Diabetic Macular Edema

Supplement to January/February 2009 New Insights Into the Management of Diabetic Macular Edema and Related Conditions Highlights of a symposium held in New York City. Neil M. Bressler, MD, Program Coordinator Presentations by: Susan B. Bressler, MD Mark S. Blumenkranz, MD David M. Brown, MD Jointly sponsored by the Dulaney Foundation and Retina Today

NEW INSIGHTS INTO THE MANAGEMENT OF DIABETIC MACULAR EDEMA AND RELATED CONDITIONS Jointly sponsored by the Dulaney Foundation and Retina Today. Release date: February 2009. Expiration date: February 2010. This continuing medical education activity is supported by unrestricted educational grants from Allergan, Inc., Carl Zeiss Meditec, Inc., Genentech, Inc., and OptiMedica Corporation. STATEMENT OF NEED According the National Institutes of Health, 7.8% of the US population, or 23.6 million people, have diabetes. The Centers for Disease Control and Prevention reports ophthalmic complications of diabetes are the leading cause of blindness in adults aged 20 to 74 years. A common cause of vision loss in patients with diabetes is diabetic macular edema (DME). The prevalence of DME among US diabetics approaches 30% in adults who have had the disease for 20 years or more. 1 Although laser photocoagulation remains the gold standard therapy, 2 clinicians continue to explore new treatments, including modifications to laser therapy and combinations of laser therapy with pharmacologic therapy. A 2008 survey by Retina Today shows that 55% of its readers are using combination or triple therapy for DME. A thorough understanding of current management options as well as new and novel approaches is critical for clinicians to effectively treat patients with DME and related conditions, such as central retinal vein occlusions (CRVOs). 1. Klein R, Klein BE, Moss SE, et al. The Wisconsin epidemiologic study of diabetic retinopathy: IV. Diabetic macular edema. Ophthalmology. 1984;91:1464-1474. 2. Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report No. 1. Arch Ophthalmol. 1985;103:1796-1806. TARGET AUDIENCE Retina specialists and other ophthalmologists. LEARNING OBJECTIVES Upon successfully completing this learning program, participants should be able to: 1. Discuss the prevalence and natural history of DME. 2. Review the relevance of findings from the Diabetes Control and Complications Trial (DCCT) and the Early Treatment Diabetic Retinopathy Study (ETDRS). 3 Describe potential pharmacologic options for treating DME. 4. Discuss the pathogenesis of CRVO. 5. Describe current treatment options for CRVO, including systemic, photocoagulation, pharmacologic, and surgical. METHOD OF INSTRUCTION Participants should read the continuing medical education (CME) activity in its entirety. After reviewing the material, please complete the self-assessment test, which consists of a series of multiple-choice questions. To answer these questions online and receive real-time results, please visit http://www.dulaneyfoundation.org and click Online Courses. Upon completing the activity and achieving a passing score of over 70% on the selfassessment test, you may print out a CME credit letter awarding 2 AMA PRA Category 1 Credits. The estimated time to complete this activity is 2 hours. ACCREDITATION This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Dulaney Foundation and Retina Today. The Dulaney Foundation is accredited by the ACCME to provide continuing education for physicians. The Dulaney Foundation designates this educational activity for a maximum of 2 AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. DISCLOSURE In accordance with the disclosure policies of the Dulaney Foundation and to conform with ACCME and the US Food and Drug Administration (FDA) guidelines, anyone in a position to affect the content of a CME activity is required to disclose to the activity s participants: (1) the existence of any financial interest or other relationships with the manufacturers of any commercial products/devices or providers of commercial services; and (2) identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved. CONTENT VALIDATION In compliance with ACCME standards for commercial support and the Dulaney Foundation s policy and procedure for resolving conflicts of interest, this CME activity was peer-reviewed for clinical content validity to ensure the activity s materials are fair, balanced, and free of bias; the activity materials represent a standard of practice within the medical profession; and any studies cited in the materials upon which recommendations are based are scientifically objective and conform to research principles generally accepted by the scientific community. FACULTY CREDENTIALS Neil M. Bressler, MD, is James P. Gills Professor of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University in Baltimore. Participation by Dr. Bressler in this activity does not constitute or imply endorsement by the Johns Hopkins University, the Johns Hopkins Hospital or the Johns Hopkins Health System. Susan B. Bressler, MD, is the Julia G. Levy, PhD, Professor of Ophthalmology at the Wilmer Eye Institute at the Johns Hopkins University School of Medicine in Baltimore. Mark S. Blumenkranz, MD, is Professor and Chair of Ophthalmology at Stanford University School of Medicine, Stanford, CA. David M. Brown, MD, is the Director of the Greater Houston Retina Research Center and practices at Vitreoretinal Consultants and The Methodist Hospital in Houston, TX. FACULTY/STAFF DISCLOSURE DECLARATIONS Neil M. Bressler, MD: Grants to investigators at The Johns Hopkins University are negotiated and administered by the institution, which receives the grants, typically through the Office of Research Adminstration. Individual investigators who participate in the sponsored project(s) are not directly compensated by the sponsor, but may receive salary or other support from the institution to support their effort on the project(s). Dr. Neil Bressler is Principal Investigator for the following: Allergan, Inc., Bausch & Lomb, Inc. (B&L), Carl Zeiss Meditec, Inc., Genentech, Inc., Notal Vision, Othera Pharmaceuticals, Inc., QLT, Inc., Regeneron Pharmaceuticals, Inc., Steba Biotech. Dr. Bressler s spouse has been or is currently consultant for the following: AstraZeneca, Genentech, Inc., Notal Vision, Pfizer, Inc. Susan B. Bressler, MD: Grant/research support from B&L, Genentech, Inc., Novartis Ophthalmics; investigator for Genentech, Inc. Mark S. Blumenkranz, MD: Grant/research support from Alcon Laboratories, Inc.; consultant for Allergan, Inc., Eli Lilly and Company, Genentech, Inc.; consultant and shareholder for MacuSight/OptiMedica. David M. Brown, MD: Grant/research support from Alcon Laboratories, Inc., Allergan, Inc., Alimera Sciences, Eli Lilly and Company, Genentech, Inc., Jerini AG, NeoVista, Inc., Neurotech, Novartis Ophthalmics, Othera Pharmaceuticals, Inc., Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Sirion Therapeutics, Inc.; consultant for Genentech, Inc., Novartis Ophthalmics, Regeneron Pharmaceuticals, Inc. The following faculty members have indicated they will discuss off-label, experimental, and/or investigational use of drugs or devices: Neil M. Bressler, MD: Ranibizumab, bevacizumab, triamcinolone. Susan B. Bressler, MD: Ranibizumab, bevacizumab, triamcinolone. David M. Brown, MD: Intravitreal steroids, bevacizumab. All those involved in the planning, editing, and peer review of this educational activity have indicated they have no financial relationships to disclose. 2 I SUPPLEMENT TO RETINA TODAY I JANUARY/FEBRUARY 2009

New Insights Into the Management of Diabetic Macular Edema and Related Conditions Highlights of a symposium held in New York City. Contents 4 Laser Therapy s Role in Managing DME By Susan B. Bressler, MD 8 Exploring the Potential of Combination Therapies for DME By David M. Brown, MD 11 Potential Role of Vitrectomy for Treating Diabetic Retinopathy By Mark S. Blumenkranz, MD 13 The Potential Role of Long-acting Steroids By Mark S. Blumenkranz, MD 15 Diabetes Control and Complications Trial: An Ophthalmologist s Understanding By Susan B. Bressler, MD 18 Treatment of Retinal Venous Occlusive Disease By Mark S. Blumenkranz, MD 20 Considering Anti-VEGF Therapies for Vein Occlusions By David M. Brown, MD JANUARY/FEBRUARY 2009 I SUPPLEMENT TO RETINA TODAY I 3

