New stroke treatments are being explored

Host Amber Smith: Upstate Medical University in Syracuse, New York invites you to be "The Informed Patient" with the podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith. At the recent International Stroke Conference, doctors discussed some potential new ways of treating patients with strokes caused by a blockage in a blood vessel. Here to explain these new ideas is Dr. Hesham Masoud. He's a vascular and interventional neurologist, one of the members of the Upstate Stroke Team who specializes in the diagnosis and treatment of stroke. And he uses minimally invasive procedures and imaging to diagnose and treat strokes, aneurysms, and a variety of other problems. Welcome back to "The Informed Patient," Dr. Masoud.

Hesham Masoud, MD: Thanks for having me. It's a pleasure to be here.

Host Amber Smith: Now, as I understand it, we'll talk about at least three potential new ways of treating patients using mechanical thrombectomy. But why don't we start by having you explain what mechanical thrombectomy is, because that's your specialty.

Hesham Masoud, MD: A mechanical thrombectomy is a descriptive term that is essentially describing the retrieval of a blockage from a large artery in the brain. And so that retrieval is done mechanically, which is to say it is ensnared in a device and then withdrawn out of the body, or it is sucked out of the artery that it's blocking, using a vacuum pump, as opposed to breaking down the clot with a medication, be that medication delivered through a vein in the arm and eventually it gets its way to all of the blood vessels in the body, including the brain, or in a more targeted fashion where the drug is administered right at the site of the blockage. So mechanical thrombectomy is just about the physical method of retrieving these large clots that can cause pretty devastating strokes because of the size of arteries that they block in the brain.

Host Amber Smith: So how do you decide which patient is best for a mechanical thrombectomy versus using a medication instead?

Hesham Masoud, MD: Everyone who has a stroke should get the intravenous -- which is to say, the medical therapy of stroke -- if they can get it, regardless of whether or not they need the additional lift of having someone come in and actually take out the clot because of the burden of the clot.

So the burden of the clot, meaning the size of the clot, and the size of the clot is inherent to the size of the artery that it's blocked. So that's how we select our patients. It's patients who have these arteries that are large in size that are blocked. And we're able to diagnose that with patients by the bedside exam because arteries correspond to function, and a big artery has big function, and a smaller one has smaller function. And so at the bedside, we're very quickly able to high probabilistically make decisions about this being a large artery that's involved.

And then the patient gets sent to a scanner, and then the scanner excludes the possibility -- which sometimes up to 20% of the time it can be a bleed and not a blockage. And so we exclude that it's not a bleed. And then we're able to also get a scan from the cat (or CT, computerized tomography) scanner that demonstrates the arteries that feed the head and neck. And in that, we're able to rapidly take a look, in the context of the exam that we have, to demonstrate which artery could be the culprit as the blockage.

So it's this combination of bedside clinical assessment, and it's verified with evidence that we get visually, from scans, which are pictures of the brain that happen very quickly in the emergency room.

Host Amber Smith: So how big might these clots be?

Hesham Masoud, MD: Oh, the average size artery I would say that receives most of these clots is the middle cerebral artery. That's the name of it. And the size of it is up to three millimeters in size is the trunk, maybe a little bit bigger than that. In the more proximal, which is to say the bigger road that leads to the middle cerebral artery, can be in the realm of five or six millimeters.

So essentially you're talking about clots that are less than half a centimeter in size that we're considering as being large clots, again, size to these arteries.

Host Amber Smith: OK. So the mechanical thrombectomy, how well does it work? Are you able to always get a hold of the clot and remove it?

Hesham Masoud, MD: That's a great question because it also speaks to how do we define well. How do we define how well something is working?

Well, we have two categories of a definition. One is visual benefit of, which is to say the arteries that were blocked are now open in totality or partially. So that degree of reopening of the blood vessel, I should say, that's a grading system. And if you have more than 50% of those branches open, that's great. If you have less than 50%, that's not great. And if you have full, that's even better. So there's that visual feedback loop of, "oh, this worked because I see what wasn't there before, I see now." So there's that visual metric, or analysis, I should say.

