[Pharmacoeconomic analysis of anti-angiogenic drugs for diabetic macular edema]. / Farmakoekonomicheskii analiz primeneniya antiangiogennykh preparatov pri diabeticheskom makulyarnom oteke.

Diabetic macular edema (DME) is a degenerative disease of the macular area in diabetes mellitus and can lead to vision loss, disability, and significantly reduced quality of life. Faricimab is the only bispecific antibody for DME therapy that targets two pathogenic pathways (Ang-2 and VEGF-A). PURPOSE: This study comparatively evaluates the clinical and economic feasibility of faricimab and other angiogenesis inhibitors in patients with DME. MATERIAL AND METHODS: This article analyzed literature on the efficacy and safety of intravitreal injections (IVI) of ranibizumab 0.5 mg, aflibercept 2 mg, and faricimab 6 mg. A model of medical care was developed for patients with DME receiving anti-angiogenic therapy. Pharmacoeconomic analysis was performed using cost minimization and budget impact analysis (BIA) methods. Modeling time horizon was 2 years. The research was performed from the perspective of the healthcare system of the Russian Federation. RESULTS: The efficacy and safety of faricimab in a personalized regimen (up to one IVI in 16 weeks) are comparable to those of aflibercept and ranibizumab, administered in various regimens. The use of faricimab is associated with the lowest number of IVIs. Over 2 years, the maximum costs of drug therapy were associated with the use of ranibizumab (about 914 thousand rubles), while the minimum costs were associated with the use of faricimab (614 thousand rubles). The reduction in inpatient care costs with faricimab therapy was 36% compared to aflibercept (216 and 201 thousand rubles in inpatient and day hospitals, respectively) and 82% compared to ranibizumab (486 and 451 thousand rubles in inpatient and day hospitals, respectively). BIA demonstrated that the use of faricimab will reduce the economic burden on the healthcare system by 11.3 billion rubles (9.8%) over 2 years. CONCLUSION: The use of faricimab is a cost-effective approach to treatment of adult patients with DME in Russia.

[Application of optical coherence tomography in the assessment of the posterior lens capsule during anti-angiogenic therapy]. / Primenenie opticheskoi kogerentnoi tomografii v otsenke zadnei kapsuly khrustalika na fone provedeniya antiangiogennoi terapii.

Intravitreal injection (IVI) of anti-angiogenic drugs is one of the most common therapeutic procedures in ophthalmology. In recent years, a new non-contact study method has been developed - anterior segment optical coherence tomography (AS-OCT), which allows the formation of three-dimensional images of the lens and provides more detailed information about its structure and morphology. PURPOSE: This study uses optical coherence tomography method to analyze the risks of developing changes in the posterior lens capsule in patients after IVI of an anti-angiogenic drug. MATERIAL AND METHODS: The study involved 100 people (14 men and 86 women) with a natural lens and neovascular age-related macular degeneration (nAMD). The average age was 70.57±7.98 years. During the study (12 months), all patients underwent IVI of an anti-angiogenic drug aflibercept in the treat-and-extend (T&E) mode. All subjects were divided into 2 groups: with a total number of IVI less than 10 - group 1 (50 patients), and more than 10 IVI - group 2 (50 patients, of which 49 were included in the study). All patients underwent OCT using the Optopol REVO NX device (Poland) with the Anterior B-scan Wide protocol before inclusion in the study, as well as after 3, 6 and 12 months. RESULTS: It was found that the risk of developing a posterior lens capsule rupture, visualized using OCT, depends on the total number of IVI (correlation coefficient 0.473 p=0.001): the more IVI, the higher the probability that damage to the posterior capsule will occur after the next IVI, and after the 15th injection the risk of developing damage to the posterior capsule increases sharply. CONCLUSION: The astudy analyzed the risk factors for the development of posterior lens capsule damage that can be detected using OCT, and presented three risk groups for the development of rupture (or damage) of the posterior lens capsule depending on the number of intravitreal injections performed.

Association between the arm-to-choroidal circulation time and clinical profile in patients with polypoidal choroidal vasculopathy.

