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Antagonism of Vascular Endothelial Growth Factor for Macular Edema Caused by Retinal Vein Occlusions: Two-Year Outcomes
Antagonism of Vascular Endothelial Growth Factor for Macular Edema Caused by Retinal Vein Occlusions: Two-Year Outcomes Peter A. Campochiaro, MD, Gulnar Hafiz, MD, Roomasa Channa, MD, Syed M. Shah, MD, Quan Dong Nguyen, MD, Howard Ying, MD, Diana V. Do, MD, Ingrid Zimmer-Galler, MD, Sharon D. Solomon, MD, Jennifer U. Sung, MD, Beena Syed, MD Purpose: To determine the long-term effects of intraocular antagonism of vascular endothelial growth factor (VEGF) in patients with macular edema caused by retinal vein occlusions (RVOs). Design: Prospective randomized trial. Participants: Twenty patients with macular edema caused by branch RVOs (BRVOs) and 20 patients with central RVOs (CRVOs). Methods: After the month 3 primary end point, patients were seen every 2 months and received injections of an anti-VEGF agent as needed for recurrent edema. Main Outcome Measures: Mean change from baseline best-corrected visual acuity (BCVA) at month 24 with assessment of other parameters of visual function and center subfield thickness (foveal thickness [FTH]). Results: For 17 patients with BRVO who completed 2 years of follow-up, the mean improvement from baseline in BCVA at month 24 was 17.8 letters compared with 15.6 letters at month 3. Improvement by at least 6, 3, or 2 lines occurred in 18%, 59%, and 76% of patients, respectively. The Snellen equivalent BCVA at month 24 was 20/40 or better in 10 patients. With an average of 2 injections of ranibizumab during year 2, the mean FTH at month 24 was 245.8 m compared with 217.1 m at month 3 and 481.5 m at baseline. For 14 patients with CRVO who completed 2 years of follow-up, the mean improvement in BCVA at month 24 was 8.5 letters compared with 12.0 letters at month 3. Improvement by at least 6, 3, or 2 lines occurred in 14%, 21%, and 43% of patients, respectively. The Snellen equivalent BCVA at month 24 was 20/40 or better in 4 patients. With an average of 3.5 injections of ranibizumab in year 2, mean FTH at month 24 was 338 m compared with 278 m at month 3 and 533 m at baseline. Duration of RVO ⬎1 year at study entry and nonperfusion of perifoveal capillaries for 360 degrees correlated with reduced visual outcomes. Conclusions: Antagonism of VEGF provides substantial long-term benefit to patients with macular edema caused by RVO, but frequent injections are required in some patients with BRVO and most patients with CRVO. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2010;117:2387–2394 © 2010 by the American Academy of Ophthalmology.
Retinal vein occlusions (RVOs) are the second most prevalent retinal vascular disease after diabetic retinopathy and constitute an important cause of vision loss, primarily from macular edema.1,2 Recent studies have demonstrated that vascular endothelial growth factor (VEGF) is an important stimulus for macular edema secondary to RVOs and that intraocular injections of ranibizumab lead to resolution of edema and large improvements in visual acuity (VA) in the majority of patients.3–5 These dramatic results led to phase III multicenter clinical trials to test the effects of ranibizumab in patients with macular edema caused by RVO: BRAVO for branch retinal vein occlusions (BRVOs) and CRUISE for central retinal vein occlusions (CRVOs). After 6 monthly injections of 0.3 or 0.5 mg of ranibizumab in © 2010 by the American Academy of Ophthalmology Published by Elsevier Inc.
patients with BRVO, the mean change from baseline bestcorrected visual acuity (BCVA) letter score was 16 to 18 compared with 7 in the sham group, and the percentage of patients who gained 3 or more lines was 55% to 61% compared with 28% in the sham group.6 The results were similar in patients with CRVO. The mean change from baseline BCVA letter score after 6 monthly injections of 0.3 or 0.5 mg of ranibizumab was 13 to 15 compared with 1 in the sham group, and the percentage of patients who gained 3 or more lines was 46% to 47% compared with 17% in the sham group.7 The median percentage reduction in excess foveal thickness (EFT) was 97% (BRVO) and 94% (CRVO) in ranibizumab-treated patients, indicating the elimination of macular edema in the majority of patients. These data ISSN 0161-6420/10/$–see front matter doi:10.1016/j.ophtha.2010.03.060
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Ophthalmology Volume 117, Number 12, December 2010 demonstrated that ranibizumab is an effective short-term treatment for macular edema caused by RVO, but the longterm results are still unclear. This study reports the 2-year outcomes in patients with macular edema caused by RVO treated with injections of anti-VEGF agents.
Materials and Methods The protocol for this study was designed to test the effect of 2 doses of ranibizumab, 0.3 and 0.5 mg, in patients with macular edema caused by CRVO or BRVO and was approved by the Federal Drug Administration under a physician-initiated Investigational New Drug Application and by the institutional review board of the Johns Hopkins Medical Institutions. The study was registered on December 1, 2006, at www.clinicaltrials.gov (NCT00407355) and conducted in compliance with the Declaration of Helsinki, US Code 21 of Federal Regulations and the Harmonized Tripartite Guidelines for Good Clinical Practice (1996). Twenty patients with CRVO and 20 patients with BRVO were randomized 1:1 to receive 3 monthly intraocular injections of 0.3 or 0.5 mg of ranibizumab, with both patients and investigators masked with respect to treatment group. The results at the month 3 primary end point have been published, and that report contains eligibility criteria and details regarding study design.3 After the primary end point, patients were seen at months 4, 5, 6, 9, and 12, and an attempt was made to hold all injections to determine whether a period of rebound edema would be followed by final resolution of edema; however, standard care was allowed at the discretion of the treating ophthalmologist. Beginning at month 12, patients were seen every 2 months and given an injection of their originally assigned dose of ranibizumab if optical coherence tomography (OCT) showed evidence of recurrent edema involving the fovea. Three patients with CRVO reached the month 12 visit before approval of the amendment allowing injection of ranibizumab and had recurrent edema that was treated with bevacizumab. One patient with CRVO received 2 injections of triamcinolone acetonide during the second year, and 1 patient with BRVO received grid laser therapy at month 6. At each study visit, patients had BCVA measured by an experienced examiner using the Early Treatment Diabetic Retinopathy Study protocol,8 a complete eye examination, and OCT. Fluorescein angiograms (FAs) were done at baseline and months 3, 4, and 24. Patient identification numbers consist of a letter (B for BRVO or C for CRVO), a digit between 1 and 20 to show the order of entry into the respective group of the trial, and a decimal (0.5 or 0.3) to show the dose of ranibizumab that was received.
Administration of Study Drug Povidone iodine was used to clean the lids, and a lid speculum was inserted. Topical anesthesia was applied, and the conjunctiva was irrigated with 5% povidone iodine. A 30-gauge needle was inserted through the pars plana, and 0.05 ml of ranibizumab was injected into the vitreous cavity. Funduscopic examination was done to confirm retinal perfusion.
Optical Coherence Tomography Optical coherence tomography was performed by an experienced investigator with a StratusOCT3 (Carl Zeiss Meditec, Dublin, CA) using the Fast Macular Scan protocol. This protocol consists of 6 line scans that are 6.0 mm long centered on fixation and spaced 30 degrees apart around the circumference of a circle. Each line consists of 128 A-scan measurements. With each A-scan, the OCT
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software measures the distance between the inner surface of the retina and the anterior border of retinal pigmented epitheliumchoriocapillaris complex on the basis of changes in reflectivity. In some cases, the retinal pigmented epithelium/choriocapillaris layer is obscured because of excessive edema, and StratusOCT software misinterprets the outer boundary of the retina. We used the RetinaTomographer (version 1.1 RIRRC, Baltimore, MD) to correct the outer boundary of the retina for cases in which StratusOCT software identified it erroneously. The center point thickness, also known as the foveolar thickness, is a mean value generated by the StratusOCT software from the 6 central A-scan thickness values of each of the radial lines comprising the fast macular thickness map. We did not use this value generated from only 6 data points for our primary measure of central retinal thickness, but instead used the foveal or central 1 mm thickness, which is an average interpolated value based on central 21 scans of each of the 6 lines passing through the patient’s fixation (126 data points). Macular volume throughout the entire 6-mm zone is calculated using extrapolated values between the line scans. Excess foveal thickness was calculated by subtracting the measured foveal thickness (FTH) value from the normal mean value of 212 m calculated from measurements on a large population of subjects.9
Statistical Analysis Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL). The Mann– Whitney test was performed to determine whether there was a statistically significant difference in final VA between groups with acute and chronic disease and between groups with partial or complete destruction of perifoveal capillaries.
Results Disposition of Patients with Macular Edema Caused by Central Retinal Vein Occlusion In a relatively small trial, it is important to evaluate each patient in detail. In patients with macular edema caused by BRVO, 17 of 20 completed 2 years of follow-up (Table 1, available at http:// aaojournal.org). The following is a brief explanation regarding the 3 patients (B2.5, B7.3, and B19.3) who exited the study before month 24. (1) After 3 injections of 0.5 mg of ranibizumab, patient B2.5 had complete elimination of macular edema and improvement in BCVA of 39 letters. With no additional injections, there was no edema and improvement in BCVA of 35 letters at the 12-month visit. The patient declined to participate in the second year of the study because the patient’s condition was stable. (2) Patient B7.3 had elimination of macular edema and improvement in BCVA of 7 letters after 3 injections of 0.3 mg of ranibizumab. At month 9, there was an improvement of 7 letters in BCVA and recurrence of EFT to 204 m, the baseline level. After month 9, the patient withdrew consent because of transportation difficulties. (3) Patient B19.3 had elimination of macular edema and improvement in BCVA of 10 letters after 3 injections of 0.3 mg of ranibizumab. At month 4, there was no recurrent edema and improvement in BCVA of 11 letters. The patient withdrew consent because of transportation difficulties. Thus, the 3 patients who dropped out had excellent anatomic responses and fairly good functional responses and decided to leave the study for logistic reasons.
Campochiaro et al 䡠 Ranibizumab for Macular Edema in Vein Occlusions
Figure 1. Course of patients with BRVO who had transient recurrent edema followed by spontaneous resolution and stabilization without additional injections. After 3 injections of ranibizumab, 5 patients with BRVO had mild recurrent edema followed by resolution and long-term stability (A–E). The line graph shows change from baseline in BCVA in letters measured on an Early Treatment Diabetic Retinopathy Study chart at 4 m at each visit of the study. The bars show excess FTH at each visit. The arrows indicate visits at which an injection of ranibizumab was done. BCVA ⫽ best corrected visual acuity; BL ⫽ baseline; BRVO ⫽ branch retinal vein occlusions; ETDRS ⫽ Early Treatment Diabetic Retinopathy Study; FTH ⫽ foveal thickness; R ⫽ ranibizumab; VA ⫽ visual acuity.
Anatomic Outcomes and the Need for Anti-Vascular Endothelial Growth Factor Injections in Patients with Macular Edema Caused by Branch Retinal Vein Occlusion At the primary end point, there was no difference in any outcome measure between the 0.3 mg and 0.5 mg groups3–5; therefore, for long-term outcomes they have been consolidated into a single group. A previous study in which ranibizumab was tested in patients with diabetic macular edema had suggested that blockade of VEGF with ranibizumab seemed to result in up-regulation of VEGF production, resulting in a rebound effect when ranibizumab was withdrawn.10 After the primary end point, an attempt was made to stop injections; therefore, ranibizumab initially was not provided as part of the trial for time points between M3 and M12. Several patients had recurrent edema followed by spontaneous resolution and stabilization without additional injections (Fig 1). However, some patients experienced a substantial decrease in BCVA during the rebound period, prompting the treating ophthalmologist to give an injection of bevacizumab as part of standard care (Fig 2). As it became apparent that many patients
required additional injections, the protocol was amended to allow injections of the originally assigned dose of ranibizumab if there was any evidence of edema according to OCT. In year 2, patients were seen every 2 months and thus could receive a maximum of 6 injections. Mean FTH at baseline and months 3, 12, and 24 was 481.5 m, 217.1 m, 252 m, and 245.8 m, respectively (Table 1, available at http://aaojournal.org). Of the 17 patients who completed a month 24 visit, FTH was ⱕ250 m in 11 patients, between 250 and 300 m in 3 patients, and between 300 and 400 m in 3 patients. During year 2, the mean number of injections was 2; 5 patients required no injections (Fig 1), 5 patients required 2 or fewer injections, and the remaining 7 patients required frequent injections (Fig 2 A,C,D).
