NEW PARADIGMS IN DME DIAGNOSIS AND MANAGEMENT · NEW PARADIGMS IN DME DIAGNOSIS AND MANAGEMENT 6 SUPPLEMENT TO RETINA TODAY MAY/JUNE 2015 Prof. Soubrane: If nothing shows up on biomicros-copy,

Supplement to May/June 2015

A roundtable discussion among retina experts that includes treatment options and management strategies for diabetic retinopathy

and diabetic macular edema in their respective countries.

DME DIAGNOSIS AND MANAGEMENT

NEW PARADIGMS IN

Supported via advertising by Allergan and Carl Zeiss Meditec

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Educational program developed in collaboration with:

Find and register for an upcoming meeting near you at www.DMe2020.com Diabetic macular edema (DME) is the leading cause of visual impairment in the diabetic population.

By 2020, more than 42 million people will be living with diabetes in the US. Given these alarming statistics, understanding the complex mechanisms of DME and the clinical implications is critical.

PrOGrAM eDUCATiOnAl ObJeCTives Gain understanding of diabetes mellitus and the effects of

systemic disease

Gain insights into the effects of diabetes on retinal and vascular components of the eye

Learn about the emerging understanding of the multifactorial pathophysiology of DME and potential clinical implications

Quan Dong nguyen, MD, MscProgram Chair, University of Nebraska Medical Center

nicola Abate, MD The University of Texas Medical Branch

Jay Ambati, MDUniversity of Kentucky

David s. boyer, MDRetina-Vitreous Associates Medical Group

Diana v. Do, MDUniversity of Nebraska Medical Center

Pravin Dugel, MDRetinal Consultants of Arizona

seenu Hariprasad, MDUniversity of Chicago Medicine

Untitled-1 1 5/1/15 3:35 PM

NEW PARADIGMS IN DME DIAGNOSIS AND MANAGEMENT

MAY/JUNE 2015 SUPPLEMENT TO RETINA TODAY 3

As rates of diabetes are projected to rise in coming years, so will the increasing number

of patients with ocular complications from diabetes. Retina Today convened a panel of

world-renowned experts to discuss the treatment options and management strategies of

diabetic retinopathy and diabetic macular edema in their respective countries.

DME DIAGNOSIS AND MANAGEMENT

NEW PARADIGMS IN

PANELISTS:

Rishi P. Singh, MD, ModeratorDr. Rishi is Staff Physician at Cole Eye Institute and Medical Director of the Clinical Systems Office at The Cleveland Clinic. He is also Assistant Professor of Ophthalmology at Case Western University in Cleveland, Ohio. He serves as a consultant for Alcon, Bayer, Genentech, Regeneron, Shire, and Thrombogenics. Dr. Singh may be reached at [email protected].

Paolo Lanzetta, MD, is an Associate Professor in the Department of Ophthalmology at the University of Udine, Italy. He reports having a financial relationship with Alcon, Alimera, Allergan, Bausch + Lomb, Bayer, Genentech, Lutronic, Novartis, Roche, and Teva. Dr. Lanzetta may be reached at [email protected].

Anat Loewenstein, MD, is Director of the Department of Ophthalmology at Tel-Aviv Medical Center, and a Professor and Vice Dean of the Sackler School of Medicine at Tel-Aviv University, Israel. She reports having a financial relationship with Allergan, Alcon, Bayer, Lumenis, NotalVision, and Novartis. Dr. Loewenstein may be reached at [email protected].

Edoardo Midena, MD, PhD, is Professor and Chairman of the Department of Ophthalmology at University of Padova in Italy. He reports no financial interests. Dr. Midena may be reached at [email protected].

Gisèle Soubrane, MD, PhD, is Professor and Chair In Ophthalmology at the Eye University Clinic of Créteil in France. She reports having a financial relationship with Allergan, Bayer, Biocodex, and Théa. Dr. Soubrane may be reached at [email protected].


4 SUPPLEMENT TO RETINA TODAY MAY/JUNE 2015

A Roundtable Discussion onNew Paradigms in DME Diagnosis and Management

Dr. Singh: To begin, let us discuss diabetic patients in your region. How do diabetic patients get to you as a specialist in your region?

Prof. Midena: At our clinic in Italy, we see patients after a telemedicine screening. Most of that occurs in the diabetes clinics, so patients are not attending our clinics for naïve evaluation. They are already pre-screened for DR, which, of course, means they need immediate treatment.

Prof. Soubrane: At my hospital in France, we have a special unit called diabetic ophthalmology. The endo-crinology department refers all patients (diabetic or sus-pected diabetics) to that unit where they will be seen on a regular basis, depending on their initial presenting state of retinopathy.

Prof. Loewenstein: In Israel, we have a combination of telemedicine and direct retinal examinations. There is a great system of primary care physicians who are all fel-lowship trained, and they know they need to screen the patients. These patients are usually fairly well controlled systemically, know their A1c level and they are informed about treatments. But we also have a growing popula-tion of immigrants, mainly from Russia and Ethiopia, who present with extremely poor vision and advanced disease. So, we address the combination.

