Final 4-year results of the RAINBOW real-world study: intravitreal aflibercept dosing regimens in France in treatment-naïve patients with neovascular age-related macular degeneration.

PURPOSE: The purpose of this study is to evaluate real-world treatment outcomes in patients with neovascular age-related macular degeneration (nAMD) treated with intravitreal aflibercept (IVT-AFL) in routine clinical practice in France. METHODS: RAINBOW (NCT02279537) was an ambispective, observational, 4-year study assessing IVT-AFL effectiveness, treatment patterns, and safety in patients with nAMD in France. Treatment-naïve patients prescribed IVT-AFL and treated according to local practice (pro re nata or treat-and-extend) were eligible. Three treatment cohorts were retrospectively identified based on their treatment pattern within the first 12 months: regular (3 initial monthly IVT-AFL injections received within 45-90 days after the first injection in month 0 and followed by injections every 2 months), irregular with the initial monthly injections, and irregular without the initial monthly injections. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline to month 12. The 48-month results are described here. RESULTS: Overall, the study included 516 patients (each with one study eye), and 30.2% of patients completed 48 months of IVT-AFL treatment. Mean change in BCVA from baseline (56.5 letters) to month 48 for patients with an assessment at both time points was + 1.1 (regular cohort, n = 47), + 0.1 (irregular cohort with initial monthly injections, n = 115), and - 1.3 letters (irregular cohort without initial monthly injections, n = 26), representing a decrease from the gains achieved at month 12. Mean number of IVT-AFL injections received by month 48 in the treatment cohorts was 14.9, 13.7, and 11.9, respectively. The safety profile of IVT-AFL was consistent with previous studies. CONCLUSION: In RAINBOW, the 48-month results demonstrate a lack of long-term effectiveness of IVT-AFL treatment of nAMD due to progressive undertreatment in routine clinical practice in France. These real-world findings highlight the importance of 3 initial monthly IVT-AFL injections followed by continuous proactive treatment beyond the first year to achieve optimal functional outcomes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT02279537.

ASSESSMENT OF EARLY CHANGES IN SPECTRAL DOMAIN-OPTICAL COHERENCE TOMOGRAPHY AFTER INITIATION OF TREATMENT WITH INTRAVITREAL AFLIBERCEPT (EYLEA) OVER A 12-WEEK PERIOD FOR PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Multicenter French Study (START).

PURPOSE: To assess early changes in spectral-domain optical coherence tomography during the loading phase with intravitreal aflibercept therapy in patients with neovascular age-related macular degeneration. METHODS: In this prospective, open-label, single-arm, multicenter study, patients with neovascular age-related macular degeneration, who were antivascular endothelial growth factor treatment-naïve, received three monthly initial doses of intravitreal aflibercept 2 mg. The primary outcome was the proportion of patients with dry spectral-domain optical coherence tomography at 12 weeks, defined as an absence of intraretinal edema, intraretinal cysts, subretinal fluid, and subretinal pigment epithelium fluid. RESULTS: Fifty eyes of 50 patients were investigated. At 12 weeks, 34.0% (17/50) had dry spectral-domain optical coherence tomography. Marked reductions were observed for all other spectral-domain optical coherence tomography parameters. The mean macular central thickness fell significantly from 463.2 ± 184.3 µm at baseline to 288.9 ± 76.8 µm at Week 12 (P < 0.0001). The mean best-corrected visual acuity also improved significantly from 61.0 ± 16.0 letters at baseline to 66.6 ± 19.0 letters at Week 12 (P = 0.0006). CONCLUSION: The anatomic and functional outcomes improved over the 12-week study period. All outcome variables peaked after the third aflibercept injection, confirming the benefit of three initial doses.

Ranibizumab for vascularized pigment epithelial detachment: 1-year anatomic and functional results.

