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Perspectives in Optimizing the Timely Delivery of Stroke Care

  • Authors: Greg W. Albers, MD; Jeffrey L. Saver, MD, FAHA, FAAN, FANA; Eva A. Mistry, MBBS, MSCI, FAHA
  • CME / CE Released: 10/8/2022
  • Valid for credit through: 10/8/2023
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  • Credits Available

    Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™

    Nurses - 1.00 ANCC Contact Hour(s) (0.5 contact hours are in the area of pharmacology)

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    • Letter of Completion

Target Audience and Goal Statement

This activity is intended for neurologists, nurse practitioners (NPs), and nurses involved in the care of patients with stroke.

The goal of this activity is that learners will be better able to identify patients with ischemic stroke who are candidates for endovascular and/or thrombolytic therapies.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Factors involved in the identification of patients with stroke for thrombolytic therapy
    • Clinical data for thrombolytic therapies for the management of stroke
    • Guideline-recommended use of endovascular treatment for the management of stroke
    • Clinical data on long-term patient outcomes associated with the use of endovascular therapy for the management of stroke
    • Recent clinical data examining the effect of use of stroke therapeutics outside of the established timeline for use


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Session Chair

  • Greg W. Albers, MD

    Stanford Stroke Center
    Stanford University
    Stanford, California


    Greg W. Albers, MD, has the following relevant financial relationships: 
    Consultant or advisor for: Genentech


  • Eva A. Mistry, MBBS, MSCI, FAHA

    Assistant Professor of Neurology
    University of Cincinnati
    Cincinnati, Ohio


    Eva A. Mistry, MBBS, MSCI, FAHA, has no relevant financial relationships.

  • Jeffrey L. Saver, MD, FAHA, FAAN, FANA

    Professor and SA Vice Chair for Clinical Research
    Carol and James Collins Chair
    Department of Neurology
    Director, UCLA Comprehensive Stroke and Vascular Neurology Program
    David Geffen School of Medicine at UCLA
    Los Angeles, California


    Jeffrey L. Saver, MD, FAHA, FAAN, FANA, has no relevant financial relationships.


  • Meg Monday

    Senior Director, Content Development, Medscape, LLC


    Meg Monday has no relevant financial relationships.

  • Nancy Ashley, MSN, APRN, ANP-BC

    Medical Education Director, WebMD Global, LLC


    Nancy Ashley, MSN, APRN, ANP-BC, has no relevant financial relationships.

Compliance Reviewer/Nurse Planner

  • Stephanie Corder, ND, RN, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Stephanie Corder, ND, RN, CHCP, has no relevant financial relationships.

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Perspectives in Optimizing the Timely Delivery of Stroke Care


