tPa Clinical Policy

[Arcan57]

Undoubtedly this is old news to some of you, but the latest ACEP News had a piece of the ACEP clinical policy for giving t-PA. It's now stating that it "should be offered" to patients in the window w/o exclusion criteria. It won't change my practice, but I've got to think for a lot of the anti-tPA crowd that $%$ just got real.

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[name?]

Yep. It's amazing that it's got such strong support on such weak evidence, but now you've got our largest national organization saying to lyse away without a good reason not to. Crazy. I have to imagine that if you had to cut someone open to cure their stroke with the same benefit:harm concerns, no one would agree with truly informed consent. It's looks so innocuous and sounds so helpful in that little syringe...

 

[xaelia]

I kicked the hornet's nest on this last month when it was announced:
http://www.emlitofnote.com/2013/01/new-acep-tpa-clinical-policy.html

You'll see a significant response in the coming weeks, but I can't provide any details at this time.

Write your local chapter or the national office with your concerns.

 

[iridesingltrack]

Yep. It's amazing that it's got such strong support on such weak evidence, but now you've got our largest national organization saying to lyse away without a good reason not to. Crazy. I have to imagine that if you had to cut someone open to cure their stroke with the same benefit:harm concerns, no one would agree with truly informed consent. It's looks so innocuous and sounds so helpful in that little syringe...

I kicked the hornet's nest on this last month when it was announced:
http://www.emlitofnote.com/2013/01/new-acep-tpa-clinical-policy.html

You'll see a significant response in the coming weeks, but I can't provide any details at this time.

Write your local chapter or the national office with your concerns.

Opposition to the use of tPA in the 0-3 hour window makes no sense to me what so ever. In the interest of full disclosure, I am EM trained and currently a neurocritical care and stroke fellow that continues to attend in a community and academic ED. The point in stating this is to share that I have significant first-hand experience with the use of tPA from the ED perspective as well as the down-stream in patient perspective. Also, I am well informed on the literature on tPA for stroke and I simply don't understand where the reluctance arises from. By no means am I a so-called tPA "zealot." I just accept the data. NINDS has been re-analyzed to the point of being boring...and the results stand, excepting Dr. Hoffman's paper. The paper that Dr. Hoffman published cannot stand methodologically. ECASS III demonstrated justification for the 4.5 hr window.

I know everyone is saying, what about IST-3...What about IST-3? That study, was a very different trial by design and cohort; it clearly showed that we should not treat beyond 4.5 hrs and should be very cautious in the elderly. However, the 0-3 hour window is clearly confirmed by IST-3, even in the elderly. Which is interesting.

I find the statement above regarding "weak evidence" to be staggering. Ultimately, I am not understanding why so much energy is dedicated to opposition of what amounts to be one of the most studied therapies that we use. I would not argue better mortality, few would; however, this treatment can give someone their life back by improving their possibility of recovery.

I support the ACEP clinical policy and think that it is somewhat embarrassing that it has taken this long for it to be published.

FWIW, I have never received a dime from pharma.

iride

 

[deleted109597]

FWIW, I have never received a dime from pharma.

iride

Perhaps you should. All of the authors of those studies did.
I can't tell you what you should do. I can tell people what to consider.
As I've said before, there probably are people out there that tPA would help. We just don't have a good way of identifying them yet.
Policy statements like this harm the specialty by handcuffing physician's in states with terrible medicolegal climates into basically having to give the drug. Hell, I remember neurologists in North Carolina saying that people who are aphasic don't even have to consent.
http://www.thennt.com/nnt/thrombolytics-for-stroke/

Even scarier, what's the next step? http://www.medpagetoday.com/MeetingCoverage/AAN/38017

 

[WilcoWorld]

iride: NINDS had better results than Hoffman gives it credit for, but I don't think ECASS III demonstrated anything convincingly.

To the uninitiated: NINDS is what's typically used to support tPA at 0-3 hours. ECASS III is what supports tPA from 3-4.5 hours.

 

[WilcoWorld]

http://www.medpagetoday.com/MeetingCoverage/AAN/38017

Grrr. That study appears to be comparing apples to rotten apples.

As in, "Hey, this new therapy works better than another therapy (IV plus intra-arterial tPA)! That must mean it works."

This is a common (but wrong) technique employed to support unsupportable interventions.

It's like saying that a punch in the face and a kick in the groin has better outcomes than a punch in the face and a bucket of tar, so we should clearly be punching faces and kicking groins.

OK, I see I'm getting a bit ridiculous with my analogies...I'll stop here.

 

[WilcoWorld]

I guess I lied, one more EBM point.

The studies that showed that tPA performs less well at non-stroke centers were interpreted through, what seems to me, a clearly biased lens; When an intervention is re-tested, and the original results aren't found, the scientific response should be to question the first experiment's results. This is not what's happened with tPA. Rather, the results showing that tPA didn't work as well when tested in the community were interpreted to say that we should divert stroke patients to Stroke Centers(TM) so that more people can get tPA.

That's some brilliant MBM (marketing based medicine) there.

 

[justaregularmed]

NINDS was a very strict study you either got better or you didn't, it showed TPA made more people get better at increased risk of fatal ICH.

Per the NNT "Benefit = NNT of 8 for post-hoc ‘favorable' outcome measure".

Favorable is almost neurologically intact, whats the problem here.

I don't understand why the NNT is so skeptical, did he not see "Scores of 95 or 100 on the Barthel index, <1 on the NIHSS and the modified Rankin scale, and 1 on the Glasgow outcome scale were considered to indicate a favorable outcome."

