Purpose
To describe the risk factors for the development of geographic atrophy (GA) following intravitreal ranibizumab injection treatment for retinal angiomatous proliferation (RAP).
Design
Retrospective interventional series.
Methods
Forty-three eyes (38 South Korean patients) from patients being treated for naïve RAP with intravitreal ranibizumab injection were included in this study. All patients were treated with an initial series of 3 monthly loading injections, followed by further injections as required. Baseline ocular characteristics and lesion features assessed using fluorescein angiography (FA), indocyanine angiography (ICGA), and spectral-domain optical coherence tomography (SD OCT) were evaluated as potential risk factors for GA through 2 years of follow-up.
Results
At 2 years follow-up, GA had developed in 16 of 43 eyes (37.2%). The mean number of ranibizumab injections was 7.52 ± 2.11. Using multiple logistic regression, thinning of the subfoveal choroid at baseline (odds ratio [OR], 0.955; 95% confidence interval [CI], 0.929-0.982; P = .002), presence of reticular pseudodrusen (OR, 1.092; 95% CI, 1.017-1.485; P = .039), and presence of GA in the fellow eye at baseline (OR, 1.433; 95% CI, 1.061-1.935; P = .025) were identified as significant risk factors for GA development.
Conclusions
GA developed in 37.2% of eyes with RAP during the 24 months following intravitreal ranibizumab injections. Subfoveal choroidal thinning at baseline, the presence of reticular pseudodrusen, and the presence of GA in the fellow eye at baseline were associated with increased risk of GA development after treatment.
Retinal angiomatous proliferation (RAP) is a clinical condition generally classified as a subtype of neovascular age-related macular degeneration (AMD), and is characterized by retinal neovascularization or chorioretinal anastomosis. It has been reported that the prevalence of RAP in newly diagnosed neovascular AMD is approximately 5%-20%.
In recent times, intravitreal injection of anti–vascular endothelial growth factor (VEGF) has been used extensively for the treatment of neovascular AMD. Because RAP is considered to be a distinct subtype of neovascular AMD, anti-VEGF administration is a commonly used treatment for the condition. Treatment for RAP using anti-VEGF has shown promise in terms of its therapeutic efficacy.
Morphologic changes to the macula following anti-VEGF treatment can vary, and may include geographic atrophy (GA), atrophy of the retinal pigment epithelium (RPE), and choriocapillary atrophy. When the GA lesion involved the fovea, the visual prognosis was markedly poor.
A recent study reported GA development in approximately 18% of patients after intravitreal anti-VEGF treatment for neovascular AMD over a 2-year period. A second report using the same patient population has also identified RAP as a risk factor for GA development following anti-VEGF treatment. It has been reported that GA frequently develops in patients with RAP. However, not much is known about the risk factors for GA development following anti-VEGF treatment for RAP.
The present investigation describes the 2-year cumulative incidence of GA in RAP patients treated with intravitreal ranibizumab injections and the associated risk factors.
Subjects and Methods
We performed a computerized search and medical record review for patients who had been diagnosed with RAP and treated with anti-VEGF (Ranibizumab; Lucentis, Genentech Inc, South San Francisco, California, USA) injections between June 2011 and August 2013. All patients were examined and treated at the Retina Center of Kim’s Eye Hospital at Konyang University College of Medicine. This study was approved by the Institutional Review Board of Kim’s Eye Hospital, Konyang University College of Medicine. The study conformed to the recommendations provided in the Declaration of Helsinki (IRB No A-2014-016).
Subjects
The following inclusion criteria were used: (1) age >50 years; (2) confirmation of RAP with funduscopy, spectral-domain optical coherence tomography (SD OCT [Spectralis; Heidelberg Engineering, Heidelberg, Germany and Spectral OCT/SLO; OTI Ophthalmic Technologies Inc, Miami, Florida, USA]), fluorescein angiography (FA), and indocyanine green angiography (ICGA), performed using a confocal laser scanning system (Spectralis HRA+OCT; Heidelberg Engineering) at the first visit; (3) no previous treatment prior to diagnosis; (4) treatment with ranibizumab; and (5) a minimum follow-up period of 24 months.
The diagnosis of RAP was based on the characteristic features of the condition, which include intraretinal hemorrhage, intraretinal vascular anastomoses, and findings of retinal pigment epithelial detachment with overlying cystic retinal edema using OCT. Patients with RAP were classified as stage 1, 2, or 3 according to established grading criteria. The diagnosis and staging of RAP were evaluated by 2 independent investigators (H.J.C. and H.S.K.). When a consensus could not be reached, the senior investigator (T.G.L.) made the final decision.
