Issue: February 2021
Source: Healio Interviews
Disclosures: Cheung reports she is a consultant for Bayer, Novartis, Roche, Allergan, Boehringer Ingelheim, Topcon, Zeiss and Heidelberg Engineering. Eliott reports he is a consultant for Alcon, Aldeyra, Allergan, Dutch Ophthalmic, Genentech and Glaukos. Loewenstein reports she is a consultant for Allergan, Novartis, Bayer and Notal Vision. Roca reports he is a speaker for Alcon, Allergan, Sophia and Quantel Medical. Schmidt-Erfurth reports she is a consultant for Genentech/Roche, Novartis and Heidelberg Engineering.
February 16, 2021
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ASRS’ Global Trends survey shows growing homogeneity of retina treatment, part 1

Issue: February 2021
Source: Healio Interviews
Disclosures: Cheung reports she is a consultant for Bayer, Novartis, Roche, Allergan, Boehringer Ingelheim, Topcon, Zeiss and Heidelberg Engineering. Eliott reports he is a consultant for Alcon, Aldeyra, Allergan, Dutch Ophthalmic, Genentech and Glaukos. Loewenstein reports she is a consultant for Allergan, Novartis, Bayer and Notal Vision. Roca reports he is a speaker for Alcon, Allergan, Sophia and Quantel Medical. Schmidt-Erfurth reports she is a consultant for Genentech/Roche, Novartis and Heidelberg Engineering.
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The results of the 2020 Global Trends in Retina Survey reveal a world that is more interconnected and where interactions between groups and individuals in the ophthalmology community increasingly grow across global borders.

“Overall, what is most interesting about this survey is that the views and approaches of retina specialists in all regions of the world are fairly similar. We all read the literature; we all come to roughly the same conclusions; we communicate regularly via our meetings. It shows that people around the world are staying up to date with research and innovation, and make data-informed choices among options,” Dean Eliott, MD, chair of the American Society of Retina Specialists International Affairs Committee, said.

Dean Eliott, MD
Genetic testing for age-related macular degeneration is currently not supported by Medicare in terms of reimbursement, which may play a role in its limited use in the U.S., according to Dean Eliott, MD.

Source: Dean Eliott, MD

The ASRS has been conducting a Preferences and Trends (PAT) survey in the United States for more than two decades. The Global Trends survey, currently in its seventh year, is an extension of the original PAT survey, aimed at testing the opinions and practice patterns of retina specialists in four other regional groups: Asia-Pacific, Africa and Middle East, Central-South America and Europe.

“Our aim is to identify new and evolving therapies and surgical techniques, controversies, preferences and trends in retina and to help retina specialists know if they are practicing along the lines of their colleagues nationally and globally,” Eliott said.

Genetic testing

The first question in the 2020 survey investigated the breadth of use of commercial genetic testing for assessing the risk for age-related macular degeneration. Answers were fairly uniform across continents, with a large majority of respondents (89% to 99%) stating that they never order this test.

Gemmy Cheung, MD, FRCOphth, professor at National University of Singapore, was not surprised about this result and found it reassuring that the trend seems to be similar all over the world.

“This means that at the moment it is not very clear what is the value of doing such a test in our patients. However, the technology is emerging, so all of us need to learn how to apply it and understand how to counsel our patients about the results in the future,” she said.

Cheung looks forward to exploring the potential of this new area in the future but is aware that clinicians need the appropriate training.

Gemmy Cheung, MD, FRCOphth
Gemmy Cheung

“We need to learn more and maybe consider incorporating genetic counselors into our clinical services one day when there is proven benefit,” she said.

“I also currently do not order a genetic test for my patients,” Anat Loewenstein, MD, MHA, professor at Tel Aviv University, Israel, said. “There is not enough evidence to show that there is any difference genetic-wise in the management of patients with neovascular AMD with the treatments that we have nowadays. There may be a rationale for it in non-neovascular AMD since we know that variants in the CFH gene are associated with progression to geographic atrophy. So at present, some genetic variants can be included in clinical trials and probably will have a role in the future, but for now there is no proven treatment available for non-neovascular AMD, and understandably people see no point in using genetic testing in routine clinical care.”

