Efficacy and Safety of Anti-VEGF Agents for Macular Edema

W. Lloyd Clark, MD: Diana, review for us at a high level the overall safety and efficacy of this class of agent. We have 3 FDA-approved agents, ranibizumab, first approved for the various indications; aflibercept approved for all the various indications; and now, a recent joiner to the party, brolucizumab is approved for age-related macular degeneration. Can you talk to us on a high level about the overall efficacy and safety of these drugs as a class, and then any specific differences among the 3?

Diana V. Do, MD: Over the past 15 years, we’ve discovered that both FDA-approved aflibercept and ranibizumab are extremely safe and efficacious. These drugs have been given to millions of patients worldwide, and we see that with proper technique in using the injection into the eye with betadine and antiseptic therapy, that patients do well, and adverse effects are very rare. More recently, a new agent, brolucizumab, was also FDA approved for the treatment of wet age-related macular degeneration. Although this drug is very effective, there is a new safety signal associated with brolucizumab, specifically an increased risk of intraocular inflammation, which is about 4%. There is also increased risk for retinal vasculitis and retinal artery occlusion. Therefore, many retina specialists are pausing the use of brolucizumab given this safety signal, but fortunately, we do have both aflibercept and ranibizumab, which have had excellent safety profiles.

W. Lloyd Clark, MD: That’s great. Ehsan, what patient factors do you consider when choosing an initial therapy with these various drugs? And are there any factors that you use in terms of making decisions to switch agents?

Ehsan Rahimy, MD: We obviously are looking at patient-specific characteristics, and we also look at disease-specific characteristics. There are a host of clinical trial data that have shown us, at least with wet age-related macular degeneration, we are OK starting with Avastin [bevacizumab]. I’m an Avastin-first type of guy in our practice. And then judging by a patient’s response or suboptimal response within the first 3 injections, I’ll have a low threshold to switch to one of the other VEGF inhibitors. I have a similar approach with DME [diabetic macular edema], although I still believe in what we saw in Protocol T, that there may be an incremental benefit from aflibercept when we’re dealing with patients with a lot more severe DME, 20/50 or worse off the bat. If they’re eligible and able to, I’ll try to get them aflibercept first. But that being said, my take-home point from Protocol T was that all 3 of the VEGF inhibitors work great. Otherwise, we’d be doing focal laser if we didn’t have the VEGF inhibitors, and they don’t do as well in terms of visual acuity gains.

Patient-specific factors are very important as we already alluded to with AMD. With DME it’s quite different, but first and most important, is the patient even bothered by their reduced vision, because that then plays a role in how motivated or willing is this patient to seek treatment and to continue treatment? I mentioned with our AMD population, I look for signs of a family or social support system around them. That will be critical to continue to keep this patient coming to their visits, getting their therapies, because injection fatigue is a real thing. We deal with it all the time with our patients. One year in, 2 years in, and they’ve really plateaued at that point or potentially, even degrading a little bit. It’s easy for them to want to quit. Having that support system around them is key, or as Joe said, getting them to buy in and training them to look at their own OCT [optical coherence tomography] images, so you share in those wins with them. That helps keep the patient engaged in their treatment. I look at their living situation, do they live alone, do they have a spouse, are they in a retirement community, are they relying on transportation to get to and from the office, what is their distance traveled to come into the office?

These types of things play a role, maybe not in our initial treatment plan, but in terms of how readily we’re willing to start extending a patient out. Because as we all know, at the end of the day, some of this is a compromise. We have patients who maybe look stable every 8 weeks, and they tell you, “Doctor, I can’t keep coming in this frequently. I want to go longer. I want to go to 10 weeks or 12 weeks,” even beyond. Some patients now they’re getting extended out to 4 months, 5 months, and this is the compromise, this is the art of medicine, honestly. And this is honestly part of the reason we’re seeing in the real world long-term visual acuity partly degrading. But from our standpoint on a day-to-day basis, it’s better that I get this patient treatment rather than them quitting coming to the office altogether.

Then finally, I definitely consider other medical comorbidities, how healthy, or potentially unhealthy is this patient. I think that’s very relevant for the type of patients we take care of who need injections. They either have diabetes, or if they’re at the state where they have diabetic retinopathy, they’re potentially very sick already. I worry about their cardiovascular health, neurovascular health, their kidneys. Then also, our patients with AMD are elderly, so they may also be subject to the same type of conditions, cardiovascular disease, age-related things with neurology, dementia, etc.

W. Lloyd Clark, MD: Joe, a question to you. What factors do you use to judge effectiveness of treatment with anti-VEGF agents? Obviously, we all lean heavily on OCT, but are there other clinical markers that you utilize? Are there specific things that you do with patients with diabetes versus other indications? How do you judge effectiveness with this class of therapy?

Joseph M. Coney, MD: Lloyd, that’s a very good question. The most important thing, first of all, is correct staging of individuals with diabetic retinopathy. The biggest risk factor patients have, that we have, is the baseline examination when they come in. I find a widefield angiogram is helpful in staging the disease of the eye. A lot of times, eyes may not look so bad. There may not be much microangiopathy, no swelling, good vision. But you do a widefield angiogram, and you’d be surprised by how much ischemic change you see in the periphery. This sometimes has led me to be a little bit more aggressive in these eyes, maybe follow them a little bit closer, and sometimes even start therapy when they don’t have any sight-threatening problems.

Now, when they have center-involved diabetic edema, obviously the OCT is my tool of choice, and I’m getting more familiar with OCTA [optical coherence tomography angiography]. It’s very helpful when I get eyes that don’t have the recovery in vision that we normally see. The patients we’re seeing who have poor vision, when they come in with 20/40, 20/50, or 20/60, when they become more symptomatic, we don’t know how long the swelling has been there. In this country, individuals with diabetes should be screened at the time of diagnosis, but unfortunately, they can have diabetes for several years because they’re not screened early enough. I do think that’s a main problem that we have. The United States Preventive Services Task Force will help in that category because they just decreased the screening age for prediabetics, or if someone has a family history of diabetes, from age 40 to 35.

By catching these eyes earlier, we may end up having longer vision by catching that earlier disease. If someone comes in at the severe nonproliferative state, we know that their risk of having diabetic edema could be as high as 51%. If they have had that disease for a long time, it could be irreparable vision loss. Looking at these scans helps me to figure out the health of the retina, looking at the photoreceptors, things that I can’t always get from a fluorescein angiogram. I really think you have to look at everything in total to get a great picture of what’s going on with that patient.

W. Lloyd Clark, MD: To our audience, thank you very much for watching this HCPLive® Peer Exchange. If you enjoyed this content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your inbox.

Transcript edited for clarity.