Prof. Lanzetta: In Udine, patients are either referred by general ophthalmologists or by a diabetologist in the medical department. Similar to what Prof. Loewenstein discussed with her first patient group, we are rela-tively lucky because we usually see very well-controlled

According to the International Diabetes Federation, there are cur-rently 387 million people living with diabetes (a preva-lence rate of 8.3%), and this figure is expected to top 590 million by 2035.1 Europe has the highest prevalence of type 1 diabetes in children.1 The prevalence of diabetes is slightly lower than the world-wide figures, at 7.9%.

The World Health Organization now counts dia-betes among the top 10 causes of death worldwide, respon-sible for 1.7 million deaths in 2012 (up from 1.0 million in 2000).2 The numbers are just as dire when it comes to the ophthalmic complications of diabetes—there are about 93 million people with diabetic retinopathy (DR), 17 mil-lion with proliferative DR, 21 million with diabetic macular edema (DME), and 28 million with vision-threatening DR.3

It is clear that retina specialists around the world will

continue to see increasing numbers of patients with ocu-lar complications from diabetes. Retina Today convened a panel of world-renowned experts to discuss the treat-ment options and management strategies of DR and DME in their respective countries. Here is what they had to say.

−Rishi P. Singh, MD

Source: International Diabetes Federation. Reprinted with permission.



patients. Additionally, we have started a pilot project to screen for DR with the aim of increasing awareness of this condition among diabetic patients and decreasing the rate of severe cases.

Dr. Singh: It sounds as though a subset of patients are aware of their diabetes diagnosis and what is needed to manage it. But how much awareness is there of their diabetic eye disease in these patient populations?

Prof. Soubrane: In France, there are patient associations for a number of diseases, which educate them on diabetes or diabetic complications, including diabetic eye dis-ease. But a more challenging issue is that not all the diabetic patients belong to these associations. Some of the younger patients with type 1 diabetes and some newly diagnosed adult patients are not as aware, depending on the information provided by their general practitioner or diabetologist.

Prof. Loewenstein: In Israel, most patients are very much aware of their diabetic eye disease. The physicians make it their business to know that patients need to get their systemic disease and their diabetic eye disease under control. Physicians are incentivized to refer diabetic patients to an ophthalmologist, because it is a parameter considered in the quality-of-care evaluation. So, patients are very aware they need to have their eyes examined regularly.

Prof. Midena: The amount of awareness depends on the patient, and I think this will change over time. Right now, health care professionals in a diabetic clinic are fol-lowing about 50% of the diabetic population, so they are being educated about eye disease. But in our healthcare system, the general practitioner will have a major role in the future diagnosis and treatment of diabetes. I expect the number of patients who are aware of diabetic eye disease will be reduced in the upcoming years if general practitioners are not aware of the importance of patient education.

Prof. Lanzetta: In my region, the majority of the diabetic population is unaware of very specific details of ocular complications like DR. However, they are well aware that if they can better manage their diabetes over-all, they may reduce their complications in general.

Dr. Singh: We have a lot of diagnostic tools in our armamentarium. Do you routinely run angiography

on your patients? Do you perform optical coherence tomography (OCT) on all your patients when they present for diabetic eye evaluations? What other diag-nostic tests and tools do you typically use during the initial evaluation?

Prof. Loewenstein: We know that DME occurs very rarely, unless the patient has at least moderate non-proliferative diabetic retinopathy (NPDR). If I do not see signs of DR when I see a patient, or if it is really very mild retinopathy (less than 5 microaneurysms), I would not do an OCT if I do not see a thickened retina on clini-cal exam (Figure 1). But if I see any signs, even if I am not convinced there is retinal thickening, I would do an OCT because it is more sensitive than my eye. So, if the patient presents with more than mild NPDR, I do an OCT. I do not use fluorescein angiography (FA) unless I think that the patient needs treatment.

Prof. Soubrane: In adult patients, we typically perform FA and get an OCT initially in order to have a baseline document. After 5 to 10 years of active systemic disease, or if abnormalities are observed on a biomicroscopy exam in young and adult patients, we will always take another OCT. If we are considering treatment, we take another FA then as well.

Dr. Singh: So, duration of diabetes is more important than classification of the patient’s DR state.

Prof. Soubrane: I think that it is a good cut-off. Not in every case, but as a general rule of thumb.

Prof. Loewenstein: Do you do an OCT even if the patient has nothing?

Figure 1. Example of very mild edema for laser or for observation.



Prof. Soubrane: If nothing shows up on biomicros-copy, I do not do an OCT. There has to be some progres-sion of disease first.

Prof. Midena: Most of our patients are referred to us after already being diagnosed with retinopathy, so we check everyone with OCT. FA is limited to patients with DME; we perform FA at baseline to determine treatment plans for those with DME and to see what—if any—involvement there is in the periphery. But if there is no sign of DR, we will not use FA.

Prof. Lanzetta: FA is not part of our routine diagnos-tic workup, unless the patient has proliferative disease or we need it to confirm DME progression. For us, our standard evaluation and monitoring regimen includes a visual acuity exam and an OCT (even if the patient does not have major signs of DR). I believe OCT should be part of our standard work-up screening program.

