DIABETIC MACULAR EDEMA

CM EA CT IV ITY Steroids for the Treatment of DIABETIC MACULAR EDEMA November/December 2011 Supplement to Retina Today A Roundtable Discussion Fea...
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CM EA CT IV ITY

Steroids for the Treatment of

DIABETIC MACULAR EDEMA November/December 2011

Supplement to Retina Today

A Roundtable Discussion Featuring:

David S.Boyer, MD

Pravin U.Dugel, MD

Szilárd Kiss, MD

Dante J.Pieramici,MD

STEROIDS FOR THE TREATMENT OF DIABETIC MACULAR EDEMA Release date: November 2011. Expiration date: November 2012. Jointly sponsored by the Dulaney Foundation and Retina Today. Supported by an educational grant from Alimera Sciences. STATEMENT OF NEED Diabetic retinopathy is the leading cause of new cases of blindness in adults ages 20-74.1 The estimated prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy was recently found to be 28.5% and 4.4% among US adults with diabetes, respectively.2 This finding is significant when considered in the context of explosive growth in the incidence of type 2 diabetes, which commonly leads to diabetic retinal disease.3 A gap between optimal and actual care of diabetic eye disease also exists among patients with type 1 diabetes. During a 25-year period, the Wisconsin Epidemiologic Study of Diabetic Retinopathy found relatively high cumulative rates of progression of diabetic retinopathy and proliferative diabetic retinopathy in this population.4 A separate analysis of more recently diagnosed patients from the same study demonstrated the potential benefit of closing this gap.5 Improvements in diabetes care were believed to possibly have contributed to a much lower prevalence and less severe retinopathy than expected on the basis of a previous report from the same region of Wisconsin. To address these gaps, retina specialists and other ophthalmologists must master new insights on pathogenesis and a proliferation of therapeutic advances spawned by the introduction of new technologies and techniques in recent years.6 1. American Diabetes Association: Diabetic retinopathy (Position Statement). Diabetes Care. 2000; 23 (Suppl. 1): S73-S76. 2. Zhang X, Saaddine JB, Chou CF, et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA. 2010;304(6):649-656. 3. McGarry JD. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes. 2002;51(1):7-18. 4. Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of retinopathy in persons with type 1 diabetes. Ophthalmology. 2008;115(11):1859-1868. 5. Lecaire T, Palta M, Zhang H, Allen C, Klein R, D'Alessio D. Lower-than expected prevalence and severity of retinopathy in an incident cohort followed during the first 4-14 years of type 1 diabetes: the Wisconsin Diabetes Registry Study. Am J Epidemiol. 2006;164(2):143-150. Epub 2006 May 26. 6. Lattanzio R, Torres Gimeno A, Battaglia Parodi M, Bandello F. Retinal vein occlusion: current treatment. Ophthalmologica. 2010;225(3):135-143. [Epub ahead of print]

TARGET AUDIENCE This certified CME activity is designed for retina specialists and general ophthalmologists involved in the management of patients with retinal disease. LEARNING OBJECTIVES Upon completion of this activity, the participant should be able to: 1. explain the multiple pathophysiology of DME; 2. discuss the evidence regarding the association between inflammation and DME and the implications of treatment; 3. identify the relationship between ocular anatomy and visual function in DME; and 4. discuss the evolution of the diagnosis, classification, and monitoring of DME in light of emerging therapeutic options. METHOD OF INSTRUCTION Participants should read the 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 self-assessment test, you may print out a CME credit letter awarding 1 AMA PRA Category 1 Credit.™ The estimated time to complete this activity is 1 hour. 2 I SUPPLEMENT TO RETINA TODAY I NOVEMBER/DECEMBER 2011

ACCREDITATION AND DESIGNATION 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 enduring material for a maximum of 1 AMA PRA Category 1 Credit.™ Physicians should claim only the 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 US Food and Drug Administration guidelines, anyone in a position to affect the content of a CME activity is required to disclose to the activity 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. FACULTY CREDENTIALS David S. Boyer, MD, is a Clinical Professor of Ophthalmology at the University of Southern California Keck School of Medicine, Department of Ophthalmology, in Los Angeles. Dr. Boyer may be reached at [email protected]. Pravin U. Dugel, MD, is Managing Partner of Retinal Consultants of Arizona and Founding Member of the Spectra Eye Institute. He can be reached via e-mail at [email protected]. Szilárd Kiss, MD, is an Assistant Professor of Ophthalmology and Director of Clinical Research at Weill Cornell Medical College and an Assistant Attending Physician at the New York Presbyterian Hospital. He may be reached at +1 646 962 2020; or via e-mail at [email protected]. Dante J. Pieramici, MD, practices at California Retina Consultants in Southern California. He is the Director of the California Retina Research Foundation and Clinical Assistant Professor of Ophthalmology at the Doheny Eye Institute. He may be reached at +1 805 963 1648; fax: +1 805 965 5214; or e-mail at [email protected]. FACULTY/STAFF DISCLOSURE DECLARATIONS David S. Boyer, MD, has received grant/research support from Alcon Laboratories, Inc., Allergan, Inc., Genentech, and Novartis. He is a consultant and speaker for Alcon Laboratories, Inc., Genentech, Novartis, and Pfizer. Pravin U. Dugel, MD, states that he is a consultant to Alcon, Abbott Medical Optics, Macusight, Neovista, ArcticDx, Ora, and Regeneron, and is a minor shareholder in ArcticDx and Neovista. Szilárd Kiss, MD, states that he is a consultant to Alimera, Allergan, and Optos and receives research support from Genentech and Regeneron. Dante J. Pieramici, MD, states that he is consultant for Genentech, Lumenis, and Opthotech; is on the speakers’ bureau for Genentech, and Novartis; and receives research grants from Genentech, QLT, Novartis, Optimedica, and Thrombogenics. All of those involved in the planning, editing, and peer review of this educational activity report no financial relationships. ■

STEROIDS FOR THE TREATMENT OF DIABETIC MACULAR EDEMA

Figure 1 reprinted from Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008 ;115(9):1447-1449; with permission from Elsevier.

