0409RT_ALLERGAN_CME.qxd
4/14/09
6:24 PM
Page 1
Jointly sponsored by the Dulaney Foundation and Retina Today. Supplement to
April 2009
The Future of Diabetic Macular Edema:What Lies Ahead for Your Patients?
FEATURING: Rajendra S. Apte, MD, PhD
Peter K. Kaiser, MD
Scott W. Cousins, MD
Baruch D. Kuppermann, MD, PhD
Jeffrey S. Heier, MD
Mathew W. MacCumber, MD, PhD
0409RT_ALLERGAN_CME.qxd
4/14/09
6:24 PM
Page 2
THE FUTURE OF DIABETIC MACULAR EDEMA
Jointly sponsored by the Dulaney Foundation and Retina Today. Release date: April 2009. Expiration date: April 2010. This continuing medical education activity is supported by unrestricted educational grant from Allergan, Inc. TARGET AUDIENCE This activity is designed for retina specialists and other ophthalmologists. LEARNING OBJECTIVES Upon completion of this activity, the participant should be able to: 1. Understand the cause and pathophysiology of macular edema 2. Understand the role of inflammation in retinal disease 3. Understand the types of macular edema and their corresponding treatments 4. Apply current therapies and practices for treating macular edema 5. Understand the relative utility of laser, steroid and antiVEGF therapies for treating macular edema 6. Understand the efficacy of steroid preparations in retinal disease 7. Understand the use of implantable drug delivery systems for treating macular edema 8. Implement current and future strategies (both short-term and long-term) for macular edema and how to use them in your practice 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, and the course evaluation. 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 1.5 AMA PRA Category 1 Credits.™ The estimated time to complete this activity is 1 hour. 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 educational activity for a maximum of 1.5 AMA PRA Category 1 Credits.™ Physicians should only claim credit commensurate with the extent of their participation in the activity.
2 I SUPPLEMENT TO RETINA TODAY I APRIL 2009
DISCLOSURE In accordance with the disclosure policies of the Dulaney Foundation and to conform with ACCME and FDA 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. 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 Rajendra S. Apte, MD, PhD, is Assistant Professor, Ophthalmology and Visual Sciences and the Developmental Biology Program at Washington University School of Medicine. He may be reached at +1 314 747 5262; fax: +1 314 362 6793 or e-mail:
[email protected]. Scott W. Cousins, MD, is Professor of Ophthalmology and Immunology and Director for the Center for Macular Diseases at Duke University Eye Center in Durham, NC. Jeffrey S. Heier, MD, is a Clinical Ophthalmologist specializing in diseases of the retina and vitreous at Ophthalmic Consultants of Boston and a member of the Retina Today editorial board. Peter K. Kaiser, MD, is in the Vitreoretinal Department at the Cole Eye Institute, Cleveland Clinic. He is a member of the Retina Today Editorial Board. Dr. Kaiser may be reached at
[email protected]. Baruch D. Kuppermann, MD, PhD, is a Professor and Chief of the Retina Service at the Gavin Herbert Eye Institute in the Department of Ophthalmology at the University of California, Irvine. Dr. Kuppermann is a member of the Retina Today editorial board. He may be reached at
[email protected]. Mathew W. MacCumber, MD, PhD, is Associate Professor, Associate Chairman for Research, Rush University Medical Center. He may be reached at
[email protected]; phone: 773-871-8444; or fax: 773-871-4781.
0409RT_ALLERGAN_CME.qxd
4/14/09
6:24 PM
Page 3
WHAT LIES AHEAD FOR YOUR PATIENTS? FACULTY/STAFF DISCLOSURE DECLARATIONS Dr. Apte states that he is a consultant for Eyetech, Genentech, Allergan, Inc., Gerson Lehman Group, and Ophthotech. He is on the advisory boards of Genentech and Allergan, Inc., and he receives research grants from and serves on the speakers’ bureau for Genentech. Dr. Cousins states that he is a consultant to Alcon Laboratories, Inc., Allergan, Inc., Eyetech, Genentech, Inc., Heidelberg Engineering, and Novartis. He is on the speakers’ bureau for Pfizer and Novartis, and is a scientific advisor for Jerini Ophthalmics. Dr. Heier states that he receives research support from Allergan Inc., and Ista; and is on the scientific advisory board for Allergan, Inc., Genentech, and Ista. Dr. Kaiser states that The Cole Eye Institute has received research grant support from Alcon Laboratories, Allergan, Eyetech Pharmaceuticals, Genentech, Regeneron, Novartis, QLT, and Sirna Therapeutics. Dr. Kaiser states that he is a member of the scientific advisory boards and/or a consultant for Alcon, Allergan, Novartis, and TargeGen. Dr. Kuppermann states that he is a consultant to Allergan. Dr. MacCumber states that he has received research funds, speakers’ fees and honoraria for serving on the advisory boards for Genentech, Allergan, Inc., and Optos.
All of those involved in the planning, editing, and peer review of this educational activity have indicated that they have no financial relationships to disclose. STATEMENT OF NEED Diabetes mellitus and its systemic and ophthalmic complications represent an enormous public health threat in the United States in the 21st century. The prevalence of diabetes in the US is currently 7%, meaning that 24.5 million of the 350 million Americans alive today have diabetes. The ophthalmic complications of diabetes are the leading cause of blindness in adults aged 20 to 74 in the US. Diabetic retinopathy has been estimated to cause 12,000 to 24,000 new cases of blindness annually in the US. Fortunately, numerous major clinical trials have demonstrated that complications of diabetes—including diabetic eye disease—can be reduced with adequate control of blood glucose, blood pressure, and hemoglobin A1C (HbA1C) levels. Unfortunately, as many as 30% to 40% of Americans with diabetes are currently undiagnosed and are not being monitored and treated to control their disease and prevent systemic complications. One of the most common causes of vision loss in patients with diabetes is diabetic macular edema (DME). In this discussion and subsequent enduring material, we will review the pathophysiology of DME, as well as existing and future treatment options. The prevalence of DME among US diabetics approaches 30% in adults who have had diabetes for 20 years or more, and varies with the stage of diabetic retinopathy. It can occur at any stage of diabetes and can predate the appearance of other findings of diabetic retinopathy. In eyes with mild nonproliferative retinopathy, the prevalence of DME is 3%. This rises to 38% in eyes with moderate to severe nonproliferative retinopathy, and reaches 71% in eyes with proliferative retinopathy. Untreated, 20% to 30% of patients with DME will experience a
