All right, great discussion and we're going to touch on a few of those points in a minute. So we're going to switch to port-based evacuations in the NRICH trial. My first disclosure is that I am the principal investigator for NRICH and NRICH is an industry-sponsored trial sponsored by NICO Corporation and we'll be discussing an FDA-approved indication for the Brain Path Board in the Myriad resection tool. So if you look at the program for the meeting and you look at the vascular section, you'll see that on that 5% of survival in NRICH, we're probably having 80% of the program. We talk a lot about aneurysms. Ischemic stroke is growing and growing as our experience with the latest trials becomes more and more positive, but ICH is still a very small percentage of our discussions and to me, I was telling Adam this morning, it's very interesting to see how many more people are becoming interested, like all of you, in what's happening in these clinical trials. I became interested because this is the stroke belt, this density map here, and that's where I am in Atlanta and Adam is close by and Rob as well. So we are in the heart of this cerebrovascular disease center in the country and we have to deal with a lot of these patients. And in addition to the things we discussed about mortality, one of the things that we look at is economics and it's about $12.5 billion that we're spending. Taking care of these cerebrovascular patients, and ICH is a particularly demanding economic entity because the length of stay is long, their ICU care is very demanding, and then when they go to rehab, they're severely disabled. So there's a lot of that that comes into play. And the etiologies are expanding because, at least in our center, coagulopathy becomes more and more prevalent as we see all of these new generation anticoagulants come to market. Thankfully, indexa just came out, so the 10A inhibitors have an antidote. But I'm sure as an antidote comes up, we're going to see another new anticoagulant coming to market. So we're dealing with a lot of these issues. We've had a lot of discussions about timing and about spot signs. And one of the things that we talk about when we design trials is the timing of intervention. Because if you have a patient that shows up with a scan like that, you will probably admit that patient to your ICU. And that would be a patient that would look fairly well for first three or four days, but this dark halo of perihematoma ledema will begin to form if you leave the hematoma in place. And that secondary cascade of inflammation will be triggered. And then that patient will get intubated, they will start showing signs of herniation, and then you guys will be called to see if you will do an emergent decompressive craniotomy for intractable intracranial hypertension. That's what we're all dealing with. The guidelines for American Heart and American Stroke Association haven't been updated since the last publication a couple years back. And for medical interventions, all of the things that we do are pretty well supported by level one data. But for surgical interventions, only cerebellar hematomas have class one data for intervention, which means that everything that we do in surgery is class two or less. And the language in the guidelines is very ambiguous, you know. We are not sure if surgery makes any difference whatsoever. And the last version of the guidelines was prior to the publication of MISTI-3, but it just said this may be something of benefit, we'll have to wait and see. So in terms of levels of evidence, we really don't have a lot of supporting things. Medical trials in ICH are incredibly numerous. And when you look at those, our neurointensive care colleagues have done everything they could. Blood pressure control, hemostatic therapy, iron chelation, neuroprotection. Unfortunately, the majority of those were negative. Our last blood pressure control was attached to, and it was stopped by futility. And on IVH, there's been some interesting progress and good data. But surgical trials are definitely a very, very small number in comparison. And when you look at those in a meta-analysis format, the results continue to be insufficient evidence or trends towards improved outcome, but not statistically significant. We've talked about the STICH trial. For those of you who are not that familiar with STICH, STICH was the classic conventional craniotomy for clot evacuation. And the reason I bring it up is because STICH had a fair amount of variability within the surgical protocol. If you look at some patients in some centers, some got a decompressive craniotomy, big decompressive craniotomy, opened the dura, and that was the end of the procedure. Other centers had a small craniotomy, microscope, cortisectomy, very focal clot evacuation. So there was a lot of variability. And part of the subgroup analysis showed that the way the clot was accessed also varied significantly. And one of the questions that was left was, did that have any implications in the patient's outcomes, which way you resected, and how much it varied. The subgroup that did well in that study, as Adam mentioned, the lower hematoma patients with no IVH were tested in STICH 2, and the results were the same. There was no statistically significant difference, but it was a 21% crossover to the surgical group. And if