PURPOSE: To assess the anatomical and functional efficacy of ranibizumab on vascularized pigment epithelial detachment (V-PED) secondary to neovascular age-related macular degeneration (nAMD). METHODS: One hundred and nine patients (116 eyes) were retrospectively selected from medical records of 2097 patients who benefited from intravitreal injection between January 2011 and June 2013 in a tertiary-care University-based Department of Ophthalmology. Inclusion criteria were: nAMD, treatment-naive eyes, presence of V-PED higher than 250 µm, intravitreal ranibizumab with a loading phase, followed by a pro-re-nata regimen, and 1-year follow-up. Baseline characteristics and type of choroidal neovascularization (CNV) were analyzed. PED height, central macular thickness (CMT) and best-corrected visual acuity (BCVA, logMAR) were measured at baseline, months 3, 6 and 12. RESULTS: CNV was of type 1 in 91 eyes (78.4 %), type 2 in seven (6 %), type 3 in six (5.2 %), and polypoidal choroidal vasculopathy in 12 (10.3 %). Mean CMT at baseline was 572.1 µm and decreased to 396.6 µm (p < 0.0001) at 12 months. Mean height of PED was 458.2 µm at baseline and 306.8 µm (p < 0.0001) at 12 months. Mean BCVA improved from 0.46 at baseline to 0.39 at 12 months (p = 0.013). CONCLUSIONS: Treatment with ranibizumab improved visual and anatomical outcome in nAMD patients with V-PED.

Clinical Characteristics and Risk Factors of Extensive Macular Atrophy with Pseudodrusen: The EMAP Case-Control National Clinical Trial.

PURPOSE: To assess the association of clinical and biological factors with extensive macular atrophy with pseudodrusen (EMAP) characterized by bilateral macular atrophy occurring in patients aged 50 to 60 years and a rapid progression to legal blindness within 5 to 10 years. DESIGN: A national matched case-control study. PARTICIPANTS: Participants were recruited in 10 French Departments of Ophthalmology and their associated clinical investigation centers. All 115 patients with EMAP had symptoms before the age of 55 years due to bilateral extensive macular atrophy with a larger vertical axis and diffuse pseudodrusen. Three controls without age-related macular degeneration (AMD) or retinal disease at fundus examination were matched for each patient with EMAP by gender, age, and geographic area (in total 415). METHODS: Subjects and controls underwent an eye examination including color, red-free autofluorescent fundus photographs and spectral-domain optical coherence tomography with macular analysis. The interviews collected demographic, lifestyle, family and personal medical history, medications, and biological data. Associations of risk factors were estimated using conditional logistic regression. MAIN OUTCOME MEASURES: Extensive macular atrophy with pseudodrusen status (cases vs. controls). RESULTS: Extensive macular atrophy with pseudodrusen most frequently affected women (70 women, 45 men). After multivariate adjustment, family history of glaucoma or AMD was strongly associated with EMAP (odds ratio [OR], 2.3, P = 0.008 and OR, 1.5, P = 0.01, respectively). No association was found with cardiac diseases or their risk factors. Mild and moderate kidney disease and higher neutrophil rate were associated with a reduced risk of EMAP (OR, 0.58, P = 0.04; OR, 0.34, P = 0.01; and OR, 0.59, P = 0.003, respectively). On the contrary, eosinophilia (OR, 1.6; P = 0.0002), lymphocytosis (OR, 1.84; P = 0.0002), increased erythrocyte sedimentation rate (OR, 6.5; P = 0.0005), decreased CH50 (P = 0.001), and high plasma C3 level (P = 0.023) were significantly associated with a higher risk of EMAP. CONCLUSIONS: This study documents an association between EMAP and family history of AMD and glaucoma, a clear female predominance, and a systemic inflammatory profile. The reduced CH50 and increased C3 plasma values could reflect a more severe complement pathway dysfunction than in AMD, leading to early pseudodrusen and rapid development of geographic atrophy. There is no association of EMAP with AMD cardiac diseases or cardiac risks, including cigarette smoking.

Short-term results of switchback from aflibercept to ranibizumab in neovascular age-related macular degeneration in clinical practice.