Visual Outcome at 24 Months in Patients with Macular Edema Caused by Branch Retinal Vein Occlusion For the 17 patients who completed 2 years of follow-up, the mean improvement in BCVA at month 24 was 17.8 letters compared with 16.1 letters at the month 3 primary end point (Table 2,
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Figure 2. Course of patients with BRVO who had multiple recurrences of edema requiring many injections. Some patients with BRVO, such as B12.5 (B), required only a few injections to control edema, but others achieved only modest control of edema despite injections as frequently as every 2 months (A,C,D). The line graph shows change from baseline in BCVA in letters measured on an Early Treatment Diabetic Retinopathy Study chart at 4 m at each visit of the study. The bars show excess FTH at each visit. The arrows indicate visits at which an injection of ranibizumab or bevacizumab was done. B ⫽ bevacizumab; BL ⫽ baseline; BRVO ⫽ branch retinal vein occlusions; ETDRS ⫽ Early Treatment Diabetic Retinopathy Study; FTH ⫽ foveal thickness; R ⫽ ranibizumab; VA ⫽ visual acuity.
available at http://aaojournal.org). Analysis of all 20 patients at month 24 with last observation carried forward showed a mean improvement in BCVA of 17.8 letters. One patient had no change from baseline in BCVA at month 24, but all others (94%) showed improvement of at least 1 line; 3 patients (18%) showed improvement of 6 or more lines, 10 patients (59%) showed improvement of 3 or more lines, and 13 patients (76%) showed improvement of 2 or more lines. The Snellen equivalent BCVA at month 24 was 20/40 or better in 10 patients, 20/60 or better in 14 patients, 20/80 or better in 16 patients, and 20/100 in 1 patient. Only 1 patient with BRVO received grid laser therapy during the trial; the patient was treated at month 6, and the change in BCVA between baseline and month 24 was 0 letters. Thus, laser treatment did not contribute to the good visual outcome seen in the study.
Fluorescein Angiograms in Patients with Macular Edema Caused by Branch Retinal Vein Occlusion The right side of Table 2 (available at http://aaojournal.org) shows the results of masked grading of FAs for leakage, capillary nonperfusion in the posterior pole, and disruption of the perifoveal capillaries. In some patients, leakage or nonperfusion at baseline could not be graded because of retinal hemorrhages. Fourteen of the 16 FAs that could be graded showed severe leakage. Leakage was reduced in 14 of 16 patients who had gradable FAs at baseline and were still in the trial at month 24, but there was still some leakage in all but 1 patient. Capillary nonperfusion in the posterior pole was gradable at baseline in 14 patients, negligible in 6 patients, moderate in 5 patients, and
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severe in 3 patients. In the 17 patients remaining in the trial at month 24, capillary nonperfusion was negligible in 6 patients, minimal in 2 patients, moderate in 4 patients, and severe in 5 patients. One patient showed worsening of nonperfusion, and 1 patient showed improvement. Seven patients showed no disruption of perifoveal capillaries, 5 patients showed disruption of 180 degrees or less, and 6 patients showed disruption of more than 180 degrees.
Factors Affecting Visual Outcome in Patients with Macular Edema Caused by Branch Retinal Vein Occlusion Table 3 (available at http://aaojournal.org) shows possible causes for reduced BCVA in patients with BRVO at month 24. Five patients had recurrent edema, and 2 patients had recent edema that was likely contributing to reduced vision. Of the 17 patients who completed a month 24 visit, the onset of BRVO was ⱕ1 year before study entry in 9 and ⬎1 year in 8. In patients with BRVO ⱕ1 year, the median and mean values for improvement in BCVA were 16 and 19.4 letters and for final BCVA were 44 and 45.1 letters, respectively. In patients with BRVO ⬎1 year, the median and mean values for improvement in BCVA were 15 and 15.9 letters and for final BCVA were 36 and 36.5 letters, respectively. The difference in final BCVA at month 24, but not the change in BCVA from baseline, was statistically significant (P ⬍ 0.05). In 11 patients who had disruption of ⱕ180 degrees of the perifoveal capillaries, the median and mean values for improvement in BCVA were 16 and 17.4 letters and for final BCVA were 44 and
Campochiaro et al 䡠 Ranibizumab for Macular Edema in Vein Occlusions 45.1 letters, respectively. In 6 patients who had disruption of ⬎180 degrees of the perifoveal capillaries, the median and mean values for improvement in BCVA were 15 and 18.5 letters and for final BCVA were 34 and 33.0 letters, respectively. In 3 patients who had disruption of 360 degrees of the perifoveal capillaries, the median and mean values for improvement in BCVA were 14 and 16.7 letters and for final BCVA were 32 and 27.7 letters, respectively. Compared with patients with disruption of ⱕ180 degrees of the perifoveal capillaries, the other 2 groups showed a statistically significant difference (P ⬍ 0.05) in the final BCVA at month 24, but not in change in BCVA from baseline.
Disposition of Patients with Macular Edema Caused by Central Retinal Vein Occlusion In patients with macular edema caused by CRVO, 14 of 20 completed 2 years of follow-up (Table 4, available at http:// aaojournal.org). One of these patients (C1.3) missed the month 24 visit. The month 22 BCVA was improved by 9 letters compared with baseline and FTH was 390 m, and these data were carried forward to month 24. The following describes the course of the 6 patients who withdrew consent before month 24. (1) Patient C2.3 had improvement in BCVA of 18 letters and FTH of 172 m at month 2 but failed to return for additional visits. Communication with the patient indicated that he found it difficult to return for study visits, and therefore he withdrew consent. Month 2 values were carried forward to month 3. (2) Patient C3.3 had an FTH of 159 m and improvement in BCVA of 18 letters at the primary end point. With no additional injections, at month 6 the FTH was 278 m and the improvement from baseline in BCVA was 10 letters. After the month 6 visit, the patient had a fatal myocardial infarction that was not thought to be drug related because it was more than 4 months since the last injection of ranibizumab. (3) Patient C4.5 had 2 injections of ranibizumab, and at the month 2 visit the patient reported mild pain and discomfort since the last injection, but showed no evidence of inflammation. The BCVA had improved by 20 letters compared with baseline, and FTH was 247 m. The patient requested that injection be deferred. At the month 3 primary end point, there was some recurrent edema with an FTH of 297 m and BCVA was improved by 9 letters compared with baseline. Without any additional injections, there was improvement at the M12 visit; FTH was 241 m, and BCVA was improved by 15 letters. The patient lived a long distance away, requiring a flight for each visit, and she decided to exit the trial because she thought her condition was stable. (5) At the month 3 primary end point, patient C12.3 had an FTH of 174 m and improvement from baseline in BCVA of 16 letters. Despite the lack of edema, the patient was extremely concerned that visual benefits would be lost if additional treatment was not given and exited the trial, but agreed to return for safety visits. The patient received an injection of 1.25 mg of bevacizumab, and at the month 4 visit there was recurrent edema with an FTH of 565 m, although the BCVA was still improved by 12 letters compared with baseline. The patient received another injection of 1.25 mg of bevacizumab and refused to return for safety visits thereafter. (5) One week after the first injection of ranibizumab, patient C14.5 had improvement in FTH to 199 m from 493 m at baseline and improvement in BCVA of 2 letters. The patient missed the month 1 visit and thus the second injection. At month 2, FTH was 291 m and BCVA was reduced by 11 letters compared with baseline. The patient stated she had difficulty getting time off from work for study visits and withdrew consent, but she returned on a weekend for a safety and close-out visit at month 6. At that time, FTH was 433 m and BCVA was reduced by 8 letters compared with baseline. (6) Patient C20.3 had an FTH of 182 m and improvement in BCVA of 15 letters at the primary end point. At month 6,
with no additional injections, there was no recurrent edema because the FTH was 196 m and BCVA was improved by 12 letters compared with baseline, but the patient decided to exit the trial because he did not want to take time off from work for study visits.
Anatomic Outcomes and the Need for Ranibizumab Injections in Patients with Macular Edema Caused by Central Retinal Vein Occlusion A course in which there was a brief rebound in edema followed by improvement and stabilization without additional injections occurred in only 1 patient with CRVO, patient C4.5 (Fig 3A). As described, this patient had the third injection held because of prolonged discomfort after the second injection and 1 month later had recurrent edema and reduced vision that resolved without any injections. The patient exited the trial, but follow-up by phone has indicated that VA has remained 20/20 beyond month 24 with no additional injections. Only 3 other patients remained edema-free without any injections during the second year (Table 4, available at http://aaojournal.org): patient C9.5, who had a poor visual outcome because of ischemic maculopathy (Fig 3B), and patients C6.3 and C19.3 (Fig 3C), who had optimal outcomes achieving excellent vision with long-term stability. Most patients had severe rebound edema that was prolonged despite repeated injections of bevacizumab after the primary end point in year 1 and repeated injections of ranibizumab in year 2 (Fig 3D–F). The average number of injections in year 2 was 3.4. Mean FTH at baseline and months 3, 12, and 24 was 533 m, 272.5 m, 404 m, and 337.7 m, respectively (Table 4, available at http://aaojournal.org). Of the 14 patients who completed a month 24 visit, FTH was ⱕ250 m in 6, between 250 and 300 m in 1, between 300 and 400 m in 4, and greater than 400 m in 3.
Visual Outcome at 24 Months in Patients with Macular Edema Caused by Central Retinal Vein Occlusion For the 14 patients who completed 2 years of follow-up, the mean improvement in BCVA at month 24 was 8.5⫾14.8 letters compared with 12⫾9.8 letters at the month 3 primary end point (Table 5, available at http://aaojournal.org). Analysis of all 20 patients at month 24 with last observation carried forward showed a mean improvement in BCVA of 9 letters. Of the 14 patients who had a month 24 visit, the improvement from baseline in BCVA was 6 or more lines in 2 (14.3%), 3 or more lines in 4 (28.6%), 2 or more lines in 6 (42.9%), and at least 1 line in 9 (64.3%). Three patients had essentially no change from baseline (⫹3, ⫹1, ⫺2), and 2 patients lost vision (⫺7 and ⫺20 letters). The Snellen equivalent BCVA at month 24 was 20/40 or better in 4 patients, 20/60 or better in 7 patients, 20/80 or better in 8 patients, better than 20/200 in 11 patients, and worse than 20/200 in 3 patients.