doubling of the visual angle within 3 years; with current treatment, this risk drops by 50%. Macular edema develops when fluid and protein deposits accumulate in the macula. The edema, caused by abnormal retinal capillary permeability secondary to a breakdown of the blood-retinal barrier, is a major cause of vision loss in diabetic retinopathy and other retinal diseases. Macular edema, or central extravascular swelling of the retina, causes significant vision loss. Therapy includes laser photocoagulation and corticosteroids—topical, oral, sub-Tenon’s, and most recently intravitreal. Delivery of steroids via injection is viable but, due to medication half-life, impractical for clinical management of disease. Intravitreal drug delivery systems can allow slow release of a drug, such as a steroid, to attain a therapeutic steady state. A May 30, 2008, survey by Retina Today shows that 55% of its respondents are currently using a combination or triple therapy treatment for DME. Twenty-five percent use steroids, 19% use antiangiogenic agents, and 1% use some other treatment. CORTICOSTEROID THERAPY FOR DIABETIC MACULAR EDEMA Increasingly, corticosteroids have been employed to treat macular edema. Recently, intravitreal injection of triamcinolone acetonide has become a popular treatment. Subsequently, a number of corticosteroid-based intravitreal implants have been developed to provide sustained release of drug and make repeated intravitreal injections unnecessary. Drug delivery via intravitreal implant is not a novel concept. The first intravitreal implant used a pars plana approach to deliver ganciclovir for the treatment of cytomegalovirus (CMV) retinitis. The implant provided sustained therapeutic drug levels for up to 6 to 8 months; over 10,000 implants have been implanted. There are currently three corticosteroid-based intravitreal implants under development. They are the dexamethasone biodegradable implant (Posurdex, Allergan, Irvine, CA); the fluocinolone acetonide implant (Retisert, Bausch & Lomb, Rochester, NY); and a fluocinolone acetonide–based implant that is injectable (Medidur, pSivida, Boston, MA/Alimera Sciences, Alpharetta, GA). Inhibition of inflammation with corticosteroids and inhibition of vascular endothelial growth factor (VEGF) have become topics of interest in recent years in the treatment of age-related macular degeneration (AMD). The permeability and proliferative properties of VEGF, and the consequences of its inhibition, also suggest a role for this approach in the management of DME. Blockade of many if not all involved growth factors will likely be necessary to suppress all of the detrimental effects of ischemia, but even isolated blockade of VEGF may have beneficial effects on DME. VEGF increases vascular permeability by relaxing endothelial cell junctions, which increases permeability and leakage. Inhibition of VEGF blocks this effect to some extent, as demonstrated in several recent clinical trials and case series employing the anti-VEGF molecules pegaptanib sodium (Macugen, OSI/Eyetech), ranibizumab (Lucentis, Genentech), and bevacizumab (Avastin, Genentech). APRIL 2009 I SUPPLEMENT TO RETINA TODAY I 3
0409RT_ALLERGAN_CME.qxd
4/14/09
6:24 PM
Page 4
THE FUTURE OF DIABETIC MACULAR EDEMA
The Role of Inflammation in Diabetic Retinopathy and Retinal Vascular Disease BY RAJENDRA S. APTE, MD, P H D
T
he role of inflammation in retinal venous occlusive (RVO) disorders and diabetic retinopathy (DR) is significant. Over the past few years, we have focused on the role of inflammation in age-related macular degeneration (AMD), but the evidence presented in the literature linking inflammation to RVO and DR is strong.1-4 Vascular endothelial growth factor (VEGF), and specifically VEGF165, is a primary factor in ischemia in DR and RVO. VEGF has also been shown to induce macular edema, choroidal neovascularization (CNV) and retinal neovascularization based on its pro-angiogenic and propermeability effects.5-10 Inflammation as a whole can be divided into two basic components: either innate or acquired. Most of the available information on inflammation in eye disease falls within the innate category, although there are data that implicate components of acquired immunity: the secreted components such as cytokines, interferons, and other interleukins that clearly play a role in promoting the vision loss associated with DR and RVO. The main factor in inflammation that has recently emerged is the macrophage. Macrophages that exist in pathologic environments such as AMD, or in ischemic environments that are rich in interleukin-10, tend to be polarized to an M2 phenotype that promotes vascular damage and new vessel growth. The evidence for inflammation in diabetes is strong, and, in terms of our therapeutic armamentarium, the agents that selectively target components of inflammation that promotes development or progression of retinopathy might indeed have a strong role. DIFFERENTIATING INFLAMMATION IN RVO AND DR Inflammation associated with retinal disorders such as AMD, RVO, and DR, is significantly different from the inflammation classically described in vasculitis and poste4 I SUPPLEMENT TO RETINA TODAY I APRIL 2009
rior uveitis, which is neutrophilic or T-cell mediated. Inflammation associated with disease progression in DR or AMD is more subtle and exists at a molecular or cellular level.
The agents that selectively target components of inflammation that promote development or progression of retinopathy might indeed have a strong role. Biomicroscopically, it may be hard to see some of the earliest evidence of inflammation in RVO or DR until pathophysiology develops. As more noninvasive diagnostic tests are developed, perhaps involving peripheral blood monocytes, the earliest evidence of inflammation may become detectable. 1. Lee HB, Pulido JS, McCannel CA, Buettner H. Role of inflammation in retinal vein occlusion. Can J Ophthalmol. 2007;42:131–133. 2. Jonas JB, Kreissig I, Degenring RF. Intravitreal triamcinolone acetonide as treatment of macular edema in central retinal vein occlusion. Graefe’s Arch Clin Exp Ophthalmol. 2002;240:782–783. 3. Sivaprasad S, McCluskey P, Lightman S. Intravitreal steroids in the management of macular oedema. Acta Ophthalmol Scand. 2006;84(6):722–733. 4. Jonas JB, Kreissig I, Kamppeter B, Degenring RF. [Intravitreal triamcinolone acetonide for the treatment of intraocular edematous and neovascular diseases. Article in German.] Ophthalmologe. 2004;101(2):113–120. 5. Wu L, Martínez-Castellanos MA, Quiroz-Mercado H, et al; Pan American Collaborative Retina Group (PACORES). Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol. 2008;246(1):81–87. Epub 2007 Aug 3. 6. Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006;113(3):363–372.e5. Epub 2006 Feb 3. 7. Vinores SA, Xiao WH, Aslam S, et al. Implication of the hypoxia response element of the VEGF promoter in mouse models of retinal and choroidal neovascularization, but not retinal vascular development. J Cell Physiol. 2006;206(3):749–758. 8. Apte RS, Richter J, Herndon J, Ferguson TA. Macrophages inhibit choroidal neovascularization in age-related macular degeneration. PLoS Med. 2006;3:1371–1381. 9. Kelly J, Khan AA, Yin J, Ferguson TA, Apte RS. Senescence regulates macrophage polarization and angiogenic fate at sites of tissue injury. J Clin Invest. 2007;117:3421–3426. 10. Dace D, Khan AA, Kelly J, Apte RS. Interleukin-10 promotes pathologic developmental angiogenesis by regulating macrophage responsiveness to hypoxia. PLoS One. 2008;3:3381.
0409RT_ALLERGAN_CME.qxd
4/14/09
6:24 PM
Page 5
WHAT LIES AHEAD FOR YOUR PATIENTS?
