Twelve-Month Outcomes Using Aflibercept 8 mg in Treatment-Naïve and Pretreated Diabetic Macular Edema: A Swiss Retina Research Network Report.

AimsEvaluate the efficacy and safety of faricimab for treatment-naïve and pre-treated diabetic macular oedema (DME) in a real-world setting.MethodsThis multicentre, retrospective cohort study examined consecutive DME patients treated with faricimab for ≥1 year. Data were collected at predefined time points. Primary outcomes were mean changes in corrected visual acuity (VA), centre-point retinal thickness (CRT) and central subfield thickness (CST) and treatment intervals and adverse events (AEs).Results184 eyes with DME were included: 61 (33.2%) were treatment-naïve, and 123 (66.8%) were pretreated. In treatment-naïve eyes, VA improved from 69.7±15 Early Treatment of Diabetic Retinopathy Study letters at baseline to 73.9±14.1 after 12 months (p=0.014), while it remained stable in pretreated eyes (71.2±14.2 vs 73.0±12.9; p=0.14). CST decreased significantly in both groups (treatment-naïve (366.1±108.3 µm to 316.4±113.5 µm, p<0.001); pretreated (339.1±93.1 µm to 298.3±65.8 µm, p<0.001)). Thirty-one percent of naïve eyes and 21.1% of pretreated eyes were completely dry after 12 months. In treatment-naïve eyes, the mean treatment interval was 12.7±6.4 weeks at 12 months. In pretreated eyes, the interval increased from 6.0±3.0 to 7.8±3.6 weeks (p<0.001). Over 12 months, 8.1±2.1 and 9.4±2.5 injections were administered to naïve and pretreated eyes, respectively (p<0.001). Of the five recorded AEs, two cases of non-infectious intraocular inflammation and one cerebrovascular event were reported.ConclusionOver 12 months, faricimab demonstrated good efficacy and safety in both treatment-naïve and pretreated eyes with DME. There was a reduction in CST and improved VA in treatment-naïve eyes and stable VA in pretreated eyes. The low number of AEs supports a favourable risk-benefit profile of faricimab in a real-world setting.

This multicenter, longitudinal, observational real-world study evaluated the efficacy and safety of switching to intravitreal aflibercept 8mg (Afl 8) in pretreated eyes with neovascular age-related macular degeneration (nAMD) within the Swiss Retina Research Network. A total of 283 eyes from 245 patients previously treated with other anti-vascular endothelial growth factor (anti-VEGF) agents (aflibercept 2mg, faricimab, and ranibizumab) were included, with 1-year efficacy outcomes analyzed in 246 eyes and safety assessed in all treated eyes. We recorded demographics, baseline functional and anatomical parameters-including spectacle-corrected visual acuity (VA) and optical coherence tomography (OCT) data-treatment history and outcomes over 12months after switching to Afl 8. The main outcome measures were change in VA, central subfield thickness (CST), presence of intra- and subretinal fluid (IRF/SRF) and pigment epithelial detachment (PED), treatment intervals, and adverse events. Twelve months after the switch to Afl 8, mean VA remained stable, while mean CST decreased from 329.1 to 302.8µm (p < 0.001). The portion of eyes without retinal fluid increased from 29.9% at baseline to 47.5% after 12months. In parallel, the mean treatment interval was extended by 32.3% from 7.1 to 9.4weeks (p < 0.001). At 1 year, 35.4% of eyes reached intervals of 8-11weeks, while 20.2% achieved intervals of 12weeks or longer. Intraocular inflammation was reported in 11 cases (3.9%). In pretreated nAMD eyes with high treatment demand, switching to Afl 8 resulted in a significant anatomical improvement and longer treatment intervals in a majority of patients. These real-world results highlight the therapeutic potential of Afl 8, with no new or unexpected safety issues.