PURPOSE: To investigate the association between the arm-to-choroidal circulation time (ACT) on indocyanine green angiography (IA) and clinical profile in patients with polypoidal choroidal vasculopathy (PCV). STUDY DESIGN: Single-center retrospective study. METHODS: We included 38 eyes of 38 patients with PCV diagnosed using multimodal imaging and did not undergo previous treatment. All patients were treated with monthly aflibercept injections for 3 months and treat-and-extend regimens for the subsequent 12 months. Posterior vortex vein ACT was assessed on the first visit using Heidelberg IA. The patients were divided into two groups: ACT ≥20 s (L group; eight eyes) and ACT <20 s (S group; 30 eyes). The clinical profiles before and after treatment were analyzed to assess associations with ACT. RESULTS: The mean ACT was 16.39±3.3 s (L group: 21.25±1.49 s, women:men=2:6, mean age: 77.3±6.5 years; S group: 15.10±2.17 s, women:men=7:23, mean age: 75.5±6.9 years). No significant difference was observed in the mean subfoveal choroidal thickness between the L and the S groups (176±75 µm vs. 230±79 µm, P=0.10). However, there were significant differences between the L and S groups in retinal fluid accumulation and hemorrhage recurrence (eight/eight eyes, 100% vs. 13/30 eyes, 43%, P<0.001), mean aflibercept injections (8.8±1.6 vs. 7.0±1.6, P<0.01) during the 12-month period, and the number of polypoidal lesions (1.8±0.7 vs. 1.3±0.5, P<0.05). CONCLUSION: Patients with PCV and ACT >20 s are more likely to experience exudative change recurrence in the retina during treatment because they have more polypoidal lesions.

Long-term dynamic changes and influencing factors of corneal morphology after multiple intravitreal injections of anti-VEGF drugs.

To observe alterations in corneal morphology caused by repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF). Prospective cohort study. Seventy-seven eyes were treated with intravitreal injection of anti-VEGF from June 2021 to March 2023. There were 25 eyes of neovascular age-related macular degeneration (nAMD), 24 eyes of diabetic macular edema (DME), and 28 eyes of retinal vein occlusion (RVO). Aflibercept was used in 37 eyes and Ranibizumab was used in 40 eyes. 3 + PRN was used. Corneal endothelium and corneal thickness were measured using a corneal endothelial microscope. The data related to central corneal thickness, corneal endothelial cell density (ECD), average cell size, coefficient of variation (CV), proportion of hexagonal cells (Hex%) was collected. A comparison was also made between baseline and the dynamic changes of all indexes 1 year following the last injection. It was observed that in comparison to baseline, ECD and Hex% decreased significantly after the 3rd injection of Aflibercept and Ranibizumab. However, ECD did not decrease further and remained at the same level as after the last injection. Hex% and average cell size increased to a certain extent in comparison to the last injection. All the changes were found to be statistically significant (P < .01). After 3 injections, ECD in DME group was markedly lower than that in nAMD and RVO group, but the CV in DME group was higher than that in nAMD as well as RVO groups, and all the differences were statistically significant (P < .05). Following intravitreal anti-VEGF therapy, DME is more likely than other disorders to result in a decrease in ECD. Repeated intravitreal injections of anti-VEGF drugs can reduce the Hex% and ECD to a certain extent. After the last injection, Hex% can progressively recover, and ECD can remain stable without further declining. After injections, ECD in DME group was found to be significantly lower than that in nAMD and RVO groups, but CV in DME group was significantly higher in comparison to the other 2 groups. In patients with macular edema, repeated intravitreal injections of anti-VEGF may have certain effects on corneal morphology. Patients with diabetes mellitus in particular should pay special attention to corneal safety following repeated intravitreal injections if they have significantly reduced ECD at baseline.

Retinal and choroidal efficacy of switching treatment to faricimab in recalcitrant neovascular age related macular degeneration.

Aim of this study was to evaluate the efficacy of switching treatment to faricimab in neovascular age-related macular degeneration (nAMD) from other anti-VEGF agents. Fifty-eight eyes of fifty-one patients with nAMD and a full upload series of four faricimab injections were included. Demographic data, multimodal imaging and treatment parameters were recorded. The primary outcome measures were changes in central subfield thickness (CST) and subfoveal choroidal thickness (SFCT). A subgroup analysis was performed for eyes with prior ranibizumab (R) or aflibercept (A) treatment. Mean injection intervals before and after switching were comparable (33.8 ± 11.2 vs. 29.3 ± 2.6 days; p = 0.08). Mean CST of 361.4 ± 108.1 µm prior to switching decreased significantly to 318.3 ± 97.7 µm (p < 0.01) after the third faricimab injection, regardless of prior anti-VEGF treatment (p < 0.01). Although SFCT slightly improved for the whole cohort from 165.8 ± 76.8 µm to 161.0 ± 82,8 µm (p = 0.029), subgroup analysis did not confirm this positive effect (subgroup R: p = 0.604; subgroup A: p = 0.306). In patients with a suboptimal response to aflibercept or ranibizumab in nAMD, farcimab can improve CST and slightly improve or maintain SFCT. Further prospective randomized trials are warranted.