Factors Affecting Visual Outcome in Patients with Macular Edema Caused by Central Retinal Vein Occlusion Table 6 (available at http://aaojournal.org) shows possible causes for reduced BCVA in patients with CRVO at month 24. Seven patients had recurrent edema that was likely to be a major contributor to reduced vision. Of the 14 patients who completed a month 24 visit, the onset of CRVO was ⱕ1 year before study entry in 10 and ⬎1 year in 4. In patients with CRVO ⱕ1 year, the median and mean values for improvement in BCVA were 11 and 13.6 letters and for final BCVA were 37 and 34.3 letters, respec-
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Figure 3. Course of patients with CRVO treated with antagonists of VEGF. The line graph shows change from baseline in BCVA in letters measured on an Early Treatment Diabetic Retinopathy Study chart at 4 m at each visit of the study. The bars show excess FTH at each visit. The arrows indicate visits at which an injection of ranibizumab, bevacizumab, or triamcinolone was administered. The first 3 patients (A–C) had resolution of macular edema after only 3 injections of ranibizumab. The second 3 patients (D–F) are representative of the remainder of the patients; they required frequent injections to achieve partial control of edema. B ⫽ bevacizumab; BCVA ⫽ best corrected visual acuity; BL ⫽ baseline; CRVO ⫽ central retinal vein occlusions; ETDRS ⫽ Early Treatment Diabetic Retinopathy Study; FTH ⫽ foveal thickness; R ⫽ ranibizumab; T ⫽ triamcinolone; VA ⫽ visual acuity; VEGF ⫽ vascular endothelial growth factor.
tively. In patients with CRVO ⬎1 year, the median and mean values for improvement in BCVA were ⫺4.5 and ⫺4.8 letters and for final BCVA were 10.5 and 14.8 letters, respectively, significantly worse (P ⬍ 0.05) than that in patients with CRVO ⱕ1 year. In 3 patients who had disruption of the entire circumference of the perifoveal capillaries, the median and mean values for improvement in BCVA were ⫺7 and ⫺8.7 letters and for final BCVA were 0 and 0.3 letters, respectively. The remaining 11 patients who had disruption of ⱕ180 degrees of the circumference of the perifoveal capillaries, the median and mean values were 8.5 and 10.5 letters for improvement in BCVA and 37.5 and 34.5 letters for the final BCVA, respectively, significantly greater (P ⬍ 0.05) than that seen in patients with complete disruption of the perifoveal capillaries.
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Discussion The natural history of CRVO and BRVO is somewhat variable. Some patients improve spontaneously, but the majority have problems from macular edema. Until recently, grid laser therapy was the only treatment option for macular edema caused by BRVO, and there was no treatment for macular edema caused by CRVO. Although the lack of a control group necessitates caution in interpreting the results, the current study suggests there may be a role for VEGF antagonists in both of these disease processes. Three monthly injections of 0.3 or 0.5 mg of ranibizumab in
Campochiaro et al 䡠 Ranibizumab for Macular Edema in Vein Occlusions patients with macular edema caused by CRVO or BRVO reduced EFT by approximately 90% and substantially improved BCVA.3 The 0.3 mg and 0.5 mg doses had similar results and when combined showed that 20 patients with BRVO had mean and median improvements in BCVA of 16.1 and 15 letters and 20 patients with CRVO had mean and median improvements of 12.0 and 15 letters, respectively. After the primary end point, we attempted to wean patients from ranibizumab. Five patients with BRVO and 1 patient with CRVO had some recurrence of macular edema with little change in BCVA, followed by resolution of the edema with no additional injections. This confirms our hypothesis that after suppression of leakage and resolution of macular edema by blockade of VEGF in patients with RVO, there may be rebound in edema when blockade of VEGF is withdrawn that can resolve spontaneously. It is useful to know that this can occur when trying to wean patients from ranibizumab, but several patients had a substantial decrease in BCVA accompanying the rebound in edema. Whether these patients would have had spontaneous improvement, as was the case for the patients shown in Figure 1, cannot be determined, but their subsequent course during which they had frequent bouts of recurrent edema suggests that it is unlikely. After 2 years of follow-up, only 5 of 17 patients with BRVO and 3 of 14 patients with CRVO were edema-free with no injections for at least 1 year. (One patient with CRVO had resolution of edema and excellent vision, and left the trial after 1 year because there had been no need for injections after month 2. This patient reports continued stability since exiting the trial ⬎1 year ago.) Thus, a majority of patients with macular edema caused by BRVO or CRVO require intermittent injections of an anti-VEGF agent for at least 2 years. It is important to know whether visual benefits achieved with monthly injections of ranibizumab can be maintained with less frequent injections given for recurrent edema. The answer is yes for patients with BRVO, because even with an average of only 2 injections during year 2, the mean improvement in BCVA at month 24 was 17.8 letters compared with 16.1 letters at month 3. Thus, visual benefits were maintained and final visions at 2 years were excellent with 59% and 82% of patients achieving 20/40 or better and 20/50 or better, respectively. However, it is likely that not all patients realized their full visual potential, because 7 patients had edema at or soon before month 24 that was likely contributing to persistent reduction in vision. The mean best improvement in VA in these 7 patients was 18.4 letters, and their mean improvement at month 24 was 12.1 letters (Table 3, available at http://aaojournal.org), suggesting that on average these patients’ VA could improve by another line if macular edema was completely controlled. In the 14 patients with CRVO who completed 2 years of follow-up, the mean improvement in BCVA at month 24 was 8.5 letters compared with 12.0 letters at month 3, indicating that unlike the situation in patients with BRVO, patients with CRVO did not maintain the same level of vision when treated only as frequently as every 2 months compared with every month. This is supported by the OCT results that showed that mean FTH was 338 m at month 24 compared with 273 m at month 3. The FTH at month 24
was ⱖ300 m in 7 patients and ⱖ500 m in 3 patients, which is clearly inadequate. The mean best improvement in VA in these 10 patients was 14.7 letters, and their mean improvement at month 24 was ⫺0.3 letters, suggesting that on average these patients’ VA could improve by 3 lines if macular edema was completely controlled (Table 6, available at http://aaojournal.org). This suggests that injections of 0.5 mg of ranibizumab as frequently as every 2 months for recurrent edema are inadequate for a substantial number of patients with CRVO. Likewise, it has been demonstrated that treatment with ranibizumab every 3 months for recurrent edema is inadequate.4 Several patients in this study achieved excellent final visions, indicating that the visual potential after some RVOs is extremely good and justifies the time, effort, and expense of aggressive treatment. Three possible predictors of a suboptimal visual outcome were identified: chronic edema before the onset of treatment, closure of more than half of the perifoveal capillaries, and closure of all of the perifoveal capillaries. Patients with these features can still obtain a large improvement in VA, and some patients with the first 2 features obtained a final vision of ⱖ20/40, but the best VA obtained in a patient with complete closure of the perifoveal capillaries was 20/63. These results are based on data from a small number of patients and are preliminary, but they should be investigated for their predictive value in larger studies, such as BRAVO and CRUISE. Although this study is relatively small, the visual results were good and suggest that anti-VEGF treatment provides long-term benefit in patients with macular edema caused by BRVO or CRVO. In BRVO, the mean improvement of 17.8 letters at 2 years compares favorably with the 2-year outcomes in the BRVO SCORE study, in which the mean improvements were 11.3, 6.3, and 4.0 letters in the grid laser, 1 mg triamcinolone, and 4 mg triamcinolone groups, respectively.11 In CRVO, the mean improvement of 8.5 letters at 2 years compares favorably with the 2-year outcomes of the CRVO SCORE study, in which the mean improvements were ⫺10.4, ⫺4.4, and ⫺2.4 letters in the observation, 1 mg triamcinolone, and 4 mg triamcinolone groups, respectively.12 It will be important to determine whether these promising results are confirmed by 1-year outcome data from BRAVO and CRUISE and longer outcomes from the Horizon trial (The registry number for the Horizon study at clinical trials.gov is NCT00379795). In conclusion, despite the promising 2-year visual outcomes, this study suggests that excessive production of VEGF is a long-term problem in many patients with RVO. Treatment of recurrent edema only as frequently as every 2 months with injections of 0.5 mg of ranibizumab is not optimal for most patients. A more aggressive treatment regimen of injections of 0.5 mg of ranibizumab as frequently as every month for recurrent edema in patients with CRVO resulted in a mean improvement in BCVA of 18.5 letters at 1 year with an average of 8.5 injections.5 Additional studies are needed to determine the long-term effects of injections as frequently as every month or the use of higher doses of ranibizumab. We are currently investigating the effects of injections of 2.0 mg of ranibizumab. Also, it is important to determine why continued excessive produc-
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Ophthalmology Volume 117, Number 12, December 2010 tion of VEGF is a problem for more than 2 years after RVO in many patients. Essentially all of these patients have collaterals, and it seems that the hope has been dashed that the problem of macular edema after RVO would be solved by a brief period of injections of an anti-VEGF agent to buy time until collaterals develop. Something other than the original occlusion becomes the driver for VEGF production in the majority of patients with RVO, and the most likely candidate is peripheral capillary nonperfusion. We are currently testing this hypothesis. Hopefully, a period of aggressive pharmacologic blockade of VEGF combined with reduction of the source of its production will maximize VA and free patients with RVO from long-term injections.
References 1. Cugati S, Wang JJ, Rochtchina E, Mitchell P. Ten-year incidence of retinal vein occlusion in an older population: the Blue Mountains Eye Study. Arch Ophthalmol 2006; 124:726 –32. 2. Klein R, Moss SE, Meuer SM, Klein BE. The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch Ophthalmol 2008;126:513– 8. 3. 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: 791–9. 4. Pieramici DJ, Rabena M, Castellarin AA, et al. Ranibizumab for the treatment of macular edema associated with perfused central retinal vein occlusions [report online]. Ophthalmology 2008;115:e47–54.
5. Spaide RF, Chang LK, Klancnik JM, et al. Prospective study of intravitreal ranibizumab as a treatment for decreased visual acuity secondary to central retinal vein occlusion. Am J Ophthalmol 2009;147:298 –306. 6. 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;117:1102–12. 7. 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 –33. 8. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report no. 1. Arch Ophthalmol 1985;103:1796 – 806. 9. Hee MR, Izatt JA, Swanson EA, et al. Optical coherence tomography of the human retina. Arch Ophthalmol 1995;113: 325–32. 10. Nguyen QD, Tatlipinar S, Shah SM, et al. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol 2006;142:961–9. 11. SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study report 6. Arch Ophthalmol 2009;127: 1115–28. 12. SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study report 5. Arch Ophthalmol 2009;127: 1101–14.
Footnotes and Financial Disclosures Originally received: December 21, 2009. Final revision: March 23, 2010. Accepted: March 26, 2010. Available online: July 13, 2010.
Manuscript no. 2009-1738.
The Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. This article contains online-only material. The following appear only online: Tables 1– 6. Financial Disclosure(s): PAC receives research support from and has institutional consultancy agreements with Genentech and GlaxoSmithKline (JHU receives the remuneration), was a consultant for LPath and Potentia, serves on the Data and Safety Monitoring Committee for the View1 trial sponsored by Re-
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generon, and receives research support from Alimera. QDN is a consultant for Bausch and Lomb and receives research support from Genentech and Regeneron. HY had a consultancy with Genentech that ended in 2007. DD received a lecture fee from Heidelburg and receives research support from Genentech. None of the other authors have any conflicts. Supported by an Investigator Initiated Study grant from Genentech, Inc. PAC is the George S. and Dolores Doré Eccles Professor of Ophthalmology and Neuroscience. Correspondence: Peter A. Campochiaro, MD, Maumenee 719, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287-9277. E-mail: [email protected].
Campochiaro et al 䡠 Ranibizumab for Macular Edema in Vein Occlusions Table 1. Foveal Thickness and Injections for Patients with Branch Vein Occlusion Foveal Thickness (m)
No. of Injections Year 1
Year 2*
ID
BL
M3
M12
M24
R
B
T
R
B1.5 B2.5 B3.3 B4.5 B5.5 B6.3 B7.3 B8.3 B9.5 B10.5 B11.3 B12.5 B13.5 B14.3 B15.3 B16.5 B17.3 B18.5 B19.3 B20.3 Mean⫾SE Median
508 571 534 524 637 507 409 366 495 632 477 504 331 665 495 411 412 382 486 284 482⫾22.7 495
210 136 206 242 245 272 185 301 205 204 217 239 277 177 177 205 194 242 206 202 217⫾8.7 206
224 168 203 410 248 295 LTF 265 281 185 246 209 301 192 397 219 193 217 LTF 282 252⫾16 235
226 LTF 219 187 253 313 LTF 243 238 196 250 203 274 200 393 209 192 304 LTF 278 246⫾13.1 238
3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 3 4 3 3 3.2⫾0.1 3
0 0 0 0 0 3 0 0 2 3 1 1 3 2 0 1 0 0 0 0 0.8⫾0.3 0
0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.1⫾0.1 0
0 0 0 4 0 4 LTF 2 4 6 5 1 6 5 2 0 0 2 LTF 1 2.3⫾0.5 1.5
B ⫽ bevacizumab; BL ⫽ baseline; ID ⫽ subject identification number followed by dose of ranibizumab received; LTF ⫽ lost to follow-up; R ⫽ ranibizumab; SE ⫽ standard error of the mean; T ⫽ triamcinolone. *Patients received only ranibizumab in year 2.
