Thank you so much for that introduction and thank you all for sticking around for this session. I really appreciate it. So today I'm going to be talking about what's kind of happened within the field of neurocritical care over the last year. So 2023 was a busy year in neurocritical care and there would be a lot to cover, but much like the heiress tour, I can't cover all of your favorite hits, just the highlights. There might even be a secret song in there as well. So I do have a disclosure to report, but it has nothing to do with the content of this presentation. And to start our discussion, I want to present a case to kind of frame some of the lessons from the trials that we're going to go over. So you can directly apply this to patients that you may see in your practice. So your patient is a 67 year old man, the history of type two diabetes, who presents to the ED with left-sided weakness and is found to have a proximal M1 large vessel occlusion. He's eligible for and receives tenecteplase and is taken for thrombectomy, achieving ticcy three reperfusion. If you're not familiar with that term, we'll cover that in a moment. And he's found to be in atrial fibrillation on telemetry the next morning. So what should this patient's post-thrombectomy blood pressure goal be? This is a question that commonly comes up in the unit. These patients come out of the angio suite and we're left with this target in mind. And it's a lot of controversy as to exactly what that target should be. And additionally, now that this patient has been found in atrial fibrillation, when should this patient start on anticoagulation for his AFib? So we'll start with the blood pressure discussion. So as you may be familiar with ischemic stroke, there's a constant balance between trying to have optimal perfusion of the brain tissue while trying to limit any secondary neurologic injury that may be caused by the stroke. And blood pressure is commonly thought of as a modifiable factor for that. And so especially after thrombectomy when a clot is aspirated out of the cerebral circulation, you definitely wanna avoid hypotension and potentially hypoperfusion of that brain tissue, but also avoid hypertension where you may cause reperfusion injury and hemorrhage into that stroke bed. And so the 2019 acute stroke guidelines have a fairly vague recommendation that it's reasonable to maintain a blood pressure less than 180 over 105 during and 24 hours after the thrombectomy procedure. But there has been a large bank of observational evidence that suggests allowing systolic blood pressures to get up to that 180 millimeters per mercury range may be associated with worse functional outcomes and a higher rate of symptomatic intracranial hemorrhage. And so we really need to figure out where's the sweet spot with blood pressure control? Is this a lever we can pull to try to optimize outcomes for our stroke patients? And so the first trial I'm gonna go over is the Optimal BP Trial. So this was a trial that randomized patients with acute ischemic stroke who went for mechanical thrombectomy, so had a large vessel occlusion that was amenable to for intervention, and after their mechanical thrombectomy achieved excellent reperfusion. Now, excellent reperfusion is defined on the ticcy scale, which I have here on the slide. It's a scale that goes from zero to three and grades 2B and higher are graded as excellent reperfusion. So patients who achieved that ticcy 2B or greater scale who had a systolic blood pressure greater than 140 after the procedure were randomized essentially to intensive blood pressure control, keeping that systolic blood pressure less than 140, or a more conventional systolic blood pressure goal of 140 to 180. Now, an important point is that there's a range, but they did not press patients up to 140. They just only initiated antihypertensive therapy if they remained above 180. Now, their primary outcome was the difference in proportion of patients who achieved a modified Rankin scale of zero to two. For those of you who are unfamiliar with the MRS scale, this is a degree of functional impairment in zero to two is generally considered to be a good functional outcome. With secondary outcomes of symptomatic intracranial hemorrhage at 36 hours, the shift in functional outcomes at 90 days, their NIHSS stroke severity score at 24 hours, and the presence of malignant cerebral edema on CT scan. Now, this trial was actually stopped early in light of a similar trial that was published the year previously, which demonstrated a shift towards harm when patients were brought to a systolic blood pressure goal of less than 120. So it's still a little bit unclear as to whether 140 was a safe goal, but out of an abundance of caution, they stopped the trial given that signal. And it's a good thing that they did. And so I'm gonna present the baseline characteristics here. They're relatively well balanced between groups. Most patients, of course, had a cardioembolic stroke as you might expect, and a large portion of patients had a more severe stroke as well. And essentially what they found is actually patients who underwent intensive blood pressure control with systolic blood pressures targeting less than 140 had significantly worse functional outcomes at 90 days. And interestingly, what you might expect is a lower rate of symptomatic intracranial hemorrhage, but that was not found, even though those patients were having blood pressures tightly controlled, there was no difference in that safety outcome. And when you looked at the shift, the shift was consistent across all scales of the modifying Rankin scale, demonstrating that driving patients' blood pressures down to 140, if they were hypertensive after thrombectomy, caused harm in this population of South Korean acute ischemic stroke patients. Now, interestingly, there was a relatively small separation in the curves. And