Rishi P. Singh, MD

Let’s talk about some of the unmet needs. We talked about all the things we already know about this condition. What are the unmet needs you would say in retinal vein occlusion management at this given stage?

 We have wonderful treatment options, we’ve got to start there. I’d be very grateful. It’s a lot easier to be a retina specialist treating a retinal vein occlusion now than it was 20 years ago. We don’t achieve perfection. One of the things we talked about at the beginning was we say OK, you’re going to get your vision better, but we don’t promise that they’re going to get them back to baseline. One big unmet need is, can we reverse some of the initial damage? There’s something there in some of these patients that even if you capture them early and treat them early, they don’t get back to their baseline visual acuity. Maybe they have disorganization of the retinal layers which term drill. That’s the anatomic feature. But the point is that the retinal tissue has experienced something where it does not function at the same level as it did previously. For our patients that’s the biggest unmet need. The second unmet need is what do we do with those patients who cannot come off treatment? They are grateful that they have options. They just wish that their option didn’t include a needle in their eye every couple of months for what they see is the foreseeable future. We have drugs, obviously for other conditions in trials now that offer benefits that may be more sustained release. Maybe something involving gene therapy. None of those are being targeted directly at vein occlusion in relation to other retinal vascular disease to be looked at. For me those would be the 2 biggest unmet needs. Can you get back to baseline, restore some normal retinal architecture? Can you get to the point where the patient no longer needs…more of these patients can get off treatment completely?

I would agree. I’ve been working on some artificial intelligence [AI] ways of predicting who needs chronic therapy and one of the things you’ll see from my research in 2022 will be some of our research focusing on the AI-based interpretation of where we may be able to determine who will require a higher low frequency of injections based upon some of the clinical trial data. And the answer is there are some predictive factors that we see there. They’re very few but there are some. And they’re the anatomical change between day 0 and week 4 and week 8. That’s really the ones that are predictive of the future results. For that I think we’re going to learn a lot about how we might be able to predict the chronicity of these patients. But you’re right. Predicting the chronicity, the future need for injections is always difficult to do. I would see the other unmet need. A topic we didn’t even discuss today is around ischemic vein occlusions. Those patients who have the worst of the worst come in with count fingers, hand motion, vision and totally nonperfused retinas. We don’t have an acute way of managing these patients even when they present to our office these cases. That’s an unmet need I would say regarding that. The last unmet need is around determining in the younger patient what the cause of this is. Obviously, the older person we can blame it on atherosclerosis or blood pressure related issues. The younger patients, I’m sure you see them too. I get patients all the time—that young patient, healthy individual, marathon runner, athlete. Not obese. Not any risk factors. No coagulopathies. And subsequently they have a vein occlusion. You’re then managing that and that can be devastating especially for a young patient who has many years ahead in their lives. There’s another unmet need that probably we need to factor and summarize at some point as well with all of that stuff that we’re doing. Let’s share some final thoughts on vein occlusion and I can add mine as well.

 It’s been a pleasure talking to you. I always learn a lot talking to you about retinal vein occlusion. We have great drugs that work. Anti-VEGF works. Steroids work. We still employ laser in certain scenarios. We have great treatment options. I’m excited to see your research. There’s a lot to look forward to in the future. I would end but one thing I think just to reiterate for people out there who are treating these patients, keep an eye on your central retinal vein occlusion patients. I feel like that was one I mentioned already, but that was one of the things myself and other people, when they left training and went into practice, those are the patients that I found myself undertreating when I first started and realized very quickly that you need to be vigilant and continue treatment, at least with current therapies in those patients. That would be my one takeaway to reemphasize that point. That point gets lost sometimes. Something that wasn’t so apparent to me when I came out into training.

I would say that that’s also very important to understand. This idea of the past couple years of anti-VEGF therapy has taught us a lot about how to manage those patients. The idea of scattered laser coagulation doesn’t work. It’s not necessary for these patients. A lot of retina specialists still do that thinking it’s beneficial. A good follow-up and management of the complications is obviously key to success in these patients. I know that a lot of these patients may develop some other related activities or issues and that can be devastating when they occur. But still, we can manage those well for the most part. I would say that again while the drugs may look similar to us at face value, as we’ve seen from some of the recent studies. We’ve seen some major differences regarding their effectiveness and what the clinical trial data shows. And that’s something we can all take with some grain of salt knowing that we necessarily need to find the right agent for the right patient per se because there’s differences in the agents for each patient.