Steroids for the Treatment of Diabetic Macular Edema CLINICAL TRIALS IN DME David S. Boyer, MD: In the last 3 to 4 years, there have been several clinical trials that have demonstrated efficacy of new paradigms for the treatment of diabetic macular edema (DME). I’d like to review some of these studies and discuss what has been learned thus far. Dante J. Pieramici, MD: The Diabetic Retinopathy Clinical Research Network (DRCR.net) trial was one of the first phase 3 clinical trials to demonstrate the positive role of antivascular endothelial growth factor (anti-VEGF) for

DME. Protocol I compared ranibizumab (Lucentis, Genentech) either with prompt or deferred laser to laser alone and laser plus steroids. The results of this trial showed for the first time that anti-VEGF could improve vision to a significant level, greater than that with the standard of care, which is laser photocoagulation.1 The results were striking, and they have changed how many of us are managing our patients with DME. We can now not only stabilize vision, which is what we could achieve with laser photocoagulation, but we can also expect vision improvement for many of these patients.

Figure 1. Table 5 from DRCR.net Protocol B. Patients with vision worse than 20/200 had better outcomes with steroids than with laser. NOVEMBER/DECEMBER 2011 I SUPPLEMENT TO RETINA TODAY I 3

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Pravin U. Dugel, MD: Going back to where much of this began, we have to look at Protocol B from the DRCR.net, which compared laser photocoagulation with corticosteroids.2 This trial was performed because clinicians were beginning to use corticosteroid injections (Kenalog, Bristol-Myers Squibb) more frequently to treat DME, and there was some important information that was gained. The results of Protocol B certainly taught me that laser still has a place in DME. It is unfortunate, however, that this publication led to a misunderstanding as to the role of steroids in this disease. In Protocol B there was a comparison made with steroids in patients who had visual acuity of 20/40. I would submit that most of us do not use steroids as first-line therapy for patients who have vision close to 20/40 or better. Rather, we reserve the use of steroids for patients who have worse vision. Indeed, Table 5 from Protocol B (Figure 1) shows the subdivision of visual acuity data: patients who had vision of 20/200 or worse had better outcomes with steroids than with laser photocoagulation. This illustrates that although both laser and steroids have a place in treating DME, the best choice depends on the degree to which the disease has progressed. Szilárd Kiss, MD: It is encouraging that we are moving beyond laser photocoagulation as the only treatment option for DME. As we learn more about the underlying pathology of DME, we are gaining more data on the role of antivascular endothelial growth factor (anti-VEGF), but also the role of inflammation, which is where steroids come into play. In the DRCR.net Protocol I study, the subset of pseudophakic patients did very well with steroid treatment in comparison to anti-VEGF treatment. As Dr. Dugel mentioned, the disease stage is a critical factor in how a patient responds to a particular treatment—there may be a significant difference in response between a patient with long-term diabetic retinopathy and one who is newly diagnosed. And then, we have to consider patients who have been receiving a combination of treatments. For example, there were patients in the FAME clinical trial for the fluocinolone acetonide insert (Iluvien, Alimera Sciences) who had received laser and then the insert; however, during the 2-3 year follow-up, they were also receiving whatever the “standard of care” was, and so the comparison arm was not to just laser alone, but it was also to anti-VEGF injections and other treatments that may have been given. Also, there were clearly patients who had macular edema for more than 3 years, and there was a significant added benefit to using the steroid in addition to laser and in 4 I SUPPLEMENT TO RETINA TODAY I NOVEMBER/DECEMBER 2011

addition to what we can presume was anti-VEGF during that time period.3 Dante Pieramici, MD: Going back to Protocol I from the DRCR.net, I was amazed that patients who were pseudophakic seemed to do equally well with steroids plus laser as they did with ranibizumab plus laser. Dr. Dugel: We are learning that DME is a continually evolving disease. As time goes on, we continue to gain more insight. We will increasingly apply all available treatment modalities either alone or in combination depending on the stage of the disease. DME CLASSIFICATION Dr. Boyer: The old classification with which we are familiar is clinically significant macular edema (CSME).4,5 With the new treatments (steroids, anti-VEGF) does this classification still stand? Additionally, how do you utilize optical coherence tomography (OCT)? This is an important point, as certain cases of CSME require slit lamp and a fine microscopic diagnosis. How are the new modalities of imaging, such as spectral-domain OCT (SD-OCT) changing your treatment? Dr. Dugel: We are still learning how to classify macular edema. Currently the first step in choosing my treatment algorithm is determining whether the DME has a mechanical etiology, and if it does, I tend to use a surgical approach. It not, I will treat with a medical approach. If I see that the disease is purely focal, laser photocoagulation still has an important role; however, I usually see patients when the disease has progressed to diffuse or ischemic DME and has become more complex. This is where combination treatments are most effective. How should we follow treatment efficacy? OCT is a good indicator of VEGF, but as we know, DME is more than a VEGF-driven disease. In some cases, there is a significant disconnect between what we see on OCT and what we see in functional testing.6-8 The FAME studies have recently shown this, as have other previous studies evaluating therapy for DME. The bottom line is that a thinner retina is not always better because neuronal loss is a factor in DME; OCT, although helpful, is not the sole indicator of progress; and, finally, DME is more than a VEGF driven disease—it is multifactorial. Dr. Kiss: When patients come in with newly diagnosed diabetes or for one of their early eye exams, I take both OCT and fluorescein angiography (FA) into consideration. If I see even just 1 or 2 cysts on OCT or

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EMERGING DATA ON DME TREATMENTS

Laser vs Triamcinolone: No Injection Benefit at 3 Years Results from a subset of patients who completed the 3-year follow-up of the Diabetic Retinopathy Clinical Research Network (DRCR.net) trial comparing focal/grid photocoagulation and intravitreal triamcinolone are consistent with previously published 2-year results, according to a report in the Archives of Ophthalmology.1 The 3-year data do not indicate a long-term benefit in visual acuity for 1- or 4-mg doses of preservative-free intravitreal triamcinolone compared with focal/grid photocoagulation for the treatment of diabetic macular edema. In the randomized trial, eyes with diabetic macular edema and visual acuities of 20/40 to 20/320 were randomly assigned to focal/grid photocoagulation or 1 mg or 4 mg of triamcinolone. Although the primary trial outcome was assessed at 2 years, 115 eyes in the laser group, 93 eyes in the 1-mg triamcinolone group, and 98 eyes in the 4-mg triamcinolone group had 3-year follow-up data at the time the trial ended. Between 2 and 3 years, more eyes improved than worsened in all three treatment arms. Mean visual acuity increased by more than 5 letters in the laser group vs no mean change in each triamcinolone group. Moreover,

leakage or peripheral nonperfusion on FA, I explain to the patient that the cascade of DME has begun if it is not yet CSME. I then will talk to the patient about systemic control and how we will treat the DME. As our diagnostic technology improves, it allows us to treat patients earlier. If there is obvious vitreomacular traction or another component that may be amenable to surgical intervention, then we will go down that path. In general, however, I am loosening my criteria in terms of how much edema is present to initiate treatment. In terms of what my first-line of treatment is, if there is a circinate exudate coming from a focal point, I will use laser, particularly if it is not directly in the macula. However, I tend to use combination therapy for the majority of my patients. I think that some of us forget to also tell our patients that no matter what we do, if they do not work to control their blood pressure and blood glucose levels, the DME will need to be treated far more frequently. Dr. Pieramici: I still find the classification system of