Comparison of ranibizumab, aflibercept, and dexamethasone implant monotherapy in treatment-naive eyes with diabetic macular edema: A 12-month real-life experience.

PURPOSE: To compare the functional and anatomical outcomes of ranibizumab, aflibercept, and dexamethasone implant monotherapy in treatment-naive eyes with diabetic macular edema (DME) in real-life conditions. METHODS: In this retrospective cohort study, data were obtained from the hospital database of treatment-naive patients diagnosed with DME with at least 12 months of follow-up. Best corrected visual acuity (BCVA) and central retinal thickness (CRT) at baseline, third month, sixth month, ninth month, and 12th month were recorded. In addition, a subgroup analysis was performed based on having good (below 0.4 log of minimum angle of resolution [logMAR]) or poor (0.4 logMAR and above) vision. RESULTS: A total of 219 eyes of 142 patients were included in the study. The change in the mean BCVA from baseline to 12th month was from 0.62 logMAR to 0.42 logMAR (P < 0.001) in the ranibizumab group, from 0.56 logMAR to 0.39 logMAR (P < 0.001) in the aflibercept group, and from 0.46 logMAR to 0.5 logMAR (P = 0.653) in the dexamethasone group. There was no significant difference between the treatment groups at any time point (P > 0.05). The mean amount of CRT change was statistically significant at 12 months in all groups (ranibizumab: -175.4 µm, aflibercept: -153.3 µm, dexamethasone: -71.4 µm) (P < 0.05). In eyes with initially good vision, the final BCVA at 12 months was significantly better in the ranibizumab group compared to the dexamethasone group (P = 0.008). The aflibercept group had better visual acuity than the dexamethasone group, but there was no statistically significant difference (P = 0.059). There was no significant difference in final BCVA in eyes with initially poor vision. No serious ocular/systemic complications were noted. CONCLUSION: At the 12th month, a significant decrease in CRT was achieved in all treatment groups, whereas only ranibizumab and aflibercept groups had a significant BCVA increase. In eyes with initially good vision, the final BCVA at 12 months was better in the ranibizumab group compared to the dexamethasone group, whereas it was similar in all groups having initially poor vision.

Baseline characteristics of eyes with early residual fluid post loading phase of aflibercept therapy in neovascular AMD: PRECISE study report 3.

PURPOSE: To compare the baseline characteristics in patients with and without early residual fluid (ERF) after aflibercept loading phase (LP) in patients with treatment naïve neovascular age related macular degeneration (nAMD). METHODS: Patients with nAMD initiated on LP of three intravitreal aflibercept doses were recruited from December 2019 to August 2021. Baseline demographic and OCT features associated with any ERF were analysed using Generalised Estimating Equations to account for inter-eye correlation. Receiver operating characteristic (ROC) curve was performed for selection of CST threshold. RESULTS: Of 2128 patients enrolled, 1999 eyes of 1862 patients with complete data were included. After LP, ERF was present in 1000 (50.0%), eSRF in 746(37.3%) and eIRF in 428 (21.4%) eyes. In multivariable analysis of baseline features, eyes with increased central subfield thickness (CST) (OR 1.31 per 100 microns increase [95% CI 1.22 to 1.41]; P < 0.001), eyes with IRF and SRF at baseline (1.62 [95% CI 1.17 to 2.22]; P = 0.003), and those with SRF only (OR 2.26 [95% CI 1.59 to 3.20]; P < 0.001) relative to IRF only were determinants of ERF. CST ≥ 418 microns had 57% sensitivity and 58% specificity to distinguish ERF from no ERF at visit 4. CONCLUSION: On average, 50% of eyes have ERF after aflibercept LP. Clinically relevant baseline determinants of ERF include CST ≥ 418 µ and presence of only SRF. These eyes may require further monthly treatment before extending treatment intervals.

Efficacy and safety of Aflibercept for the treatment of inflammatory choroidal neovascularization: The ALINEA study.