Intravitreal triamcinolone acetonide (IVTA) has increasingly been applied as treatment for various intraocular neovascular and oedematous diseases. Comparing the various diseases with respect to effect and side-effects of the treatment, the best response in terms of gain in visual acuity (VA) has been achieved for intraretinal oedematous diseases such as diffuse diabetic macular oedema, branch retinal vein occlusion, central retinal vein occlusion and pseudophakic cystoid macular oedema. In eyes with various types of non-infectious uveitis, including acute or chronic sympathetic ophthalmia and Adamantiadis-Behcet's disease, VA increased and the degree of intraocular inflammation decreased. Some studies have suggested that intravitreal triamcinolone may be useful as angiostatic therapy in eyes with iris neovascularization and proliferative ischaemic retinopathies. Intravitreal triamcinolone may possibly be helpful as adjunct therapy for exudative age-related macular degeneration (AMD), particularly in combination with photodynamic therapy. In eyes with chronic, therapy-resistant ocular hypotony, intravitreal triamcinolone can induce an increase in intraocular pressure (IOP) and may stabilize the eye. The complications of intravitreal triamcinolone therapy include: secondary ocular hypertension in about 40% of the eyes injected; medically uncontrollable high IOP leading to antiglaucomatous surgery in about 1-2% of the eyes; posterior subcapsular cataract and nuclear cataract leading to cataract surgery in about 15-20% of elderly patients within 1 year of injection; postoperative infectious endophthalmitis occurring at a rate of about one per 1000; non-infectious endophthalmitis, perhaps due to a reaction to the solvent agent, and pseudo-endophthalmitis with triamcinolone acetonide crystals appearing in the anterior chamber. Intravitreal triamcinolone injection can be combined with other intraocular surgeries, including cataract surgery, particularly in eyes with iris neovascularization. Cataract surgery performed some months after the injection does not show a markedly elevated complication rate. The injection may be repeated if the resultant benefits decrease after the initial IVTA injection. In non-vitrectomized eyes, the duration of the effect and side-effects of a single intravitreal injection of triamcinolone is about 6-9 months for a dosage of about 20 mg, and about 2-4 months for a dosage of 4 mg. So far, it has remained unclear whether the solvent agent should be removed, and if so, how.

To assess the efficacy, duration of effect and safety of one intravitreal injection of bevacizumab in diabetic macular oedema (DMO). Bevacizumab (1 mg/0.04 ml) was injected intravitreally into eyes with DMO (29 with and nine without previous treatments). Best corrected visual acuity (BCVA), intraocular pressure and central retinal thickness (CRT) were measured; slit-lamp examination, macular biomicroscopy, optical coherence tomography and fluorescein angiography were performed before and at 2-4, 8 and 12 weeks post-injection. Best corrected VA and CRT were analysed in both groups. In the non-pretreated group, mean BCVA improved from 0.76 +/- 0.33 (baseline) to 0.57 +/- 0.30 and 0.54 +/- 0.27 at 2-4 weeks and 8 weeks post-injection, respectively (p = 0.02, p = 0.014, paired t-test). Mean CRT decreased from 632.4 +/- 196.0 microm (baseline) to 392.3 +/- 113.6 microm and 370.4 +/- 141.7 microm at the same time-points, respectively (p = 0.01, p = 0.01). There was no difference in BCVA or CRT at 12 weeks. In the pretreated group, mean BCVA improved from 0.62 +/- 0.30 (baseline) to 0.53 +/- 0.33 at 2-4 weeks post-injection (p = 0.01), and mean CRT decreased from 583.9 +/- 180.7 microm (baseline) to 404.1 +/- 197.9 microm at 2-4 weeks post-injection (p < 0.001). Mean BCVA was unchanged at 8 weeks and 12 weeks post-injection, although mean CRT remained lower at 8 weeks (p = 0.004). No ocular or systemic side-effects developed during follow-up. One intravitreal injection of bevacizumab for DMO seems to be effective and safe in both eyes that have been treated previously and eyes that have not. The therapeutic effect is temporary and repeat treatment may be needed.