Dr. Singh: What about ultra-widefield FA? Where do you see its role in your patients right now?

Prof. Midena: The use of widefield FA is an advantage because it is easier for a clinician to perform. Even in the past, we were checking the periphery of the retina. We never limited FA to the posterior pole, even as far back as 20 years ago. But the advantage of widefield FA is that just one shot will encompass the entire retina, including the periphery.

Prof. Soubrane: Examining the periphery with ultra-widefield imaging is an interesting concept—it is easy, and it provides us with more documentation. But if ultra widefield imaging is not available, at the mini-mum, clinicians should be performing biomicroscopy. More and more patients are being followed for their macular edema on OCT, but only taking into account the posterior pole and neglecting the periphery until there are symptoms. It is more and more of a trend that we presently do not pay enough attention to the peripheral ischemia.

Prof. Loewenstein: Because I examine the patients carefully, and I always look at the periphery, I know wide-field photography gives beautiful images. But remember that also, even in the EDTRS, we just did the panretinal photocoagulation (PRP) up to the equator, so we did not reach the far periphery, and it still worked. I think as of right now, we do not have enough evidence-based data to determine if widefield imaging is really crucial in the treatment of the patients. It is nice to have the addi-

tional information, but I do not know if it would influ-ence me in my treatment decisions.

Prof. Lanzetta: The idea of checking the far periphery in DR in search of retinal ischemia or new vessels has been widely accepted in Europe for years now, even in times when widefield angiography was not available. This has been taught for years by well-known experts such as Prof. Brancato and Prof. Coscas. We have been carefully checking the periphery for years. As a consequence, I do not think of widefield angiography as a “must-have” instrument, but I do like the idea that with one image you can see the whole retina, including the periphery.

Prof. Soubrane: To recognize retinal ischemia clini-cally, you need proper training, but not all ophthalmolo-gists are so specialized.

Dr. Singh: Generally speaking, what are your treat-ment algorithms for a patient with DME?

Prof. Midena: That is a very complicated story. There are probably too many algorithms for the treatment of DME. I have a personal view, but this is very personal and limited: I think about DME as a retinal disorder with different retinal (local) phenotypes. And fundus biomi-croscopy is not the right way to differentiate them. So we need at least spectral domain OCT, analyzed in detail, not limited to central retinal thickness. There are differ-ent growing hypotheses now: VEGF is prevalent, but it is not the only driver of DME. The studies are showing a higher rate of nonresponders compared with patients who have age-related macular degeneration. We are now checking patients to differentiate if there is more inflam-mation or more VEGF.

Dr. Singh: Everyone here agrees that VEGF is not the only mediator of this disease state. So, how do you approach the patient?

Prof. Midena: I use the OCT to determine if there is more inflammation, and if so, I do not treat with an anti-VEGF.

Dr. Singh: What are the situations where you do not treat with an anti-VEGF?

Prof. Midena: We do not think VEGF is the most prevalent mechanism of DME in an individual patient. If we believe patients have more retinal inflammation, our first line of therapy is corticosteroid or a combined treat-ment, mainly if the patient is pseudophakic.



Prof. Loewenstein: I usually start with an anti-VEGF and, unless a specific patient cannot come for frequent, monthly dosing for those first few months. If I do not see any improvement, I usually do not wait the 6 months suggested in the DRCR.net Protocol I.4 If I see that there is no response after 3 months, I may switch to another anti-VEGF, but I would tend to immediately prescribe a steroid. And we get very good results using this strategy.

Prof. Soubrane: If we find a serous retinal detachment on OCT, it would be a good sign to prescribe a steroid.

Dr. Singh: Serous retinal detachment on the OCT is an indicator that VEGFs are present. There is much more inflammatory stimulus than you would see with use of a corticosteroid.

Prof. Soubrane: A retinal serous detachment is a sign of rupture of the outer retinal barrier. This breakdown is not VEGF-dependent and suggests inflammatory players. Improved glycemic and systemic hypertension control is, therefore, a part of our treatment.

Prof. Lanzetta: This year at the Macula Society meet-

ing,5 an interesting presentation showed that the addition of personalized education and risk assessment during retinal ophthalmology visits do not result in improved diabetes control. However, during my first visit with dia-betic patients, I still extensively discuss the role of optimal disease control with the aim to limit DR progression. In selected patients with DME with very good visual acuity and minor thickening at OCT, I may consider observation at first, trying to improve metabolic control.

Dr. Singh: Would you summarize that presentation?

Prof. Loewenstein: Basically, Protocol M from the DRCR.net looked at the influence of the ophthalmolo-gists to educate the patient on the control of the disease. And unfortunately, the ophthalmologist’s education was not very helpful. And it did not cause any difference in patients’ blood control or their glucose control.

Prof. Lanzetta: There were a number of questions from that presentation that need to be answered. One must ask why ophthalmologists are less efficacious in guiding the patient toward a better management of diabetes compared with diabetologists. In other words, which instruments should we use to “convince” our patients on the importance of improving their A1c levels?