PURPOSE: To evaluate mean change in best-corrected visual acuity (BCVA) at 52 weeks in patients with inflammatory choroidal neovascularization (CNV) treated with aflibercept. METHODS: We conducted a prospective non-comparative open-label trial. Following one mandatory intravitreal injection of aflibercept, patients were treated under a pro re nata (PRN) dosing regimen with monthly visits. RESULTS: A total of 19 patients were included, but one presented exclusion criteria; 16 patients were followed for the whole 52-week study, and data for the primary endpoint analysis were available for 14. At baseline, mean BCVA and mean central retinal thickness (CRT) were 64.53 (±19.64) letters and 351.79 (±97.77) µm, respectively. At 52 weeks, the mean change in BCVA was +9.50 (±12.90) letters [95%CI = +2.05-+16.95]. One patient had lost more than 15-letters at 24 weeks, and another one at 52 weeks. CRT change was -62.77 (±100.73) µm at 24 weeks and -66.53 (±97.47) µm at 52 weeks. There was a mean number of 3.56 (±3.29) intravitreal injections at 52 weeks (min = 1; max = 12). No serious ocular adverse events related to the treatment were reported. CONCLUSIONS: Our study shows that aflibercept is clinically effective, both anatomically and functionally in the treatment of inflammatory CNV. Following the first injection, the PRN strategy appears sufficient for treating most choroidal neovessels.

RISK OF INTRAOCULAR INFLAMMATION AFTER INJECTION OF ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR AGENTS: A Meta-analysis.

PURPOSE: This meta-analysis investigates the incidence of intraocular inflammation (IOI) after intravitreal antivascular endothelial growth factor injections in neovascular age-related macular degeneration. METHODS: A systematic search was performed on Ovid MEDLINE, Embase, and Cochrane Central from January 2005 to April 2021. Randomized controlled trials comparing IOI after intravitreal bevacizumab, ranibizumab, brolucizumab, or aflibercept in neovascular age-related macular degeneration were included. Primary outcomes were sight-threatening IOI, final best-corrected visual acuity, and change in best-corrected visual acuity from baseline. Secondary outcomes included the incidence of other IOI events. Meta-analysis was performed using a random-effects model. RESULTS: Overall, 11,460 unique studies were screened, of which 14 randomized controlled trials and 6,759 eyes at baseline were included. There was no difference between agents for the risk of endophthalmitis and retinal vascular occlusion. Compared with aflibercept, brolucizumab had a higher incidence of generalized IOI (risk ratio = 6.24, 95% confidence interval = [1.40-27.90]) and vitreous haze/floaters (risk ratio = 1.64, 95% confidence interval = [1.00-2.67]). There were no significant differences between comparators for other secondary end points. CONCLUSION: There was no difference in the risk of severe sight-threatening IOI outcomes between intravitreal antivascular endothelial growth factor agents. There was a significantly higher risk of generalized IOI after brolucizumab relative to aflibercept. Our results alongside other recent safety findings suggest the need for further investigation in the risk-benefit profile of brolucizumab for the treatment of neovascular age-related macular degeneration.

Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema.

BACKGROUND: In 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. METHODS: At 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. RESULTS: A 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. CONCLUSIONS: In 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.).

Effect of Intravitreal Aflibercept vs Laser Photocoagulation on Treatment Success of Retinopathy of Prematurity: The FIREFLEYE Randomized Clinical Trial.

