Here is one of my favorite segments from the 2014 EMCrit/ISMMS Conference. My chair Dr. Andy Jagoda debates my friend Dr. Anand Swaminathan.
The debate seemed relevant because ACEP, a major US emergency medicine organization, released clinical guidelines markedly increasing stress on thrombolysing stroke. These clinical guidelines were sent back by ACEP's council for further commentary and assessment, a move unprecedented in the history of the organization.
ACEP Clinical Guidelines from 2013
Pro Side
Dr. Jagoda took the Pro stance.
Con Side
Dr. Swaminathan took the con stance. Check out his site, EM Lyceum for more FOAM goodness.
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Editor-in-Chief, at EMCrit.org
An ED Intensivist from NY.
Professor
Nassau University Medical Center
No conflicts of interest (coi).
Professor
Nassau University Medical Center
No conflicts of interest (coi).
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Nice debate! As always nice podcast! 2 major questions: 1. tPA (Tissue plasminogen activator) is an enzyme-like protein that is supposed to accelerate the conversion of plasminogen to plasmin which should lead to a fibrinolysis and blood clot breakdown. From these basic hemostatic or coagulation considerations, the level of fibrinogen should dramatically drop after tPA, assessing the good quality of thrombolysis. However, in various studies the level of fibrinogen before and after is not reported. Why the hell is that? So simple to assess the effectiveness of this therapy. Patients may exhibit different inflammation profiles, one with high basal fibrinogen… Read more »
Great points here. I only got to touch on this topic of whether the pathophysiology made sense. I agree that very little of the drug gets delivered to the location where it needs to go. However, I don’t think anyone has shown that catheter directed thrombolysis is beneficial either or we’d all be pushing for that. Michelle Johnston talks about this in more depth here: http://journals.lww.com/em-news/Fulltext/2014/01000/Breaking_News__Why_Use_a_Treatment_for_Stroke_that.2.aspx Higher doses of tPA have been used but the Cochrane collaborative found that dose (as well as agent) made no difference. This is important because the NINDS and ECASS III supporters make a point… Read more »
so although it was fun i would have liked to hear Swami ask andy how he explains and rationalizes all the data mining and the gross inconsistencies in Ics3 with the time window helping for 4.5-6 but hurting for 3-4.5 and the FACT that we need to better define who and when people will benefit.
Also, how does Andy explain the lack of benefit at 24 hours if the clot is breaking up and every time the pt improves in the first few hours we declare it a success.
We didn’t get too much into IST-3 because the ACEP clinical committee sort of understood the limitations of this study and didn’t really use it to back up their recommendations. I did bring it up briefly as a good defense of the fact that time probably doesn’t matter nearly as much as NINDS would make us believe. Completely agree with you on the second part and I think Andy would as well. We shouldn’t be celebrating an improvement at 24 hours as a success of tPA because no study has ever shown that and in fact NINDS clearly shows that… Read more »
I would not base any conclusions on IST-3, not on the safety on large bleeds nor on time-to-drug. If you are going to give tPA, give it as quickly as possible. The trial was flawed from the get-go, all we can say is it wasted a lot of people’s time.
Agree. It does, however, speak to the terrible inconsistency in the literature on this drug.
First, I am quite the fan of emcrit, emrap, resus.me and consorts – I admire your rebel-like ability to question the most basic assumptions in emergency medicine, even it it is tPA. I consider myself an emergency neurologist and do all of the daytime thrombolysis assessments (i.e. strokes in the first few hours) of our hospital myself. This amounts to about 200 tPA for stroke (of our ~400) yearly, so that I have overseen about 600 tPA patients personally and about 1000 in total on my stroke unit. Let me also add that we do proximal artery occlusions with good… Read more »
Thank you for your thoughtful comments. I’ll start by saying that for this particular debate, NINDS is not irrelevant. In fact, it is the heart of the debate as the debate centers on the ACEP clinical policy which centers on the level A recommendation for the use of tPA in stroke < 3 hours based on NINDS. Registry data is nice but it's not the quality of data upon which a Level A recommendation should be based. We focus on NINDS because it highlights many of the issues we see with research. A single study of 300 patients showing a… Read more »
As folks know, I am in a state of equipoise on this topic. I believe there is a group that will benefit and I believe we have not figured out the parameters of that group yet, so the question then is do you want to overtreat or undertreat–I can see compelling arguments for both sides. I hope the ANZICS folks or similar will do a real RCT and settle this once and for all. >>What about stroke mimics? I don’t care – they don’t bleed. What I will say in response to Felix’s comments is that unfortunately these folks can… Read more »
This is fun, really. 1. Proving tpa? There are two conflicting perspectives – a) politics aka guidelines b) medical. If you forget about the fact that you don’t like the NINDS study and try to find a way to make tpa use safe. Let me think… We should do a registry. Okay. Did that. Even got plenty of subgroups to dissect (such as mimics). Or we should try to increase the time window that we can use the drug, so that it looks safer in the first hours. Okay. Did that – is dangerous, because later strokes are bigger, so… Read more »
IST-3 could have been the trial–they just needed to randomize. Most of these clinicians had equipoise, they were willing to do half-ass randomization.
