Thanks a lot. So my chairman would be upset with me if I didn't correct you. It's University of Louisville, not University of Lexington. That's all right. So we're going to talk a little bit about spontaneous intracerebral hemorrhage overall. The state of the disease and how we got to where we are today. Including the mystery three results which as Gustavo just mentioned were just published back in February. And then I'm going to briefly discuss one of the studies going on because that study's PIs aren't here. And leave it to the other gentleman to discuss the two randomized control trials. So I don't have any disclosures related to this talk but I did receive a grant from Penumbra which is one of the companies sponsoring some of this technology several years ago. But it's a grant not related to the topic. So just a little overview of what we'll talk about briefly. So intracerebral hemorrhage is a type of hemorrhagic stroke and it's a small portion of the total volume of strokes. The largest being ischemic of course. But it has the poorest prognosis of all stroke subtypes. And this wasn't clear to me when I was in my, beginning of my residency. I always assumed that the ischemic disease had the worst outcomes. Mostly because we couldn't reverse it back then. But as I learned and grew and became obvious that the ICHs were the ones that just had awful prognosis. The 30 day mortality is based on a number of things including the size of the ICH, the amount of blood, whether or not there's blood in the intraventricular system and how much. Whether they have early deterioration or not and how much edema they have. And the majority of survivors are dependent on follow up. So this is a review of several different studies looking at intracerebral hemorrhages and ICH. If you look on the right side of the column this is without intracerebral hemorrhages. These are the mortality rates that you would expect typically from these types of studies. And you see how it dramatically increases when you add intracerebral hemorrhage as well. So this is a pretty bad disease. And you know when the ICH is greater than 20 to 30 cc's the expectation for functional dependence is on the order of less than 20%, less than 10% in some studies. So these patients don't have good outcomes if you do nothing for them. Which is what we've been doing for a while. The standard of care is to prevent hematoma expansion by correcting anticoagulation, thrombocytopenia, blood pressure control. We'll put a ventriculostomy in cases where there's significant intraventricular hemorrhage or hydrocephalus. Supportive care in the ICU and rehabilitation. For a long time we were not doing surgical evacuation of these deep ICH's or even sometimes not deep ICH's just because the data didn't support it. So I like this quote. It's from Dr. Hanley. He's a neurologist at Johns Hopkins and he was the PI and study chair for MISTI 3. It says the state of care for ICH is similar to the care for ischemic stroke three decades ago. Care is frequently not rendered. When it is rendered it is palliative and supportive of cardiorespiratory function rather than reversing the brain injury. So we just weren't, we didn't have any aggressive efforts to try to reverse this brain injury like we have recently had in ischemic stroke with thrombectomy and other types of treatment options. So there was multiple studies looking at the medical management of this disease. None of them showed any significant improvement in outcomes. There was the stitch and stitch. Stitch one and two trials which were looking at open craniotomy and early resection of the ICH or early evacuation of the ICH. Again not showing significant differences between the surgical treatment group and the control groups for either one of the studies. They thought there was potential benefit in the more superficial hemorrhages but when they repeated the study looking at stitch two, looking at certain subtypes they did not see benefit. And then different authors published some data on some minimally invasive techniques. The thought being if we don't do these large open craniotomies and we kind of restrict our surgical injury, minimize the surgical injury, try to do these minimally invasive techniques, would there be an advantage with that technical variation that tries to minimize the surgical injury result in better outcomes? Would that unmask a treatment effect? And sorry, wrong way. So this was a Fischer plot showing a systematic review of meta-analysis of some of these studies looking at that it favored minimally invasive treatment. So then we go to MISTI 2 which is where prior to this recent publication of MISTI 3 where most of our enthusiasm for doing these types of minimally invasive ICH evacuations recently stem from was the results of this study. So they looked at 96 patients randomized to medical management versus their surgical management which was placement of a 14-frame sheath in the long axis of the ICH. They would aspirate the hematoma and then they would leave a ventricular catheter behind and give TPA, one milligram every eight hours up to three days. And in that they proved that number one, they could get rid of the clot. So this is the medical control group in MISTI 2 that showed the size of the volume over time. And this shows the size of volume over time in the MISTI 2 group that was treated with minimally invasive surgery. And then they show in the top left, this is a busy slide, but in the top left you can see that as they improve on residual volumes after the surgical medical treatment, the one on the left there is where there's less than 10 