Hello, I'm Aarti Sarwal. I'm a professor in neurology at Wake Forest School of Medicine and the Director of Neurocritical Care. Thank you for joining us in learning about advances in acute ischemic stroke from thrombectomy to tenecteplase. So all of us are familiar with the burden of acute ischemic stroke to our society. Stroke in general is the leading cause of death and a leading cause of major disability in the U.S. About 800,000 people every year get affected by stroke, ischemic stroke being a majority of these kinds, with 200,000 deaths annually. Stroke is the single highest Medicare reimbursement entity for long-term adult care, showing how much society bears the cost of taking care of disabled patients from stroke. The burden of stroke and the amount of effort going into creating clinical paradigms to improve stroke care and reduce the burden of stroke can be foreseen by the amount of guideline revisions that have taken place by the American Stroke Association in response to emerging clinical trials, emerging information that impacts standard of care in the last few years. So the landmark evolution in stroke care came around 1995, when after two decades of frustratingly failed trials on fibrolysis in acute stroke led to a very well-designed positive trial that showed positive outcomes when patients received thrombolysis with TPA and after meeting certain eligibility criteria. There was a significant trend in improved outcomes when patients had younger age at presentation and relatively lower stroke scales at presentation. We did see some benefit in the patients with more severe stroke scales and elderly people as well. The use of stroke scales from measuring stroke severity after the fact came to pre-hospital evaluation of these patients with standardized stroke scales to actually get them to acute thrombolysis treatment rightly. Due to several reasons, despite this trial, until 2005, only 5% of the patients who were potentially candidates for intravenous TPA received it. Over the next decade, significant effort was created in creating stroke systems of care, get with the guidelines registry. And although we had made significant leaps and bounds of progress in offering stroke therapy, one in five patients still continue to not receive treatment despite being eligible for a myriad of causes with some implicit biases, racial disparities, healthcare disparities playing into that. At least with a multitude of RCTs and extensive community experience and epidemiological data to get with the guidelines registry, we know TPA is safe, efficacious, and the standard of care. Over the last two decades, we have spent extensive amount of time refining the eligibility criteria to make sure that we expand the TPA to more and more patients, but we continue to challenge our paradigms to see if we can make it safer. Maybe giving lower doses to mild non-disabling strokes. So ongoing trials hopefully will shed some light into it. While we're looking at TPS being the solution for acute thrombolysis, we also found with emerging data that a small subset of patients, significant, but small subset of patients continue to do poorly. These are the patients with large vessel occlusions. So multiple trials showed us that patients that have a large vessel occlusion in the ICA or the MCA had significantly poor outcomes to the tune of 75 to 80% despite TPA and mortality to the amount of 27 to 41%. And with radiological data, we found that intravenous TPA alone was looking at the recanalization rate would only help 10 to 14% of the IC occlusions and less than a third or half of the MCA occlusions. And while we're focusing our trials on patients that have suffered a stroke, looking at different kind of hemicraniectomy paradigms, we still continue to be plagued by this challenge. There are significant amount of patients that are presenting with high stroke scales at onset and not benefiting from TPA while we're still in the window of doing something. So as we go through these paradigms, we are doing thrombectomy, translating the data from coronary artery disease and other organs where it seems to be pretty physiologically common sense to try to address large vessel occlusions by actual mechanical thrombectomy. And with these anecdotal data, we start designing trials. And over the next 10 years, multiple trials emerge that test different paradigms of thrombectomy and also start aiming at recanalization rather than just reperfusion, rather than just recanalization. So a revised thrombolysis and cerebral infarction scale gets implemented in trials that actually looks at reperfusion of the brain rather than just mechanical recanalization. The other innovation that happened at the same time was in imaging. We also realized that we could distinguish ischemia from infarct, penumbra from core infarct through imaging like CT imaging. And over the next few years, evolution of artificial intelligence allowed us rapid access to this kind of imaging in a manner that could be useful for acute triage when time is of the essence. While we find ways to identify these patients in time, identify patients who will benefit better, faster, we are also refining the devices we will use to recanalize and reperfuse them. From MRSI, penumbra, we now evolve into stent retrievers and adapt that seem to be much safer, that seem to be proving efficacious in getting us much higher rate of reperfusion at the first pass. So with these evolution in imaging, with this evolution in devices, we are refining our evidence-based medicine. And in 2015, after a run of a decade of negative thrombectomy trials, we finally had five major prospective RCTs that turned out to show significant efficacy in thrombectomy when done in eligible patients in less than six hours since onset. Netherlands, MRCLEAN, North American trial ESCAPE, Australian trial EXTEND-IA, trial in Europe and U.S., SWIFT-PRIME, and a Spanish trial, REVASCAT, all together