Macular edema (ME) is the most common

MANAGEMENT OF RETINAL VEIN OCCLUSIONS * Peter A. Campochiaro, MD ABSTRACT Macular edema (ME) is the most common cause of reduced vision in patients with retinal vein occlusions (RVOs). The primary cause for ME was previously thought to be transudation due to increased venous pressure caused by obstructed outflow, but we now have a greater understanding of the critical role of retinal ischemia leading to release of vascular endothelial growth factor (VEGF). An early pilot study of ranibizumab conducted at the Wilmer Eye Institute in patients with ME due to either branch or central RVOs (BRVO or CRVO) showed a rapid and robust decrease in excess central retinal thickening and a corresponding rapid and robust increase in visual acuity. There was a negative correlation between aqueous VEGF level at baseline and visual outcome, indicating that particularly high VEGF levels were a disadvantage. These results led to pivotal, randomized, controlled trials in patients with BRVO (BRAVO [Efficacy and Safety of Ranibizumab Injection in Patients with ME Secondary to BRVO] study) and CRVO (CRUISE [Efficacy and Safety of Ranibizumab Injection in Patients with ME Secondary to CRVO] study), which have demonstrated impressive benefits over the course of 6 months. Although the long-term effects of ranibizumab are not completely established, continued follow-up for 2 years in patients *Based on a presentation by Dr Campochiaro at a roundtable symposium held in Fort Lauderdale, Florida, on April 30, 2010. George and Dolores Eccles Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. Address correspondence to: Peter A. Campochiaro, MD, George and Dolores Eccles Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Maumenee 719, Baltimore, MD, 21287. E-mail: pcampo@jhmi.edu. enrolled in the initial pilot trial suggest that as-needed ranibizumab results in complete and partial maintenance of benefits in patients with BRVO or CRVO, respectively. Considering the recent approval of ranibizumab for treatment of RVO by the US Food and Drug Administration, new recommendations for management of RVO are offered. (Adv Stud Ophthalmol. 2010;7(2):42-47) Macular edema (ME) is the most common cause of reduced vision in patients with retinal vein occlusions (RVOs). Other causes include retinal hemorrhages, which are reversible, and macular ischemia, which is permanent. ME is initially reversible, but over time, permanent loss of vision occurs from structural damage to the macula. In patients with RVO, veins distal to the obstruction become dilated and tortuous, suggesting increased venous pressure, which has been felt to be the primary reason for leakage of plasma and red blood cells into surrounding retina. Efforts to develop treatments have focused on attempting to eliminate or bypass the obstruction with thrombolytics, surgery, or creation of shunt vessels by inducing arteriovenous anastomoses. However, these concepts have been challenged by new data suggesting that retinal ischemia and release of vascular endothelial growth factor (VEGF) play a critical role. A pilot study conducted at the Wilmer Eye Institute compared 3 monthly injections of 0.3- or 0.5-mg ranibizumab (Lucentis; Genentech, Inc, South San Francisco, CA) in patients with ME due to either branch or central RVOs (BRVO or CRVO). With either dose, there was a substantial reduction in excess central retinal thickness within 1 week; by month 3 it was reduced by approximately 90%. This was accom- 42 Vol. 7, No. 2 December 2010

Table 1. Primary Results from the BRAVO and CRUISE Studies of Ranibizumab for RVO BRVO CRUISE 0.3-mg 0.5-mg Sham 0.3-mg 0.5-mg Sham ranibizumab ranibizumab ranibizumab ranibizumab Mean change from baseline 16.6 18.3 7.3 12.7 14.9 0.8 in BCVA letter score* (14.7 18.5) (16 20.6) (5.1 9.5) (9.9 15.4) (12.6 17.2) (-2 3.6) Patients who gained >15 55.2% 61.1% 28.8% 46.2% 47.7% 16.9% letters in BCVA, %* Median percent reduction 97% 97.6% 27.9% 94% 97.3% 23.9% in excess foveal thickness Median reduction in excess 337.3 345.2 157.7 434 452 168 foveal thickness, µm* *P <.0001 for each ranibizumab group vs sham, BRAVO, and CRUISE. BCVA = best corrected visual acuity; BRAVO = Efficacy and Safety of Ranibizumab Injection in Patients with Macular Edema Secondary to BRVO; BRVO = branch RVO; CRUISE = Efficacy and Safety of Ranibizumab Injection in Patients with Macular Edema Secondary to CRVO; CRVO = central RVO; RVO = retinal vein occlusion. Data from Campochiaro et al 2 and Brown et al. 3 panied by an average improvement in visual acuity of 15 Early Treatment Diabetic Retinopathy Study letters in all patient groups, a very large effect. Patients with the highest levels of VEGF in the aqueous at baseline tended to have the worst outcomes. 1 These results provided the rationale and assistance in design for 2 pivotal trials, the BRAVO study (Efficacy and Safety of Ranibizumab Injection in Patients with ME Secondary to BRVO; 397 patients with ME following BRVO) and the CRUISE study (Efficacy and Safety of Ranibizumab Injection in Patients with ME Secondary to CRVO; 392 patients with ME following CRVO), comparing monthly intraocular injections of 0.3- or 0.5-mg ranibizumab with sham injections. The results at the 6- month primary end point are shown in Table 1 and mirror those from the pilot study of ranibizumab. 