Dr. Singh: My presentation at the Macula Society meeting was a post hoc analysis of the RISE and RIDE studies with regard to the treatment response of patients with anti-VEGF therapy in light of their base-line factors.6 The study demonstrated that there was no difference in patients within the trial, with no change noted in hemoglobin A1c from the time they entered the trial until the end. So, 2 years later, after all the intervention, they did not realize any difference in their A1c values.

Prof. Lanzetta: We are also learning that A1c, renal function, or blood pressure do not influence visual improvement after anti-VEGF treatment. This is different from the common observation that patients with most difficult to control disease have worse outcomes after laser treatment.

Prof. Midena: At a certain point in DME, more advanced retinopathy appears in the patient, which this is not really related to the patient’s general situation. There are a lot of hard exudates all around the posterior pole, or perhaps numerous cotton-wool spots. At this point, none of our treatments is effective.

Prof. Soubrane: Ophthalmologists need to intervene much, much earlier. By the time the patient presents with DME or proliferative DR, it is already too late. In our department, the waiting room chatter among patients with various levels of DR is what clicks for those with milder disease. They hear how much worse their vision can become and start to realize that systemic control of their disease is necessary.

Dr. Singh: Your first-line treatment for patients is anti-VEGF therapy, and you would consider anti-VEGF in patients with serous retinal detachment and pseudo-phakia. Are there any situations in which anti-VEGFs are not your first-line therapy? For example, how would you treat a patient with clinically significant DME but did not involve the fovea?

Prof. Lanzetta: I am not fully convinced that anti-VEGF is the first-line therapy in patients with diabetes now that we have dexamethasone implant 0.7 mg (Ozurdex, Allergan) approval.

Prof. Midena: I agree—it depends on the population.

Prof. Lanzetta: To be honest, I do not know what is first-line therapy. I use both approaches. There are advantages and disadvantages to both treatments.



Dr. Singh: Do you have the fluocinolone implant (Iluvien, Alimera) approved in your countries? In the US, it is approved for treatment of DME in patients who have been previously treated with a course of corticoste-roids and did not have a clinically significant rise in intra-ocular pressure (IOP).7

Prof. Midena: I do not think that Iluvein is a good option for patients because it is coming from purely pre-specified analysis.8 The 3-year cut-off is theoretical. I have asked different clinicians presenting these data how one can be sure about the duration of DME. In the UK, where there is a 1- or 2-year screening process in all diabetic patients, they know the duration of disease. But in most of the other countries, we do not. We do not know the duration before presentation.

Prof. Soubrane: In France, there is strict record-keep-ing about the exams, so physicians will know within a certain time frame when the DME began.

Prof. Lanzetta: The problem is what we see in clinical trials does not really correspond to what we obtain in real-life scenarios. If you look at the RISE and RIDE trials,9 36 months of continuous monthly anti-VEGF injections result in the best outcomes in terms of 3-line or more improvement in visual acuity. Although this is remarkable, few clinics may have the capacity to inject on a monthly basis for 3 years. Real-life management is a different story, with fewer injections and visits. Therefore, outcomes are usually less favorable. The possibility to use a long-lasting drug such as the dexamethasone implant 0.7 mg may allow fewer injections still with reasonable outcomes.

Dr. Singh: Are you finding your therapy outcomes haven’t matched what they’ve found in the studies or that you need to inject more frequently to continue the outcomes? In other words, how are your real-life expecta-tions/experiences differing from the clinical study results?

Prof. Loewenstein: We know that we have to inject more frequently than was done in all the Ozurdex clinical trials. Ozurdex does not hold for 6 months. The COMO study is the first head-to-head comparison of ranibizumab (Lucentis, Novartis and Roche/Genentech) to Ozurdex, but that was in patients with retinal vein occlusion.10 There is also a study comparing the two drugs in DME, but these results are not yet available.

Dr. Singh: It sounds as though some of us here are evaluating combining an anti-VEGF with a steroid. How do you manage that?

Prof. Loewenstein: We are not using both simultane-ously right now. I do know some groups in Germany are investigating simultaneous dosing, but we are not. We will use one, and if there is no response after a month or so, we will consider the other, but that is not quite the same as simultaneously dosing.

Dr. Singh: If we term it “multimodality,” then, how are you incorporating that into your treatments?

Prof. Lanzetta: I think in Europe many people still use intravitreal therapy plus laser, even though we are lack-ing evidence that using a laser adds anything beneficial to a drug regimen. Obviously, today, we are using the laser very differently than how we have used it in the past. We are treating less invasively and less destructively by applying less energy or by using subthreshold modalities.

Prof. Soubrane: I use photocoagulation laser for lesions not involving the center of the macula.

Prof. Midena: I began using subthreshold micropulse (diode, and then yellow) laser in the past 8 years to avoid the possibility of damaging the retina.

Dr. Singh: What are some of its benefits of using a micropulse laser, aside from not being photodestructive?

Prof. Midena: From a dosing frequency, it is the same as with standard laser (every 3 months), even though the likely pathophysiology of the micropulse laser is likely dif-ferent. We have worked on this topic for years, and now, we are trying to show this clinically.