Exclusion criteria included the following: (1) the presence of GA at baseline; (2) treatment with another anti-VEGF agent (bevacizumab [Avastin, Genentech Inc]); (3) the treatment combined with photodynamic therapy (PDT); (4) GA development as a result of an RPE tear caused by the treatment; (5) other concomitant ocular diseases, such as diabetic retinopathy, high myopia (more than spherical equivalent of 6 diopters), vein or artery occlusion, or epiretinal membrane; or (5) the presence of any other ocular disease that could affect visual acuity.
Patient Assessment
The development of GA in patients was evaluated over a 2-year study period. The atrophic lesions associated with choroidal neovascularization (CNV) treatment are clinically indistinguishable from de novo GA. In addition, it is not known whether the histology and functional effects are similar in de novo GA and GA associated with CNV. Cases of de novo GA have been classified as GA in this study, which is consistent with previous studies. Atrophic drusen (ie, degenerating drusen associated with RPE atrophy at its margins) was not considered to be GA unless the drusenoid material was completely encircled by a rim of atrophy.
Color fundus photography, SD OCT, and FA were used to diagnose GA. For a GA diagnosis to be considered, there should be an area of hypopigmentation or hyperfluorescence of at least 250 μm at its minimum linear dimensions within the macular vascular arcades, which has at least 2 of the 3 following characteristics: (1) circular shape, (2) sharply demarcated borders seen using color fundus photography and/or FA, and (3) visibility of underlying choroidal vessels with an “excavated or punched-out” appearance on color fundus photography stereoscopy and/or FA. Any GA lesions detected were confirmed by SD OCT findings of increased signal transmission in the choroid and atrophic changes to the RPE (acquisition for SD OCT consisted of 19 or 31 horizontal lines).
The presence of reticular pseudodrusen based on the appearance of reticular patterns was identified using at least 2 of the following imaging modalities: color fundus photography, SD OCT, and ICGA. Reticular patterns were identified on ICGA as distinct groupings of hypofluorescent dots present in the late phase. Using SD OCT, reticular lesions were defined as ≥5 hyperreflective mounds or triangular lesions above the RPE in ≥1 B-scan.
Subfoveal choroidal thickness was defined as the vertical distance from the hyperreflective line of the Bruch membrane to the hyperreflective line of the inner surface of the sclera on fovea-centered SD OCT images. For the measurement of subfoveal choroidal thickness, the OCT image was taken at baseline with an enhanced depth imaging (EDI) technique using a Spectralis SD OCT machine as previously reported. All scans were taken horizontally, as close to the center of the fovea as possible, such that the thinnest point of the macula was assessed. Central foveal thickness was defined as the vertical distance from the internal limiting membrane to the Bruch membrane on SD OCT images. The subfoveal choroidal thickness and central foveal thickness were estimated using Heidelberg Eye Explorer software (v. 5.6.4.0; Heidelberg Engineering). The images were assessed by 2 retinal specialists (H.J.C. and H.S.K.), who were given no information about the patient.
Intravitreal Ranibizumab Treatment
All patients were given a loading dose of 3 intravitreal ranibizumab injections (0.5 mg/0.05 mL; Lucentis, Genentech Inc) with a 1-month interval between treatments. After the loading injections were performed, additional injections were performed on an “as-needed” basis if any of the following conditions was observed: (1) visual deterioration of more than 2 lines (>0.2 logarithm of the minimal angle of resolution [logMAR]), (2) OCT evidence of persistent fluid or hemorrhage involving the macula for at least 1 month following the previous injection, (3) an increase in central foveal thickness of at least 100 μm on OCT, or (4) evidence of an active RAP lesion found on FA, ICGA, or OCT. Follow-up of the patients, scheduled on a monthly basis during the first year and every 2 or 3 months thereafter, included best-corrected visual acuity (BCVA) measurement, color fundus photography, and SD OCT. In addition to the routine follow-ups, patients were told to visit the clinic immediately if they experienced loss of vision and/or metamorphopsia exacerbation or recurrence. Additional FA, ICGA, and SD OCT examinations were performed whenever RAP recurrence or GA development was suspected.
Statistical Analysis
SPSS version 13.0 (SPSS Inc, Chicago, Illinois, USA) was used for all statistical analysis. A paired t test was used to compare the mean BCVA at each time point with baseline BCVA. A t test was used for the analysis of continuous variables, and a χ 2 or Fisher exact test was used for categorical variables. Stepwise logistic regression was used to investigate the relationship between GA development and baseline clinical characteristics; forward and backward stepwise regression was performed using the likelihood-ratio model, in which change in the likelihood-ratio statistic, based on the maximum partial likelihood estimates for the covariate, was used for variable selection. A P value of less than .05 was considered statistically significant.