51 eyes in the laser group, 23 eyes in the 1-mg group, and 37 eyes in the 4-mg group had improvement of 10 or more letters from baseline to 3 years, and 14, 24, and 22 eyes, respectively, had worsening of 10 or more letters. Optical coherence tomography demonstrated that eyes in all 3 treatment groups had a decrease in central subfield thickness from year 2 to 3. At 3 years, central subfield thickness was less than 250 µm in 75 eyes in the laser group, 37 eyes in the 1-mg triamcinolone group, and 45 eyes in the 4-mg triamcinolone group. Based on the 3-year cumulative probability of cataract surgery for all eyes that were phakic at baseline, 83% eyes receiving 4-mg triamcinolone will require cataract surgery, compared with 31% in the laser group and 46% in the 1-mg group (P < .001). Conversely, it is predicted that few eyes will require surgery due to glaucoma. Mean intraocular pressure was 6 mm Hg in the laser group, 17 mm Hg in the 1-mg triamcinolone group, and 16 mm Hg in the 4-mg triamcinolone group, with 6 eyes, 14 eyes, and 10 eyes, respectively, having an intraocular pressure greater than 21 mm Hg. 1. Diabetic Retinopathy Clinical Research Network (DRCR.net), Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris F, Glassman AR, Hartnett E, Ip MS, Kim JE, Kollman C. Three-year follow up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009;127(3):: 245-251.

CSME helpful. My initial thoughts when I see a patient for the first time include: Is there CSME and is it involving the center of the fovea? If CSME is present but it is not involving the foveal center, then I will use laser. When the edema involves the foveal center, I will tend to use agents like anti-VEGF or steroids, which more directly address the edema. OCT and FA can be very complimentary to making the diagnosis and deciding on how you are going to treat these patients, OCT determining foveal involvement and helping us quantify the efficacy of treatment. FA, however, in my opinion, is more important for determining the stage of the disease and for identifying ischemia. Dr. Boyer: Do you use widefield FA, and if so, do you alter your treatment decisions based on this mode of imaging? Dr. Kiss: I use widefield FA almost exclusively. The evidence toward the significance of the peripheral retina is NOVEMBER/DECEMBER 2011 I SUPPLEMENT TO RETINA TODAY I 5

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emerging, so more data are required. However, it makes sense that viewing the retina at 200° offers an advantage. For example, we may not see anything on examination in diabetics who have hemoglobin A1c levels of 9 or 10, but then all of the sudden, standard of FA will reveal large areas of ischemia and nonperfusion that clearly must have been visible in the periphery at an earlier stage. We have looked at widefield FA compared with standard fields and how ischemia is related to ME.9 There appears to be a loose association between the amount of ischemia and, although not necessarily the amount, but the presence of edema. So if the periphery plays a role, then how do we use this in clinical practice? Targeted panretinal laser photocoagulation (PRP) has been tried in the past, but I do not think that these attempts were looking far enough out into the retina. Lasering the entire retina, even the perfused retina, may not be necessary if the patient has controlled his or her diabetes and hypertension. Dr. Boyer: We also have indirect laser that can go further out and treat some areas in the peripheral retina, increasing access. Does anyone else use widefield FA?

starting to understand this. Remember that decades ago we did not refer to diabetic retinopathy as such, rather, it was termed diabetic retinitis. Steroids have a powerful effect on DME because of the inflammatory factors involved in the disease. I remember hearing the late Judah Folkman, MD, saying that there are no drugs he knew of that changed a cell as profoundly and in so many ways as a steroid. It is not just the type of steroid that we choose, but the dose of the steroid as well as the stage of disease in which we use the steroid that determines its efficacy. The same steroid may have different effects depending on its dose and the pharmacokinetics of how it is delivered. We are at the tip of the iceberg in our knowledge concerning steroids and the role of inflammation in DME. A bolus of a drug may work very differently than drug released in a sustained zero order or near zero order kinetics distribution (Figure 2). The data from

THE ROLE OF INFLAMMATION IN DME Dr. Boyer: Dr. Dugel, you indicated that depending on the stage of diabetic change, there may be different factors in play, including an early role of inflammation. How does inflammation play a role in this condition? Dr. Dugel: There is little doubt that inflammation plays an important role in DME. I think we are

Figure 2. The Iluvien insert releases fluocinolone acetonide in a sustained zero order or near zero order kinetics distribution.

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Figure 2 reprinted from Kane FE Burdan J, Cutino A, Green KE. Iluvien™: a new sustained delivery technology for posterior eye disease. Expert Opin Drug Delivery. 2008;5(9):1039-1046; with permission from Elsevier.

Dr. Pieramici: We use widefield FA to a limited extent. In my opinion, you can achieve a similar evaluation of the patient just using standard-field FA with nice sweeps into the periphery. FA is a helpful staging tool because there are patients with very severe nonproliferative or early PDR that might be overlooked with ophthalmoscopic exam alone. Knowing the patient is going to need PRP might also push us to address non-center involved CSME or non-CSME prior to initiating the PRP.