The Evidence for Steroids in RVO BY MATHEW W. MACCUMBER, MD, P H D
T
he data on the treatment of retinal vein occlusion (RVO) with steroids is, to date, limited. We hope to have the results of the SCORE (Standard Care vs COrticosteroids for Retinal Vein Occlusion) study by fall of 2009, although a number of smaller trials have already suggested a short-term benefit of intravitreal triamcinolone acetonide (IVTA) for macular edema in diabetic macular edema and edema secondary to branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO).1-5 The main problem with these smaller studies is that follow-up generally does not go beyond 6 months, so we cannot determine the long-term benefit of steroids. TRIAMCINOLONE ACETONIDE Recently, the Diabetic Retinopathy Clinical Research Network (DRCR.net) published the results of Protocol B: a randomized trial comparing 1-mg or 4-mg IVTA to focal/grid laser photocoagulation for the treatment of diabetic macular edema (DME). The study found that laser was slightly more effective with fewer side effects at 2 years.6 Because of the frequency with which ophthalmologists are using IVTA to treat RVO, the SCORE study will hopefully answer our questions as to the safety and efficacy of this treatment modality. DEXAMETHASONE Dexamethasone has a short but potentially strong antiinflammatory effect. The half-life of dexamethasone has been shown to be approximately 3 hours after intravitreal injection, with no detectable traces of the drug after 72 hours. One study showed no evidence of retinal toxicity.7,8 It is well known that the mechanism of action of dexamethasone, like other corticosteroids, is to suppress inflammation via inhibition of edema, fibrin deposition, capillary deposition, and cellular migration within the inflammatory response. We are currently awaiting phase 3 data on the intravitreal biodegradable sustained-delivery dexamethasone device (Allergan, Irvine, CA) for treating macular edema secondary to BRVO and CRVO.
FLUOCINOLONE ACETONIDE Ramchandran et al9 performed a small study showing that eyes with persistent macular edema from RVO received significant benefit from the fluocinolone acetonide implant. This study provided 1-year follow-up for a type of patient who has not previously been studied past 6 months. Although the study was small and showed a benefit for only 14 eyes, it was the first to show this prolonged effect. COMBINATION TREATMENT Combination treatment with a steroid and an antivascular endothelial growth factor (anti-VEGF) agent has been used by some investigators, and other have combined these with vitrectomy for a three-pronged approach to treating macular edema secondary to RVO. The steroid addresses the inflammation, the anti-VEGF is directed toward the VEGF pathway, and a small-core vitrectomy has the potential to improve oxygenation via decreasing hyalocytes, as shown by Holekamp et al.10 As the data on steroids for RVO continue to grow, we hope to have a better understanding of how to apply the information we gather to the development of therapies with more robust effects and acceptable side-effect profiles. 1. Dusova J, Studnicka J, Rencova E, Korda V, Hejcmanova D. Triamcinolone in the treatment of diabetic macular edema: one year results [article in Czech]. Cesk Slov Oftalmol. 2008;64(4):149–152. 2. Kogure A, Ohkoshi K, Kogure S, Yamaguchi T, Kishi S. Efficacy and retention times of intravitreal triamcinolone acetonide for macular edema. Jpn J Ophthalmol. 2008;52(2):122–126. Epub 2008 Apr 30. 3. Hauser D, Bukelman A, Pokroy R, et al. Intravitreal triamcinolone for diabetic macular edema: comparison of 1, 2, and 4 mg. Retina. 2008;28 (6):825–830. 4. Cakir M, Dogan M, Bayraktar S, et al. Efficacy of intravitreal triamcinolone for the treatment of macular edema secondary to branch retinal vein occlusion in eyes with or without grid laser photocoagulation. Retina. 2008;28(3):465–472. 5. Kim JE, Pollack JS, Miller DG, Mittra RA, Spaide RF; Isis Study Group. ISIS-DEM: a prospective, randomized, dose-escalation intravitreal steroid injection study for refractory diabetic macular edema. Retina. 2008;28(5):735–740. 6. 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. 7. Graham RO, Peyman GA. Intravitreal injection of dexamethasone. Treatment of experimentally induced endophthalmitis. Arch Ophthalmol. 1974;92:149–154. 8. Kwak HW, D’Amico DJ. Evaluation of the retinal toxicity and pharmacokinetics of dexamethasone after intravitreal injection. Arch Ophthalmol. 1992;110:259–266. 9. Ramchandran RS, Fekrat S, Stinnett SS, Jaffe GJ. Fluocinolone acetonide sustained drug delivery device for chronic central retinal vein occlusion: 12-month results. Am J Ophthalmol. 2008;146(2):285–291. Epub 2008 Jun 4. 10. Holekamp NM, Shui YB, Beebe DC. Vitrectomy surgery increases oxygen exposure to the lens: A possible mechanism for nuclear cataract formation. Am J Ophthalmol. 2005;139(2):302–310. APRIL 2009 I SUPPLEMENT TO RETINA TODAY I 5
0409RT_ALLERGAN_CME.qxd
4/14/09
6:24 PM
Page 6
THE FUTURE OF DIABETIC MACULAR EDEMA
DISCUSSION: CHOOSING TREATMENT OPTIONS FOR RVO Scott W. Cousins, MD: Are some types of vein occlusion more sensitive to steroids than others? Mathew W. MacCumber, MD, PhD: Several years ago, Finklestein et al1 published a follow-up report from the Branch Retinal Vein Occlusion Study that showed that ischemic BRVOs (those that have a broken ring of capillary vessels surrounding the foveal avascular zone) can improve on their own. So, for many of these cases, I will merely follow them and not treat with grid laser or steroid. Eyes with perfused BRVO and a significant amount of cystic edema are the ones that tend to respond best to early intervention with steroids. Rajendra S. Apte, MD, PhD: The report by Finkelstein et al1 described ischemic edema as intracellular and thus unresponsive to external stimuli, such as laser or antiinflammatory agents, primarily because what is going on is within the cell. Conversely, because nonischemic edema is extracellular, it is more likely to respond to an external laser or antiinflammatory agents. As far as I am aware, there has been no research done to electrophysiologically or mechanistically test whether a difference truly exists with these entities. Most retina specialists, however, seem to agree that the more diffuse or cystic the edema, the better it responds to pharmacotherapy vs laser. Dr. Cousins: The formation of shunt vessels usually signifies a change in the flow and ultimately the resolution of the edema. Do you find this true in your practice, and if so, do steroids or anti-VEGF agents actually change the formation of those shunt vessels? Dr. MacCumber: Previous studies of drugs for RVO have focused on their effect on macular edema; however, shunt vessel development is another important marker in RVO because these eyes tend to stabilize. So it will be important to evaluate the effect of our treatments on the natural course of these vessels as well. Jeffrey S. Heier, MD: In RAVE (Rubeosis Anti-VEGF 8Trial for Ischemic Retinal Vein Occlusion), which is led by David M. Brown, MD, from Retinal Consultants of Houston, ranibizumab is being used to curb neovascularization. Dr. Brown has said that shunt vessels do not appear to be inhibited by the presence of an anti-VEGF agent; further, he has also said that the presence of shunt vessels seems to accompany more positive outcomes (Personal communication).
