Eva Mistry (00:01): Hello everyone. My name is Eva Mistry. I'm an assistant professor at University of Cincinnati and I will be talking about emerging clinical data and clinical practices in timing of stroke care today. You have heard from the speakers that talked about this before me, is that there are certain indications for which acute stroke therapies are indicated with high level of evidence and standard of care. I just wanted to break this indications down according to the sizes of vessel occlusion as well as the most important factor in acute stroke treatment, which is the time window within which the stroke patient presents to us after the last known well or the onset of their stroke. So, what you can see here in blue highlight is currently a standard of care treatment options with high quality evidence. If a patient presents within zero to four and a half hours, doesn't matter what kind of vessel occlusion they have, large versus medium versus small, endovascular therapy plus or minus tPA or TNK, which is thrombolysis, is indicated for these patients. However, if they present within four and a half to nine or nine to 24 hour window, which is traditionally called extended time window of treatment in setting up acute stroke. Only endovascular therapy has a high level of evidence for large vessel occlusion stroke patients. In that too, they have to meet certain criteria, for example, non large core, their stroke scale has to be more than six and they cannot have a preexisting disability. Within this time window, medium and small vessel occlusion strokes however have no definite evidence currently of any of these therapies, but are great interest for ongoing as well as future research. Talking about extended window thrombolysis, let's just break it down for ease of discussion of level of evidence into two parts. The first for which there is a high quality evidence and recommendation for standard of care thrombolysis treatment, are those patients that present beyond four and a half hours of their last known well. And last known well is the key here, where patients cannot reliably ascertain the time of onset of their stroke and have unwitnessed onset of stroke symptoms. These can further be broken down into wake up strokes or non wake up stroke, but last known well is beyond four and a half hours. The second bucket is those of true extended window strokes. They present to us beyond four and a half hours of a known onset of their stroke. And this is the area where there is this little bit of a gray indication for thrombolysis and definitely a lot of current ongoing research that I will talk about at length. So let's just talk about the true extended window thrombolysis and why tPA or TNK is not a 100% indicated for these indications. [Dr. Alberts 00:03:05] has talked to you about the wake up trial, which tested tPA versus placebo for unknown onset patients who presented beyond four and a half hours of their last known well. Majority, 94% of these patients, had a sleep onset of stroke or a wake up onset of stroke. And a hundred percent of the patients had unknown onset. Thus, the results are not directly applicable to true extended windows. Thrombolysis where patients have a known onset of stroke beyond four and a half hours. The other one is EXTEND trial, which he also has mentioned to you. tPA versus placebo for greater than four and a half to nine hours of stroke onset or awakening with stroke symptoms. This trial used CT perfusion based selection of patients. And those that were destined for endovascular treatment were not included. 65% of this population had sleep onset stroke or another wet spell in the bucket of unknown onset of stroke. Only 89 patients were possibly true extended window stroke, where they had a known onset beyond four and a half hours. Although it is recently come to light that within the extended data itself, we cannot certainly tell how many patients exactly were within that true extended window versus not. Squarely, thrombolysis within this true extended window of known last known well or known symptom onset beyond four and a half hours is not currently recommended by American heart and American stroke association guidelines. There are many ongoing, very promising studies however in this place. The two that are worthy of mention are TIMELESS. This study is testing tenecteplase, for acute stroke patients who have a large vessel occlusion and present within four and a half to 24 hours of symptom onset. So, these are the true extended window patients. TEMPO-2 is an interesting trial as well to look out for the results. Tenecteplase for mild acute stroke or TIA with large vessel occlusion within 12 hours of symptom onset. There are novel lytics that also could expand indication of thrombolysis to include patients who are within true extended window. Some of these are of notable mention. TS23 is one of them, which is a monoclonal antibody, Anti-alpha2-antiplasmin molecule, which has shown longer therapeutic window in pre-clinical models up to 24 or even 48 hours of stroke onset. And it does have reduced hemorrhagic complication as well as promising efficacy in comparison to tPA in these preclinical models. It is an exciting molecule, hopefully will be in human studies very, very soon. [inaudible 00:05:54] is another molecule, one with a [inaudible 00:05:56] factor inhibitor. It has been known to cause rapid recanalization of large vessel occlusion in preclinical models as well, and maybe some promise of extended therapeutic window as well. And while we are at novel lytics for indication expansion, this is not particularly pertaining to true extended window thrombolysis. But just because we're talking about new practices, tPA TNK plus antiplatelet agents are worthy of mention. Currently ongoing NIH funded large clinical trial called MOST is testing efficacy of TNK or tPA plus eptifibatide or argatroban as a lytic adjunct. However, these patients are super selected. They present within three hours of last known well. So, not really expanding in the indication to extended window, but testing thrombolysis plus strategies adjunctively. So, switching gears and anchoring back to this acute ischemic stroke space that I had showed you before. We talked that ongoing research focuses on this orange bar here of medium vessel occlusions, as well as small vessel occlusion. Again, imaging selected patients that are truly beyond four and a half hours of their symptom onset, and we should have really great answers for some of these