Jean François Korobelnik

Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration.

OBJECTIVE Two similarly designed, phase-3 studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW 1, VIEW 2]) of neovascular age-related macular degeneration (AMD) compared monthly and every-2-month dosing of intravitreal aflibercept injection (VEGF Trap-Eye; Regeneron, Tarrytown, NY, and Bayer HealthCare, Berlin, Germany) with monthly ranibizumab. DESIGN Double-masked, multicenter, parallel-group, active-controlled, randomized trials. PARTICIPANTS Patients (n = 2419) with active, subfoveal, choroidal neovascularization (CNV) lesions (or juxtafoveal lesions with leakage affecting the fovea) secondary to AMD. INTERVENTION Patients were randomized to intravitreal aflibercept 0.5 mg monthly (0.5q4), 2 mg monthly (2q4), 2 mg every 2 months after 3 initial monthly doses (2q8), or ranibizumab 0.5 mg monthly (Rq4). MAIN OUTCOME MEASURES The primary end point was noninferiority (margin of 10%) of the aflibercept regimens to ranibizumab in the proportion of patients maintaining vision at week 52 (losing <15 letters on Early Treatment Diabetic Retinopathy Study [ETDRS] chart). Other key end points included change in best-corrected visual acuity (BCVA) and anatomic measures. RESULTS All aflibercept groups were noninferior and clinically equivalent to monthly ranibizumab for the primary end point (the 2q4, 0.5q4, and 2q8 regimens were 95.1%, 95.9%, and 95.1%, respectively, for VIEW 1, and 95.6%, 96.3%, and 95.6%, respectively, for VIEW 2, whereas monthly ranibizumab was 94.4% in both studies). In a prespecified integrated analysis of the 2 studies, all aflibercept regimens were within 0.5 letters of the reference ranibizumab for mean change in BCVA; all aflibercept regimens also produced similar improvements in anatomic measures. Ocular and systemic adverse events were similar across treatment groups. CONCLUSIONS Intravitreal aflibercept dosed monthly or every 2 months after 3 initial monthly doses produced similar efficacy and safety outcomes as monthly ranibizumab. These studies demonstrate that aflibercept is an effective treatment for AMD, with the every-2-month regimen offering the potential to reduce the risk from monthly intravitreal injections and the burden of monthly monitoring. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies

PURPOSE To compare efficacy and safety of 2 dosing regimens of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for diabetic macular edema (DME). DESIGN Two similarly designed, randomized, phase 3 trials, VISTA(DME) and VIVID(DME). PARTICIPANTS Patients (eyes; n=872) with type 1 or 2 diabetes mellitus who had DME with central involvement. METHODS Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser control. MAIN OUTCOME MEASURES The primary end point was mean change from baseline in best-corrected visual acuity (BCVA) at week 52. This report presents the 100-week results including mean change from baseline in BCVA, proportion of eyes that gained ≥15 letters, and proportion of eyes with a ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) score. RESULTS Mean BCVA gain from baseline to week 100 with IAI 2q4, IAI 2q8, and laser control was 11.5, 11.1, and 0.9 letters (P < 0.0001) in VISTA and 11.4, 9.4, and 0.7 letters (P < 0.0001) in VIVID, respectively. The proportion of eyes that gained ≥15 letters from baseline at week 100 was 38.3%, 33.1%, and 13.0% (P < 0.0001) in VISTA and 38.2%, 31.1%, and 12.1% (P ≤ 0.0001) in VIVID. The proportion of eyes that lost ≥15 letters at week 100 was 3.2%, 0.7%, and 9.7% (P ≤ 0.0220) in VISTA and 2.2%, 1.5%, and 12.9% (P ≤ 0.0008) in VIVID. Significantly more eyes in the IAI 2q4 and 2q8 groups versus those in the laser control group had a ≥2 step improvement in the DRSS score in both VISTA (37.0% and 37.1% vs. 15.6%; P < 0.0001) and VIVID (29.3% and 32.6% vs. 8.2%; P ≤ 0.0004). In an integrated safety analysis, the most frequent serious ocular adverse event was cataract (2.4%, 1.0%, and 0.3% for 2q4, 2q8, and control). CONCLUSIONS In both VISTA and VIVID, the 52-week visual and anatomic superiority of IAI over laser control was sustained through week 100, with similar efficacy in the 2q4 and 2q8 groups. Safety in these studies was consistent with the known safety profile of IAI.