“It is not just the type of steroid that we choose, but the dose of the steroid as well as the stage of disease in which we use the steroid that determines its efficacy.” -Pravin U. Dugel, MD

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Ranibizumab Plus Laser Resulted in Visual Improvement in Diabetic Macular Edema Intravitreal injections of ranibizumab (Lucentis, Genentech, Inc.) in combination with prompt or deferred laser treatment, resulted in better vision than laser treatment alone in patients with diabetic macular edema (DME), a study found.1 The National Institutes of Health (NIH) study, published online in Ophthalmology, showed that nearly 50% of patients who received ranibizumab plus prompt or deferred laser experienced substantial visual improvement after 1 year, compared with 28% who received laser treatment alone. "These results indicate a treatment breakthrough for saving the vision of people with diabetic macular edema," Neil M. Bressler, MD, chair of the Diabetic Retinopathy Clinical Research Network (DRCR.net) and Chief of the Retina Division at the Wilmer Eye Institute, Johns Hopkins University, in Baltimore, said in a news release. “Eye injections of ranibizumab with prompt or deferred laser treatment should now be considered for patients with characteristics similar to those in this clinical trial.” The study involved 52 clinical sites within the DRCR.net and included a total of 854 eyes of 691 people. Participants, who were on average in their early 60s, were diagnosed with type 1 or 2 diabetes and macular edema. Patients were randomly assigned to one of four study groups: sham injection plus prompt laser treatment (n = 293); ranibizumab 0.5 mg plus prompt laser treatment (n = 187); ranibizumab 0.5 mg plus deferred laser treatment (≥24 weeks; n = 188), or triamcinolone 4 mg plus prompt laser treatment (n = 186). In general, treatment was continued until vision or retinal thickness returned to normal. Injections of ranibizumab could be given as often as every 4 weeks, and triamcinolone injections or laser treatments could be administered as often as every 16 weeks. At the 1-year follow-up, mean change in the visual acuity letter score from baseline was significantly greater for patients who had received ranibizumab with prompt (9 ±11, P < .001) or deferred laser (9 ±12, P < .001) treatment compared with the group treated with laser alone (3 ±13). Visual acuity in patients treated with prompt or deferred laser treatment improved by at least 2 lines compared with baseline. Fewer than 5% of eyes in these groups experienced a

visual loss of 2 or more lines, with similar results for the prompt and deferred treatment groups. In comparison, 30% of eyes that received laser treatment alone or triamcinolone plus laser gained 2 or more lines, while 13% to 14% of eyes lost 2 or more lines. Reduction in mean central subfield thickness in the triamcinolone plus prompt laser group was similar to both ranibizumab groups and greater than the sham plus prompt laser group. In the subset of eyes pseudophakic at baseline (n = 273), visual acuity improvement in the triamcinolone plus prompt laser group was comparable with the ranibizumab groups. However, patients who received triamcinolone injections reportedly had greater complication rates. About 30% of people in the triamcinolone group developed high intraocular pressure (IOP) requiring medications, and about 60% developed cataracts that required surgery. No systemic events attributable to study treatment were apparent, the study authors said. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups, whereas elevated IOP and cataract surgery were more frequent in the triamcinolone plus prompt laser group. DRCR.net researchers will continue to monitor the study participants for at least 3 years to obtain additional information about the safety and effectiveness of these treatments for DME. “This is a seminal study of which ophthalmology should be very proud,” George A. Williams, MD, a board member of the American Academy of Ophthalmology, and Ophthalmology Department Chair of the Oakland University William Beaumont School of Medicine, said in a news release. “First and most importantly, it provides patients an improved therapy for diabetic macular edema. Second, the DRCR Network study is the first multicenter, randomized clinical trial to show how ranibizumab and the laser work together to improve treatment." Although ranibizumab is US Food and Drug Administration (FDA)-approved for use in age-related macular degeneration (AMD), its use for DME is off-label.The study was supported by the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, parts of the NIH. For more information about this clinical trial (NCT00444600), visit www.clinicaltrials.gov. 1. Elman M, Aiello L, Beck R, et al. Randomized trial evaluating ranibizumab plus promptor deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064-1077.

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clinical trials, such as FAME3 and other studies, clearly show that there is a significant difference in effect when you manipulate how a drug is released. Dr. Boyer: Not all steroids are equal. For example, there are common genes that are upregulated by fluocinolone acetonide, dexamethasone, and triamcinolone acetonide, but there are unique genes that each of these activate. Additionally, the side-effects profiles for these 3 steroids are different. Our experience with intravitreal injections of triamcinolone acetonide is different than that with sustained-release fluocinolone acetonide and sustained-release dexamethasone (Ozurdex, Allergan, Inc.). Dr. Kiss: I agree. Just as with the anti-VEGF agents where we would agree that the molecular makeup of pegaptanib sodium (Macugen, Eyetech) is not the same as ranibizumab, which is in turn not the same as aflibercept (Eylea, Regeneron), there are different molecules that make up each different steroid. With steroids, this difference is even greater than antiVEGF because they have a stronger and more broad effect. In regard to the treatment paradigm, patients with diabetes and DME tend to be younger than our patients with age-related macular degeneration (AMD) and have more chronic disease than those with retinal vein occlusion (RVO), so DME may require a sustained-delivery drug release more because patients will be on a drug regimen for a longer period of time. Injecting a patient aged 50 years frequently with anti-VEGF or steroids is not an optimal regimen for the long term. DME is where sustained-release drug formulations will play a significant role. I think that we need to gain a better understanding of how these steroids affect genes at a micro-level in the retina. If we can find the exact amount of steroid that is effective over a period of time with minimal side effects, we will have an even better treatment for some of our patients. Dr. Pieramici: Steroids as a treatment make perfect sense in the presence of inflammation. Injecting intravitreal triamcinolone has been the approach that many of us have taken because it is convenient and seems to last longer than injecting a bolus of dexamethasone. However, we have essentially been treating a disease that is more akin to a marathon with an approach suited to a 100-yard dash. With an intravitreal injection of triamcinolone, we treat and the ME comes back, so we treat again, and it comes back, and 8 I SUPPLEMENT TO RETINA TODAY I NOVEMBER/DECEMBER 2011