PURPOSE: This work was undertaken to analyze the efficacy of switchback from aflibercept to ranibizumab in patients with neovascular age-related macular degeneration (nAMD) who had previously switched from ranibizumab to aflibercept. METHODS: This retrospective double-center study included 45 patients with nAMD who were previously treated with ranibizumab, then aflibercept, and then ranibizumab again, regardless of the number of intravitreal injections received. The primary outcome was change in best-corrected visual acuity (BCVA) measured on the Early Treatment Diabetic Retinopathy Study ETDRS chart before (T0) and after (T1) the switch, and 3 months after the switchback (T2). Secondary outcomes included changes in central foveal thickness (CFT) measured at T0, T1, and T2, as analyzed on spectral-domain optical coherence tomography (SD-OCT), and the percentage of patients gaining five letters or better. RESULTS: Forty-seven eyes of 45 patients were switched back from aflibercept to ranibizumab. The mean BCVA was 67.4 ± 13.4 at T0, 66.7 ± 14.4 at T1, and 68.2 ± 13.9 at T2. BCVA was significantly improved between T1 and T2 (p = 0.0230), but not between T0 and T1 (p = 0.5153) or between T0 and T2 (p = 0.4248). The mean CFT decreased from 317.8 µm ± 89.6 at T0 to 306.9 µm ±68.0 at T1, and to 291.2 µm ± 76.6 at T2. The decrease in CFT was not statistically significant between either T0 and T1 or T1 and T2, but was significant between T0 and T2, when compared before switch and after switchback (p = 0.0027). However, when considering eyes that received three or more consecutive intravitreal injections of aflibercept before switchback, the statistical significance between T1 and T2 was lost, although a trend towards significance remained (p = 0.06). Thirteen eyes (27.7 %) gained five letters or more (range, 5-15 letters) after switchback. CONCLUSIONS: A short-term benefit of switchback from one anti-VEGF agent to another was observed in patients with nAMD who had shown no benefit from the initial switch.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FEATURES OF SUBRETINAL FIBROSIS IN AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To report the imaging features of subretinal fibrosis secondary to exudative age-related macular degeneration (AMD) on optical coherence tomography angiography. METHODS: All consecutive patients diagnosed with subretinal fibrosis complicating exudative AMD were imaged by color retinal photographs or multicolor imaging, fluorescein angiography, spectral domain optical coherence tomography, and optical coherence tomography angiography. Eyes with active exudative features observed during the last 6 months were compared with those without any sign of exudation >6 months. RESULTS: Forty-nine eyes of 47 consecutive patients were included. A blood flow inside the fibrotic scar could be detected in 46 of 49 cases (93.8%). Three patterns of vascular networks could be distinguished, that were described as pruned vascular tree (26 of 49 eyes; 53.1%), tangled network (14 of 49; 28.6%), and/or vascular loop (25 of 49; 51.0%). Furthermore, 2 types of hyporeflective structures, large flow void, and/or dark halo were observed in 63% and in 65% of eyes, respectively. The observed patterns did not differ between eyes with active or inactive lesions. CONCLUSION: Optical coherence tomography angiography of subretinal fibrosis showed almost constantly a perfused, abnormal vascular network and collateral architectural changes in the outer retina and the choriocapillaris layer. These features were associated with both active and inactive fibrotic choroidal neovessels.

CHANGES IN VISUAL ACUITY IN PATIENTS WITH WET AGE-RELATED MACULAR DEGENERATION TREATED WITH INTRAVITREAL RANIBIZUMAB IN DAILY CLINICAL PRACTICE: The TWIN Study.

PURPOSE: The real-life LUMIERE study on patients with wet age-related macular degeneration treated with intravitreal ranibizumab in 2006 to 2009 showed that failure to follow recommendations was associated with lower efficacy than had been observed in the development phase. The TWIN Study reviewed the situation in 2010 to 2011. METHODS: Retrospective, descriptive purely observational study of data acquired after 12 months of treatment with intravitreal ranibizumab. RESULTS: In 881 patients (68% women, mean age, 79 years) treated by 21 ophthalmologists, the mean gain in visual acuity was +4.3 ± 15.4 letters (up from 3.2 ± 14.8 in 2006-2009; NS). Significant improvements were documented in the mean interval between diagnosis and treatment initiation (down from 12.6 ± 26.4-7.7 ± 10.9 days; P < 0.001), and in the percentage of patients who received a full course of induction treatment (56.6 vs. 39.6%; P < 0.001). After induction, hardly any patients were monitored every month as recommended, although retreatment was more assiduous (5.6 ± 2.3 vs. 5.1 ± 2.1 injections; P < 0.001). CONCLUSION: Despite improvements in key parameters, the effectiveness of intravitreal ranibizumab is still compromised by poor compliance with the guidelines, especially the frequency of postinduction monitoring that is now the most important determinant of successful treatment.

