Dabigatran and Wet AMD, Results From Retinal Pigment Epithelial Cell Monolayers, the Mouse Model of Choroidal Neovascularization, and Patients From the Medicare Data Base.

Background: Age-related macular degeneration (AMD), the leading cause of irreversible blindness in elderly Caucasian populations, includes destruction of the blood-retina barrier (BRB) generated by the retinal pigment epithelium-Bruch's membrane complex (RPE/BrM), and complement activation. Thrombin is likely to get access to those structures upon BRB integrity loss. Here we investigate the potential role of thrombin in AMD by analyzing effects of the thrombin inhibitor dabigatran. Material and Methods: MarketScan data for patients aged ≥65 years on Medicare was used to identify association between AMD and dabigatran use. ARPE-19 cells grown as mature monolayers were analyzed for thrombin effects on barrier function (transepithelial resistance; TER) and downstream signaling (complement activation, expression of connective tissue growth factor (CTGF), and secretion of vascular endothelial growth factor (VEGF)). Laser-induced choroidal neovascularization (CNV) in mouse is used to test the identified downstream signaling. Results: Risk of new wet AMD diagnosis was reduced in dabigatran users. In RPE monolayers, thrombin reduced TER, generated unique complement C3 and C5 cleavage products, led to C3d/MAC deposition on cell surfaces, and increased CTGF expression via PAR1-receptor activation and VEGF secretion. CNV lesion repair was accelerated by dabigatran, and molecular readouts suggest that downstream effects of thrombin include CTGF and VEGF, but not the complement system. Conclusions: This study provides evidence of association between dabigatran use and reduced exudative AMD diagnosis. Based on the cell- and animal-based studies, we suggest that thrombin modulates wound healing and CTGF and VEGF expression, making dabigatran a potential novel treatment option in AMD.

Longitudinal assessment of type 3 macular neovascularization using 3D volume-rendering OCTA.

OBJECTIVE: To investigate the evolution of treatment-naive type 3 macular neovascularization (MNV) undergoing anti-vascular endothelial growth factor (VEGF) treatment through volume rendered three-dimensional (3D) optical coherence tomography angiography (OCTA). DESIGN: Retrospective observational study. PARTICIPANTS: Patients with type 3 MNV and age-related macular degeneration (AMD). METHODS: Included subjects had three loading injections of an anti-VEGF agent. The OCTA volume data at baseline and follow-up were processed with a previously published algorithm in order to obtain a volume-rendered representation of type 3 MNV. Progressive changes in type 3 lesions were analyzed via 3D OCTA volume rendering. RESULTS: A total of 14 treatment-naive eyes with type 3 MNV from 11 AMD patients (7 females) were included. At both baseline and follow-up visits, a type 3 MNV complex was identifiable. Each complex was composed of a mean number of 2.5 ± 0.7 vascular branches at baseline and 1.4 ± 0.6 at the follow-up visit (p < 0.0001). The mean changes in central macular thickness and visual acuity were significantly correlated with modifications in the number of type 3 MNV branches (ρ = -0.533, p = 0.049, and ρ = -0.581, and p = 0.040, respectively). CONCLUSIONS: This study demonstrated that type 3 lesions do not disappear completely after loading treatment, as indicated previously by histopathologic studies. Importantly, quantitative volume changes in type 3 lesions are directly associated with treatment response.

Assessment of a New Nanostructured Microemulsion System for Ocular Delivery of Sorafenib to Posterior Segment of the Eye.