6 I SUPPLEMENT TO RETINA TODAY I APRIL 2009
Dr. Cousins: How would you compare the relative efficacy in vein occlusion between an anti-VEGF agent and a steroid? Baruch D. Kuppermann, MD, PhD: With BRVO, I am inclined to initially observe without treatment because the natural history frequently results in resolution of macular edema. In my opinion, steroids work better than anti-VEGF agents for macular edema secondary to BRVO, but in certain cases I will consider bevacizumab (Avastin, Genentech, Inc.) to avoid complications with cataract and glaucoma. Overall, if I had to choose one agent, it would be a steroid. When considering nonischemic vs ischemic disease, I think that the earlier stages respond better to an anti-VEGF agent. Later, when there is more of an edematous permeability component, I think steroids are more effective because we are treating the macular edema. I also use the patient’s phakic and nerve status to help guide my treatment decisions. Dr. Heier: I do agree that for BRVO, if laser can be used, it should be the first option. However, many of these patients have macular hemorrhages and are not candidates for laser. At this point, I will individualize the treatment to the patient. Although I do not consider myself cavalier when it comes to cataracts, patients with RVO have a significant problem and I am unlikely to be as concerned about inducing cataracts, which can be easily resolved, as I am with achieving good outcomes with RVO treatment. I am much more concerned when it comes to either ocular hypertension or glaucoma. For these patients I will use an anti-VEGF agent, but for other cases I will consider the use of a steroid. In general, the initial effect of steroids can be very strong, so that one injection may eliminate edema. Patients may have similar responses with anti-VEGF injections, but the maintenance is far more frequent than with steroids. Peter K. Kaiser, MD: Peripheral ischemia is important to this discussion. I am not convinced that one treatment is necessarily better than the others, especially when we talk about using an anti-VEGF agent compared with a steroid in RVO. I prefer to use anti-VEGF agents first to decrease the risk of side effects, not because I think it is better than a steroid in terms of visual outcomes. I switch to a steroid if the anti-VEGF agent does not work. Dr. MacCumber: I tend to use steroids for patients who are pseudophakic with no history of glaucoma. I tend to use a steroid because the effect is longer, typically lasting about 4 months. During that time shunt vessels can often present
0409RT_ALLERGAN_CME.qxd
4/14/09
6:24 PM
Page 7
WHAT LIES AHEAD FOR YOUR PATIENTS?
DISCUSSION: CHOOSING TREATMENT OPTIONS FOR RVO themselves, and then the patient’s eye will have a much higher chance of remaining stable. Conversely, I will use an anti-VEGF agent for patients who have glaucoma or ocular hypertension, and I am more likely to use one for an eye that is phakic. The disadvantage, however, is that patients who receive an anti-VEGF agent frequently require multiple injections. Dr. Apte: I am sure that we have all had patients, usually those with CRVO with diffuse macular edema, who respond to a steroid initially and then lose that response, even with repeated injections. Sustained-release steroid preparations may be able to help these patients.
Sustained delivery of a steroid, once available, will change the way we treat patients with CRVO and BRVO. -SCOTT W. COUSINS, MD Dr. Cousins: What is the role of combination therapy in RVO treatment? Is there any evidence that the use of an antiVEGF agent plus a corticosteroid, or sequential use of these two agents, has increased benefit over monotherapy? How about pharmacologic therapy combined with laser or surgery? Dr. Kuppermann: Major questions remain unanswered on how to manage RVO with anti-VEGF and/or steroid combination therapy. Do you use an anti-VEGF agent early on and then use steroids later? If an anti-VEGF agent is used early on, does it inhibit the formation of shunt vessels in some regard, or does it help the healing response? We need to sort out the relative interplay between steroids and antiVEGF agents to determine how they should be applied to treat RVO. Dr. Heier: Combination therapy with steroids plus laser has been studied for several years in DME. The initial idea was that using a combination of steroid and laser would improve the outcomes, both in terms of initial treatment effect and duration of treatment.2 This question is being evaluated by the DRCR.net. Dr. Apte: Although it is difficult to extrapolate data from the DME research to RVO, the information from the DRCR.net Protocol B study will undoubtedly provide good insight. It showed that the robust, short-term effect of triam-
cinolone was not sufficient to last out to 2 years, while focal laser appeared to improve patient’s vision progressively. In Protocol I and J, however, combination therapy (anti-VEGF and laser or steroids) was evaluated, and these data may be useful for application to RVO. Dr. Cousins: How would pars plana vitrectomy used in combination with corticosteroids affect RVO management? Does vitrectomy alter the clearance of intravitreal injections? Dr. Heier: Combination therapy with vitrectomy has many potential advantages for RVO, including increased oxygenation as well as lysis of any vitreoretinal adhesions. But with our current therapy, vitrectomy should always be a lastditch effort because it may negate any benefits achieved with intraocular injections. In other words, vitrectomy may decrease the duration of action of intravitreal injections with removal of the vitreous scaffold. What is interesting about the intravitreal biodegradable sustained-delivery dexamethasone device, however, is that there are animal data suggesting that there is a similar release of the drug in a vitrectomized eye and that the duration of the steroid is not affected.3 Dr. Kupperman: All of the drug delivery systems that are under development have the benefit that the vitreous no longer needs to act as a reservoir. As we progress in our research on delivery systems for steroids, however, we are finding that some of the steroids may potentially induce less glaucoma and may be able to be more readily used for patients who have already experienced glaucomatous changes. Dr. Cousins: There seems to be a consensus that both steroids and anti-VEGF work in both CRVO and BRVO. Exactly which one is superior to the other is complex because of lack of data and different subtypes, ischemic and nonischemic. We do agree, however, that steroids will play a major role in the treatment of these diseases as we move forward, and sustained delivery of a steroid, once available, will change the way we treat these patients. 1. Finkelstein D. Ischemic macular edema. Recognition and favorable natural history in branch vein occlusion. Arch Ophthalmol. 1992;110(10):1427–1434. 2. 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. 3. Kupperman BD, Chang-Lin JE, Burke JA, Peng Q, Robinson MR, Whitcup SM. Pharmacokinetics of dexamethasone after intravitreal implantation of 700 µg dexamethasone posterior segment drug delivery system in vitrectomized and nonvitrectomized eyes. Paper presented at the 7th Euretina Congress; May 17-20, 2007; Monte Carlo.
APRIL 2009 I SUPPLEMENT TO RETINA TODAY I 7
0409RT_ALLERGAN_CME.qxd
4/14/09
6:24 PM
Page 8
THE FUTURE OF DIABETIC MACULAR EDEMA
The Mechanism of Action of Steroids in Treating RVO BY BARUCH D. KUPPERMANN, MD, P H D Note: The use of brand names in this article and subesquent discussions is necessary to distinguish between similar formulation of drugs and/or delivery mechanisms.