Gray hyper-reflective subretinal exudative lesions in exudative age-related macular degeneration.

PURPOSE: To investigate the effects of ranibizumab 0.5 mg on gray hyper-reflective subretinal lesions diagnosed by spectral-domain optical coherence tomography (SD OCT) in patients with exudative age-related macular degeneration (AMD). DESIGN: Retrospective interventional study. METHODS: Data from 28 consecutive patients affected with neovascular AMD that presented subretinal hyper-reflective lesions as visualized by SD OCT were collected. Gray hyper-reflective subretinal lesion characteristics were analyzed before and after intravitreal ranibizumab 0.5 mg injection. RESULTS: Thirty eyes of 28 patients (5 male, 23 female, aged 57-91 years) were included. At study entry, gray lesion was associated with exudative features in 24 of 30 eyes (80%), including subretinal fluid (SRF) in 20 of 30 eyes (67%) and retinal cystoid spaces in 11 of 30 eyes (37%). Twenty-four eyes with exudative features at study entry received prompt treatment; 6 eyes without exudative features at study entry received deferred treatment (after 1 month observation), when exudative signs emerged (SRF in 3/6 eyes and retinal cystoid spaces in 5/6 eyes). Ninety-three percent of the gray lesions responded to ranibizumab treatment at 2 months and 77% at 6 months. Gray hyper-reflective subretinal lesion thickness was significantly reduced after treatment at both 2 months (from 482±116 µm to 367±102 µm, P<.0001) and 6 months (from 482±116 µm to 369±71 µm, P<.0001). CONCLUSION: Our findings suggest that gray hyper-reflective subretinal lesions might be considered as a qualitative criterion for retreatment of exudative AMD. They may represent an early sign of active choroidal neovascularization, and should prompt to early treatment.

Imaging in retina units: changes observed during the last 12 years.

PURPOSE: The last decade has seen many improvements in the imaging of the choroids, retina, and vitreous. However, there are no available data about changes in the practice of imaging in retina units. The present study was therefore undertaken to document the 12-year changes in this practice in retina units in France, particularly the relative changes in the distribution of the different imaging methods. METHODS: This retrospective study was performed in 4 different retina units considered to be representative of retina units in France. They comprise 2 departments of ophthalmology in university-based hospitals in Paris and Nantes, one in a non-university-based general hospital in Orleans, and one private tertiary care clinical center located in Paris. The annual numbers for the different retinal imaging methods performed in the 4 units between 2000 and 2011 were recorded, analyzed, and compared. RESULTS: The total of images performed increased during the last decade, from 16,084 in 2000 to 76,318 in 2011. The distribution of the imaging techniques performed each year changed significantly during this period (p<0.0001, χ² test): the share of fluorescein angiography decreased from 78.7% in 2000 to 7.0% in 2011. During this period, the share of indocyanine green angiography also dropped from 11.3% to 1.3%. The share of optical coherence tomography increased from 26.4% in 2003 to 53.4% in 2012. CONCLUSIONS: The present study documents the increasing share of noninvasive imaging and the decreasing share of angiography in retina units over the last 12 years.

Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE study.