“DME is a chronic disease that affects the working population, and having patients come in for a monthly injection of anti-VEGF, for example, is not a sustainable solution.” -David S. Boyer, MD so forth. A lower level sustained release of a steroid will most likely have a better long-term effect for maintaining reduction in ME and stabilizing vision in patients. Dr. Kiss: We always talk about the VEGF pathway and the inflammatory pathway, when in fact, VEGF is part of the inflammatory pathway. It is not that one is more important than the other. Dr. Boyer: These pathways do overlap. If you look carefully at what activates VEGF, it is the inflammatory pathway, which then activates hypoxic inducible factors and tissue necrosis factor (TNF). I think that we will be using combination therapies more frequently in the future, including pharmacotherapy with laser in order to address residual edema and to improve visual acuity. THE NEED FOR A SUSTAINABLE TREATMENT MODEL Dr. Boyer: A key point that was made earlier is that DME is a chronic disease that affects the working population, and having patients come in for a monthly injection of anti-VEGF, for example, is not a sustainable solution. There is a definite need for longer-delivery treatment options. Dr. Dugel: Sustainability is definitely an issue. It is very difficult for patients to take off time once a month to come in for an injection. Additionally, we know that physiologically there are hundreds, if not thousands of factors that contribute to DME, and if we inhibit just 1 of these (VEGF), we are missing the mark. Both combination therapy and sustained-release drug delivery make sense in this setting. Dr. Pieramici: There may be a downside to taking a VEGF inhibition approach. There certainly is some physiologic response or pathophysiologic response in patients with diabetes that causes the body to upregulate VEGF. It is possible that VEGF may be a neuro-

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EMERGING DATA ON DME TREATMENTS

FAME: 36-Month Results Support Efficacy of Fluocinolone Acetonide Insert Lower-dose fluocinolone acetonide (Iluvien, Alimera Sciences) was most effective in patients with diabetic macular edema (DME) who had the disease for 3 years or more, according to a recent analysis of the data from the 36-month FAME study, presented by Andrew N. Antoszyk, MD, at ARVO.1 The FAME study consisted of two identical, double masked, sham-controlled, multicenter, phase 3 studies—trial A and trial B—and included 956 patients with DME. Participants were randomized 2:2:1 to receive 0.2 µg fluocinolone acetonide (n = 376), 0.5 µg fluocinolone acetonide (n = 395), or control/sham (n = 185). The primary endpoint was the proportion of patients who gained 15 letters or more in best corrected visual acuity (BCVA) at month 24. As previously reported, the prespecified primary endpoint for the FAME study was met for low-dose fluocinolone acetonide in both trial A and trial B. “The FAME trial showed that it did meet its primary readout, but the question arose, ‘Was there a particular subgroup of patients with DME that had a greater benefit- to-risk ratio?’” Dr. Antoszyk said. “The ideal subgroup would have to have a statistically significant visual acuity result at months 24 and 36, a greater benefit-to-risk ratio, and should be identifiable prior to administration of the Iluvien implant.” The subgroups consisted of 536 patients who had had DME for 3 years or more and 416 patients who had had DME for less than 3 years. Of the fluocinolone acetonide-

protective agent in such an instance and if we are applying pan-VEGF suppression, although we are reducing neovascularization and helping the retina look better, we may causing harm in the long term. Although this is just a theory, it is logical to say that in a disease with so many contributing factors, we cannot just take 1 target factor and completely eliminate the pathology. Instead, we should try to manipulate a number of factors to achieve the best response. Dr. Dugel: This is a valid point. There have been experimental studies in rodent models that show that chronic VEGF suppression causes changes in the choroidal vasculature.10 This may not be as important in patients with AMD because they tend to be older,

treated patients with DME for 3 years or more, 33.6% in trial A and 42.4% in trial B achieved an improvement in BCVA of 15 letters or more at month 30. At month 36, 31.8% of the patients in trial A and 36.4% of the patients in trial B had an improvement in BCVA of 15 letters or more. Of the patients who received the control treatment, 13.6% in trial A and 13.2% in trial B had an improvement in BCVA of 15 letters or more at 36 months. No statistically significant improvement in BCVA was observed in the subgroup of patients with DME of less than 3 years’ duration. Consistent with the full patient population, approximately 75% of the patients treated with fluocinolone acetonide received only 1 insert during the 36-month study. At 36 months, the IOP had increased to 30 mm Hg or more at any time point in 14.8% of fluocinolone acetonide-treated patients in the subgroup vs 18.3% of fluocinolone acetonidetreated patients in the full patient population. In addition, 5.3% of fluocinolone acetonide-treated patients in the subgroup underwent an incisional surgical procedure to reduce elevated IOP compared with 4.8% in the full patient population. In the subgroup, the incidence of cataracts among fluocinolone acetonide-treated patients who had a natural lens at baseline was 86%, with 85% undergoing a cataract operation, compared with 80% and 74.9%, respectively, in the full patient population. Based on the results of the FAME study, Alimera has submitted a new drug application to the FDA for regulatory approval of lower-dose fluocinolone acetonide. 1. Antoszyk A, for the FAME Study Group. Efficacy and safety of Iluvien (fluocinolone acetonide [FAC] intravitreal insert) for the treatment of diabetic macular edema. Paper presented at: Association for Research in Vision and Ophthalmology Annual Meeting; May 3, 2011; Fort Lauderdale, FL. Abstract #6645.

but it is important in younger patients who we will be treating for longer periods of time. At this point, we simply do not know how important this is, but it is something to keep in mind. CASE EXAMPLES Dr. Boyer: Let’s consider some cases and how we would approach them. A man aged 45 years presents with 20/40 vision, an A1c hemoglobin level of 9, and hypertension. The patient is relatively asymptomatic because his vision in the fellow eye is 20/20. How would you approach this patient? Dr. Kiss: I would examine the patient with widefield NOVEMBER/DECEMBER 2011 I SUPPLEMENT TO RETINA TODAY I 9

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EMERGING DATA ON DME TREATMENTS

Ranibizumab Improved Visual Outcomes in DME Patients with DME achieved better long-term visual outcomes when treated with ranibizumab (Lucentis, Genentech) and focal/grid laser combination therapy than with ranibizumab or laser alone, according to the results of the phase 2 READ-2 study published in Ophthalmology.1 Combining the 2 treatments also reduced the frequency of ranibizumab injections needed to control DME, the study authors said. READ-2 was a 24-month prospective, randomized, interventional multicenter trial in patients (n=126) with DME. The purpose of the study was to determine if ranibizumab was a superior treatment to focal/grid laser photocoagulation or a combination of both in patients with DME. Patients were randomized 1:1:1 to receive 0.5 mg ranibizumab at baseline and months 1, 3, and 5 (group 1); focal/grid laser photocoagulation at baseline and month 3 if needed (group 2); or a combination of 0.5 mg ranibizumab and focal/grid laser photocoagulation at baseline and month 3 (group 3). At the 6-month primary endpoint, the mean gain in best corrected visual acuity (BCVA) was significantly greater in group 1 (+7.24 letters) than in group 2 (-0.43 letters) or group 3 (+3.8 letters). For patients with data available at 6 months, a gain of three lines or more occurred in eight of 37 (22%) in group 1 compared with 0 of 38 (0%) in group 2 and three of 40 (8%) in group 3. Excess foveal thickness (FTH) was reduced by 50%, 33%, and 45% in groups 1, 2, and 3, respectively. For the remaining 18 months, patients in group 1 were evaluated every 2 months and were eligible to receive

