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Tenecteplase for Treatment of Acute Ischemic Stroke
In this episode, Christina Wilson, MD, compares and contrasts alteplase and tenecteplase for acute ischemic stroke. She characterizes the population of stroke patients that may benefit most from tenecteplase treatment and she helps us to recognize potential barriers to tenecteplase implementation.
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Learn more about Christina Wilson, MD
Christina Wilson, MD
Christina Wilson, MD, PhD is an Associate Professor of Neurology at the University of Florida College of Medicine. She serves as the Neurology Residency Program Director, Vascular Neurology Fellowship Director, and Associate Chair of Education for the Department of Neurology.Learn more about Christina Wilson, MD
Transcription:
Scott (preroll): The University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of 0.25 AMA PRA category one credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.
Melanie Cole (Host): Welcome to UF Health Med Ed Cast with UF Health Shands Hospital. I'm Melanie Cole and I invite you to listen as we examine tenecteplase for treatment of acute ischemic stroke. Joining me is Dr. Christina Wilson. She's an Associate Professor of Neurology at the University of Florida College of Medicine, and she practices at UF Health Shands Hospital. Dr. Wilson, it's a pleasure to have you join us today as alteplase remains the only FDA approved thrombolytic for acute ischemic stroke. Can you tell us a little bit about the history and evolution of thrombolytics for stroke?
Christina Wilson, MD (Guest): Absolutely. And thank you for having me. So as you noted, alteplase is currently our standard of care for the treatment of acute ischemic stroke. We've been using this in clinical practice for just about 25 years now, based on the initial NINDS trial that was conducted in 1996. This demonstrated that alteplase had a benefit for patients when they presented early in an acute ischemic stroke. And we still are tied to that very early time window. Although some subsequent studies have shown that we can go out to four and a half hours in most cases and potentially even a little bit longer with some select patient populations. But, to date, alteplase remains our standard of care.
Host: Well, then now tell us about tenecteplase. How has this entered the picture?
Dr. Wilson: So tenecteplase is actually very similar to alteplase. We're really talking about a recombinant form with a modification of only a few amino acids. But those amino acids do make potentially a significant difference. So alteplase has a couple of limitations that make it a little bit difficult to use in certain situations.
One is that it has a very short half-life. And so what that means in clinical practice is that you have to provide a bolus right upfront, but then also a one hour infusion. And this can be a challenge, if there was a patient, for example, who is being transported to a higher level of care, often transportation doesn't want to move the patient if they're on an active infusion.
And so this can slow things down. Also, it takes a lot of nursing involvement, to monitor that drip for an hour. And so that can tie up resources and then can also be challenging especially in the COVID pandemic where we're trying to, sometimes limit the amount of time that, the personnel are spending in a patient's room, for infection purposes.
And so the nice thing about tenecteplase, is that as a result of the modification, it has increased resistance to degradation in the bloodstream. So this gives it a longer half-life and it can be administered as a single bolus injection. So, really bypasses a lot of those concerns about needing to be on an active infusion.
The other limitation that we're all familiar with, with alteplase is that, the potential downside and one of the risks that we need to take into consideration when the patient is being considered, you know, risks and benefits is that there is a risk of hemorrhage associated with the medication, and tenecteplase doesn't completely remove this risk, but there is, in theory, because it has a greater specificity for the plasminogen that's bound to fibrin, so attached to a clot, it should be more specific for attacking that clot and not just kind of causing hemorrhages. So, there should be a lower risk of hemorrhage overall. And then another benefit is that it is less expensive than alteplase.
So neither of these medications is particularly inexpensive. But it can be a little bit helpful that this is a less expensive medication. And then the final limitation with alteplase, that we are certainly aware of is that the larger the clot; and so when we have large vessel occlusions, for example, these are the most devastating types of stroke; we know that alteplase doesn't work particularly well in opening up those types of clots. Thankfully, we do have mechanical thrombectomy as a treatment, in certain situations. But, because tenecteplase again, attacks the plasminogen, or it's bound to fibrin and potentially is more specific for the clot; what we found in some of our clinical trials is that it's particularly helpful for that patient population with large vessel occlusions.
Host: Well, thank you for that. And I'd like you to expand on what you just said as you've been comparing and contrasting alteplase and tenecteplase for stroke. Can you characterize the population of patients that would benefit the most from tenecteplase treatment, expand on your patient selection for us? You just mentioned one. Can you give us some others?