it wasn't for MISTI, I think we wouldn't be talking about ICH today. MISTI 2 was a great study. The protocol for MISTI, I think it's pretty accessible to everybody. Placing a catheter into the hematoma, doing some aspiration, and then letting the clot work. But there are some important things, and this is why I bring this up. The first one is the stability scan question. So you do have to have a cavity that is dry to start a thrombolytic. That just makes perfect sense. And that will get you to this very nice result that you see on the far right, but that's 52 hours post-surgery. And if you look at the timing in the MISTI 2 trial, that was a critical thing. The second important thing is that this is a passive diffusion drug protocol. You're not pumping the TPA into the cavity. You're just letting it drip and do its job. So to do that, the clot position had to be perfect. So oftentimes, you had to go back and reposition the catheter to get it right where it should be, or the drug would not be as effective as it was expected. So those were important things. We talk about the outcomes. MISTI 2 looked a lot at the economics. So the 38-day length of stay reduction and the $44,000 in savings for the patients that were in the surgical group were two of the strongest factors for them to proceed with MISTI 3. And we learned a lot of lessons from that. The other one was, as Rob mentioned, is this relationship to volume. So if you look at this graph, these are modified ranking scores. So 0 to 3 are your good outcomes, 4 to 6 are your bad outcomes, 6 are your mortalities. And in MISTI 2, there was a volume relationship. So if you left less than 10 cc's, these were your bad outcomes. If you left more than 35, these were your bad outcomes. And that was another important thing. When you look at what happened to the brain, according to volume, this is also from the MISTI investigators, the more clot that you had, the more of this perihematoma edema you saw. And the worse the perihematoma edema, the worse the patients did. So there is a relationship from volume to edema to outcome. And those were critical lessons that we learned. So when we looked at the results of MISTI 3, these lessons ranked through again and again. Meaning, if you are able to get to a reasonable end of treatment volume of less than 15 cc's, your outcomes seem to be better. And these are your survival curves, which are important. I mean, we sort of knew that intuitively patients would survive if you remove the hematoma. But what we wanted to see was if it was a functional outcome there. This is your end of treatment volume relationship to the patient's outcome. And this is your as-treated difference. So in the as-treated group, there was a 10.5 difference in the modified ranking score. So my lesson from MISTI, I think as you've heard before, is that if you get to that volume, less than 15 cc's, there is a chance that you'll get to a significant outcome. And unfortunately, they couldn't get there in over 60% of the patients got there. 40% of the patients did not. So what are the opportunities when we look forward from STITCH and MISTI? One is the stability scan question. 30% to 40% of the patients will expand more than 30% of their initial volume within three hours of onset. So if you have to wait for a stability scan, you're missing out on a lot of patients that you could be helping. And this picture I see over and over again. We go from this on the right where we get called from the ER. We see that patient. We start blood pressure control. We're waiting for an ICU bed. And about 30, 45 minutes later, we get a call that the patient has now blown pupils. We re-scan them and they expanded. So that to me is a tremendous opportunity to do something. The spot sign obviously is an exclusion criteria for thrombolytic therapies. And I think that's another really important opportunity because we know from all of the studies done on the spot sign that these are the patients that do the worst. The ones that have a positive spot sign. And then finally, rapid correction of intercranial hypertension. If you have a patient that comes in with a 30cc hematoma, that patient may be okay if you are very aggressive with the medical management. Somebody with a 60 or 70cc hematoma, that's going to be a very different story. So if you can correct the mass effect rapidly, that is a pretty big window. And then finally, most of our patients get really sick or die from being in the ICU. They develop pneumonias, respiratory failure, DVTs, PEs, et cetera. And if we can shorten even by one day, they're led to say the number of these complications drops just by pure nature of reduction of the exposure. So that's to me a pretty important thing. When you look at the, as I said, the STITCH results, this was the map of what was considered eloquent brain when that study was designed. And when we look at those other non-eloquent areas of the brain, and we look at the data from the Human Connectome Project with high field strength magnets, we look at the awake neurophysiology mapping literature telling us that all of this non-eloquent brain is actually pretty eloquent. Then we see that all of these subcortical connectivity has a lot to do with dysfunction in patients with intercerebral hemorrhage. And if we design strategies or interventions, we need to be cognizant