 

[deleted109597]

NINDS was a very strict study you either got better or you didn't, it showed TPA made more people get better at increased risk of fatal ICH.

Per the NNT "Benefit = NNT of 8 for post-hoc ‘favorable’ outcome measure".

Favorable is almost neurologically intact, whats the problem here.

I don't understand why the NNT is so skeptical, did he not see "Scores of 95 or 100 on the Barthel index, <1 on the NIHSS and the modified Rankin scale, and 1 on the Glasgow outcome scale were considered to indicate a favorable outcome."

Uh, you pick one of the two positive studies, and ignore all the negative ones?

 

[UnderwaterDoc]

Whether TPA works or not, now that ACEP changed their policy we are basically stuck giving it, since that is the standard that we will be judged by when we are on the stand.

 

[justaregularmed]

Uh, you pick one of the two positive studies, and ignore all the negative ones?

What paper clearly shows no benefit of TPA when given in < 3 hours? I have two NINDS and IST-3. What do you have?

Again IST-3 shows Alive and favourable outcome (0+1) 363 (24%) 320 (21%) 1·26 (1·04 to 1·53) 0·018, which is in line with NINDS. This was overall too not just within 3 hours.

 

[iridesingltrack]

Perhaps you should.

http://www.thennt.com/nnt/thrombolytics-for-stroke/

I generally enjoy looking at the NNT website but this article gives me pause. My biggest problem is that we know there is shift in the NNT for benefit and harm based on the timing of the administration of the tPA and this has been completely ignored on the website. It is clear that if we give tPA nearer the onset of symptoms they are more likely to have a good recovery and less likely to hemorrhage.

Also, the results they show on the website don't jive with peer-reviewed published results. For those interested, just Google "tpa for stroke number needed to treat" and you will find several articles that are peer reviewed in reputable journals that show vastly different numbers than the NNT website.

iride: NINDS had better results than Hoffman gives it credit for, but I don't think ECASS III demonstrated anything convincingly.

WW I don't disagree with anything you've stated. I think that the 4.5 hr window may be used clinically with caution and careful consideration.

Uh, you pick one of the two positive studies, and ignore all the negative ones?

While I do enjoy the pithy comment and entertaining photo you and I both know that these studies are not all created equally. Some of the studies had very small sample sizes and were pilot studies. Several of the "negative" studies used higher doses of tPA and were dose finding studies (higher doses cause harm). Others gave concomitant antiplatelet therapy as part of the tPA dose (we now routinely hold antiplatelet and anticoagulation for 24 hrs after tPA and safety imaging). Still others had protocols that gave tPA out to 6 hrs. Obviously, these studies are not ignored, they greatly inform our clinical use of tPA. That is, they were negative for good reason. When each of those studies started we had equipoise about a question and these studies have helped improve the safety profile of the drug and target how, when, and to whom we give it.

iride

 

[xaelia]

What paper clearly shows no benefit of TPA when given in < 3 hours? I have two NINDS and IST-3. What do you have?

Again IST-3 shows Alive and favourable outcome (0+1) 363 (24%) 320 (21%) 1·26 (1·04 to 1·53) 0·018, which is in line with NINDS. This was overall too not just within 3 hours.

Negative studies for benefit:
MAST-I
MAST-E
ECASS
ECASS II
NINDS, part 1.
ASK
ATLANTIS-A
ATLANTIS-B
DIAS-2
IST-3

ECASS III is positive, but is unbalanced between treatment arms favoring tPA and its results should be confirmed in a non-pharma-funded trial.

IST-3 is an open-label, unblinded study with a flawed outcomes measurement methodology that was negative for its primary outcome. If you believe IST-3 is positive, you don't know anything about sources of bias in trial design and interpretation.

And you can't just pick and choose the < 3h patients from these studies to combine them for meta-analysis because it removes the protection of randomization, doesn't account for heterogeneity between enrollment/treatment criteria, and doesn't account for the other confounding effects of post-stroke treatment which have magnitude of benefit greater than the purported benefit from tPA.

tPA probably helps some people. It also harms people. The stroke literature is replete with evidence of variable efficacy between subgroups. We ought to be doing more work to tailor and narrow the treatment population to the few that are the best candidates for benefit, rather than irresponsibly expand the treatment to all comers. Not to mention, even at academic stroke centers with in-house vascular neurology, we're treating a ton of stroke mimics (I got a tPA'd aortic dissection in sign-out the other day) – there's a big difference between clinical trial efficacy and real-world effectiveness that is probably erasing any theoretical margin for benefit for tPA.

This policy will only stand if no one speaks out. tPA is still an experimental therapy with unclear benefits and unclear ideal treatment population, and we shouldn't let ourselves be pushed to give it.

 

[Rendar5]

I generally enjoy looking at the NNT website but this article gives me pause. My biggest problem is that we know there is shift in the NNT for benefit and harm based on the timing of the administration of the tPA and this has been completely ignored on the website. It is clear that if we give tPA nearer the onset of symptoms they are more likely to have a good recovery and less likely to hemorrhage.

Also, the results they show on the website don't jive with peer-reviewed published results. For those interested, just Google "tpa for stroke number needed to treat" and you will find several articles that are peer reviewed in reputable journals that show vastly different numbers than the NNT website.



WW I don't disagree with anything you've stated. I think that the 4.5 hr window may be used clinically with caution and careful consideration.



