Redefining Stroke Therapy: A Paradigm Shift Across the Globe

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Daniel Simon, MD: Hello everyone. Thank you for listening to another Science@UH Podcast. I am your host, Dr. Dan Simon and today I am happy to be joined by Dr. Amrou Sarraj, Director of the Cerebral Vascular Center in Comprehensive Stroke Center at UH Cleveland Medical Center, Director of Stroke Systems at University Hospitals Neurological Institute, Professor of Neurology at Case Western Reserve University School of Medicine and the George M Humphrey II Endowed chair. Dr. Sarraj is an internationally recognized vascular neurologist and physician scientist with the primary interest in endovascular, thrombectomy and optimal patient selection.

Welcome, Amrou.

Amrou Sarraj, MD: Thank you, Dr. Simon. Pleasure to be with you and the University Hospital audience.

Daniel Simon, MD: So, today for our audience, you know, we're joined, as we say, by a physician scientist royalty. Dr. Sarraj was recognized in 2024 as one of the top ten clinical research achievement awardees in the United States by clinical research forum. He served as the global principal investigator of the clinical study called SELECT2, a randomized controlled trial to optimize patient selection for endovascular treatment in acute ischemic stroke. And this was first published in the New England Journal of Medicine. So I guess Amrou, you know, this is quite an achievement. And as you say, you hit the hat trick in 2023 with publications in New England Journal, JAMA and Lancet; that's a career for some people, and you did it in one year.

Let's back up a little bit and tell our audience. How did you get to this point of approaching treatment of large ischemic stroke? With the thrombectomy device, in other words, sucking out the clot as a cardiologist, as an interventional cardiologist, versus a clot busting drug like TPA, how did we get here?

Amrou Sarraj, MD: Well, thank you again for the kind compliments. As I told my co-investigators throughout the trial, this is about the patient. It starts with the patient, the research that we did and that we do is to shed light on treatments and other elements in patients’ care that would improve patients care, improve their outcomes, get them back to their families, to their good ones, to their society.

And this population… large coarse strokes to illustrate to the audience in some words, these are patients with very large strokes coming in with already significant ischemic changes on the CAT scan, a large stroke on the perfusion or the MRI, that physicians, would have till recently said there is no treatment that can be offered in terms of opening the blood vessel as you described and removing the clots because the stroke is too big. The horses already left the barn and there is higher risk with opening the blood vessel into a large stroke that would result in bleeding and dying and other complications, though, these patients were not treated and they are a significant population, about 20 to 25% of all large vessel occlusion and these are strokes with large impact and they were doing very poorly.

The vast majority of these patients, without intervening, without removing the clot more than 80%, will end up with severe disability, being bedridden or dying. And we did this in a methodological manner, that we initially did a phase two non-randomized trial SELECT, hence the SELECT2 name, where we looked at these patients in an unrandomized mixed fashion, as I mentioned at nine sites in the United States. And we found that there is potential benefit, albeit, with non-randomization that are always biased that people may have treated patients who they thought would do well.

Well, we went on randomized these patients and we found that, actually, thrombectomy results in one and a half the likelihood of improving the functional outcome at 90 days - that is 40% of the patients being able to walk independently at 90 days, that is 20% - one in five patients being able to be fully independent at 90 days, where we measured the functional outcome of stroke and that is significantly better than medical management. The number needed to achieve improvement was one in five patients and this is a great number.

If we put things into context and having a cardiologist on this with me, you give aspirin to 3,000 patients to prevent one non-fatal MI to 2,000 patients to prevent one non-fatal stroke that this is one of the most powerful treatments in the history of medicine and we found that it is effective, it is safe in this large core population that was not treated. So we started by the patients we delivered for the patients and their family and effective treatment that can improve their lives and outcomes.

Daniel Simon, MD: So Amrou the initial results of the SELECT2 trial were 90 days. Tell us about the results at one year.

Amrou Sarraj, MD:  Yeah well, this was really an important aspect of what we plan to do in SELECT2. Patients with large vessel occlusion, specifically large core by definition have very large strokes that are different than the usual strokes, where the usual recovery is 3 months and we look at the outcome and say patient’s plateau, then there is no potential benefit.

So in SELECT2, we plan to look at beyond three months. We look at one year outcomes because we believe that these patients can continue to improve. They require more time to improve and we wanted to see if the treatment effect was maintained beyond what some might consider just a snapshot at 90 days.

The other component of this is the societal outcome, as in the quality of life. And how the patients and their families look at their stroke after it sits with them beyond the acute phase with the hospitalization, with the rehab and the patient now is back home with their family. Do they believe that the benefit is still there? Do they believe that they were given a better life with this? Are they satisfied? Is their depression less? Is their functionality higher? And refreshingly, the functional outcome, the clinical outcome continued to be better than medical management at one year. Patients, 21% of the patients improved from what they were at 90 days to one year, which is a great message that patients can continue improvement beyond three months. And the patients and their families came back and said, indeed, their quality of life is better with thrombectomy and they had less depression, they had better functionality and societal scores as compared to medical management. And this sends, a major message that patients support rehabilitation and further cares may be provided beyond the regular three months that because patients can continue to benefit and have improvement.

Daniel Simon, MD: Wow, that's a great result to hear that the benefit continues to accrue out to 12 months.