Central Retinal Vein Occlusion 36-Month Outcomes with Anti-VEGF: The Fight Retinal Blindness! Registry

The determination of optical coherence tomography (OCT) central subfield thickness (CST) is an objective measure, and visual acuity (VA) is a subjective measure. Therefore, using OCT CST changes as a surrogate for VA changes in diabetic macular edema seems reasonable. However, studies suggest that change in OCT CST following anti-vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema is correlated with changes in VA but varies substantially among individuals, and so may not be a good surrogate for changes in VA. To determine associations between changes in VA and changes in OCT CST across 3 anti-VEGF agents (aflibercept, bevacizumab, or ranibizumab) used in a randomized clinical trial for diabetic macular edema. Post hoc analyses were conducted of DRCR Retina Network Protocol T among 652 of 660 participants (98.8%) meeting inclusion criteria for this investigation. The study was conducted between August 22, 2012, and September 23, 2015. The post hoc data collection and analysis were performed from May 29 to July 11, 2018. Six monthly intravitreous anti-VEGF injections (unless success was achieved after 3-5 months) were administered; subsequent injections or focal/grid laser photocoagulation treatments were given as needed per protocol to achieve stability. Association between changes in VA letter score with changes in CST at 12, 52, and 104 weeks after randomization to aflibercept, bevacizumab, or ranibizumab. Of the 652 participants, 304 were women (46.6%); median age was 61 years (interquartile range, 54-67 years). The correlation between CST and VA at the follow-up visits was 0.24 (95% CI, 0.16-0.31) in 616 patients at 12 weeks, 0.31 (95% CI, 0.24-0.38) in 609 patients at 52 weeks, and 0.23 (95% CI, 0.15-0.31) in 566 patients at 104 weeks. The correlation coefficients of change in VA vs change in OCT CST for these time intervals were 0.36 (95% CI, 0.29-0.43) at 12 weeks, 0.36 (95% CI, 0.29-0.43) at 52 weeks, and 0.33 (95% CI, 0.26-0.41) at 104 weeks. Changes in CST appear to account for only a small proportion of the total variation in changes in VA. These findings do not support using changes in OCT CST as a surrogate for changes in VA in phase 3 clinical trials evaluating anti-VEGF for diabetic macular edema or as a guide to inform the physician or patient about changes in VA after anti-VEGF treatment. ClinicalTrials.gov identifier: NCT01627249.

To compare functional and anatomical outcomes of continued anti-vascular endothelial growth factor (VEGF) therapy versus dexamethasone (DEX) implant in eyes with refractory diabetic macular edema (DME) after three initial anti-VEGF injections in a real-world setting. To be included in this retrospective multicenter, case-control study, eyes were required: (1) to present with early refractory DME, as defined by visual acuity (VA) gain ≤ 5 letters or reduction in central subfield thickness (CST) ≤ 20%, after a loading phase of anti-VEGF therapy (three monthly injections) and (2) to treat further with (a) anti-VEGF therapy or (b) DEX implant. Main outcome measures were change in visual acuity (VA) and central subfield thickness (CST) at 12months. Due to imbalanced baseline characteristics, a matched anti-VEGF group was formed by only keeping eyes with similar baseline characteristics as those in the DEX group. A total of 110 eyes from 105 patients were included (anti-VEGF group: 72 eyes, DEX group: 38 eyes). Mean change in VA at 12months was - 0.4 ± 10.8 letters (anti-VEGF group), and + 6.1 ± 10.6 letters (DEX group) (P = 0.004). Over the same period, mean change in CST was + 18.3 ± 145.9µm (anti-VEGF group) and - 92.8 ± 173.6µm (DEX group) (P < 0.001). Eyes in the DEX group were more likely to gain ≥ 10 letters (OR 3.71, 95% CI 1.19-11.61, P = 0.024) at month 12. In a real-world setting, eyes with DME considered refractory to anti-VEGF therapy after three monthly injections which were switched to DEX implant and had better visual and anatomical outcomes at 12months than those that continued treatment with anti-VEGF therapy.