NEW INSIGHTS INTO THE MANAGEMENT OF DIABETIC MACULAR EDEMA AND RELATED CONDITIONS Laser Therapy s Role in Managing DME Laser photocoagulation remains the most effective treatment for diabetic macular edema. BY SUSAN B. BRESSLER, MD Laser therapy has been part of our armamentarium for treating diabetic macular edema (DME) since the mid-1980s. Twenty-plus years later, the question is: Is this a procedure we still want to be doing and doing regularly, or are we ready to cast it aside in favor of pharmacologic means for treating macular edema? FOCAL/GRID LASER IN THE ETDRS I am using the term focal/grid laser photocoagulation to refer to the technique that was evaluated in the Early Treatment Diabetic Retinopathy Study (ETDRS), a two-part treatment performed at one sitting. 1 For the focal component of the treatment, you first identify the focal leakage sites within the area of thickened retina, namely microaneurysms, and directly ablate them with light intensity and small spots of photocoagulation. For the grid component, you place a limited macular scatter pattern within the areas of edematous or thickened retina, being careful to place these spots between spots that have already addressed the focal leaks. The grid treatment generally corresponds to areas of leaking capillary beds on fluorescein angiography. This is the treatment that we have been using for more than 20 years. We call it modified now because we use a lighter-intensity burn, and most clinicians use the 50-µm spot size. LESSONS FROM THE ETDRS From the ETDRS, we learned that performing focal/grid treatment reduced the risk of moderate vision loss three or more lines of acuity as compared with no treatment. We also learned that, when monitored for 3 years, only 15% of patients with clinically significant macular edema, center-involved or noncenter-involved, who received focal/grid treatment experienced moderate vision loss. This was half as frequently as the eyes assigned to observation. That summarizes the primary outcome of the ETDRS, which has led us to do focal/grid treatment for eyes with DME for the last 20 years. We also learned in the ETDRS that eyes with less severe (not considered clinically significant) macular edema in the treatment group had reduced rates of moderate vision loss as compared with eyes with equivalent degrees of macular edema in the observation group. We concluded, however, that it was probably reasonable to monitor eyes with lesser degrees of macular edema, follow them until they developed clinically significant edema, and then perform the focal/grid treatment rather than intervene during earlier phases of macular edema. At the end of the ETDRS, we were disappointed that, despite successful treatment and decreased retinal thickening, only 17% of patients recovered three or more lines of acuity relative to their entry levels of vision. That is why we have been searching for better treatments. In addition to being able to stop vision loss over time, we would like to be able to restore vision in a greater proportion of patients. TWENTY YEARS LATER At the beginning of this decade, some isolated cases and then small case series touted the benefits of intravitreal steroid administration. 2,3 After putting steroids into the vitreous, several researchers observed that some eyes experienced a rapid reduction in retinal thickening, as confirmed by optical coherence tomography (OCT). Some of those patients also had an associated improvement in visual acuity as their edema improved. So with the presentation and publication of those short-term, small case series, the retina community began experimenting with intravitreal steroids. In the 2005 Preferences and Trends survey conducted by the American Society of Retina Specialists, more than 90% of the 370 respondents reported they were using intravitreal steroids to manage patients with persistent DME. That set the stage for a randomized clinical trial to compare our gold standard treatment, focal/grid laser, with intravitreal steroids. The Diabetic Retinopathy Clinical Research Network (DRCR.net) recently completed and published results from such a study. 4 STUDY DESIGN, OBJECTIVE, ELIGIBILITY The recently completed DRCR.net trial was a multicenter, randomized clinical trial with three treatment arms: photo- 4 I SUPPLEMENT TO RETINA TODAY I JANUARY/FEBRUARY 2009

HIGHLIGHTS OF A SYMPOSIUM HELD IN NEW YORK CITY Figure 1. Researchers took cataract off the table in this analysis. Figure 2. Laser-treated eyes had most resorption by month 16. coagulation and two dosages (1 mg or 4 mg) of preservative-free triamcinolone acetonide delivered intravitreally. The primary goal was to compare the efficacy and safety of the steroid vs laser therapy. We looked at two dosages of triamcinolone because we expected complications, such as glaucoma and cataract, and we wanted to find out if a lower dosage would reduce the frequency of complications while providing the same degree of efficacy. Follow-up visits were quarterly for 3 years, and all patients were eligible for retreatment with the treatment assigned at entry as often as every 4 months if edema persisted. The primary outcome assessment was at the 2-year visit, and the major outcome variable was visual acuity, specifically the average change in vision over time. The scientific objective was mean change in visual acuity; the regulatory objective, as proposed by the US Food and Drug Administration, was the proportion of patients with a decrease of 15 letters. An important secondary measure was retinal thickening on OCT. Patients were eligible to participate if they had type 1 or type 2 diabetes. Every patient had DME with center involvement, which was confirmed on OCT with a central subfield thickness reading of at least 250 µm. Best-corrected visual acuity could not be better than 20/40 or worse than 20/320. We studied 840 eyes (about 140 people had both eyes in the study) with about 250 people enrolled in each of the treatment arms. Follow up at the 2-year visit was nearly 90%. KEY STUDY RESULTS At 2 years, individuals who had been assigned to laser, on average, gained one letter of acuity on standardized eye charts; whereas, those receiving the lower dose steroid, on average, lost two letters, and those receiving the higher dose steroid, on average, lost three letters, which is equivalent to half a line of vision. When you compare the distribution of changes in vision over time, the differences in outcomes always favored laser treatment. Looking at the median acuity, note that all three groups began balanced somewhere between 20/50 and 20/60 (Snellen equivalent) and 4 months into the study, the steroid group showed improvement. Relative to the laser group, on average, vision in both steroid groups was improving, particularly patients receiving the higher-dose steroid. A year later, however, visual acuity in the laser group was slowly improving, while visual acuity in the steroid groups was declining from their initial upturn. The difference between the groups became significant at month 16 in favor of laser, and that significant difference was maintained through month 24. The laser-treated eyes had a slight improvement overall relative to baseline, and the steroidtreated eyes had a slight diminution, so that there was a significant difference when comparing laser to either of the steroid groups. Considering that vision in the steroid-treated groups improved initially and then declined, you might wonder if these patients were developing cataracts from the repeated intravitreal steroid injections. We took the presence of cataract off the table by analyzing the data and confining our review to people who were pseudophakic when they joined the study or who had undergone cataract surgery at some point before the 2-year visit, or people for whom the retina surgeon determined had minimal or no cataract at the 2- year visit. Even isolating the analysis to these individuals, the laser-managed eyes did better over time than those receiving steroids (Figure 1). Even if we look only at the relatively small number of people who were pseudophakic at baseline maybe one-sixth of the participants if anything, the 2-year outcomes favored laser. So we cannot blame cataract for interfering with the vision outcomes in the steroid group. JANUARY/FEBRUARY 2009 I SUPPLEMENT TO RETINA TODAY I 5