Improvement in Vision-Related Function with Intravitreal Aflibercept: Data from Phase 3 Studies in Wet Age-Related Macular Degeneration

PURPOSE To evaluate the effect of intravitreal aflibercept injection on visual function in wet age-related macular degeneration (AMD). DESIGN Prospective, multicenter, double-masked, active-controlled, parallel-group, randomized phase 3 clinical studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW] 1 and 2 [clinicaltrials.gov identifiers, NCT00509795 and NCT00637377, respectively]). PARTICIPANTS Patients (n=2419) with active, treatment-naïve, exudative AMD. This analysis included patients who received intravitreal aflibercept 2.0 mg every 8 weeks (2q8; n=607) or ranibizumab 0.5 mg every 4 weeks (0.5q4; n=595). INTERVENTION Patients were randomized 1:1:1:1 to receive intravitreal aflibercept 2q8 (after 3 initial monthly doses), intravitreal aflibercept 2q4, intravitreal aflibercept 0.5q4, or ranibizumab 0.5q4 in the study eye. Patients in the intravitreal aflibercept 2q8 group received a sham injection alternating with active treatment. MAIN OUTCOME MEASURES The 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) was administered at baseline and at weeks 12, 24, 36, and 52. The NEI VFQ-25 subscale scores were compared between intravitreal aflibercept 2q8 and ranibizumab 0.5q4 treatment arms, the approved dosing for each agent worldwide. Change in composite NEI VFQ-25 score was evaluated based on categorical change in visual acuity (worsened, unchanged, improved). RESULTS Baseline NEI VFQ-25 scores were similar for both treatments in both studies. Mean change from baseline to 52 weeks was similar for ranibizumab 0.5q4 and intravitreal aflibercept 2q8 across all 12 subscales, with the greatest improvements noted for mental health and general vision (9.0-11.6 points, both treatments, both studies). Improvement of 4 points or more (both treatments, both studies) also was observed for subscales near vision, distance vision, role difficulties, and dependency. Mean change from baseline to 52 weeks in NEI VFQ-25 composite score (pooled data) stratified by clinical response showed meaningful improvement only in patients who gained 5 Early Treatment Diabetic Retinopathy letters or more (7.3 and 7.8 points for intravitreal aflibercept 2q8 and ranibizumab 0.5q4, respectively). CONCLUSIONS Visual function outcomes were similar across all NEI VFQ-25 subscales over 52 weeks for intravitreal aflibercept 2q8 and ranibizumab 0.5q4, with clinically meaningful improvement recorded in 6 of 12 subscales.

Intravitreal Aflibercept Injection in Eyes With Substantial Vision Loss After Laser Photocoagulation for Diabetic Macular Edema: Subanalysis of the VISTA and VIVID Randomized Clinical Trials