patients very soon. However, we also do not have answers right now regarding large vessel occlusion patients when they do not meet these asterisk criteria of having non large core, high NIH stroke scale and no pre-stroke disability. There are very, very exciting studies ongoing in this field as well and I will talk about them briefly in the next few slides. So, just to come back to what [Dr. Saber 00:07:43] and Dr. Alberts has already talked to you about, acute ischemic stroke patients presenting within zero to six hours. For them, endovascular treatment, if they have a large vessel occlusion, is currently standard of care, using a non-contrast CT brain selection criteria. The only thing that they have to have is an ASPECTS score greater than equal to six. Squarely, a large core within this window of zero to six hours, is defined as having an ASPECTS score on non-contrast CT brain of zero to five. In contrast to that large vessel occlusion patients when they present within six to 24 hours, endovascular therapy standard of care for perfusion selected patients, they have to have certain criteria including cerebral blood flow less than 30%, area less than or equal to 70 CCs, as well as a mismatch ratio with the area of Tmax are in a six seconds of 1.7 or more. Squarely, large core in this patient population is defined as having this area of cerebral blood flow less than 30% of the contralateral side. That volume has to be more than 70 CCs to be defined as a large core, generally speaking, within this time window. We do have one randomized clinical trial in this space of large four. It is out of Japan. It's called RESCUE-Japan LIMIT trial that enrolled MRI based low ASPECTS patients and randomize them to endovascular treatment versus medical management. As you can see, median ASPECTS, again, MRI based ASPECTS for this population was three and four. So, relatively large core patients. And as you can see, the 90 day modified Rankin score, which is a standard way of quantifying stroke outcomes. As the score grows from zero to six, zero, meaning no symptoms, six, meaning dead. You can see that the top bar, which is endovascular treated patients, fared much better than those who were assigned to medical management group, which is the lower bar here, with much lower modified Rankin score. Meaning, more independence and more symptom free outcomes for these patients as well. Currently, the Japan rescue limit trial is not consistently adopted in clinical practice at United States for various reasons. One important one being that the baseline aspect selection was based on MRI rather than non-contrast CT brain, which is standard in United States across most of the centers. MRI based ASPECTS quantification tends to be more conservative than CT brain. So, you could imagine that if the CT brain based ASPECTS selection was to occur, the patients would have much lower MRI based ASPECTS score. Two, our benefit, there are several ongoing studies however in the United States as well as outside, that are testing exactly that. Several are listed here. Tesla is testing acute ischemic stroke patients who have a large vessel occlusion and a baseline NIH stroke scale more than six. They have to be presenting within 24 hours of a last known well, and they have to have a non-contrast CT brain ASPECTS score of two to five. So, these are true non-contrast CT brain based large cores. And similar across all studies [IN EXTREMIS–LASTE 00:11:11], past to present, patient has to present within six and a half hours of last known well, and they also have CT or MRI based ASPECTS selection. Select two similar patient population within zero to two hours. They are allowing ASPECTS based or CT perfusion based selection, where CT perfusion core volume has to be greater than equal to 50 CCs. And the last one is TENSION. Also, similar patient population presenting within 11 hours, limiting the baseline ASPECTS to three to five. Again, large core, but not very, very large core. So, excluding ASPECTS zero to two, which is the largest of the cores that you could have. Switching gears a little bit to the second point in the asterisk for large vessel occlusion patients, is low NIH stroke scale or mild neurologic deficits. This is an area of great research. As you can recall, current AHA/ASA guidelines do not recommend thrombectomy as standard of care for patients who have NIH stroke scale less than six at their time of their presentation. However, several observational studies have tried to compare the effects of endovascular treatment to medical management in this particular patient population. However, they have shown quite heterogeneous results. For example, this particular study did not really show a benefit in terms of 90 day modified Rankin score of patients who were treated with endovascular treatment versus medical management, who had a presenting NIH stroke scale, less than six. It is important to note however, that these studies also showed marginally higher rate of hemorrhagic complications, including symptomatic as well as asymptomatic hemorrhage intracranially. Again, as I mentioned, no real difference in 90 day modified Rankin score or early NIH stroke scale outcomes for endovascular treatment when compared to medical management for this patient population. One must wonder however that, if this lack of efficacy is truly no treatment effect of endovascular treatment versus a limitation of the current outcome measures that we use, such as mRS, where they have floor effects in terms of recognizing treatment differences when there are small, but tangible changes in patient's neurological outcomes. HERMES collaboration, which is the figure that is shown over here on the right, is really the only randomized evidence that we have so far in terms of treatment effects of endovascular therapy for low NIH stroke scale patients. As you can see, only 14 of those patients enrolled in the HERMES collaboration, which was a large consortium study of initially positive endovascular trials. Only 14 had NIH stroke scale zero to five. It does still show, as you can see, a treatment effect of endovascular therapy, where the higher bar on the figure is showing endovascular treatment generally having, or medical management generally having worse outcomes than endovascular treatment, which is shown in the lower bar or the red. It is also important to note that majority of the observational studies that I am talking about here, have performed endovascular treatment reactively in response to neurologic