NEW INSIGHTS INTO THE MANAGEMENT OF DIABETIC MACULAR EDEMA AND RELATED CONDITIONS What about central subfield thickness on OCT? Note that the three groups started balanced with central subfield thickness measurements of about 400 µm. At 4 months, as anticipated, the steroid group rapidly acted like a reverse sponge, drying up. The laser-treated eyes slowly demonstrated further reductions in central subfield thickness, however, so that by month 16, they had the most edema resorption (Figure 2). This is a significant difference that persisted through 24 months, favoring the laser-treated eyes. We saw few complications, such as retinal detachments or endophthalmitis, from intravitreal injections; however, four patients in the 4-mg dosage group needed filtration surgery to manage elevated IOPs. Roughly 30% of individuals in this treatment group had IOP increases of 10 mm Hg or more during the study. Investigators were encouraged to remove visually significant cataracts that developed during the study, and some older patients in the laser group had cataract surgery during the 2 years. The rate of cataract surgery doubled in the lower-dose steroid group, and then doubled again with the higher dose relative to the laser-treated eyes. In the 4-mg triamcinolone group, one-half of the initially phakic eyes needed cataract surgery during the 2 years while receiving, on average, three intravitreal steroid injections. STUDY RESULTS PROMPT NEW QUESTION The visual acuity benefit at 4 months favored the higherdose steroid, which was consistent with results from the small case series reported earlier. By 1 year, however, there was no advantage for the steroids, and by 2 years, there was a clear-cut advantage for laser treatment in terms of visual outcome and fewer adverse effects. The OCT findings paralleled the visual acuity outcomes. Twenty years after the ETDRS report, we have evidence that focal/grid photocoagulation is very much here to stay and in our patients best interests. It is the most effective means of managing DME, and looking forward, it must remain the benchmark for any further clinical trials. Given what we know now about the importance of photocoagulation in managing eyes with DME, we need to ask: Should we forego the focal component of laser treatment and the angiograms required to identify the focal sites of leakage and just grid the posterior pole? The DRCR.net addressed this question in a prospective randomized study. DRCR.NET PILOT STUDY This study of 263 patients compared the modified ETDRS (metdrs) focal/grid laser technique with a mild macular grid (MMG), a technique in which burns were placed throughout a zone within 3,000 µm of the fovea, about one burn width apart, whether or not the retina was thickened. 5 Figure 3 shows an eye that was treated with the metdrs focal/grid treatment. You can barely see the light intensity burns. In contrast, Figure 4 shows the MMG grid treatment that we explored. Treatment spots began about 500 µm from the foveal center and extended almost to the arcade, about 2 disc diameters in every direction, utilizing a light intensity such that 6 weeks later, not much is visible in the fundus. With 200 patients enrolled, we had excellent power to detect a minimum difference of 50 µm in central retinal thickening between these two laser modalities on OCT. There were 323 eyes randomized within this trial, about half in each laser technique group. Follow up at the 12-month visit was 88%. As Figure 5 shows, the differences in central subfield thickness between groups are not statistically significant, but we see a trend toward thinner measurements in the metdrs laser technique group. What about vision improvement? At follow-up visits at 3, 8, and 12 months, a higher proportion of patients in the metdrs group are achieving moderate vision improve- Figure 3. Eye treated with modified ETDRS focal/grid laser. Figure 4. Note the fundus 6 weeks post treatment. 6 I SUPPLEMENT TO RETINA TODAY I JANUARY/FEBRUARY 2009

HIGHLIGHTS OF A SYMPOSIUM HELD IN NEW YORK CITY Figure 5. Note trend toward thinner measurements in metdrs group. ment. Similarly, for vision loss of three or more lines of acuity at 3.5 months and again at 12 months, a smaller proportion of those who are receiving focal/grid treatment are losing vision compared to those in the grid group (Figure 6). The bottom line is: The MMG treatment appears to be less effective in reducing retinal thickening than the metdrs treatment, as confirmed by OCT. These results suggested that a much larger trial exploring grid photocoagulation is not necessary because it is unlikely we would find it superior to the more traditional focal/grid technique. We saw no data that suggested we should change the technique we have been using. We did recognize, however, that by 1 year, edema had resolved in only 30% of subjects who had undergone metdrs treatment. These outcomes support the need for us to continue to explore other treatments. LASER PREVAILS AS SEARCH CONTINUES Is focal/grid treatment still indicated to treat DME? My answer is an emphatic yes. By performing this procedure in eyes with clinically significant edema, particularly centerinvolved, we are reducing the risk of moderate vision loss over a 2-year period to about 20%. We now also recognize there is more vision improvement than we thought previously. Unfortunately, 20% of patients will decline, so we must continue to search for more ways to treat them. In this trial, we evaluated eyes that started at 20/40 or worse, so that every eye had the potential to recover 3 or more lines of vision. In fact, one of three study eyes had two or more lines of acuity improvement with focal/grid laser treatment. That frequency of vision improvement is much better than we formerly thought. So the bar for improved outcomes with new treatment modalities is somewhat higher than we formerly thought. Although there are other Figure 6. A smaller proportion of patients in the metdrs group are losing vision compared to those in the MMG group. potential therapies intravitreal steroids, bevacizumab, ranibizumab we need to remind ourselves that none of these agents has been shown to have a greater and more durable effect than laser therapy for eyes with DME. 1. Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report No. 1. Arch Ophthalmol. 1985;103:1796-1806. 2. Jonas JB, Söfker A. Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema. Am J Ophthalmol. 2001;132:425-427. 3. Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002;109:920-927. 4. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115:1447-1449. 5. Fong DS, Strauber SF, Aiello LP, et al. Diabetic Retinopathy Clinical Research Network. Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol. 2007;125:469-480. JANUARY/FEBRUARY 2009 I SUPPLEMENT TO RETINA TODAY I 7

NEW INSIGHTS INTO THE MANAGEMENT OF DIABETIC MACULAR EDEMA AND RELATED CONDITIONS Exploring the Potential of Combination Therapies for DME While laser monotherapy remains the gold standard, researchers continue to seek more efficacious treatments. BY DAVID M. BROWN, MD From the Early Treatment Diabetic Retinopathy Study (ETDRS), we know laser treatment is the primary and only proven therapy for clinically significant macular edema. 1 Laser therapy, performed according to the ETDRS protocol, basically doubled the chances that a patient would not experience significant vision loss compared to observation. Less than 3% of eyes in the ETDRS gained 15 letters at 3 years, and many eyes started the study with excellent visual acuity. The Diabetic Retinopathy Clinical Research Network (DRCR.net) compared the modified ETDRS laser technique and the mild macular grid technique for diabetic macular edema (DME). 2 That trial found that when patients with 20/40 or worse vision received modified ETDRS focal laser, they had a 29% chance of a three-line gain and a 49% chance of a two-line gain. Many researchers in pharmaceutical trials had no idea laser was this good because they were comparing their results with historical ETDRS data in which most patients had visual acuity better than 20/40 and, thus, were unlikely to be able to improve. Two illustrative cases follow. CASE EXAMPLES Figures 1 and 2 show a patient before and after focal laser. I have always said that for small areas of edema, focal/grid laser works great. For large diffuse edema, laser has been suggested as not being as effective, but there is no uniform definition of diffuse edema. 3 In the DRCR.net study, patients with very thickened DME were more likely to have resolution of edema with laser than with intravitreal triamcinolone. In addition, visual acuity outcomes were not superior with triamcinolone compared with focal/grid laser. Figures 3 and 4 show a macula with a great deal of edema. I might have suspected that laser would not have helped, but this patient responded nicely to macular laser therapy. What other treatment options do we have? Researchers also have explored the potential of pharmacologic agents. STEROIDS AND ANTI-VEGF AGENTS The short-term benefit of intravitreal steroids is obvious, but we often see problems, such as cataract; and endophthalmitis and glaucoma can develop over time. As the DRCR.net study showed, steroids win at month 4. By month 12, they are equal to laser, and by month 16 and beyond, laser wins. 4 We also have explored the use of anti-vegf agents, such as ranibizumab (Lucentis, Genentech, Inc.) and bevacizumab (Avastin, Genentech, Inc.). In the phase 2 Ranibizumab for Edema of the Macula in Diabetes (READ) study, Nguyen Figure 1. Patient before focal laser treatment. Figure 2. Patient after focal laser treatment. 8 I SUPPLEMENT TO RETINA TODAY I JANUARY/FEBRUARY 2009