Results
Baseline Characteristics
A total of 83 eyes (72 patients) were diagnosed with RAP at our institution during the study period; of these, 55 eyes completed the 2-year follow-up. Of the 55 eyes diagnosed with RAP, 12 were excluded for the following reasons: presence of GA at baseline (4 eyes), treatment with combined PDT (2 eyes), treatment with bevacizumab (6 eyes), and development of GA as a consequence of an RPE tear (3 eyes). As a result, a total of 43 eyes with RAP in 38 patients (18 men, 20 women) were enrolled in the study. All patients were South Korean, and the average age for the entire study group was 74.8 ± 7.1 years. Table 1 outlines the clinical details for the patients included in the study.
| Total Eyes (n = 43) | Eyes That Developed GA During Treatment (n = 16) | Eyes That Did Not Develop GA During Treatment (n = 27) | P | |
|---|---|---|---|---|
| Age (y ± SD) | 74.8 ± 7.1 (59-89) | 76.5 ± 5.2 | 73.7 ± 6.6 | .342 a |
| Sex | ||||
| Male, n (%) | 18 (47.4%) | 6 (46.2%) | 12 (48.0%) | |
| Female, n (%) | 20 (52.6%) | 7 (53.8%) | 13 (52.0%) | .423 b |
| Mean of baseline BCVA (logMAR; Snellen equivalent) | 0.73 ± 0.56 (20/107; 0.1-1.9) | 0.75 ± 0.33 | 71.8 ± 0.52 | .326 a |
| Baseline BCVA (logMAR) (Snellen equivalent) | ||||
| <0.54 (20/70) | 9 (21.0%) | 2 (12.5%) | 7 (25.9%) | |
| 0.54 (20/70) to 1.0 (20/200) | 19 (44.2%) | 8 (50.0%) | 11 (40.7%) | |
| >1.0 (20/200) | 15 (34.8%) | 6 (37.5%) | 9 (33.4%) | .782 c |
| Mean central foveal thickness ± SD (μm) | 339 ± 186 | 310 ± 155 | 341 ± 187 | .218 a |
| Mean subfoveal choroidal thickness ± SD (μm) | 137 ± 57 (65-262) | 94 ± 31 | 169 ± 61 | <.001 a |
| Lesion location, n (%) | ||||
| Subfoveal | 10 (23.3%) | 3 (18.8%) | 7 (25.9%) | |
| Juxtafoveal | 26 (60.5%) | 10 (62.4%) | 16 (59.3%) | |
| Extrafoveal | 7 (16.2%) | 3 (18.8%) | 4 (14.8%) | .782 c |
| Mean GLD ± SD (μm) | 1725 ± 882 | 1722 ± 692 | 1761 ± 772 | .967 a |
| Mean lesion size ± SD (mm 2 ) | 2.2 ± 1.3 | 2.1 ± 1.2 | 2.4 ± 1.6 | .231 a |
| Stage of RAP | ||||
| Stage 1 | 5 (11.6%) | 2 (12.5%) | 3 (11.1%) | |
| Stage 2 | 27 (62.8%) | 10 (62.5%) | 17 (63.0%) | |
| Stage 3 | 11 (25.6%) | 4 (25.0%) | 7 (25.9%) | .923 c |
| Presence of PED, n (%) | 27 (62.8%) | 14 (87.5%) | 13 (48.1%) | .029 b |
| Reticular pseudodrusen, n (%) | 26 (60.5%) | 13 (81.3%) | 13 (48.1%) | .023 b |
| Presence of GA at fellow eye, n (%) | 6 (14.0%) | 5 (31.3%) | 1 (4%) | .009 c |
| Mean number of injections ± SD | 7.52 ± 2.11 | 7.32 ± 1.99 | 7.63 ± 2.27 | .790 a |
Most of subjects had various degrees of pigmentary alterations and drusen at baseline. Soft drusen were seen in 39 of the 43 eyes (90.7%), and 1 eye (2.3%) had cuticular drusen that had a “stars-in the sky” appearance on FA. Reticular pseudodrusen were seen in 26 eyes (60.5%).
Subjects received a mean of 7.52 ± 2.11 intravitreal ranibizumab injections during the 24-month study period (range 5-11). No complications associated with the injections, including endophthalmitis, traumatic lens injury, or retinal detachment, were observed. None of the patients developed any systemic complications, such as cerebrovascular accident, as a result of the injections.
Development of Geographic Atrophy After Intravitreal Ranibizumab Injections and Risk Factors
GA developed in 16 of 43 eyes (37.2%) during the 24-month follow-up period. GA had developed in 25.0% of eyes (4/16) during the first year and 75.0% of eyes (12/16) during the second year. Of the 16 eyes that developed GA, 5 (31.2%) developed GA at the site of RAP, 8 (50.0%) developed GA at the site of pigment epithelial detachment (PED), and 3 (18.8%) developed at other lesion sites. At the end of the 2-year follow-up, 11 of the patients with GA had extrafoveal GA (68.8%) and 5 patients (31.2%) had foveal GA. Figures 1 and 2 show images taken of the eyes of 2 representative patients who had developed GA after intravitreal ranibizumab injections.
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