It could still be done in Australia and New Zealand where tPA has not become near standard care yet.
EGDT was standard of care in the US for a decade and now there is a national RCT.
I think there are some weaknesses in the pathophysiologic explanation that time is brain in comparison to time is heart. In an MI, you lyse (or stent) and there is a rapid response of the cardiac muscle to resuming flow. This doesn’t happen in CVA. If it did, shouldn’t we see a benefit at 24 hours (or sooner)? In the MR RESCUE trial, revascularization was 67% in the endovascular treatment group but this didn’t translate to improved outcomes. Revascularization doesn’t necessarily seem to equal good outcomes as it does in MI.
You are right, but that exactly proves the point of time is brain. It does not suffice to open up the artery. If blood comes the ischemic tissue suffers first, quite a lot sometimes, depending on the amount of damage through ischemia and reperfusion (which does harm at first). It swells, convulses, might even bleed. The more damage there was the longer it takes to recover – this takes days in mice. In patients it can take up to weeks (as a good model take reperfusion syndrome after carotid endarterectomy for filiform stensoses with bad collaterals, which sometimes lasts for… Read more »
In response to: “In an MI, you lyse (or stent) and there is a rapid response of the cardiac muscle to resuming flow.” This is not true. After complete ischemia for > 1 hour, it takes days to many weeks to recover cardiac function, called “myocardial stunning.” Similarly, ischemic brain takes a long time to recover (if it does). Also, one writer was skeptical that tPA could have any effect in a tiny, occluded MCA. But it is clearly effective in tiny, occluded, coronary arteries. It does make sense that tPA would not work in embolic, as opposed to thrombotic,… Read more »
Wonderful debate that was fascinating to listen to. This does remind me in several ways of political debates – in which whether one is Republican/Conservative or Democratic – I’ve found it near impossible to sway anyone from their beliefs that usually are firmly fixed. So realizing poor Scott is “stuck” in equipoise (for obvious reasons given that his Chair is one of the debaters …. ) – I have to support Anand Swaminathan’s point that NINDS is not irrelevant – because it was based on NINDS data that the Level A recommendation was made. I thought Anand very effectively pointed… Read more »
I keep hearing from some pro-tPA folks that the NNT for thrombolysis is 2. Even in the optimistic views I had not seen any analysis suggesting it’s less than 6 or 7; anyone have any idea what they’re referring to?
What other ‘routine’ treatment (surgical or medical) in acute care has a NNT of 8 and of NNH 16 with no proven mortality benefit. If all you have is a hammer….
: )
Even the most optomistic numbers don’t show this but I’ve heard some stroke specialists give an NNT of 3 or 4 so 2 isn’t out there from their perspecitve. This idea must be based on data dredging and/or misinterpretation of the data. There is no evidence from any study that gives you that number.
To be honest that was like listening to the equivalent of David Brent v Obama. Almost too embarrassing to follow, but I was on a bike……
who is david brent?
The original Office.
I just had the same sense of squirming discomfort.
I found what Jagoda was saying to be extremely troubling. He kind of boils it down to: regardless of what you think about the data, tPA for stroke is a level 1 recommendation of ACEP and multiple professional societies, is now the standard of care, and so the debate is over. Nevermind how that came to be or what you think the data truly show or don’t show. The science is settled. And if you as a clinician have concluded that this therapy is neither proven to be safe or effective and don’t use it, ‘you better document really well.’… Read more »
Yes, it was a disturbingly recurring theme in the discussion.
And just remember the NNT to save one additional life with tPA is………….
Infinity
Coming to this a little late, but then again we only had our official “strokologist” tele-stroke speech last week. Unlike Dr Jagoda, our regional neurologist outright stated that “if you don’t use it, you will get sued.” Interestingly, he also cited a number needed to treat of 2. Tpa clinician-lobbyists appear to share an interesting template of a) appeals to authority, b) legal threat, and c) rather robust claims of efficacy (NNT2!). Lest this give way to despair over the death of science and the rise of eminence-based medicine, we can take heart in the great discovery which lies hidden… Read more »
I eagerly await for his paper that shows a NNT of 2. :-p
Love the debate, but it confuses me even more. I liked at the end when Scott asked about what both would tell patients, but neither clarified what data (i.e. risk and benefit percentage/NNTs) to present to the patient/family to obtain true informed consent. I’ve tried the “it’s complicated and controversial with a few studies showing benefit in three months, a bunch showing no benefit, and some showing harm due to bleeding in the brain. The risks and benefits depend on which studies we believe” but patients and/or families get frustrated and ask about the chances of helping or harming as… Read more »