HIGHLIGHTS OF A SYMPOSIUM HELD IN NEW YORK CITY (Image courtesy of David Boyer, MD.) (Image courtesy of David Boyer, MD.) Figure 3. Before grid laser treatment. Figure 4. After grid laser treatment. and colleagues showed a gain of one to two lines over 6 to 12 months with continued ranibizumab injections. 5 Is there a problem with attacking DME with a relatively short-acting anti-vegf agent? The difference between the use of these agents in age-related macular degeneration (AMD) is that in AMD, there is only minimal VEGF. In diabetes, VEGF is present in high concentrations and is produced continuously. You cannot keep using sponges to try to dry up a waterfall. So short-acting anti-vegf agents may not be the answer for long-term diabetes care. NEXT STEP: COMBINING THERAPIES? We know that laser therapy works fairly well, and we see short-term benefits from steroids or anti-vegf agents, so why not combine them? The DRCR.net is studying those options in the Laser-Ranibizumab-Triamcinolone for DME Study. Patients with clinically significant DME are randomized to four groups: 1. Focal/grid laser plus sham. 2. Focal/grid laser plus ranibizumab. 3. Ranibizumab alone, and then focal/grid laser if needed. 4. Focal/grid laser plus triamcinolone. The primary efficacy outcome is visual acuity. The secondary efficacy outcomes are the number of injections in the first year and the change in retinal thickening of central subfield and retinal volume measured on optical coherence tomography (OCT). The main safety outcomes are: injection-related (endophthalmitis, retinal detachment); ocular drug-related (inflammation, cataract, cataract surgery, increased IOP, glaucoma medications, glaucoma surgery); and systemic drug-related (cardiovascular events). Hopefully, this and other well-designed studies will uncover additional options. EARLY EXPERIENCE: LASER WITH ANTI-VEGF Anti-VEGF therapy stops macular edema, but our current agents provide only short-term VEGF blockade, thus limiting the utility of anti-vegf therapy. What is the answer to this dilemma? If you want to stop your bathtub from overflowing, you turn off the spigot. Should we, in effect, turn off VEGF? I believe we soon will determine the source of the VEGF, which will help us understand how to control it. I am not necessarily advocating that we ablate it, but I would like to find out what it is and either kill it pharmacologically or make it healthier. Although it is not proven, I postulate that it is possible that most of the VEGF that is causing macular edema could be coming from ischemia in the peripheral retina. Figure 5 shows an early phase angiogram (left) with large areas of capillary nonperfusion; the late phase is on the right. Figure 6 shows diffuse central macular edema on Figure 5. Early (left) and late-phase (right) angiogram. Note large areas of capillary nonperfusion. JANUARY/FEBRUARY 2009 I SUPPLEMENT TO RETINA TODAY I 9

NEW INSIGHTS INTO THE MANAGEMENT OF DIABETIC MACULAR EDEMA AND RELATED CONDITIONS Figure 6. Diffuse central macular edema on OCT. Figure 8. Outcome after targeted PRP and concomitant triamcinolone injection. Figure 8 shows the 6-month results with this patient after we treated the areas that looked the most ischemic with targeted PRP and a concomitant triamcinolone injection. This case appears to be a success, but this technique needs to be validated before we can recommend it. Figure 7. Laser treatment directed at the most ischemic areas. OCT. Figure 7 shows the laser treatment directed at the most ischemic areas. This patient also has proliferative disease, but we are performing some panretinal (scatter) photocoagulation (PRP) to treat macular edema only. This approach was proven to not work in the original ETDRS, but at that time, anti-vegf agents were not available, and we were unable to target our PRP to areas that looked angiographically compromised. So if we can decrease the VEGF drive, we hypothesize that we may be able to decrease the need for monthly or every 6-week anti- VEGF therapy. I think this needs further study. We discovered early on that even with micropulsed pattern scan laser therapy delivered to targeted ischemic areas, we saw rebound edema. So we began to use targeted PRP for areas of nonperfusion in combination with intravitreal bevacizumab and then ranibizumab. We often saw significant rebound edema, probably an inflammatory response to the laser burns. In the end, we had to treat patients concomitantly with a steroid. FURTHER STUDY NEEDED Treatment of DME requires ongoing management of patients underlying systemic conditions, and it begins with focal/grid laser as applied in the DRCR Network studies. It is yet to be determined if combining some type of laser treatment with an intravitreal agent will be superior to ETDRS laser alone. I encourage everyone who treats DME to consider supporting one or more of the DRCR.net trials to help advance the treatment of this common problem. 1. Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report No. 1. Arch Ophthalmol. 1985;103:1796-1806. 2. Fong DS, Strauber SF, Aiello LP, et al. Diabetic Retinopathy Clinical Research Network. Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol. 2007;125:469-480. 3. Browning DJ, Altaweel MM, Bressler NM, Bressler SB, Scott IU; Diabetic Retinopathy Clinical Research Network. Diabetic macular edema: What is focal and what is diffuse? Am J Ophthalmol. 2008;146:649-655. 4. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115:1447-1459. 5. Nguyen QD, Tatlipinar S, Shah SM, et al. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol. 2006;142:961-969. 10 I SUPPLEMENT TO RETINA TODAY I JANUARY/FEBRUARY 2009

HIGHLIGHTS OF A SYMPOSIUM HELD IN NEW YORK CITY Potential Role of Vitrectomy for Treating Diabetic Retinopathy Ongoing studies are examining this option. BY MARK S. BLUMENKRANZ, MD Vitrectomy is reported to be effective in resolving macular edema, but the data sets have been limited, and the published studies to date have, for the most part, not been well-controlled, prospective, randomized trials. 1-4 An important question is: Why should vitrectomy work at all? One theory is that mechanical stress or stretch causes leakage. Another is that there is a physiologic improvement in oxygenation in the vitreous, and a third is that intravitreal VEGF levels are reduced. 5,6 EARLY STUDIES In the 1992 paper that first described the potential benefits of vitrectomy for macular edema, we reported on 10 patients who were failures of prior photocoagulation. 1 We postulated that an abnormally thickened hyaloid was exerting traction on the vitreoretinal interface and causing leakage. Some of these eyes had epiretinal membranes, and approximately 60% were judged to be successes. Several years later, I reviewed my results on a second cohort of 15 patients. 7 Before surgery, none of these patients had visual acuity better than 20/80, but after surgery, about two-thirds of them had better than 20/80 vision. In fact, 20% had better than 20/50, suggesting that vitrectomy was helping these patients. Interestingly, these findings did presage some later understandings. With monochromatic blue-light photography, one could see 2 x 2 disc diameter shiny, circular zones in the macula that corresponded to leakage in the later fluorescein angiogram and which seemed distinct from a macular pucker (Figure 1). At that time, we described it without postulating what it was. Now, we recognize it is the contracted internal limiting membrane (ILM). Subsequently, we performed en face histologic examination after vitrectomy on peeled membranes after placing them on a glass slide rather than embedding them in paraffin. The impact was to examine them as we would with an ophthalmoscope as opposed to conventional histology, which is analogous to optical coherence tomography (OCT). We could see that these very modestly hypocellular membranes were composed primarily of ILM of the retina (Figure 2). 7 Another interesting finding was that many membranes contained very small vessels. These were, in effect, vascularized epiretinal membranes that were causing localized traction. Now, we suspect that the ILM in DME is probably important. Some vitreoretinal surgeons globally consider vitrectomy a primary form of therapy that may precede focal or grid photocoagulation in selected settings. This view, however, is not a standard of care in the United States and is considered controversial. PROSPECTIVE COHORT STUDY Data should drive best clinical practice, and the Diabetic Retinopathy Clinical Research Network (DRCR.net) has pioneered a host of studies on treatment of diabetic retinopathy. One is the Evaluation of Vitrectomy for Diabetic Figure 1. Subsequent observations on surgical ophthalmoscopic features of DME: the importance of ILM abnormalities and ERM. Figure 2. Histopathologic observations: components include thickened ILM and vascular ERMs. JANUARY/FEBRUARY 2009 I SUPPLEMENT TO RETINA TODAY I 11