of what we are doing to disconnect this white matter as we access this hematoma. So it begs the question, are we getting there the right way? So when we thought about designing this enriched trial, the first question was, who? And patient selection is critical. We, I think the three of us have probably had patients that have a great radiographic result. You look at that scan, and it's 99% cloud evacuation. But the patient is an alcoholic. They go into withdrawal. They go into status epilepticus. They're still in the ICU for a month, and they do horribly. So patient selection is still something that we're trying to elucidate in these trials. Timing of intervention is also still up in the air. Biologically, there is reasonable data in animal models that early intervention can arrest that secondary inflammatory cascade. But in clinical trials, we don't. I'll discuss a little bit of our early data intervention here. But we do think that earlier is better because of the edema and the perihematoma edema formation. And then technique, I think STITCH proved conclusively that big craniotomies were not going to be better. But these less invasive techniques are all under investigation. Technology has evolved tremendously. If you think about where we were when the STITCH trials were designed to what we can do now in imaging and intervention, it's a completely different paradigm. And then finally, training and education. I think the endovascular world has taught us that you cannot start an intervention without educating people. And if you want to use a new device, you need to go to a course, get trained, get proctored, do some cases, and then you qualify to be in a study. And we're seeing that model being rigorously applied over and over again. That's not something that was traditionally done in neurosurgery. And I think it's to the benefit of our trials and our patients and our specialty. So to us, the ideal procedure was to do these things. Get rid of the mass effect as soon as you can. Remove as much clot as you can with the least amount of injury. And then finally, to your question, how can we reduce the rate of re-bleeding? Because that was another problem in STITCH. It was a 25% rate of post-operative re-bleeding. Some of those re-bleedings may not be symptomatic. But what can we do in addition to blood pressure control to prevent all of those ring bleeding episodes? So this is what the EnRICH protocol is based on. One is using image interpretation and trajectory planning. Two is using intraoperative navigation. Three is using these minimal access ports. This is called the brain pad system. Four is using a visualization tool that has been designed to look down these small corridors. Five is using this resection device that will efficiently remove the clot. And then lastly is collecting data, right? I have access to the clot, to the perihematoma, edema. What can we learn about all these microenvironment of these patients that can help us improve their outcome after that? So this is sort of summarizing that. So this is an anterior basic ganglion hemorrhage. And in this case, we're coming to a similar approach that Adam described. This is an anterior frontal approach. We're entering through a sulcus. So this port is 13 and a half millimeters in the outside, but the tip is 0.9 millimeters. And it was designed to access through the sulcus. In this case, we have DTI represented here. So here is the cingulate fasciculus. And here's the superior longitudinal fasciculus. And we're picking a trajectory that looks at the long axis of those fiber tracks. So we transect the least amount of fibers entering that hematoma. Once we are there, and we're doing that under stereotactic guidance, then we are looking with an exoscopic device to deliver as much light and magnification as we can at the bottom of that cavity. And then once you're there, you're using the things that you're used to using in any surgery. You have suction, you have a bipolar device, you have a resection tool to evacuate the clot, and then you can do hemostasis. So we think that if you do that, it's less invasive than a traditional craniotomy. We sort of standardize how you do it. We can let you see, be bimanual in your technique. You can do direct hemostasis, and hopefully decrease re-bleeding, because you remove a lot of the hematoma. You don't need to leave a catheter behind for thrombolytics. And you've removed a lot of the mass effect right away. So this is a prototypical case, 70-year-old patient, large basal ganglia hemorrhage. This is the trajectory that we're picking. So we're planning our approach here. This is our DTI scan in the traditional conventional view. And you're seeing the cingulate fasciculus medially, the SLF displaced laterally. Here's the cingulate, SLF is displaced right over here. And we're picking this anterior trajectory to do that. This is our other plane. So that's how the cannulation is gonna go. So we're pretty happy with that trajectory. We think the fiber anatomy is gonna be favorable. Then we simulate how that port is going to enter. And we can simulate how many degrees of freedom, what happens if I move five degrees in any direction with that port, and what fiber tracks I'm gonna be interacting with when I do that. And if I'm happy with that, then we export the plan and execute. This is a