While I do enjoy the pithy comment and entertaining photo you and I both know that these studies are not all created equally. Some of the studies had very small sample sizes and were pilot studies. Several of the "negative" studies used higher doses of tPA and were dose finding studies (higher doses cause harm). Others gave concomitant antiplatelet therapy as part of the tPA dose (we now routinely hold antiplatelet and anticoagulation for 24 hrs after tPA and safety imaging). Still others had protocols that gave tPA out to 6 hrs. Obviously, these studies are not ignored, they greatly inform our clinical use of tPA. That is, they were negative for good reason. When each of those studies started we had equipoise about a question and these studies have helped improve the safety profile of the drug and target how, when, and to whom we give it.

iride

We've got guesses as to the ideal patient population, but stopped studying because it was pushed so hard to become standard of care (which prevents further randomized evidence-based studies) that it became "unethical" to actually not give it to someone. Subgroup analysis are often misused. When it should be used to help design the next experiment, it's instead used as "proof" of something, just see that one spine doctor continue to push steroids in spinal injury even in Cochrane. The reason there's the pushback from EM is that we are made to give it, and we see people die from the therapy, both from giving it to stroke mimics (aortic dissection, and that one conversion disorder lady), and from giving it to actual stroke patients with relatively minor symptomatology. when I did academics, I saw neuro push to give tpa on a guy with some numbness in his pinky finger... you know, risks:benefits and all that.

 

[xaelia]

Annals of Emergency Medicine Journal Club on IST-3, free fulltext:
rt-PA and Stroke: Does IST-3 Make It All Clear or Muddy the Waters?

(disclosure: I'm the first author)

 

[WilcoWorld]

Annals of Emergency Medicine Journal Club on IST-3, free fulltext:
rt-PA and Stroke: Does IST-3 Make It All Clear or Muddy the Waters?

(disclosure: I'm the first author)

Oh, c'mon, everyone knows Annals of EM is a throwaway...

 

[iridesingltrack]

Apologies for a long post. However, a smidge of detail is important to understanding why these trials Xaelia referenced were negative.

This policy will only stand if no one speaks out. tPA is still an experimental therapy with unclear benefits and unclear ideal treatment population, and we shouldn't let ourselves be pushed to give it.

For patients < 80 yrs presenting within 0-3 hrs of symptom onset, no it is not experimental. This question is as settled as it ever will be. To study this further is unethical. For patients either >/=80 or windows from 3 - 4.5 hrs, I agree it remains worthy of investigation. I think that treatment windows beyond 6 hours are also settled for fibrinolytic therapy, this likely harms people.

For residents and medical students, do yourselves a favor and learn about this on your own. There is a reason, based on data, that the ACEP policy came to be...just read for yourselves.

Negative studies for benefit:
MAST-I
MAST-E
ECASS
ECASS II
NINDS, part 1.
ASK
ATLANTIS-A
ATLANTIS-B
DIAS-2
IST-3

ECASS III is positive, but is unbalanced between treatment arms favoring tPA and its results should be confirmed in a non-pharma-funded trial.

IST-3 is an open-label, unblinded study with a flawed outcomes measurement methodology that was negative for its primary outcome. If you believe IST-3 is positive, you don't know anything about sources of bias in trial design and interpretation.

MAST-I: 1. Not a tPA study they used Streptokinase. 2. Allowed concomitant ASA use. 3. Treatment window of up to 6 hrs.

MAST-E: 1. Not a tPA study they used Streptokinase. 2. Treatment window of 6 hours (half were treated beyond 4 hours). 3. 2/3rds had heparin given with lysis (turns out this doesn't work well).

ECASS: 1. Used a 1.1mg/kg dose of tPA (higher than usual). 2. Treatment window of 6 hours. Mean treatment time was over 4 hrs. 3. If you exclude the 100 or so major protocol violations that are rightly included in the intention to treat analysis, the trial is positive. Interestingly, the majority of the protocol violations were obvious evidence of infarction on the initial head CT suggesting time from onset was even further out than estimated by witnesses.

ECASS II: 1. Treatment window of 6 hours with only 1/5 being treated within 3 hrs.

NINDS, part 1. 1. The primary outcome of this study was at 24 hours. When combined with Part 2, the results at 90 days remained positive. For those who didn't know there were two parts to the original NINDS trial, they were published together in the same journal and were ultimately combined for analysis.

ASK: 1. Not a tPA study they used Streptokinase. 2. Per protocol patients were given ASA within 4 hours of Streptokinase. 3. Treatment window to 4 hours.

ATLANTIS-A: 1. Treatment window of 6 hours. Trial was stopped early for large number of hemorrhages occurring during the 5-6 hour mark. They only enrolled 140 something patients.

ATLANTIS-B: 1. Recapitulation of part A with new protocol using a treatment window of 0-5 hours. However, due to FDA approval of tPA the window changed from 0-5 to 3-5 hrs. Only 30 patients were enrolled in the 0-5 window. The mean time to tPA was over 4 hours.

DIAS-2: 1. Not a tPA study they used Desmoteplase. 2. They seriously used a window of 9 hours, 'nuff said.

IST-3: I really liked your journal club article in Annals. However, you know that we can't have it both ways: either it is garbage and we throw it out, which is reasonable, or we keep it in and recognize the positive results at 0-3 hours, in an overall negative study. Personally, I say trash it. It hasn't changed my clinical practice at all.