Importance: Laser photocoagulation, which is the standard treatment for retinopathy of prematurity (ROP), can have adverse events. Studies of anti-vascular endothelial growth factor injections have suggested efficacy in the treatment of ROP, but few studies have directly compared them with laser treatments. Objective: To compare intravitreal aflibercept vs laser photocoagulation in infants with ROP requiring treatment. Design, Setting, and Participants: This noninferiority, phase 3, 24-week, randomized clinical trial was conducted in 27 countries (64 hospital sites) throughout Asia, Europe, and South America. Overall, 118 infants (gestational age ≤32 weeks at birth or birth weight ≤1500 g) with ROP severity (zone I stage 1+ [stage 1 plus increased disease activity], zone I stage 2+, zone I stage 3, zone I stage 3+, zone II stage 2+, or zone II stage 3+) requiring treatment or with aggressive posterior ROP in at least 1 eye were enrolled between September 25, 2019, and August 28, 2020 (the last visit occurred on February 12, 2021). Interventions: Infants were randomized 2:1 to receive a 0.4-mg dose of intravitreal aflibercept (n = 75) or laser photocoagulation (n = 43) at baseline. Additional treatment was allowed as prespecified. Main Outcomes and Measures: The primary outcome was the proportion of infants without active ROP and unfavorable structural outcomes 24 weeks after starting treatment (assessed by investigators). The requirement for rescue treatment was considered treatment failure. Intravitreal aflibercept was deemed noninferior if the lower limit of the 1-sided 95% bayesian credible interval for the treatment difference was greater than -5%. Results: Among 118 infants randomized, 113 were treated (mean gestational age, 26.3 [SD, 1.9] weeks; 53 [46.9%] were female; 16.8% had aggressive posterior ROP, 19.5% had zone I ROP, and 63.7% had zone II ROP) and 104 completed the study. Treatment (intravitreal aflibercept: n = 75; laser photocoagulation: n = 38) was mostly bilateral (92.9%), and 82.2% of eyes in the intravitreal aflibercept group received 1 injection per eye. Treatment success was 85.5% with intravitreal aflibercept vs 82.1% with laser photocoagulation (between-group difference, 3.4% [1-sided 95% credible interval, -8.0% to ∞]). Rescue treatment was required in 4.8% (95% CI, 1.9% to 9.6%) of eyes in the intravitreal aflibercept group vs 11.1% (95% CI, 4.9% to 20.7%) of eyes in the laser photocoagulation group. The serious adverse event rates were 13.3% (ocular) and 24.0% (systemic) in the intravitreal aflibercept group compared with 7.9% and 36.8%, respectively, in the laser photocoagulation group. Three deaths, which occurred 4 to 9 weeks after intravitreal aflibercept treatment, were considered unrelated to aflibercept by the investigators. Conclusions and Relevance: Among infants with ROP, intravitreal aflibercept compared with laser photocoagulation did not meet criteria for noninferiority with respect to the primary outcome of the proportion of infants achieving treatment success at week 24. Further data would be required for more definitive conclusions regarding the comparative effects of intravitreal aflibercept and laser photocoagulation in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT04004208.

Arm-to-retina time predicts visual outcome of anti-vascular endothelial growth factor treatment for macular edema due to central retinal vein occlusion.

To explore the factors associated with best-corrected visual acuity (BCVA) after anti-vascular endothelial growth factor (anti-VEGF) treatment for macular edema secondary to central retinal vein occlusion (CRVO). We retrospectively reviewed the medical charts of 22 eyes of 22 treatment-naïve patients with CRVO diagnosed between September 2014 and December 2020. They received anti-VEGF treatment and follow-up for > 12 months. Mean patient age was 64.3 years; 13 (59.1%) were men. Eyes with baseline arm-to-retina (AR) time ≥ 16 s had better BCVA at 12 months (adjusted for baseline BCVA and age; B, - 0.658; 95% confidence interval - 1.058 to - 0.257; P = 0.003), greater mean BCVA change (P = 0.006), lower frequency of residual macular edema at 12 months (P = 0.026) and recurrent and/or unresolved macular edema during 12 months (P = 0.046), and higher frequency of reduction in central retinal thickness ≥ 150 µm at 1 and 12 months (both P = 0.046). Delayed AR time was associated with a better visual outcome and macular edema improvement in CRVO after anti-VEGF treatment regardless of initial BCVA and age. Our results may help understand the pathogenesis and predict the visual prognosis of patients before anti-VEGF therapy initiation.

Novel volumetric imaging biomarkers for assessing disease activity in eyes with PCV.

