Anti-VEGF Agent Safety


Nancy M. Holekamp, MD, and Carl Regillo, MD, FACS, discuss the safety aspects of anti-VEGF agents when treating age-related macular degeneration.

Karl Csaky, MD, PhD: Nancy, how about you? We have some relatively easy patients, who respond right away, and everybody is happy. We expect some patients to improve, in some cases significantly. You’re going along and all of a sudden, and they’re needing injections frequently, they’re not fully dry even after the 4 or 5 or 6 monthly injections. What’s the next approach for you? How do you have the discussions with the patient at that point? They’ve been seeing you every month, getting a shot. Can you tell us what you’re having to tell them and what you’re thinking at that point?

Nancy M. Holekamp, MD: If they don’t respond to anti-VEGF therapy, the first thing I do is, I go back and make sure I have the right diagnosis. Carl mentioned some masquerades like central serous choroidopathy, adult vitelliform macular dystrophy. These anti-VEGF agents are both therapeutic and diagnostic. If the patient responds, they have VEGF-mediated disease. I might check my diagnosis. But if I’m convinced it’s age-related macular degeneration, sometimes I will give an injection and see them back in 2 weeks to see if there’s a response, because if we see people at monthly intervals, we don’t know what’s happening in between those 2 visits. Occasionally we’ll see the maximal response at 2 or 3 weeks. By the time we see them again, they’re back where they started. That’s someone with a very high VEGF need, and that’s a person who may need monthly anti-VEGF injections in order to have the best result. We know those high VEGF-need patients are out there.

Karl, what you’re getting at is, if we go through this strict loading-dose phase of every-4-weeks dosing and we’re a little underwhelmed, as Jennifer [Lim] says, we continue for 5 or 6 additional doses and still have fluid. We know that is true for about 20% to 30% of our patients: we treat aggressively, and they might still have either intraretinal fluid or subretinal fluid. Back to what Lloyd was talking about, we might use a treat-and-extend or a maintenance program, so we maintain the visual gains; those are the tough patients. Those are the ones we have to think hard about in our clinics—how we’re going to manage patients and how frequently they need injections.

In my own clinic, subretinal fluid is less damaging to vision. At the end of the day, it’s about vision for patients, and intraretinal fluid is proving to be very damaging to vision. I treat intraretinal fluid to complete eradication if I can.

Karl Csaky, MD, PhD: Absolutely. Carl, you too, right? We have these problematic patients. Walk us through your approach as well, as well as the discussions, because many times it’s the children who are bringing the parents in, you’ve been sharing with them the OCTs [optical coherence tomography scans] as part of your dialogue with them as patients. Walk us through what Nancy was talking about, persistent subretinal fluid and what you’re thinking about those groups of patients where we just can’t get full resolution in some cases. You’re one of the experts on treat and extend. Share with us some of your thinking in regard to some persistent subretinal fluid.

Carl Regillo, MD, FACS: This has been a great discussion. The good news is that these are not common patients. These nonresponders are suboptimal responders. They aren’t rare, but as Nancy mentioned, in most clinical trials we can get complete or near-complete drying of the macula in 70%, 75% of our patients with the current drugs: off-label bevacizumab, on-label ranibizumab, aflibercept, and brolucizumab, which was recently FDA approved. All these drugs work well for the vast majority of patients. But as Lloyd pointed out, there are some subtle differences sometimes that may not be teased out in the normative data of clinical trials. In our own anecdotal experiences, there have been publications that point to differences in drying and differences in durability. That’s when we start to think about the switching that you alluded to and Nancy was referring to.

As Jennifer mentioned, starting off monthly injections, I’ll give 3, 4, or 5 treatments just like that. Nancy made a great point: if I’m seeing no response, is it a masquerade? Is it not wet AMD? Is it a vascularized pigment epithelial detachment? Vitelliform lesion, central serous? Those are the first things I think about. If it is, I may stop treatment and watch very closely. That’s usually 0 response, though. There hasn’t been a change in 4 or 5 monthly injections.

Nancy also mentioned bringing the patient back a little earlier. If you’re seeing a change in 2 weeks, then you probably have neovascular AMD [age-related macular degeneration], which has some benefit from an anti-VEGF. You’ve got to stay aggressive and stay the course. Nancy also mentioned subretinal fluid. A lot of these suboptimal responders are not suboptimal. They show persistent mild subretinal fluid. Those patients sometimes do very well. If they’re 20/30, I’ll start to extend some of those, and often it’s stable. If it starts to increase, I’ll bring it back.

You mentioned treat and extend. What the audience should know is treat and extend means treating at every visit with an intravitreal injection but varying the treatment interval based on a specific patient’s need, to keep the macula in the best possible shape. Dry ideally—that’s a good rule of thumb—but that’s not necessarily achievable in everybody or necessary in everybody. Now you have to decide, is this a tolerable amount of residual exudation, SRF [subretinal fluid]? It could be, and it might start to extend. As long as the vision is good, it’s not decreasing, the fluid is not changing, that might be actually acceptable. If we start to see intraretinal fluid come back, subretinal fluid increase, then I’m not going to extend, I’m going to start to retract and treat more frequently.

The bottom line is that most patients are going to need ongoing treatment, everyone is different, and it’s a trial-and-error process. We don’t know anything at baseline that accurately predicts the treatment intensity or how frequently we’re going to need these injections. It’s figured out over the course of 6 or 12 months typically, and that’s what I’ll tell our patients. We’ll figure it out as time goes on, but we have to play with that treatment interval and maybe switch drugs, for drugs that have a better drying effects and more durability after 3, 4, 5 injections if you’re not getting the goals of exudative control that you’re hoping for.

This transcript has been edited for clarity.

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