Current and Emerging Approaches to Thrombolytic Therapeutics for Stroke



Greg Albers (00:08): Hi there. I'm Greg Albers, the Director of the Stroke Center at Stanford University and Professor of Neurology. I'm going to talk about current and emerging approaches to thrombolytic therapeutics for stroke. So, we'll start with some ancient history. If we go back to 1995, we have the NINDS tPA Stroke Trial. This is the trial that treated patients with tPA versus placebo within three hours of symptom onset, and was the first positive stroke trial, and led to the first FDA clearance of a medication to treat stroke. So, many of the trials that we'll talk about today use the modified Rankin Scale as the primary outcome and a favorable Rankin Outcome Scale would be zero, one, or two. The unfavorables are four, five, or death. And what you can see here is that in the placebo group, there were many more patients who had unfavorable outcomes, and fewer patients who had those favorable outcomes. So, there was a favorable shift in the Rankin Scale with an increase in good outcomes and fewer bad outcomes, leading to the FDA approval of tPA within three hours of symptom onset. So, a few years later, the window was expanded to four and a half hours by the ECASS III Study. Again, a similar trial comparing tPA known as Alteplase to placebo and showing more good outcomes, and about the same on the unfavorable outcomes. The amount of benefit here at three to four and a half hours was less than what was seen at zero to three, but it was still statistically significant. And although this was not enough to convince the FDA to bump the window out to four and a half hours, the American Heart Association as well as guideline groups worldwide bumped their guidelines out to four and a half hours. And here is a detailed slide from the 2019 AHA Guideline update, which gives some of the recommendations for who should be treated with tPA. And obviously, these should be patients who have a significant neurologic deficit. They need to have a disabling neurologic deficit and can be treated within four and a half hours. Blood pressure is an important issue. If the blood pressure is over 185/110, it needs to be brought down with medication before the patient is treated. And it's important to do a blood glucose, at least a finger stick, to make sure that the patient is not having neurologic symptoms because of hypoglycemia. So, this has been in effect for many years since ECASS III, providing us with the four and a half hour window. And the question has been, can we treat patients who wake up with a stroke with tPA? Because the thought is that many wake-up strokes or strokes that occurred within the four and a half hours prior to that wakening time. So, actually many wake-up strokes can be early strokes, early window strokes, and an imaging-based trick, it's called the DWI-FLAIR mismatch. What you do here is an MRI scan. The stroke will show up immediately on DWI, but it typically takes many hours before you can see it on FLAIR. So, if there's a mismatch, meaning you don't see it on FLAIR, but you do see it on DWI, that is a surrogate for the patient likely being within four and a half hours of symptom onset. So, that was the premise of this study that was done in Europe, published in the New England Journal in 2018 and showed a benefit. You can see the primary endpoint, 53% favorable rank and outcomes versus 42% on the placebo. So, it was positive using this strategy to find wake-up [inaudible 00:04:00] patients who were within a few hours of symptom onset. And you can see that there was a trend toward more deaths in the tPA group and a slight increase, but not statistically significant in symptomatic intracranial hemorrhage. So, this has been incorporated into the AHA Guidelines. It received a 2A recommendation to use MRI to select wake up patients to try to figure out which of these patients may be within four and a half hours of symptom onset. Now, what about breaking that four and a half hour barrier? Can we treat patients beyond four and a half hours successfully with an IV thrombolytic? And if you look over the history of all of these trials that are summarized in the right side of this slide, these were all unsuccessful in breaking that four and a half hour barrier. They fell victim to this time is brain curve that shown on the left, where you can see favorable response to therapy declines over time. We all know time is brain. And with IV thrombolysis, as you're getting out to four and a half hours or beyond, you're not seeing statistically significant benefits, but that barrier has now been broken by the EXTEND trial. This was published in 2019. TPA versus placebo between four and a half and nine hours after onset. So, these are not just patients with unknown onset assumed to be early. These are patients who could have witnessed onset up to nine hours and still be eligible for the trial. The way they accomplished this was using advanced imaging using CT perfusion to identify tissue that is likely irreversibly injured, and then using it to identify the tissue that is likely to be critically hypoperfused and likely to be incorporated into the final infarct. So, if you see a mismatch, in other words, a small pink lesion indicating a small amount of tissue has very low blood flow and is likely to be irreversible injured, but a much larger green area indicating tissue that has significant delay in the arrival of the contrast material and is likely to be critically hypoperfused, and at high risk of going on to infarct. If there's a mismatch there, those were the patients who were selected for the EXTEND trial, and you can see that there was a statistically significant benefit in clinical outcomes in this study. So, for the first time treating patients all the way out to nine hours with an IV thrombolytic and showing benefit. Here, you can see on the Rankin Scale, the favorable outcomes were more common in the tPA, the Alteplase group. Unfavorable outcomes, there was a slight trend there to being less favorable on the unfavorable side of the scale. And to understand this better, the investigators combined their data with two other trials. And you could see here that if you looked at this data, which is including EXTEND, ECASS III, and EPITHET, that when you look and see which of the patient that's in those trials had a automated perfusion mismatch, in other words, the green area bigger than the pink, that those patients had very favorable outcomes on this graph. However, there were patients included in some of these trials where they didn't meet the automated profusion mismatch criteria. And for those patients, at the bottom, you can see that the trends are opposite. If you look at mortality rate, which is the black bar, 17% in the Alteplase group versus 4% in placebo. So, a strong trend toward increase in