Transcript
Katherine Talco...:Welcome to the New Retina Radio Journal Club with VBS. My name is Katherine Talcott from Cole Eye Institute. I'm so happy to be joined today by Akshay Thomas from Tennessee Retina.
Akshay Thomas:Thanks for having me, Kat.
Katherine Talco...:And Nita Valikodath from the University of Michigan.
Nita Valikodath:Thanks for having me.
Katherine Talco...:Thank you so much for being here. Today, we'll be discussing a paper entitled Comparative Analysis [00:00:30] of Ocular Adverse Events Between Aflibercept Eight Milligrams and Faricimab, A Global Population-Based Study Across 65 Countries. The senior author was Moiz Lakhani, and this was published in Ophthalmology Retina in April of 2026. Nita, do you mind summarizing the paper for us?
Nita Valikodath:Yeah. This was an interesting study that tried to understand post-marketing safety profiles for intraocular injections. The authors compared ocular adverse events among aflibercept two milligram, aflibercept eight milligram, and faricimab. [00:01:00] The investigators performed a retrospective pharmacovigilance analysis of FDA Adverse Event Reporting System, or FAERS, and these were reports submitted between January 2004 and June 2025. They removed duplicate reports, and identified approximately 8,000 reports for aflibercept two milligram, 4,000 reports for faricimab, and 300 for aflibercept eight milligram. Adverse events were coded using standardized terminology and grouped anatomically. [00:01:30] The authors used disproportionality analyses, including the reporting odds ratio, ROR, Bayesian signal detection methods to identify adverse events reported more frequently than expected. Importantly, because FAERS lacks denominator data, these analyses identify reporting signals rather than true incidents or relative risk score rates.
The authors found distinct profiles for each agent. Aflibercept eight milligram demonstrated the strongest reporting signals [00:02:00] for inflammatory complications. These included anterior chamber flare, vitritis, retinal vasculitis, and both infectious and sterile endophthalmitis, as well as blindness and reduced visual acuity. Faricimab demonstrated stronger signals for events like hypopyon, retinal pigment epithelial tears, choroidal hemorrhage, and pseudoendophthalmitis. Aflibercept two milligram showed a broader profile of structural and procedural complications, and this included elevated IOP, vitreous hemorrhage, [00:02:30] retinal detachment, and PC tear. Based on these findings, the authors concluded that each anti-VEGF agent appears to have a distinct post-marketing safety profile that warrants continued surveillance.
So the major takeaway from this study is that pharmacovigilance databases can identify rare safety signals that may not emerge from clinical trials, but these findings should be viewed mostly as hypothesis-generating rather than evidence of causality. ROR, reporting odds ratio, [00:03:00] doesn't measure incidents or comparative risk. It's identifying a particular adverse event that's reported disproportionately often for one drug within this specific database, the FAERS database. Therefore, these signals should prompt further investigations in studies with known exposure denominators.
Katherine Talco...:Awesome, Nita, that was a great summary, and I think this is a really timely paper and I'm glad that we're discussing it, because us as retina specialists, safety is obviously top of mind. Akshay, any quick thoughts [00:03:30] on this paper? Do the findings that Nita discussed align with your experience using these drugs?
Akshay Thomas:Yeah. I think we need to be careful talking about our individual experiences. The one thing I can say is that there's not a single anti-VEGF agent I've used where I haven't encountered some form of sterile inflammation, and that's about as much as we can say. I think everything else, when you're talking about rare events, you require tens of thousands of injections and numerous, numerous events to truly see causality or specific pattern generation. So [00:04:00] I think, like what Nita said, this is really hypothesis-generating, and it's really a plug for us to report events, either to the ReST Committee, where we can get a little bit more granular with what pattern of inflammation, what sort of potential adverse effects we're truly seeing.
Katherine Talco...:Yeah. I think that's a great point. I really appreciate how the both of you both mentioned the limitations with these types of studies, that we don't actually know how many people received injections, and there's also other complications potentially that people don't submit to this organization. [00:04:30] Nita, has this paper changed the way you approach these different agents?
Nita Valikodath:I don't think it would change my clinical practice in terms of how I evaluate a patient, their imaging, their vision, and the decision of which agent to start with or when to switch. I think it does make me think about the whole injection procedures, from patient risk factors, to how we do the injection, sterile technique, [00:05:00] paying more attention post further dilated exams, for example, to try to pick up some of these things early, and then if I see a complication or one of these adverse events, just to follow that more closely. I think it's hard for me to understand which of these events is really correlated with which agent. So I don't think it changes in terms of what agent I reach for, but just is, again, hypothesis-generating, I think, makes me more aware [00:05:30] of trying to report to this database if I need to, if I'm seeing a complication or something that I'm worried about.
Katherine Talco...:Yeah. I think those are really good points, with taking these reporting of the adverse events into account, but also keeping in mind the potential limitations of the study and maybe tempering that with how we practice. All right. We're going to take a break, and we will have a more in-depth discussion on the other side. Thanks so much.