Prof. Loewenstein: I have used the Lumenis Novus Spectra (Sigmacon) micropulse laser, but I have a pro-totype. So there is a relatively large spot size of 200 microns, which means I will limit the use to extrafoveal lesions. In the few dozen or so patients in whom we have used it, however, we have had excellent responses..

Prof. Midena: Even today, when there are poor or limited results, we deem it the ceiling effect. Even in the RESTORE study, there did not seem to be much benefit to adding laser.11

Prof. Soubrane: I used micropulse lasers a long time ago (and with the caveat that it is not the same technol-ogy as we have today), but I was not really overwhelmed by their efficacy.

Prof. Lanzetta: I have been using subthreshold irradia-



tion since the early 2000s with various modalities, such as micropulse, or continuous wave and low energy. I am fully convinced that this is the way we should use lasers today. Up to now, only a single study has shown that micropulse subthreshold high-density laser irradiation may provide outcomes similar or superior to anti-VEGF therapy.12

What should be known is that a subset of patients with DME may benefit from laser, that it takes time for the beneficial effect to manifest, and that multiple treat-ment sessions may be necessary.

FOLLOW-UPDr. Singh: How are you managing your follow-up? Let

us presume the patient has center-involving DME with elevated retinal thickness, and you have initiated anti-VEGF therapy, with the multimodal therapy with combi-nation Ozurdex.

Prof. Soubrane: It is pre-planned every month, with Ozurdex every 4 to 6 weeks and every month for anti-VEGFs.

Prof. Midena: We do not see the patient even after the loading phase. I see the patient at baseline, they have three injections promptly, and then I see them at 4 months.

Dr. Singh: Is someone else doing the injections for you?

Prof. Midena: Yes, and I see the patient in 6 months because I perform the loading phase and then I see the patient. I never see the patient monthly.

Dr. Singh: Another ophthalmologist is doing the injections?

Prof. Midena: Yes, absolutely an ophthalmologist. In my case, if I prescribe a steroid, and someone else is check-ing the pressure, then I am completely comfortable for 2, even 3 months—unless I did not see any response from previous injections. With anti-VEGF, I do give monthly injections for 3 months, and then I see the patient the month after the third injection. However, the person who is providing the injections has make sure there is no endo-phthalmitis, detachment, or other complications.

Prof. Soubrane: While I may not personally see my patients every month, I want them to be seen just to ensure that the treatment is working.. Just to be sure the treatment the working.

Prof. Midena: Theoretically speaking, I would like to see the patients receiving anti-VEGF therapy on a

monthly basis, after the loading phase and even with cor-ticosteroid implant. I typically like to see these patients within 1 month to check for IOP changes. After the first month, I might check these patients between 2 to 3 months.

Dr. Singh: If you are bringing the patient back to check the IOP, what is your ideal time frame?

Prof. Loewenstein: Ozurdex peaks in 6 weeks. But I also think that the patients need to have the pressure checked after 2 weeks to determine if there is an increase in IOP.

Prof. Lanzetta: I do not think IOP increases are a dra-matic problem for most patients treated with dexameth-asone implant 0.7 mg but can be for some, probably the younger individuals. I do not want to miss those patients, so I usually ask them to come back and have their IOP checked after 2 weeks.

Dr. Singh: How do you treat/manage the patient with an IOP spike?

Prof. Loewenstein: I consult with my glaucoma special-ist if the patient does not improve on topical medications. I prescribe beta-blockers, or perhaps a prostaglandin.

Prof. Soubrane: If there is a huge rise—up to 50 mm Hg, despite three IOP-lowering drops—I will try to push for a vitrectomy to remove the implant rather than having a trabeculectomy performed.

Dr. Singh: Would anyone else remove the Ozurdex implant rather than perform incisional glaucoma surgery?

Prof. Loewenstein: I would not. I have one such patient who had a trabeculectomy and then needed Ozurdex, and I was completely comfortable prescribing Ozurdex.

Prof. Lanzetta: I had a female patient who spiked up to 50 mm Hg. She did very well immediately after dorzol-amide and timolol and prostaglandin analog drops.

Prof. Soubrane: I had one patient who did not improve with medical treatment and went onto under-going a trabeculectomy. This patient now has a severe hypotensive globe.

Prof. Midena: If you have a patient whose IOP spikes and still has recurrent edema after 5 or 6 months, are



you comfortable injecting again with Ozurdex, or do you change your treatment?

Prof. Lanzetta: I probably would consider switching.

Prof. Loewenstein: So would I.

Dr. Singh: What about the patient with an IOP rise but improvement in the edema, who then has a recurrence?

Prof. Loewenstein: If his or her IOP is really easy to con-trol, and for some reason the patient is more comfortable with receiving Ozurdex, it would not be a big, big problem.

Dr. Singh: By “easy to control,” we mean one or two topical drops?

Prof. Loewenstein: Yes.

OTHER TREATMENTSDr. Singh: What are your thoughts on some of the

newer agents we have been hearing about? Should we be considering these as another potential therapy? Are there other DME therapies you are looking forward to hearing about in the future?