But there's also the real world of, how is the patient doing? And how is the patient doing is on a couple of things. So one is at the bedside, doing the clinical exam. And in follow-up, are these patients getting the gamut of the benefit that they should from having had the arteries open, which is to say is all of the salvage tissue been salvaged?

And so there is a discrepancy. So we're able to open up the branches to a very high degree, which is to say really more than 50% of them open and above, in 90% of the time, so much so that it's kind of peaking in terms of the technology. It's really great. Sixty percent of the time it's a complete reopening of the blood vessel. But still, up to 30% of those patients are having strokes on the MRI (magnetic resonance imaging scan) that have a territory larger than what you would assume to be involved after having opened the artery. And subsequently, they're not getting the full benefit in their improvement as they would if they had not had that discrepancy of all the branches open, but still, somehow some damage left behind.

And so that's what brings up this question of, OK, well, what else is going on and how else can we target this system to get that extra added value?

Host Amber Smith: This is Upstate's "The Informed Patient" podcast. I'm your host Amber Smith. I'm talking with Dr. Hesham Masoud about new ways of treating certain stroke patients using mechanical thrombectomy.

One of the studies at the conference, from doctors in China, looks at adding a medication after the mechanical thrombectomy. What can you tell us about this?

Hesham Masoud, MD: This dovetails nicely into looking at the problem as a mechanistic one, and targeting that mechanism that is hypothesized to be the difference maker.

So this discrepancy between opening up the blood vessels but still not getting the full benefit has been termed a phenomena of "no reflow," which is to say, even though you've opened it, you're not really getting the full refilling and fuel to that territory, that flow. And so no reflow phenomena is how it's been termed. And the thought is that, while you might have the larger arteries open on the big picture. If you zoom in on the microscopic level, these tiny little blood vessels are still not opened, and so that is the thought that, well, if they're still not open, it could be from a variety of different things.

One of those things could be clot that's on that micro level that I can't see. And that's where these trials come into play, testing the hypothesis that, well, maybe if I give now some more targeted clot-busting drugs, I'm going to be able to move the needle on reopening that which I cannot see, the microscopic clot.

Now, it's also important to mention that there's other hypotheses as to why these microscopic vessels are still compromised, despite the larger arteries being opened, and those are things like the microscopic vessel might be collapsed. It might be reacting to some changes that are occurring on the cellular level and spasming, which is to say, actively clamping down. So those are different mechanisms than clot.

But these clinical trials looked at what is considered a high probability mechanism and high efficacy as a target, I should say, of the clot being the culprit here. And that's where they did these trials of delivering the clot-busting drug after reopening the vessel successfully, to a certain degree, of then adding this medical therapy in a targeted fashion and seeing, do these patients do better? And, do they do worse?

Host Amber Smith: Well, are there risks of administering these clot-busting medications afterward?

Hesham Masoud, MD: Yeah, the big risk that comes to mind is intuitive. It's the risk of bleeding. And bleeding as a consequence of trying to get the extra mile out of something can be a lot more devastating than bleeding while trying to do heroic measures. Almost snatching defeat from the jaws of victory, that kind of fear.

And so in the design of these early trials, there was much about really trying to target on the group that they think could have benefited the most, which is this discrepant group of open vessels, but maybe not getting the full benefit down the line. And limiting clot-busting drugs that may be administered intravenously through the veins, such that if we're going to administer something, we're doing it right at the site. And these are thoughts that were to limit the risk profile. But the big risk is bleeding.

Host Amber Smith: So these doctors in China, what happened with this study? Did they come to any conclusions?

Hesham Masoud, MD: So there were a couple of studies that came out, and they were all sort of looking at questions that had been also attempted to be studied in the past and sort of improving on them with different ways in their study design, in regards to the dosing of the drug, the choice of the drug, the protocol, so on and so forth.