W
hen considering the mechanism of action of steroids in macular edema, the two main areas of concern are inflammation and the breakdown of the tight junction proteins that form the blood-retina barrier. The cascade of events in the formulation of macular edema related to RVO involves both prostaglandins and leukotrienes. Whereas, for instance, nonsteroidal antiinflammatory drugs (NSAIDs) address the prostaglandin component of the inflammatory cascade, they do not have any effect on the leukotriene pathway. Steroids, however, are broad based and cover both pathways, attacking every conceivable mechanism with robust potency. The introduction of a steroid modifies the gene expression of these inflammatory cytokines, inhibiting the inflammatory cascade via the receptors. One steroid, however, can have a different effect on the steroid receptors than others, and individuals can express those receptors differently too, which complicates the process further. We have been using triamcinolone acetonide because it is convenient and it works. There is a potential, however, to look at other steroids based on the information that we currently have and individualize treatment based on how the genes express themselves. DIFFERING SOLUBILITY/CELL BIOAVAILABILITY The solubility of the three available steroids—triamcinolone acetonide, fluocinolone, and dexamethasone—vary significantly. Triamcinolone acetonide and fluocinolone acetonide are designed to be relatively insoluble. Fluocinolone is available in a drug delivery system. Triamcinolone acetonide is a depot formulation and is able to function as its own drug delivery system because of its relative insolubility. Interestingly, triamcinolone is different from triamcinolone acetonide, which we tend to use, in potency and solubility. Triamcinolone is less potent and more soluble than triamcinolone acetonide. The modification with acetonide makes triamcinolone more potent and less soluble. Dexamethasone is the most potent among these steroids 8 I SUPPLEMENT TO RETINA TODAY I APRIL 2009
but is also the most soluble, making it an appealing compound for a strong antiinflammatory effect but limited to a short period of action (in free injection form). Once dexamethasone is placed into a drug delivery system, in my opinion, it comes close to being the ideal steroid: when it is released from the drug delivery system, it goes to its target receptors and, because it has a short duration of action, the collateral side effects of steroid are minimized. Additionally, the posterior placement of the drug is advantageous. The more posterior a drug is placed, the more likely it is that the drug will get to the macula and the less likely will migrate anteriorly. Some recent modeling work has shown that as implants are moved further posteriorly, the amount of drug that is measurable quadruples at the macula and is minimized to an almost nonmeasurable amount in the anterior chamber. The intravitreal biodegradable sustained-delivery dexamethasone device (Posurdex, Allergan, Inc., Irvine, CA) lasts approximately 6 months with initial high induction doses for the first 6 weeks or so, followed by lower maintenance level doses out to 6 months or more.1 The system releases a significant amount of drug almost immediately—100,000 ng/mL—well above the pulse delivery that we use for high-dose steroids to achieve a strong effect. This induction phase inhibits the cytokine cascade in a dramatic fashion. After approximately 6 weeks, the levels drop to low, yet therapeutic, levels, about 10 ng/mL. By comparison, the fluocinolone acetonide implant for uveitis (Retisert; Bausch & Lomb, Rochester, NY) has been shown to have significant effect at a concentration in the 10 ng/mL to 15 ng/mL range.2,3 In the biodegradable Posurdex dexamethasone drug delivery system, the patient can then be reinjected after 6 months or when disease recurs. Not injecting at 6 months allows the eye to have a drug holiday, which may potentially minimize some of the ocular complications of the steroid. However allowing disease to recur may be associated with less efficacy, so the paradigm for using a drug delivery system like this one is still in evolution. CHOOSING DRUG DELIVERY SYSTEMS How should we manage patients using these devices? On one hand, we have an injectable drug delivery system that
0409RT_ALLERGAN_CME.qxd
4/14/09
6:24 PM
Page 9
WHAT LIES AHEAD FOR YOUR PATIENTS?
THE INFLAMMATORY CASCADE AND THE MECHANISM OF ACTION OF STEROIDS ON MACULAR EDEMA
Figure 1. The cascade of events in inflammation involves both prostaglandins and leukotrienes.
Figure 2. Corticosteroids are a broad-based therapy that attack various mechanisms in the pathway to macular edema.
Figure 3. Steroids and anti-VEGF agents act against breakdown of the tight junction proteins that form the blood-retina barrier.
acts for a limited time. Do we reinject on a regular basis before the disease remanifests? Or do we wait for disease to remanifest and then inject, giving the patient a drug holiday to further lower the risk of cataract and glaucoma? Although I do not think that we currently know the answer to these questions, it is hoped that the results from the Posurdex clinical trial, in which investigators are reinjecting on a schedule of every 6 months, will help guide us. Results are anticipated later this year. We know that chronic low-grade steriod drug delivery over a period of years can result in significant ocular adverse effects. The fluocinolone-based Retisert implant has chronic low-dose drug delivery—the total dose of 0.59 mg releases less than 0.5 µg per day over periods of up to 3 years. But despite that low dose, it still has a significant effect against macular edema. The side effects, however, of cataracts and glaucoma are surprisingly frequent given the low dose. After 18 months to 3 years of even minimal exposure with Retisert, the data show, approximately 95% of eyes develop cataracts, approximately 50% of eyes develop significant glaucoma, and 40% require surgical intervention for glaucoma. One potentially significant difference between the available implants is that the Retisert is sutured to the eyewall, whereas the Posurdex implant and a new intravitreal fluocinolone delivery system that is being tested for DME (Iluvien, Alimera Sciences, Alpharetta, GA) are injected through the pars plana. These injected nonsutured implants situate themselves in the inferior vitreous base, in a position more posterior than the sutured Retisert implant. It will be interesting to see whether data from the FAME (Fluocinolone Acetonide in Diabetic Macular Edema) Iluvien implant study for DME will show a lower incidence of the complications seen with Retisert. In the FAME study, patients are treated with either a low dose (approximately 0.23 µg per day) of fluocinolone for 36 months or with a high dose (approximately 0.45 µg per day) for 18 months. By contrast, the Retisert implant was sutured to the eye wall and released drug at the rate of the high dose Iluvien implant but with the longer 36-month duration of the low dose Iluvien implant. So both location and drug exposure are different in the Retisert implant compared with the Iluvien implant. TOXICITY OF OCULAR STEROID FORMULATIONS We have looked at the effect of various steroid formulations on retinal cells in culture, testing both cell viability and cell damage as predictors of subsequent cell death. With most of the crystalline steroid preparations, including triamcinolone acetonide, we observed a significant decrease in cell viability on both neurosensory retina and retinal pigment epithelial cell lines. Dissolving the steroids decreased but did not eliminate the decrease in cell viability. Additionally, we saw increases in caspase 3/7 levels suggesAPRIL 2009 I SUPPLEMENT TO RETINA TODAY I 9
0409RT_ALLERGAN_CME.qxd
4/14/09
6:24 PM
Page 10
THE FUTURE OF DIABETIC MACULAR EDEMA
tive of apoptosis when cells were exposed to the dissolved steroids. All the steroid formulations exhibited measurable toxicity in this cell culture system at clinically relevant doses except dexamethasone, which was the least toxic. Toxicity was not observed until cells were exposed to doses 10 times the clinical dose of dexamethasone in free drug injections (400 µg), and at least 100 times the intravitreal dexamethasone level associated with the Posurdex implant. Additionally, the bulk of the toxicity observed with 10 times the clinical dose dexamethasone was caused by the preservative in dexamethasone, benzyl alcohol. TOXICITY OF DRUG AND VEHICLE Triamcinolone is available in various formulations, including preservative-containing triamcinolone (Kenalog, BristolMyers Squibb), preservative-free triamcinolone acetonide (Triesence, Alcon Laboratories, Inc.), and a hydrogel-based triamcinolone, which is also preservative-free (Trivaris, Allergan, Inc.). The Kenalog formulation of triamcinolone, which has highly variable particle size as a result of its manufacture, has been used in ophthalmology for many years. In 2006, however, a mini-epidemic of sterile endophthalmitis occurred associated with the use of this formulation. As a result, many ophthalmologists switched to using preservative-free triamcinolone, which at the time was available only through compounding pharmacies. This preservativefree formulation of triamcinolone acetonide from compounding pharmacies used micronized drug, which results in uniform particle size, smaller on average than the particles in Kenalog. Clinicians commonly noted that the com-
pounding pharmacy preservative-free triamcinolone acetonide appeared to last for a shorter duration of time (1 month) than the traditional Kenalog formulation (1 to 3 months). The variable particle size is important in this discussion because if the particle size was uniform, it would not be as effective a drug delivery system because the particles would all break down at the same time. On the other hand, with variable particle size, the drug stays in the eye for a longer period of time because the larger crystals take longer to break down—in effect, a drug-delivery system in itself. Triesence appears to be similar in particle size and variability to Kenalog and different from the smaller uniform particle size seen with compounding-center micronized preservative-free triamcinolone acetonide. The formulation of Trivaris is that of a hydrogel, another type of drug delivery vehicle. The hydrogel may act as a potential buffer that rests on the retina in a vitrectomized eye, so that the crystal of the steroid does not. This, however, remains a hypothesis because I am just beginning to test the hydrogel formulation of triamcinolone. Initial rabbit studies have shown that the Trivaris formulation appears to last at least as long as Kenalog and possibly longer. Further studies are being performed to evaluate this. 1. Kuppermann BD, Blumenkranz MS, Haller JS, et al. Randomized, controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthal. 2007;125(3):309–317. 2. Driot JY, Novack GD, Rittenhouse KD, et al. Ocular pharmacokinetics of fluocinolone acetonide after Retisert intravitreal implantation in rabbits over a 1-year period. J Ocul Pharmacol Ther. 2004;20:269–275. 3. Callanan DG, Jaffe GJ, Martin DF, Pearson PA, Comstock TL. Treatment of posterior uveitis with a fluocinolone acetonide implant: three-year clinical trial results. Arch Ophthalmol. 2008;126(9):1191–1201.