Regarding the unbalanced stroke severity in ECASS 3, to be clear to those that have not read the study, we are talking about an NIHSS of 10 vs 11. This was indeed statistically significant, but few feel this is clinically relevant.

I would add that in the recent IMS-3 trial the outcomes in the IV-tPA arm also replicated the NINDS trial.

So, of the 10 trials you reference, 4 simply are not tPA studies. I am not sure of your goal here. But, you hold a megaphone on SDN and on your websites; the above was a misleading post. I doubt it was purposeful. I suspect you had this already in a slide set or something and you just pasted it in, but the post you were referring to was specifically about tPA. The remaining 6 trials represent important iterations and protocol changes made to better utilize tPA, IST-3 notwithstanding.

Based on the data, I believe time to recannulization is the most important feature of thrombolytic therapy. Delay clearly results in a decrease in benefit and an increase in harm.

Cheers,
iride

 

[iridesingltrack]

We've got guesses as to the ideal patient population, but stopped studying because it was pushed so hard to become standard of care (which prevents further randomized evidence-based studies) that it became "unethical" to actually not give it to someone. Subgroup analysis are often misused. When it should be used to help design the next experiment, it's instead used as "proof" of something, just see that one spine doctor continue to push steroids in spinal injury even in Cochrane. The reason there's the pushback from EM is that we are made to give it, and we see people die from the therapy, both from giving it to stroke mimics (aortic dissection, and that one conversion disorder lady), and from giving it to actual stroke patients with relatively minor symptomatology. when I did academics, I saw neuro push to give tpa on a guy with some numbness in his pinky finger... you know, risks:benefits and all that.

The ideal patient population is an acute ischemic stroke up to age 80 yrs, within 3 hours of symptoms onset. Consider therapy in the 3-4.5 hrs window with care.

The risk of intracerebral hemorrhage from tPA in the stroke mimic is 0.8%. If you aren't sure if this is conversion disorder/complex migraine etc or not, and can't get a timely MRI, the general ED doc should err on the side of treatment assuming the patient otherwise qualifies.

Treating an aortic dissection with tPA based on missed diagnosis is a clean kill. No doubt about it. This is indeed suboptimal. To be clear, this is not a tPA problem, this is a diagnosis problem. We all make errors but tPA didn't harm this patient the decision making did.

Treating a person with fibrinolytics for what amounts to be an NIHSS of 0-1 for isolated finger numbness is dumb. I hope you told your consultant to get out of your ED (though, I wonder what the circumstances were that led them to be called in the first place). It is common sense that the person you describe should not be treated.

Cheers,
iride

 

[Hamhock]

Thank you xaelia and irdesingltrank (and others). This is a very useful discussion.

I am especially grateful to irdesingltrank, as I lean more towards xealia's interpretations and conclusions. I don't have access to many people on the other side of things who will discuss this in a manner other than dismissive or blind.

With that in mind, I have three more questions for irdesingltrank:

1. Why toss out IST-3? How can it NOT change your practice? It seems to me the most applicable of all studies for the way tpa is used in academic centers (from what I have seen and heard from friends)?
-if you keep it, how can you tpa at greater than 3 hours?

2. Do you only tpa based on the strict NINDS criteria? Do you "consent" with the IST-3 data as a background?

HH

HH

 

[zinjanthropus]

this is the best discussion on sdn in a long time - thanks

 

[xaelia]

I suspect you had this already in a slide set or something and you just pasted it in,

Heh, nah, just a list in my head of fibrinolytics studies that were negative. Your critiques of each of them are accurate.

Except ECASS III &#8211; where NIHSS on presentation is the greatest determinant of eventual outcome &#8211; yes, I do believe that was a clinically significant difference. I'd also point out that the ECASS III publication was modified in 2011 to reflect a statistical error regarding the difference in "history of stroke" between the two groups &#8211; which now becomes significant favoring the tPA group (7.7% tPA vs. 14.1% placebo). Throwing out the the 11% of folks with a history of stroke, the OR for benefit becomes 1.19 (CI 0.89 to 1.59). There are very few patients I would consider tPA as likely beneficial therapy in the 3 to 4.5 hour window.

The risk of intracerebral hemorrhage from tPA in the stroke mimic is 0.8%. If you aren't sure if this is conversion disorder/complex migraine etc or not, and can't get a timely MRI, the general ED doc should err on the side of treatment assuming the patient otherwise qualifies.

Why so accepting of collateral damage? The bleed rates aren't high &#8211; but it's still embarrassing we're treating so many mimics. And all these studies are from academic stroke centers, not community. The "Cleveland Experience" isn't applicable to current knowledge by now, but still, you can see how easily tPA turns into a weapon.

The ideal patient population is an acute ischemic stroke up to age 80 yrs, within 3 hours of symptoms onset.

No. Within that population, we still ought not be treating all comers. We know there are patients who have a lower risk of benefit, and we shouldn't be lysing them. DRAGON, iScore, SPAN-100, ASTRAL, HAT, SEDAN, SITS-ICH, Stroke-TPI etc. it's clearly an area of active research to parse out a decision instrument for use at the bedside to stratify these folks &#8211; and, even under 3 hours, you're going to have folks that aren't ideal for tPA. You, me, <3 hours &#8211; if you believe the data &#8211; sure. 76 years old, glucose 450, SBP 190, wheelchair bound &#8211; no, please, no.

It also bothers me to see the evolution of the pro-tPA argument, which you allude to for ECASS I &#8211; "the reason these patients in these trials failed is because they were outside the strict NINDS criteria/protocol violations!" ... but now we're trying to lyse wake-up strokes and all sorts of other folks either outside the time window and outside the strict physiologic criteria of NINDS. There are industry forces at work here.