Table 2. Visual Acuity and Fluorescein Angiography for Patients with Branch Vein Occlusion
ID B1.5 B2.5 B3.3 B4.5 B5.5 B6.3 B7.3 B8.3 B9.5 B10.5 B11.3 B12.5 B13.5 B14.3 B15.3 B16.5 B17.3 B18.5 B19.3 B20.3 Mean⫾SE Median
Duration (mos)
Visual Acuity BL
⌬M3
⌬M12
⌬M24
Fluorescein Angiography Grade M24 VA
2 2 34 31 42 44 4 0 39 35 LTF LTF 1 21 8 27 26 47 15 36 2 ⫺5 0 36 30 5 21 41 37 42 30 19 11 17 16 35 4 31 7 LTF LTF LTF 8 37 6 5 5 42 13 32 16 16 17 49 3 31 22 12 16 47 1 9 34 31 34 43 1 20 19 8 12 32 90 26 14 9 11 37 16 4 22 22 14 18 6 35 5 9 6 41 2 35 10 19 18 53 1 41 16 21 16 57 28 9 16 24 24 33 7 28 10 LTF LTF LTF 20 30 9 5 8 38 14.1⫾20.5 22.6⫾3 16.1⫾2.3 18.2⫾2.8 17.8⫾2.8 40.8⫾2.2 7 27 15 18 16 42
M24 Snellen PF Caps CNP BL BL Leak CNP M24 M24 Leak 20/32 LTF 20/32 20/50 20/40 20/50 LTF 20/40 20/25 20/32 20/40 20/63 20/50 20/100 20/40 20/25 20/20 20/63 LTF 20/50
180 NG 0 180 270 270 0 0 0 90 180 360 0 360 0 90 0 360 NG 270
NG NG 0 2 2 2 0 0 0 NG NG 3 0 2 2 NG 0 3 NG 3
NG NG 1 3 3 3 3 3 3 3 NG 3 2 3 3 NG 3 3 3 3
3 LTF 0 2 1 2 LTF 0 0 2 0 3 0 3 2 1 0 3 LTF 3
1 LTF 0 1 2 2 LTF 1 2 1 2 1 1 2 1 1 1 2 LTF 1
BL ⫽ baseline; CNP ⫽ capillary nonperfusion; ID ⫽ subject identification number followed by dose of ranibizumab received; LTF ⫽ lost to follow-up; NG ⫽ not gradable; PF caps ⫽ disruption of perifoveal capillaries in degrees; SE ⫽ standard error of the mean. Grading for CNP and leakage: 0 ⫽ none; 1 ⫽ mild; 2 ⫽ moderate; 3 ⫽ severe.
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Ophthalmology Volume 117, Number 12, December 2010 Table 3. Causes of Decreased Vision in Patients with Branch Retinal Vein Occlusion after Two Years of Anti-Vascular Endothelial Growth Factor Treatment ID
⌬VA Best
Good VA with Resolved B17.3 21 B16.5 20 B1.5 42 B3.3 27 B5.5 41
⌬VA M24 Edema 16 18 42 26 37
M24 Snellen 20/20 20/25 20/32 20/32 20/40
Good VA with Edema Controlled by Continued B9.5 20 17 20/25 B10.5 22 16 20/32 B8.3 9 5 20/40 B11.3 37 34 20/40
Possible Causes of Reduced VA None PDPC (90 degrees) PDPC (180 degrees) None CD (30 mos), PDPC (270 degrees) Injections CD (13 mos) PDPC (90 degrees) Cataract RE
Good VA with Uncontrolled Edema* B15.3 11 6 20/40
393 m
Moderate VA with Edema Controlled by Continued Injections B4.5 7 0 20/50 RE, CD (15 mos), PDPC (180 degrees) B12.5 23 12 20/63 RE, DPC B14.3 25 14 20/100 CD (16 mos), DPC Moderate VA with Uncontrolled Edema* B6.3 20 16 20/50 B13.5 B20.3
18 12
11 8
20/50 20/50
B18.5
24
24
20/63
313 m, PDPC 274 m, 278 m, PDPC 304 m, DPC
CD (30 mos), CD (90 mos) CD (18 mos), (270 degrees) CD (28 mos),
CD ⫽ chronic disease; DPC ⫽ 360 degrees disruption of perifoveal capillaries; ID ⫽ patient identification number; PDPC ⫽ partial disruption of perifoveal capillaries (number of degrees of disruption are in parentheses); RE ⫽ recent edema (recurrent edema shortly before M24); VA ⫽ visual acuity; ⌬VA Best ⫽ greatest improvement from baseline at any time in the study in Early Treatment Diabetic Retinopathy Study (ETDRS) letters read at 4 m; ⌬VA M24 ⫽ improvement from baseline at month 24 in ETDRS letters read at 4 m; M24 Snellen ⫽ Snellen equivalent VA at month 24. *Central subfield thickness at month 24 is listed.
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Campochiaro et al 䡠 Ranibizumab for Macular Edema in Vein Occlusions Table 4. Foveal Thickness and Injections for Patients with Central Retinal Vein Occlusion Foveal Thickness (m)
No. of Injections Year 1
No. of Injections Year 2
ID
BL
M3
M12
M24
R
B
T
R
B
T
C1.3 C2.3 C3.3 C4.5 C5.5 C6.3 C7.5 C8.5 C9.5 C10.5 C11.3 C12.3 C13.3 C14.5 C15.5 C16.3 C17.5 C18.5 C19.3 C20.3 Mean⫾SE Median
549 630 514 378 721 485 480 465 596 555 615 489 404 493 591 697 263 549 637 555 533⫾24.3 549
541 172‡ 159 297 247 547 175 277 125 280 233 174 241 291‡ 177 617 246 228 240 182 273⫾30.6 241
494 LTF LTF 241 659 310 345 288 126 973 507 LTF 413 LTF 199 437 254 597 214 LTF 404⫾56.7 345
390* LTF LTF LTF 548 203† 336 196 142 791 251 LTF 170 LTF 634 303 331 225 208 LTF 338⫾51.5 277
3 3 3 2 3 3 3 3 3 3 3 3 6 2 3 4 4 7 3 3 3.4⫾0.3 3
3 0 1 0 2 0 2 3 0 4 3 2 0 0 2 1 1 0 1 0 1.3⫾0.3 1
0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.1⫾0.1 0
0 LTF LTF 0 4 0 3 4 0 5 4 LTF 5 LTF 4 6 5 6 0 LTF 3.1⫾0.6 4
0 LTF LTF 0 1 0 0 0 0 1 1 LTF 0 LTF 0 0 0 0 0 LTF 0.2⫾0.1 0
2 LTF LTF 0 0 0 0 0 0 0 0 LTF 0 LTF 0 0 0 0 0 LTF 0.1⫾0.1 0
B ⫽ bevacizumab; BL ⫽ baseline; ID ⫽ subject identification number followed by dose of ranibizumab received; LTF ⫽ lost to follow-up; R ⫽ ranibizumab; SE ⫽ standard error of the mean; T ⫽ triamcinolone. *Month 22 FTH value carried forward because of missed visit on month 24. † Month 28 value carried back because of missed visit on month 24. ‡ Month 2 value carried forward because of missed visit on month 3.
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Ophthalmology Volume 117, Number 12, December 2010 Table 5. Visual Acuity and Fluorescein Angiography for Patients with Central Retinal Vein Occlusion Visual Acuity
Fluorescein Angiography Grading
ID
Duration (mos)
BL
⌬M3
⌬M12
⌬M24
M24
C1.3 C2.3 C3.3 C4.5 C5.5 C6.3 C7.5 C8.5 C9.5 C10.5 C11.3 C12.3 C13.3 C14.5 C15.5 C16.3 C17.5 C18.5 C19.3 C20.3 Mean⫾SE Median
7 8 5 1 11 1 19 36 2 43 6 26 12 52 20 1 2 2 7 10 13.6⫾3.3 8
8 2 3 40 4 18 20 28 0 7 24 0 32 39 23 19 34 32 36 18 19.4⫾3.1 20
6 18§ 18 9 16 20 ⫺16 18 9 20 18 16 9 ⫺11§ 13 10 14 15 23 15 12⫾2.2 15
5 LTF LTF 15 ⫺3 32 ⫺2 17 7 ⫺7 21 LTF 2 LTF ⫺3 0 10 1 22 LTF 7.8⫾2.9 5
9* LTF LTF LTF 5 38‡ ⫺20 10 1 ⫺7 30 LTF 6 LTF ⫺2 11 3 12 23 LTF 8.5⫾3.9 8
17* LTF LTF LTF 9 56‡ 0 38 1 0 54 LTF 38 LTF 21 30 37 44 59 LTF 28.9⫾5.6 34
M24 Snellen
PF Caps
CNP BL
BL Leak
CNP M24
M24 Leak
20/125 LTF LTF LTF 20/160 20/20 20/250 20/50 20/250 20/250 20/20 LTF 20/50 LTF 20/100 20/63 20/50 20/32 20/16 LTF
0 360 0 0 0 NG 360 90 360 360 0 90 180 0 180 180 0 0 0 360
0 1 0 0 0 0 1 0 3 NG 0 0 1 0 1 NG 0 NG 0 3
3 3 2 2 3 3 3 3 3 3 3 3 2 3 3 3 3 3 3 3
0† LTF LTF LTF 0 LTF 3 0 3 3 0 LTF 1 LTF 2 1 0 0 0 LTF
2† LTF LTF LTF 3 LTF 3 1 3 3 1 LTF 1 LTF 3 2 1 1 0 LTF
BL ⫽ baseline; CNP ⫽ capillary nonperfusion; ID ⫽ subject identification number followed by dose of ranibizumab received; LTF ⫽ lost to follow-up; NG ⫽ not gradable; PF Caps ⫽ disruption of perifoveal capillaries in degrees; SE ⫽ standard error of the mean. Grading for CNP and leakage: 0 ⫽ none; 1 ⫽ mild; 2 ⫽ moderate; 3 ⫽ severe. *Month 22 FTH value carried forward because of missed visit on month 24. † Month 18 FA grading carried forward because of missed visit on month 24. ‡ Month 28 value carried back because of missed visit on month 24. § Month 2 value carried forward because of missed visit on month 3.