FA and OCT to see how much damage exists. I would then talk to the patient about systemic control and explain that that, although he may not realize the effects, damage is occurring in the affected eye, the unaffected eye, along with his heart, kidneys, and brain. I routinely tell my patients that once they have lost visual acuity, it is harder to regain it vs maintaining vision. I usually start treatment with an anti-VEGF agent, if there is not enough focal leakage to treat with laser. Once the retina is flattened, I may choose to use laser. Often I find that the threat of an injection or laser is enough to motivate patients to improve their systemic 10 I SUPPLEMENT TO RETINA TODAY I NOVEMBER/DECEMBER 2011

0.5 mg ranibizumab if FTH was 250 µm or more. Patients in group 2 were evaluated every 2 months, and if FTH was 250 µm or more, they could receive focal or grid laser treatment or 0.5 mg of ranibizumab. Patients in group 3 were evaluated every 3 months, and if FTH was 250 µm or more, they could receive 0.5 mg ranibizumab followed by focal/grid laser treatment or ranibizumab alone. At month 24, the mean gain in BCVA in group 1 was 7.7 letters. Patients in group 2, who were originally assigned to the laser group, were predominantly treated with ranibizumab for persistent or recurrent DME between 6 and 24 months; at month 24, they showed a gain of 5.1 letters. Patients in group 3 gained an average of 6.8 letters. The percentage of patients who gained three lines or more of BCVA between baseline and month 24 was 24%, 18%, and 26% in groups 1, 2, and 3, respectively, and the percentage of patients with FTH of 250 µm or less was 36%, 47%, and 68%, respectively. The visual outcomes at month 24 were not significantly different in groups 2 and 3 from those in group 1, whereas anatomic outcomes were better, with fewer injections of ranibizumab during year 2. The additional focal/grid laser treatment in groups 2 and 3 helped reduce persistent or recurrent DME during months 6 to 24 and the frequency of injections needed, the study authors concluded. The READ-3 study will investigate if a higher dose of ranibizumab (2.0 mg) is more effective than the standard dose (0.5 mg) in improving vision and decreasing retinal thickness; it will also evaluate if higher doses can reduce the frequency of subsequent treatments for DME. 1. Campochiaro PA, Eliot D, Nguyen QD, et al. Two-year outcomes of the ranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology. 2010;117(11): 2146-2151.

control and so when they return in 3-6 months, their blood sugar and hypertension is much better, changing the cycle of DME. If, however, nothing has improved, I open a dialogue with the patient about long-term management of the DME, with repeated intravitreal injections and laser. If there are peripheral areas of ischemia or nonperfusion, they may be contributing to the diffusion of the edema, or I may detect something on OCT that can be addressed with surgery. In sum, my approach with this patient would be to get more information, educate the patient, and then apply a step-wise treatment regimen.

STEROIDS FOR THE TREATMENT OF DIABETIC MACULAR EDEMA

EMERGING DATA ON DME TREATMENTS

Aflibercept Safe, Provided Benefit in DME Aflibercept (Eylea, formerly VEGF Trap-Eye, Regeneron Pharmaceuticals/Bayer HealthCare) was safe and provided significant benefit in the treatment of diabetic macular edema (DME), according to a paper presented at the 2011 ASRS meeting.1 Diana V. Do, MD, Assistant Professor of Ophthalmology at the Wilmer Eye Institute, Johns Hopkins School of Medicine in Baltimore, Maryland, presented the results of the DA VINCI study, a double-masked randomized prospective multicenter phase 2 study that included 219 patients (219 eyes) who were randomized and treated with either aflibercept or photocoagulation. The aflibercept group was divided into four groups: aflibercept 0.5 mg every 4 weeks (0.5q4); 2 mg every 4 weeks (2q4); 2 mg every 8 weeks following 3 initial monthly doses (2q8); and 2 mg as needed following 3 initial monthly doses (2PRN). Eligible patients had clinically significant DME with central involvement, defined as thickness of greater than 250 µm in the central subfield on optical coherence tomography (OCT), and best corrected visual acuity (BCVA) of between 20/40 and 20/320 Snellen equivalent. The change in BCVA was measured at week 24 (primary endpoint) and week 52. Additional secondary endpoints assessed at week 52 included the proportion of patients who gained ≥15 letters in BCVA and mean change in central retinal thickness from baseline. In the 176 patients who followed to the completion of the study at 1 year, eyes that were randomized to aflibercept gained 9.7 to 13.1 letters, compared with a 1.3 letter loss in the laser group (P < .0001). No statistically significant differences were observed among the groups that received aflibercept. Also at 1 year, 45% to 71% of eyes treated with aflibercept gained 10 or more letters; and

Dr. Pieramici: This is a good approach. This patient’s main problem is his medical control and showing him the damage it has caused on FA and OCT may be valuable, not only from a clinical standpoint, but also from an educational standpoint. Coordinating care with the patient’s primary care physician is important to bring him under control. I would also treat this patient with an anti-VEGF agent to address the edema. What I add later depends

