 Going home in for this? Yeah. Good. Yeah. I thought you were going to come tomorrow. Sorry. You're going first then? Yeah. Your career. Yeah. Her rest then. That's right. That's right. Now it doesn't really matter. I can go first. I can go last. It doesn't matter. It doesn't matter to me. I've never gone first, probably. Otherwise, you're like sitting here for half an hour. Yeah. That's a tradition. Yeah. Better than Chris does that. That's true. That's true. That's true. I'll go up. Let's start it up, man. The pressure is off, honey. All right. Good morning. We're very few in numbers. Maybe seven of us here, I guess. We'll go ahead and get started. I'm just going to briefly introduce both of our speakers today. We're excited to have two of our residents talking to us. First, we're going to hear from Marshall Huang. He's one of our first years of PGY2 residents. And he's going to talk about passing on side pass. So I don't see any alcohol on reps here. That's good. And then we're going to hear from Chris Bear. He's going to talk to us about the ocular hazards of trumpet playing. We all kind of got our hopes up that there would be a live performance. But Chris Bear is not feeling up to it today. So excited to have both of them take it away, Marshall. Thanks to Dr. Burrow for that wonderful introduction. My name is Marshall Huang, PGY2 resident here at the Murray and I Center. And today I'll be talking about side pass. And why we decided to pass on it. So the story for side pass, at least for the general public, begins in 2016 when they announced the side pass microstem at the AAO meeting. This was approved after a two-year data study that suggested that it was safe with no significant adverse events. But then the story changed two years later, less than two years later, in 2018 when they decided to withdraw the side pass microstem. They cite in the release that at the two-year post-surgery group, there's little difference in endothelial cell loss between the side pass microstem and the cataract surgery only groups that were the controls. However, they extended the study from the Compass, the Compass XT trial, where they collect an additional three-year data on the, adding on to the two-year data they initially had. At five years they showed a statistically significant difference in endothelial cell loss compared to the group that was cataract only. This was really the only adverse event that they cited, and because of that they decided to withdraw the side pass. They do note that it was out of abundance of caution, and they suggest that they may consider changing the labeling and reintroduce the side pass at a later date. They don't suggest what changes they might make. So, as far as they, at least as far as they report, the endothelial cell loss was the only concern that they had. But when did we care about endothelial cells, at least in the setting of glaucoma? So the question is, what causes endothelial cell loss? There have been many reports that suggest that increased IOP by itself, so glaucoma by itself, can cause endothelial cell loss, and there is indeed a trend towards decreasing endothelial cells with increasing intraocular pressure. There are also studies that suggest aging causes a consistent decline in endothelial cell density. Reports show that there's a decrease anywhere from 0.3% per year to 1% per year in patients who aren't on other treatments or had other surgeries. This paper here is based on 211 patients from 20s to 90s showing a consistent decline. There's even a question of whether top glaucoma medication might cause endothelial cell loss. I don't think it's accepted that it does, but there are some studies that suggest that it might. In this paper, they looked at dorsolamide, timelaw, and betaxalol, which all showed a decrease in endothelial cell density. On average, this shows about 3.6 to 4.5% decrease year over year. On the left here, this is looking at corneal thickness. You can see that there's no significant change in corneal thickness over this period of time. So this endothelial cell loss they saw wasn't clinically significant. On average, the patients here were about 80 years old, and they all had glaucoma or ocular hypertension that deserved treatment with glaucoma medications. And then eye surgery itself. That could be cataract surgery, corneal transplants, or glaucoma surgery, all of which have been reported to decrease endothelial cell density over time. The suggested mechanisms include mechanical damage, whether that's from direct corneal touching from either the implant or intraoperative techniques, or even from the turbulence of the aqueous that goes through the implant or during the operation. Other studies suggest that it could be changes in the aqueous environment that causes damage to endothelial cells over time. Here's a review looking at some of the major glaucoma surgeries over time, and these are the reported endothelial cell losses year over year. They range from 2.6% of the deep sclerotomy, all the way up to 18% with the auto-intuitive in that particular study. You can see that's pretty significant. If you can imagine, that's a year over year decline. And these are basically our most common major glaucoma surgeries that we continue to do today. So the question is, what about the MIGS surgeries, or the microinvasive glaucoma surgeries? So first, we want to define what that might mean. And Zahab and Ahmed define MIGS with the following five factors, which are still relatively accepted today. First is an