Importance Information on the effect of anti–vascular endothelial growth factor therapy in eyes with diabetic macular edema (DME) with vision loss after macular laser photocoagulation is clinically valuable. Objective To evaluate visual and anatomic outcomes in a subgroup of macular laser photocoagulation treatment control (hereafter laser control) eyes with substantial vision loss receiving treatment with intravitreal aflibercept injection. Design, Setting, and Participants This investigation was a post hoc analysis of a subgroup of laser control eyes in 2 phase 3 trials—VISTA (Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema) and VIVID (Intravitreal Aflibercept Injection in Vision Impairment Due to DME)—in a multicenter setting. One hundred nine laser control eyes with center-involving DME were included. Interventions Treatment with intravitreal aflibercept injection (2 mg) every 8 weeks after 5 monthly doses with sham injections on nontreatment visits starting at week 24 was initiated on meeting prespecified criteria of at least a 10-letter visual acuity loss at 2 consecutive visits or at least a 15-letter visual acuity loss from the best previous measurement at 1 visit and vision not better than at baseline. Main Outcomes and Measures Visual and anatomic outcomes in a subgroup of laser control eyes receiving treatment with intravitreal aflibercept injection. Results Through week 100, a total of 63 of 154 eyes (40.9%) in VISTA and 46 of 133 eyes (34.6%) in VIVID initially randomized to laser control received treatment with intravitreal aflibercept injection. The median time from week 24 to the first intravitreal aflibercept injection treatment was 34.0 (VISTA) and 83.5 (VIVID) days. In this subgroup, the mean (SD) visual gain from baseline to week 100 was 2.2 (12.5) (VISTA) and 3.8 (10.1) (VIVID) letters. At the time of intravitreal aflibercept injection initiation, these eyes had a mean (SD) loss of 11.0 (10.1) (VISTA) and 10.0 (6.5) (VIVID) letters from baseline, and they subsequently gained a mean (SD) of 17.4 (9.7) (VISTA) and 13.6 (8.6) (VIVID) letters from the initiation of treatment with intravitreal aflibercept injection through week 100. There was a minimal mean change in central subfield thickness from baseline in these eyes at the time of intravitreal aflibercept injection initiation (an increase of 3.9 &mgr;m in VISTA and a decrease of 3.0 &mgr;m in VIVID), after which further mean (SD) reductions of 285.6 (202.6) &mgr;m (VISTA) and 313.4 (181.9) &mgr;m (VIVID) occurred through week 100. Conclusions and Relevance Intravitreal aflibercept injection improves visual and anatomic outcomes in eyes experiencing substantial vision loss after macular laser photocoagulation treatment for DME. Trial Registration clinicaltrials.gov Identifiers: NCT01363440 and NCT01331681

Skin autofluorescence, renal insufficiency and retinopathy in patients with type 2 diabetes

OBJECTIVES Advanced glycation end-products (AGEs) are involved in diabetic retinopathy (DR). Their accumulation in tissues can be analyzed by measuring the skin autofluorescence (sAF). We hypothesized that renal insufficiency, another cause of high sAF, may disturb the relation between sAF and DR. RESEARCH DESIGN AND METHODS We measured sAF with an AGE-Reader in 444 patients with type 2 diabetes (T2D), and we analyzed their retinal status. The associations of sAF with DR, and interaction with renal insufficiency were estimated by multivariate logistic regression analysis. RESULTS Mean age was 62years (standard deviation (SD) 10years), diabetes duration 13 (9) years and mean HbA1C 8.9% (1.8). The prevalence of DR was 21.4% and increased with age, diabetes duration, arterial hypertension, renal parameters (serum creatinine and albumin excretion rates), and sAF. The prevalence of macular edema (ME) was 8.6% and increased with the duration of diabetes, but not with sAF (p=0.11). There was a significant interaction between renal insufficiency and sAF for the relation with DR or ME (p=0.02). For the 83% patients without renal insufficiency (estimated GFR>60mL/min/1.73m2), sAF was related to DR or ME after multivariate adjustment: OR 1.87 (1.09-3.19). The 17% patients with renal insufficiency had the highest rates of DR or ME (38.6%) and the highest sAF, unrelated to each other. CONCLUSIONS In T2D patients with renal insufficiency, the high sAF does not relate to retinopathy, which should be systematically searched due to its high frequency. For other patients, a high sAF argues for DR screening.

Optical coherence tomography in hydroxychloroquine retinopathy: two observational case reports.

PURPOSE To describe the optical coherence tomography (OCT) findings in two cases of hydroxychloroquine retinopathy. METHODS Two patients with hydroxychloroquine retinopathy at the bulls eye stage were identified. Each patient underwent rigorous historical questioning to rule out known causes of macular atrophy and to determine contributing factors. Comprehensive ocular examination was performed, including dilated biomicroscopic examination of the macula and indirect ophthalmoscopic evaluation of the retinal periphery. Additional evaluation included fundus color photography with fluorescein angiography and OCT. RESULTS Both patients had a medical history of arthritis treated by hydroxychloroquine (Nivaquine; total dose, 365 g). At the bulls eye stage, OCT confirms the presence of macular atrophy, as shown in our two cases. The retinal atrophy seems to be related to the whole thickness of the retinal layers. CONCLUSION We report the OCT findings of two cases of macular atrophy associated with hydroxychloroquine retinopathy.