New clinical trials for diabetic macular oedema (DMO) are being designed to prove superiority over aflibercept when this agent is already very effective in improving visual acuity (VA) and DMO. The aim of this study was to determine the optimal inclusion–exclusion criteria for trials to aim for superiority in visual outcomes with newer agents. As Phase 1 studies are short duration, we aimed to evaluate the early response of aflibercept in a real-world cohort initiated on monthly aflibercept for 3 consecutive injections and observed the effects at 4 months. The sub-optimal responders were pre-defined based on different cut-offs for VA and central sub-field thickness (CST). 200 patients with treatment naïve DMO treated with 3 loading doses of aflibercept were included in the study. We found that those presenting with baseline VA of 35–54 ETDRS letters (n = 43) had higher proportion of sub-optimal responders compared to other categories (p < 0.001). Patients with baseline CST of less than 400 µm (n = 96) responded less well functionally and anatomically to loading dose than eyes with baseline CST of 400 µm or more (n = 104, p = 0.02), indicating that eyes with CST ≥ 400 µm is another inclusion criteria. There was minimal correlation between change in CST and change in VA at 4 months (r = − 0.27), suggesting that both these inclusion criteria are non-exclusive. However, for maximal efficacy, patients that meet both these inclusion criteria are more likely to show benefit from an alternative intervention. New trials should aim to include patients with treatment naïve DMO with VA between 35–54 letters and CST of 400 µm or more when aflibercept is used as the comparator.

To determine whether a dexamethasone intravitreal implant 0.7 mg (dexamethasone delivery system [DDS], Ozurdex) combined with bevacizumab 1.25 mg (Avastin) provides greater benefit than bevacizumab monotherapy in eyes with diabetic macular edema with incomplete response to multiple antivascular endothelial growth factor injections. Eyes with diabetic macular edema were randomly assigned to receive combination therapy (bevacizumab plus DDS) or bevacizumab monotherapy. Combination therapy eyes received intravitreal bevacizumab at baseline, DDS at Month 1, and subsequent DDS (at Months 5 and 9), whereas monotherapy eyes received bevacizumab (monthly) if indicated. Eyes were eligible for retreatment if the central subfield thickness measured >250 μm, and Early Treatment of Diabetic Retinopathy Study visual acuity was <80 letters (20/25). Forty eyes of 30 patients were enrolled. The mean visual acuity changes from baseline to 12 months were similar in the 2 groups (combined: +5.4 letters; bevacizumab: +4.9 letters; difference = 0.2 letters, 95% confidence interval = -5.9 to 6.3; P = 0.75). The mean reduction in central subfield thickness was greater in the combination group (-45 μm vs. -30 μm, difference = 69 μm, 95% confidence interval = 9-129; P = 0.03) and more patients in the combination group had central subfield thickness <250 μm. The combined treatment group received three fewer supplemental injections of bevacizumab, but this was counterbalanced by the need for an average of 2.1 DDS injections. The dexamethasone implant combined with bevacizumab significantly improves visual acuity and significantly improves macular morphology in eyes with refractory diabetic macular edema, although visual acuity changes are not superior to continued bevacizumab monotherapy.

To evaluate real-world, short-term anatomical and functional outcomes of faricimab versus aflibercept 2 mg in diabetic macular oedema (DMO). This retrospective, parallel-cohort comparative study included 300 consecutive patients with DMO from Moorfields Eye Hospital. Eligible eyes were treatment-naïve and treatment-experienced not receiving therapy for ≥6 months and subsequently initiated on loading phase of faricimab or aflibercept 2mg. Follow-up was 4 months. Data were collected from the Moorfields electronic medical records system. Changes in visual acuity (VA) and central subfield thickness (CST) from baseline to the fourth injection were analysed using multiple linear regression adjusted for baseline covariates (age, gender, ethnicity, diabetes type, baseline retinopathy status, baseline VA or CST and treatment interval). Of 300 eyes enrolled, 292 were ultimately analysed (191 aflibercept; 101 faricimab), with 246 eyes (84.2%) completing follow-up. Mean unadjusted VA gain was +3.9±10.4 letters with aflibercept and +5.2±11.8 letters with faricimab. Adjusted marginal mean VA gain was +4.2 letters for aflibercept and +4.7 letters for faricimab, with a non-significant difference of -0.5 letters (p=0.7). Baseline VA and treatment interval were significant predictors of functional response, with baseline VA exerting approximately 3.4 times the impact of treatment interval. Mean CST reduction was 87.3±106.1 µm with aflibercept and 113.1±136.7 µm with faricimab. Adjusted mean reductions were 95.4 µm and 99.8 µm, respectively (difference -4.4 µm, p=0.7). Baseline CST was the only independent predictor of anatomical response. Faricimab and aflibercept achieved comparable short-term anatomical and functional outcomes, with greater anatomical improvement associated with higher baseline CST and larger visual gains observed with lower baseline VA. Treatment interval influenced functional response, underscoring the importance of timely therapy. Baseline disease features and treatment adherence are key determinants of early outcomes, rather than drug selection.