In the debate about the role of genetic testing in prescribing AREDS supplements for non-neovascular AMD, Loewenstein agrees with the side that says there is no evidence supporting the need to check the genetic variant before prescribing supplements.

Anat Loewenstein, MD, MHA
Anat Loewenstein

“Data are not convincing, and genetic testing would not dissuade me from prescribing supplements that proved to be beneficial in big studies,” Ursula Schmidt-Erfurth, MD, PhD, professor at the Medical University of Vienna, Austria, said. “There is no point in relying more on genetic testing than on morphological biomarkers such as large drusen, RPE changes and hyperreflective foci that we can observe on OCT.”

She rather believes in artificial intelligence, on which her department is working extensively, as a more reliable method, capable of consistently identifying a wide range of retinal biomarkers for risk assessment and early diagnosis.

Genetic testing for AMD is not currently supported by Medicare in terms of reimbursement, and this may play a role in its limited usage in the U.S., according to Eliott. In Latin America it is not even available, José Antonio Roca, MD, professor at Cayetano Heredia Peruvian University in Lima, Peru, said.

“Samples have to be sent outside of our countries, so very few of us do genetic testing,” he said.

“It is a controversial topic,” Eliott said. “Some believe strongly that genetic testing has a role in evaluating and treating AMD patients, and others strongly believe that it has no place in our practice. My opinion is that it should play a role. We may or may not make specific treatment recommendations based on it, but the more information we have about our patients, the better. Genetic analysis of AMD patients at this time may prove to be valuable in future retrospective studies.”

Best agent for fluid resolution in AMD

The survey results showed that Eylea (aflibercept, Regeneron/Bayer) is by far and across continents the anti-VEGF agent with the highest reputation for fluid resolution in wet AMD, as well as the agent that physicians would choose to treat their own diabetic macular edema.

Ursula Schmidt-Erfurth, MD, PhD
Ursula Schmidt-Erfurth

“I do agree that Eylea is an excellent substance, definitely more durable and more efficient than Avastin (bevacizumab, Genentech/Roche) and equal to Lucentis (ranibizumab, Genentech/Novartis), in my opinion. Yet, Lucentis is more expensive in my country, so we most commonly use Eylea. The other option would be Beovu (brolucizumab, Novartis), but I don’t think that the difference in the comparison trial was very convincing, and Eylea comes with an excellent safety profile as well,” Schmidt-Erfurth said.

Previous surveys had shown that about 60% of retina specialists use Avastin as first line for financial and reimbursement reasons.

“This survey makes it clear that without these limitations Eylea would be first choice for most of us,” Loewenstein said. “Between 60% and 79% of respondents across continents feel that it delivers the best fluid resolution, and this is based for sure on the results of studies, such as the VIEW 1 and VIEW 2, but also on real-life experience. Whenever we switch poor responders to Eylea, they do better.”

Eylea is the most expensive drug in Latin America, and Roca hopes that in the future better reimbursement policies will be implemented to make it more largely available.

“In Latin America, we have a high prevalence of polypoidal choroidal vasculopathy, and Eylea has shown to be the most effective also in this subset of patients,” he said.

In the PLANET study, the Eylea monotherapy arm achieved almost 80% dry retinas after the first three injections in patients with polypoidal choroidal vasculopathy, Cheung said.

“We cannot compare across different studies. However, the proportion of patients with dry retina after initial loading with ranibizumab in the EVEREST study was less than 50%,” she said.

How would you treat your own DME?

In the U.S., like in all other regions, the majority of retina specialists would choose Eylea also for their own center-involved DME with decreased visual acuity.