cc's of residual hematoma. And you can see that the modified Rankin scale, which six is death and zero is no symptoms, we're looking at if you were to dichotomize it to what's a good outcome, what's a bad outcome, three or less is considered a good outcome and someone would be independent. And greater than three would be somebody being dependent. So you can see that there was a favorable improvement as the amount of the ICH was evacuated. And then top right side you can see the difference between surgery and medical treatment looking at the modified Rankin score at 180 days and on the right hand side at 365 days. And there was an improvement between the two groups that they saw of about 14%. Now that was not powered statistically to show statistical significance and it was not significant in their study, which is what the purpose of MISTI 3 was. In the bottom left you can see here that if you look at certain outcome scales, stroke impact scale and the activities of daily living, that there starts to be a separation between the medical managed group and the surgical treatment group starting at about 180 days where those graphs start to diverge. And so that suggests that these patients, the benefit may not be instantaneous, it may take several months to see the effect of the treatment. So then MISTI 3 was published in February 2019 in Lancet. And this was a randomized controlled open label blinded end point phase 3 trial using the same surgical technique as the MISTI 2 trial. It was international. They enrolled 506 subjects from 70 hospitals internationally. The requirements was that the ICH was spontaneous, 30 cc's or larger and that they had to prove stability of the ICH prior to randomization. And then the patient had to have a neurological deficit related to the ICH. So this is their screening and enrollment graph that shows they screened over 19,000 patients to get their 500 patients that were enrolled. Different reasons for why patients were excluded along the way. And they used a modified intention treat analysis in the end to study the two groups. So again the procedure was the same as MISTI 2. They placed a sheath along the long axis of the ICH, aspirated from the sheath, placed a catheter in the hematoma cavity and then gave TPA every 8 hours with a maximum of 9 doses versus standard medical treatment of blood pressure control and ICU care. So this was their baseline characteristics between the two groups. They were very similar in both groups. There was no areas of significant divergence between the two groups. We expect it might modify the results. When you look at this table, these are some of the treatment variables that came back. The important one to look at is the end of treatment ICH volume. You can see that in the MISTI group there's about a third one down. So you can see in the third one down that the residual average ICH volume was about 12.5 CCs in the surgical group and 43.7 CCs in the control group. That was a significant difference. So their procedure was showing effectiveness. But when you look at the volume here of end of treatment less than 15 CCs, they showed that only 58% of the patients actually achieved that target surgical goal of less than 15 CCs residual volume. So when looking at the outcomes of this, these are the modified Rankin scale showing the two different groups here with the MISTI 2 and the surgical procedure versus the standard medical care. You can see there's not a significant difference between the two graphs. There's a little bit of a significant difference in the mortality which was shown statistically. But the difference in what is considered a good outcome which is basically from this difference between the yellow and green here in the two groups was marginal. And not significant. So this was at the end of the modified Rankin scores. This is the extended Glasgow outcome scores and again the same effective scene. But when you look at, and this is the total amounts here, you can see that the modified Rankin of a good functional outcome was 45% in the MISTI group, 41% in the control group and again not significant. The all cause mortality was improved in the MISTI group so they did improve prevent patients from going on to death. But they did show an association between the extent of clot removal and good outcome. Where the odds ratio of having good outcome was favorable and significant as you increase the amount of blood that you remove. So this combined with this basically says that if you, the more blood you're able to remove you can reach your surgical target, there is the possibility that you may result in favorable good outcomes. Unfortunately this was not their primary end point of the study to evaluate this aspect of it. And there was not a good mechanism in the study to reliably force the removal of enough blood to reach the target goals. So, but of those who achieved the clot removal size less than 15 cc's, 10.5% increased chance of Modified Rankin 0-3 compared to the control groups and that was significant. So when you look at this subgroup of those who did achieve the surgical target, there was a favorable outcome. So, where does that leave us? Well, overall the authors felt like they could not recommend the MISTI procedure for intracerebral hemorrhage. And the importance of the minimally invasive removal for ICH to target a surgical outcome of less than 15 cc's was highlighted in this study. And that alternative minimally invasive surgical methods may help reduce the, to reduce ICH to 15 cc's or less should be studied. So if we have a more reliable way than just achieving it in 58% of the