BackgroundIn eyes with diabetic macular edema, the relative efficacy of administering aflibercept monotherapy as compared with bevacizumab first with a switch to aflibercept if the eye condition does not improve sufficiently (a form of step therapy) is unclear.MethodsAt 54 clinical sites, we randomly assigned eyes in adults who had diabetic macular edema involving the macular center and a visual-acuity letter score of 24 to 69 (on a scale from 0 to 100, with higher scores indicating better visual acuity; Snellen equivalent, 20/320 to 20/50) to receive either 2.0 mg of intravitreous aflibercept or 1.25 mg of intravitreous bevacizumab. The drug was administered at randomization and thereafter according to the prespecified retreatment protocol. Beginning at 12 weeks, eyes in the bevacizumab-first group were switched to aflibercept therapy if protocol-specified criteria were met. The primary outcome was the mean change in visual acuity over the 2-year trial period. Retinal central subfield thickness and visual acuity at 2 years and safety were also assessed.ResultsA total of 312 eyes (in 270 adults) underwent randomization; 158 eyes were assigned to receive aflibercept monotherapy and 154 to receive bevacizumab first. Over the 2-year period, 70% of the eyes in the bevacizumab-first group were switched to aflibercept therapy. The mean improvement in visual acuity was 15.0 letters in the aflibercept-monotherapy group and 14.0 letters in the bevacizumab-first group (adjusted difference, 0.8 letters; 95% confidence interval, −0.9 to 2.5; P=0.37). At 2 years, the mean changes in visual acuity and retinal central subfield thickness were similar in the two groups. Serious adverse events (in 52% of the patients in the aflibercept-monotherapy group and in 36% of those in the bevacizumab-first group) and hospitalizations for adverse events (in 48% and 32%, respectively) were more common in the aflibercept-monotherapy group.ConclusionsIn this trial of treatment of moderate vision loss due to diabetic macular edema involving the center of the macula, we found no evidence of a significant difference in visual outcomes over a 2-year period between aflibercept monotherapy and treatment with bevacizumab first with a switch to aflibercept in the case of suboptimal response. (Funded by the National Institutes of Health; Protocol AC ClinicalTrials.gov number, NCT03321513.)

Evaluating the treatment outcomes of diabetic macular oedema (DMO) in routine clinical practice provides data for comparison with those of clinical trials. Phase 3 clinical trials of vascular endothelial growth factor (VEGF) inhibitors for DMO have reported significant improvements in visual acuity (VA) not previously reported with laser and steroid treatments. Retrospective analysis of observational data from routine clinical practice. Eyes receiving treatments for DMO tracked in the Fight Retinal Blindness! Registry. We analysed 510 eyes (347 patients) that started DMO treatment between 2009 and 2014. Changes in DMO treatment patterns and mean change in VA (letters logMAR) and central subfield thickness (CST) 5 years after starting treatment. Treatment choice for DMO changed to predominantly VEGF inhibitors from 2009 to 2014. A total of 238 eyes (47%) were followed for at least 5 years. The mean VA at the start of treatment improved from 2009 (58 letters) to 2014 (68 letters) while mean VA change at 5 years were + 4.5 and + 5.3 letters for eyes starting treatment in 2009 and 2014, respectively. The mean CST dropped from 401 μm at baseline to 314 μm at 5 years. Eyes received a median of four injections in the first, two in the second, third and fourth and three in the fifth years. Changing the treatment of DMO from macular laser and intravitreal triamcinolone to VEGF inhibitors from 2011 onwards was associated with better VA outcomes, part of which were due to better VA at the start of treatment. The outcomes of treatment in eyes in real-world practice were, however, worse than those reported by clinical trials, likely because they were undertreated.