mortality, and then the Rankin five, which is that dark blue box, as you can see, that was also twice as high in the Alteplase than the placebo, suggesting that for some patients who don't have this mismatch, or have a very large core, that the tPA leads to less favorable outcomes. So, when you mix those patients in with the patients who have the mismatch, that's why you could get those trials that had a neutral result. But if you can use the advanced imaging to not treat the patients who don't have the profusion mismatch, then you can get the positive results that were seen in the EXTEND trial. All right, let's shift gears now and talk about another agent that can be used for thrombolysis in the acute stroke setting, and this is tenecteplase, also known as TNK. There's many advantages of this agent, and this is why it's becoming quite common for stroke treatment. I'll note at the beginning here, it is not yet FDA approved for treatment of acute stroke, but as you'll see, there's a considerable database supporting the advantages of this agent, and they're summarized here. This is a bolus drug rather than an hour of infusion, which means that you can do an MRI scan while during thrombolysis. It also means that you can transfer a patient in an ambulance rather than waiting for that infusion to finish. So, it's better for drip and ship. It appears to have better recanalization and functional outcome rates than tPA, no significant differences in hemorrhage rates, and substantially lower cost. This is a three amino acid change off tPA. So, it's a variant of tPA, gives it the longer half-life and much higher fibrin specificity. So, this has some theoretical advantages that have been confirmed in a number of clinical trials. Starting first in 2012, Mark Parsons had a New England Journal article showing that in patients selected with CT perfusion, that the TNK, at the favored dose of 0.25 mg/kg, appeared to be safer and more efficacious than tPA. The next major trial showing benefits of this was the EXTEND-IA TNK study in 2018. The results are summarized here. What was done in this trial was used TNK rather than tPA as the bridging therapy as the patient was on their way to a plan thrombectomy. So here, these are patients with the large vessel occlusions. They're treated with TNK versus tPA. And what you can see is by the time the patient made it into the angiography suite, 22% of the TNK treated patients, the clot was already dissolved. It was already gone versus 10% in the tPA group. So, a substantial, significant benefit there, which translated into better clinical outcomes. At the top, you see the TNK outcomes, more patients having these favorable Rankin zero to one outcomes, fewer patients having the unfavorable Rankin five to six outcomes, so a clinical benefit using TNK as the bridging therapy. And then, the most impactful, large trial has just recently been published 2022 in The Lancet. This study, called AcT, looked at 1,600 patients randomized to TNK versus tPA. These are your standard, early window thrombolysis patients mean time to treatment about two hours. And you can see good outcome rates of about 37% in the TNK group versus about 35% in the tPA group. No difference in ICH. Here, the Rankin bar is showing that slight benefit in TNK versus Alteplase. And the comments of the investigators that were published saying that this evidence from AcT combined with the other trials that have been published, provides a compelling rationale to switch the global standard for thrombolysis to TNK at the 0.25 mg/kg dose in patients with acute ischemic stroke. And they recommended this be done all the way out to four and a half hours. So, many sites, even before AcT, had already decided that this was the way to go. So, a considerable number of comprehensive stroke centers, but also a number of primary stroke centers have made this switch. This was data presented by Steve Warach regarding the experience at the Ascension hospitals in Texas, over 15 months of using TNK rather than tPA for stroke treatment. And what they were able to find here is that there were shorter door to needle times, there were better overall outcomes, and a tremendous reduction in cost. Pharmacy cost savings over one year, about $400,000. Here, you can see more patients with independent ambulation and more patients discharged to home with independent ambulation with the TNK versus the historical data from the tPA. In terms of safety, no concern, symptomatic intracranial hemorrhage trended lower with TNK than Alteplase in this large set of community hospital experience. So, we're going to finish up with talking about the future. There is a very large trial that is trying to shatter the stroke stopwatch for IV thrombolysis all the way out to 24 hours using TNK. This is the TIMELESS trial. It's being done in a large number of sites, so it'd be more than 450 patients who will be enrolled. This study will complete this year, in 2022, and it will try to show using the same selection strategy that allowed the time window for thrombectomy to be expanded to 24 hours, this mismatch related imaging. It will try to show that TNK ,can be used all the way out to 24 hours. So, these are patients with large vessel occlusions, ICAM-1 or ICAM-2, most of them are on their way to a thrombectomy, but some of the M-2s are not being treated with thrombectomy. So, it's just TNK versus placebo for them. But the majority, it's being used as bridging therapy. And the idea is that the way to treat stroke patients, regardless of time, if they have salvageable tissue, is you get the thrombolytic going and then you head to the thrombectomy suite, if they still have a large vessel occlusion, to remove that with thrombectomy. So, the imaging criteria, virtually identical to the DEFUSE 3 Study, we're looking at patients who will have a mismatch with a small area of very low CBF or diffusion weighted imaging injury, if it's a patient selected by MR. Versus a Tmax delay, which these green maps show you how large the stroke is likely to be if you don't intervene. So, this would be an eligible patient for the TIMELESS Study, and you're trying to remove the approximately 50% of patients who in the late time window have a large vessel occlusion, but do not have favorable imaging. This is a matched deficit where you can see the pink area of irreversible injury is already the same size, or actually a little bit bigger here than the area of profusion abnormality. So, this is the type of patient that is not going to do well with reperfusion therapy, and they are excluded from the study. So, very exciting time as we see that we have now new thrombolytic agents to work with as well as the possibility of treating many, many more patients at later time windows. So, thank you so much for listening in, and take care.

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