2,3 Although the short-term data with ranibizumab treatment are impressive and compelling, there is less information regarding the long-term effects. The 2- year outcomes are now available for the initial pilot study. After the 3-month primary end point, patients were seen every 2 months and given an injection of ranibizumab if there was recurrent or persistent ME. Five patients with BRVO and 3 with CRVO required 0 or 1 additional injection after the primary end point and had good vision and no edema at the 2-year end point, but the majority of patients required many injections throughout the follow-up period for recurrent edema. As shown in Table 2, with continued asneeded (PRN) ranibizumab injections, most patients Table 2. Level of Improvement After 3 Monthly Ranibizumab Injections, Followed by PRN Injections Over 2 Years, in Patients with BRVO and CRVO BRVO CRVO Level of improvement Month 3 Month 24 Month 3 Month 24 No change 0 1 0 2 (14%) 5 letters 19 (95%) 16 (94%) 18 (90%) 9 (64%) 10 letters 14 (70%) 13 (76%) 14 (70%) 6 (43%) 15 letters 10 (50%) 10 (59%) 11 (55%) 3 (21%) 30 letters 3 (15%) 3 (18%) 0 3 (21%) Reduced 5 letters -- -- 2 (10%) 2 (14%) Mean improvement 16.1 17.8 12.0 8.5 BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion; PRN = as needed. Data from Campochiaro et al. 4 Johns Hopkins Advanced Studies in Ophthalmology 43

with BRVO were able to maintain the level of vision benefits achieved after 3 monthly injections with an average of 2 injections of ranibizumab during the second year. Mean foveal thickness was also fairly well maintained, but was slightly higher at 2 years compared to 3 months. 4 The situation was somewhat different for patients with CRVO because most but not all of the visual benefits were maintained during the follow-up phase; mean improvement from baseline in visual acuity was 8.5 letters at 2 years compared to 12 letters in the same patients at 3 months (Table 2). 4 The reason for the decline was there was recurrent edema in many patients despite the availability of ranibizumab every 2 months. Such findings suggest that more aggressive follow-up is needed for many patients with CRVO, perhaps visits every month with injections of ranibizumab if needed. Two baseline characteristics were found to predict visual outcome: chronicity of edema and extensive disruption of the perifoveal capillary bed. Patients who had BRVO for 1 year or longer at baseline had no difference in the amount of visual improvement at 2 years compared to patients with shorter duration of disease, but their final vision at 2 years was significantly lower (Table 3). 4 Likewise, patients with BRVO who had disruption of more than 180 of the perifoveal capillary bed were able to achieve substantial improvement in vision, but had a final vision at 2 years that was significantly less than that seen in patients with less than 180 disruption of the perifoveal capillaries. In patients with CRVO, these 2 baseline characteristics had an even greater impact. Patients who had CRVO for more than 1 year at baseline or had extensive disruption of the perifoveal capillaries had significantly less visual improvement and worse final vision at 2 years than patients with CRVO for less than 1 year or patients with minimal disruption of the perifoveal capillaries, respectively. 4 These studies indicate that ranibizumab provides very good benefit in patients with ME due to vein occlusions, out to 2 years, with a good safety profile. However, several questions remain. Can higher doses of ranibizumab provide greater benefit? Can laser to areas of nonperfusion reduce the need for continued injections without sacrificing visual benefit? Should we expect the same results with bevacizumab as ranibizumab? Are they interchangeable? And what is the role of steroids in RVO treatment? TREATMENT RECOMMENDATIONS Ranibizumab has recently been approved for treatment of ME due to BRVO or CRVO. Based on the study results to date, the following treatment regimen is recommended. For patients with ME due to BRVO, treat initially with ranibizumab monthly for 6 months and then observe for approximately 3 months. If recur- Table 3. Factors Affecting Visual Outcome After 3 Monthly Ranibizumab Injections, Followed by PRN Injections Over 2 Years, in Patients with BRVO and CRVO BRVO CRVO N Mean increase in P BCVA at P N Mean increase in P BCVA at P ETDRS letters month 24 ETDRS letters month 24 at month 3 at month 3 RVO 1 y 9 19.4 NS 45.1.05 10 13.6.05 34.3.05 RVO >1 y 8 15.9 36.5 4-4.8 14.8 PCD 180º 11 17.4 NS 45.1.05 11 10.5.05 34.5.05 PCD >180º 6 18.5 33 -- -- -- PCD = 360º 3 16.7 27.7 3-8.7 0.3 BCVA = best corrected visual acuity; BRVO = branch RVO; CRVO = central RVO; ETDRS = Early Treatment Diabetic Retinopathy Study; NS = not significant; PCD = perifoveal capillary perfusion; PRN = as needed; RVO = retinal vein occlusion. Data from Campochiaro et al. 4 44 Vol. 7, No. 2 December 2010