So without getting into that, for the purposes of this interview, essentially what these two trials did -- and they were both Chinese trials that included multiple sites, but all of them within China -- so one trial had 19 sites, and that yielded a little bit above 200 patients. And the other trial had 28 sites, and they had north of 300 patients. And they essentially both treated patients the same way when it came to reopening the blood vessel. But one of the trials had a protocol such that if you were going to be enrolled, you would not get the medical therapy that is considered standard.

So they sort of withheld the intravenous or medical therapy that you would get before the mechanical thrombectomy. And the other trial, I think of maybe 40% of them did have the medical therapy. So that's an interesting point to look at because in real world practice, we are administering it in 100% of the patients. And that's what the guidelines are recommending, and it's based on data demonstrating that you benefit from getting both treatments. Even if you're going to get mechanical thrombectomy, you should still get the intravenous medical clot-busting drug too. And you should get it as quickly as you can. So, that kind of flies a little bit antithetical to this patient population and how they were treated, where that medication was withheld, and in our circumstances that wouldn't be the case.

But essentially both of these trials were looking at this added step of, after I've retrieved the clot and I look at the arteries and they're open to a really successful degree, which is to say more than 50% or even completely open, I'm going to now deliver through a small catheter that's right there at the location of where the clot was, just into that area, I'm going to deliver a small infusion of a clot-busting drug that's weight-based, with a maximum dose as a ceiling, and I'm going to do that over 15 minutes. And so that was the extra move.

And then they followed those patients after the fact and found that for the most part patients -- and you know, it's kind of interesting because both trials generally had similar numbers, so I'm going to lump them, average them out as a quotation -- but generally, using standard care -- and again, put an asterisk on standard because a lot of these patients did not get that standard medical IV clot-busting drug. But in their protocol standard was just taking the clot out, not adding the local clot-busting drug on top of it -- it was around 30% of patients, 25 to 30% that had this excellent outcome, which is to say minimal or no disability. And in the treatment arm, which is the group of patients that got that added step, that added treatment, , it was around, 30, 40%, generally. So that's a pretty decent difference.

And it looked like the bad outcomes were about the same, and bad outcomes are typically described as bleeding within a certain timeframe, major bleeding, that means bleeding that's changed the patient's physical exam. Typically it's a deterioration in the exam. And obviouslydeath. And those numbers were about the same, which is to say somewhere in the realm of 25 to 30% for patients who are bleeding, up to 20% mortality across these trials.

So this is what gave us a signal that doing this added move is maybe safe and has some value proposition, within the limitations of the study and the population. One thing to keep in mind, as well, they're Chinese patients, sure. And you all should also pay attention to the percentage of men versus women in the cohort. In one of the trials, there were only 30% women. So this, again, things being truly reflective of patient populations is always in mind, but these are some of the signals of benefit of doing this added move.

Host Amber Smith: So when you and your colleagues go to these conferences and learn about this research, do you bring it back and start applying it to patients at Upstate?

Hesham Masoud, MD: That's a great question. We're an academic institution, to our credit, which keeps us practicing within the boundaries of evidence-based medicine. And so we take clinical trials that have been presented, and we grade them by quality of evidence, guideline statements, our own policy reviews. And based on that and the quality and level of evidence, we then make changes to our protocols. And so, that's essentially how we go about staying on the bleeding edge of therapeutics for our patients, but in a way that has guardrails, and isn't pushing the latest and greatest without it being truly demonstrative of evidence-based practice, which is the highest qualityevidence. And these trials are randomized controlled trials, so that is a high degree of evidence there.

But like I said, we also consider things like dosing protocols or hospital protocols and patient populations. So generally speaking, it's a safety based assessment.

Host Amber Smith: So I think the second study that I was going to ask you about from the doctors in China compared two different types of clot-busting medications. Is that right?

Hesham Masoud, MD: This question has had to evolve with an evolution in therapeutics. So there's been a shift from one of the clot-busting drugs to another one in stroke care. And it's been a shift that's been related to certain additional value brought by that swap from things like ease of delivery to how long it lasts in the system, to how specific it is to binding to the factor there that will break down the clot, the fibrin, I should say more specifically.

