Dr Darius Moshfeghi Outlines the Impact of Delayed Treatment in ROP

Retinopathy of prematurity (ROP) that occurs in preterm babies can progress fast, which requires quick decisions early about treatment, explained Darius M. Moshfeghi, MD, chief, Retina Division, and professor at the Horngren Family Vitreoretinal Center, Byers Eye Institute, Department of Ophthalmology, Stanford University School of Medicine.

During an interview with The American Journal of Managed Care^® (AJMC^®), Moshfeghi discussed the conversations he has with families about the need for treatment, as well as the impact of delaying treatment.

In part 1 of his interview, Moshfeghi discussed the results of the BUTTERFLEYE trial and early identification of progressive disease that requires treatment

AJMC: Since you are treating very young, premature babies, what are the conversations with the parents like when you have to talk about the need for treatment and what their options are? How do or should those kinds of conversations go?

Moshfeghi: Oftentimes, when the examiner or the screener is at the bedside, the family isn't there and they get notification of the results by the nurse. The disease can progress relatively rapidly. I screen my babies by telemedicine, and we do a mandated screening interval, which is weekly or more often. Usually when we're doing bedside binocular indirect ophthalmoscopic examinations, we base the follow-up on findings. We say, “Well, you have this level of disease, we'll see you in 1 week. You have that level of disease, we'll see you in 2 weeks. And this third level of disease, we'll see you in 2 weeks. Or you got really bad disease, we'll see you in 3 days.”

What happens is, if the baby is really small, let's say 23-and-a-half weeks and has a birthweight of 450 grams, they can go from no disease to requiring treatment in a week. It often comes as a surprise to the parents that the baby had no disease and all of a sudden you're knocking on their door saying, “We want to treat your baby.” “When?” “Right now.” And that results in a lot of surprise and consternation on the family side, and also on the physician side that the family hasn’t been kept updated.

Usually, when I have baby that's getting sick, I reach out to them and document in the chart that I'm doing it. But oftentimes there's language barriers and the family is not there and the family doesn't answer. Or when they call back, you’re in the operating room and things like that happen. You really rely on the nursing team and the primary care pediatrician team in the hospital to help you communicate the findings with the family, so when it comes time to actually discussing what the treatment is, the families have concerns. “Will my baby feel pain? Will my baby end up losing vision or going blind? I don't know about the drug.” There is no approved drug in the United States, so everything that we do use is off label. “What does off label mean? What are the risks? Will I ever have to bring my baby back for another treatment? Will they have to be examined again?” They don't like the examinations, because they're stressful on the baby.

There's a lot of care and thought that has to go into how you're going to present this data to the family. There's another layer on top of that when the family does not speak English and you don't speak their language, because everything you say is going through an interpreter. Things get literally lost in translation. I tried to make it simple. Like when I do anti-VEGF therapy, I say, “Listen, this is a drug that usually works really well. The risks are largely related to the injection itself, meaning putting a needle into the eye increases the risk of cataract, retinal detachment if you hit the lens, or you hit the retina in the wrong spot. Or you create a hole in the eye and that predisposes to infection.”

Then the next problem is: Do you get all the drug into the eye? We're injecting miniscule doses and miniscule volumes of the drug into the eye. More often than not, if you don't get a therapeutic response, it's because the drug didn't get injected into the eye. Finally, you know, if the drug actually works and gets into the eye, what does that mean? Well, oftentimes, we'll get control of the disease relatively rapidly. But maybe it's only for a short while: a few weeks or 6 or 7 weeks. We call that early failure, and you get recurrence at that timeframe. You may have to inject again or do a more definitive treatment, such as laser.

Why do I call a laser more definitive? Typically, after 9 weeks after laser, it's not at all common for the disease to recur. The downside is it's associated with known, well-characterized adverse effects: decreased night vision, decreased peripheral vision, and very high myopia. We call high myopia minus 6; some of these babies can be minus 25 after laser. That's a substantial impairment of its own accord, and it's one of the reasons why—among many reasons—that we really want to go in and switch to anti-VEGF, particularly in the smallest, sickest babies, where the amount of laser that you put into the eye may cause too much damage to the eye. It might shut down the disease but result in what we call anterior segment ischemia. You win the battle and lose the war, as the eye shrinks and involutes from the amount of laser necessary to shut down the amount of disease that's present in the eye.