 Just to add on what you said about complications. On one hand scattered laser photo coagulation you referenced does not seem to decrease injection burden in macular edema. But if you have a patient who is [at] risk for any vascular complications, multiple trials have shown anti-VEGF works up to a point but with cessation of therapy, gaps in therapy we saw with the pandemic. Those patients are at high risk for neovascularization of the iris and CRVOs [central retinal vein occlusion] and posterior neovascularization of the branch. Don’t be afraid to use scattered laser in those patients with ischemic occlusions as they are the ones who can really benefit. Not necessarily to treat their macular edema but to prevent complications of the occlusion.

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Expert perspectives on the ongoing unmet needs in the management of macular edema following retinal vein occlusion. 

Unmet Needs in Treating Macular Edema Following Retinal Vein Occlusion

Since you talked about anti-VEGF [vascular endothelial growth factor] therapy, and some of those trials, you didn’t touch on steroids. Tell me about utilization of steroids. When you incorporate that with your vein occlusion patients?

 As you said earlier, steroids have been around before anti-VEGF was around. Steroids are very efficacious, they are anti-inflammatory. They hit multiple mediators. Not just VEGF when they act. We all know the reasons that we don’t jump to, most of us don’t use steroids first-line because of adverse effects. Cataract formation in phakic patients and then intraocular pressure increase. I do have a subset of patients I use steroids in. What’s my typical steroid patient? Now there’s 2 scenarios. One is if there’s a patient, I’ve tried 1 anti-VEGF and they’re not responding, I switch to another 1. If they’re not responding, typically my switch drug is aflibercept. I don’t generally go to the third drug. A lot of times at that point I’ll pivot to a steroid. Either off-label triamcinolone or on-label dexamethasone. But I do have a subset of patients that they only respond well to steroids. More common than that, because it tends to be very VEGF responsive, is the patient who is on anti-VEGF but even on aflibercept or ranibizumab [Lucentis] can’t extend that far. And I take care of many patients who snowbird. They live in Florida part of the year. They travel somewhere else. Some of them snowbird to South America or other parts of the world where they may not want to go get injections every 6 or 7 weeks. And some of those patients, especially the older pseudo-phakic patients, I’ll trial a steroid. If there’s no IOP [intraocular pressure] increase, I’ll maintain them. And, a lot of times, I can maintain them with a couple injections. Two or 3 injections a year with a steroid that works really well. And I have a subset of patients on the dexamethasone implant injection who do well with that. Do you also incorporate steroids in a cellular manner or any other scenarios where you would likely use a steroid? Maybe pregnancy would be one.

I follow that same kind of gestalt for most of my patients, too. I guess my only hesitancy would be I don’t think phakic status necessarily deters me from using it especially if a patient has an advanced cataract already and is headed for cataract surgery in the near-term future. I mean that could be a nice scenario to use an Ozurdex [dexamethasone intravitreal implant] or a steroid implant in that patient to get that steady state. We tend to want to make sure our patients don’t develop an IOP response. And there’s some interesting data that’s come out recently that’s helped with that more. Essentially what those patients want. Two medications are greater for glaucoma drops are the ones that are most sensitive or concerning for a steroid-related response. It’s important to make sure we differentiate those patients from the general routine clinical patient that we might see and generally separate them out. Because those patients are probably the highest risk. I don’t give anyone with multiple glaucoma medications an injection of a steroid in case that was the case with that patient. I focus on anti-VEGF therapy. We lack good head-to-head studies. There are some studies out there that compared the 2. I’m not sure that’s the best study we have. Do you know of any other combination treatments, or have you used combination treatments in your patients for that matter?

 I have colleagues who have talked about that. I don’t have a lot of patients who I use combination therapy and maybe that’s just my bias. I find that combination therapy for other conditions is most effective where you need the double whammy. You need the dual mechanism to achieve the maximum anatomic effect. I find it uncommon to find a retinal vein occlusion patient with macular edema where the macular edema is nonresponsive to both anti-VEGF and a steroid and I need both. The steroids usually allow you such a long period between your injections when they do work that maybe adding a combination therapy between doesn’t have that extra added benefit for me. Do you use it in your practice?

I don’t. I tend to either go 1 or the other. It’s just too hard because there’s not enough good data to overlying talk about it. If a patient I put with IOP response or they’re having issues with the steroids, then I’ll switch back to the anti-VEGF, but I don’t tend to do hormonal therapy or bi-hormonal therapy for those patients. There’s not a lot to go on regarding that.

 You referenced the 2-drop scenario. The other lesson I’ve learned from my glaucoma clients—I used to be petrified about using steroids in any glaucoma patient—if they’ve already had some sort of surgery, filtering surgery, a tube, something that’s bypassing the trabecular meshwork, they’re a much lower risk at that point. Which makes intuitive sense, but I needed my glaucoma colleagues to talk to me and say you can use a steroid and this patient should be OK. We’ll monitor them. Those are scenarios too if you have because we know glaucoma is a risk factor. Advanced glaucoma you already had a tube in place. You think they might do well with a steroid. It’s something to run it by the glaucoma person but usually they’ll give you the blessing to go ahead.