Prof. Loewenstein: I am not convinced any other treatment will replace what we have now. There is very little data on the angioinhibitors, for example, even though they are higher up on the VEGF pathway.

Dr. Singh: I agree—very little data. How about phar-macological vitreolysis? One of the theories is that vit-reolysis in those patients (without traction) can actually prevent DR/DME from progressing.

Prof. Midena: It is a very nice idea. Physiologically, it is a very consistent concept. Vitreolysis is not useful when thickening of internal retinal membrane or epireti-nal membranes are present in patients with diabetes, because the membranes are not purely collagenous material, but neurites or glial cells are present in the epiretinal/retinal thickened area.

Prof. Loewenstein: I think the most important thing recently has been the Protocol T trial13 results that have just been published.

TAKE-AWAY POINTS FROM PROTOCOL TDr. Singh: What was your take-away point from the

Protocol T study?

Prof. Loewenstein: The most important take-away point was that the three treatments worked very well. We now have data on as needed p.r.n. regimens that we did not have before. Finally, we now know when afliber-cept 2.0 mg will work better than ranibizumab 0.3 mg.

Dr. Singh: Did that surprise you?

Prof. Loewenstein: Yes—all the other trials had shown no differences between the two compounds. However, Protocol T used 0.3 mg.13 It is unclear what the results would have been if they had studied 0.5 mg. In RIDE and RISE,7 there was a small difference in effi-cacy between those two concentrations. But again, in Protocol T it was a p.r.n. regimen, even if it was a very strict p.r.n. regimen. So, for me, in lower visual acuities if the cost is the same between the two compounds, I have to lean toward the more efficacious one.

Prof. Soubrane: I am also frustrated we do not have results with the 0.5-mg concentration. However, it is obvious that our patients do not lose their chance for improvement if we inject aflibercept. To me, that is a major point.

Prof. Lanzetta: I fully agree. One other observation is from a practicality perspective—we do not really have to give five initial monthly injections before moving to a dif-ferent regimen. We can probably start p.r.n. much sooner.

Prof. Midena: There are three main points from Protocol T.13 The number of injections of aflibercept in the p.r.n. regimen was the same as in VISTA.14 So we do not need a p.r.n.; a fixed regimen is much simpler for my patients. The working population does not like to be checked every month; it is a lot of time away from work. Second, we need to stop considering aflibercept as a pure anti-VEGF. It is a completely different molecule. If pharmacologists consider it a different drug, we should, too. And I think that is the story behind why the results are much better—aflibercept also has another property. Third, there was an astonishing number of laser treat-ments. More than 30% of patients underwent some type of laser therapy in each eye? Laser is not dead!

Dr. Singh: What does everyone else think? After read-ing Protocol T, is laser dead?

Prof. Soubrane: I think laser may still have a role in treatment of DME, but not everywhere. In France, afliber-cept is presently an acceptable treatment for DME and will be reimbursed soon, but not yet.



Prof. Midena: In Italy, it is registered, but we just received reimbursement.

NONRESPONDERS OR LIMITED RESPONDERSDr. Singh: Now that we have discussed several thera-

py options, how do you define treatment failure? What are your criteria?

Prof. Loewenstein: I consider a treatment failure as a patient whose visual acuity does not improve or if his or her retinal thickness does not improve. There may be several reasons for limited visual acuity improvement, but if there is no response on OCT at all, especially if there is also no visual acuity improvement, that is a treatment failure. For me, the OCT is the most impor-tant parameter.

Prof. Soubrane: Do you treat OCTs or do you treat patients? Just OCT is not enough. I want an FA to try to identify the reason of lack of response.

Prof. Loewenstein: For me, OCT is the most impor-tant parameter.

Prof. Soubrane: If the patient’s vision improved, and he or she is more comfortable, that is equally important.

Dr. Singh: Is vision as important as the OCT?

Prof. Soubrane: Both are important. I take into con-sideration OCT and vision when I am considering treat-ment. The problem arises when there is a discrepancy.

Prof. Loewenstein: I think you have to treat the retina—if it remains thick for a long time, vision decreases.

Prof. Lanzetta: Defining the so-called low responders is really the most difficult part of our job. I agree that OCT is the major guidance to determine if we should keep injecting. But you also have to combine the mor-phology with visual acuity. If you cannot decrease the retinal thickness, you need to keep injecting for a reason-able time.

Prof. Soubrane: What is a reasonable amount of time?

Prof. Lanzetta: At least 4 to 6 months. On the other hand, there are some other patients who are responders, but do not have visual acuity improvement. A very thin retina and no visual acuity change may suggest macular atrophy. In this case, I would stop injecting.

Prof. Midena: I think the two parameters are equal. We can have visual acuity improvement if the retina is not atrophic, but this is not as common in patients with diabetes as it is in those with wet AMD. If one of the two parameters is not improving after four injections, we will switch treatments. We cannot show which patients will continue to progress over the long term. We need to be on the patient’s side, but in Italy, we cannot spend so much money at the end of 1 year, after nine or 10 injec-tions, unless there is a clear improvement.