In addition, to be a great democratizer, if you will, anti-VEGF works really quickly, and takes some of those risks off the table. Does it add other risks? Yes, it does. The risks that I mentioned earlier: causing a cataract, causing a retinal detachment if you inject in the wrong spot, causing an infection. And then you have to be more aware that the disease is more likely to recur, and this is for all the anti-VEGF agents, and you have to be cognizant that you may have to bring the baby in at some later date when the baby's older and stronger, to potentially put in a more definitive treatment at that point, which may have less adverse effects at that point, because more of the retina may have grown, the baby’s bigger and less at risk.

The single biggest reason why I like anti-VEGF is that it offers us a treatment that's more likely to work in lower zones. It's kind of like a dartboard, where zone I is the bullseye, zone II is an outer ring, and zone III is the outermost rings. We treat disease in zone I and zone II. In America, those are where we treat the disease. Zone I tends to respond uniformly poorly to laser, whereas it has a pretty good result with anti-VEGF therapy, and so, anti-VEGF therapy, in addition to working in zone I, works really quickly. Within 24 to 48 hours, we'll get a therapeutic response. Whereas laser tends to take about 2 weeks to work. You can do a laser, but for the next 2 weeks, it can be getting worse. You really have to be on your therapeutic window when you're using laser.

AJMC: If treatment is delayed in ROP—whether from a delayed diagnosis or maybe the family takes a long time to decide how they want to move forward with treatment—how does the disease typically progress and affect children as they age?

Moshfeghi: That's the money question here. We're relying on old studies, and those old studies did not have access to anti-VEGF therapy. So, when you are using a treatment that takes anywhere from 7 to 14 days to demonstrate its efficacious response, in those studies, the recommendation was: From the moment that treatment-warranted disease was identified, you had 48 to 72 hours to go ahead and impact it. If you did not, anywhere from 50% to 75% of the patients that you recommended treatment on would go on to have an adverse outcome that was defined as retinal detachment or retrolenticular mass or a macular fold or dragging of the blood vessels. If any of those occurred, you'd end up with a functional outcome that was bad—basically, legally blind.

When we moved into the anti-VEGF trials, we had no predicate, meaning we don't know when the optimal time to intervene is. But we do know that you'll get a positive therapeutic response, often within 24 hours or usually no later than 48 hours. Those treatment responses were dragged over, meaning that we said we would recommend that the treatment occur within 48 hours of therapeutic treatment in response. And it's still widely believed that babies—anywhere from 50% to 75% of those infants—will progress to blindness once they meet type 1 disease or a ROP in that timeframe. You don't have a long time to sit around and make the decision.

It's very important not to put stress on the family. You can't come in there hot saying, “Your baby's going to go blind in 48 hours.” You have to gain trust and explain what's going on and have them feel empowered to make the decision. If they feel that they're under the stress that you're bringing, and everything is bang, bang, bang, it's not going to be conducive when you have to retreat the infant or the disease progresses. Because the treatment isn't always going to be 100% effective, and you'll have lost some credibility with the family if you haven't given them the opportunity to ask questions and have them answered. You should let them know that you're under the kind of window up to 24 hours and let them consult with their family members and their primary care and research it on Google and look it up and have multiple conversations. But let them know that it's a time-limited process.

That's why when I'm doing telemedicine, or when I'm actually screening in person, if I either have an infant that's very high risk—low birth weight, high gestation, multiple comorbidities—or I've seen that they're moving, and I have documented, as evidenced by photographs, I can show it to the family. And they can see, even though they don't understand what the disease level is, they can look at the photograph, and they can see that there's change occurring. Even the layperson can understand that change is occurring, and oftentimes, it's very dramatic. You can say, “This occurred over 24 hours,” and “This occurred over 48 or 72 hours.”

Even before a treatment event threshold has been surpassed, you can start having that conversation, and say, “Your baby doesn't meet this yet, but based on what I've seen and how fast this is changing, I think your baby is going to be high risk in 48 hours. In fact, when I look at that baby in 48 hours, don't be surprised that I'm going to come knocking on your door and say ‘I think we should treat your baby.’” And they're prepped at that point, maybe they already have some questions. It just makes it that much easier to kind of bring them to where the baby needs to be.

There are 3 opinions in this group: There's mine, there's the family’s, and then there's the baby’s. The baby isn't going to have an opinion until they reach the age of majority of 21 years, but they're definitely going to have an opinion at that point. I'm advocating both from my opinion and my fiduciary responsibility lies with the patient, which is the baby and what they're going to be thinking 21 years from now. I don't know, and it's very presumptuous of me to know that, but I have to make an educated guess for that opinion. Oftentimes, that's guided by, “I want to see” vs “I don't want to see, and I want to have multiple surgeries.” But you just don't know how that's going to play out.