DISCUSSION: DRUG VEHICLE Dr. Kaiser: In the DRCR.net study,1 a gel matrix solution of triamcinolone acetonide was used, rather than the particulized version that we currently use in clinic. Do you think that the gel formulation, because it essentially globs near the injection site as opposed to permeating throughout the eye, played a role in the conclusion that steroid was less effective than laser in the trial? Dr. Kuppermann: This is a relevant point because the solubility, location, and dispersion characteristics of the two versions of triamcinolone acetonide (Kenalog and Trivaris) may be very different. Dr. Cousins: Dr. Heier, what is your opinion on the efficacy of the drug delivery systems based on design and how they are placed in the eye?
10 I SUPPLEMENT TO RETINA TODAY I APRIL 2009
Dr. Heier: I believe that most retina specialists would prefer an injectable implant as opposed to one that is sutured to the eyewall because this method is less traumatic; however, the ultimate choice will be driven by efficacy. Dr. Kaiser: We also need to await the results of the injected, nonerodable delivery system for fluocinolone acetonide to evaluate the side effects of this treatment. We know steroids are effective, but cataracts and glaucoma are always issues we need to follow, and it is difficult to remove this implant. It is important to note that the injected nonerodable implant releases a much lower dose of steroid than Retisert, so the side effect profile may be better. However, it is nice to be able to inject a device that delivers steroids for up to 3 years. Dr. MacCumber: The recent data from the DRCR study
0409RT_ALLERGAN_CME.qxd
4/14/09
6:24 PM
Page 11
WHAT LIES AHEAD FOR YOUR PATIENTS?
DISCUSSION: DRUG VEHICLE regarding DME can offer some insight as to how long an implant should provide drug effect. In that study, the grid laser started showing improved efficacy over steroid after 16 months, so for this disease we may not need a drug that lasts past that point. Potentially, a shorter-acting steroid could have benefit for patients over longer-acting delivery systems, such as the fluocinolone implant that provides steroid release for 3 years.
tion does not have the efficacy or durability that we desire, we cannot assume that all of these steroids are the same. Given the differential effects that these formulations have on various cell structures, it is important not to take a marginally negative trial result as the end of the issue. Rather, we should look at the DRCR.net results as a first step toward the development of steroids as agents that can be targeted to more effectively treat disease.
Dr. Cousins: Only one steroid, triamcinolone acetonide, was used in the DRCR.net trial, and, because one formula-
1. 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.
The Current Status of DME and Steroid Treatment BY JEFFREY S. HEIER, MD
W
hen reviewing the literature of steroids for treatment of diabetic macular edema (DME), there are many studies through which to sort. There have been numerous small series, medium-sized series, and small prospective studies with varying degrees of design; however, to date no large randomized clinical trials with controls over factors such as age, glycemic control, or previous treatments exist. THE GOLD STANDARD Recently, the results of the Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol B study, which compared steroid with focal/grid laser photocoagulation, reconfirmed the benefit of laser for treating DME.1 However, questions remain regarding steroids vs laser, some of which include dosing, formulation, and method of drug delivery. More large-scale studies are required to come to the conclusion that steroid therapy, or a combination of therapies, would not be advantageous in treating our patients with DME. STUDIES ON DURATION OF EFFICACY Additionally, although a small number of studies looked at the effect of periocular or sub-Tenon’s injec-
tions with triamcinolone, most studies have looked at the effect of intravitreal triamcinolone. The time duration of these studies has also been relatively short, which means that the primary outcomes may appear better than if the study period was longer. For example, the ISIS (Intravitreal Steroid Injection Study)-DME Study Group found that the benefit of 2 mg and 4 mg intravitreal triamcinolone acetonide (Kenalog) was greater at 3 months than 6 months.2 Another study evaluated the retention times of triamcinolone acetonide particles in relation to efficacy.3 That study found that retention time was 114 days in DME, but that retention time and decrease of inflammation seen on optical coherence tomography (OCT) did not correlate. An interesting finding from this study was that the retention time was higher in younger patients because of the more formed vitreous. ANALYZING THE AVAILABLE LITERATURE Grover et al4 performed an analysis of seven different studies with a total of 632 eyes on the use of steroids for treating DME. Four of the studies used intravitreal triamcinolone vs laser photocoagulation, and three evaluated either intravitreal fluocinolone or dexamethasone implants vs laser photocoagulation. The analysis found benefit of steroids; patients randomized to some APRIL 2009 I SUPPLEMENT TO RETINA TODAY I 11
0409RT_ALLERGAN_CME.qxd
4/14/09
6:25 PM
Page 12
THE FUTURE OF DIABETIC MACULAR EDEMA
sort of treatment with steroid showed improvement of visual acuity and a decrease in retinal thickness on OCT. No patients, however, showed evidence of a three-line gain in visual acuity. Unlike the ETDRS (Early Treatment Diabetic Retinopathy Study), where a two-line gain was a primary endpoint, these studies are looking for a three-line gain. This will be an important point as we look at the outcomes that the US Food and Drug Administration feels are important for longer studies of steroid implants. Three-line gain is one of their major concerns as opposed to two-line gain like the ETDRS studies. Uniform to almost all of these studies is a focus on refractory DME. These were not patients who first presented with either focal edema or first-time edema. A large majority of these patients had already undergone treatment with laser and possibly intravitreal anti-
vascular endothelial growth factor agents. There have also have been small studies that showed 1 mg and 2 mg injections of triamcinolone were as effective, if not more effective, than the 4 mg injections. Other studies, however, contradict these and suggest that higher doses of triamcinolone may have a longer duration of effect, as long as 7 to 8 months. 1. 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. 2. Kim JE, Pollack JS, Miller DG, Mittra RA, Spaide; ISIS Study Group. ISIS-DME: a prospective, randomized, dose-escalation intravitreal steroid injection study for refractory diabetic macular edema. Retina. 2008;28(5):735–740. 3. Kogure A, Ohkoshi K, Kogure S, Yamaguchi T, Kishi S. Efficacy and retention times of intravitreal triamcinolone acetonide for macular edema. Jpn J Ophthalmol. 2008;52(2):122–126. Epub 2008 Apr 30. 4. Grover D, Li TJ, Chong CCW. Intravitreal steroids for macular edema in diabetes. Cochrane Database of Systematic Reviews. 2008;1:CD005656. DOI:10.1002/14651858.CD005656.pub2.