So this idea of it's a more precise drug. It lasts longer. It's easier to deliver. That shift from the old drug, which was called alteplase or tPA, to the newer use -- very old drug, but newer use, in this realm -- TNK or tenecteplase also was mirrored in some of these trials. So you would see the first drugs that they used for this was tPA, and then the newer trials were able to incorporate TNK. And TNK has a lot of good data behind it as being ... If you wanted to make a decision about a clot-busting drug that targets blood clots that are large and in the brain, you would choose TNK.

There's clinical trial data in that cohort of patients that TNK really demonstrated its value, relative to tPA. It has other values related to the ease of delivery for transferring centers. It's a drug that doesn't get interrupted because you just have to give the one dose. You don't have to give a dose and a drip. And there's data that we know that with alteplase or tPA, those interruptions can really affect the efficacy of the clot breakdown.

So those are all value propositions that tenecteplase filled in with. And then you saw that in your clinical trials, as opposed to it being a deliberate difference, I think on some level.

Host Amber Smith: Well, we talked about the risk for bleeding from these medications, but I guess the reason you're using them is so that you can improve a patient's neurological outcome, right?

Hesham Masoud, MD: Yeah. It's really to address this mismatch. You get the blood vessel open, and to a high degree of success on the picture. Picture looks great. But then the patient still doesn't benefit from it. That's happening 30% of the time. So that means there's something else that's at play here, and I think this is an exciting, avenue to explore -- and with some good safety data behind it, which is truly valuable.

Host Amber Smith: Well, what sorts of things do you look for in a patient to determine their neurological outcome?

Hesham Masoud, MD: There's some basic things. So, we can look at it in different spheres, or different methods, and some are more useful than others. So one is, just intuitively, if I have a large artery that was blocked and it's reopened, and my MRI doesn't show a lot of damage, then the patient will likely do better. Even if the exam lags behind the picture somewhat, they will typically do better than how I see them at the moment. And they always will have been better off than me not taking out the clot. So, the value of this therapy -- and by this therapy, I mean mechanical thrombectomy -- is so high that we're finding benefit in all kinds of groups of patients with this stroke.

Even patients that have large amount of damage already done, we're finding that there's still some benefit to be gained in certain circumstances. And it's still safe to try to open up these blood vessels. So it's one of those things where it's kind of hard not to show some value. But from a functional standpoint, I'm at the bedside now, or I'm rounding with my residents, and I teach this often because you get questions about prognosis, and we don't have great tools. But one thing that we do know that's a good surrogate for outcomes is the movement of your upper limbs. So, on the affected side, if you are able to elevate your elbow up, which is to say spread it up, almost like you're rising a chicken wing up, on that deltoid, and you're able to do that early, that's a great sign. If you're able to extend your wrist and your fingers on the affected side early, that's a great sign. So these are early predictors of stroke outcome, and there's data behind that, and there's fascinating work being done in neuro rehab to protect those outcomes and improve on them.

But that's one of the scores that we might look at, early indicators of what you're doing on your physical exam in the affected territory, and to what degree, as being a signal to its potential of a full recovery.

Host Amber Smith: You're listening to Upstate's "The Informed Patient" podcast. I'm your host, Amber Smith. My guest is Dr. Hesham Masoud, and we're talking about new ways of treating certain stroke patients using mechanical thrombectomy.

One of the things I remember about that earlier drug tPA was that it had to be given quickly. Is that the same case with TNK? Does speed matter?

Hesham Masoud, MD: Yeah. And I think the reason why speed matters is not related to the drug itself as much as it's related to the endeavor that the drug is going to start when it's there, which is to say it will start breaking down clot. And clot is the problem.

So the sooner you get that work in, the more benefit you're going to see in it being started, and even early benefit. And we have lots of data about the earlier administration of tPA being more and more beneficial. And that's because that was the drug that we were getting our time targets on.