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Katherine Talco...:Welcome back to the New Retina Radio Journal Club with VBS. Let's get into a longer conversation about the paper that Nita just summarized in the first part [00:06:30] of the episode. So Akshay, one of the things that I found interesting when I was reading this paper was how they decided to group some of these adverse events. Specifically, they talked about structural complications versus inflammatory or infection-related complications. Is that how you think about complications? Any comments on that and how they structured it?
Akshay Thomas:Not really. I mean, to be honest, I think of things pretty binary, which is either there's a complication related to the medication or a complication related to the procedure. [00:07:00] So if we talk about things like posterior capsular rupture, retinal tears, retinal detachment, vitreous hemorrhage perhaps, we can all agree that those are probably related to how the procedure was performed. And then, everything else is really related to the medication. And then, you could say that even that can be subcategorized into inflammatory events, infectious events, and perhaps structural things, like RPE rips and tears. But yeah, typically, I really think of it as is it medication-related or procedure-related, [00:07:30] which would've happened with any agent you were using.
Katherine Talco...:Yeah. I think that's a really good comment to think about, is it the medication itself or is it how the medication was administered? Nita, I think you referred to this a little bit in your summary, but do you have similar feelings on the categories? Do you think about it differently?
Nita Valikodath:Yeah. I think Akshay made a great point. I similarly think about medication-related complications versus the procedure-related. And one of the things I was thinking about when reading this paper [00:08:00] is sometimes the procedure-related complications could be more related to who is doing the procedure. Is it earlier in your training versus the patient moves or something happens where it's more related to that procedure, not necessarily the medication that you're injecting? Also, I think about underlying patient risk, and I think that is a limitation of this kind of reporting. We're not reporting underlying past medical history, other [00:08:30] immune reactions that patients may have had that may make them more susceptible to these types of adverse events.
Katherine Talco...:And could you tell us a little bit about more what you mean by that? I mean, I think about when I'm using these second-generation agents, especially with the way my insurance climate is in Ohio, where we often have to start with other agents before we switching, but often we're not using these agents as first line. I just wonder in some of these cases if [00:09:00] providers chose to use certain medicines on certain patients, and that might've increased their risk of having a complication, like an RPE rip?
Nita Valikodath:Yeah. That's a great point. I similarly am restricted in terms of what medication I can start with. So typically, starting with bevacizumab or aflibercept two milligram, and then switching to the second generation if they are failing the first-generation agent. So usually, those patients are, in a lot of ways, more refractory or more [00:09:30] complicated, and so in most cases, the insurance does not let me use the second-generation agents as first line. And so they may have larger PEDs, they may be more susceptible to RPE rips, and then I'm switching to some of these newer agents.
Katherine Talco...:Akshay, I'm curious for your thoughts as a uveitis specialist, I mean, you must, when you read a paper like this, really think about and want more details of these inflammatory infectious events and want to know what sort of workup [00:10:00] is. Is there other things that you wish a paper like this would include? Does this help you be able to tell that the inflammatory events were truly inflammatory events and not infectious? What are your thoughts on how to interpret this data?
Akshay Thomas:Yeah. It's extremely challenging. I think first off, I really enjoyed the paper, but again, I think [inaudible 00:10:21] manuscripts like this can really tell you that there's a signal, but really not how much of a signal there is, because if you just look at it, it's kind of intrinsic [00:10:30] to the FAERS reporting system, which is very, very flawed. There's really no double checking about what you're reporting. You can essentially go in and report whatever you'd like, and the authors noted this. And we also know that there are reporting biases. They kind of alluded to this Weber effect, which there's going to be increased reporting after you have a new agent hit the market, and then this notoriety bias, so if you have an agent where people are talking about, "Oh, I had this inflammatory event," there's more likely to then go and report it. I can say that I have not reported [00:11:00] every single inflammatory event I've seen with all my patients and all my different agents.
So it's a little bit hard to tease apart exactly the extent of the problem. What I would say I find far more helpful, and this is getting back to what I said before, is when we actually receive case series or reports from doctors to the ReST Committee, then we can identify clusters and we can identify unique phenotypes. For example, a hypertensive anterior [00:11:30] uveitis with corneal edema is a very distinct inflammatory characteristic we see with sterile inflammation. So I think having a lot more granularity is going to happen with a case series out of specific sites or reports from the ReST Committee, which are probably even more helpful.
Katherine Talco...:Yeah. I think that's a really good point. I have found it really helpful when I have seen case presentation or case series where I can look at the images myself and have it presented to me. And I think the ReST Committee has [00:12:00] done a great job of curating when there's things that come up. I just want to though applaud the authors for being able to look at the data that is there to be able to collate it together. I think it's really important, as we integrate new agents into our practice, that we look at safety. But I really appreciate the discussion that we've had, just about the limitations of this database and what we can take away from it as clinicians. So I just want to thank the audience for listening to the New Retina Radio Journal Club with VBS, and [00:12:30] please stay tuned for further episodes.