worsening in these patients. So, it is not an immediate endovascular treatment regardless of neurologic worsening or not. When we break the observational studies down to just looking at those studies that take the patients to immediate endovascular therapy as against reactive or rescue endovascular therapy. These studies have shown good efficacy of endovascular treatment with nearly threefold improvement in good functional outcomes or 90 day mRS, in those patients who receive immediate clot retrieval compared to reactive clot retrieval in response to neurologic worsening when compared to medical management only. There are really great ongoing trials that should hopefully give us a definitive answer into this question. Two of the ones that are notable are ENDOLOW, which is currently enrolling acute ischemic stroke patients with LVO as well as some M2 occlusions with presenting NIH stroke scale zero to five. And [IN EXTREMIS–MOSTE 00:15:38] is enrolling acute ischemic stroke patients with large vessel occlusion. And they have to have an NIH stroke scale at presentation zero to five, and they are enrolling within 23 hours of last known well as against ENDOLOW, which is enrolling within 12 hours of last known well. Switching gears to the last point in the asterisk, which was pre-stroke disability. Patients who have a disability prior to their stroke, represent about one third of acute ischemic stroke patients. However, they're nearly universally excluded from stroke clinical trials. In fact, we have noted that about 81% of ongoing or recently completed endovascular treatment clinical trials, have excluded patients with a pre-stroke modified Rankin, two, three or greater. This is a group with large evidence gap regarding all, in especially endovascular therapy type acute stroke treatments. And there is a resulting heterogeneity in clinical practice. It is notable however, the patients who have a pre-stroke disability or disability at baseline within the United States, are more likely to be females, minorities and older in age. There have been several studies that have compared the benefit of endovascular treatments in disabled patients compared to non-disabled patients in the form of observational retrospective studies. One of the ones that I have shown here, as you can see, when the pre-stroke mRS grows from 0, 1, 2, 3, 4, 5, the corresponding 90 day modified Rankin score... These are all patients treated with thrombectomy only. Their corresponding 90 day modified Rankin score distribution is fairly similar, if you look at change in pre-stroke mRS from baseline. So for example, 17% of patients with pre-stroke mRS zero, retain a pre-stroke mRS zero at 90 days, compared to that 22% of pre-stroke mRS one retain a pre-stroke mRS one at 90 days and 14% with two and so on and so forth. And so, proportion wise, this really tells us that endovascular treatment at least might retain the Treatment effect comparable to those without a pre-stroke disability. However, definitive studies that compare it to medical management are needed and coming in future as well. And just to touch a little bit upon the medium vessel occlusion and distal occlusion in sense of thrombectomy or device based treatment in acute ischemic stroke as well, we have to understand first what a medium vessel occlusion means. Usually this is defined in terms of vessel diameters. All initial thrombectomy trials included, as I have been mentioning before, large vessel occlusions, they are usually defined as vessels that are two millimeters or greater in their diameter. Vessel that range in between 0.75, which is the cutoff for more small vessels and this two millimeters, which is the cutoff for large vessels, at least in terms of the [inaudible 00:18:45] and their radius and et cetera. The vessels in between are called medium vessels and these usually include M3, M4 branches as MCA, more medium and distal branches of intercerebral and posterior cerebral artery and some of the posterior circulation artery such as PICA AICA and SCA. This is not small proportion of the strokes. They actually constitute of anywhere from 25% to 40% of all acute ischemic strokes per some epidemiologic estimates. And they can occur either as a primary thromboemboli, just like any other large vessel occlusion stroke, or they could occur as embolization during an endovascular treatment for a large vessel occlusion stroke. It is important to note that occlusions of these vessels cause distinct and often disabling neurologic symptoms. And they are really great targets for both thrombolytic and endovascular retrieval treatments. They are also amenable to core per number of recognition by our standard profusion imaging technologies. So, really great targets for ongoing acute stroke research. Thrombolysis is not often enough for these patients. As you can see in this graph, only 50% actually achieve a mRS of zero to one in this population. And there have been considerable advances in catheter technology with smaller diameter, operator control and increased flexibility to allow endovascular treatment for these patients. And there is some precedent of success of endovascular clot retrieval for these patients, including HERMES study, that I talked to you about before, where there were some patients with M2 MCA that were included. Successful profusion in about 60% across the studies for this population. And there have been new studies such as ASTER trial, that have also shown benefit of thrombectomy, at least in the M2 vessels. There are however exciting ongoing trials both in Europe and US. Both are called DISTAL and DISTALS. They are including acute ischemic stroke patients with medium vessel occlusion within six and 24 hours of last known well, and both of these trials are using some kind of imaging selection for these patients. So, stay tuned for results. The future of acute stroke is very bright with several methodologic advances to allow simultaneous testing of treatments as well as patient populations, so that we don't take 30 more years to come up with the next big thing in terms of thrombolysis or endovascular treatment for acute stroke patients. For example, we're using multi-arm multi-stage design trials, randomized and adaptive platform trials. You might remember REMAP-CAP type studies for COVID 19, et cetera. In fact, NINDS has put out an initiative for a thrombectomy platform trial called STEP. And so this will expedite stroke research in a matter of decades in the future. So stay tuned for that. Thank you.