“This really means they think it is the best drug. It has the best fluid resolution in most conditions. For myself, I would definitely choose Eylea as a treatment, and I treat most of my patients with Eylea,” Eliott said.

With no exceptions, the other four specialists interviewed for this article would choose Eylea for themselves.

“I would easily go for ranibizumab if I didn’t have aflibercept but wouldn’t start with bevacizumab if it were my own eye. In Israel, patients can only be reimbursed for bevacizumab because we are conducting a study on it, and it would be difficult to tell them that they need to pay out of pocket $1,500 per injection for 10 or 20 injections,” Loewenstein said.

In the survey, respondents also opted for prefilled syringes over vials, and a marked preference for prefilled syringes emerged in the U.S., Africa/Middle East and Europe.

“Prefilled syringes are even safer from the infection prevention standpoint, but I think that Eylea by vial is fine. Our university pharmacy prepares the individual doses on a daily basis, and we never had any infection,” Schmidt-Erfurth said.

Subretinal fluid controversy

Another question addressed the controversial topic of residual subretinal fluid (SRF) in patients with AMD treated with anti-VEGF. Specifically, respondents were asked how much recurrent SRF they would tolerate in a patient recently diagnosed with neovascular AMD on a treat-and-extend (T&E) protocol. While U.S. respondents were equally divided between those who would tolerate some SRF and would continue T&E and those who would not tolerate it and would reduce the treatment interval, respondents from other regions in various proportions showed preference for continuing T&E.

“We are learning that some SRF can be tolerated in wet AMD, acknowledging that it is not what we are aiming for. I think it depends on patient-specific factors. Some patients have areas of SRF extrafoveally that are difficult to treat, and it may be reasonable to keep them on a certain interval of injections, whereas in others the fluid continues to accumulate, and it would be better to shorten the interval and reduce the fluid. I recommend close monitoring and a case-by-case approach,” Eliott said.

Schmidt-Erfurth recommended a zero-tolerance approach to the presence of fluid in neovascular AMD.

“Subretinal fluid is pathological fluid; there’s no doubt about it. It does not destroy neurosensory retinal structures such as photoreceptors to the same extent as intraretinal fluid (IRF) does, but it is toxic and should be treated,” she said.

The FLUID study showed that patients treated with ranibizumab T&E in which some SRF was tolerated had visual acuity outcomes comparable to those achieved when SRF was resolved completely and with fewer injections. However, a new analysis of the study conducted by Schmidt-Erfurth’s group with the study authors highlighted some methodological weaknesses in the quantification of fluid.

“Central SRF height does not correlate with overall SRF volume; therefore, the actual quantity of SRF might be underrated. Other big studies such as HAWK and HARRIER have demonstrated that patients with recurrence of SRF are losing vision, not to the extent they do with IRF, but still significantly. There is clearly a functional benefit in treating SRF, so in a T&E protocol, I would definitely shorten the intervals,” she said.

Loewenstein said she would not tolerate large and growing quantities of SRF, but if it is stable and not approaching the fovea, she said she might “not chase it to the last drop.”

“Survey results reflect the many debates I was involved in, both in my country and abroad, and it seems that opinions are more or less equally split, depending on how you pose the question. I think that everyone will not tolerate extra foveal fluid if it increases significantly and approaches the fovea. But if it is stable, you can try to extend [the treatment interval] although there is SRF,” she said.

According to Cheung, it is important to emphasize that the question is about “recently diagnosed” AMD.

“The key word here is ‘tolerate.’ Given the choice, we would like to have a dry retina, but when we cannot get it, at which point do we give up and tolerate a little bit of subretinal fluid? I would personally still try hard within the first year to aim for as dry as possible. After 1 year, if there is persistent fluid, at least we have the data from the FLUID study that show us that in the short period, up to 2 years, a small amount of fluid causes no harm. However, a slightly wet retina would certainly not be my first goal. I would only tolerate it if the patient has had a good course of intensive therapy and still the retina is not dry from 1 year onward. I would rather not tolerate it in the first year,” she said.