showed, in addition to pooled analysis from previous trials, that the odds ratio of patient benefiting from thrombectomy, if they met a certain eligibility criteria, significantly made this the go-to treatment for large vessel effusion. And these data from the five trials and then looking back at the subset of patients that benefited from thrombectomy in previous trials led to the 2015 update to the American Stroke Association guideline where now thrombectomy in less than six hours became the standard of care if you met certain eligibility criteria. And it was not just the fact that we improved outcomes. The magnitude of outcome improvement was tremendous. The functional outcomes changing from 20% to 32%, from 35% to 60% was something that we really needed to see to make this the new standard of care. And the attribution of this improvement in these trials was not just the devices, not just the eligibility criteria, which definitely was informed by our previous experience, but also by the fact that now we had more cohorted people that were taking care of these patients and spending more time understanding the paradigms that went into taking better care of these patients. We have more experienced neurodimensionalists, we have stroke neurologists triaging stroke care, and then we have a robust stroke triage systems of care with periprocedural teams, pre-hospital as well as post-acute care that went into improving these outcomes. The other thing that came to light, at the same time when we are trying to extend the windows of reperfusion therapy from three hours for the TPA to 4.5 hours for extended TPA based on the e-CASH trial, then six hours for thrombectomy patients, we're also realizing going back into this data that time to reperfusion still matters. For every 30 minutes, patient has a 10% loss in the chance of a good outcome. So there is still a significant need to emphasize time is brain, and despite extending the window for reperfusion, we need to continue to emphasize getting the eligible patients to the right reperfusion therapy faster in a more efficient manner. Then trying to extend the reperfusion therapies to patients beyond six hours, two other landmark trials, DON and Diffuse 3 gave us the solution in 2017. So both of these trials were remarkable for two things. One, they used imaging-based criteria to distinguish patients that were at risk of large malignant strokes but had not suffered from large malignant strokes. So imaging was used to stratify these patients and then specific clinical paradigms including eligibility criteria as well as post-acute care was used that was a little different from the standard of care at that time. And both of these trials showed significant improvement in the thrombectomy arm to the amount of 48.6% compared to the medical arm, 13.1% for the numbers needed to treat 2.8. There are not many trials in medicine that give you a number needed to treat of 2.8, and you can see the respective NMTs for other different paradigms in clinical medicine. So this led to the 2018 update guidelines that recommended the extended window of thrombectomy to 16 hours or 24 hours based on the eligibility criteria but restricted the recommendation for thrombectomy for patients who meet the criteria based on DON and Diffuse with further trials assessing patients outside these eligibility criteria. Again, we've learned from decades of failed trials, successful trials, failed trials, we need to continue honing who benefits the most from these trials and who gets possible potential harm so we can start directing these patients to other clinical trials. So in that manner, we have looked at our thrombectomy trials from imaging perspectives, look at the collateral grade, maybe patients that have good collaterals benefit more from early reperfusion therapies versus patients that don't. Or if there was a significant delay in a patient after a certain hour based on the collaterals, they may not benefit and they may actually get harmed. So we've looked at the level of acetyl occlusion, we've looked at the clot burden, we've looked at the logical criteria to continue to hone which patients benefit the most with the least harm with our acute therapies. And while we are taking care of the devices and the drugs, we're also improving medical management in stroke. Extensive efforts have been put in in creating evidence-based medicine to recommend things like early nutrition. We used to not feed these patients for the risk of aspiration. Optimal glucose control, which has now been found to be an independent predictor in outcomes. Mobilization of these patients. We used to put these patients supine for optimizing their CPPs and were concerned about aspiration. Although early trials for mobilization have not quite shown positive outcomes, we feel that now sub-segmenting the patients from perfusion-dependent patients, large vessel occlusion, separating them out, the patients that have blood pressure variability might give us better signals on who benefits from early mobilization in post-stroke therapy as well. Fever prevention has been a paradigm, a pretty standard for stroke because high fevers do adversely affect outcomes. Although we continue to find no benefit from actual induction of hypothermia in these patients. In addition, we realized that if you put a group of people together to take care of a clinical paradigm, they really get good at it and they provide better care. So comprehensive, very procedural care teams, stroke systems of care has really been emphasized as one thing that has changed paradigms and outcomes in stroke care. Blood pressure in stroke, the holy grail. We can talk ad nauseum about this. From the perspective of immense amount of work that has gone into finding the optimal blood pressure goal prior to the perfusion era, we continue to recommend permissive hypertension with no treatment above 220 unless it's the patients above 220 by 120 and patients