Dr. Wilson: So there've been two pools of patient populations that have been addressed in the clinical trials. The first is kind of an all-comers, the folks who are having an acute ischemic stroke, are presenting within the time window, where they would benefit from treatment with a tissue plasminogen activator.
And so we have several clinical trials that were smaller comparing tenecteplase and alteplase. And that patient population showed that tenecteplase, likely works as well as alteplase in that population. But really there's only been one published trial that looked at a larger patient population in kind of all-comers of stroke.
And that was the NOR-TEST trial that was published in 2017. This looked at a higher dose of tenecteplase than is used in some of the other studies. So this is 0.4 milligrams per kilogram of tenecteplase, rather than the lower dose of 0.25 that was used in some of the other trials.
But so using this higher dose and looking at, enrolling a little over a thousand paitients, the NOR-TEST trial again, compared all-comers, folks who came in and met kind of the standard alteplase treatment definitions within four and a half hours. And within this patient population, again, you know, tenecteplase and alteplase where across the board fairly similar, no benefit to one over the other.
But it's important to realize, number one, that this trial skewed towards a milder stroke population. So most of the folks in this trial, had an NIH stroke scale of seven or less. And so that's an important thing to keep in mind when you're assessing whether your patient might benefit. And so, they did do some subgroup analyses after the fact and showed that in patients who had more moderate levels or severe strokes when they came in, that they likely benefited as well.
But of course, a subgroup analysis with smaller numbers, it's always a little bit challenging to really, determine whether that is truly an effect. And so, it would be helpful to have some additional studies looking at this. These are ongoing, but have not yet been replicated. So, the 2019 American Heart Association and American Stroke Association Guidelines, consider this patient population of all folks who are presenting with an acute ischemic stroke in that treatment window.
And they say that the higher dose, the 0.4 milligrams per kilogram can be considered as an alternative to alteplase. So again, in those situations, where there is a nursing issue or a transport issue, or, there's currently a national shortage of alteplase.
And so that may make tenecteplase look a little bit more attractive in certain situations. But I would say that the bigger population that we are focusing on at the moment is those patients with the large vessel occlusion, as I mentioned, earlier.
Host: So, where are we now in trials? And what do you think will happen and when?
Dr. Wilson: So I think, it's an interesting time. There's a lot of potential and judging from the feel on the ground at the International Stroke Conference when folks are talking about this, it seems like there's a lot of excitement and I envision that at some point we're going to make a full transition after we have a little bit more trial data.
Here at UF Health Shands Hospital, we have actually started to make that transition. So specifically looking at the patient population with large vessel occlusion, given that we have a bit more data there to suggest that those patients actually open up that clot, before you even take them for mechanical thrombectomy, that that's more likely to happen with tenecteplase than with alteplase.
And so we've incorporated that in, into our protocol here. And so if someone presents with what appears to be a clinical large vessel occlusion, which we subsequently confirm on our CTA, which is part of our stroke alert process, but we certainly don't wait to treat, you know, until we've determined that. So, if they present with a clinical large vessel occlusion, they are being treated with tenecteplase at this point.
Host: Really? That's amazing. And what an exciting time to be in your field. Dr. Wilson, as we wrap up, anything you're doing at UF Health Shands Hospital that other providers may not know about? Any research studies related to thrombolytics for acute ischemic stroke and really what you would like the key message to be about tenecteplase and what you're doing there.
Dr. Wilson: So I think there's lots of potential to explore this a bit further and one patient population that we don't have data yet, but I think might be of interest is in the extended time window of treatment. Many of our treatments, especially with thrombolytics have been very time locked that we have really focused on that four and a half hour time window. And unfortunately, a lot of patients present outside of that window. It's later. They don't necessarily recognize that they're having stroke symptoms. They don't realize that they should call emergency medical services. And so, may drive themselves to the hospital, and be stuck in triage or something like that, where they're not getting that treatment within the time window.
So there are some ongoing trials looking at tenecteplase within that extended window. And it's certainly, hoped that, that patient population may show a benefit as well. So I think in summary, where we are currently, it's really an exciting time, for particularly large vessel occlusions that we not only have the mechanical thrombectomy, which has been shown in multiple clinical trials to have an efficacy, especially in those patient population, with the anterior circulation, large vessel occlusion.
But now this data from the Extend IA tenecteplase trial that was published in 2018, showing that, patients would potentially benefit from tenecteplase over alteplase as well.