robotic assisted visualization tool. So this is a robot with six degrees of freedom. This is the optical exoscopic system mounted on that. This is what the OR setup looks like. So as opposed to a microcube case, this is a videoscopic setup, similar to when you're doing a ventriculoscopic or an nasal skull base surgery, where you're looking at a high definition large monitor and you're sitting and operating in that fashion. So this is what the case looks like. So in this case, we don't give any mannitol or hyperventilation. We use that intercranial pressure to deliver the clot into the port. We open the arachnoid just enough over the sulcus to do our cannulation. And then this is a 75 millimeter port. We are aligning using our navigation system to get the optimal trajectory. And once we reach our target, that intercranial pressure of 30 is gonna equilibrate with our atmospheric pressure of about 12, and the clot starts to spontaneously extrude. So we remove our obturator. We align our optical system. This optical system use this digital image processing so you can enhance the image. And here is our suctioning device. And then we bring our resection tool. You can see the clot just erupts naturally. This is that automated resection tool that suctions and eats up the hematoma. And then the most important thing about this is this. You can see that is the vessel that we thought caused the problem. We have suction, we have bipolar. We're able to cauterize that like you would in any normal case, and continue with your evacuation. So at the end, you're able to do whatever your standard protocol is for hemostasis, surgery cell, flow seal, what have you, and get the hemostasis that you feel comfortable with. And if you are gonna do this procedure, our goal is that you don't compromise on anything that you would do doing any other microsurgical procedure. If you don't have good light, good magnification, or good hemostasis, I don't think you should be doing this or you're gonna get in trouble. So that's the final part of the approach. And then we're going to decannulate. So we start pulling the port about a centimeter at a time. Then we inspect the banks of the cavity, do some additional hemostasis, and then close. So the incision in this case is a forehead crease incision. It's a four centimeter incision, and the craniotomy is about three centimeters. The dural opening is just the size of the port to maintain the turgor of the brain and that high ICP. So I'm gonna speed that up just a little bit for the sake of time. I can't do that there for some reason. But there's a port coming out, and then you'll see that the brain is now pulsatile, and that high ICP has been treated, and that's what the hematoma evacuation looks like. We did this in a lot of locations, a lot of volumes, and we learned a lot of important lessons that we put together in a prospective registry that was called the MySpace Registry. I have 50 patients. We published the results of that analysis a couple years back that had the traditional inclusion and exclusion criteria for those, and that was that study. Mark Bain from the Cleveland Clinic used the same protocol in a single center study, and Jerome Kopins also used the same protocol in a single center study, and these are the results of those things. So most of those hemorrhages were basal ganglia or thalamic hemorrhages. The volume was about 30 to 40 cc's on average, and the clot evacuation, which was the most exciting part of this, was greater than 90% in both series. In Mark's series, it was actually greater than 95%. The GCS improved from a median of 10 to a median of 14 immediately post-op in both studies, and the modified ranking scores at up to six months showed a large number of patients were above that 0 to 3 good outcome threshold. There were no mortalities in that multi-center study, and one small re-bleed that was asymptomatic, but again, those were very carefully selected, cherry-picked patients. This is Jerome's series at SLU. Clot evacuation was 92%, same thing. GCS improved from 10 to 14 immediately post-op, and the 30-day mortality was 6.2%. When you looked at those MRIs when compared to MISTI, it looked more favorable, and same with the clot reduction. So that's what we used to design ENRICH, and this is the study group for ENRICH. We have neurointensivists, neuroradiologists, healthcare economists, stroke doctors, and two neurosurgeons, Dan Barrow and myself. NINCO Corporation is the sponsor for the trial. Our CROs, Janae and Barry Consultants, is our biostatistician core, and one of the things that is critical about that, and I think Adam has more experience than I do in this, is if you look at what happened to the stroke world before we were starting to use Bayesian statistics and adaptive design trials, to what happened afterwards, the difference was dramatic, because we're trying to use trial designs that are smarter, that can use sample sizes that can change as the data starts to come in, and maximizes your chances to finding a good response. And that's what we tried to do in this, and ENRICH uses the same kind of statistical design. These are our participating sites. We have 30 sites in the trial. If you want to learn more about the protocol, ENRICHtrial.com is our website, and you can get a lot of information there. Our study is looking at functional