NEW INSIGHTS INTO THE MANAGEMENT OF DIABETIC MACULAR EDEMA AND RELATED CONDITIONS Macular Edema Study. 5 This study provides an opportunity to collect data prospectively, using standardized protocols to assess benefits and risks. The results can be used to stimulate the design and execution of a prospective, randomized clinical trial with Level 1 evidence, and it also can be used to help design other studies. A series of patients, aged 18 years old, were enrolled in one such study. Figure 3 summarizes eligibility criteria. Surgery was performed according to the investigator s usual routine. About half of the patients had small-gauge vitrectomy, and the other half had standard 20-gauge surgery. About two-thirds of the patients had epiretinal membranes removed. Clearly, the surgeons felt some degree of traction was present, although not in every patient. There are those who argue that performing a vitrectomy alone, with or without ILM peeling, still helps DME. This prospective, nonrandomized but controlled study showed no significant change in mean visual acuity from baseline to 3 months or to 6 months. Although some patients improved, and more patients improved at 6 months than at 3 months, some became worse. So the aggregate effect was that there was no improvement in the mean visual acuity overall. It is unknown how these eyes would have fared if they had not received vitrectomy, so the proportion with improvement may be better than no vitrectomy, and the proportion with loss may be better than no vitrectomy. At the least, this information provides some guidance regarding expectations for patients considering this surgery for these circumstances. There was a benefit in the OCT-measured macular thickness. There was a considerable decrease in thickness from about 500 µm to just under 300 µm. All factors being equal, we would have assumed that if the mean macular thickness decreased, the mean visual acuity would improve, yet it did not. Cataract could have been a factor, or perhaps these maculas did not have reasonable potential for visual improvement because of prior damage from diabetes. When an epiretinal membrane is present, we know that time-domain OCT in the autocalculation mode shows the retina to be thicker than it might really be. So the OCT central subfield thicknesses may not reflect as much reduction in retina thickness; much of the reduced thickness may have been from removing the epiretinal membranes. WEIGHING BENEFITS/RISKS Whenever we judge the efficacy of a therapy, we must take into account the positive benefits and subtract the Figure 3. The Evaluation of Vitrectomy for Diabetic Macular Edema Study will collect data prospectively, using standardized protocols to assess benefits and risks. complications. The net of those two determines whether or not treatment is beneficial. Many treatments are beneficial but have unacceptably high risk, while others are not especially beneficial but they have minimal risk. The treating physician and the patient must decide how to achieve the best balance for the patient. These data show the surgery was fairly successful in the sense that it was not likely to lead to serious adverse events, but we also know that most patients older than 40 years will develop a cataract after vitrectomy, and a small percentage will experience a detachment or other complications. 6 What these data show is that we do not know everything we need to know to make an informed judgment about whether vitrectomy is or is not safe and effective for DME. They do suggest, however, that vitrectomy reduces macular thickness. So a conclusive recommendation remains an open issue at this time, and there should be additional studies looking at this. My hope is that within several years we will have more information to guide us. 1. Lewis H, Abrams GW, Blumenkranz MS, Campo RV. Vitrectomy for diabetic macular traction and edema associated with posterior hyaloidal traction. Ophthalmology. 1992;99:753-759. 2. Harbour JW, Smiddy WE, Flynn HW Jr, Rubsamen PE. Vitrectomy for diabetic macular edema associated with a thickened and taut posterior hyaloid membrane. Am J Ophthalmol. 1996;121:405-413. 3. Tachi N, Ogino N. Vitrectomy for diffuse macular edema in cases of diabetic retinopathy. Am J Ophthalmol. 1996;122:258-260. 4. Pendergast SD. Vitrectomy for diabetic macular edema associated with a taut premacular posterior hyaloid. Curr Opin Ophthalmol. 1998;9:71-75. 5. Stefánsson E. Ocular oxygenation and the treatment of diabetic retinopathy. Surv Ophthalmol. 2006; 51:364-380. 6. Funatsu H, Yamashita H, Ikeda T, Mimura T, Eguchi S, Hori S. Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology. 2003;110:1690-1696. 7. Blumenkranz MS. Paper presented at: Retinal Subspecialty Day; October 1991; Jules Stein Eye Institute, Los Angeles, CA. 12 I SUPPLEMENT TO RETINA TODAY I JANUARY/EBRUARY 2009

HIGHLIGHTS OF A SYMPOSIUM HELD IN NEW YORK CITY The Potential Role of Long-acting Steroids Researchers are investigating intravitreal implants. BY MARK S. BLUMENKRANZ, MD Dramatic advances are being made in the emerging field of retinal pharmacotherapy. 1 It is important to remember, however, that laser photocoagulation remains the gold standard of treatment for diabetic retinopathy 2 until it can be directly compared to pharmacotherapy or alternative treatments in well-controlled prospective, randomized clinical trials. Various studies of corticosteroids to treat diabetic macular edema (DME) are under way. Some are being conducted by the Diabetic Retinopathy Clinical Research Network. 3-5 The following is a brief survey of some of the steroid implants under development for DME, known to the author of the time of the preparation of this lecture. FLUOCINOLONE ACETONIDE Early data on a fluocinolone acetonide bioerodable intravitreal implant (Retisert; Bausch & Lomb, Rochester, NY) suggested that steroids work but also highlighted that steroids can be dangerous. 6 The study is being repeated using lower doses. In the initial study, patients showed significant improvement, albeit with complications. If we consider only the reduction in macular thickening and the visual acuity at 6 months, the improvements are obvious. After that, however, the problems appear to overwhelm the benefits with the longer-acting, high-dose steroids. Fifty percent of the eyes had elevated pressures, and approximately 40% required filtration surgery. A small, nonbioerodable fluocinolone acetonide implant (Medidur; Alimera Sciences, Alpharetta, GA) is also under development. It stays in the vitreous cavity and releases drug for up to 2 years, according to the manufacturer. Clinical trials are under way. DEXAMETHASONE The results were somewhat better with this bioerodable polymer implant, which contains the long-acting steroid dexamethasone (Posurdex; Allergan, Inc., Irvine, CA) This was likely because less drug was being released and possibly because of differences in the inherent potency of the active agent. A phase 2 study showed a positive dose response relationship for all groups combined (Figure 1). 7 At day 90 and day 180, there was a statistically significant increase in patients achieving 2 and 3 lines or more of visual acuity after receiving the steroid, compared with no treatment. These were patients who had previously failed laser therapy. Angiograms graded by masked readers indicated that there was a 2-step reduction in leakage compared with untreated controls (Figure 2). This was the first randomized, prospective clinical trial that used optical coherence tomography (OCT) as an endpoint. When used as a surrogate measure for Figure 1. Note positive dose response relationship for all groups combined. JANUARY/FEBRUARY 2009 I SUPPLEMENT TO RETINA TODAY I 13

NEW INSIGHTS INTO THE MANAGEMENT OF DIABETIC MACULAR EDEMA AND RELATED CONDITIONS can be screwed into the eye and removed as needed. A clinical trial is under way. 8 Figure 2. Note 2-step reduction in leakage compared with controls. AWAITING FURTHER STUDY One oversimplification that we occasionally use in teaching is that steroids for DME are beneficial in the short term but less so in the long term. On the other hand, laser therapy is less effective in the short term but very good in the long term. Perhaps combining the two modalities will provide the optimum benefit of short-term plus long-term efficacy while minimizing side effects. We await results from further studies to make this determination. 9 For now, as a monotherapy, intravitreal steroids have not been shown to be superior to focal/grid photocoagulation at improving the chance for vision gain, decreasing the risk of vision loss, or causing regression of edema. 3 This outcome is true whether the eye is pseudophakic at baseline, has had prior macular laser for DME, has a very thickened retina, or relatively poor visual acuity. 3 Whether combining these drugs with laser is shown to be superior to focal/grid laser alone remains to be determined. For now, the standard care for DME remains focal/grid photocoagulation. Figure 3. OCT showed dose-related improvement. improvement, as opposed to vision or fluorescein angiography, OCT showed a fairly dramatic improvement that was also dose-related (Figure 3). Later observations may be confounded by cataract or glaucoma, which impact visual acuity. 7 TRIAMCINOLONE ACETONIDE De Juan and colleagues have developed a nonbioerodable helical coil containing triamcinolone acetonide (Ivation, Surmodics, Eden Prairie, MN), which essentially 1. Blumenkranz MS. The current status of steroids in treating diabetic retinopathy. Retinal Physician. 2007;9:42-47. 2. Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report No. 2. Ophthalmology. 1987;94:761-774. 3. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115:1447 1459. 4. Chieh JJ, Roth DB, Liu M, et al. Intravitreal triamcinolone acetonide for diabetic macular edema. Retina. 2005;25:828-834. 5. Blumenkranz MS. Ongoing studies of intraocular sustained release drug delivery implants for macular edema. Retinal Physician. 2008;Jan. 6. Pearson P, Levy B, Comstock T, and Fluocinolone Acetonide Implant Study Group. Fluocinolone acetonide intravitreal implant to treat diabetic macular edema: 3-Year results of a multicenter clinical trial. Invest Ophthalmol Vis Sci. 2006;47: E-Abstract 5442. 7. Kuppermann BD, Blumenkranz MS, Haller JA, Williams, GA et al. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol. 2007;125:309-317. 8. Dugel PU, Cantrill HL, Eliott D, et al. Clinical safety and preliminary efficacy of an intravitreal triamcinolone implant (I-vation TA) in DME. Poster presented at the Association for Research in Vision and Ophthalmology, May 6 10, 2007, Fort Lauderdale, FL. Abstract 1413. 9. Grover D, Li t, Chang C. Intravitreal steroids for macular edema in diabetes. Cochrane Database of Systematic Reviews. 2008;23:CD005656. 14 I SUPPLEMENT TO RETINA TODAY I JANUARY/FEBRUARY 2009