Background: The prevalence of polypoidal choroidal vasculopathy (PCV) is significantly higher amongst Asian populations compared to Caucasian, and evidence regarding the clinical outcomes of Caucasian patients is limited. Objective: This retrospective study sought to investigate real-world clinical outcomes of Caucasian PCV patients treated with polypoidal verteporfin photodynamic therapy (PDT) in combination with anti-VEGF therapy up to 36 months post-treatment. Methods: Consecutive PCV patients who received PDT between 2011 and 2017 were included. Mean change in visual acuity (VA) measured by ETDRS letter score and mean change in central subfield thickness (CST) were the main outcome measures. Data were collected at baseline, 3, 12, 24 and 36 months. Regression analyses were carried out on pre-treatment clinical features to determine if there were any factors associated with a good visual outcome (better than or equal to 70 ETDRS letters at 12 months). Results: Seventy six patients (96% Caucasian) and seventy eight eyes were included in the analysis. Mean change in VA was -1, -4, and 0 ETDRS letters at 12, 24, and 36 months, respectively. CST was reduced by a mean of -51, -54, and -55 microns at 12, 24, and 36 months, respectively. Better pre-treatment VA was the only pre-treatment clinical feature associated with a good visual outcome at 12 months (OR 1.16, p&lt;0.001). Conclusion: PDT, in combination with anti-VEGF therapy, maintains VA and may reduce the anti-VEGF therapy burden in Caucasian patients with PCV. Better pre-treatment VA is associated with a good visual outcome.

Factors predictive for response of diabetic macular edema (DME) to intravitreal bevacizumab (IVB) remain unclear. In this study, we assess the predictability of DME response to IVB based on the response to IVB in a previously treated fellow eye and other known pre-injection factors in (DME). Retrospective chart review was conducted on 28 patients (56 eyes) with bilateral DME who underwent bilateral IVB therapy. Responses in both eyes were measured by change in central subfield thickness (CSFT) via optic coherence tomography (OCT), and change in visual acuity. Age, lens status, and starting macular thickness were recorded. We found 21% of the reduction in CSFT after IVB on OCT in the study eye may be explained by the percentage change in CSFT in the previously treated fellow eye [CI: 0.092-0.716; p-value = 0.0141]. Also, the pre-injection CSFT predicts 14% of the response to IVB in the same eye [R² = 9.6%, p-value = 0.018]. When combined in a multi-factorial model, 33% of the change in CSFT following IVB may be explained by these two factors. Lens status, change in visual acuity, and age were not statistically significant predictors of response. In DME, the response to IVB in an eye is partially explained by the pre-injection retinal thickness in the same eye and by the response to IVB in the previously treated fellow eye. Lens status, change in visual acuity, and age were not statistically significant predictors of response in this study.

BackgroundDiabetic retinopathy (DR) is a leading cause of vision impairment in working-age adults. Patients with DR need extensive follow-ups with timely proper treatment. In Jordan, a complete lockdown was decided during the COVID-19 pandemic including the closure of outpatients’ clinic. In this study, we assess the effect of the lockdown on the progression and visual outcome for patients with DR who had interruption in their plan.MethodsRetrospectively, we identified all patients who were scheduled for procedures for the management of diabetic retinopathy (DR) during the COVID-19-related quarantine period in Jordan from March 16th to June 6th, 2020. All demographics and clinical data, procedure information, and visual outcome were collected. Another control group of patients with similar characteristics who were scheduled for procedures related to DR before the COVID-19 pandemic from October 15th to December 31st, 2019 were included.ResultsOne hundred and thirty-seven eyes planned for procedures from 89 patients were included. The case group comprises 56 eyes (40.9%). The mean age of the patients was 61.4 years. The right eye was involved in 69 procedures (50.4%). The mean change in visual acuity for the case group in the procedure eye was 0.176 in LogMAR (drop of almost 9 LogMAR letters) and the mean change in visual acuity for the control group in the procedure eye was −0.103 LogMAR (gain of about 5 LogMAR letters). Also, the central subfield thickness (CST) values were significantly worse in the case group. Furthermore, patients in the case group had significantly more disease progression (new findings and worsening of the already established findings).ConclusionInterrupting the important procedures for DR patients and delaying their follow-up may adversely affect their visual outcome. National decisions should consider conducting these procedures and exempt those patients from any lockdown with proper precautions. Moreover, certain measures would be considered, such as treat-and-extend protocol, home screening and portable OCT examination, and newer long-acting anti-VEGF drugs.