rent ME is observed 3 months after stopping ranibizumab, start PRN treatment with ranibizumab. If frequent injections are needed to control edema during PRN treatment, consider grid laser therapy. If frequent ranibizumab injections are still required 3 months after grid laser, consider steroid therapy (dexamethasone intravitreal implant [Ozurdex; Allergan, Inc, Irvine, CA] or triamcinolone acetonide injectable solution [Kenalog; Bristol-Myers Squibb Company, Princeton, NJ]). For macular edema due to CRVO, the recommendations are similar: monthly injections for 6 months, observation for 2 to 3 months, and then monthly follow-up with PRN ranibizumab injections. If frequent injections are needed to control edema during a PRN treatment phase, one could consider the addition of steroids (dexamethasone intravitreal implant or triamcinolone acetonide injectable solution). We are currently testing whether scatter photocoagulation to areas of nonperfusion can reduce the need for frequent injections of ranibizumab and what effect it has on visual acuity. Patient with BRVO Diana V. Do, MD RH is a 68-year-old man who complains of decreased vision in his left eye for 1 month. His previous medical history includes systemic hypertension. Previous ocular history includes a retinal tear in his left eye, for which he received retinopexy, and glaucoma in the left eye, for which he is receiving topical intraocular pressure-lowering agents. Visual acuity is 20/16 OD, 20/100 OS. Funduscopy of the left eye reveals superotemporal BRVO with intraretinal hemorrhages. Fluorescein angiography was performed in the left eye and demonstrated blockage from the intraretinal hemorrhages. In the late frames of the angiogram, there is some retinal vascular leakage but the hemorrhages obscure much of the leakage. Optical coherence tomography (OCT) of the left eye revealed severe cystoid ME involving the center of the fovea. When would you recommend treatment? If you decide to treat him, what treatment option would you recommend? How long would you follow this patient? For further discussion of the challenges in managing these real-life situations, please go to www.jhasio.com/retinaldiseases. DISCUSSION DEFINING A PRN REGIMEN Dr Nguyen: Would you recommend a more regular treatment regimen than PRN for CRVO, given that the results you saw were not as good? Dr Campochiaro: This is still a fluid situation as we wait for more long-term data. I think it is reasonable to consider following these patients and treating edema as it recurs because, in general, the recurrences did not leave permanent loss of vision over the short term and therefore you have some flexibility in the way that you approach this. I could not argue vociferously at this point to have a longer period of monthly treatment for patients with CRVO. Dr Kuppermann: What is your PRN approach? What are your criteria for re-treatment? How much edema do you tolerate before you would reinject? Dr Campochiaro: In our long-term trial, for the first year it was ME greater than 250 µm with time domain OCT. In the second year, it was the presence of any intraretinal fluid. That gives you the flexibility to treat, but you do not have to treat. In the patients with BRVO at 2 years, there was on average slightly greater foveal thickness, but the vision was the same. It appears that periodic reduction in edema is enough to salvage the retina from permanent visual loss. Dr Flynn: Are there any data regarding more frequent dosing (eg, every 4 6 weeks) in venous occlusive disease? Dr Campochiaro: In our trial, we chose followup of every 2 months to make the protocol less difficult for patients. The data suggest that this frequency is not ideal for BRVO, but it works pretty well. Their vision is maintained out to 2 years, despite some recurrent edema. For CRVO, every 2 months is probably not sufficient, but there is individual variability so we recommend that you tailor it for individual patients. I think the issue is going to be, after a period of maintenance, whether injections every 6 weeks still work for the patient. The physician could discuss other options to decrease the frequency of visits and reinjections, such as laser and steroids. The approach is likely to evolve. COMPARING RANIBIZUMAB TO BEVACIZUMAB Dr Flynn: Because ranibizumab is not approved for venous occlusive disease, most people are using bevacizumab (Avastin; Genentech, Inc, South San Johns Hopkins Advanced Studies in Ophthalmology 45