Host: Such an informative episode. Thank you so much, Dr. Wilson for joining us today. To refer your patient or to listen to more podcasts from our experts, please visit UFhealth.org/medmatters. And that concludes today's episode of UF Health Med Ed Cast with UF Health Shands Hospital. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole.
Scott (preroll): The University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of 0.25 AMA PRA category one credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.
Melanie Cole (Host): Welcome to UF Health Med Ed Cast with UF Health Shands Hospital. I'm Melanie Cole and I invite you to listen as we examine tenecteplase for treatment of acute ischemic stroke. Joining me is Dr. Christina Wilson. She's an Associate Professor of Neurology at the University of Florida College of Medicine, and she practices at UF Health Shands Hospital. Dr. Wilson, it's a pleasure to have you join us today as alteplase remains the only FDA approved thrombolytic for acute ischemic stroke. Can you tell us a little bit about the history and evolution of thrombolytics for stroke?
Christina Wilson, MD (Guest): Absolutely. And thank you for having me. So as you noted, alteplase is currently our standard of care for the treatment of acute ischemic stroke. We've been using this in clinical practice for just about 25 years now, based on the initial NINDS trial that was conducted in 1996. This demonstrated that alteplase had a benefit for patients when they presented early in an acute ischemic stroke. And we still are tied to that very early time window. Although some subsequent studies have shown that we can go out to four and a half hours in most cases and potentially even a little bit longer with some select patient populations. But, to date, alteplase remains our standard of care.
Host: Well, then now tell us about tenecteplase. How has this entered the picture?
Dr. Wilson: So tenecteplase is actually very similar to alteplase. We're really talking about a recombinant form with a modification of only a few amino acids. But those amino acids do make potentially a significant difference. So alteplase has a couple of limitations that make it a little bit difficult to use in certain situations.
One is that it has a very short half-life. And so what that means in clinical practice is that you have to provide a bolus right upfront, but then also a one hour infusion. And this can be a challenge, if there was a patient, for example, who is being transported to a higher level of care, often transportation doesn't want to move the patient if they're on an active infusion.
And so this can slow things down. Also, it takes a lot of nursing involvement, to monitor that drip for an hour. And so that can tie up resources and then can also be challenging especially in the COVID pandemic where we're trying to, sometimes limit the amount of time that, the personnel are spending in a patient's room, for infection purposes.
And so the nice thing about tenecteplase, is that as a result of the modification, it has increased resistance to degradation in the bloodstream. So this gives it a longer half-life and it can be administered as a single bolus injection. So, really bypasses a lot of those concerns about needing to be on an active infusion.
The other limitation that we're all familiar with, with alteplase is that, the potential downside and one of the risks that we need to take into consideration when the patient is being considered, you know, risks and benefits is that there is a risk of hemorrhage associated with the medication, and tenecteplase doesn't completely remove this risk, but there is, in theory, because it has a greater specificity for the plasminogen that's bound to fibrin, so attached to a clot, it should be more specific for attacking that clot and not just kind of causing hemorrhages. So, there should be a lower risk of hemorrhage overall. And then another benefit is that it is less expensive than alteplase.
So neither of these medications is particularly inexpensive. But it can be a little bit helpful that this is a less expensive medication. And then the final limitation with alteplase, that we are certainly aware of is that the larger the clot; and so when we have large vessel occlusions, for example, these are the most devastating types of stroke; we know that alteplase doesn't work particularly well in opening up those types of clots. Thankfully, we do have mechanical thrombectomy as a treatment, in certain situations. But, because tenecteplase again, attacks the plasminogen, or it's bound to fibrin and potentially is more specific for the clot; what we found in some of our clinical trials is that it's particularly helpful for that patient population with large vessel occlusions.
Host: Well, thank you for that. And I'd like you to expand on what you just said as you've been comparing and contrasting alteplase and tenecteplase for stroke. Can you characterize the population of patients that would benefit the most from tenecteplase treatment, expand on your patient selection for us? You just mentioned one. Can you give us some others?
Dr. Wilson: So there've been two pools of patient populations that have been addressed in the clinical trials. The first is kind of an all-comers, the folks who are having an acute ischemic stroke, are presenting within the time window, where they would benefit from treatment with a tissue plasminogen activator.