Trends in operating room-based glaucoma procedures in France from 2005 to 2014: a nationwide study

Purpose To report the trends in operating room-based glaucoma procedures from 2005 to 2014 in France. Methods We identified operating room-based glaucoma procedures (trabeculectomies, deep sclerectomies, aqueous shunts and ciliary body destructions) performed in France from 2005 to 2014 by means of billing codes from a national database. The annual rates and incidence of these procedures per 100 000 inhabitants were analysed globally and in three age groups: 0–14 years, 15–59 years and over 60 years. Results The annual rate of trabeculectomies decreased slightly during the study period, while the rate for other surgical techniques (deep sclerectomies, aqueous drainage procedures and ciliary body destructions) increased. The overall rate of glaucoma surgeries was higher in areas with populations of African descent than in areas predominantly composed of Caucasian populations: 1.60 (95% CI 1.51 to 1.70, p<0.0001). Conclusions Trabeculectomy was the most commonly performed operating room-based glaucoma procedure in France from 2005 to 2014. Other modalities such as deep sclerectomies, aqueous drainage procedures and ciliary body destruction gained greater acceptance among French ophthalmologists during this 10-year period.

Association of Acute Endophthalmitis With Intravitreal Injections of Corticosteroids or Anti–Vascular Growth Factor Agents in a Nationwide Study in France

Importance The number of patients affected by retinal diseases treated with intravitreal injections (IVTs) has resulted in a rapidly growing number of procedures. One of the worst complications after these injections is endophthalmitis. Objective To evaluate the incidence of acute endophthalmitis after IVTs of corticosteroids or anti–vascular endothelial growth factor (anti-VEGF) agents. Design, Setting, and Participants This population-based cohort study included patients undergoing IVTs from January 1, 2012, through December 31, 2015, in France. Data were acquired from the French medical-administrative database (Système National d’Information Inter-Régime de l’Assurance Maladie), which collects hospitalization discharge abstracts and out-of-hospital care information for the whole country. Data were analyzed from March through July 2017. Exposures Intravitreal injections of corticosteroid or anti-VEGF agents. Main Outcomes and Measures Incidence of acute endophthalmitis within 6 weeks after IVT by means of billing codes from a national database. Results During the study period, 1 811 977 IVTs of corticosteroids or anti-VEGF agents performed on 254 927 patients (60.4% female; median age, 79 years [interquartile range, 70-85 years]) were analyzed. A total of 444 acute endophthalmitis cases (crude incidence, 0.0245%) were recorded. In multivariable analysis, which did not include adjustment for when the endophthalmitis occurred during the study period, the risk of endophthalmitis was lower in male patients (incidence rate ratio [IRR], 0.78; 95% CI, 0.63-0.96; P = .02), higher for corticosteroids than for anti-VEGF agents (IRR, 3.21; 95% CI, 2.33-4.44; P < .001), and higher for nonprefilled syringes of anti-VEGF medications than prefilled syringes for ranibizumab (IRR, 1.63; 95% CI, 1.15-2.30) and aflibercept (IRR, 1.82; 95% CI, 1.25-2.66; P < .001). Conclusions and Relevance The findings from this study of a nationwide database appear to have confirmed the low incidence rate of acute endophthalmitis after IVTs of corticosteroids or anti-VEGF agents. Although an association may not necessarily indicate a cause and effect, the risk for acute endophthalmitis after IVTs appeared to be higher for corticosteroids compared with anti-VEGF agents, while a lower risk of endophthalmitis appeared to be found with prefilled syringes of anti-VEGF medications.

Baseline Characteristics of the Fellow Eye in Patients with Neovascular Age-Related Macular Degeneration: Post Hoc Analysis of the VIEW Studies.