PURPOSE: To survey compliance with recommended intravitreal ranibizumab treatment protocols in daily clinical practice in France, with reference to outcomes. METHODS: A retrospective, descriptive, observational study in patients with subfoveal wet age-related macular degeneration treated with ranibizumab. All historical data for the study period, including demographic, treatment, and disease details and visual acuity measurements (baseline, Month 3, and Month 12), were recorded retrospectively at least 12 months after the beginning of treatment. RESULTS: In 551 patients followed by 16 ophthalmologists, 12 months of intravitreal ranibizumab treatment induced a mean visual acuity gain of 3.2 ± 14.8 Early Treatment Diabetic Retinopathy Study-equivalent letters. Fewer than 40% of patients received the recommended treatment of initial 3 monthly injections. More than 50% had to wait >8 days between diagnosis and treatment. At Month 3, visual acuity gain was greater in patients who had received recommended induction and in whom treatment was initiated quickly. At Month 12, the induction-related effect had largely disappeared but the time-to-treatment effect persisted. Patients had an average of 5.1 injections (2.6 during induction period). No patients were monitored monthly as stipulated in the guidelines. CONCLUSION: Although poor compliance with recommendations has been reflected in mediocre outcomes, there is evidence that practice is improving.

Causes of unsuccessful ranibizumab treatment in exudative age-related macular degeneration in clinical settings.

PURPOSE: To identify the causes of loss of vision after ranibizumab therapy in patients with exudative age-related macular degeneration treated in three clinical settings. METHODS: A retrospective multicentric analysis of 290 consecutive eyes comprising cohorts from 3 clinical settings showed that 21 eyes lost ≥ 15 letters on the Early Treatment Diabetic Retinopathy Study chart 1 year after the start of ranibizumab treatment. Fundus images of these eyes were analyzed by two independent readers to investigate the causes of visual loss. The three cohorts were compared. A search was made for factors predisposing to visual loss. A second analysis was performed to compare the baseline characteristics of patients who gained (visual acuity gainers) or lost (visual acuity losers) ≥ 15 letters. RESULTS: Among the 290 eyes included, the proportions from each center experiencing visual loss were not significantly different (mean, 7.24%, P = 0.2631). Mean visual loss of affected eyes was 27 letters. There was no significant difference between these eyes and others as regards age and gender of patients, laterality, type of choroidal neovascularization, number of visits, or initial visual acuity. Visual loss was secondary to the progression of atrophy in eight eyes, fibrosis in five eyes, a combination of fibrosis and atrophy in three eyes, severe subretinal hemorrhage in three eyes, and retinal pigment epithelial tear in two eyes. A significant difference between visual acuity gainers and losers was observed for 2 parameters: age of patients, 80.9 ± 5.3 years in visual acuity losers versus 77.5 ± 7.3 years in visual acuity gainers (P = 0.0473) and visual acuity at diagnosis, respectively, 56.2 ± 11.2 versus 49.0 ± 12.0 (P = 0.0288). CONCLUSION: Although uncommon, visual loss may occur during ranibizumab treatment and is because of the natural course of age-related macular degeneration in most cases.

Inject and extend dosing versus dosing as needed: a comparative retrospective study of ranibizumab in exudative age-related macular degeneration.

PURPOSE: The purpose of this study was to compare two strategies for retreatment with ranibizumab in exudative age-related macular degeneration. METHOD: Two series of consecutive patients treated with ranibizumab in a hospital-based department of ophthalmology were analyzed retrospectively: the first series (n = 52), after as-needed reinjections (PRN group) and the second (n = 38) after reinjections according to the Inject and Extend dosing method (IaE group). Patients' baseline characteristics, type of choroidal neovascularization, and Early Treatment Diabetic Retinopathy Study initial and final visual acuity (at 52 ± 4 weeks) were recorded in each group. Groups were compared by the Mann-Whitney U test or Fisher's exact test. RESULTS: Groups were well balanced at baseline for age (P = 0.58), sex (P = 0.66), laterality (P > 0.99), and initial visual acuity (P = 0.33). At 1 year, the mean gain in visual acuity was greater in the IaE group than in the PRN group (+10.8 ± 8.8 vs. +2.3 ± 17.4 letters, P = 0.036), but eyes in the IaE group were given significantly more injections (7.8 ± 1.3 vs. 5.2 ± 1.9 injections, P < 0.001). The number of follow-up visits attended was similar (8.5 ± 1.1 vs. 8.8 ± 1.5, P = 0.2085). CONCLUSION: Patients reinjected by the IaE dosing method had a far better visual outcome but after more injections.