patients that are taken to surgery. If we have a way to do it in 80%, 90% of patients that are taken to surgery and can get to that surgical outcome in a larger portion of patients, then we might start to see an actual treatment effect between the two groups that becomes significant when we randomize between the two groups. So it may just be that this procedure was not as effective as alternative minimally invasive procedures that are out there. And I think that's where we're at today with the results. There's three ongoing studies that Gustavo mentioned. We're going to talk about those today. And preliminary data from some of these studies and from user experiences with these other techniques is that these techniques may be better at getting rid of the blood and getting a reliable 15 cc or less surgical outcome. So I'm going to move on to another talk. I'm going to talk about the other two. So this brings up one of the three studies. This is INVEST. It's a single arm feasibility study of minimally invasive endoscopic surgical treatment with the Apollo Artemis system for a supertentorial ICH. They also have a registry version of this. So if the patient doesn't qualify for the study, but you decide that medically the patient would benefit or you think the patient would benefit from this surgical treatment or approach, that you have the option to also enroll that into a study, into the registry rather and get sort of real world post market data on the device and the technique. So again this one is different from MIND which is going to be using a similar evacuation system in that it's a single arm study. And they're looking at their primary efficacy out point as the modifiant score at six months. And whether or not it's less than or equal to three. The safety end point is the rate of mortality at 30 days. And they're also going to look at the secondary out points, secondary end points which includes stroke impact scale, quality of life score, length of stay, and global disability. And then also the technical efficacy, how likely they were to achieve the surgical goal. This is the flow of how they see patients enrolling into both different studies. And you can see how they cross over from the left side to the right side when they don't qualify for the actual study and they go over to the registry. And this is their inclusion criteria. They're looking for patients who are baseline modifiant score of zero to one. Supercentorial volume of ICH greater than 30 CCs but less than 80. They're looking for stability scan six hours after admission. They're looking for patients who have neurological deficit from the ICH. And symptom onset less than 24 hours from the initial head CT. So they don't want people who have been obviously like four, five, six days after their ICH test presenting to the hospital. And then they have to initiate the surgical treatment within 72 hours of the hemorrhage with good blood pressure control. So you can include cases that do have ventricular hemorrhage but the ventricular hemorrhage can't be so substantial that you require a ventriculosomy catheter to decompress or treat that intraventricular hemorrhage. They're excluding patients who have radiological signs such as a spot sign, expanding hematoma. Cerebellar hemorrhages are excluded. And they exclude patients who have a propensity for bleeding for various reasons. And also exclude patients who may not benefit because their GCS score is too low, have other types of causes of the hemorrhage or other risks associated with being in a study. And then this is sort of the schedule of assessments. So they are doing a three month, six month and 12 month follow-ups on these patients in the feasibility study. But their primary end point is a six month time point. This just describes the procedure a little bit. I'm going to skip over this because Adam is going to go into this in more detail. It's essentially the same procedure between the two groups, between the two studies. And these are just the clinical assessments in the study. What needs to happen at the end. And they're going to track serious adverse events throughout the end of the study. So they're currently at, their goal is to enroll 50 subjects in the feasibility arm of the study. As well as additionally enrolling people in the registry. They've enrolled 25 of the 50 so far. So they're about halfway through. The PI is run out of Mount Sinai. And one of the key differences between this study and the mine besides it being a single arm study is that Penumbra gave a grant for the money to fund the study but they're not actively enrolled in running the study. So this is an investigator initiated and run study from Mount Sinai. They are still looking at adding additional sites. So if anyone is interested in their center joining the invest study, they can contact Mount Sinai and Jay Mako. And if you need their contact information, let me know. And that's it for that. How am I doing on time? I think that's good. Any questions for my initial stuff? Yeah, they're very similar across the studies. There's a little minor differences here and there. For instance, I think the mine study will take an initial ICH volume of 20 cc's as a minimum cut off. Whereas the invest is 30 cc's. So there's a small little variations like that. But for the most part they're very similar, yeah. And a lot of these study protocols were modeled after MISTI 3 at the time because that's what was going on. And it was felt that's what we would have to compare to. Thank you.

spontaneous intracerebral hemorrhage

prognosis

treatment options

MISTIE 2 study

surgical treatment