ad-internal microincisional approach. There are some people who consider an external approach part of the MIGS category, but in general, most MIGS are ad-internal. They're minimally traumatic to the target tissue. So what that means is that we really want to preserve real estate in the eye, in the event that they need additional glaucoma surgeries in the future. They obviously need to lower IOP because that's the goal. So all of these surgeries show some kind of IOP lowering efficacy. And there must be a high safety profile. Because these patients are usually mild to moderate glaucoma patients, we need this to be a first line option so there can't be high safety issues. And then there needs to be a rapid recovery with minimal impact. This is usually accomplished by combining it with cataract surgery, so there's little recovery time beyond what would be standard for them. So there are four general types of MIGS. The first is trabecular, which improves the trabecular outflow through Schlem's canal, generally either with an implant or by bypassing it through trabeculotomy or trabeculotomy. In this presentation, I'll be focusing mostly on the implantable devices, the eyeset and the hybrids. In this photo, this is an example of the hydras. This is a crescent-shaped device which helps the stent open the Schlem's canal, whereas the eye stent is a heparin-coded device that kind of creates a passage through Schlem's canal. The suprachoroidal version is what the Psypass is. And here is an example. So this improves the uveous curl outflow as opposed to the conventional outflow by connecting the anterior chamber to the suprachoroidal space. You can see here it's kind of like a straw that goes right from the anterior chamber out and into the suprachoroidal space. The eye stent suprach does a similar technique except it uses a titanium sleeve over a PES tube. And then in terms of a subcontractable type of MIGS, here's the Zen gel stent, which is a collagen-based device that directly shunts the flow to the subcontractable space. This kind of device is considered to be more effective, considered to have higher IOP lowering efficacy, and therefore has a less of a concern on the safety profile. This was approved because it was shown to be relatively similar to other tube-shut devices, so it didn't require the same kind of approval processes that the trabecular device is required. And then finally, the endocyclofoam coagulation attacks the ciliary body epithelium to decrease aqueous humor production directly. So the question is how effective are these MIGS and how can we compare the safety profile versus the benefit of the MIGS? You can see here, here's one of the ones I'll mainly focus on in this presentation. You can see the ranges from about 7.4 to 9.4 in terms of IOP lowering efficacy of all these implantable MIGS devices. Here, this is the I step. This is the high-dress, the side-pass, and the Zen. These are probably the most comparable in terms of their desired safety efficacy and their IOP lowering efficacy. So what was the data that finally caused them to recall the side-pass? You can see here, for the first two years, this is what they published initially. There's no significant difference between the side-pass and the control, which were cataract distraction-only patients. At year four, they first detect a significant difference, and here's the year five published data. This chart here shows a percentage of patients who had greater than 30% endothelial cell loss. The paper suggests that the industry or regulators, rather, requested that they include this data. Again, it shows a significant difference in the percentage of patients that have greater than 30% endothelial cell loss between control and the side-pass patients. It's notable that the month 36 time point is hard to interpret because they only had about 15, 16 patients or so in that time point. But looking at that, how can we compare it to the safety outcomes of the other MIGS devices? Here at the top, this is from Der and Ahmed. It's a great chart showing all the randomized control trials, showing safety data and efficacy data of these MIGS devices. The ISTEN inject, you can see that all they have is 24-month follow-up time, at least with endothelial cell loss data. They've 10 years of data published for the ISTEN overall, but they did not initially look at endothelial cell densities. So all we have is 24 months, which shows a significant difference. They'll show the p-values or anything, but you can believe that. The hydrous microstat showing also no large difference between the treatment groups and the control groups, and not a large difference in the number of patients with greater than 30% endothelial cell loss. But if you see here, there's almost double and almost triple in these groups. This is reported at 60 months, but it's actually with knowing this is a 48-month time point that they report here, and this is indeed a 60-month time point. As I mentioned before, the ZEN GELSTEN was considered similar enough to other subcontractival shunting devices, so they didn't require as much approval, and therefore they only have 12 months, and this was only with 11 patients or so. So not much safety data for the ZEN. So this is the raw data that was published with the Compare XT trial. It's kind of a busy chart, but I want to draw your attention to right down there. So this is the 24-month time point. Up here, this shows the endothelial cell densities that they measure. This is the change, and this is the percentage