Francisco, CA) preferentially for that issue. Do you agree with that? Dr Campochiaro: I think that question cannot be answered right now. The results from case studies in which bevacizumab was used are not nearly as good as those from BRAVO and CRUISE or the results that I reported from the long-term follow-up. It is not a completely fair comparison, but some of those cases were treated monthly and the results are just not as good. Anecdotally, clinicians who have used both VEGF antagonists feel that perhaps in diabetic ME and central vein occlusion, there may be advantages to ranibizumab. It is not understood exactly why that would be. It may simply be that the levels of VEGF are higher in those conditions than in neovascular agerelated macular degeneration and BRVO. Dr Do: Although the medical evidence for bevacizumab is level 2 and level 3 for a vein occlusion, there was a recently published prospective study in Europe that included 29 eyes with ME due to vein occlusion, among which the majority had BRVO. The investigators chose a regimen in which they administered 1-mg bevacizumab in 3 scheduled injections, then PRN treatment thereafter. In this small, prospective, nonrandomized study, after 12 months, the mean gain in visual acuity was 16 letters. 5 Although we cannot draw definite conclusions, this study shows that there is good biologic activity with bevacizumab, even though it is off-label use in this condition, too. Until we have a head-to-head comparison, I think it is reasonable to extrapolate and use it in the interim. START WITH LASER OR ANTI-VEGF THERAPY? Dr Davis: Why do you recommend starting with ranibizumab injections rather than starting with grid laser (the current standard of care)? Dr Kuppermann: We should note that, in the BRAVO study, 50% of the sham group received rescue laser, but still did significantly worse than the therapeutic arm. Thus, I do not think we can interpret that as laser being equally efficacious as ranibizumab. Dr Campochiaro: There are some misconceptions about comparing laser to pharmacologic treatments. It is a very difficult comparison because they are such different treatments. There is information coming out that will indicate why it is a good idea to start treatment with ranibizumab early in these conditions. It appears that VEGF becomes part of the driving force of the disease so that patients with CRVO or BRVO start off with capillary nonperfusion from the occlusion. But then over time, their capillary nonperfusion increases. By contrast, in the BRAVO and CRUISE studies, patients who were treated with ranibizumab did not have increased capillary nonperfusion whereas those in the sham group did. This indicates that VEGF causes that increase in nonperfusion, and that by blocking VEGF, the damage can be limited. Also, practically speaking, most of these patients cannot be treated with laser initially because they have hemorrhages throughout their macula. I suggest starting with 6 monthly doses of ranibizumab; some people may want to reduce that to try to decrease the number of injections if retinal hemorrhages are cleared within 3 months and switch to grid laser therapy. But is there a penalty with regard to final visual outcome with grid laser? It has never been studied. The 1-year results with grid laser in the SCORE (Standard Care vs Corticosteroid for RVO) study are much worse than the ranibizumab results. Is it because it takes so much longer for laser that you lose vision because of chronic edema? Or does the grid laser play some role in that loss of vision? Those are unanswered questions. Dr Schmidt-Erfurth: The best parameters for PRN dosing may vary between the different diseases. Vein occlusion is driven mostly by VEGF levels, and VEGF levels correlate with visual acuity and with vision gain, but there are also other cytokines involved. VEGF levels also correlate with OCT thickness, but only early in the disease. During the sham follow-up treatment in BRAVO and CRUISE, the retina flattens even if with sham treatment. That means that there is atrophy of the retina and I think this is the reason why VEGF levels decrease with disease duration in vein occlusion. But it does not mean that visual acuity will become better. Thus I think, early in the disease, it is more VEGF driven but later on, there are other things that add to the mechanism of the vision loss. Dr Kuppermann: Is vein occlusion a biphasal disease is it primarily VEGF-driven initially then an inflammatory disease subsequently in the chronic phase? If so, should we start our treatment with anti- VEGF drugs and then follow up with steroids? Dr Campochiaro: It is an interesting hypothesis that there may be other permeability factors that contribute to ME. There are no good data to really suggest that at this point. If you suppress VEGF, there is a profound effect on ME. 46 Vol. 7, No. 2 December 2010

REFERENCES 1. Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator. Mol Ther. 2008;16:791-799. 2. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion. Sixmonth primary end point results of a phase III study. Ophthalmology. 2010;117:1102-1112. 3. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion. Six-month primary end point results of a phase III study. Ophthalmology. 2010;117:1124-1134. 4. Campochiaro PA, Hafiz G, Channa R, et al. Antagonism of vascular endothelial growth factor for macular edema caused by retinal vein occlusions: two-year outcomes. Ophthalmology. 2010;Epub ahead of publication. 5. Prager F, Michels S, Kriechbaum K, et al. Intravitreal bevacizumab (Avastin) for macular oedema secondary to retinal vein occlusion: 12-month results of a prospective clinical trial. Br J Ophthalmol. 2009;93:452-456. Johns Hopkins Advanced Studies in Ophthalmology 47