I couldn’t agree more. Thank you all for watching this 

Experts reflect on the role of steroids in macular edema following retinal vein occlusion and discuss the limited benefit of combination therapy.

Treating MEfRVO: Considerations for Steroids and Combination Therapy

 Let’s transition to what we do in the real world. It’s not just about efficacy. There is a durability component that’s important. It’s hard for patients to come in for visits. There may be durability differences between these drugs that would not be picked up in the study, such as SCORE2. As you said it’s a monthly treatment with both drugs but my question for you is let’s say you have [a] new patient come in, they have a vein occlusion macular edema. Let’s take insurance issues off the table, do you initiate treatment that first day, what drug do you start with and what do you tell the patients in terms of how often we are going to do this? When am I going to see you back?

Great question. Again, the one piece you didn’t tell me about was your vision. If their vision is 20/20 or 20/25, I will observe that patient because I am not sure there is a clinical benefit especially in the younger patients. A lot of them have resolve macular edema over time just by getting a single injection or watching for that matter for the first couple of injections and seeing how their response is. The patient’s vision factors into that discussion. I look at the vision and determine is the vision person who has count fingers vision or worried about nonperfusion. Is that person who has 21/100 visual acuity, which is a perfused nonischemic retinal vein occlusion, which is ready for prime time and ready for studies and how I determine treatment or is it a patient who has really good vision where I might tend to observe and see how they do over time. How about you? What is your threshold for treating these patients?

 Vision is super important. Even if they have mild macular edema, but they are happy that it is asymptomatic, vision is in the good range then I don’t necessarily jump to treatment. But I will schedule that visit for a month and repeat the OCT [optical coherence tomography] because some of these patients can tip over and get worse. Same goes for the patient with vein occlusion, no macular edema, sometimes they will get referred to me and I will say, you know what, we don’t necessarily know if you are going to get macular edema, your vision is very good, let’s watch you closely, and have the conversation about treatment. If they do have macular edema and it is significant, their vision is down then I will usually initiate treatment. I tend to initiate bevacizumab [Avastin] in a lot of these patients. Insurance ties into some of that. I don’t have an opposition to starting with other drugs as you referenced from LEAVO that there may be a benefit to using ranibizumab [Lucentis] and aflibercept but what I tend to tell patients as we are going to start with this drug, and I am going to reassess you in a month, and we are probably going to do monthly injections for the first couple of months, maybe up to 3 months. But, like you said, if the edema completely goes away then we might change that plan. The other thing I will tell them it’s a little different, there are branch retinal vein occlusion [BRVO], I will sometimes say look if we get out to 3 months and the edema is completely gone based on older data there is about a third chance that you may not need continued therapy, but there is a chance we will need continued therapy at a longer duration or if you’re not having a full response at that point I will usually offer another anti-VEGF [vascular endothelial growth factor] and I will talk about that upfront. CRVO [central retinal vein occlusion] I am more cautious about talking to them and stopping therapy. They tend to be more resistant to complete cessation and a lot of those patients need prolonged therapy even if it’s extended. I don’t know if you detect the same difference between these 2 entities.

Absolutely. With CRVO it has a higher rate of VEGF production and VEGF vitreous levels. It makes total sense that you may need more frequent injections with CRVO versus BRVO patient. I would add to that. I think the method of treatment must be discussed. We just did analysis of all the treat and extend studies out for retinal vein occlusion. There are very few out there. Though the vast majority of retinal specialist according to things like SPAT [INAUDIBLE] and others use treat and extend format for these patients. I tend to do PRN [pro re nata] form just as starters to see how their response is and how they are progressing and how they are doing. And then I titrate based upon if they are chronic frequent fliers, need constant injections, it’s time to start to consider more of treat and extend approach. But if there are 1 or 2 injections in a year because I did PRN approach and they are doing great and they know the signs and symptoms to watch out for, I could not let them go and I don’t treat them proactively. I don’t know what your thoughts on that are.

 It’s a great point especially we all have the home run injection patient. You give them 1 injection, they come back in a month, they are super happy, vision is great. The edema is completely gone. Do you need to continue treat and extend versus the PRN approach, maybe you watch them and see them back in a month? Both are reasonable, but it does sometimes help to test and see what kind of vein occlusion it is. How are they going to behave over time? I think the other interesting thing to think about, if you do use treat and extend approach is how aggressive are you about recurrent intraretinal fluid [IRF]. We know from other conditions it is macular degeneration, maybe we don’t need to be as aggressive as we previously thought but recurrent IRF in a vein occlusion patient, obviously it depends on the vision degree but let’s say you are a patient who has been extended forward to 6 to 8 years realize that they have extended over time. And now they have a little bit of intraretinal fluid, but the vision is still good. Do you intervene? Do you want them back in a month? What’s your take? How aggressively to titrate those patients?