Dr. Singh: Let us talk about the financial impact—how are these drugs reimbursed in your countries?

Prof. Lanzetta: Laser would be a much better option, of course. In Italy, intravitreal therapy will be an issue, but not yet, because we just started treating DME with reim-bursed drugs. We have many more patients with bilater-al disease as compared to those with wet AMD, however, which means a relatively large number of injections per year, so it is going to be an issue. And the solution is to allocate more resources to ophthalmology given the fact that the newer therapies can significantly decrease the incidence of legal blindness due to macular diseases.

Prof. Midena: Since just last year, we have been forced by law to move from Lucentis and Eylea to Avastin. That is not for patients with diabetes, but we did not have Protocol T results, either. That will be against us—we may be told that for people with relatively good visual acuity, we have to use Avastin. Protocol T did not show enough of a difference between the drugs.

Dr. Singh: So Protocol T will be used to create a step therapy?

Prof. Midena: It may be. One of the consequences may be that more patients will be treated later, even with the right drug.

Prof. Soubrane: In France, there is no obligation to use Lucentis or Avastin. Eylea is approved but not yet reimbursed for DME. The choice would have been dif-ficult without Protocol T.

Dr. Singh: How about Ozurdex for your cases?

Prof. Soubrane: Ozurdex is reimbursed in France.

Prof. Midena: In Italy, Ozurdex is approved but not officially reimbursed. It is reimbursed through a different bureaucratic system.



Prof. Lanzetta: Limitations with the dexamethasone implant 0.7 mg in Italy are very similar to the original US limits. Only patients who are pseudophakic or non-responders to anti-VEGF treatment will be reimbursed.

Prof. Loewenstein: In Israel, regardless of the disease, we have to start with Avastin for at least three injec-tions. And we have to prove Avastin does not work by showing the exact OCT measurements and visual acuity before and after treatment. Only then can we switch.

CASE STUDYDr. Singh: Let us discuss this one case (full disclosure:

he was my patient). This is a 53-year-old male with a 10-year history of systemic diabetes. He has 20/50 visual acuity in the right eye, 20/40 in the left eye. He has bilateral, moderate, nonproliferative disease. See Figure 2 for the OCT images. How would you treat this patient?

Prof. Lanzetta: This is a relatively young patient with what I consider to be significantly decreased visual acu-ity. Because of the lens status and patient’s age, I would not consider using a dexamethasone implant because of the potential for cataract and elevated IOP. I would consider the anti-VEGFs first, and based on the Protocol T results, I would prefer aflibercept.

Prof. Lanzetta: I would either use the DRCR.net treat-ment scheme, or I would be tempted to give the first injection and then to switch to an individualized regimen.

Prof. Loewenstein: I would initially start with an FA, just to have a baseline to figure out if there is nonperfu-sion in the macula. (Based on the images here, I do not believe he does, but I would like to ensure that.) Then I would start with an anti-VEGF. As I mentioned, in Israel, I

have to start with Avastin, although now Protocol T has provided us with the weapons we need to get the gov-ernment to approve aflibercept and ranibizumab. If I had the choice, then I would start with aflibercept if a patient has a relatively low visual acuity.

Prof. Soubrane: In the right eye, the vision is not that great, and it seems as though there is a little serous detachment. Because of that, my first treatment strategy would be to use the Ozurdex implant in his right eye. But in his left eye, I would use Eylea. I would not treat the two eyes simultaneously, either.

Prof. Midena: My preference is a drug with some anti-inflammatory properties.

Prof. Soubrane: I would use both. But as an important caveat, I tend not to treat both eyes on the same day unless out of necessity for the patient.

Dr. Singh: In your own practices, are you doing bilat-eral injections?

Prof. Midena: Never.

Dr. Singh: Never.

Prof. Soubrane: Sometimes.

Prof. Loewenstein: I did always bilateral the same day. Last month, I had my first case of endophthal-mitis in a patient bilaterally injected with afliber-cept. Luckily, it only happened in one eye, but it was extreme enough that the patient lost visual acuity. I am trembling from the thought the patient could have lost vision in both eyes. So, now I have stopped per-forming bilateral injections.

Prof. Lanzetta: I usually do not inject bilaterally unless the patient is elderly and cannot travel back and forth to the office in a timely manner.

Dr. Singh: One last point—Lucentis and Eylea were recently approved in the US for DR. Protocol S will look at both panretinal photocoagulation (PRP) and anti-VEGFs in the DR population. How would you use either of the anti-VEGFs if they were approved for DR in your countries?

Prof. Midena: I have been involved in the protocol in Europe for both PRP eyes and anti-VEGF: one arm is PRP and the other is combined PRP and anti-VEGF. It is

Figure 2. Long-standing systemic diabetes in a patient with

moderate nonproliferative diabetic retinopathy.



similar to the DRCR’s Protocol S, but this is the European group (http://evicr.net/). We do not have a standard treatment for anti-VEGF in proliferative DR yet.