change. So overall, you see a 12% decrease and a 9% decrease compared to the microstat group and the control group. It's only until you get to year 4 and year 5 that they see the significant difference appear. And as I mentioned before, we really don't have any data at all for the other devices. And if you look at just the data up to the two-year time point, which is all we have for the other devices, it's about the same as what the other devices report. And then again, this highlights the 60-year time point. This is what they reported in that last chart. It's the 48-month, but showing the same information. So here, this again shows a proportion of eyes with greater than 30% endothelial cell loss. If you note down here, there's no significant difference here. It only appears at month 60, where it's not even statistically significant based on this analysis, but definitely approaching it. And in this paper, there's separate also how many rings are available in the side-pass device. So I'll explain that in the next slide, but basically there are three retention rings that you can visualize as you plant the side-pass. In this case, they separate the people with less than one ring available. So no rings available, one ring available, and two or more rings available. And you can see not so much difference here, but as you move to years four and years five, you can see that the difference in the percentage of patients with greater than 30% endothelial cell loss is significantly different. Three or four times more with the patients with greater than two rings available. It is worth noting that they recommend in planting the device with one ring available. And if you do see multiple rings available, especially early on, you can consider moving the device or trimming the device, which they did in the study. In this study, they showed that there are three patients with focal corneal edema, but not corneal decompensation. There are also four patients that require trimming of the side-pass implant. Usually trimming was done if it was found that more than two rings were seen within the first post-operate, the first post-operative week. And here is a chart kind of showing the last table's data. So here's the control, which they took the endothelial cell densities of patients six months into the control. So six months after cataract surgery. Here's the side-pass overall, the statistically significant difference between the endothelial cell losses per year. And here, this is no rings, one ring, and two rings and three rings available, showing a trend towards increasing endothelial cell loss as you have more of the side-pass protruding. Again, this is what they initially published as a recommended implantation technique, one ring available. And the difference between control and that one ring is about 1% difference. It's also worth noting that the control that they published here is only 0.36% endothelial cell loss per year. As I mentioned before, even in the natural course of aging, they published 0.3% to 1% endothelial cell loss per year. And these are patients that have undergone cataract surgery in addition to their normal aging process. Previous studies have reported much higher endothelial cell losses in the control itself. So here's an example of what I was talking about with the implantation. Here you can see three rings, one, two, three retention rings available. This is the collar that sits in the front. And here is optimal implantation position. One ring available right here in the collar that's at the level of the, excuse me, Schwalbe's line. It's important to know that there shouldn't be any contact with the corneal endothelium, because that would require either trimming or replacement of the device. And here's another view. This one shows no rings available. And this here is implanted at the collar. This is an interior chamber OCT showing the implantation of the device going into a super corroded space. So the question overall is, does Cypass really deserve a recall? The endothelial cell loss was a subclinical finding. Nobody had corneal decompensation related to this endothelial cell loss, which makes sense because studies report that people generally have corneal decompensation at around 300 to 500 square millimeters of endothelial cell density. Sometimes they have issues as high as 800, but most of these patients were far from that threshold. The two- to three-year data that was initially published when the device was approved is quite similar to other mixed devices, notably the hydrous and the isent. No other data currently has any five-year data that show endothelial cell loss. The hydrous currently published their third-year data and they're working on four- and five-year data, so they will be published soon, but we currently don't have it. And when we compare the endothelial cell loss and the treatment versus the control arm, the control arm is very important. And in this arm, they had very low endothelial cell loss among the lowest reported in these randomized control trials. And then further, when you subcategorize the groups into patients with just zero or one retention ring available, they had even lower endothelial cell losses, almost consistent with the other mixed devices or with other reported controls. In previous sense. It's worth noting that they do recommend having one retention ring available, at least in the initial publication, because they suggest that the device might be less effective if it was implanted too deeply with one zero