Acute Stroke Therapies: A Rapidly Evolving Landscape

Podcast Transcript

Introduction:

Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD:

The rapidly evolving landscape of stroke therapies, including thrombolysis and mechanical thrombectomy, have revolutionized care for patients with acute stroke. In this episode of Neuro Pathways, we're surveying the current landscape of stroke treatment and looking towards what's on the horizon. I'm your host Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. And joining me for today's conversation is Dr. Gabor Toth. Dr. Toth is an interventional neurologist with Cleveland Clinic's Cerebrovascular Center. Gabor, welcome to Neuro Pathways.

Gabor Toth, MD:

Thank you, Glen. It's great to be here.

Glen Stevens, DO, PhD:

So you may not recall this, but I was preparing to do a Gamma Knife case in February of 2020 just before COVID started, and the patient lived some distance away and had stayed at a hotel overnight. And his wife drove him, we always start early in the morning, and his wife drove him to the cancer center. And as she's pulling up to the cancer center, he becomes aphasic and hemiparetic on the right side. And they bring him down to the Gamma Knife Center, and we quickly identify he's probably having an acute stroke and we call a two clot. And he gets taken over to the emergency department, and he has a CTA done that showed a proximal ICA occlusion and he underwent a thrombectomy.

And my recollection is that he re-stenosed or re-clotted within 24 hours and then had a second thrombectomy and did quite well. And about a week later, we did his Gamma Knife. I actually went over to see him in the hospital and he said to me, "Let's do that Gamma Knife now." And I said, "I don't think you understand the severity of what could have happened to you here today." I said, "No, we're going to let everything settle down and we'll do it shortly."

And I have to tell you that I've seen him recently and he has minimal neurologic deficits and his cancer has stayed stable. So it's one of those things that he was in the right place at the right time with the right procedure and people that were available to do this. If he would've been at home and his wife would've been driving him three hours, it's sad to think of probably what would've happened.

But let's start with that as an introduction and tell us about the landscape of acute stroke therapy options as it's changed over the years, and what we can offer to patients, both medically and interventionally, for stroke. I know it's a huge thing. You can probably talk for an hour on it, but give us the Coles Notes version.

Gabor Toth, MD:

Yes, certainly it's a big topic, but I'm glad you brought this case up. I mean, it's a good representation of what we can do and how we can manage patients, especially if they're in the right place, the right time and the right team assembled and quickly help these patients. And yes, although it's not typical, but if you need us to be performing more procedures because there's recurrent problems, obviously we can do that as well. I'm just really pleased to hear how this patient did. I think that's one thing drives us always, and it's a rewarding thing to hear these patients stories and the successes because it certainly makes it all worthwhile.

So as far as treatment options for acute stroke, you certainly touched on it that a lot has happened. A long time has passed since the introduction of tPA, or tissue plasminogen activator, in the mid 1990s, which was the first real acute stroke treatment option for stroke patients.

So we had to wait about 20 years for the next major milestone. There have been a lot of trials and attempts to help stroke patients in the meantime, and things have certainly gotten better systems of care. But the next milestone occurred around 2014, 2015, when several large randomized controlled trials, which is the highest degree of clinical trials, basically were able to demonstrate the efficacy and safety of endovascular therapies, what you just described. And although large vessel occlusion, we call it, which is a blockage of one of the main arteries of the brain, is just a portion of acute strokes, but it certainly is one of the most devastating types of ischemic stroke.

And the degree of benefit of this endovascular therapy or mechanical thrombectomy has been basically proven to be one of the highest degrees of benefit, almost in the history of medicine. And the field continues to evolve rapidly with better and newer generation devices that help us achieve the goal of reopening blocked blood vessels in the brain and neck. Also, we were able to show that patients that happen to come in later, potentially after a stroke, we can always evaluate them and expand treatment options for some of those patients as well. We have the option now to extend treatment options for acute stroke patients for up to 24 hours after symptoms onset in select patients. So certainly this has been a game changer.

On the medical side, though there has been some new developments over the last few years, because other than the tissue plasminogen activator, a new player showed up called 10 tenecteplase, or TNK. And more and more data has come out providing benefit of this new agent. And certainly there are a few considerations that make tenecteplase actually even more advantageous than tPA. And that's certainly one of the newer agents that we have come out with and basically introduced to our system and enterprise that we can use.

On the other end, there have been a few other attempts to help acute stroke patients, and without going into too much detail, there have been research studies looking at giving certain medications before the patients get to the hospital in the ambulance. Certain neuroprotective agents have been studied and even cooling of patients, that has been useful for cardiac arrest patients, but thus far, we still don't have a strong evidence that those work as well as the other methods and treatment options that I just mentioned.