And so we have several clinical trials that were smaller comparing tenecteplase and alteplase. And that patient population showed that tenecteplase, likely works as well as alteplase in that population. But really there's only been one published trial that looked at a larger patient population in kind of all-comers of stroke.
And that was the NOR-TEST trial that was published in 2017. This looked at a higher dose of tenecteplase than is used in some of the other studies. So this is 0.4 milligrams per kilogram of tenecteplase, rather than the lower dose of 0.25 that was used in some of the other trials.
But so using this higher dose and looking at, enrolling a little over a thousand paitients, the NOR-TEST trial again, compared all-comers, folks who came in and met kind of the standard alteplase treatment definitions within four and a half hours. And within this patient population, again, you know, tenecteplase and alteplase where across the board fairly similar, no benefit to one over the other.
But it's important to realize, number one, that this trial skewed towards a milder stroke population. So most of the folks in this trial, had an NIH stroke scale of seven or less. And so that's an important thing to keep in mind when you're assessing whether your patient might benefit. And so, they did do some subgroup analyses after the fact and showed that in patients who had more moderate levels or severe strokes when they came in, that they likely benefited as well.
But of course, a subgroup analysis with smaller numbers, it's always a little bit challenging to really, determine whether that is truly an effect. And so, it would be helpful to have some additional studies looking at this. These are ongoing, but have not yet been replicated. So, the 2019 American Heart Association and American Stroke Association Guidelines, consider this patient population of all folks who are presenting with an acute ischemic stroke in that treatment window.
And they say that the higher dose, the 0.4 milligrams per kilogram can be considered as an alternative to alteplase. So again, in those situations, where there is a nursing issue or a transport issue, or, there's currently a national shortage of alteplase.
And so that may make tenecteplase look a little bit more attractive in certain situations. But I would say that the bigger population that we are focusing on at the moment is those patients with the large vessel occlusion, as I mentioned, earlier.
Host: So, where are we now in trials? And what do you think will happen and when?
Dr. Wilson: So I think, it's an interesting time. There's a lot of potential and judging from the feel on the ground at the International Stroke Conference when folks are talking about this, it seems like there's a lot of excitement and I envision that at some point we're going to make a full transition after we have a little bit more trial data.
Here at UF Health Shands Hospital, we have actually started to make that transition. So specifically looking at the patient population with large vessel occlusion, given that we have a bit more data there to suggest that those patients actually open up that clot, before you even take them for mechanical thrombectomy, that that's more likely to happen with tenecteplase than with alteplase.
And so we've incorporated that in, into our protocol here. And so if someone presents with what appears to be a clinical large vessel occlusion, which we subsequently confirm on our CTA, which is part of our stroke alert process, but we certainly don't wait to treat, you know, until we've determined that. So, if they present with a clinical large vessel occlusion, they are being treated with tenecteplase at this point.
Host: Really? That's amazing. And what an exciting time to be in your field. Dr. Wilson, as we wrap up, anything you're doing at UF Health Shands Hospital that other providers may not know about? Any research studies related to thrombolytics for acute ischemic stroke and really what you would like the key message to be about tenecteplase and what you're doing there.
Dr. Wilson: So I think there's lots of potential to explore this a bit further and one patient population that we don't have data yet, but I think might be of interest is in the extended time window of treatment. Many of our treatments, especially with thrombolytics have been very time locked that we have really focused on that four and a half hour time window. And unfortunately, a lot of patients present outside of that window. It's later. They don't necessarily recognize that they're having stroke symptoms. They don't realize that they should call emergency medical services. And so, may drive themselves to the hospital, and be stuck in triage or something like that, where they're not getting that treatment within the time window.
So there are some ongoing trials looking at tenecteplase within that extended window. And it's certainly, hoped that, that patient population may show a benefit as well. So I think in summary, where we are currently, it's really an exciting time, for particularly large vessel occlusions that we not only have the mechanical thrombectomy, which has been shown in multiple clinical trials to have an efficacy, especially in those patient population, with the anterior circulation, large vessel occlusion.
But now this data from the Extend IA tenecteplase trial that was published in 2018, showing that, patients would potentially benefit from tenecteplase over alteplase as well.
Host: Such an informative episode. Thank you so much, Dr. Wilson for joining us today. To refer your patient or to listen to more podcasts from our experts, please visit UFhealth.org/medmatters. And that concludes today's episode of UF Health Med Ed Cast with UF Health Shands Hospital. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole.