Cases From the Real World: 64-Year-Old Man With Moderate NPDR

Dr. Talcott: 
I have a 64-year-old man with moderate NPDR who was unfortunately lost to follow-up. Hear how I treated him and how his case may have gone differently with new treatment options. This is CME on ReachMD. I'm Katherine Talcott, and I'm so happy to be joined today by Dr. Durga Borkar. 

 Dr. Borkar: 
Thanks for having me. Tell me about your case? What happened? 

Dr. Talcott: 
Yeah, so this is a 64-year-old man. He has moderate NPDR in the right eye. Unfortunately, had trauma in the left eye when he was a child, and he actually got his left eye enucleated 16 years ago due to a painful blind eye. So we've been following him for the right eye. His last A1c was 8.5. He's had multiple injections over a 5-year period for diabetic macular edema, including aflibercept, 2 mg — 12 of those. Unfortunately, over the course of his treatment, he's really had a lot of unintended lapses in ophthalmic care. His past medical history is notable for hypertension, hyperlipidemia, and heart failure. 

So here's an OCT, sort of showing him at where he's been recently in his right eye. He presents for follow-up 6 weeks after his last aflibercept injection. This was 2 mg, and his vision was 20/30, and you can see on the OCT that he's got significant center-involving diabetic macular edema. He was supposed to return 4 to 6 weeks later, but unfortunately, he returned 9 months later. His mother had been in hospice, and he's been just having a lot of challenges managing everything that's going on in his life.

So he comes back. His OCT shows more intraretinal fluid than there was previously. His vision declined slightly to 20/40 and he was restarted on aflibercept 2 mg. He comes back 4 weeks later. He still has persistent fluid on the OCT, but it does look improved slightly compared to the last one, and his vision improved to 20/30. Unfortunately, we wanted him to come back 4 weeks later, but he came back 8 weeks later. His vision is stable, and the OCT is really unchanged from the last one. Intraretinal fluid maybe looks a little bit worse. 

So Durga, I was just hoping to get your sort of thoughts on this case. This is I think a patient who is not unlike a number of patients I sort of take care of in my practice, and I'm sure that you do too, where, although we want to see people regularly and do injections regularly, he's unfortunately had multiple unintended delays in his care. I'm sort of wondering what you would do at this state. Would you keep him on the same medicine? Would you consider switching him to a different medicine? And if you were going to switch, would it be an anti-VEGF medicine, or would you think about a steroid injection? 

Dr. Borkar: 
Yeah, these are good questions. I agree with you. This is not dissimilar to a lot of patients that I see in my practice with multiple unintended treatment lapses. It is hard to tell what he might look like 2, 3, 4 weeks after aflibercept 2 mg. Maybe the drug is working, but it's not quite durable enough, so it becomes a treatment decision then whether you'd consider aflibercept 8 mg or faricimab. I’d like to give him a chance. I mean, he does need a more durable agent. I’d potentially try to switch to aflibercept 8 mg. I think steroids are a great idea for many patients that have an OCT that looks like this with that large central cyst. A lot of times, there are a lot of inflammatory cytokines in the eye that respond really well to steroids.                                                                                                                           

I think a couple things make me a little bit nervous about that. If I give him a dexamethasone implant, and then he doesn't come back and has pressure issues, that could be problematic. And if he's phakic, then we do need to talk to him about cataracts. And he's monocular, he may be a little more hesitant for surgery. So I might consider aflibercept 8 mg or faricimab as a next step rather than steroids in this case. 

Dr. Talcott: 
Yeah, I think these situations end up being tricky. We want to get these patients sort of the best vision that they can, but when there's sort of these gaps in care, which totally understandable, these patients have a lot of things, often appointments to sort of balance with, it's hard to. And I think steroids can be really good options for these cases, but I do worry if we're not going to see someone, of those things as well. 

For this patient, we had actually been thinking about potentially switching him over to aflibercept 8 mg over the past few visits, because maybe, although we can't always sort of control if patients having lapses in care, maybe an agent with more drying or durability would allow him to be sort of stretched out a little longer, or if we didn't see him, he would at least be covered during that time. 

So we had gotten approval at one of the prior visits, and then we actually switched him over at this point to aflibercept 8 mg. So this is just 4 weeks later. The vision has not changed. It's still 20/30, but the intraretinal fluid is looking a little bit better.

So I was just sort of curious to hear your thoughts because I think a lot of us, and I certainly do this, when I was integrating some of these second-generations into my practice, I would often first switch over my sort of recalcitrant patients, rather than starting just like on treatment-naïve patients. So if you are going to switch over, do you load those patients? Do you inject them sort of every 4 weeks to start? And sort of, what are your markers for success? Are you looking for the fluid to sort of go away? Do you keep the interval the same before you stretch it out? What's your approach? 

Dr. Borkar:  
Yeah, great question. I think for the loading doses, the short answer is, it sort of depends. So I think if I'm switching them primarily for durability, so say their disease is well controlled, but we'd like to get beyond your q6, q7 week injections, then I may not load them, actually. And I think the reason for that is twofold, especially if going from aflibercept 2 mg to aflibercept 8 mg, I know that the drug itself works for the patient, and we're trying to get a few extra weeks, potentially more than a few extra weeks, if we can. And then I also think from the patient perspective, they are really looking for a switch in a lot of these cases in order to have less injections. So the idea of going from q6 or q7 or q8 week treatment back to q4 often feels like a step backward for them. So oftentimes, they're not on board. In this case, I think we're switching both for efficacy and durability. The disease is not well controlled and so I would definitely load in this case. 

In terms of markers for success, at the end of the loading phase, I'd love to see that those central cysts, that intraretinal fluid, is much better controlled, and that we have an opportunity to extend out. How much? I don't necessarily tell the patient an amount, because that is actually very difficult to predict.                                                                                                                                                                                            

Dr. Talcott:  
Yeah, I think those are really good points. In general, I totally agree with you. When I switch patients over. If we're switching patients over to a different medicine, especially if it's aflibercept 2 mg to 8 mg, it's hard to explain that this medicine is going to be better for them if you're asking them to go from like every 8 weeks to every 4 weeks. It's a little harder to sort of get buy-in and it would be different, I think, if you were switching between different medicines, like aflibercept to like faricimab, it would be different.  

This is a little bit, as you mentioned, of a different situation because we want to sort of get him as dry as possible so we can see what his potential, like visual potential is, before we would extend him out. So, we're trying to see him like every 4 weeks at the beginning, so loading makes sense here. 

But I agree, I think it depends on sort of different patients in front of you. And it's a little hard. I don't know how you feel, but I think it's a little hard to know what to do just based on the clinical trials in these patients, because, the clinical trials for aflibercept 8 mg and faricimab didn't focus on patients who had already gotten treatment. So it's a little different to apply this to patients who we're treating for recalcitrant fluid or for the durability. 

For those just tuning in, you're listening to CME on ReachMD. I'm Dr. Katherine Talcott, and here with me today is Dr. Durga Borkar. We're discussing real-world use of second-generation retinal treatments in patients with diabetic macular edema. 

So we switched this patient over to aflibercept 8 mg. So, unfortunately, although we wanted the patient to come back at 4 weeks, they actually returned at 12 weeks. You can see on the OCT here they had persistent fluid that was there, but the vision actually stayed stable at 20/30. Unfortunately, then they returned 4 months later. Actually, the vision got better, and the OCT actually showed improved fluid. And then they returned 2 months later. The vision actually here is 20/20, and now they’ve had a total of 4 injections of the aflibercept 8 mg. 

So, Durga, I was hoping to get your input on this. Should we consider agents with improved drying and durability earlier in patients who have lost to follow-up? How about monocular patients? And should we think about port delivery system for these patients? 

Dr. Borkar: 
Yeah, these are great questions. I think improved drying and durability earlier in the treatment course is important, not just for patients who are lost to follow-up. So I think for all of our DME patients, there is a sense of, hey, we'll try things and go through step therapy. But there are data to suggest that once patients have had quite a bit of fluid, exudates that are just sitting there, even once you've controlled the macular edema, their vision doesn't quite recover back to 20/25, 20/20, so it is better to try to get it right earlier on. 

And then, certainly when they're lost to follow-up, that becomes a little harder to do, because it's harder to assess treatment responses because they're not coming back. But the drug is working, we just didn't see that soon enough. Or are we using agents that maybe are not as effective? 

And I think the port delivery system, in theory, is a great idea for this patient,  particularly because one of the things — we're focused on diabetic macular edema here, but in these cases, the peripheral retinopathy can progress to quite a bit if the patient's not receiving consistent treatment. And with something like port delivery system, there is an opportunity to also control that peripheral retinopathy, which,  PAGODA showed as well. 

And so I think it is a good idea. I think a couple things might make me a little bit nervous about this patient. He's monocular. He doesn't come back necessarily for regular appointments because of, as you mentioned, just life things that come up. So putting in an implant in his eye might make me a little bit nervous, but from a disease control perspective, I think this would be perfect for him. 

Dr. Talcott:  
Yeah, I agree. It's hard with port delivery system for these patients. Because in some ways, the reasons that it's so attractive is that if patients get lost to follow-up, they still have that anti-VEGF delivery, is attractive. At the same time, if they have those lapses in care, you just worry, if there's a complication, are you going to catch it at an early stage where you can still intervene, like making sure the implant's covered, that there's no erosion, that sort of thing. 

Well, thanks so much for your comments on that case. I really appreciated it, and learned a lot from you.  

So I just wanted to spend a few minutes just sort of going over some of the issues that we talked about. As Durga mentioned, and sort of this case highlighted, patients with diabetic retinopathy, unfortunately, have multiple barriers to care. These patients can have other medical problems as well. They often have a whole host of medical appointments that they need to tend to, and these patients often tend to be sort of working age. 

There's been a lot of work done by Dr. Hsu and his group at Wills, sort of looking at lapses of care and showing that this is not uncommon in patients with diabetic macular edema. They actually did a study looking at how many patients with DME were lost to follow-up, meaning that they didn’t have any office visits for 12 months following an injection. And they actually found this to be the case in 25% of patients. Risk factors included race as well as adjusted gross income. 

Interestingly though, when they followed these patients who had lapses in diabetic macular edema, and they looked at patients who had a lapse of at least 6 months after injections. Although the vision declined after the lapse, there was actually no significant change in vision at 3 months, 6 months, or 12 months like at the final follow-up, suggesting that there actually might be opportunities for us still, even though they have declining vision after a lapse, to recover some vision, which is a good sign.

And actually, in clinical trials, including DRCR Protocol S, they looked at what's the incidence of having a long lapse in care, which is at least 8 weeks. And interestingly, they found that in that study, over 55% of patients had at least one or more long lapse in care, which I think is really surprising. Because, in a study such as this, they have a research coordinator who's constantly checking in with patients. It's very easy for patients to get in, and patients, in general, in clinical trials, I think, are less likely to have a lapse in care. So you can see it in studies like this, the risk is very real. 

Sort of longer-acting medicines, and with more drying and durability, might be able to help with this. Aflibercept 8 mg was studied in PHOTON and had noninferior visual acuity gains, although patients who were getting aflibercept 8 mg every 12 and 16 weeks got fewer injections. 

The PHOTON extension study then showed how people did in year 3 following the initial study, and patients on 2 mg every 8 weeks of aflibercept were then switched over to 8 mg and allowed to go longer. In this extension study, patients were able to be shortened, their interval, or extended. They could go as short as every 8 weeks, or they could go as long as every 24 weeks. And despite these patients really being extended out in the extension study, they were able to maintain their visual acuity gains that they had in the earlier part of the study, even those who were switched from 2 mg to 8 mg, as well as maintain good control on their OCT of the intraretinal and subretinal fluid that was present. And actually, at the end of this extension study, patients were really able to be extended out, with almost 50% of them able to go every 20 weeks.  

There’s been some early real-world studies also looking at how retina specialists have integrated aflibercept 8 mg into their practice, both looking at the IRIS Registry and the Vestrum database. 

Here’s some work that’s been done looking at patients who did not receive any treatment before. And in the initial loading dose phase in IRIS and Vestrum, patients had an average of 41 and 42 days in between their injections, but after the dosing phases, were able to be extended out to a mean of 77 and 75 days. Most of these patients who had previously been treated were switched from 2 mg to 8 mg. And those patients who were able to be switched, they found that there was an injection interval extension at about 3 to 4 weeks when they were switched to aflibercept 8 mg, if they were people who were getting a lot of injections beforehand. So on the interval of every 4 to 6 weeks. If patients weren’t requiring as many injections before — if their preinterval injection interval was 6 to 8 weeks, they were typically able to be extended 2 to 3 weeks following. 

So in summary, as we know, lapses in the care of patients with diabetic macular edema is not uncommon, but agents with improved drying and durability, or we could consider using the port delivery system to be able to reduce treatment burden for these patients. But it needs to be balanced with the need for appropriate monitoring as well as being able to get insurance approval for these injections. 

Well, that’s all the time we have for today. Thank you so much to our audience for joining us, and thank you so much, Durga, for joining me today. 

Dr. Borkar: 
Thanks for having me.