retention ring available. They don't really make a comment on that in the CompareXT, so we might have to see whether or not there's an efficacy change if you were into implants a little bit deeper. But this does suggest that zero retention rings available at least causes less endothelial cell loss. And so I would ask, maybe if anyone has a comment, what if instead of recalling the device, they changed implant implementation instructions to suggest that it had to be either one or zero retention ring available? Does anyone have any thoughts about how that could have changed things, Dr. Sinclair? Yeah, have they looked at the relationship with the maybe corneal OCT between the depth of the implantation, not the extent, but maybe the depth of the implantation, those relatively closer to the cornea, causing more localized swelling of the cornea in that area and suggesting more endothelial cell loss? Have they looked at all of that? I don't know if they did it with OCT, but they definitely did it clinically. So the three patients that had some corneal edema, they're noted all to be a focal corneal edema right near the stem. One of those patients had two or more retention rings available, so that was trimmed. The other two were seen as subclinical, so they just watched those. Initially, they weren't even reported as adverse events and only in post-analysis that they decided those were adverse. So I think overall they agree that the closer it is to the corneal endothelium, the more likely there is to be an issue, and that's kind of done with the retention rings, because the more out it is, because of the position, it's more vertical in the angle, the further out it is, the closer it is going to be to the anterior chamber. Now these were the same concerns that we had with the augment and the bear valve that were coming from posterior and sort of angled, that the deeper you could implant it under the sclera and going into the anterior chamber and the less amount of the tube available in the anterior chamber would seem to be associated with less corneal secondary changes when you're trying to implant it in the anterior chamber. I think that's a good point and that's kind of what they're trying to suggest here. They definitely do care about the same adverse events as they do with the tubes. The problem is that when you do a tube, you more likely have a need for a higher intervention, higher IOP lowering, and you care a little bit less about the safety profile compared to these MIGS devices. So you certainly have the same concern, but I think with the MIGS, we have to be very careful about having a much higher bar of safety. In terms of whether or not it's close to the endothelium, I think that could be worth checking with a more objective test. Bill? I think it's a really interesting question if they could have just changed the recommendations. And also find it interesting that you asked the question, did it deserve a recall? Because as you stated, they hadn't had patients with decompensated coordinates. They just had this accelerated endothelium cell loss. And if I'm the company thinking about this, one, I'm really thinking about, yes, I'm thinking about the patient, but I'm really projecting forward what's the potential financial cost if we do have patients that begin to decompensate. And I would assume that was the primary driver of why they recalled them. Brian, I'm curious, in my conversation with our Guacoma faculty, I never started inserting this because they said the complications were quite significant. I mean, when you did have a complication, it was really, really difficult to manage. And I also wonder if you think that might have something to do with holding a trigger on the recall. Yeah, I'm not plugged in, so I don't know all their decision process. But I think it did like... So some of the other ones, like the eye stent or the hydras, have a better risk-to-benefit profile. So for the side pass, I don't think it worked much better than those, but it's definitely riskier just in terms of the surgery. And so I don't know about their implantation, how many they thought they were doing, or I don't know. It probably was more than played into it than just the endothelial cell loss, I think. Yeah, I agree. I think those are both really good points. I think the endothelial cell loss was the only thing they pointed to. And the published data doesn't make it obvious how different the adverse events are between the different MIGs devices. And there was an article that suggested that perhaps they were more worried about future litigation by doing the recall early. They protected themselves from future lawsuits and issues for the patients that have had it implanted already, since they've made this recall decision. And furthermore, they do seem to suggest to spin it off into potentially a sub-company where they might repackage it and re-release it. Dr. Rammels. I can't really tell you anything or I have to kill you first, but I can say I do not disagree at all with your statements. Does that put nicely enough? You say. Okay, very good. And I think it's worth noting that other... Oh, sorry, yes. No, one more. We've always done microstents and stuff in the superior quadrants because that's where we did the trajectory of the drug. That was our history. But that's where patients rub their eyes and maybe distorting the stints more. Has anybody tried surgical procedures below? I'm not sure, actually. That's a good thought. I hadn't thought about the eye-rubbing