HIGHLIGHTS OF A SYMPOSIUM HELD IN NEW YORK CITY Diabetes Control and Complications Trial: An Ophthalmologist s Understanding With eye disease progression as its primary endpoint, this trial validates the importance of tight glycemic control. BY SUSAN B. BRESSLER, MD The Diabetes Control and Complications Trial (DCCT), published in the early 1990s, is still relevant today because it relates the importance of a patient s systemic health to eye health and confirms that controlling blood sugar is critical to decreasing disease progression, particularly eye disease. 1 Before the DCCT, animal studies and observational studies linked elevations in blood glucose to severity of diabetic disease complications. 2-7 It was the DCCT, however, that strove to validate the glucose hypothesis by looking directly at an intervention to control and lower blood sugar and ask if it reduces the morbidity associated with diabetes. Fortunately for ophthalmologists, eye disease, because it is so readily classifiable, was the primary endpoint in the DCCT as investigators used ophthalmic variables to monitor treatment efficacy. STUDY DESIGN AND ELIGIBILITY This study involved individuals who had type 1 diabetes. A total of 1,441 relatively young patients without hypertension, significant kidney disease, or hypercholesterolemia were about equally divided between 2 cohorts. Within each cohort, subjects were randomly assigned to intensive or conventional management of their glycemia. The primary cohort joined the study with no retinopathy, and the question they served to address was: By instituting tight control, could you decrease the development Figure 1. Three steps was considered progression. Figure 2. Note positive effect of intensive therapy. JANUARY/FEBRUARY 2009 I SUPPLEMENT TO RETINA TODAY I 15

NEW INSIGHTS INTO THE MANAGEMENT OF DIABETIC MACULAR EDEMA AND RELATED CONDITIONS Figure 3. Glycemic control over 10 years. of diabetic eye disease? The secondary cohort joined the study with mild or moderate nonproliferative disease, and the question they helped answer was: By instituting tight control, could you slow the rate at which the eye disease would progress? CONVENTIONAL VS INTENSIVE THERAPY In the mid-1980s, the goal of conventional therapy was to avoid symptoms of hyperglycemia or hypoglycemia. That meant using injections of insulin once or twice a day; daily self-monitoring of control, blood or urine testing; quarterly feedback of control, using glycosylated hemoglobin (HbA1c) levels; general information about the importance of diet and exercise; and an office visit four times a year. The annual price tag for that type of regimen in late- 1980s dollars was about $1700. In contrast, the goal of intensive treatment in the DCCT was to keep blood glucose values as close to normal as possible, 24/7. To do that, individuals could self-select use of multiple doses of insulin (MDI) per day, or they could use an external insulin pump. They were required to monitor their glycemia levels by finger-stick blood determinations a minimum of four times a day. They received monthly feedback of their HbA1c levels; they were supported monthly with calls from nutritionists and nurse practitioners; and they had monthly clinic visits. The annual cost to deliver that type of care was two to three times more than conventional therapy: $4000 (MDI), $5800 (pump). FOLLOW-UP Seven-field photographs were taken annually and read at a masked reading center. Three steps of progression on the retinopathy scale (1 to 25 steps) was considered progression (Figure 1). Figure 4. Note a five-fold reduction in diabetic eye disease progression by intensive management. Figure 2 shows how well the intensive treatment regimen worked to control blood sugar levels over 24 hours. Even though the intensive group was aiming for preprandial blood glucose concentrations between 70 and 120 mg/dl, they do not quite achieve it, but they are much lower and closer to normoglycemia than the value of 231 ±55 mg/dl obtained in the conventional group. Figure 3 shows the HbA1c profiles over the 10 years of the study. On average, HbA1c levels were 7% for the intensive therapy group and 9% for the conventional therapy group with no overlap between the groups. So the intensive regimen used in the DCCT was effective at decreasing glycemia. Figure 4 shows the primary cohort and the proportion of people who developed a sustained 3 step progression in eye disease, meaning these eyes enrolled without any retinopathy and they progressed to mild non-proliferative disease. Comparing conventional therapy to intensive therapy, there was a five-fold reduction in progression of diabetic eye disease by intensive management. This is very clinically relevant and obviously statistically significant. You can prevent development of mild disease with intensive control. In the secondary cohort (Figure 5), by 10 years, there was a three-fold reduction in progression of diabetic eye disease by intensive management. Figure 6 shows another important endpoint: the need for photocoagulation. Again, there was a three-fold reduction of rates at which these patients required laser treatment. ADVERSE EVENTS With tight glycemic control, the risk of a significant hypoglycemic event increases, and there was a three-fold increase in the incidence of hypoglycemia in the intensive therapy group. Another adverse effect with intensive 16 I SUPPLEMENT TO RETINA TODAY I JANUARY/FEBRUARY 2009

HIGHLIGHTS OF A SYMPOSIUM HELD IN NEW YORK CITY Figure 5. Note three-fold reduction in progression of diabetic eye disease in intensive management group. therapy was an increase in body weight. With tight control, patients are less prone to lose glucose in their urine, rather they are forced to metabolize it, so there is greater potential for weight increase. The intensively managed individuals gained more weight gain, and that can be a real problem among young type 1 diabetics, particularly women. CONCLUSIONS FROM THE DCCT There is undeniable evidence from the DCCT that tight glycemic control reduces the morbidity associated with diabetes. A general recommendation to every patient with diabetes as we extrapolate DCCT data to individuals with type 2 diabetes, as well is to maintain the best control possible, safely within their sensitivity levels to detect impending hypoglycemia, to try to decrease long-term organ damage. In the interest of time, we did not review the DCCT data in depth, which would have emphasized that the benefits get wider and more substantial over time. The DCCT provided positive data monitoring participants over one decade. Imagine how these graphs might continue to separate if participants were monitored for a second or third decade of tight control. Additionally, benefits were seen over a range of ophthalmic endpoints and over the gamut of retinopathy. What s more, investigators looked at kidney disease, cardiovascular disease, and cognitive functioning, all of which showed benefits with tight control. POST-TRIAL OBSERVATIONAL STUDY At the conclusion of the DCCT, most patients agreed to further follow-up within an observational study called the Epidemiology of Diabetes Interventions and Figure 6. Note three-fold reduction of rates at which intensive management group required laser therapy. Complications (EDIC) study. 8 At entry into the EDIC study, all patients were advised to aim for tight control, but they no longer received assistance through the study. The patients originally assigned to conventional management tried to follow the instructions, and their HbA1c levels fell to 8% over the 4-year period. Lacking their accustomed support, the patients who had been in the intensive management group in the DCCT saw their HbA1c levels drift upward. So 4 years after the DCCT, HbA1c levels for both groups were equivalent at 8% in the EDIC study. Despite that, patients who had been in the intensively managed group of the DCCT continued to show a reduction in disease progression, even after they slacked off to a degree. This shows us that a big investment up front still pays dividends in the later years, even if control becomes less stringent. 1. The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986. 2. Engerman R, Bloodworth JM Jr, Nelson S. Relationship of microvascular disease in diabetes to metabolic control. Diabetes. 1977;26:760-769. 3. Engerman RL, Kern TS. Progression of incipient diabetic retinopathy during good glycemic control. Diabetes. 1987;36:808-812. 4. Cohen AJ, McGill PD, Rossetti RG, Guberski DL, Like AA. Glomerulopathy in spontaneously diabetic rat: impact of glycemic control. Diabetes. 1987;36:944-951. 5. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol. 1984;102:520-526. 6. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA. 1988;260:2864-2871. 7. Chase HP, Jackson WE, Hoops SL, Cockerham RS, Archer PG, O Brien D. Glucose control and the renal and retinal complications of insulin-dependent diabetes. JAMA. 1989;261:1155-1160. 8. EDIC Research Group. Retinopathy and nephropathy in patients with Type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000; 342:381-389. JANUARY/FEBRUARY 2009 I SUPPLEMENT TO RETINA TODAY I 17