Incidentally, she said that the cause-effect relationship between presence of fluid and geographic atrophy has never been demonstrated and is only a correlation.

PRP and anti-VEGF in PDR

The approach to managing a 30-year-old patient with type 1 diabetes with high-risk proliferative diabetic retinopathy (PDR), 20/20 visual acuity and no DME was significantly different between U.S. specialists and their colleagues abroad. In the U.S., the combination of anti-VEGF with panretinal photocoagulation (PRP) seems to be the dominant choice (40.5%), whereas most respondents in other regions more often use complete PRP in two or more sessions.

“Protocol S showed that PDR eyes treated with anti-VEGF are still doing quite well over 5 years, and it appears that this concept is particularly well taken up in the U.S., while in the rest of the world, PRP appears to be preferred,” Cheung said.

Compliance may be an issue in some countries more than others. The efficacy of anti-VEGF for PDR relies on regular follow-up, and in Asia overall, this is a problem, she said.

“The concern is that some patients may have one or two injections and not come back. I offer my patients both options, that anti-VEGF without immediate PRP is possible on the condition that they come back regularly and expect up to eight injections in the first year. A lot of patients choose PRP when they hear that,” she said.

The same applies in Latin America, according to Roca.

“Patients don’t come as frequently as needed to visit us in our offices. So, we prefer to do a treatment that is more long-lasting,” he said.

According to Loewenstein, there is no evidence of the benefits of combining anti-VEGF and PRP.

“I’m actually surprised by the large percentage of people who are doing combined therapy upfront because we don’t have sufficient data to support this combination,” she said.

Her approach, which reflects what is most commonly done in her country, is to offer both options to patients. If they are willing to comply with frequent follow-up and regular anti-VEGF injections, she considers suggesting anti-VEGF only, but if there are doubts about commitment to such a strict schedule, she goes for PRP.

“This is not saying that I will not combine anti-VEGF with PRP in case vascularization persists after PRP alone. But I would not plan the combination of the two treatments upfront,” Loewenstein said.

The 2020 survey results show that habits are changing in the U.S. and that an increasing number of surgeons are integrating anti-VEGF in their management of PDR.

“Looking at the U.S. data in the past, people were doing PRP, and now they do PRP plus injections. However, also in our country, access to care plays a role. Ipractice in a city and have patients with low economic resources and limited access to care who would not be able to come back for regular injections. The downside of PRP is small in comparison to the risk of anti-VEGF undertreatment, which is neovascular glaucoma, a very serious disease most often leading to blindness,” Eliott said.

Young patients with diabetes are at a higher risk for PDR and should be closely followed up, according to Schmidt-Erfurth.

“If no DME is present and vision is good, I would observe the patient closely with OCT, and I would do an OCTA to assess capillary dropout and the extent of ischemic areas. If there are large ischemic areas, I would do a PRP; otherwise, I would continue with observation. I would definitely not use anti-VEGF,” she said.

Anti-VEGF should be ruled out as a choice in her opinion because recent studies by the French group of Gaudric and Tadayoni have demonstrated that it has little more than a cosmetic effect. Despite what appeared as an improvement in DR severity on color photographs, fluorescein angiography showed that no vessel reperfusion occurred.

“There is a reduction in the number of microaneurysms and little hemorrhages but no actual benefit to the retinal vasculature,” she said.

Schmidt-Erfurth sees no added benefit in combining laser with anti-VEGF either.

“We are speaking of a young person, and I would not build my management on a lifelong injection therapy,” she said. “There is a lot of promotion for anti-VEGF therapy in PDR, particularly in the U.S., but it has not convinced me, as it has not convinced most Europeans, as I can see from the results of the survey.”

Editor’s note: The Global Trends in Retina survey is accessible online at https://www.asrs.org/sections/international/global-trends-in-retina.

Click here to read the Point/Counter to this Cover Story.