for the guy with nothing but anecdotal personal experience that tPA doesn't work along with the same tired arguments about the irrelevant trials conducted outside of the 4.5 hour window- absolutely ridiculous. Hope you are prepared to get sued/peer reviewed and defend your substandard care- as others point out the legal risk is appropriately almost all on the side of not offering when it should have been offered.

Such an important point about telestroke, I am not sure why it is not more common in the US. In Canada telestroke is ubiquitous, ED physicians activate a stroke protocol and that is it.

If I was an ED physician who uncommonly administers tPA and evaluates acute stroke patients, and all I had for support was a telephone conversation and someone else reading the CT/CTA scan for me telling me what they see, and I was asked to take on that liability and administer tPA, I too would not be happy with that situation.

 

[DD214]

If I was an ED physician who uncommonly administers tPA and evaluates acute stroke patients, and all I had for support was a telephone conversation and someone else reading the CT/CTA scan for me telling me what they see, and I was asked to take on that liability and administer tPA, I too would not be happy with that situation.

Hence, my Eddie Haskell reference

I'm glad you're finally able to acknowledge the perils of medical practice outside of your bubble

 

[xenotype]

Such an important point about telestroke, I am not sure why it is not more common in the US. In Canada telestroke is ubiquitous, ED physicians activate a stroke protocol and that is it.

If I was an ED physician who uncommonly administers tPA and evaluates acute stroke patients, and all I had for support was a telephone conversation and someone else reading the CT/CTA scan for me telling me what they see, and I was asked to take on that liability and administer tPA, I too would not be happy with that situation.

It is becoming ubiquitous here and is already available in small town ERs. I think the telephone call to the neurologist to discuss tPA is very antiquated and should just go away. Who wants to be on the other end of that call not having examined a patient themselves?

 

[Lexdiamondz]

Telestroke gets rid of all these problems for you. Neurologist examines patient, directly takes history, orders the tPA in the EMR themselves, and is virtually present when tPA is administered and managing blood pressure directly. Sure, you carry liability as well but no longer the largest amount of liability as you did not order it. Telestroke is also now available pretty much anywhere including many very remote, 'podunk' ERs along with free standing EDs.

As for the guy with nothing but anecdotal personal experience that tPA doesn't work along with the same tired arguments about the irrelevant trials conducted outside of the 4.5 hour window- absolutely ridiculous. Hope you are prepared to get sued/peer reviewed and defend your substandard care- as others point out the legal risk is appropriately almost all on the side of not offering when it should have been offered.

I work in the largest metro area in north america. Most ERs who don't have 24h neuro coverage in house dont have telestroke either.

 

[johnny_bananas]

I work in the largest metro area in north america. Most ERs who don't have 24h neuro coverage in house dont have telestroke either.

Do you mind if I ask, just curious how it works. So you evaluate the patient yourself, and the CT/CTA is read by the radiologist. Do you review with neurology over the phone, or make the decision on your own?

 

[Lexdiamondz]

Do you mind if I ask, just curious how it works. So you evaluate the patient yourself, and the CT/CTA is read by the radiologist. Do you review with neurology over the phone, or make the decision on your own?

the former

to clarify, I've never disagreed w neuro regarding giving tPA. but for people who operate in a similar environment to mine where the ER doc is the one physically in front of the pt, I understand having some skepticism.

 

[johnny_bananas]

the former

to clarify, I've never disagreed w neuro regarding giving tPA. but for people who operate in a similar environment to mine where the ER doc is the one physically in front of the pt, I understand having some skepticism.

How do you feel about that arrangement?

To me it sounds unnecessarily stressful for both physicians, the neurologist is relying on the neurological exam and history from the ED physician, while the ED physician is relying on sound advice from the neurologist who did not examine the patient, and the ED physician in the end takes on a lot of liability.

Not sure why telestroke doesn't exist in your region, that would be a great solution, a single stroke neurologist could cover multiple hospitals at a time.

 

[Lexdiamondz]

How do you feel about that arrangement?

To me it sounds unnecessarily stressful for both physicians, the neurologist is relying on the neurological exam and history from the ED physician, while the ED physician is relying on sound advice from the neurologist who did not examine the patient, and the ED physician in the end takes on a lot of liability.

Not sure why telestroke doesn't exist in your region, that would be a great solution, a single stroke neurologist could cover multiple hospitals at a time.

I'm not a fan of it to be honest.

That being said, the reality behind this is often times economic and political, not practical. I'm 100% sure the neuro group that staffs our hospital would push back on it, and nobody wants to pay for coverage in house.

I trust (most) of the neuro peeps though so I'm usually okay with their judgement over the phone

 

[xenotype]

I work in the largest metro area in north america. Most ERs who don't have 24h neuro coverage in house dont have telestroke either.

I also work in a large metro area and almost every small to medium sized hospital has telestroke coverage, even many of the FSEDs. This is a problem with your region, and the big telestroke groups provide coverage in the majority of states in the country already.

I'm not a fan of it to be honest.

That being said, the reality behind this is often times economic and political, not practical. I'm 100% sure the neuro group that staffs our hospital would push back on it, and nobody wants to pay for coverage in house.

I trust (most) of the neuro peeps though so I'm usually okay with their judgement over the phone

TPA rate across several studies and internally in major telestroke providers indicate the tPA rate for patients that receive telestroke as opposed to just telephone consults typically doubles with no difference in rates of sICH. Link provided to AHA summary on the data.

The only reason many places aren't forced to pay for telestroke yet is because some local guy is for whatever reason willing to wake up overnight and provide phone consults for free, or drop whatever they are doing in busy clinic to answer the phone. This model is dying rapidly as it doesn't make sense for outpatient neurologists lifestyle wise, liability wise, for clinic productivity/financially, and the patient care isn't as good as fewer patients actually get tPA. Anyone providing acute stroke care should be doing a lot of it and not just giving tPA once a month. It'd be like you providing cross coverage overnight for 50 inpatient beds because they couldn't get a hospitalist to provide the coverage- a total waste of your time and inappropriate.

Edit- link fixed

 

[johnny_bananas]

I also work in a large metro area and almost every small to medium sized hospital has telestroke coverage, even many of the FSEDs. This is a problem with your region, and the big telestroke groups provide coverage in the majority of states in the country already.


TPA rate across several studies and internally in major telestroke providers indicate the tPA rate for patients that receive telestroke as opposed to just telephone consults typically doubles with no difference in rates of sICH. Link provided to AHA summary on the data.

The only reason many places aren't forced to pay for telestroke yet is because some local guy is for whatever reason willing to wake up overnight and provide phone consults for free, or drop whatever they are doing in busy clinic to answer the phone. This model is dying rapidly as it doesn't make sense for outpatient neurologists lifestyle wise, liability wise, for clinic productivity/financially, and the patient care isn't as good as fewer patients actually get tPA. Anyone providing acute stroke care should be doing a lot of it and not just giving tPA once a month. It'd be like you providing cross coverage overnight for 50 inpatient beds because they couldn't get a hospitalist to provide the coverage- a total waste of your time and inappropriate.

Do you mind linking that study, I would love to read it but the link doesn't seem to work.