24% to 46% of eyes treated with aflibercept gained 15 or more letters, compared with 12% of eyes in the laser-treated group, Dr. Do said. At 6 months, central retinal thickness on OCT was greater in the aflibercept treatment groups than in the laser group (P < .0001). The greatest decrease at 6 months, -194.5 µm from baseline, was seen in the 2q4 treatment arm, although the differences among the aflibercept treatment arms were not statistically significant. The decreases in thickness seen at 6 months were maintained or numerically improved at 1 year. “All doses and dosing regimens of [aflibercept] produced statistically significant improvements in visual acuity compared to the laser treatment group. And these improvements were associated with a greater reduction in anatomic retinal thickening on OCT,” Dr. Do said. “Because of these positive phase 2 results, a phase 3 randomized clinical trial is currently underway to further investigate [aflibercept] for diabetic macular edema.” In addition to improving visual acuity, aflibercept was also associated with an improvement in diabetic retinopathy. At 1 year, 31% to 64% of eyes treated with aflibercept had an improvement in their diabetic retinopathy improvement scale, compared with 12% of eyes in the laser-treated group, Dr. Do said. Aflibercept was generally well tolerated. There were 2 cases of injection-related endophthalmitis, but no serious ocular adverse events were related to the study drug. Additionally, there were no serious systemic adverse events. Six deaths occurred in the 175 patients who received the study drug (3.4%) and 1 death occurred in the 44 patients who were treated with laser (2.3%) over the course of 1 year. Dr. Do said that none of the deaths were attributed to the study drug, and most were due to the patients’ underlying medical illness. 1. Do DV. One-year results of the DA VINCI study of VEGF trap-eye in diabetic macular edema. Presented at the American Society of Retina Specialists Annual Meeting; August 21, 2011; Boston.

on his response and how often I will need to treat. Dr. Boyer: Let’s say a patient presents with a history of diabetes for the past 12-14 years. He is in his late 60s, and his visual acuity is 20/200 with massive amounts of edema. The patient is generally noncompliant and does not follow up with his internist as often as required, and so he has no idea what his A1c levels are. How would you approach this patient? NOVEMBER/DECEMBER 2011 I SUPPLEMENT TO RETINA TODAY I 11

STEROIDS FOR THE TREATMENT OF DIABETIC MACULAR EDEMA

Dr. Dugel: I see this type of patient frequently. I follow steps similar to what Drs. Kiss and Pieramici described in terms of patient counseling. For treatment, the first thing that I want to do is to ensure there is no mechanical component that I could address with surgery. It is more than likely with this type of patient that I will find many areas of ischemia on FA. If there is a history of noncompliance, I believe it is unrealistic to think that this patient will come in for injections every month for several years. I would counsel this patient toward a sustained-delivery steroid to lower the frequency with anti-VEGF injections that would be needed. I may consider laser also. In addition to treatment, I would want to work with their diabetologist to ensure better compliance and systemic control. Dr. Boyer: The mechanical component to DME has been brought up a few times in this discussion. I have been pleasantly surprised that in some cases, mild epiretinal membranes (ERMs) that I considered to be a contributing factor returned to a normal contour after treatment with anti-VEGF or steroid. The edema may recur more frequently due to the ERM, but the patients’ vision improves with injections. Dr. Dugel: The problem with anti-VEGF agents for DME is that we are addressing a long-term, frequently recurring disease. The short-term data that we have is important, but in DME, even 2-year data is short term because this is a disease that endures for decades. There is no doubt that monotherapy with anti-VEGF agents has proved successful in the short-term, but it is the long-term sustainability that makes me think that a combination approach will be needed. Dr. Kiss: With my patients who have diffuse edema, I am not always getting as a robust response from antiVEGF agents that I can get from a steroid injection. In some cases, I find that a bolus injection of steroid will flatten massive amounts of edema much faster than repeated injections of anti-VEGF. Dr. Pieramici: The noncompliant patient with large amounts of diffuse edema is, unfortunately, fairly typical. Like Dr. Dugel, I am starting to treat these patients with more than anti-VEGF agents because unlike with AMD, these patients have several comorbidities and to add on a burden of monthly injections can be overwhelming for everyone involved. I will definitely use combination therapy, whether with anti-VEGF and laser, anti-VEGF and steroids, or steroids and laser. 12 I SUPPLEMENT TO RETINA TODAY I NOVEMBER/DECEMBER 2011

“This is an interesting time be a clinician because instead of working with a cookbook approach, we will have to practice medicine using the studies as guidelines but customizing the care to the individual.” -Dante J. Pieramici, MD We are going to have clinical evidence suggesting that all of these are beneficial, but how we put them together will be on a case-by-case basis. It is easy to forget that when we look at results from clinical trials, we are generally looking at an idealized average patient. With our individual patients, we will have to tailor the care. This is an interesting time be a clinician because instead of working with a cookbook approach, we will have to practice medicine using the studies as guidelines but customizing the care to the individual. Dr. Boyer: I find that many times I will start treatment with an anti-VEGF agent, and if I do not see the response I am seeking, which is relatively good flattening, I will add a steroid. Certainly, if we have a long-term steroid available, this will be better for both the patient and the doctor. TAKE-HOME POINTS Dr. Boyer: What are some important take-home messages for those who are participating in this continuing medical education activity? Dr. Dugel: I believe it is important to closely review the recent studies that have evaluated anti-VEGF, laser, and steroids for DME. For example, in Protocol B, it is interesting to look at the patients who were selected and who benefitted vs those who did not from steroids and laser (Figure 1). Although this represented just a few patients, there is a signal that I think is important as to where steroids may fit in: in the study, it is a marker for the importance of inflammation. Additionally, the FAME data subanalysis showed a significant difference in how patients responded based on the duration of the diabetes. FAME was actually 2 studies, A and B, conducted in very different regions and demographics, but the results were remarkably consistent. It is also important to note that in both A and B studies, there was a complete OCT/visual acuity disconnect. There is a good amount of emerging evidence that will help us to see DME more as a staged disease, with each stage requir-

STEROIDS FOR THE TREATMENT OF DIABETIC MACULAR EDEMA

ing a different combination of treatments. Dr. Kiss: As we are understanding more about diabetes, we are learning that a multifactorial approach will be the way to treat. The 2 patients that Dr. Boyer described illustrate this. DME is a different disease process at each stage, and each patient is different also, so we have to individualize our treatment to account for lens status, systemic status, and even to the age of the patient, because the current treatment paradigm of monthly intravitreal injections for the next 40 years in the life of a patient is unrealistic. If you consider other areas of medicine, such as cancer, there is not 1 drug that works for all patients; the same is true in DME. Dr. Pieramici: It is a wonderful time for treating patients with DME. We used to have only 2 tools, laser and surgery, which was frustrating for us and for our patients because we would treat and treat again, and the edema would persist with the vision rarely improving. We now have many more things we can pull off the shelf with others in development. We also have a better understanding of diabetes itself and the importance of good medical care. The clinical trial data are helpful to us in that they help guide treatment, but as has been said before, we will have to take a customized approach. Dr. Boyer: In the future, I think we will have better ways to identify who is going to respond to the various drugs. The direction where we are headed with research is to look at genetics and attempt to identify those who

Suggested Additional Reading Antonetti DA, Barber AJ, Bronson SK, et al; JDRF Diabetic Retinopathy Center Group. Diabetic retinopathy: seeing beyond glucose-induced microvascular disease. Diabetes. 2006;55(9):2401-2411. Tang J, Kern TS. Inflammation in diabetic retinopathy. Prog Retin Eye Res. 2011;30(5):343-358. Epub 2011 May 25.