IST-3 &#8211; basically junk science. A lot of folks are highly entertained by the fact that this is open-label with all the biases favoring the treatment arm, they were patients for whom the treating clinician thought they were ideal candidates otherwise outside the license criteria &#8211; and there ain't much there. In my book, when you run a trial all set to be solidly positive, and you have to resort to adjusted secondary endpoints to make it positive, it's probably hiding harms. It's basically a litmus test for lunacy when you see something like the editorial that accompanied it in the Lancet, screaming about how it's positive up to 6 hours and the "default situation" should be to lyse everyone.

And, then &#8211; this is where you'll find we have irreconcilable differences &#8211; you have to believe the data. John Ionnadis writes about this a lot &#8211; that negative sponsored trials beget more sponsored trials. Positive trials &#8211; we're done! We rolled double sevens with NINDS, and now it's approved and we're going to stop providing tPA and placebo to IST-3. You can see this with the MERCI group persistently killing folks with mechanical rescue devices &#8211; or like with cangrelor in STEMI, try a third study and change the primary outcome &#8211; someday, you'll get lucky and roll a benefit! There's just too much conflict-of-interest across the stroke literature for me to believe the data.

I would add that in the recent IMS-3 trial the outcomes in the IV-tPA arm also replicated the NINDS trial.

Careful, it's a fallacy to compare any groups from trials performed under different conditions at different centers. Contemporary post-stroke care (pneumonia prevention, metabolic treatment, antiplatelets, coordinated stroke rehab, etc) is far different today than it was in NINDS. You ought to expect the placebo and tPA groups from NINDS to both do _much_ better today. To get excited because an IMS-3 arm is equivalent to a trial from the 1990s where there's no experience with a new drug is meh.

I believe time to recannulization is the most important feature of thrombolytic therapy. Delay clearly results in a decrease in benefit and an increase in harm.

I usually write something akin to that when discussing stroke therapy on my blog &#8211; recanalization (which doesn't happen as often as most assume with tPA!) is great, earlier the better, just need to be more careful about selecting patients, and the treatment effect probably isn't as large as its made out to be &#8211; but the new endovascular rescue trials with the "favorable penumbra" on imaging makes me wonder about the physiologic basis of tPA treatment. Brain is dead is died with stroke, and the theory of the "penumbra" at the edge of the watershed that can be salvaged with recanalization &#8211; why didn't endovascular recanalization help those folks? Just claiming those crappy old devices were causing more procedural harms that outweighed the treatment effects?

 

[Old_Mil]

Should be offered doesn't automatically mean should be given.

My stroke talk usually goes something like I'm sure that you've heard of the stroke drug. Here are the benefits, but the risk is that you can bleed into hour brain and die or have a worsening of your disability. Here is the function that Mr/Mrs Jones has lost. Some patients accept the risks and the drug, others dont. My documentation always reads that the drug was offered and that after an explanation of the risks and benefits the patient/family accepted or refused TPA.

I have found that with this approach most families or patients will, self select themselves out of the TPA group with a low NIH score, and hey you did offer.

Sent from my A110 using Tapatalk 2

 

[iridesingltrack]

With that in mind, I have three more questions for irdesingltrank:

1. Why toss out IST-3? How can it NOT change your practice? It seems to me the most applicable of all studies for the way tpa is used in academic centers (from what I have seen and heard from friends)?
-if you keep it, how can you tpa at greater than 3 hours?

2. Do you only tpa based on the strict NINDS criteria? Do you "consent" with the IST-3 data as a background?

HH

I agree with xaelia about the quality of IST-3. This study went on for around 10 years, starting in 2000. The study initially planned to enroll 6000 people but some time in 2007 they realized this would never happen. So, they completely changed their analysis plan and their planned sample size to about 3000. Big changes mid-stream in a study always make me skeptical about the quality.

Additionally, I really don't like (trust) the design of the trial. They set out to enroll people older than 80, up to 6 hrs post symptoms in an open label study. They also used something termed a "pragmatic" design in that if the individual clinician had uncertainty of the efficacy of tPA in that particular scenario then the patient should be enrolled. As you might imagine, this could vary dramatically from clinician to clinician. My desire to toss this study are for the following: the design is fraught with bias, the study plan changed significantly during the course of the study, and they used atypical outcome measures and follow up period for stroke trials.

So, the design I feel is too flawed to even consider for alteration in practice. The change they would like is for clincians to begin treating people over age 80 with longer time windows. I am not there. Will I treat over age 80 in the 0-3 window, with extreme caution and great clincal situation. Time windows beyond 0-3 and over 80, some of my colleagues do, but this is really rare and frankly, based on gestalt with hundreds of treats, long family discussions, and less so on data. I do not follow just the NINDS inclusion criteria. In the right clinical situation, I will treat out to 4.5 hrs.

Do IST-3 results generalize to the broader use of tPA? No. This cohort was, by design, selected at inclusion into the study to reflect a very different popluation than those generally treated. Over half the population was over 80. The mean age in the NINDS trial was in the mid-60's, by contrast. Only 1/3 were treated within 0-3 hrs. A very large number, about 1/3 of patients had extremes of stroke severity. Larger strokes are much more likely to bleed and smaller strokes may not benefit from therapy. As Rendar5 pointed out, risk:benefit.