Purpose: The aim was to describe baseline characteristics of the fellow eye of patients with neovascular age-related macular degeneration (nAMD). Methods: A pooled, post hoc analysis of patients with nAMD enrolled in the VIEW studies was carried out. The VIEW studies compared intravitreal aflibercept (monthly or every 2 months after 3 monthly injections) with monthly ranibizumab. Baseline choroidal neovascularization (CNV) status of fellow eyes and baseline best-corrected visual acuity (BCVA) and lens status of all eyes were evaluated. Additional analyses evaluated the presence of drusen and pigment in fellow eyes. Results: When comparing both eyes, baseline BCVA was worse in 23.8% of fellow eyes and in 75.2% of study eyes. Lens status of fellow eyes and study eyes was similar. Baseline visual acuity of the study eye and that of the fellow eye were not correlated. Most fellow eyes had signs of early AMD, with 34.6% (n = 843) of fellow eyes having evidence of scarring. Conclusions: In patients in the VIEW studies, most fellow eyes had evidence of AMD, highlighting the importance of examining both eyes, with close follow-up thereafter, in order to detect and treat CNV earlier as needed.

Dexamethasone intravitreal implants for retinal vein occlusion in a clinical setting

Editor, S tandard treatments of macular oedema (ME) due to retinal vein occlusion (RVO) include macular laser photocoagulation (The Branch Vein Occlusion Study Group 1986), intravitreal injections of antivascular endothelial growth factor agents (Brown et al. 2010; Boyer et al. 2012) and intravitreal corticosteroid injection. Recently, a sustained-release biodegradable dexamethasone intravitreal implant (DEX implant; Ozurdex ; Allergan, Inc., Irvine, Calif.) has been shown to reduce ME and improve visual acuity (VA) in patients with RVO (Haller et al. 2010, 2011). The aim of our study was to report the results and safety of DEX implant in clinical settings. The charts of 55 consecutive patients were reviewed. As a general rule, DEX implant was not used for patients requiring more than one medication to control their intraocular pressure (IOP), having undergone filtering surgery or with a history of steroidinduced IOP. During the treatment period, patients attended consultations every 2 months. At each visit, a complete eye examination was performed with best corrected visual acuity (BCVA) measurement using the ETDRS chart and OCT assessment of central macular thickness (CMT) (SDOCT, Spectralis , HRA Heidelberg, Heidelberg, Germany and Cirrus OCT, Carl Zeiss, Dublin, CA, USA). Reinjections were done from the 4th month of follow-up, when the retinal thickness was greater than 250 lm and a 2-line BCVA loss was observed. Changes in BCVA and CMT from baseline were analysed using a paired student’s t-test with significance level at ≤0.05. The main safety parameter measured was the IOP changes. Increased IOP was defined when intraocular pressure (IOP) rose above 24 mmHg or IOP increased by 10 mmHg. Patients’ mean age was 66 12 years. Proportions of central andbranch RVO among studied eyes were 54%and 46%, respectively. The mean BCVA (LogMar) was 0.69 35 at baseline, increased significantly to 0.54 0.42 at 2 months (p < 0.001) and then decreased to 0.57 0.42 at 6 months and 0.64 0.53 at 12 months. A 15-letter gain in BCVA from baseline was achieved by 32% and 22% of eyes at 2 and 12 months, respectively. At 2 months, the mean CMT significantly decreased from 589 178 lm at baseline to 300 103 lm (range: 184–787) (p < 0.001), with a mean reduction of 289 75 lm. At 6 and 12 months, the mean CMT was of 386 192 lm (range: 181–962) (p < 0.001) and 293 111 lm (range: 216–575) (p < 0.001), respectively. Reinjections were needed in 43%, 58% and 56% of patients at 4, 6 and 12 months, respectively. After 4, 6 and 12 months of follow-up, 58%, 42% and 11% of patients had only one injection, respectively. We observed a mean interval of 5 months between the first and second injection and 5 months between the second and third injection. Two months after DEX implant injection, the IOPwas elevated in 28%of patients. These patients were successfully managed with topical IOP-lowering medication. None required laser or surgical intervention. These IOP results were similar to those of the GENEVA study, where IOP-lowering medication was needed in 26% of cases (Haller et al. 2011). Our results were also in accordance with the GENEVA study in terms of efficacy on VA and ME (Haller et al. 2010, 2011), but differed in terms of duration of DEX implant efficacy and frequency of reinjections. Indeed, differently from the Geneva study where no control visit was done between the