DISCUSSION: CRITERIA FOR REINJECTION Dr. MacCumber: It is interesting that in the DRCR Protocol B study the investigators were encouraged to be aggressive with their use of steroid and grid laser, but if you look at the data, many patients did not receive aggressive therapy for a variety of reasons. I think a more aggressive approach could have altered the outcomes.
A drug delivery system may improve not only patient compliance but also physician compliance. -BARUCH D. KUPPERMANN, MD, PHD
Dr. Cousins: How do you decide to reinject with steroid? Dr. MacCumber: My criterion for reinjection is visual response. I will, however, sometimes continue to reinject for patients who may not have an impressive visual response, but who, on OCT, show a good anatomic response. For DME patients, I frequently combine intravitreal steroids with grid laser. In my opinion, the DRCR study was tilted somewhat against steroids because the visual acuity response was measured 4 months after the injection. In that interval, there may have been a significant clinical effect that was missed. Additionally, focal grid laser is easier to deliver when you have a dry macula compared with a thick macula. By injecting with steroid before applying laser, the laser treatment may be
12 I SUPPLEMENT TO RETINA TODAY I APRIL 2009
more effective than if it was delivered to a thicker macula. Dr. Cousins: Do you think that certain DME subtypes respond better to laser vs pharmacotherapy? Dr. Heier: There are reports in the literature that cystoid macular edema associated-DME tends to respond better to pharmacotherapy.1 Dr. Kaiser: I am looking forward to seeing the follow-up paper from the DRCR.net that will analyze these factors because the EDTRS, along with almost every major paper, showed that patients with cysts do better with steroids. Dr. Heier: As Dr. MacCumber stated, the clinicians in the DRCR.net study tended to undertreat so that is also a factor to consider in viewing the initial results and also the results of the extension studies. Dr. Kuppermann: We frequently consider patient compliance, but we rarely discuss physician compliance. For example, in the DRCR.net laser vs triamcinolone study, is it possible that many investigators may have undertreated patients with steroids? A drug delivery system may improve not only patient compliance but also physician compliance in delivering the correct amount of steroid for maximal efficacy. Patients would also benefit from the decreased frequency of reinjections. 1. Bhagat N, Grigorian R, Tutela A, Zarbi M. Diabetic macular edema: pathogenesis and treatment. Surv Ophthalmol. 2009;54(1):1–32.
0409RT_ALLERGAN_CME.qxd
4/14/09
6:25 PM
Page 13
WHAT LIES AHEAD FOR YOUR PATIENTS?
Ongoing Studies of Steroids in Retinal Disease BY PETER K. KAISER, MD he DRCR.net Protocol B results1 have changed some companies’ thinking about the direction they are going with steroids, and this is disappointing. Although there are important lessons to be gained from these results, to say that steroids do not work in diabetes is incorrect. The correct conclusion from this study is that laser works better than previously thought. The DRCR.net has several other studies that are ongoing, and some of them are evaluating combination treatments, including surgery, laser plus steroids, the preservativefree hydrogel triamcinolone acetonide plus laser plus ranibizumab, and also ranibizumab alone vs laser alone. The DRCR.net is also conducting studies on panretinal photocoagulation (PRP) in combination with steroids vs antivascular endothelial growth factor (anti-VEGF) to see if the addition of the anti-VEGF agent or steroid will decrease the incidence of macular edema from PRP.
T
DME STUDIES All the manufacturers of sustained-release drug delivery implants have their technology in clinical studies for DME. The intravitreal biodegradable sustained-delivery dexamethasone is being studied for DME vs laser, and also a combination of sustaineddelivery dexamethasone and laser is being studied for patients with diffuse refractory DME. The Retisert fluocinolone device performed well in clinical trials for DME and was one of the few drugs that decreased, and even in some cases reversed, diabetic retinopathy scores. The problems with this device, however, were that almost all patients developed cataracts, and a high percentage of patients developed glaucomatous complications. Because of these complications, the FDA label for Retisert remains only for uveitis. There is another intravitreal sustained-release, nonerodable implant that can be injected through a 25-gauge in-office procedure, which is currently in phase 3 studies for DME. Although this implant is based on similar technology as the Retisert implant, it is considerably smaller, is injected in the office more
posteriorly in the eye than Retisert, and is half the dose of what is delivered by Retisert.
The agents that selectively target components of inflammation that promote development or progression of retinopathy might indeed have a strong role. RVO STUDIES There are also multiple studies evaluating sustainedrelease implants in retinal venous occlusive disease. The dexamethasone device is being studied for both BRVO and CRVO, and the fluocinolone sustained release implant is being studied in a small study for BRVO. The largest study currently under way for RVO is the National Eye Institute’s SCORE study (Standard Care versus Corticosteroid for Retinal Vein Occlusion), which is using the hydrogel preservative-free triamcinolone acetonide for both BRVO and CRVO. Results of this trial are expected in the fall of 2009. UVEITIS STUDIES Currently, Retisert is the only FDA-approved steroid implant for noninfectious uveitis. Enrollment in the clinical trial for intravitreal biodegradable sustained-delivery dexamethasone for noninfectious uveitis is complete. The results of this trial will be interesting because of the biodegradable nature of the device. It requires an easy injection technique and does not require an invasive surgical procedure. The shorter duration of the dexamethasone device is advantageous because the longer a steroid is in the eye, the greater the risk of steroidinduced cataracts and glaucoma. 1. 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.
APRIL 2009 I SUPPLEMENT TO RETINA TODAY I 13
0409RT_ALLERGAN_CME.qxd
4/14/09
6:25 PM
Page 14
THE FUTURE OF DIABETIC MACULAR EDEMA
DISCUSSION: COMPLICATIONS WITH INTRAVITREAL STEROIDS Cousins: What are some of the concerns that you have with the sustained-delivery devices for DME and RVO currently under investigation? Dr. Kuppermann: I have some theoretical concerns with the Iluvien device that is being tested for DME and RVO. By cutting the dose in half from what the Retisert delivers, the risk of complications may be lowered, but I wonder if the reduction will make the drug subtherapeutic. Dr. MacCumber: The complication that most concerns me is a rise in IOP requiring glaucoma surgery. In my experience, this is associated with the greatest amount of disappointment for patients. A small rise in IOP is manageable with drops, but if the rise is significant, I think we have to weigh this complication carefully against any visual benefit that the treatment can offer the patient. Dr. Heier: Some studies report that roughly 30% of patients treated with triamcinolone have significant rises in IOP.1,2 What is interesting is that rises in IOP do not appear to be dose dependent. Additionally, different studies report these pressure rises at different levels; some report IOP spikes to 21 mm Hg, and others report 25 mm Hg. Dr. Cousins: In patients who are phakic, how frequently do cataracts significantly progress as a side effect of steroids?
true mechanistic explanation for what causes this condition. The inflammatory component in the anterior segment is concerning, and diagnosis can be difficult because of the worry of infection. It has inflammation in the vitreous and/or in the anterior chamber. True infectious endophthalmitis is a bacterial response to the injection process itself rather than the drug. Typically, in bacterial endophthalmitis, the patient will experience acute pain in the conjunctival injection. Visual acuity loss is progressive, and the time of onset tends to be longer—several days postoperative, rather than immediate. Sterile endophthalmitis, however, is not associated with pain (although pain can be mild to moderate) and is more immediate in its presentation. Dr. Apte: The vitreous differs in bacterial and sterile endophthalmitis. In bacterial endophthalmitis, the vitreous has more membrane. In cases of sterile endophthalmitis, single inflammatory cells can be seen.