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Campochiaro et al 䡠 Ranibizumab for Macular Edema in Vein Occlusions Table 6. Causes of Decreased Vision in Patients with Central Retinal Vein Occlusion after Two Years of Anti-Vascular Endothelial Growth Factor Treatment ID Good VA C19.3 C4.5 C6.3
⌬VA Best
⌬VA M24
M24 Snellen
with Resolved Edema 29 23 20/16 20 15* 20/20* 33 32 20/20
Possible Causes of Reduced VA None PDPC (90 degrees) None
Good VA with Edema Controlled by Continued Injections C11.3 31 30 20/20 RE C18.5 12 15 20/32 RE Moderate VA with Edema Controlled by Continued Injections C8.5 18 10 20/50 CD (36 mos), PDPC (90 degrees) C13.3 9 6 20/50 PDPC (90 degrees) Moderate C16.3 C17.5 C15.5 C1.3 C5.5
VA with Uncontrolled Edema† 15 11 20/63 393 m, PDPC (180 degrees) 15 3 20/50 331 m 17 ⫺2 20/100 634 m, CD (20 mos), PDPC (180 degrees) 12 7 20/125 393 m 16 9 20/160 548 m
Poor VA with Resolved Edema C9.5 9 1 20/250 Poor VA with Uncontrolled Edema† C7.5 3 ⫺20 20/250 C10.5 25 ⫺7 20/250
Ischemic maculopathy (central thinning) 331 m, CD (19 mos), DPC, PI 791 m, CD (43 mos), DPC
CD ⫽ chronic disease; DPC ⫽ 360-degree disruption of perifoveal capillaries; ID ⫽ patient identification number; PDPC ⫽ partial disruption of perifoveal capillaries (number of degrees of disruption are in parentheses); RE ⫽ recent edema (recurrent edema shortly before M24); PI ⫽ progressive ischemia; VA ⫽ visual acuity; ⌬VA Best ⫽ greatest improvement from baseline at any time in the study in ETDRS letters read at 4 m; ⌬VA M24 ⫽ improvement from baseline at month 24 in ETDRS letters read at 4 m; M24 Snellen ⫽ Snellen equivalent VA at month 24. *Month 12 values, but patient states that vision has remained normal beyond month 24 with no additional treatment. † Central subfield thickness at month 24 is listed.
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Retinal vein occlusions (RVOs) are the second most prevalent retinal vascular disease after diabetic retinopathy and constitute an important cause of vision loss, primarily from macular edema.1,2 Recent studies have demonstrated that vascular endothelial growth factor (VEGF) is an important stimulus for macular edema secondary to RVOs and that intraocular injections of ranibizumab lead to resolution of edema and large improvements in visual acuity (VA) in the majority of patients.3–5 These dramatic results led to phase III multicenter clinical trials to test the effects of ranibizumab in patients with macular edema caused by RVO: BRAVO for branch retinal vein occlusions (BRVOs) and CRUISE for central retinal vein occlusions (CRVOs). After 6 monthly injections of 0.3 or 0.5 mg of ranibizumab in © 2010 by the American Academy of Ophthalmology Published by Elsevier Inc.
patients with BRVO, the mean change from baseline bestcorrected visual acuity (BCVA) letter score was 16 to 18 compared with 7 in the sham group, and the percentage of patients who gained 3 or more lines was 55% to 61% compared with 28% in the sham group.6 The results were similar in patients with CRVO. The mean change from baseline BCVA letter score after 6 monthly injections of 0.3 or 0.5 mg of ranibizumab was 13 to 15 compared with 1 in the sham group, and the percentage of patients who gained 3 or more lines was 46% to 47% compared with 17% in the sham group.7 The median percentage reduction in excess foveal thickness (EFT) was 97% (BRVO) and 94% (CRVO) in ranibizumab-treated patients, indicating the elimination of macular edema in the majority of patients. These data ISSN 0161-6420/10/$–see front matter doi:10.1016/j.ophtha.2010.03.060
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Ophthalmology Volume 117, Number 12, December 2010 demonstrated that ranibizumab is an effective short-term treatment for macular edema caused by RVO, but the longterm results are still unclear. This study reports the 2-year outcomes in patients with macular edema caused by RVO treated with injections of anti-VEGF agents.
Materials and Methods The protocol for this study was designed to test the effect of 2 doses of ranibizumab, 0.3 and 0.5 mg, in patients with macular edema caused by CRVO or BRVO and was approved by the Federal Drug Administration under a physician-initiated Investigational New Drug Application and by the institutional review board of the Johns Hopkins Medical Institutions. The study was registered on December 1, 2006, at www.clinicaltrials.gov (NCT00407355) and conducted in compliance with the Declaration of Helsinki, US Code 21 of Federal Regulations and the Harmonized Tripartite Guidelines for Good Clinical Practice (1996). Twenty patients with CRVO and 20 patients with BRVO were randomized 1:1 to receive 3 monthly intraocular injections of 0.3 or 0.5 mg of ranibizumab, with both patients and investigators masked with respect to treatment group. The results at the month 3 primary end point have been published, and that report contains eligibility criteria and details regarding study design.3 After the primary end point, patients were seen at months 4, 5, 6, 9, and 12, and an attempt was made to hold all injections to determine whether a period of rebound edema would be followed by final resolution of edema; however, standard care was allowed at the discretion of the treating ophthalmologist. Beginning at month 12, patients were seen every 2 months and given an injection of their originally assigned dose of ranibizumab if optical coherence tomography (OCT) showed evidence of recurrent edema involving the fovea. Three patients with CRVO reached the month 12 visit before approval of the amendment allowing injection of ranibizumab and had recurrent edema that was treated with bevacizumab. One patient with CRVO received 2 injections of triamcinolone acetonide during the second year, and 1 patient with BRVO received grid laser therapy at month 6. At each study visit, patients had BCVA measured by an experienced examiner using the Early Treatment Diabetic Retinopathy Study protocol,8 a complete eye examination, and OCT. Fluorescein angiograms (FAs) were done at baseline and months 3, 4, and 24. Patient identification numbers consist of a letter (B for BRVO or C for CRVO), a digit between 1 and 20 to show the order of entry into the respective group of the trial, and a decimal (0.5 or 0.3) to show the dose of ranibizumab that was received.
Administration of Study Drug Povidone iodine was used to clean the lids, and a lid speculum was inserted. Topical anesthesia was applied, and the conjunctiva was irrigated with 5% povidone iodine. A 30-gauge needle was inserted through the pars plana, and 0.05 ml of ranibizumab was injected into the vitreous cavity. Funduscopic examination was done to confirm retinal perfusion.
Optical Coherence Tomography Optical coherence tomography was performed by an experienced investigator with a StratusOCT3 (Carl Zeiss Meditec, Dublin, CA) using the Fast Macular Scan protocol. This protocol consists of 6 line scans that are 6.0 mm long centered on fixation and spaced 30 degrees apart around the circumference of a circle. Each line consists of 128 A-scan measurements. With each A-scan, the OCT
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software measures the distance between the inner surface of the retina and the anterior border of retinal pigmented epitheliumchoriocapillaris complex on the basis of changes in reflectivity. In some cases, the retinal pigmented epithelium/choriocapillaris layer is obscured because of excessive edema, and StratusOCT software misinterprets the outer boundary of the retina. We used the RetinaTomographer (version 1.1 RIRRC, Baltimore, MD) to correct the outer boundary of the retina for cases in which StratusOCT software identified it erroneously. The center point thickness, also known as the foveolar thickness, is a mean value generated by the StratusOCT software from the 6 central A-scan thickness values of each of the radial lines comprising the fast macular thickness map. We did not use this value generated from only 6 data points for our primary measure of central retinal thickness, but instead used the foveal or central 1 mm thickness, which is an average interpolated value based on central 21 scans of each of the 6 lines passing through the patient’s fixation (126 data points). Macular volume throughout the entire 6-mm zone is calculated using extrapolated values between the line scans. Excess foveal thickness was calculated by subtracting the measured foveal thickness (FTH) value from the normal mean value of 212 m calculated from measurements on a large population of subjects.9
Statistical Analysis Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL). The Mann– Whitney test was performed to determine whether there was a statistically significant difference in final VA between groups with acute and chronic disease and between groups with partial or complete destruction of perifoveal capillaries.
Results Disposition of Patients with Macular Edema Caused by Central Retinal Vein Occlusion In a relatively small trial, it is important to evaluate each patient in detail. In patients with macular edema caused by BRVO, 17 of 20 completed 2 years of follow-up (Table 1, available at http:// aaojournal.org). The following is a brief explanation regarding the 3 patients (B2.5, B7.3, and B19.3) who exited the study before month 24. (1) After 3 injections of 0.5 mg of ranibizumab, patient B2.5 had complete elimination of macular edema and improvement in BCVA of 39 letters. With no additional injections, there was no edema and improvement in BCVA of 35 letters at the 12-month visit. The patient declined to participate in the second year of the study because the patient’s condition was stable. (2) Patient B7.3 had elimination of macular edema and improvement in BCVA of 7 letters after 3 injections of 0.3 mg of ranibizumab. At month 9, there was an improvement of 7 letters in BCVA and recurrence of EFT to 204 m, the baseline level. After month 9, the patient withdrew consent because of transportation difficulties. (3) Patient B19.3 had elimination of macular edema and improvement in BCVA of 10 letters after 3 injections of 0.3 mg of ranibizumab. At month 4, there was no recurrent edema and improvement in BCVA of 11 letters. The patient withdrew consent because of transportation difficulties. Thus, the 3 patients who dropped out had excellent anatomic responses and fairly good functional responses and decided to leave the study for logistic reasons.
Campochiaro et al 䡠 Ranibizumab for Macular Edema in Vein Occlusions
Figure 1. Course of patients with BRVO who had transient recurrent edema followed by spontaneous resolution and stabilization without additional injections. After 3 injections of ranibizumab, 5 patients with BRVO had mild recurrent edema followed by resolution and long-term stability (A–E). The line graph shows change from baseline in BCVA in letters measured on an Early Treatment Diabetic Retinopathy Study chart at 4 m at each visit of the study. The bars show excess FTH at each visit. The arrows indicate visits at which an injection of ranibizumab was done. BCVA ⫽ best corrected visual acuity; BL ⫽ baseline; BRVO ⫽ branch retinal vein occlusions; ETDRS ⫽ Early Treatment Diabetic Retinopathy Study; FTH ⫽ foveal thickness; R ⫽ ranibizumab; VA ⫽ visual acuity.
Anatomic Outcomes and the Need for Anti-Vascular Endothelial Growth Factor Injections in Patients with Macular Edema Caused by Branch Retinal Vein Occlusion At the primary end point, there was no difference in any outcome measure between the 0.3 mg and 0.5 mg groups3–5; therefore, for long-term outcomes they have been consolidated into a single group. A previous study in which ranibizumab was tested in patients with diabetic macular edema had suggested that blockade of VEGF with ranibizumab seemed to result in up-regulation of VEGF production, resulting in a rebound effect when ranibizumab was withdrawn.10 After the primary end point, an attempt was made to stop injections; therefore, ranibizumab initially was not provided as part of the trial for time points between M3 and M12. Several patients had recurrent edema followed by spontaneous resolution and stabilization without additional injections (Fig 1). However, some patients experienced a substantial decrease in BCVA during the rebound period, prompting the treating ophthalmologist to give an injection of bevacizumab as part of standard care (Fig 2). As it became apparent that many patients
required additional injections, the protocol was amended to allow injections of the originally assigned dose of ranibizumab if there was any evidence of edema according to OCT. In year 2, patients were seen every 2 months and thus could receive a maximum of 6 injections. Mean FTH at baseline and months 3, 12, and 24 was 481.5 m, 217.1 m, 252 m, and 245.8 m, respectively (Table 1, available at http://aaojournal.org). Of the 17 patients who completed a month 24 visit, FTH was ⱕ250 m in 11 patients, between 250 and 300 m in 3 patients, and between 300 and 400 m in 3 patients. During year 2, the mean number of injections was 2; 5 patients required no injections (Fig 1), 5 patients required 2 or fewer injections, and the remaining 7 patients required frequent injections (Fig 2 A,C,D).