Again, if the vision is good, I tend to watch this patient at least initially. They must develop some level of chronicity before I am willing to continue therapy indefinitely. It just depends on the patient. I am making sure that we hit that goal for them. Ultimately, Jay, a lot of us when we look at this, we always say is the vision sufficient for ADL [activities of daily living]. If your patient is 20/25 or 20/30 and they can do things they want to do and they don’t have any detriment or they have no concerns around it, I just continue watching them at that point if their macular edema is resolved or minimal and not the difference there.

Two experts discuss real-world treatment and observation of patients with macular edema after retinal vein occlusion.

Practical Advice on Treating Macular Edema Following Retinal Vein Occlusion

 How about comparing agents for you? I don’t think anyone knows more about the LEAVO study, for example, than you. That’s one of the trials we have that’s comparing agents head-to-head. How do you look at the data and interpret them and decide, which of these agents, between my off-label bevacizumab option and my on-label ranibizumab or aflibercept options, how do I weigh the pros and cons of each of these agents?

LEAVO was a great study to look at the comparative effectiveness of head-to-head drugs for the treatment of retinal vein occlusion. This was CRVO [central retinal vein occlusion], and this study found that there were slight imbalances in final visual acuity in favor of aflibercept and ranibizumab in comparison to bevacizumab for the treatment of retinal vein occlusion. In addition, they found that more people on LEAVO had 15-line gains as result of receiving aflibercept. And with regard to the final acuity outcome, this was considered a noninferiority trial design, and essentially bevacizumab came out not noninferior to aflibercept and to ranibizumab, meaning that it was lesser as an agent, bevacizumab to both aflibercept and ranibizumab. Ranibizumab, while it was not the drug that was the winner in all cases, it was equivalent to aflibercept in many ways. Again, the only difference being the final visual acuity outcome, which favored aflibercept by 2 or 3 letters compared to ranibizumab. Overall it was a nice reaffirmation that all these anti-VEGF therapies are working quite well. But the important concept about LEAVO is that when you’re trying to compare these agents and you’re trying to look at what is the most effective, we know that aflibercept in this case was the most effective agent with regard to drying effect, final acuity, and 3 lines of improvement. If it was my eye, I would say I want to do aflibercept, knowing that this is an expensive drug, and we must be cautious about it. I’m not sure if you have any other interpretation of LEAVO, and then we can talk about some other studies as well.

 That’s a great summary. A common question I get from colleagues or from trainees is, a 2- or 3-letter difference, what does that mean? That’s a small difference in the real world, but I agree with you. If you’re thinking all else being equal, if I had to pick between these 2 very similar options that are very efficacious, maybe I pick the one that, at least in the study, there was a difference that was picked up, and a study that was powered for that difference. How do you interpret that in the context of SCORE2? So SCORE2, a different trial, now we are looking at bevacizumab and aflibercept. SCORE2 was not a noninferiority trial in the same sense, and it did not show that visual acuity difference when you look at the early results, but there were some anatomic differences. How you tie those 2 results together if you want to talk more about SCORE2?

SCORE2 does a good job of comparing aflibercept and bevacizumab, but the problem is SCORE2 is not a protocol we use in clinical practice. That was monthly injections for the first 6 months, and I don’t know about you, but I might give 1 or 2 injections, look at the OCT [optical coherence tomography] response, and then start to do either PRN [as needed], or a treat-and-extend regimen, depending on the patient’s desire. I don’t think I would have gone out as they did in SCORE2 as far as the treatment pattern goes. LEAVO on the other hand, the drug was given on an as-needed basis until they hit a threshold of retinal thickness and showed some differences there.

Again, the results from these studies are important to understand because both SCORE2 with head-to-head studies and LEAVO with a head-to-head trial, get maybe put together as equivalent. There are some major differences in these 2 studies, even though they might look equivalent from the design perspective. SCORE2 had patients with much older vein occlusions enrolled versus LEAVO had young fresh vein occlusions enrolled. Their chance of entry was around 30 to 45 days in LEAVO versus an almost 6-month period in SCORE2. That might have led to some imbalances with regard to final acuity outcome. Obviously, LEAVO showed a benefit in aflibercept, but SCORE2 showed an equivalence. That’s difficult because the drugs to us look different sometimes, they act differently sometimes, and we wonder if there was a difference. LEAVO tends to highlight what I see in clinical practice versus SCORE2 is not necessarily relatable to what I am seeing.

Experts consider when they would use specific VEGF inhibitors for patients with macular edema following retinal vein occlusion. 

Rishi P. Singh, MD

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