so even though 10 millimeters of mercury may not seem clinically significant, even that small difference led to a really significant clinical outcome. And so really the conclusion here is that in hypertensive patients who achieved TIKI2b to three-year perfusion, targeting systolic blood pressures of less than 140 leads to worse functional outcomes at 90 days and really should be avoided in this population. And interestingly, I also want to point out that there was a unique pattern detected in the patients who were randomized into the really intensive interventional arm. What they found is that when patients' blood pressures were driven particularly low, as you can see in this chart here on the top, there was a significantly higher likelihood of worse functional outcomes, which really suggests that while blood pressure may be associated with functional outcome, meaning that patients who tend to be hypertensive may have worse outcomes on their own, that is not a modifiable lever. In driving down that blood pressure, which may be that individual patient's marker where the brain is requesting higher reperfusion may end up leading to worse outcomes. Because in patients who had more conventional blood pressure control, there was more of a flat association with functional outcomes, basically showing that patients, their brains requested whatever blood pressure they wanted. And as long as you didn't touch it, that seemed to do just fine. So really, until more data is published, a systolic blood pressure goal of less than 180 remains reasonable in this patient population. Now, moving on, the next question is essentially when to restart or start anticoagulation in a patient with atrial fibrillation. Again, the secondary stroke prevention guidelines provide a relatively vague suggestion of initiating between two and 14 days, trying to balance the risk of recurrent ischemic stroke and hemorrhagic conversion of that stroke bed. But again, where's the sweet spot in that two week range? So the ELON trial was a randomized control trial that randomized patients with a diagnosis or found to be in atrial fibrillation in evidence of acute ischemic stroke on CT or MRI to randomize to either early or late DOAC initiation. There's quite a bit of controversy in terms of whether you should be waiting that full two weeks, or if it's safe to initiate after just a few days. And so essentially what they did is they stratified patients based on the size of their stroke on CT to early initiation of a DOAC, which was 48 hours for small or medium-sized strokes, or about a week in large strokes, versus late DOAC initiation was three to four days for small strokes, about a week for medium-sized strokes, and two weeks for major strokes. In terms of the baseline characteristics, they randomized about 2,000 patients to each of those arms, relatively well-balanced between groups. They stratified randomization by stroke severity, so there's a good distribution of patients who had moderate, mild, and severe strokes by NHSS score. And additionally, a good proportion of the patients received alteplase or another thrombolytic agent and thrombectomy. Their primary outcome was the composite of recurrent stroke embolism or major extracranial bleeding, symptomatic intracranial hemorrhage or vascular death within 30 days. And interestingly, what they found is there was a suggestion of actually an improvement in the rates of that primary outcome in early DOAC initiation, suggesting that there's at least not increased harm by earlier initiation of DOACs in this patient population. They also stratified this out to 90 days, and at 90 days, there actually was a significant difference with a significantly lower rate of the primary outcome in the early DOAC initiation arm. Now, in terms of what's driving this outcome, if you look in the supplement where all the good figures are, as we all know, it actually seems to be driven by early ischemic strokes in the late initiation phase. As you can see in this survival curve here, the blue curve is late initiation of DOAC, and there's an early spike of recurrent ischemic strokes that seems to level out at about one to two weeks when those patients would be starting their DOAC. And interesting in terms of symptomatic intracranial hemorrhage, which is, of course, the feared complication, there's no difference whatsoever. And so early DOAC initiation secondary to atrial fibrillation appears to be safe and slightly reduces the risk of recurrent events. However, this is a hard study to directly apply to our patients, as it seemed like the patients were relatively not that sick, and there was really a surprisingly low number of events detected in the trial. Notably, patients who were therapeutically anticoagulated at baseline were excluded, so it's hard to apply those to those patients. And it's also difficult to apply these to patients who had hemorrhagic conversion before the initiation of a DOAC as those patients were also excluded. Now, moving on to our next vascular neurology topic, and that is intracerebral hemorrhage. So suppose you have another patient who is an 82-year-old woman with a history of atrial fibrillation who's on a Pixaban, who presents to the emergency department after an hour of noticing difficulty reading, and is found to have a 2.3 centimeter left occipital intracerebral hemorrhage. Her presenting blood pressure is 164 over 102. And so two common questions that will come up that if you stuck around from the last session, this is gonna sound a little familiar. How should this patient's anticoagulation be reversed? And secondly, what should this patient's hemodynamic and metabolic goals be? And so the surprise song here, which is something that you've likely heard in the last talk is the early presentation of the Annexa-I trial. Now, I'll caveat this, so this is based off the presentation at the World