“DME is a different disease process at each stage, and each patient is different also, so we have to individualize our treatment.” -Szilárd Kiss, MD may respond better to anti-VEGF or possibly better to steroids, or to find out how much ischemia is necessary to create the VEGF. Early in the course of diabetes, hyperglycemia is present, and the inflammatory component starts the VEGF cycle. Often we see patients present in the middle part of the VEGF cycle when it is full blown and where antiVEGF drugs can help. It is the chronic phase of DME where sustained-release steroids will have the biggest role in conjunction with debulking VEGF. Combination therapy may help us keep patients stable for long periods of time and achieve better visual results. 1. Elman M, Aiello L, Beck R, et al. Randomized trial evaluating ranibizumab plus promptor deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064-1077. 2. Diabetic Retinopathy Clinical Research Network (DRCR.net), Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris F, Glassman AR, Hartnett E, Ip MS, Kim JE, Kollman C. Three-year follow up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009;127(3):245-251. 3. Antoszyk A, for the FAME Study Group. Efficacy and safety of Iluvien (fluocinolone acetonide [FAC] intravitreal insert) for the treatment of diabetic macular edema. Paper presented at: Association for Research in Vision and Ophthalmology Annual Meeting; May 3, 2011; Fort Lauderdale, FL. Abstract #6645. 4. Browning DJ, Glassman AR, Aiello LP, et al; Diabetic Retinopathy Clinical Research Network. Optical coherence tomography measurements and analysis methods in optical coherence tomography studies of diabetic macular edema. Ophthalmology. 2008;115(8):1366-1371, 1371.e1. 5. Baskin DE. Optical coherence tomography in diabetic macular edema. Curr Opin Ophthalmol. 2010;21(3):172-177. 6. Danis RP, Scott IU, Qin H, et al; Diabetic Retinopathy Clinical Research Network. Association of fluorescein angiographic features with visual acuity and with optical coherence tomographic and stereoscopic color fundus photographic features of diabetic macular edema in a randomized clinical trial. Retina. 2010;30(10):1627-1637. 7. Davis MD, Bressler SB, Aiello LP, et al; Diabetic Retinopathy Clinical Research Network Study Group. Comparison of time-domain OCT and fundus photographic assessments of retinal thickening in eyes with diabetic macular edema. Invest Ophthalmol Vis Sci. 2008;49(5):1745-1752. 8. Vujosevic S, Casciano M, Pilotto E, Boccassini B, Varano M, Midena E. Diabetic macular edema: fundus autofluorescence and functional correlations. Invest Ophthalmol Vis Sci. 2011;52(1):442-448. 9. Wessel M, Aaker G, Parlitsis G, Cho M, D’Amico DJ, Kiss S. Ultra-widefield angiography improves the detection and classification of diabetic retinopathy. Retina. [In Press] 10. Saint-Geniez M, Maharaj AS, Walshe TE, et al. Endogenous VEGF is required for visual function: evidence for a survival role on müller cells and photoreceptors. PLoS One. 2008;3(11):e3554.

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STEROIDS FOR THE TREATMENT OF DIABETIC MACULAR EDEMA

Steroids for the Treatment of Diabetic Macular Edema Expires November 2012

1.0 AMA PRA Category 1 Credit™

CME credit is available electronically via www.dulaneyfoundation.org. To answer these questions online and receive real-time results, please visit www.dulaneyfoundation.org and click “Online Courses.” If you are experiencing problems with the online test, please e-mail us at [email protected] or call +1-610-619-0414. Alternatively, you can fax your exam to us at +1-610-771-4443. Certificates are issued electronically, so supply your email addresses below. Please type or print clearly or we will be unable to issue your certificate. Name ____________________________________________________________________ ❏ MD participant ❏ non-MD participant Phone (required) ________________________________________ e-mail (required) __________________________________________ City _________________________________ State ________________

CME QUESTIONS

1. In the DRCR.net Protocol B, patients with vision worse than 20/200 had __________ outcomes with steroids than laser. a. poorer b. better c. similar d. none of the above 2. The sustained-delivery fluocinolone acetonide insert has the following characteristics: a. near zero-order kinetics b. sub-microgram dose delivery c. posterior point of release d. all of the above e. none of the above 3. What determines the efficacy of a steroid in DME? a. dose b. time of day when it is administered c. stage of disease when it is administered d. A and B e. A and C

4. In the DRCR.net Protocol I, patients who were pseudophakic did equally well with steroids plus laser as with ranibizumab plus laser. a. true b. false 5. The FAME data subanalyses at 36 months showed that the sustained-delivery fluocinolone acetonide insert was most effective: a. for patients with DME less than 1 year b. for patients who were phakic c. for patients with DME for 3 years or more d. for patients who were treatment naïve e. none of the above 6. There are data suggesting that long-term VEGF suppression causes changes in the choroidal vasculature. a. true b. false

STEROIDS FOR THE TREATMENT OF DIABETIC MACULAR EDEMA

Steroids for the Treatment of Diabetic Macular Edema Your responses to the questions below will help us evaluate this CME activity. This will provide us with evidence that improvements were made in patient care as a result of this activity as required by the Accreditation Council for Continuing Medical Education (ACCME). Please complete the following course evaluation and send it back to the Dulaney Foundation via fax at +1 610-771-4443. Name ___________________________________________________________________________________ Do you feel the program was educationally sound and commercially balanced? ❒ Yes ❒ No Comments regarding commercial bias: _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ Rate your knowledge/skill level prior to participating in this course: 5 = High, 1 = Low _____ Rate your knowledge/skill level after participating in this course: 5 = High, 1 = Low________ Would you recommend this program to a colleague?

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