Cheers,
iride

 

[Arcan57]

Should be offered doesn't automatically mean should be given.

The new guidelines now say it should be given for the <3 hr group and offered for the <4.5 hr. It seems crazy not to consent for tPA but I can see a doc losing after family declines on someone <3 hrs that is unable to consent for themselves that has a devastating outcome, especially in one of the more plaintiff friendly states. Regardless of your personal feelings, the standard of care has now been defined and not giving tPA has become significantly riskier.

 

[Old_Mil]

The new guidelines now say it should be given for the <3 hr group and offered for the <4.5 hr. It seems crazy not to consent for tPA but I can see a doc losing after family declines on someone <3 hrs that is unable to consent for themselves that has a devastating outcome, especially in one of the more plaintiff friendly states. Regardless of your personal feelings, the standard of care has now been defined and not giving tPA has become significantly riskier.

The problem is that even if you meet the standard of care if you push tpa and give someone a devastating head bleed you are going to get sued.

The only solution seems to be moving to Texas.

 

[iridesingltrack]

Except ECASS III – where NIHSS on presentation is the greatest determinant of eventual outcome – yes, I do believe that was a clinically significant difference.

I remain skeptical that a one point difference in NIHSS is clinically meaningful...The inter-rater reliability is pretty good but I see 1+ point differences commonly just based on who is doing the exam. By gones...

I'd also point out that the ECASS III publication was modified in 2011 to reflect a statistical error regarding the difference in "history of stroke" between the two groups – which now becomes significant favoring the tPA group (7.7% tPA vs. 14.1% placebo).

I am glad you brought this up, I had forgotten about it. This is a very reasonable critique of ECASS III. I got nothing here other than to say, and I know how people will respond, the plurality of data continues to suggest a benefit. I agree though, use time beyond 3 hours carefully. Pick the right patient.

Why so accepting of collateral damage?

I don't view it that way. My comment in no way is meant to be dismissive of the risk. It is merely that the potential benefit is >>>>> greater than the risk when you are dealing with an equivocal clinical picture.

It is indeed embarrassing to treat a mimic. It is tragic if harm befalls someone because of it. Diagnostics are definitely an area that needs significant research.

No. Within that population, we still ought not be treating all comers.

In 2005 my stroke team saw over 1800 acute ischemic strokes. Of those, only 22% presented within 3 hrs. Only 8% met NINDS inclusion criteria and fewer still were treated. 1. A well informed, well reasoned bedside clinician, talking with the family is the wisest person to make treatment decisions. 2. Taking a small number of eligible people and making it smaller without good reason does risk limiting potential benefit. 3. One of the additional reasons I don't push the longer window too hard is that ECASS III rules only increase eligible population by around 2-3%. We need people to get to the ED faster.

And, then – this is where you'll find we have irreconcilable differences – you have to believe the data.

I agree. We will have to agree to disagree. I will choose a different wording, however. I accept the data (this phrasing has less of a religious tone). Indeed, I accept the subgroup analyses. The reason is that if it were one study's subgroup, sure, I can toss that out; but, the same subgroup consistently shows benefit: < 80 yrs, < 3hrs. That is hard to ignore for me.

Careful, it's a fallacy to compare any groups from trials performed under different conditions at different centers. Contemporary post-stroke care (pneumonia prevention, metabolic treatment, antiplatelets, coordinated stroke rehab, etc) is far different today than it was in NINDS. You ought to expect the placebo and tPA groups from NINDS to both do _much_ better today. To get excited because an IMS-3 arm is equivalent to a trial from the 1990s where there's no experience with a new drug is meh.

Part of the reason that IMS-3 failed to show benefit is that medical management, beyond just tPA, but to be sure tPA is part of it, does so much better than historical expectations. This is being seen in several endovascular studies presented at ISC.

I usually write something akin to that when discussing stroke therapy on my blog – recanalization (which doesn't happen as often as most assume with tPA!) is great, earlier the better, just need to be more careful about selecting patients, and the treatment effect probably isn't as large as its made out to be – but the new endovascular rescue trials with the "favorable penumbra" on imaging makes me wonder about the physiologic basis of tPA treatment. Brain is dead is died with stroke, and the theory of the "penumbra" at the edge of the watershed that can be salvaged with recanalization – why didn't endovascular recanalization help those folks? Just claiming those crappy old devices were causing more procedural harms that outweighed the treatment effects?

IMS-3 showed tPA recanalization rates at 24 hrs to be about 65% for M1 and M2 occlusions. That was better than expected. The ICA recanalization was indeed only about 35%. Endovascular is failing I think because it just takes too damn long to open vessels mechanically, by the time they are open the infarct is completed, and medical management through acute and post acute stroke care has become quite good.

Also, combo therapy or better drugs may be on the horizon. CLEAR-ER trial was very intriguing and has potential. TNK has recanalization rates that are near endovascular levels...we'll see.

Ultimately, I accept that tPA is useful at 0-3 hrs in the < 80 yrs. I, in discussion with the patient and family and right clinical scenario will use the 0-4.5 hrs window. My read of the plurality of the data suggests this will result in a net benefit. tPA is a drug with a potential bite, to be sure, and the best bang for your buck is going to be give it as soon as possible.

iride

 

[iridesingltrack]

The problem is that even if you meet the standard of care if you push tpa and give someone a devastating head bleed you are going to get sued.

The only solution seems to be moving to Texas.

If you are following the guideline and someone has a bleed I think you will be very unlikely to suffer medicolegal ramifications.