Amrou for the audience, sometimes patients present to a thrombectomy capable hospital. You come to the academic medical center, to UH Cleveland Medical Center and we have thrombectomy. Some patients in your trial were transferred, so they ended up at two hospitals so their treatment time was prolonged. Can you tell us a little bit about the subgroup of patients that you published on who were transferred and whether or not you saw the same benefits?

Amrou Sarraj, MD: The plan was, in advance, to look at this group of patients because as you mentioned, it is the worldwide standard of care that most of the patients will go to the closest hospital and most of the hospitals are not thrombectomy capable centers, just like the nature of a higher level of care. And two thirds of the patients in SELECT2 were transfers they did not present to the main hospital. They rather presented to the outside hospitals everywhere and that's whether in North America the trial had sites in the United States and Canada, Europe sites in Spain and Switzerland or Australia and New Zealand. Most of these patients presented to the outside hospital, there were delays, they got transferred and they got treated and what we found in the paper, that you referenced, that was published in JAMA Neurology back in February, that the benefit was maintained that thrombectomy continued to deliver better outcomes as compared to medical management.

So this is another door that opened from these results that many of these patients what they were presenting to the outside hospitals and say here at UH to Elyria or Geauga or Geneva..they may be looked at as there is no benefit, there is no need to transfer, we'll keep the patients here. We found that there is benefit from transferring them even in the subgroup of patients who had low aspects or large stroke, large core in the outside hospital, they still benefited from treatment. Of course effort, just like in cardiology, you should focus on improving access and increasing the access to thrombectomy and increasing thrombectomy centers and we are doing a lot of that here, but meanwhile reality is we still, worldwide, do not have very good access and when patients present outside, now we know that they still benefit and they should be transferred for a higher level of care.

Daniel Simon, MD: Well, that's really good news for our patients, especially in the 17 counties of Northeast Ohio that there is access to thrombectomy at multiple sites.

So studies in Japan, China and Europe have demonstrated outcomes that are similar to SELECT2. I guess you would say signaling the potential for a major advancement in stroke therapy worldwide. So reproducible results, potentially practice paradigm changing.

What must happen do you think to maximize the application of your research findings in the real world clinical setting, what do you think it's going to take? I guess when will the guidelines change? When will thrombectomy be considered first line instead of a clot busting drug?

Amrou Sarraj, MD: Guidelines are the gold standard. So, you always need high level data to change the guidelines and clinical trials and randomized clinical trials are the highest level of data. And as you mentioned, that multiple clinical trials is level 1-A evidence, undoubted, confirmed, consistent results, those change the guidelines in some of the continents in Australia, the guidelines have changed. In Europe they are in the process of changing the guidelines in the United States, we as well are in the process of changing the guidelines. And once the guidelines change, this becomes the standard of care. That means patients who meet these profiles of imaging and other clinical variables would be treated unless there was a convincing reason for not treating them.

Meanwhile, patients care does not wait for that to happen. We here at UH and worldwide, the vast majority I would say, have changed their practice guidelines locally to include these populations and treat them, and we have opened the door for this population and we see more and more of them and we transfer more and more and then treat them. And it's really a great joy to see them coming back to the clinic and improving, in many instances.

Daniel Simon, MD: You know, that's really great. So I guess the question for you now…Is what is the SELECT3 going to be? So what are the next steps you've tackled in many regards, one of the toughest challenges, which are these large core strokes, what's your next trial? Tell us about where you think the field is moving.

Amrou Sarraj, MD: This is a great question to shed light on what's next. The large core and the stroke size was a major hurdle in patients care as human beings, as physicians, we like to draw lines in the sand and say beyond this, I can't do this. Beyond that, I can't do this and the stroke size was one of these major limits and I think it got busted, big time, by SELECT2 and the other randomized clinical trials. I think another major hurdle or limit of patients’ treatment and care is time. Time is brain and you need to come as soon as possible and get treated as soon as possible within 4 1/2 hours within 24 hours. But some patients, especially those elderly patients and patients who live in distant areas or who live alone and there is nobody who can observe them experiencing stroke symptoms or patients with disparities that live in areas where there is no thrombectomy centers, has significant time passes from stroke onset to presentation and the time limit in delivering thrombectomy now is 24 hours. And we believe that this is the next target, we believe that this is another limit to cross and we did SELECT at the phase two, we did SELECT Late, a large cohort study from centers across the world where we showed that patients treated up to 72 hours continued to benefit from thrombectomy as compared to medical management.

And we are now in the process of acquiring through a federal agency a grant where UH will be the leading coordinating center for a global clinical trial. SELECTLate to look at patients with large vessel occlusion up to 72 hours and see if we can have another revolution in patients care and expanding the treatment limit beyond the current 24 hours to pretty much… get to the point where we include almost all patients with large vessel occlusion with their size, with their time, without limitation.

Daniel Simon, MD: Amrou, it's an honor and a privilege to talk with you. And it's so inspiring to hear about the advances in stroke. One of my grandmothers had a large stroke back in the 70s, and she was left with a significant hemiparesis, progress through rehab. But oh my goodness, she would have benefited enormously from thrombectomy.

We're so grateful for your work, the work of your team and your SELECT investigators. We look forward to the results of SELECTLate and wish that you will enroll very quickly. Thank you for taking the time to speak with us today, Dr. Sarraj.

To learn more about research at University Hospitals, please visit uhhospitals.org/UHresearch.

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