The aim of this study was to evaluate influence of baseline imaging features on visual and anatomical outcomes in eyes with PCV treated with anti-VEGF monotherapy. In this prospective study we enrolled participants with treatment-naïve PCV who followed a treat-and-extend protocol using intravitreal aflibercept (IVA) monotherapy. Baseline clinical features evaluatedincluded best corrected visual acuity (BCVA), traditional features such as lesion size, fluid-related OCT parameters and novel parameters using automated software. This included quantitative and qualitative pigment epithelium detachment (PED) parameters [height, volume]; and choroidal parameters. [choroidal thickness (CT), choroidal volume (CV) and choroidal vascularity index (CVI). We evaluated the predictive value of each parameter on visual and anatomical outcome at month 12. We additionally evaluated initial treatment response after 3 monthly injections with respect to month 12 outcomes. Fifty-two eyes from 52 participants were included in the study. The BCVA increased from 61.1 ± 13.2 to 69.6 ± 13.2 early treatment diabetic retinopathy study (ETDRS) letters (p < 0.01) and CRT reduced from 455.7 ± 182.4 µm to 272.7 ± 86.2 (p < 0.01) from baseline to month 12. The proportion of eyes with PED decreased significant from 100% at baseline to 80% at month 12 (p < 0.01). Reduction in the mean maximum height of PED (from 381.3 ± 236.3 µm to 206.8 vs ± 146.4 µm) and PED volume (from 1322 ± 853 nl to 686 ± 593 nl) (p < 0.01) was also noted from baseline to month12. Baseline features associated with better month 12 BCVA included baseline BCVA (ß = - 0.98, 95%CI - 3.38 to - 1.61, p = 0.02) and baseline CRT (ß = - 0.98, 95%CI - 1.56 to - 0.40, p = 0.04) while the disease activity at month12 was significantly associated with lower baseline CRT (366.0 ± 129.5 vs 612.0 ± 188.0 , p < 0.001), lower baseline PED height (242.0 ± 150.0 vs 542.0 ± 298.0 µm, p < 0.01), lower baseline PED volume (0.6 ± 0.3 mm3 vs 2.2 ± 1.3 mm3 vs, p < 0.01), lower proportion with marked CVH (17.9% vs 46.2%, p = 0.02) and lower mean CVI (61.8 ± 1.4 vs 63.0 ± 1.4, p < 0.02). Additionally, a larger decrease in CRT (per 100 nm) and larger PED volume reduction (per 100 nl) at month 3 from baseline were associated with greater BCVA gain and inactive disease. PED-related volumetric parameters have an additional predictive value to traditional biomarkers of disease activity in eyes with PCV undergoing anti-VEGF monotherapy. With increasingly precise quantification, PEDs can be a crucial biomarker in addition to traditional parameters and may aid in retreatment decisions.

Diabetic macular edema and proliferative diabetic retinopathy treated with anti-vascular endothelial growth factor under the reimbursement policy in Taiwan.

The purpose of this retrospective interventional case series is to compare the functional and anatomical outcomes in eyes with diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) treated intravitreally with aflibercept or ranibizumab under the Taiwan National Insurance Bureau reimbursement policy. 84 eyes were collected and all eyes were imaged with spectral-domain optical coherence tomography (SD-OCT), color fundus photographs (CFPs), and fluorescein angiography (FA). At 24 months after therapy initiation, the logMAR BCVA improved from 0.58 ± 0.33 to 0.47 ± 0.38 (p < 0.01), the CRT decreased from 423.92 ± 135.84 to 316.36 ± 90.02 (p < 0.01), and the number of microaneurysms decreased from 142.14 ± 57.23 to 75.32 ± 43.86 (p < 0.01). The mean injection count was 11.74 ± 5.44. There was no intergroup difference in logMAR BCVA (p = 0.96), CRT (p = 0.69), or injection count (p = 0.81). However, the mean number of microaneurysms was marginally reduced (p = 0.06) in eyes treated with aflibercept at the end of the follow-up, and the incidence rates of supplementary panretinal photocoagulation (PRP) (p = 0.04) and subthreshold micropulse laser (SMPL) therapy sessions (p = 0.01) were also reduced. Multivariate analysis revealed that only initial logMAR BCVA influenced the final VA improvements (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.21 ~ 0.93, p < 0.01); in contrast, age (OR - 0.38, 95% CI - 6.97 ~ - 1.85, p < 0.01) and initial CRT (OR 0.56, 95% CI 0.34 ~ 0.84, p < 0.01) both influenced the final CRT reduction at 24 months. To sum up, both aflibercept and ranibizumab are effective in managing DME with PDR in terms of VA, CRT and MA count. Eyes receiving aflibercept required less supplementary PRP and SMPL treatment than those receiving ranibizumab. The initial VA influenced the final VA improvements at 24 months, while age and initial CRT were prognostic predictors of 24-month CRT reduction.

Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials.

BACKGROUND: Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A. We report primary results of two phase 3 trials evaluating intravitreal faricimab with extension up to every 16 weeks for neovascular age-related macular degeneration (nAMD). METHODS: TENAYA and LUCERNE were randomised, double-masked, non-inferiority trials across 271 sites worldwide. Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6·0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2·0 mg every 8 weeks. Randomisation was performed through an interactive voice or web-based response system using a stratified permuted block randomisation method. Patients, investigators, those assessing outcomes, and the funder were masked to group assignments. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 40, 44, and 48 (prespecified non-inferiority margin of four letters), in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (TENAYA NCT03823287 and LUCERNE NCT03823300). FINDINGS: Across the two trials, 1329 patients were randomly assigned between Feb 19 and Nov 19, 2019 (TENAYA n=334 faricimab and n=337 aflibercept), and between March 11 and Nov 1, 2019 (LUCERNE n=331 faricimab and n=327 aflibercept). BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [-1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [-1·7 to 1·8]). Rates of ocular adverse events were comparable between faricimab and aflibercept (TENAYA n=121 [36·3%] vs n=128 [38·1%], and LUCERNE n=133 [40·2%] vs n=118 [36·2%]). INTERPRETATION: Visual benefits with faricimab given at up to 16-week intervals demonstrates its potential to meaningfully extend the time between treatments with sustained efficacy, thereby reducing treatment burden in patients with nAMD. FUNDING: F Hoffmann-La Roche.

Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials.

BACKGROUND: To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody. METHODS: YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593). FINDINGS: 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]). INTERPRETATION: Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema. FUNDING: F Hoffmann-La Roche.

Bevacizumab and aflibercept in second-line metastatic colorectal cancer: 12 years of experience.

PURPOSE: To evaluate and compare the efficacy and safety of bevacizumab and aflibercept in second-line treatment in metastatic colorectal cancer (mCRC) in real-life clinical practice. METHODS: Retrospective observational study of patients treated with second-line bevacizumab (BFIR) and aflibercept (AFIR) in mCRC, associated with a FOLFIRI scheme, in the last 12 years (January 2009-January 2021) in a tertiary hospital. Patients with prior oxaliplatin-based treatment were included. VARIABLES MEASURED: previous chemotherapy, treatment time (TT), progression-free survival (PFS), overall survival (OS). To assess toxicity, adverse effects that caused delay in cycle administration were recorded. The lost cycles/month of treatment (CP/MT) were also calculated. RESULTS: Eighty-four patients [40 (47.6%) AFIR and 44 (52.4%) BFIR]. Average age: 60.2 ± 10.7 years. In 79.8% the previous scheme was FOLFOX type. Efficacy of AFIR vs BFIR: median HR of TT (95% CI) = 0.816 (0.527-1.266); p = 0.365, PFS HR (95% CI) = 0.674 (0.389-1.117); p = 0.159, OS HR (95% CI) = 0.566 (0.342-0.936); p = 0.026. The main reason for the delay in administration was neutropenia (28.7% AFIR vs 24.7% BFIR), and the greatest difference found was thrombopenia (13.9% AFIR vs 2.5% BFIR), without observing large differences between the rest of adverse reactions. Mean CP/MT: 0.49 ± 0.46 cycles with AFIR and 0.33 ± 0.27 with BFIR; p = 0.046. CONCLUSION: Although no statistically significant differences have been found in TT or PFS, it would be more advisable to use BFIR scheme due to its better results in OS and toxicity profile.

RESUMEN: OBJETIVO: Evaluar y comparar la eficacia y seguridad de bevacizumab y aflibercept en segunda línea de tratamiento en el cáncer colorrectal metastásico (CCRm) en la práctica clínica real. MéTODOS: Estudio observacional retrospectivo de los pacientes tratados con bevacizumab (BFIR) y aflibercept (AFIR) en segunda línea en CCRm, asociado a un esquema FOLFIRI, en los últimos 12 años (septiembre 2009-enero 2021) en un hospital de tercer nivel. Se incluyeron pacientes con tratamiento previo basado en oxaliplatino. Variables medidas: esquema previo, tiempo de tratamiento (TT), supervivencia libre de progresión (SLP), supervivencia global (SG). Para valorar toxicidad, se registraron los efectos adversos que provocaron retraso en la administración del ciclo. También se calcularon los ciclos perdidos/mes de tratamiento (CP/MT). RESULTADOS: 84 pacientes [40 (47,6%) AFIR y 44 (52,4%) BFIR]. Media de edad: 60,2 ± 10,7 años. En el 79,8% el esquema previo fue tipo FOLFOX. Eficacia de AFIR vs BFIR: HR de mediana de TT (IC95%) = 0,816 (0,527­1,266); p = 0,365, HR de SLP (IC95%) = 0,674 (0,389­1,117); p = 0,159, HR de SG (IC95%) = 0,566 (0,342­0,936); p = 0,026. El principal motivo de retraso en la administración fue neutropenia (28,7% AFIR vs 24,7% BFIR), y el que más diferencia hubo entre ambos la trombopenia (13,9% AFIR vs 2,5% BFIR), sin observarse grandes diferencias entre el resto de reacciones adversas. Media de CP/MT: 0,49 ± 0,46 ciclos con AFIR y 0,33 ± 0,27 con BFIR; p = 0,046. CONCLUSIONES: Aunque no se han encontrado diferencias estadísticamente significativas en TT ni en SLP, sería más recomendable utilizar el esquema BFIR por sus mejores resultados en SG y perfil de toxicidad.