So certainly I would say a lot has happened in the last 25 years and we still keep going forward and improving care for acute stroke patients.

Glen Stevens, DO, PhD:

Excellent. So what percentage of patients that have a thrombus get some type of intervention? Of all the patients that are out there, is it 5 percent, 10 percent?

Gabor Toth, MD:

Yeah. So the studies vary and the there's some studies that show as high as 30 percent or higher, but I think the more realistic percent is somewhere between 10 percent to 20 percent of patients.

Glen Stevens, DO, PhD:

So it sounds like we have a lot of work to do. Time is brain. And I know that you guys have been very active in this area with ambulances and the Strokemobile and these types of things and having access to

medications. But it's a complicated problem, for sure. Any insights into how we can improve that, other than education?

Gabor Toth, MD:

Yeah. I mean, education certainly is a big part, but I think that for the Cleveland Clinic as an enterprise, we were able to expand our systems of care successfully over the years because of the coordinated efforts of a large number of people, stroke coordinators, research coordinators, physicians, nurses, technicians. We were able to build teams in all of our hubs.

And basically what happens if a stroke patient rolls into one of the Cleveland Clinic enterprise hospitals that's part of our network, then basically the emergency room physicians and the setup is such that we are able to triage and transfer the patients to the best place possible where the best treatment is available. Some patients don't stay there. If the best care can be provided locally, obviously, the patients will stay there. But specifically for thrombectomy, we have several hubs in Ohio where patients are rapidly transferred to where we're able to help.

And again, as I said before, it takes a village, all the nurses, technicians, fellows and physicians, and a lot of people are involved in making this happen and for us to be able to provide as rapid care as possible to acute stroke patients. Education is a big part of it, but again, building the network efficiently and safelyGabor Toth, MD:, I think, is also a major component here.

Glen Stevens, DO, PhD:

So I assume that the TNK is a second generation tPA or slightly different. What's the difference between the drugs? What's the benefit of the newer drug?

So both achieve their effect by binding to fibrin in clots and converting the entrapped plasminogen to plasma, and then plasma in turn breaks up the clot or the thrombus. And tenecteplase is a modified form of alteplase. There are a couple of mutations in the genetics that basically renders it a larger molecule with a little bit longer half-life. And so these properties allow us to intravenously administer the medication as a single bolus, as opposed to tPA that had to be given over an hour infusion. So TNK can be given just like a rapid short bolus and immediately is effective.

And again, there is scientific research that is showing that there's possibly an improved efficacy of re-cannulization certain blocked vessels. And the safety profile is very favorable compared to tPA. Certainly there are some thoughts that if the efficacy of the revascularization, opening up the vessels, is more efficient, it could actually help patients, especially in the early phase after stroke onset, even open up large vessels that previously needed thrombectomy and maybe can spare a procedure for the patients. But this is currently in an early stage. We will certainly need more data, but very, very promising. And I'm very proud to announce that the Cleveland Clinic, as an enterprise, just switched over to tenecteplase in the entire system now.

Glen Stevens, DO, PhD:

Good. Excellent. So obviously, we have to get better at getting patients medical care, which is going to be a difficult effort to do for many reasons. But there may be a lot of individuals out there on the other end of things. And what are the most important risk factors that we should work on to decrease the likelihood of ending up with this problem?

Gabor Toth, MD:

Yeah, I mean, there's a large number of potential risk factors that can lead to strokes in general and blockages in large vessels. But the most common ones are high blood pressure, high cholesterol, uncontrolled diabetes, active smoking, drug use. And certain heart conditions also predispose to blood clot formation and strokes, especially if they're not detected and not treated appropriately, many times with blood thinners.

Glen Stevens, DO, PhD:

Yeah. So my commercial out there is just to make sure that we're on our patients to have them do the right things.

Gabor Toth, MD:

Absolutely.

Glen Stevens, DO, PhD:

So we mentioned this a little bit, with large vessel occlusions that obviously are a high risk, we have highly efficacious therapy available in the form of mechanical thrombectomy. And I still wonder with my patient, because it was pre-COVID, if the patient had COVID. Because I thought I had read some data that they're at a little more risk of more proximal stenosis. Is that true, or did that not show out? Or what's happened with that?

Gabor Toth, MD:

Yeah, there is also growing literature on COVID and stroke, and certainly it has been shown that COVID can be a predisposing factor to having a stroke, especially I think the most prominent that was shown is something called a hypercoagulable state. So COVID, resulting in a cascade in the blood stream that results in blood clot formation, not just in the arteries, but potentially in the veins as well. There have been other associated types of strokes with COVID that result in some sort of vessel wall abnormality, or we call it vasculopathy. We had a few patients, even young ones, who developed basically narrowing of the blood vessels requiring intervention after a COVID infection. I think we still have a whole lot more to work on and understand with COVID and stroke, but these are the main points that we have learned in the recent years.