I don't work in a great medicolegal environment and my group treats a lot of people (thus, we see hemorrhages) and this has not been a well founded worry.

Talk to the family; talk to the patient; document the conversation; be well informed; and do it fast.

iride

 

[glorfindel]

Fantastic thread. Thank you to all the posters. I've learned a lot.

 

[glorfindel]

The sad fact about tPA is that this medical treatment really is the perfect storm. If you were looking to describe a situation where "informed consent" was monumentally difficult, you'd pick this one.

Patients suffering from a stroke (or stroke mimic) could not be in a worse position to make an informed decision about tPA. Consider the obstacles:

1) It is difficult to obtain clear, reliable, reproducible advice about the topic at hand. When Xaelia and iride can duke it out about the quality of the evidence for and against tPA for as long as they have on this thread, one can't reasonably expect patients to be able to get consistent information from their local ER doctor or neurologist about the pros and cons of tPA while lying in an ER bed, paralyzed on one side of their body and unable to speak.

2) The risk/benefit incommensurability makes the decision difficult in the best of circumstances. "Do I want to trade the risk of being in a wheelchair and drooling all day against the risk that I'll bleed into the head and (probably) die? Hmm.... I don't have much experience of either one, so it'll be difficult to choose between two outcomes I've never experienced before. The behavioral economists are telling me I can't even reliably predict how my own happiness will be affected by the car I buy, so I don't know how I'm gonna decide this one..." Never mind the fact that the decision is frequently being made by a surrogate family member because the patient in question is drooling and can't speak, and it's clear that these are not the best of circumstances.

3) Time pressure. About the only thing everyone can agree on about tPA is that if we're going to give it we'd better give it as soon as possible. So we ask Mrs Smith to make an intrinsically difficult decision for her aphasic husband and we ask her to HURRY UP ABOUT IT. Poor Mrs Smith.

These obstacles make it pretty difficult to give informed consent for tPA. In fact, I go so far as to say that informed consent for tPA is a myth.

We aren't sure in any given case whether pushing tPA will miraculously cure Mr. Smith of his hemiplegia or kill him dead right there, but at least if the outcome is bad we can step away and say, "Well, in the end it was Mrs. Smith that made the decision. She knew the risks."

 

[deleted109597]

If you are following the guideline and someone has a bleed I think you will be very unlikely to suffer medicolegal ramifications.

I disagree. Just being named is suffering.
Also, what you did isn't why they're suing. It's outcomes.

 

[la gringa]

The sad fact about tPA is that this medical treatment really is the perfect storm. If you were looking to describe a situation where "informed consent" was monumentally difficult, you'd pick this one.

Patients suffering from a stroke (or stroke mimic) could not be in a worse position to make an informed decision about tPA. Consider the obstacles:

1) It is difficult to obtain clear, reliable, reproducible advice about the topic at hand. When Xaelia and iride can duke it out about the quality of the evidence for and against tPA for as long as they have on this thread, one can't reasonably expect patients to be able to get consistent information from their local ER doctor or neurologist about the pros and cons of tPA while lying in an ER bed, paralyzed on one side of their body and unable to speak.

2) The risk/benefit incommensurability makes the decision difficult in the best of circumstances. "Do I want to trade the risk of being in a wheelchair and drooling all day against the risk that I'll bleed into the head and (probably) die? Hmm.... I don't have much experience of either one, so it'll be difficult to choose between two outcomes I've never experienced before. The behavioral economists are telling me I can't even reliably predict how my own happiness will be affected by the car I buy, so I don't know how I'm gonna decide this one..." Never mind the fact that the decision is frequently being made by a surrogate family member because the patient in question is drooling and can't speak, and it's clear that these are not the best of circumstances.

3) Time pressure. About the only thing everyone can agree on about tPA is that if we're going to give it we'd better give it as soon as possible. So we ask Mrs Smith to make an intrinsically difficult decision for her aphasic husband and we ask her to HURRY UP ABOUT IT. Poor Mrs Smith.

These obstacles make it pretty difficult to give informed consent for tPA. In fact, I go so far as to say that informed consent for tPA is a myth.

We aren't sure in any given case whether pushing tPA will miraculously cure Mr. Smith of his hemiplegia or kill him dead right there, but at least if the outcome is bad we can step away and say, "Well, in the end it was Mrs. Smith that made the decision. She knew the risks."

AGREE

for the reasons above... the "tPA talk" is my LEAST FAVORITE discussion EVER.

fortunately, it almost never comes up, for the reasons mentioned above. for me, it's usually:
1. low NIHSS
2. prolonged presentation
3. improving/TIA

 

[deleted109597]

http://www.thennt.com/blog/2012/06/delusions-of-benefit-in-the-international-stroke-trial/

Results of the largest and arguably most important trial ever of thrombolytics (clot-busting drugs) for acute stroke were published last week in The Lancet, and the study's conclusions are breathtaking. Not because of the study results, which are unsurprising, but because the authors' conclusions suggest that they have gone stark, raving mad.

The International Stroke Trial 3 (&#8216;IST-3') was a remarkable achievement. The study enrolled 3100 patients, nearly four times that of any previous stroke trial, randomly assigned either to treatment with intravenous thrombolytic drugs, or treatment without the drugs. But unlike earlier studies the &#8216;pragmatic' design of IST-3 was unblinded, used no placebos, and included the elderly, the non-elderly, and those with strokes of all severities. In other words, it enrolled common stroke patients having common strokes, a real-world test of the drugs.