OPTICAL COHERENCE TOMOGRAPHY FEATURES OF POLYPOIDAL LESION CLOSURE IN POLYPOIDAL CHOROIDAL VASCULOPATHY TREATED WITH AFLIBERCEPT.

PURPOSE: To evaluate whether optical coherence tomography (OCT) can determine polypoidal lesion (PL) perfusion in polypoidal choroidal vasculopathy eyes after 12 months of aflibercept monotherapy. Polypoidal lesion perfusion status, assessed by indocyanine green angiography, is an important anatomical outcome in polypoidal choroidal vasculopathy management. METHODS: Post hoc data from a prospective randomized, open-label, study in eyes with polypoidal choroidal vasculopathy undergoing monotherapy with aflibercept evaluated PL perfusion status based on indocyanine green angiography (gold standard) and OCT features from baseline to 12 months. RESULTS: Individual PLs (110 in total) from 48 eyes (48 patients) showed at 12 months; 57/110 PLs (51.8%) were closed on indocyanine green angiography. At 12 months, eyes with closed PLs were more likely to have the following OCT features: 1) no subretinal fluid (67.1% vs. 32.9%), 2) smaller pigment epithelial detachment height (67.2 [±43.8] vs. 189.2 [±104.9] µm), 3) densely hyperreflective pigment epithelial detachment contents (84.0% vs. 16.0%), 4) an absence of a hyperreflective ring(64.0% vs. 36.0%), and a 5) indistinct overlying retinal pigment epithelial (71.4% vs. 28.6%) (all P < 0.05). The three highest performing OCT features that differentiated perfused from closed PLs were (1), (3), and (4) (area under the receiver operating characteristic curve 0.85, 0.73, and 0.70, respectively). A combination of these three features achieved an area under the receiver operating characteristic curve of 0.90. CONCLUSION: Polypoidal lesion closure, an important anatomical treatment outcome in polypoidal choroidal vasculopathy typically defined by indocyanine green angiography, can be accurately detected by specific OCT features.

Intravitreal anti-VEGF use in France: a cross-sectional and longitudinal Nationwide observational study.

PURPOSE: To describe the sociodemographic, medical and management characteristics of patients using intravitreal (IVT) anti-vascular endothelial growth factors (VEGF) in France. METHODS: An observational study was conducted in patients treated with IVT ranibizumab or aflibercept, aged 18 years or older using the French National Health Insurance Databases covering 99% of the French population. Patients currently treated in 2018 were included in a cross-sectional approach to describe treatment history over the previous 6 years. Patients newly treated between 2014 and 2018 were included in a longitudinal approach to describe treatment management during up to 6 years of follow-up. Sociodemographic characteristics and medical history were described in both populations. The analyses were performed at the patient level, as no distinction between the eyes could be made. RESULTS: A total of 224 775 current users of IVT anti-VEGF in 2018 (mean age 78.1 ± 11.3 years, 60% female) and 330 969 new users between 2014 and 2018 (mean age 75.9 ± 12.0 years, 59% female) were included. In both populations cardiovascular comorbidities or risk factors were frequent and the main treatment indications were age-related macular degeneration and diabetic macular oedema. Among current users of IVT anti-VEGF in 2018, the mean number of years receiving a treatment was 2.9 ± 2.0 years, with a mean of 13.7 ± 11.8 dispensations. In the longitudinal approach, a 26% increase in IVT anti-VEGF initiation was observed between 2014 and 2018. For new users, the mean number of years receiving a treatment was 1.6 ± 1.6 and 67% had at least three dispensations within the first three months. A treatment interruption was observed for 83% of new users and occurred on average of 6.1 ± 8.1 months after initiation. The mean number of dispensations was 4.8 ± 2.8 in the first year and 2.2 ± 2.9 in the second year. The mean number of eye monitoring examinations was 6.5 ± 4.7 in the first year and 4.6 ± 4.4 in the second year. CONCLUSION: This study described the real-world conditions of IVT anti-VEGF dispensing at the entire French population scale. Less frequent dispensations and surveillance examinations were observed than in monthly schemes applied in registration trials for IVT anti-VEGF. These results may indicate a lack of systematic monitoring associated with fewer injections and/or clinicians' preference for more flexible and personalized injection schemes than those originally recommended.