Glen Stevens, DO, PhD:

I hate to admit it, but 30 years ago, I remember we would do an angiogram on a patient and they would have a thrombus in an acute setting. And really the only intervention we had was for the interventionalist to take the catheter and essentially poke and break up the clot. And of course, that clot would go somewhere, but it was the lesser of two evils that it would go and lodge and affect a small area versus a large area. So the advent of thrombectomy is so much more exciting. Any trials you guys have going on? There's always new devices, but anything exciting you guys are doing right now?

Gabor Toth, MD:

I'm glad you asked, yeah. So being at the Cleveland Clinic, there's always something new. There's always cutting edge and there's always new trials and studies going on. So our center, the Cerebrovascular Center, has been actively involved in a lot of national and international trials regarding acute stroke. There are a few areas that we are looking at as part of these trials and also as a group as well to try to expand and extend potentially the window, but also the indication of thrombectomy or stroke care for more patients.

One of the first ones that happened about two or three years ago were two big trials that basically ended up in extending the time window that I mentioned earlier. Previously, the well-known "time is brain" concept was very valid, but it was noted that there are some patients who, despite the stroke starting earlier, even several hours later still had salvageable brain tissue. And so the two trials called DEFUSE3 and DAWN, these are just names, they were able to demonstrate that up to 24 hours, thrombectomy can be beneficial for patients who are selected with advanced neuroimaging.

Now, as the years go on, the new areas where we are trying to identify more patients that could benefit from these treatments are a few different ones. So one is that our group in particular has been involved very much with a patient population called mild stroke with large vessel occlusion. So although most patients with these large vessel blockages have severe symptoms, but there is a few or a smaller portion that still have milder symptoms. And the concern is that if they are not helped, that over time, they turn into a larger stroke.

And so our group actually at the Cleveland Clinic, a year or two ago, published a research paper showing that if these patients are taken for thrombectomy, it can be done safely. Now this was not a randomized controlled trial, but fortunately, it paved the way for a larger trial that's currently actually happening all over in the US called ENDOLOW that looks at this particular patient population. And obviously, we are part of this trial trying to see if we can safely and efficiently help these patients. So that's one area of particular interest.

The other area is something called a large infarct core stroke. So traditionally, when patients came in with stroke symptoms, we did advanced imaging and it showed an area of a large infarct or basically a stroke already, the concept was there's really not much else to do. And unfortunately, many of those patients didn't get therapies. But more and more data has surfaced showing actually potential benefit for some of these patients. So there are few trials ongoing in the US that we're part of, one called the SELECT2 that looks at this particular patient population. And hopefully in the next year or two, we'll be able to see if actually more patients could qualify for a thrombectomy. Because even if they have a stroke already, maybe the area that's salvageable around it still can help with the recovery and that's the main concept here.

And then one more area that's becoming very popular and obviously more and more studied is blockages in what we call medium or distal vessels of the brain. So when the thrombectomy started, mostly we tried to go for vessels that are larger, closer to the skull base because those are tools that we had to safely reach those areas. But now with, as you mentioned, device development, technology innovations, we have better and better tools and we're able to go more farther and farther out in the brain.

And there are trials now that will be looking at vessels that are farther out in the brain, if we can safely remove even smaller clots from those areas. And obviously the question comes up, why would we do that? It's because sometimes some of those smaller vessels can affect brain regions that are really crucial and important, such as speech center or area that controls movements on other side of the body. And so certainly even smaller vessels can cause debilitating symptoms.

And so those are areas that we certainly are looking at and studying, including our center. There are some attempts looking at previously studied areas. For example, cooling and neuroprotective agents. I'm sure we're going to hear a lot about those in the next couple of years as well.

Glen Stevens, DO, PhD:

Excellent. I remember when I first heard the word penumbra and I thought it was just a fascinating term and it's the area at risk. And that's been the big bugaboo in terms of what's really infarcted and what's really salvageable for patients. And I'm very excited to hear about the continued prolongation of window of opportunity for patients because I think we have to give them the benefit of the doubt.

Gabor Toth, MD:

Absolutely. And to add to that, with the help of artificial intelligence and AI in the recent years, our technology to select these patients and do imaging on them, and also the timely notification of physicians of these problems have tremendously improved and certainly will also benefit more and more patients going forward.

Glen Stevens, DO, PhD:

Well, Gabor, this sounds like an exciting field to be a part of. I appreciate your sharing your insights with me today, and I always enjoy working with you. Thanks for joining me.

Gabor Toth, MD:

Same here. Thank you very much for the opportunity.

Conclusion:

This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word. And thank you for listening.