Stroke Organization Conference, and we're all patiently waiting the full manuscript, but I'll provide you a little bit of an insight as to what happened in this trial. And so this was a trial that randomized patients to andexanet-alpha versus standard of care, which was traditionally four-factor PCC or some other PCC product that's not described in the presentation in patients who have an ICH within six hours of last known well. Interestingly, they randomized patients within 15 hours of their last dose of a factor Xa inhibitor, not the traditional 18 hours. And as I mentioned, to either package-labeled andexanet-alpha dosing or some institutional care. As you heard in the last session, this was not exactly a real-world population and tried to enrich the population into those who may be most likely to benefit from anticoagulation reversal. Their primary outcome was their somewhat invented primary outcome of effective hemostasis at 12 hours, which was a less than 35% or less than 20% hematoma expansion with no greater than a six-point change in the NIHSS score at the assessment. And there was no rescue therapy administered. Mid-secondary outcomes of the change in anti-factor Xa value or thrombotic events at 30 days. As we're all likely aware from the advertising, this was stopped early after an interim analysis for a signal of improved efficacy with andexanet-alpha. What exactly does that mean? And so in terms of the baseline characteristics, they were well-balanced between the two arms. And what they found is that, surprise, surprise, andexanet does what it's supposed to do. And so compared to standard of care, andexanet led to a significantly higher rate of good or effective hemostasis in these patients, but about an 11% increase in the rates of good or excellent hemostatic efficacy. However, one thing that's really important to point out is as we kind of saw the signal in the INEXA-4 trial, there was a significantly higher rate of any thromboembolic event in the andexanet-alpha arm compared to the standard of care arm. And in particular, I do want to point out here that this rate was almost largely driven exclusively by rates of ischemic stroke. So there is a significantly higher rate of ischemic strokes in the andexanet-alpha arm compared to the standard of care arm. Now, I will point out that there was a small increase in PE in the usual care arm, but that was not as large as the stroke population. And this is relevant because while they only looked at 30 days, there was no difference in the rate of functional outcomes, which is likely the more patient-centered outcome of interest in this population. And that may be mitigated by the fact that there was more ischemic strokes in the andexanet-alpha population. Additionally, there was a small, non-significant, but numerically higher increase in mortality in the andexanet-alpha arm, something to keep in mind. And so really, again, we're left with more questions than we came with. It's really unclear whether or not hemostatic efficacy in this context is the right outcome, as we probably really want to look for more patient-centered outcomes in this population. Now, the next question we're going to answer is what the patient's hemodynamic goals should be. And so, as we pointed out, blood pressure goals are a common thing that we talk about in ICH patients, and there has still been quite a bit of controversy, even since the publication of the most recent ICH guidelines. And the Interact-3 trial was one of the most recent and largest trials to really try to evaluate blood pressure and other hemodynamic targets and metabolic targets to see if those could improve outcomes in this patient population. So the Interact-3 trial randomized patients with a spontaneous ICH who presented within six hours of onset to a bundle of care or usual care exclusively in countries that were lower and middle income that did not already have systems of care in place to care for ICH patients. And so this was a very large study done across a geographic region, primarily in China, but also in regions in South America and the Middle East to try to see whether a bundle of care, which included tight blood pressure control of less than 140 within an hour of randomization, tight blood glucose control, which was stratified by whether or not the patient had diabetes, an avoidance of pyrexia, and reversal of anticoagulation improved functional outcomes. And essentially what they found with relatively stable baseline characteristics between arms was that this bundle of care overall did improve outcomes. Now it's not a perfect trial and there are several limitations which I really don't have time to go over during this talk, but the bundle of care did improve the shift in modified Rankin scales at six months, which is an important difference between other trials as the slope and acceleration of recovery seems to be much different in ICH than ischemic stroke. And so the takeaway is that bundled care in terms of really intensive management of potentially modifiable risk factors in ICH does improve outcomes overall, but questions definitely do still remain. And so in conclusion, in terms of the major updates in acute ischemic stroke, intensive blood pressure control worsens outcomes after thrombectomy and should be avoided in hypertensive patients with excellent reperfusion. DOACs appear to be safely initiatable in patients who have stroke secondary to atrial fibrillation. And in spontaneous ICH, it appears indexin and alpha leads to improvements in hemostatic efficacy, but it's unclear whether that translates to improvements in functional outcomes. And bundled care with aggressive hemodynamic and metabolic control improves functional outcomes in patients with ICH. Thank you so much for your time. Thank you.

neurocritical care

stroke management

hemorrhage management

blood pressure control

DOAC initiation