Visual Outcome at 24 Months in Patients with Macular Edema Caused by Branch Retinal Vein Occlusion For the 17 patients who completed 2 years of follow-up, the mean improvement in BCVA at month 24 was 17.8 letters compared with 16.1 letters at the month 3 primary end point (Table 2,
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Figure 2. Course of patients with BRVO who had multiple recurrences of edema requiring many injections. Some patients with BRVO, such as B12.5 (B), required only a few injections to control edema, but others achieved only modest control of edema despite injections as frequently as every 2 months (A,C,D). The line graph shows change from baseline in BCVA in letters measured on an Early Treatment Diabetic Retinopathy Study chart at 4 m at each visit of the study. The bars show excess FTH at each visit. The arrows indicate visits at which an injection of ranibizumab or bevacizumab was done. B ⫽ bevacizumab; BL ⫽ baseline; BRVO ⫽ branch retinal vein occlusions; ETDRS ⫽ Early Treatment Diabetic Retinopathy Study; FTH ⫽ foveal thickness; R ⫽ ranibizumab; VA ⫽ visual acuity.
available at http://aaojournal.org). Analysis of all 20 patients at month 24 with last observation carried forward showed a mean improvement in BCVA of 17.8 letters. One patient had no change from baseline in BCVA at month 24, but all others (94%) showed improvement of at least 1 line; 3 patients (18%) showed improvement of 6 or more lines, 10 patients (59%) showed improvement of 3 or more lines, and 13 patients (76%) showed improvement of 2 or more lines. The Snellen equivalent BCVA at month 24 was 20/40 or better in 10 patients, 20/60 or better in 14 patients, 20/80 or better in 16 patients, and 20/100 in 1 patient. Only 1 patient with BRVO received grid laser therapy during the trial; the patient was treated at month 6, and the change in BCVA between baseline and month 24 was 0 letters. Thus, laser treatment did not contribute to the good visual outcome seen in the study.
Fluorescein Angiograms in Patients with Macular Edema Caused by Branch Retinal Vein Occlusion The right side of Table 2 (available at http://aaojournal.org) shows the results of masked grading of FAs for leakage, capillary nonperfusion in the posterior pole, and disruption of the perifoveal capillaries. In some patients, leakage or nonperfusion at baseline could not be graded because of retinal hemorrhages. Fourteen of the 16 FAs that could be graded showed severe leakage. Leakage was reduced in 14 of 16 patients who had gradable FAs at baseline and were still in the trial at month 24, but there was still some leakage in all but 1 patient. Capillary nonperfusion in the posterior pole was gradable at baseline in 14 patients, negligible in 6 patients, moderate in 5 patients, and
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severe in 3 patients. In the 17 patients remaining in the trial at month 24, capillary nonperfusion was negligible in 6 patients, minimal in 2 patients, moderate in 4 patients, and severe in 5 patients. One patient showed worsening of nonperfusion, and 1 patient showed improvement. Seven patients showed no disruption of perifoveal capillaries, 5 patients showed disruption of 180 degrees or less, and 6 patients showed disruption of more than 180 degrees.
Factors Affecting Visual Outcome in Patients with Macular Edema Caused by Branch Retinal Vein Occlusion Table 3 (available at http://aaojournal.org) shows possible causes for reduced BCVA in patients with BRVO at month 24. Five patients had recurrent edema, and 2 patients had recent edema that was likely contributing to reduced vision. Of the 17 patients who completed a month 24 visit, the onset of BRVO was ⱕ1 year before study entry in 9 and ⬎1 year in 8. In patients with BRVO ⱕ1 year, the median and mean values for improvement in BCVA were 16 and 19.4 letters and for final BCVA were 44 and 45.1 letters, respectively. In patients with BRVO ⬎1 year, the median and mean values for improvement in BCVA were 15 and 15.9 letters and for final BCVA were 36 and 36.5 letters, respectively. The difference in final BCVA at month 24, but not the change in BCVA from baseline, was statistically significant (P ⬍ 0.05). In 11 patients who had disruption of ⱕ180 degrees of the perifoveal capillaries, the median and mean values for improvement in BCVA were 16 and 17.4 letters and for final BCVA were 44 and
Campochiaro et al 䡠 Ranibizumab for Macular Edema in Vein Occlusions 45.1 letters, respectively. In 6 patients who had disruption of ⬎180 degrees of the perifoveal capillaries, the median and mean values for improvement in BCVA were 15 and 18.5 letters and for final BCVA were 34 and 33.0 letters, respectively. In 3 patients who had disruption of 360 degrees of the perifoveal capillaries, the median and mean values for improvement in BCVA were 14 and 16.7 letters and for final BCVA were 32 and 27.7 letters, respectively. Compared with patients with disruption of ⱕ180 degrees of the perifoveal capillaries, the other 2 groups showed a statistically significant difference (P ⬍ 0.05) in the final BCVA at month 24, but not in change in BCVA from baseline.
Disposition of Patients with Macular Edema Caused by Central Retinal Vein Occlusion In patients with macular edema caused by CRVO, 14 of 20 completed 2 years of follow-up (Table 4, available at http:// aaojournal.org). One of these patients (C1.3) missed the month 24 visit. The month 22 BCVA was improved by 9 letters compared with baseline and FTH was 390 m, and these data were carried forward to month 24. The following describes the course of the 6 patients who withdrew consent before month 24. (1) Patient C2.3 had improvement in BCVA of 18 letters and FTH of 172 m at month 2 but failed to return for additional visits. Communication with the patient indicated that he found it difficult to return for study visits, and therefore he withdrew consent. Month 2 values were carried forward to month 3. (2) Patient C3.3 had an FTH of 159 m and improvement in BCVA of 18 letters at the primary end point. With no additional injections, at month 6 the FTH was 278 m and the improvement from baseline in BCVA was 10 letters. After the month 6 visit, the patient had a fatal myocardial infarction that was not thought to be drug related because it was more than 4 months since the last injection of ranibizumab. (3) Patient C4.5 had 2 injections of ranibizumab, and at the month 2 visit the patient reported mild pain and discomfort since the last injection, but showed no evidence of inflammation. The BCVA had improved by 20 letters compared with baseline, and FTH was 247 m. The patient requested that injection be deferred. At the month 3 primary end point, there was some recurrent edema with an FTH of 297 m and BCVA was improved by 9 letters compared with baseline. Without any additional injections, there was improvement at the M12 visit; FTH was 241 m, and BCVA was improved by 15 letters. The patient lived a long distance away, requiring a flight for each visit, and she decided to exit the trial because she thought her condition was stable. (5) At the month 3 primary end point, patient C12.3 had an FTH of 174 m and improvement from baseline in BCVA of 16 letters. Despite the lack of edema, the patient was extremely concerned that visual benefits would be lost if additional treatment was not given and exited the trial, but agreed to return for safety visits. The patient received an injection of 1.25 mg of bevacizumab, and at the month 4 visit there was recurrent edema with an FTH of 565 m, although the BCVA was still improved by 12 letters compared with baseline. The patient received another injection of 1.25 mg of bevacizumab and refused to return for safety visits thereafter. (5) One week after the first injection of ranibizumab, patient C14.5 had improvement in FTH to 199 m from 493 m at baseline and improvement in BCVA of 2 letters. The patient missed the month 1 visit and thus the second injection. At month 2, FTH was 291 m and BCVA was reduced by 11 letters compared with baseline. The patient stated she had difficulty getting time off from work for study visits and withdrew consent, but she returned on a weekend for a safety and close-out visit at month 6. At that time, FTH was 433 m and BCVA was reduced by 8 letters compared with baseline. (6) Patient C20.3 had an FTH of 182 m and improvement in BCVA of 15 letters at the primary end point. At month 6,
with no additional injections, there was no recurrent edema because the FTH was 196 m and BCVA was improved by 12 letters compared with baseline, but the patient decided to exit the trial because he did not want to take time off from work for study visits.
Anatomic Outcomes and the Need for Ranibizumab Injections in Patients with Macular Edema Caused by Central Retinal Vein Occlusion A course in which there was a brief rebound in edema followed by improvement and stabilization without additional injections occurred in only 1 patient with CRVO, patient C4.5 (Fig 3A). As described, this patient had the third injection held because of prolonged discomfort after the second injection and 1 month later had recurrent edema and reduced vision that resolved without any injections. The patient exited the trial, but follow-up by phone has indicated that VA has remained 20/20 beyond month 24 with no additional injections. Only 3 other patients remained edema-free without any injections during the second year (Table 4, available at http://aaojournal.org): patient C9.5, who had a poor visual outcome because of ischemic maculopathy (Fig 3B), and patients C6.3 and C19.3 (Fig 3C), who had optimal outcomes achieving excellent vision with long-term stability. Most patients had severe rebound edema that was prolonged despite repeated injections of bevacizumab after the primary end point in year 1 and repeated injections of ranibizumab in year 2 (Fig 3D–F). The average number of injections in year 2 was 3.4. Mean FTH at baseline and months 3, 12, and 24 was 533 m, 272.5 m, 404 m, and 337.7 m, respectively (Table 4, available at http://aaojournal.org). Of the 14 patients who completed a month 24 visit, FTH was ⱕ250 m in 6, between 250 and 300 m in 1, between 300 and 400 m in 4, and greater than 400 m in 3.
Visual Outcome at 24 Months in Patients with Macular Edema Caused by Central Retinal Vein Occlusion For the 14 patients who completed 2 years of follow-up, the mean improvement in BCVA at month 24 was 8.5⫾14.8 letters compared with 12⫾9.8 letters at the month 3 primary end point (Table 5, available at http://aaojournal.org). Analysis of all 20 patients at month 24 with last observation carried forward showed a mean improvement in BCVA of 9 letters. Of the 14 patients who had a month 24 visit, the improvement from baseline in BCVA was 6 or more lines in 2 (14.3%), 3 or more lines in 4 (28.6%), 2 or more lines in 6 (42.9%), and at least 1 line in 9 (64.3%). Three patients had essentially no change from baseline (⫹3, ⫹1, ⫺2), and 2 patients lost vision (⫺7 and ⫺20 letters). The Snellen equivalent BCVA at month 24 was 20/40 or better in 4 patients, 20/60 or better in 7 patients, 20/80 or better in 8 patients, better than 20/200 in 11 patients, and worse than 20/200 in 3 patients.
Factors Affecting Visual Outcome in Patients with Macular Edema Caused by Central Retinal Vein Occlusion Table 6 (available at http://aaojournal.org) shows possible causes for reduced BCVA in patients with CRVO at month 24. Seven patients had recurrent edema that was likely to be a major contributor to reduced vision. Of the 14 patients who completed a month 24 visit, the onset of CRVO was ⱕ1 year before study entry in 10 and ⬎1 year in 4. In patients with CRVO ⱕ1 year, the median and mean values for improvement in BCVA were 11 and 13.6 letters and for final BCVA were 37 and 34.3 letters, respec-
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Figure 3. Course of patients with CRVO treated with antagonists of VEGF. The line graph shows change from baseline in BCVA in letters measured on an Early Treatment Diabetic Retinopathy Study chart at 4 m at each visit of the study. The bars show excess FTH at each visit. The arrows indicate visits at which an injection of ranibizumab, bevacizumab, or triamcinolone was administered. The first 3 patients (A–C) had resolution of macular edema after only 3 injections of ranibizumab. The second 3 patients (D–F) are representative of the remainder of the patients; they required frequent injections to achieve partial control of edema. B ⫽ bevacizumab; BCVA ⫽ best corrected visual acuity; BL ⫽ baseline; CRVO ⫽ central retinal vein occlusions; ETDRS ⫽ Early Treatment Diabetic Retinopathy Study; FTH ⫽ foveal thickness; R ⫽ ranibizumab; T ⫽ triamcinolone; VA ⫽ visual acuity; VEGF ⫽ vascular endothelial growth factor.
tively. In patients with CRVO ⬎1 year, the median and mean values for improvement in BCVA were ⫺4.5 and ⫺4.8 letters and for final BCVA were 10.5 and 14.8 letters, respectively, significantly worse (P ⬍ 0.05) than that in patients with CRVO ⱕ1 year. In 3 patients who had disruption of the entire circumference of the perifoveal capillaries, the median and mean values for improvement in BCVA were ⫺7 and ⫺8.7 letters and for final BCVA were 0 and 0.3 letters, respectively. The remaining 11 patients who had disruption of ⱕ180 degrees of the circumference of the perifoveal capillaries, the median and mean values were 8.5 and 10.5 letters for improvement in BCVA and 37.5 and 34.5 letters for the final BCVA, respectively, significantly greater (P ⬍ 0.05) than that seen in patients with complete disruption of the perifoveal capillaries.