improvement, safety and economic benefits of using this protocol I described, when compared to medical management, is multicenter, randomized and adaptive, and I'll talk about what that means. We're trying to treat within 24 hours, but our goal is to be in the operating room within eight hours of onset. We're using utility-modified ranking score to try to get a better sense of the meaning of bigger jumps in the MRS over time. And in addition to mortality and percentage of clot evacuation, we're also looking at economics of the trial. Our sample size is anywhere from 150 to 300 patients, and our interim analysis was at 150 in every 25 patients after that. We have two locations, anterior vasoganglia and lobar. I think you asked the questions about thalamic. When we looked at the MySpace registry, and we looked at anterior vasoganglia, lobar and thalamic, and we looked at the curve to reach the same outcomes, thalamic patients got to a comparable outcome with one requisite that could not have dissected into the midbrain. So that was one thing. The second thing is they got there a lot longer. So while the other patients got to an MRS of three or less within about six months, the thalamics took nine to 12 months to get there. So the recovery is a lot longer and has a lot to do with that midbrain dysfunction. So for this study, that's why we decided not to include thalamic patients in there. So it's only vasoganglia and lobar. We have early rules for success and futility. And when you do a Bayesian trial, what you do is you do this longitudinal modeling for interim decisions. So you get the data at this predetermined stopping standpoints, and then you predict what's gonna happen to those patients who haven't completed follow-up and to these hypothetical patients that you will continue enrolling. And if there is a strict measurement of what's gonna happen with those patients and there is no meaningful chance of you getting a positive response, then you adapt the trial, meaning you drop one of the two locations and you focus on the other one. So our inclusion and exclusion criteria are very similar to the other trials. Ages 18 to 80, primary hemorrhages, GCS 5 to 14, volumes of 30 to 80, treating within 24 hours, but ideally within eight hours, good baselines. And our exclusions are also very similar. No primary causes of the hemorrhage. Patients have to be symptomatic enough, so NHL scales greater than five. No one with fixed or dilated pupils, no stenture posturing, so patients that are salvageable. Massive IVH, so not greater than 50% of the lateral ventricles. No primary thalamics, no posterior fossa, reversible anticoagulants, no end-stage renal or liver disease patients. We learned that through MySpace as well. I had three patients that were end-stage renal disease patients that did fantastic for two days. And when they got dialyzed, their edema got out of control and we had to do a decompressive craniotomy anyway. So the fluid shifts were just too dramatic. I think they do better if they don't have this massive clot in their brain, but it's a very different population. And the end-stage liver disease, their quadrileptics are just tough to manage. And you probably are much more exposed to re-bleeding in those patients than you do in patients without liver dysfunction, obviously. And then the other exclusion criteria are very comparable to the MIND trial. This is where we are today. We've enrolled 185 patients. We did our first interim analysis at 150. We continued going with the two arms. When we got to 175 patients, the analysis told us that if we continued enrolling in the anterior basal ganglia group, the overall chance of success for the trial was lower. So we triggered an enrichment rule. So now we are only enrolling patients with lower hemorrhages. Now, the tricky thing about doing Bayesian trials is that that doesn't mean that anterior basal ganglia patients aren't going to do well. They haven't even completed their follow-up. So it's an administrative kind of decision in the trial where you say, well, if we continue going with the anterior basal ganglia hemorrhage patients, there's a chance that we could miss our statistical significance goal. Therefore, we're going to drop that arm. So in other words, we don't know what the outcome of the anterior basal ganglia hemorrhage patients is going to be yet, but we decided to enrich the trial as we predetermined in our protocol. So we're only enrolling lower hemorrhages at this point. We have looked at an early cohort of patients between Cleveland Clinic and Emory where we looked at intervention within eight hours and the mortality was no different than if we intervene within 12 or 24 hours and our outcomes were, in this very small sample, improved. Mark Bain is preparing the results of that for publication so I can't show them to you, but we have, at least on the safety side, very good data telling us that we are not hurting anyone and we think there may be a benefit for that. So that's our enrichment that has been triggered and I encourage you all to go to the website if you are more interested. So that's what EnRICH is and what the protocol is. You saw differing approaches to the same disease and overall a lot of momentum.

NRICH trial

port-based evacuations

intracerebral hemorrhage

ICH

ENRICH trial

treatments for ICH