Although a tap-and-inject protocol is traumatic to the patient, missing bacterial endophthalmitis may have devastating consequences. -PETER K. KAISER, MD
Dr. Apte: I believe they progress in 50% of patients by 2 years.3 Dr. Kuppermann: The risk of steroid-induced cataract may be dependent on how many injections are being given. The timing is also somewhat unpredictable, whereas the steroid response from a glaucoma standpoint is typically approximately 2 months after injection. Dr. Heier: In the DRCR.net study, cataract extraction was required in 13% of patients in the laser group, 23% in the 1 mg triamcinolone group; and 51% in the 4 mg triamcinolone group. Dr. Cousins: As retina specialists, we see various forms of endophthalmitis, and we must discern the difference and treat each accordingly: pseudoendophthalmitis, bacterial (infectious) endophthalmitis, and sterile (noninfectious) endophthalmitis. Pseudoendophthalmitis is when a migration of the steroid crystals to the anterior chamber occurs. The inflammatory response is not infectious and there is no
14 I SUPPLEMENT TO RETINA TODAY I APRIL 2009
Dr. Cousins: If a patient presents with what could be either bacterial or sterile endophthalmitis, do you tap and inject, or would you observe and delay your tap-and-inject protocol? Dr. Apte: Based on the criteria that we discussed, if I am fairly sure it is sterile endophthalmitis, I will follow the case closely. I may even call the patient back for follow-up 12 hours to 1 or 2 days later. If I am suspicious that it may be bacterial based on the inflammation, pain level, and vitreous status, however, I will tap and inject. Dr. Kaiser: I agree. Although a tap-and-inject protocol is traumatic to the patient, missing bacterial endophthalmitis may have devastating consequences. 1.Jonas JB, Sauder G, Budde WM, Spandau UH, Kamppeter BA, Harder B. Triamcinolone acetonide-induced ocular hypertension. J Ocul Pharmacol Ther. 2006;22(4):247–250. 2.Rodriguez-Coleman H, Yuan P, Kim H, et al.Intravitreal injection of triamcinolone for diffuse macular edema. Arch Ophthalmol. 2004;122(7):1085–1086. 3. 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.
0409RT_ALLERGAN_CME.qxd
4/14/09
6:25 PM
Page 15
WHAT LIES AHEAD FOR YOUR PATIENTS?
INSTRUCTIONS FOR CME CREDIT 1.5 AMA PRA Category 1 Credits™
Expires April 2010
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] and explain the details of any problems you encounter with the Web site. Alternatively, you can fax your exam to us at +1-610-771-4443. Indicate how you would like to receive your certificate below. Please type or print clearly or we will be unable to issue your certificate. Name ____________________________________________________________________ ❏ MD participant ❏ non-MD participant Phone (required) _______________________________________________________________________________________________ I would like my certificate sent via ❏ fax __________________________________❏ e-mail ____________________________________
CME QUESTIONS 1. The main factor in inflammation that has recently emerged is: a. acquired inflammation b. interferons c. the macrophage d. all of the above
5. The half-life of dexamethasone has been shown to be: a. 72 hours b. 40 hours c. 3 hours d. 12 hours
2. The inflammation associated with AMD, RVO, and DR is the same as is seen with posterior uveitis. a. True b. False
6. The DRCR.net Protocol B study showed that: a. laser was significantly more effective than steroids for treating DME at 2 years b. steroids were more effective than laser for treating DME at 2 years c. lasers were slightly more effective than steroids for treating DME at 2 years d. none of the above
3. Shunt vessel development has been shown to be associated with: a. poor outcomes in RVO b. natural stabilization of eyes with RVO c. adverse reaction to corticosteroid d. none of the above 4. The largest study to date on steroids for RVO is: a. The Branch Retinal Vein Occlusion Study b. The Branch Vein Occlusion Study c. The Standard Care vs Corticosteroids for Retinal Vein Occlusion Study d. Early Treatment for Diabetic Retinopathy Study
Sponsored by the Dulaney Foundation
7. When comparing triamcinolone acetonide, fluocinolone acetonide, and dexamethasone, ______________ is the most soluble. a. triamcinolone acetonide b. fluocinolone acetonide c. dexamethasone
8. The fluocinolone delivery device that is approved by the US Food and Drug Administration for the treatment of uveitis delivers a dose of less than 0.50 µm per day; the fluocinolone device being tested for DME releases a low dose of _____ per day and a high dose of ______ per day. a. 0.50 µg/0.83 µg b. 0.23 µg/0.45 µg c. 0.15 µg/0.23 µg d. 0.23 µg/0.50 µg 9. In laboratory testing, 90% of the toxicity that was seen in dexamethasone was from its preservative. a. True b. False 10. The ISIS-DME Study Group found that: a. the benefit of 2 mg and 4 mg intravitreal triamcinolone acetonide was greater at 6 months than 3 months b. the benefit of 2 mg and 4 mg intravitreal triamcinolone acetonide was greater at 1 month than 3 months c. the benefit of 2 mg and 4 mg intravitreal triamcinolone acetonide was greater at 3 months than 6 months d. none of the above
Supported by unrestricted educational grants from Allergan, Inc.. APRIL 2009 I SUPPLEMENT TO RETINA TODAY I 15
0409RT_ALLERGAN_CME.qxd
4/15/09
2:11 PM
Page 16
THE FUTURE OF DIABETIC MACULAR EDEMA
ACTIVITY EVALUATION
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 back to the Dulaney Foundation via fax at +1 610-771-4443. Name ____________________________________________________________________________________________ Do you feel the program was educationally sound and commercially balanced? Comments regarding commercial bias:
❒ Yes
❒ No
______________________________________________________________________________________________ ______________________________________________________________________________________________ ______________________________________________________________________________________________ Rate your knowledge/skill level prior to attending this course: 5 = High, 1 = Low _________ Rate your knowledge/skill level after attending this course: 5 = High, 1 = Low Would you recommend this program to a colleague?
❒ Yes
_________
❒ No
Do you feel the information presented will change your patient care? ❒ Yes ❒ No If yes, please specify. We will contact you by E-mail in 2-3 months to see if you have made this change. ______________________________________________________________________________________________ ______________________________________________________________________________________________ ______________________________________________________________________________________________ If no, please identify barriers to change. ______________________________________________________________________________________________ ______________________________________________________________________________________________ ______________________________________________________________________________________________
List any additional topics you would like to see offered at future Dulaney Foundation programs or other suggestions or comments: ______________________________________________________________________________________________ ______________________________________________________________________________________________ ______________________________________________________________________________________________
Sponsored by the Dulaney Foundation