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Discussion The natural history of CRVO and BRVO is somewhat variable. Some patients improve spontaneously, but the majority have problems from macular edema. Until recently, grid laser therapy was the only treatment option for macular edema caused by BRVO, and there was no treatment for macular edema caused by CRVO. Although the lack of a control group necessitates caution in interpreting the results, the current study suggests there may be a role for VEGF antagonists in both of these disease processes. Three monthly injections of 0.3 or 0.5 mg of ranibizumab in
Campochiaro et al 䡠 Ranibizumab for Macular Edema in Vein Occlusions patients with macular edema caused by CRVO or BRVO reduced EFT by approximately 90% and substantially improved BCVA.3 The 0.3 mg and 0.5 mg doses had similar results and when combined showed that 20 patients with BRVO had mean and median improvements in BCVA of 16.1 and 15 letters and 20 patients with CRVO had mean and median improvements of 12.0 and 15 letters, respectively. After the primary end point, we attempted to wean patients from ranibizumab. Five patients with BRVO and 1 patient with CRVO had some recurrence of macular edema with little change in BCVA, followed by resolution of the edema with no additional injections. This confirms our hypothesis that after suppression of leakage and resolution of macular edema by blockade of VEGF in patients with RVO, there may be rebound in edema when blockade of VEGF is withdrawn that can resolve spontaneously. It is useful to know that this can occur when trying to wean patients from ranibizumab, but several patients had a substantial decrease in BCVA accompanying the rebound in edema. Whether these patients would have had spontaneous improvement, as was the case for the patients shown in Figure 1, cannot be determined, but their subsequent course during which they had frequent bouts of recurrent edema suggests that it is unlikely. After 2 years of follow-up, only 5 of 17 patients with BRVO and 3 of 14 patients with CRVO were edema-free with no injections for at least 1 year. (One patient with CRVO had resolution of edema and excellent vision, and left the trial after 1 year because there had been no need for injections after month 2. This patient reports continued stability since exiting the trial ⬎1 year ago.) Thus, a majority of patients with macular edema caused by BRVO or CRVO require intermittent injections of an anti-VEGF agent for at least 2 years. It is important to know whether visual benefits achieved with monthly injections of ranibizumab can be maintained with less frequent injections given for recurrent edema. The answer is yes for patients with BRVO, because even with an average of only 2 injections during year 2, the mean improvement in BCVA at month 24 was 17.8 letters compared with 16.1 letters at month 3. Thus, visual benefits were maintained and final visions at 2 years were excellent with 59% and 82% of patients achieving 20/40 or better and 20/50 or better, respectively. However, it is likely that not all patients realized their full visual potential, because 7 patients had edema at or soon before month 24 that was likely contributing to persistent reduction in vision. The mean best improvement in VA in these 7 patients was 18.4 letters, and their mean improvement at month 24 was 12.1 letters (Table 3, available at http://aaojournal.org), suggesting that on average these patients’ VA could improve by another line if macular edema was completely controlled. In the 14 patients with CRVO who completed 2 years of follow-up, the mean improvement in BCVA at month 24 was 8.5 letters compared with 12.0 letters at month 3, indicating that unlike the situation in patients with BRVO, patients with CRVO did not maintain the same level of vision when treated only as frequently as every 2 months compared with every month. This is supported by the OCT results that showed that mean FTH was 338 m at month 24 compared with 273 m at month 3. The FTH at month 24
was ⱖ300 m in 7 patients and ⱖ500 m in 3 patients, which is clearly inadequate. The mean best improvement in VA in these 10 patients was 14.7 letters, and their mean improvement at month 24 was ⫺0.3 letters, suggesting that on average these patients’ VA could improve by 3 lines if macular edema was completely controlled (Table 6, available at http://aaojournal.org). This suggests that injections of 0.5 mg of ranibizumab as frequently as every 2 months for recurrent edema are inadequate for a substantial number of patients with CRVO. Likewise, it has been demonstrated that treatment with ranibizumab every 3 months for recurrent edema is inadequate.4 Several patients in this study achieved excellent final visions, indicating that the visual potential after some RVOs is extremely good and justifies the time, effort, and expense of aggressive treatment. Three possible predictors of a suboptimal visual outcome were identified: chronic edema before the onset of treatment, closure of more than half of the perifoveal capillaries, and closure of all of the perifoveal capillaries. Patients with these features can still obtain a large improvement in VA, and some patients with the first 2 features obtained a final vision of ⱖ20/40, but the best VA obtained in a patient with complete closure of the perifoveal capillaries was 20/63. These results are based on data from a small number of patients and are preliminary, but they should be investigated for their predictive value in larger studies, such as BRAVO and CRUISE. Although this study is relatively small, the visual results were good and suggest that anti-VEGF treatment provides long-term benefit in patients with macular edema caused by BRVO or CRVO. In BRVO, the mean improvement of 17.8 letters at 2 years compares favorably with the 2-year outcomes in the BRVO SCORE study, in which the mean improvements were 11.3, 6.3, and 4.0 letters in the grid laser, 1 mg triamcinolone, and 4 mg triamcinolone groups, respectively.11 In CRVO, the mean improvement of 8.5 letters at 2 years compares favorably with the 2-year outcomes of the CRVO SCORE study, in which the mean improvements were ⫺10.4, ⫺4.4, and ⫺2.4 letters in the observation, 1 mg triamcinolone, and 4 mg triamcinolone groups, respectively.12 It will be important to determine whether these promising results are confirmed by 1-year outcome data from BRAVO and CRUISE and longer outcomes from the Horizon trial (The registry number for the Horizon study at clinical trials.gov is NCT00379795). In conclusion, despite the promising 2-year visual outcomes, this study suggests that excessive production of VEGF is a long-term problem in many patients with RVO. Treatment of recurrent edema only as frequently as every 2 months with injections of 0.5 mg of ranibizumab is not optimal for most patients. A more aggressive treatment regimen of injections of 0.5 mg of ranibizumab as frequently as every month for recurrent edema in patients with CRVO resulted in a mean improvement in BCVA of 18.5 letters at 1 year with an average of 8.5 injections.5 Additional studies are needed to determine the long-term effects of injections as frequently as every month or the use of higher doses of ranibizumab. We are currently investigating the effects of injections of 2.0 mg of ranibizumab. Also, it is important to determine why continued excessive produc-
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Ophthalmology Volume 117, Number 12, December 2010 tion of VEGF is a problem for more than 2 years after RVO in many patients. Essentially all of these patients have collaterals, and it seems that the hope has been dashed that the problem of macular edema after RVO would be solved by a brief period of injections of an anti-VEGF agent to buy time until collaterals develop. Something other than the original occlusion becomes the driver for VEGF production in the majority of patients with RVO, and the most likely candidate is peripheral capillary nonperfusion. We are currently testing this hypothesis. Hopefully, a period of aggressive pharmacologic blockade of VEGF combined with reduction of the source of its production will maximize VA and free patients with RVO from long-term injections.
References 1. Cugati S, Wang JJ, Rochtchina E, Mitchell P. Ten-year incidence of retinal vein occlusion in an older population: the Blue Mountains Eye Study. Arch Ophthalmol 2006; 124:726 –32. 2. Klein R, Moss SE, Meuer SM, Klein BE. The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch Ophthalmol 2008;126:513– 8. 3. 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: 791–9. 4. Pieramici DJ, Rabena M, Castellarin AA, et al. Ranibizumab for the treatment of macular edema associated with perfused central retinal vein occlusions [report online]. Ophthalmology 2008;115:e47–54.
5. Spaide RF, Chang LK, Klancnik JM, et al. Prospective study of intravitreal ranibizumab as a treatment for decreased visual acuity secondary to central retinal vein occlusion. Am J Ophthalmol 2009;147:298 –306. 6. 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;117:1102–12. 7. 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 –33. 8. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report no. 1. Arch Ophthalmol 1985;103:1796 – 806. 9. Hee MR, Izatt JA, Swanson EA, et al. Optical coherence tomography of the human retina. Arch Ophthalmol 1995;113: 325–32. 10. Nguyen QD, Tatlipinar S, Shah SM, et al. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol 2006;142:961–9. 11. SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study report 6. Arch Ophthalmol 2009;127: 1115–28. 12. SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study report 5. Arch Ophthalmol 2009;127: 1101–14.
Footnotes and Financial Disclosures Originally received: December 21, 2009. Final revision: March 23, 2010. Accepted: March 26, 2010. Available online: July 13, 2010.
Manuscript no. 2009-1738.
The Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. This article contains online-only material. The following appear only online: Tables 1– 6. Financial Disclosure(s): PAC receives research support from and has institutional consultancy agreements with Genentech and GlaxoSmithKline (JHU receives the remuneration), was a consultant for LPath and Potentia, serves on the Data and Safety Monitoring Committee for the View1 trial sponsored by Re-
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generon, and receives research support from Alimera. QDN is a consultant for Bausch and Lomb and receives research support from Genentech and Regeneron. HY had a consultancy with Genentech that ended in 2007. DD received a lecture fee from Heidelburg and receives research support from Genentech. None of the other authors have any conflicts. Supported by an Investigator Initiated Study grant from Genentech, Inc. PAC is the George S. and Dolores Doré Eccles Professor of Ophthalmology and Neuroscience. Correspondence: Peter A. Campochiaro, MD, Maumenee 719, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287-9277. E-mail: [email protected].
Campochiaro et al 䡠 Ranibizumab for Macular Edema in Vein Occlusions Table 1. Foveal Thickness and Injections for Patients with Branch Vein Occlusion Foveal Thickness (m)
No. of Injections Year 1
Year 2*
ID
BL
M3
M12
M24
R
B
T
R
B1.5 B2.5 B3.3 B4.5 B5.5 B6.3 B7.3 B8.3 B9.5 B10.5 B11.3 B12.5 B13.5 B14.3 B15.3 B16.5 B17.3 B18.5 B19.3 B20.3 Mean⫾SE Median
508 571 534 524 637 507 409 366 495 632 477 504 331 665 495 411 412 382 486 284 482⫾22.7 495
210 136 206 242 245 272 185 301 205 204 217 239 277 177 177 205 194 242 206 202 217⫾8.7 206
224 168 203 410 248 295 LTF 265 281 185 246 209 301 192 397 219 193 217 LTF 282 252⫾16 235
226 LTF 219 187 253 313 LTF 243 238 196 250 203 274 200 393 209 192 304 LTF 278 246⫾13.1 238
3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 3 4 3 3 3.2⫾0.1 3
0 0 0 0 0 3 0 0 2 3 1 1 3 2 0 1 0 0 0 0 0.8⫾0.3 0
0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.1⫾0.1 0
0 0 0 4 0 4 LTF 2 4 6 5 1 6 5 2 0 0 2 LTF 1 2.3⫾0.5 1.5
B ⫽ bevacizumab; BL ⫽ baseline; ID ⫽ subject identification number followed by dose of ranibizumab received; LTF ⫽ lost to follow-up; R ⫽ ranibizumab; SE ⫽ standard error of the mean; T ⫽ triamcinolone. *Patients received only ranibizumab in year 2.