NEW INSIGHTS INTO THE MANAGEMENT OF DIABETIC MACULAR EDEMA AND RELATED CONDITIONS Treatment of Retinal Venous Occlusive Disease Focus has moved from complications to the primary process of the occlusion or the inflammation. BY MARK S. BLUMENKRANZ, MD In many ways, phenotypically if not genotypically, retinal venous occlusive disease shares certain features with diabetic retinopathy and is the second most common cause of macular edema. 1 In terms of prevalence, it is a major public health problem, with about 130,000 cases per year in the United States, and more than twice as many in other industrialized nations. 2 ROLE OF THROMBOSIS The traditional teaching is that venous thrombosis is the cause of retinal venous occlusion, and there is support for this statement from histopathologic studies as well as intuitively. 3 It is thought that the endothelium becomes damaged in response to hemodynamic stress. When the collagen under the endothelium is exposed, platelets adhere, and thrombi form, occluding the lumen. What is also clear but has not been as well appreciated until the last 4 or 5 years, is that inflammation may play a role in the etiology. Chan, Green, and colleagues showed that in 29 eyes, inflammatory cells were adjacent to the thrombus in about 48% of the cases. 4 In terms of the natural history, the severity of the occlusion and the presenting visual acuity typically determine final vision. The principal complications of branch retinal vein occlusion (BRVO) are macular edema, retinal capillary loss, and neovascularization. Although iris neovascularization rarely occurs with BRVO, it is common in central retinal vein occlusion (CRVO). When evaluating the natural history of CRVO, it is important to pay attention to presenting visual acuity. Patients who present with 20/40 or better vision at their initial visit tend to do well. About two-thirds or more will retain 20/40 or better, whereas only a small fraction of patients who present with poor vision, 20/200 or worse, have a good outcome. 5 So it behooves us to be aggressive with patients who present with poor vision and to be cautious with those who present with good vision. EVOLUTION OF THERAPIES Previously, therapies focused solely on complications, principally macular edema and neovascularization. Newer therapies now focus on the primary process of the occlusion or the inflammation. Some of the seminal studies on BRVO from the 1980s showed that laser photocoagulation was an effective form of therapy. 6 Patients who had grid laser for macular edema were about twice as likely to achieve two lines of vision improvement and twice as likely to achieve 20/40 or better vision as those who received no treatment. Obviously, this study did not look at macular edema treated by steroids, because that treatment did not exist at that time. A significant complication of BRVO is the development of retinal neovascularization or vitreous hemor- Figure 1. Hemorrhage resolved and neovascularization regressed after scatter laser photocoagulation was applied to areas of capillary nonperfusion. 18 I SUPPLEMENT TO RETINA TODAY I JANUARY/FEBRUARY 2009

HIGHLIGHTS OF A SYMPOSIUM HELD IN NEW YORK CITY rhage. Patients who had neovascularization and then received laser therapy had a reduced chance of bleeding compared to the control patients. 7 Interestingly, using the laser, you could reduce by half the number of patients who went on to develop neovascularization or vitreous hemorrhage, although this did not result in a difference in the final visual acuity. Although laser was not recommended in the comment section of that article, many clinicians apply laser when retinal neovascularization develops to reduce the chance of vitreous hemorrhage. 8 Figure 1 shows a young patient whom I treated. You can see bleeding from an area of neovascularization. We applied scatter laser photocoagulation to areas of capillary nonperfusion, and the hemorrhage resolved, the neovascularization regressed, and patient had good visual acuity. The Central Retinal Vein Occlusion Study (CVOS) Group found average visual acuity stayed about the same in the laser group pre- and post-treatment, as it did in the control group. 9 There was no visual benefit, even though the macular edema did improve on fluorescein angiography. This is one of the first studies that showed a fundamental disconnect between vision and related surrogate measures, such as fluorescein angiographic macular edema or OCT thickness. ANOMALIES EXIST Whenever you mine old, well-done studies, such as the CVOS, you may find data anomalies. One might assume intuitively that if laser works well for iris neovascularization, it would work even better if you treated earlier. This was not the case. Eyes that had more than a certain amount of capillary nonperfusion on fluorescein angiography and treated with scatter photocoagulation had less iris or angle neovascularization than eyes not treated with scatter laser. However, scatter laser did not reduce the risk of neovascular glaucoma in these eyes compared with eyes receiving scatter laser after iris or angle neovascularization developed. 10 As a result, the conventional wisdom and the standard of care based on this large trial is that we should not treat ischemic CRVOs without iris neovascularization with scatter photocoagulation. CONCLUSION Retinal vein occlusion remains a common cause of vision loss and macular edema that may benefit from laser photocoagulation in addition to newer pharmacotherapies. 1. Central Vein Occlusion Study Group. Natural history and clinical management of central retinal vein occlusion. Arch Ophthalmol. 1997;115:486-491. 2. Klein R, Klein BE, Moss SE. Meuer SM. The epidemiology of retinal vein occlusion: the Beaver Dam Eye Study. Trans Am Ophthalmol Soc. 2008;98:133-141. 3. Klein BA. Occlusion of the central retinal vein; clinical importance of certain histopathologic observations. Am J Ophthalmol. 1953;36:316-324. 4. Green WR, Chan CC, Hutchins GM, Terry JM. Central retinal vein occlusion: a prospective histopathologic study of 29 eyes in 28 cases. Trans Am Ophthalmol Soc. 1981;79:371-422. 5. Central Vein Occlusion Study Group. Central vein occlusion study of photocoagulation therapy: baseline findings. Online J Curr Clin Trials. 1993;Oct 14:doc No. 95. 6. Finkelstein D. Argon laser photocoagulation for macular edema in branch vein occlusion. Ophthalmology. 1986; 93:975-977. 7. Branch Vein Occlusion Study Group: Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion: a randomized clinical trial. Arch Ophthalmol. 1986; 104:34-41. 8. Jain A, Blumenkranz MS, Paulus Y, et al. Effect of pulse duration on size and character of the lesion in retinal photocoagulation. Arch Ophthalmol. 2008;126:78-85. 9. The Central Vein Occlusion Study Group. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. M report. Ophthalmology. 1995;102:1425-1433. 10. The Central Vein Occlusion Study Group. A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion. N report. Ophthalmology. 1995; 102:1434-1444. JANUARY/FEBRUARY 2009 I SUPPLEMENT TO RETINA TODAY I 19