component. Yep. Dr. Eric. Any patient... Do studies show any... ...chemistry studies at all? They do, yes. They call the compensation even though... Yeah, so that's a really good point and almost all of these studies do indeed look at the symmetry, central symmetry, and they don't show any significant corneal thickening associated with endothelial cell loss. And again, that's not necessarily unexpected because most of these patients still have well over 1,000 cells per cubic word square millimeter of endothelial cell density. But they don't see it in our data. And yes. One other point with these mixed devices is when you do run into a complication, how hard it is to fix it. So how can you get any of these devices out? Side pass is particularly hard, I think, to get out. And I think people have struggled with that. Yeah, so I think that is a major challenge with the side pass. They mentioned that if you're trying to modify the side pass beyond seven to ten days post-implementation, they suggest that removing it could cause more harm than good and instead they would suggest trimming it if at all possible. Before the seven-day mark, they suggest that you can move it, but the fibrosis will be too severe to move it later on. Unless it's causing corneal decompensation where the benefits are where there is. And another question I had was whether or not there's a structural propensity to cause more corneal damage with this device and other mixed devices like the hydrous or the ice then. And some papers suggest that it does. Because it's a stiffer implant, it's more likely to sit vertically in the angle. So if there's any change in the position of it, it's more likely to protrude out and touch the corneal endothelium than other mixed devices just because of how it's designed. And then my final question here would be why not just implant the hydrous? Based on the randomized control trial, it suggests that the hydrous is more effective with a similar safety profile to the ice then. And it's not recalled. And theoretically there might be higher IP load efficacy of the hydrous compared to side-pass anyways. So does anyone have any thoughts, I guess, on why not implant hydrous over any other mixed device? Or at least these implantable mixed devices? Because just do hydrous. I would totally do hydrous. Okay. Well, I think that's a good take-home point then. But in terms of related to the side-pass itself, I think some things that we need to remember are that gonioscopy is essential when we evaluate a patient with a previous side-pass implant. We don't necessarily need to intervene on them, but we need to be able to assess where exactly the side-pass is, how many retention rings available, whether or not it's touching the cornea. And only if there is actual corneal decompensation, which is clinically significant, do they recommend any kind of intervention. Overall, the safety profile is superior to traditional glaucoma surgeries. But the reason that it's not accepted is because we demand a much higher safety profile for all of these mix. And as far as I can tell, there's no good evidence that endothelial cell loss doesn't occur at a similar rate, a higher rate or a lower rate, really, for any of these other mixed devices, since we just don't have that data. That's really what I did know. And finally, why do we care so much about the endothelial cells? And in the end, of course, we care because it keeps our corneas healthy. We show that there is a decrease, a steady decline in endothelial cell density over time as we age. So it's important to preserve it as much as we can. And since there's almost no regenerative potential for the endothelial cells, there's really no going back if we cause damage that might cause issues 15 to 20 years down the line. And I think for that reason, we'd be extra cautious for these patients with just mild to moderate glaucoma, usually just undergoing cataract surgery for the purposes of decreasing the drop burden. As I mentioned, we don't see any clinical findings, no corneal decompensation, but with the amount of cells that we need to maintain detragestion, it's not unlikely that we did it. Any questions? Comments overall? Nick would know of this, too, but historically, just the early days of implants, just a critical how of this implant. I mean, think about the endothelial layer just wasn't even recognized. That was a problem. So the most common cause of corneal edema was to take the corneal edema in those years. So just how we progressed to really watch it now is to carefully be aware of it. Yeah, that's a really good point. And I saw that it looks like topical medications and intravitural medications all require a monitoring of endothelial cell loss over time in order for approval. And I was wondering if anyone knew, Dr. Manson, if that's required for IOLs these days, by any other kind of implant? It's not required at this point, but to Dr. Harry's point from 1984 to 1989, Pseudo-Fakit Bullis Caretapathy was the number one reason for corneal transplants in the U.S. So I mean, it really was a major issue. And interestingly enough, there were anterior chamber IOLs that succeeded in IOLs that were approved and did not really show any endothelial damage during the first six months when they were evaluated. But two and three years later, slowly but surely they were showing endothelial damage eventually leading to corneal decompensation. So this is something that we should be aware of and that people should be looking at. Thanks for your attention, everyone.