that are not candidates for any kind of therapy, basically from the perspective of optimizing CPP and letting the brain do what it wants to do, except if they're coexisting medical contraindications to hypertension. For patients who undergo thrombosis, we continue to see very strong signals that there is a risk of hemorrhage in patients that have higher blood pressures and higher blood pressure variability. So our continued guidelines continue to recommend a treatment of blood pressure in thrombolyzed patients if the blood pressure is above 185 and 110. In patients post thrombectomy, the jury is still out. I think we're still in that dynamic phase where early on we realized that definitely there was a value in reducing the blood pressure to 185 to 110 in patients with thrombectomy eligibility. Most of the trials that showed positive outcomes had excluded patients with higher blood pressures than these particular values. But we also realized that Dawn managed these patients post-procedurally much more conservatively, reducing the risk of reperfusion, at least that's what we thought. So they're continuing ongoing RCTs that are addressing the questions for optimal blood pressure management. At this point, we have a little disconnect between guidelines and prevalent practices, with many prevalent practices reducing blood pressures more aggressively to reduce reperfusion. But hopefully some of these trials will give us light to the best blood pressure targets after thrombectomy that optimizes cerebral perfusion in reperfused strokes, but also reduces the risk of hemorrhagic conversion. Patients who still end up having cerebral edema, we continue to have very strong evidence of not doing hypothermia, not doing hyperventilation prolonged, unless it's a bridge to therapy, not doing barbiturates and steroids. We continue to find some benefit from osmotic therapy, haven't quite found the magic pill yet, but seem to have some signals of hypertonic saline being better than many tolerant patients that have compartmentalized edema. And for hemicrania, we continue to have equal poise on the triggers. Decreasing level of consciousness seems to be a reasonable one, with the recommended hemicrania being reasonable in younger people, and more than 60 can be considered on a case-to-case basis. On the cerebellar side, we've had a little change in clinical paradigm as well. The 2014 guidelines recommended against putting an EVD in favor of suboccipital crani, but some equal poisons come to that as well. With a subset of patients, we find that EVDs might actually be able to tidy the patient up and help them through the swelling period without actually needing a suboccipital crani. We're also extending our questions and queries to posterior circulation strokes, distal MCA, ACA, PCA strokes, where we don't have robust data of which patients benefit from thrombectomy and other acute therapies that we hopefully will see more data on. The other places we are challenging are drugs. Tenecteplase came out after multiple other fibrinolytics were tested, and the benefit of using drug-like Tenecteplase is the half-life is a little bit longer, with the presumed benefit especially in long vessel occlusions. It has higher specificity for fibrin. It is an IV bolus over 5 to 10 seconds, versus a bolus followed by an hour's worth of infusion for TPA, so it has some workflow advantages. And this higher specificity of fibrin has been suggested to possibly translate into complete recanalization, which has been seen at a higher rate in the RCTs done for Tenecteplase versus TPA. But on the outcomes basis, it hasn't quite shown a superiority. All the trials have been for non-inferiority, and some cost concerns as well, although it's cheaper. It doesn't have a replacement program at this point. But there are currently ongoing trials that hopefully will show us some signals, whether something like Tenecteplase has workflow and clinical advantages or something like TPA. Overall, I think ischemic stroke has really given us the story of tenacity, persistence, that if something seems physiological sense, makes physiological sense, and you're committed towards working on improving outcomes, you just have to design the right trial. You have to continue looking at your data, continue looking at your population, and find signals that you can chase to design future trials. And both TPA thrombectomy and medical management trials have shown significant improvement in our outcomes in the last two decades. And we continue to hope that such a streak, not just continuous for ischemic stroke, but also translates onto hemorrhagic strokes and other disease processes. So where is the future research? Future research is trying to identify these patients with LDO sooner on the field, using imaging, continuing to emphasize time as brain, and doing whatever we can to translate that into our clinical paradigms, as well as research trials. So more patients can be represented addressing disparities that seem to be plaguing a significant amount of our population in their access to both stroke systems of care as well as stroke trials. Better drugs like tenecteplase, better devices like thrombectomy, and better delivery of these devices, whether we use general anesthesia, whether we use conscious sedation, we continue to investigate every single paradigm around the continuum of care. And overall, just having a disastrous stroke systems of care approach, and which ranges from pre-hospital, peri-hospital to post-acute stroke care, and making sure that these patients really get good care the moment they hit a stroke alert, and their post-acute care rehab and integration back into society is also taken care of. So I hope that gives you a little perspective into acute stroke care, and you take good care of our patients. Thank you.

acute ischemic stroke treatment

thrombolytic therapy

thrombectomy

imaging

blood pressure management

tenecteplase