Table 2. Visual Acuity and Fluorescein Angiography for Patients with Branch Vein Occlusion
ID B1.5 B2.5 B3.3 B4.5 B5.5 B6.3 B7.3 B8.3 B9.5 B10.5 B11.3 B12.5 B13.5 B14.3 B15.3 B16.5 B17.3 B18.5 B19.3 B20.3 Mean⫾SE Median
Duration (mos)
Visual Acuity BL
⌬M3
⌬M12
⌬M24
Fluorescein Angiography Grade M24 VA
2 2 34 31 42 44 4 0 39 35 LTF LTF 1 21 8 27 26 47 15 36 2 ⫺5 0 36 30 5 21 41 37 42 30 19 11 17 16 35 4 31 7 LTF LTF LTF 8 37 6 5 5 42 13 32 16 16 17 49 3 31 22 12 16 47 1 9 34 31 34 43 1 20 19 8 12 32 90 26 14 9 11 37 16 4 22 22 14 18 6 35 5 9 6 41 2 35 10 19 18 53 1 41 16 21 16 57 28 9 16 24 24 33 7 28 10 LTF LTF LTF 20 30 9 5 8 38 14.1⫾20.5 22.6⫾3 16.1⫾2.3 18.2⫾2.8 17.8⫾2.8 40.8⫾2.2 7 27 15 18 16 42
M24 Snellen PF Caps CNP BL BL Leak CNP M24 M24 Leak 20/32 LTF 20/32 20/50 20/40 20/50 LTF 20/40 20/25 20/32 20/40 20/63 20/50 20/100 20/40 20/25 20/20 20/63 LTF 20/50
180 NG 0 180 270 270 0 0 0 90 180 360 0 360 0 90 0 360 NG 270
NG NG 0 2 2 2 0 0 0 NG NG 3 0 2 2 NG 0 3 NG 3
NG NG 1 3 3 3 3 3 3 3 NG 3 2 3 3 NG 3 3 3 3
3 LTF 0 2 1 2 LTF 0 0 2 0 3 0 3 2 1 0 3 LTF 3
1 LTF 0 1 2 2 LTF 1 2 1 2 1 1 2 1 1 1 2 LTF 1
BL ⫽ baseline; CNP ⫽ capillary nonperfusion; ID ⫽ subject identification number followed by dose of ranibizumab received; LTF ⫽ lost to follow-up; NG ⫽ not gradable; PF caps ⫽ disruption of perifoveal capillaries in degrees; SE ⫽ standard error of the mean. Grading for CNP and leakage: 0 ⫽ none; 1 ⫽ mild; 2 ⫽ moderate; 3 ⫽ severe.
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Ophthalmology Volume 117, Number 12, December 2010 Table 3. Causes of Decreased Vision in Patients with Branch Retinal Vein Occlusion after Two Years of Anti-Vascular Endothelial Growth Factor Treatment ID
⌬VA Best
Good VA with Resolved B17.3 21 B16.5 20 B1.5 42 B3.3 27 B5.5 41
⌬VA M24 Edema 16 18 42 26 37
M24 Snellen 20/20 20/25 20/32 20/32 20/40
Good VA with Edema Controlled by Continued B9.5 20 17 20/25 B10.5 22 16 20/32 B8.3 9 5 20/40 B11.3 37 34 20/40
Possible Causes of Reduced VA None PDPC (90 degrees) PDPC (180 degrees) None CD (30 mos), PDPC (270 degrees) Injections CD (13 mos) PDPC (90 degrees) Cataract RE
Good VA with Uncontrolled Edema* B15.3 11 6 20/40
393 m
Moderate VA with Edema Controlled by Continued Injections B4.5 7 0 20/50 RE, CD (15 mos), PDPC (180 degrees) B12.5 23 12 20/63 RE, DPC B14.3 25 14 20/100 CD (16 mos), DPC Moderate VA with Uncontrolled Edema* B6.3 20 16 20/50 B13.5 B20.3
18 12
11 8
20/50 20/50
B18.5
24
24
20/63
313 m, PDPC 274 m, 278 m, PDPC 304 m, DPC
CD (30 mos), CD (90 mos) CD (18 mos), (270 degrees) CD (28 mos),
CD ⫽ chronic disease; DPC ⫽ 360 degrees disruption of perifoveal capillaries; ID ⫽ patient identification number; PDPC ⫽ partial disruption of perifoveal capillaries (number of degrees of disruption are in parentheses); RE ⫽ recent edema (recurrent edema shortly before M24); VA ⫽ visual acuity; ⌬VA Best ⫽ greatest improvement from baseline at any time in the study in Early Treatment Diabetic Retinopathy Study (ETDRS) letters read at 4 m; ⌬VA M24 ⫽ improvement from baseline at month 24 in ETDRS letters read at 4 m; M24 Snellen ⫽ Snellen equivalent VA at month 24. *Central subfield thickness at month 24 is listed.
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Campochiaro et al 䡠 Ranibizumab for Macular Edema in Vein Occlusions Table 4. Foveal Thickness and Injections for Patients with Central Retinal Vein Occlusion Foveal Thickness (m)
No. of Injections Year 1
No. of Injections Year 2
ID
BL
M3
M12
M24
R
B
T
R
B
T
C1.3 C2.3 C3.3 C4.5 C5.5 C6.3 C7.5 C8.5 C9.5 C10.5 C11.3 C12.3 C13.3 C14.5 C15.5 C16.3 C17.5 C18.5 C19.3 C20.3 Mean⫾SE Median
549 630 514 378 721 485 480 465 596 555 615 489 404 493 591 697 263 549 637 555 533⫾24.3 549
541 172‡ 159 297 247 547 175 277 125 280 233 174 241 291‡ 177 617 246 228 240 182 273⫾30.6 241
494 LTF LTF 241 659 310 345 288 126 973 507 LTF 413 LTF 199 437 254 597 214 LTF 404⫾56.7 345
390* LTF LTF LTF 548 203† 336 196 142 791 251 LTF 170 LTF 634 303 331 225 208 LTF 338⫾51.5 277
3 3 3 2 3 3 3 3 3 3 3 3 6 2 3 4 4 7 3 3 3.4⫾0.3 3
3 0 1 0 2 0 2 3 0 4 3 2 0 0 2 1 1 0 1 0 1.3⫾0.3 1
0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.1⫾0.1 0
0 LTF LTF 0 4 0 3 4 0 5 4 LTF 5 LTF 4 6 5 6 0 LTF 3.1⫾0.6 4
0 LTF LTF 0 1 0 0 0 0 1 1 LTF 0 LTF 0 0 0 0 0 LTF 0.2⫾0.1 0
2 LTF LTF 0 0 0 0 0 0 0 0 LTF 0 LTF 0 0 0 0 0 LTF 0.1⫾0.1 0
B ⫽ bevacizumab; BL ⫽ baseline; ID ⫽ subject identification number followed by dose of ranibizumab received; LTF ⫽ lost to follow-up; R ⫽ ranibizumab; SE ⫽ standard error of the mean; T ⫽ triamcinolone. *Month 22 FTH value carried forward because of missed visit on month 24. † Month 28 value carried back because of missed visit on month 24. ‡ Month 2 value carried forward because of missed visit on month 3.
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Ophthalmology Volume 117, Number 12, December 2010 Table 5. Visual Acuity and Fluorescein Angiography for Patients with Central Retinal Vein Occlusion Visual Acuity
Fluorescein Angiography Grading
ID
Duration (mos)
BL
⌬M3
⌬M12
⌬M24
M24
C1.3 C2.3 C3.3 C4.5 C5.5 C6.3 C7.5 C8.5 C9.5 C10.5 C11.3 C12.3 C13.3 C14.5 C15.5 C16.3 C17.5 C18.5 C19.3 C20.3 Mean⫾SE Median
7 8 5 1 11 1 19 36 2 43 6 26 12 52 20 1 2 2 7 10 13.6⫾3.3 8
8 2 3 40 4 18 20 28 0 7 24 0 32 39 23 19 34 32 36 18 19.4⫾3.1 20
6 18§ 18 9 16 20 ⫺16 18 9 20 18 16 9 ⫺11§ 13 10 14 15 23 15 12⫾2.2 15
5 LTF LTF 15 ⫺3 32 ⫺2 17 7 ⫺7 21 LTF 2 LTF ⫺3 0 10 1 22 LTF 7.8⫾2.9 5
9* LTF LTF LTF 5 38‡ ⫺20 10 1 ⫺7 30 LTF 6 LTF ⫺2 11 3 12 23 LTF 8.5⫾3.9 8
17* LTF LTF LTF 9 56‡ 0 38 1 0 54 LTF 38 LTF 21 30 37 44 59 LTF 28.9⫾5.6 34
M24 Snellen
PF Caps
CNP BL
BL Leak
CNP M24
M24 Leak
20/125 LTF LTF LTF 20/160 20/20 20/250 20/50 20/250 20/250 20/20 LTF 20/50 LTF 20/100 20/63 20/50 20/32 20/16 LTF
0 360 0 0 0 NG 360 90 360 360 0 90 180 0 180 180 0 0 0 360
0 1 0 0 0 0 1 0 3 NG 0 0 1 0 1 NG 0 NG 0 3
3 3 2 2 3 3 3 3 3 3 3 3 2 3 3 3 3 3 3 3
0† LTF LTF LTF 0 LTF 3 0 3 3 0 LTF 1 LTF 2 1 0 0 0 LTF
2† LTF LTF LTF 3 LTF 3 1 3 3 1 LTF 1 LTF 3 2 1 1 0 LTF
BL ⫽ baseline; CNP ⫽ capillary nonperfusion; ID ⫽ subject identification number followed by dose of ranibizumab received; LTF ⫽ lost to follow-up; NG ⫽ not gradable; PF Caps ⫽ disruption of perifoveal capillaries in degrees; SE ⫽ standard error of the mean. Grading for CNP and leakage: 0 ⫽ none; 1 ⫽ mild; 2 ⫽ moderate; 3 ⫽ severe. *Month 22 FTH value carried forward because of missed visit on month 24. † Month 18 FA grading carried forward because of missed visit on month 24. ‡ Month 28 value carried back because of missed visit on month 24. § Month 2 value carried forward because of missed visit on month 3.
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Campochiaro et al 䡠 Ranibizumab for Macular Edema in Vein Occlusions Table 6. Causes of Decreased Vision in Patients with Central Retinal Vein Occlusion after Two Years of Anti-Vascular Endothelial Growth Factor Treatment ID Good VA C19.3 C4.5 C6.3
⌬VA Best
⌬VA M24
M24 Snellen
with Resolved Edema 29 23 20/16 20 15* 20/20* 33 32 20/20
Possible Causes of Reduced VA None PDPC (90 degrees) None
Good VA with Edema Controlled by Continued Injections C11.3 31 30 20/20 RE C18.5 12 15 20/32 RE Moderate VA with Edema Controlled by Continued Injections C8.5 18 10 20/50 CD (36 mos), PDPC (90 degrees) C13.3 9 6 20/50 PDPC (90 degrees) Moderate C16.3 C17.5 C15.5 C1.3 C5.5
VA with Uncontrolled Edema† 15 11 20/63 393 m, PDPC (180 degrees) 15 3 20/50 331 m 17 ⫺2 20/100 634 m, CD (20 mos), PDPC (180 degrees) 12 7 20/125 393 m 16 9 20/160 548 m
Poor VA with Resolved Edema C9.5 9 1 20/250 Poor VA with Uncontrolled Edema† C7.5 3 ⫺20 20/250 C10.5 25 ⫺7 20/250
Ischemic maculopathy (central thinning) 331 m, CD (19 mos), DPC, PI 791 m, CD (43 mos), DPC
CD ⫽ chronic disease; DPC ⫽ 360-degree disruption of perifoveal capillaries; ID ⫽ patient identification number; PDPC ⫽ partial disruption of perifoveal capillaries (number of degrees of disruption are in parentheses); RE ⫽ recent edema (recurrent edema shortly before M24); PI ⫽ progressive ischemia; VA ⫽ visual acuity; ⌬VA Best ⫽ greatest improvement from baseline at any time in the study in ETDRS letters read at 4 m; ⌬VA M24 ⫽ improvement from baseline at month 24 in ETDRS letters read at 4 m; M24 Snellen ⫽ Snellen equivalent VA at month 24. *Month 12 values, but patient states that vision has remained normal beyond month 24 with no additional treatment. † Central subfield thickness at month 24 is listed.
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