Thrombolytics have remained controversial for acute stroke partly because nine of the eleven major trials to date have demonstrated either no benefit or else harm. Supporters argued, however, that early treatment (0 to 3 hours from symptom onset) in the famous NINDS trial made the study unique (other trials went up to 4 or 6 hours), and justified recommendations for use in the early time period. The 3-hour cutoff faded, however, when a 2005 trial used the drug successfully between 3 and 4.5 hours, and again when a respected review group argued that the data suggest similar effects up to 9 hours. It is now apparent to all that NINDS was not unique, and the stroke world has been waiting with bated breath for a large, high quality effort to retest the fundamental question: do thrombolytics decrease death and disability in acute stroke?

In IST-3 the drug was given between 0 and 6 hours, and the data generated two clear findings: First, the drugs failed to reduce death or dependence at six months. In the thrombolytic group 36.57% were alive and independent, while in the control group the number was 35.13%, a difference of about 1%. The difference would have had to be roughly 5% or more to be considered anything other than a wash.

And second, there was no discernible relationship between timing of administration and drug effect. The drug looked good in the first three hours, but then harmful for the next 90 minutes, and then good again for the next 90. This is a biologically nonsensical (i.e. random) distribution, suggesting that time differences are not a likely mediator of drug effect.

Thus, in one fell swoop every important argument in favor of thrombolytics for acute stroke was dashed. Worse still, the trial was unblinded, and as part of the protocol patients were enrolled only if both they and their doctor considered the drug to be "promising, but unproven." This is a distinct, and marked, advantage for the drug group. Patients and doctors tend to be more hopeful when a "promising" drug is given. Doctors and staff may treat more aggressively, or more attentively, and patients are inspired to work harder toward recovery. Non-blinded trials are known to significantly enhance the effect of any intervention in comparison to control groups. Given the results, it is thus quite possible that the unblinded design of IST-3 has hidden significant harms of thrombolytics.

Whence, then, the authors' claim of benefit? The authors describe a "secondary exploration" of their data using ordinal analysis. This uncommon method of measurement examined if thrombolytics may have &#8216;shifted' some patients toward better categories of outcome, despite not shifting them toward being alive or independent. Lo and behold, it appeared to be so (though only with the help of an unexplained statistical "adjustment"). Of course, in any group of exploratory analyses some will appear favorable by random chance&#8212;which is why there's only one primary outcome in any trial&#8212;because if you keep flipping the coin and moving the goal posts, eventually you'll hit . . . something. Most damningly, in a moment of clarity, the authors themselves have described ordinal analysis (in a separate paper about IST-3) as "not appropriate for the primary analysis of outcome." And yet they write their conclusions as if the illusory "shift" were the primary outcome.

With advances in scientific literacy it has been years since I have seen a top journal allow authors to proclaim a conclusion in direct conflict with their own primary study results. And yet the authors blithely conclude that thrombolytics "improved functional outcome." Worse, an accompanying editorial trumpets that "the role of stroke and emergency physicians is now not to identify patients who will be given rt-PA, but to identify the few who will not." Welcome to Wonderland.

These statements feel not just forced, but frankly delusional. Has neuro gone psycho? The results of IST-3 indicate, at best, a profound disappointment (even the hallucinated benefit would be tinier than any previously claimed) and at worst the beginning of the end for thrombolytics in stroke. In either case, reality may be tough to handle, but it is not a matter of debate, or interpretation, or perception. The primary outcome failed. We have a phrase for that: no benefit.

 

[WilcoWorld]

Alas my response to "what would you do, doc?" remains unchanged.

Would I rather die than live with this deficit? If yes, I push for tPA. If not, I search high and low for a contraindication to document.

 

[deleted109597]

Bump for smarter people than me supporting my stance.
http://www.smartem.org/content/guideline-science-and-gap

 

[TooMuchResearch]

Bump for smarter people than me supporting my stance.
http://www.smartem.org/content/guideline-science-and-gap

Emailed link to self. Very thorough but concise discussion from someone better known, though not necessarily smarter, than Dr.McNinja.

 

[iridesingltrack]

The AHA/ASA just published their updated guidelines for care of the acute stroke patient (first 48 hours). Of note, the lead author is an EM physician and Chairman of EM at MUSC.

This is a good read and was originally published online (I believe in January) so if you already read it, cool. Several important issues are addressed with great references and I think, thoughtful interpretation.

http://stroke.ahajournals.org/content/44/3/870.full

Cheers,
iride

 

[xaelia]

Would like to see these scientific statements authored by individuals and sponsored by organizations without financial COIs with the manufacturers of the therapies involved.

E.g., http://stroke.ahajournals.org/content/44/3/870/T13.expansion.html

 

[iridesingltrack]

Please don't throw the baby out with the bathwater. There is much more to this article than tPA. For all I care, if those on this forum read everything except the small section on fibrinolytic therapy I would be happy. This covers everything from neuroimaging recommendations to glucose and BP management.

I agree that would be ideal if there were no COI. However, that is an unrealistic ideal. The business of drug development is such that companies need the thought leaders to guide them. Otherwise, we would get irrelevant drugs, and devices on the market and patient needs would be even more unmet. Besides, I have never met a researcher who didn't believe in the work they were doing regardless of their financial interests. With that said, we are all biased. Also, note that some of these are unpaid conflicts; I am not sure that is better, but it is different.

You read, you decide. Stay open to the very important other bits of the article.

Cheers,
iride