NEW INSIGHTS INTO THE MANAGEMENT OF DIABETIC MACULAR EDEMA AND RELATED CONDITIONS Considering Anti-VEGF Therapies for Vein Occlusions Studies reveal the relationship between VEGF and neovascularization. BY DAVID M. BROWN, MD As we search for new therapies to treat retinal vein occlusions, it is important to recall what we know about the mechanisms that are in play. An ischemic CRVO occurs when venous thrombosis is closer to the optic nerve head and anterior to most preexisting collateral veins, causing venous pressure to increase to the point where arterial flow is compromised. 1 Whether this occurs at the lamina cribrosa or more posteriorly is inconsequential. What is important is the location of the occlusion in relation to the naturally occurring collaterals. With a more posterior occlusion within the CRVO as it passes through the optic nerve, collateral veins allow limited flow, so there is still arterial pressure, creating a nonischemic CRVO. According to Hayreh, the outlook is poor for ischemic CRVOs: 70% develop rubeosis; 50% develop neovascular glaucoma. 2 DIFFERENTIATING CRVO FROM ISCHEMIC CRVO For the Central Vein Occlusion Study (CVOS), 3 researchers primarily used fluorescein angiography to differentiate ischemic from nonischemic CRVOs. They preferred the term nonperfused because the nonperfusion on the angiogram does not differentiate if the retina is ischemic or infarcted. The CVOS defined a nonperfused central vein occlusion as one with at least 10 disc areas of nonperfusion. Substantial hemorrhage often exists in a CRVO, so determining if areas on angiography are nonperfused can be difficult. If hemorrhage obscured the view, a CRVO was termed indeterminate. The CVOS did determine, however, that most indeterminate central vein occlusions have a natural history similar to nonperfused vein occlusions. In summary, angiography can be used to differentiate perfused from nonperfused central vein occlusions, and if there is too much blood to make this differentiation, the vein occlusion should be considered nonperfused. In natural history studies, Hayreh has shown that several prognostic tests are sensitive and specific identifiers for ischemic CRVO (Figure 1). 1 The CVOS found that if one takes into account the visual acuity and extent of hemorrhage, then additional data from pupil responses to electroretinogram provide further prognostic information as to whether the eye will progress from nonperfusion to neovascularization. Hayreh reported the cumulative risk of developing iris neovascularization, angle neovascularization, and neovascular glaucoma is highest during the first 90 days. After 90 to 180 days, venous-venous collaterals often enlarge enough to decrease venous pressure, and improvement can occur. By about 9 months, the curve is flat (Figure 2). Figure 1. Prognostic tests for ischemic CRVO. Figure 2. Note cumulative risk is highest in first 90 days. 20 I SUPPLEMENT TO RETINA TODAY I JANUARY/FEBRUARY 2009

HIGHLIGHTS OF A SYMPOSIUM HELD IN NEW YORK CITY Figure 3. RAVE Trial: Preliminary analysis of first 10 subjects. progression to neovascularization in a way that differs from the natural history. Ongoing studies, such as the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study, 5 should tell us how steroid therapy compares with the natural history. And thus far, intravitreal anti-vegf therapy has shown promising short-term results in uncontrolled studies. Is there a rationale for using an anti-vegf agent? Pe er looked at neovascular glaucoma enucleation specimens going back to the 1920s and found messenger RNA upregulation of VEGF. 6 In another study, Boyd and colleagues performed anterior chamber taps in patients with neovascular glaucoma before and after laser treatment. They found neovascularization occurred when aqueous VEGF concentrations were 849 pg/ml to 1569 pg/ml and regressed fully when they fell below 550 pg/ml. 7 We also have good studies showing increased VEGF in proliferative diabetic retinopathy and vein occlusions. 8,9 These data confirm that VEGF correlates to neovascularization. Figure 4. Despite improved retinal thickening,va improved only slightly. Figure 5. Note vision gains with monthly ranibizumab injections. PROMISING INTERVENTIONS The list of CRVO interventions is littered with good intentions and bad results. Laser anastomosis has been shown to work in case series, but usually an adequate anastomosis cannot be created. 4 Radial optic neurotomy and optic nerve sheath fenestration have not been shown convincingly to alter visual acuity outcomes or RAVE TRIAL In the ongoing Rubeosis Anti-VEGF (RAVE) Trial for Ischemic CRVO, 10 monthly intravitreal injections of ranibizumab (Lucentis, Genentech, Inc.) were administered over 9 months. Optical coherence tomography, wide-field and conventional angiography, and Goldmann perimetry were performed monthly. The goal was to prevent neovascular glaucoma and visual field loss related to panretinal photocoagulation, and to learn more about nonperfused CRVO. Preliminary analysis of the first 10 subjects suggests that one went from marked retinal thickening to resolution of edema and even loss of normal retinal thickness (Figure 3). Despite these large improvements in retinal thickening, most subjects had only slightly improved visual acuity, usually at very low (poor) levels (Figure 4). Figure 5 shows best-corrected visual acuity changes using the 20-minute ETDRS refraction: 60% had a 4-line gain with monthly ranibizumab to month 9. Although some of these follow-up visual acuities are only in the 20/100 to 20/200 range, visual acuity appears definitively better than the initial acuity and may have some value to the patient. The next question was: What would happen when treatment was stopped? Would regression of effect occur because the treatment had led to upregulation of VEGF? JANUARY/FEBRUARY 2009 I SUPPLEMENT TO RETINA TODAY I 21

NEW INSIGHTS INTO THE MANAGEMENT OF DIABETIC MACULAR EDEMA AND RELATED CONDITIONS In about two-thirds of the eyes, the swelling did not return (Figure 6). In about one-third, the swelling returned immediately, and those subjects lost the visual acuity they had gained (Figure 7). Some of the gains from baseline to month 9 were lost by not treating from month 9 to month 12 (Figure 8). Thus far, it appears much of the edema in these cases is VEGF-driven and not necessarily related only to venous pressure, because if you give enough anti-vegf, the edema resolves, and you can prevent it if you keep giving anti-vegf. Figure 6. Note response after treatment was stopped. Figure 7. Note VA after treatment was stopped. Figure 8. Some gains were lost by not treating from month 9 to month 12. QUESTIONS REMAIN Questions remain on the management of nonperfused CRVO. Why is there a disconnect between edema and neovascularization? Why do some patients with or without edema get neovascularization? We should have more definitive data in the next year or so from trials that are currently recruiting, such as SCORE, BRAVO (A Study of the Efficacy and Safety of Ranibizumab Injection in Patients With Macular Edema Secondary to Branch Retinal Vein Occlusion), CRUISE (A Study of the Efficacy and Safety of Ranibizumab Injection in Patients With Macular Edema Secondary to Central Retinal Vein Occlusion), and the Branch Retinal Vein Occlusion or Central Vein Occlusion with Macular Edema Posurdex Implant Study, which should put us closer to answering some of these questions. 1. Hayreh SS, Klugman MR, Beri M, Kimura AE, Podhajsky P. Differentiation of ischemic from non-ischemic central retinal vein occlusion during the early acute phase. Graefes Arch Clin Exp Ophthalmol. 1990;228:201-217. 2. Hayreh, SS; Rojas, P; Podhajsky, P; Montague, P; Woolson, RF. Ocular neovascularization with retinal vascular occlusion-iii. Incidence of ocular neovascularization with retinal vein occlusion. Ophthalmology. 1983;90:488 506. 3. The Central Vein Occlusion Study Group. A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion. The Central Vein Occlusion Study Group N report. Ophthalmology. 1995;102:1434 1444. 4. Fekrat S, Goldberg MF, Finkelstein D. Laser-induced chorioretinal venous anastomosis for nonischemic central or branch retinal vein occlusion. Arch Ophthalmol. 1998;116:43-52. 5. Scott IU, Ip MS. It s time for a clinical trial to investigate intravitreal triamcinolone for macular edema due to retinal vein occlusion: the SCORE study. Arch Ophthalmol. 2005;123:581-582. 6. Pe er J, Folberg R, Itin A, Gnessin H, Hemo I, Keshet E. Vascular endothelial growth factor upregulation in human central retinal vein occlusion. Ophthalmology. 1998;105;412-416. 7. Boyd SR, Zachary I, Chakravarthy U, et al. Correlation of increased vascular endothelial growth factor with neovascularization and permeability in ischemic central vein occlusion. Arch Ophthalmol. 2002;120:1644-1650. 8. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1519-1520. 9. Augustin AJ, Keller A, Koch F, Jurklies B, Dick B. Effect of retinal coagulation status on oxidative metabolite and VEGF in 208 patients with proliferative diabetic retinopathy. Klin Monatsbl Augenheilkd. 2001;218:89-94. 10. Brown DM. Rubeosis anti-vegf (RAVE) trial for ischemic CRVO: 1-year data. Paper presented at: 40th Annual Scientific Meeting of the Retina Society; September 2007; Boston, MA. 22 I SUPPLEMENT TO RETINA TODAY I JANUARY/FEBRUARY 2009