Dr. Singh: Prof. Soubrane, what would you do if you had that approval? Would that change anything for you? Or do you still maintain that PRP is the preferred meth-od to treat patients with DR?

Prof. Soubrane: I do not have a crystal ball, but it will really depend on the result of the study.

Prof. Midena: I am not fully convinced we have the best treatment yet. It is a long, long treatment. In DME, we have seen a high number of first-year injections. The idea of treating proliferative DR that is unresponsive to PRP… well, PRP is an inexpensive treatment. I have patients who have had type I diabetes for more than 20 years, with more than 20 years of follow-up. And they have 20/20 visual acuity with PRP.

Prof. Loewenstein: We do know that the standard of care treatment for neovascular disease is PRP. However, nowadays, if I see a patient who has even a mild form of the disease, I am comfortable injecting him or her and then following. I am not necessarily running to PRP immediately, even though there is no proof yet that the anti-VEGFs are better. For now, I am comfortable doing an injection and seeing the patient again in 2 or 3 weeks. If the patient has some regression, I am comfort-able not doing PRP.

Prof. Lanzetta: I am relatively concerned by the approval of anti-VEGFs to treat DR. Even though it has been proven that anti-VEGF therapy may be beneficial on the DR severity scale, there is an efficacious therapy for the proliferative form of DR, and that is PRP—which is definitely much less expensive than anti-VEGFs.

Prof. Midena: What about the US? Can you treat patients with NPDR?

Dr. Singh: In the US, the stage of retinopathy does not matter. We can treat at every level. Patients have to have DME, but how they define DME in this setting is unknown. Can the patient have a cyst on hir or her retina? Can they have an increase in retinal thickness? No one defines what DME means.

Prof. Lanzetta: Before using anti-VEGF for delaying the progression or for regressing DR, I would really like to see more data on the visual acuity outcomes.

Prof. Soubrane: One of the remaining problems is a classification of DME, because we lump them all togeth-er. One cyst or multiple cysts or serous detachment … we treat them the same.

FINAL THOUGHTS ON TREATING DMEProf. Midena: Intravitreal drugs have significantly

modified our approach. Visual acuity recovery is now better than it was with laser treatment. Laser could only stabilize, but now we can actually improve the visual acuity; that is our core message.

Prof. Soubrane: That has been the revolutionary treatment—I do not think anyone ever expected to be able to improve vision. But we need to remember we still do not have long-term data.

Prof. Loewenstein: We can now tell our patients that they definitely have more than a 95% chance of avoiding severe vision loss through their lifetime with treatment.

Prof. Lanzetta: There are two major messages. First, we are using less laser and more intravitreal drugs. We perform less FA. We regularly do OCTs on our patients. We have a very complete diagnostic workup so we can better characterize every type of DME patient. By doing that, we might better recognize the best treatment for each patient. Second, we should improve our promotion of screening programs. Effective screening programs will hopefully lead to fewer patients who need treatment because they are being diagnosed earlier. n

1. International Diabetes Federation. IDF Diabetes Atlas, 6th ed. Brussels, Belgium: International Diabetes Federation, 2014.2. World Health Organization. The top 10 causes of death: Fact Sheet No 310. Geneva, Switzerland, 2014.3. Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556-564.4. Diabetic Retinopathy Clinical Research Network, Elman MJ, Qin H, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology. 2012;119(11):2312-2318.5. Aiello LP. Randomized Trial Assessing Personalized Point-of-Care Diabetes Complication Risk Assessment during Ophthalmology Visits on Diabetes Control. Presented at: 38th Annual Macula Society Meeting; Feb. 25-28, 2015; Scottsdale, Arizona.6. Singh RS. The impact of systemic factors on clinical response to ranibizumab for diabetic macular edema. Presented at: 38th Annual Macula Society Meeting; Feb. 25-28, 2015; Scottsdale, Arizona.7. Iluvien [package insert]. Atlanta, GA: Alimera Sciences Inc., 2014.8. Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119(10):2125-2132.9. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801.10. Loewenstein A, Bandello F, Kampik A, et al. Design and rationale of COMO, a 12-month study that compares the safety and efficacy of dexamethasone intravitreal implant versus ranibizumab in branch retinal vein occlusion. Acta Ophthalmologica. 2011;89(suppl s248); doi: 10.1111/j.1755-3768.2011.341.x.11. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118(4):615-625.12 . Do DV, Nguyen QD, Khwaja AA, et al. READ-2 Study Group. Ranibizumab for edema of the macula in diabetes study: 3-year outcomes and the need for prolonged frequent treatment. JAMA Ophthalmol. 2013;131(2):139-145.13. Diabetic Retinopathy Clinical Research Network. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema. N Engl J Med. 2015; 372:1193-1203.14. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal Aflibercept for Diabetic Macular Edema. Ophthalmology. 2014;21(11):2247-2254.

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NEW PARADIGMS IN DME DIAGNOSIS AND MANAGEMENT · NEW PARADIGMS IN DME DIAGNOSIS AND MANAGEMENT 6 SUPPLEMENT TO RETINA TODAY MAY/JUNE 2015 Prof. Soubrane: If nothing shows up on biomicros-copy,