The big differences between tenecteplase (TNK) and alteplase (tPA) are related to things of specificity and efficacy, safety and ease of administration, that I think demonstrate the value in ways beyond fast time. But fast time is always going to be the name of the game.

Host Amber Smith: Are there some patients who can't take these clot-busting medications?

Hesham Masoud, MD: Yeah, so there is a list of contraindications. And there are absolute contraindications, and you can imagine things like, oh, I have a major bleed there, or I have some major surgery, and breaking down clot would risk a consequence greater than the consequence of the stroke. So those are those absolute contraindications.

And then there are things that are relative contraindications as well. And those can be clinical judgements. So one of the big things that limits people from being able to get a clot-busting drug is if they're taking a powerful blood thinner. Not an aspirin or a Plavix or something like that, but something that works like Coumadin or Warfarin, or one of the newer drugs in that realm. We call them anticoagulants. Those are drugs that you would not, if you were on it, would make you not eligible.

Now, I will say this, just as an aside. You know, for stroke prevention, we put a lot of patients on those drugs. And then you might think, well, you're putting on someone a drug that if they have a recurrent stroke, then they're limited in the therapy. And that's true. But there's two things. One is, you're making that a lower probability event of happening, which is the key endeavor here, preventing even needing a second therapy. And two, the clots that are formed when you're on the therapy, and therefore the consequential stroke, are smaller than they would have been if you are not on the therapy.

So it's more than one thing there than prevention. We had a signal of that when we looked at this just in our small data set. But, that's just the piece I'd like to highlight about that contraindication.

Host Amber Smith: Well, before we wrap up, I wanted to ask you about a third study there. This was from doctors in Spain. They looked at ways to reduce disability from stroke after mechanical thrombectomy. What can you tell us about their research?

Hesham Masoud, MD: Yeah, and so that's an older one. And there were a couple others too. So there was the CHOICE trial. There was the POST-UK or POST-TNK trials. The CHOICE trial was the Spanish trial. It had a little bit of a different patient selection, and they used tPA as their drug.

And that also demonstrated that there was a little bit more of a benefit. I think the difference was 60% had that excellent outcome, versus around 40%. And it did have a statistically significant analysis to it. And there wasn't an increase in bleed.

So, a growing signal in the literature that, that piece of, oh, the no reflow phenomena on the microscopic level, the way to treat it might be with this local delivery of clot-busting drugs. That's the evidence that seems to be amassing with what is primarily now a global study cohort, so Spanish patients, Chinese patients.

Host Amber Smith: Well, that's good to know. It seems to me things with stroke care are always evolving, and that's a good thing, right? You go to these conferences and you learn what is working for people in other parts of the world, and you bring it back and figure out if it's going to help our patients here.

Hesham Masoud, MD: Absolutely. I think it's one of the, it's just a feedback loop of medical practice in the contemporary era. It's certainly for an academic practice that it is this constant revisiting of notions and exploration of the margins of benefit for therapeutics and looking for the latest and greatest solutions to avenues that were previously thought to be well trodden. I think that that's the real critical piece of a sort of an academic approach to practice. And I've seen it certainly yield so many dividends in neurology because it's such a fast moving field that if you're not engaged in this, you'll find yourself very quickly with an antiquated practice.

Host Amber Smith: That makes sense. I really appreciate you making time to educate us about this.

Hesham Masoud, MD: Always a pleasure. Thanks for having me.

Host Amber Smith: My guest has been Dr. Hesham Masoud, a vascular and interventional neurologist and member of the Upstate Stroke Team. "The Informed Patient" is a podcast covering health, science and medicine, brought to you by Upstate Medical University in Syracuse, New York, and produced by Jim Howe, with sound engineering by Bill Broeckel and graphic design by Dan Cameron. Find our archive of previous episodes at upstate.edu/informed. If you enjoyed this episode, please invite a friend to listen. You can also rate and review "The Informed Patient" podcast on Spotify, Apple Podcasts, YouTube, or wherever you tune in. This is your host, Amber Smith, thanking you for listening.