Eye drop formulations allowing topical treatment of retinal pathologies have long been sought as alternatives to intravitreal administration. This study aimed to assess whether a novel nanostructured microemulsions system (NaMESys) could be usefully employed to deliver sorafenib to the retina following topical instillation. NaMESys carrying 0.3% sorafenib (NaMESys-SOR) proved to be cytocompatible in vitro on rabbit corneal cells, and well-tolerated following b.i.d. ocular administration to rabbits during a 3-month study. In rats subject to retinal ischemia-reperfusion, NaMESys-SOR significantly inhibited retinal expression of tumor necrosis factor-alpha (TNFα, 20.7%) and inducible nitric oxide synthase (iNos, 87.3%) mRNAs in comparison to controls. Similarly, in streptozotocin-induced diabetic rats, NaMESys-SOR inhibited retinal expression of nuclear factor kappa B (NFκB), TNFα, insulin like growth factor 1 (IGF1), IGF1 receptor (IGF1R), vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2) mRNAs by three-fold on average compared to controls. Furthermore, a reduction in TNFα, VEGFR1 and VEGFR2 protein expression was observed by western blot. Moreover, in mice subject to laser-induced choroidal neovascularization, NaMESys-SOR significantly inhibited neovascular lesions by 54%. In conclusion, NaMESys-SOR was shown to be a well-tolerated ophthalmic formulation able to deliver effective amounts of sorafenib to the retina, reducing proinflammatory and pro-angiogenic mediators in reliable models of proliferative retinopathies. These findings warrant further investigations on the full therapeutic potential of NaMESys-SOR eye drops, aiming to address unmet needs in the pharmacotherapy of retinal neovascular diseases.

Automated Quantitative Assessment of Retinal Fluid Volumes as Important Biomarkers in Neovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate retinal fluid volume data extracted from optical coherence tomography (OCT) scans by artificial intelligence algorithms in the treatment of neovascular age-related macular degeneration (NV-AMD). DESIGN: Perspective. METHODS: A review was performed of retinal image repository datasets from diverse clinical settings. SETTINGS: Clinical trial (HARBOR) and trial follow-on (Age-Related Eye Disease Study 2 10-year Follow-On); real-world (Belfast and Tel-Aviv tertiary centers). PATIENTS: 24,362 scans of 1,095 eyes (HARBOR); 4,673 of 880 (Belfast); 1,470 of 132 (Tel-Aviv); 511 of 511 (Age-Related Eye Disease Study 2 10-year Follow-On). ObservationProcedures: Vienna Fluid Monitor or Notal OCT Analyzer applied to macular cube scans. OutcomeMeasures: Intraretinal fluid (IRF), subretinal fluid (SRF), and pigment epithelial detachment (PED) volumes. RESULTS: The fluid volumes measured in neovascular AMD were expressed efficiently in nanoliters. Large ranges that differed by population were observed at the treatment-naïve stage: 0-3,435 nL (IRF), 0-5,018 nL (SRF), and 0-10,022 nL (PED). Mean volumes decreased rapidly and consistently with anti-vascular endothelial growth factor therapy. During maintenance therapy, mean IRF volumes were highest in Tel-Aviv (100 nL), lower in Belfast and HARBOR-Pro Re Nata, and lowest in HARBOR-monthly (21 nL). Mean SRF volumes were low in all: 30 nL (HARBOR-monthly) and 48-49 nL (others). CONCLUSIONS: Quantitative measures of IRF, SRF, and PED are important biomarkers in NV-AMD. Accurate volumes can be extracted efficiently from OCT scans by artificial intelligence algorithms to guide the treatment of exudative macular diseases. Automated fluid monitoring identifies fluid characteristics in different NV-AMD populations at baseline and during follow-up. For consistency between studies, we propose the nanoliter as a convenient unit. We explore the advantages of using these quantitative metrics in clinical practice and research.

Late-phase hypercyanescence during indocyanine green angiography for assessment of myopic choroidal neovascularization.

PURPOSE: Indocyanine green angiography (ICGA) is a major diagnostic modality but the clinical implications of specific staining patterns in active myopic choroidal neovascularization (mCNV) are unclear. We examined the associations of ICGA cyanofluorescence patterns with disease characteristics and response to an as-needed intravitreal ranibizumab (IVR) treatment regimen among active mCNV patients. METHODS: Twenty-four subjects with active mCNV treated by IVR were enrolled in this retrospective cohort study. Information from medical records were reviewed, including best corrected visual acuity (BCVA), fluorescein angiography (FA) findings, ICGA cyanofluorescence patterns, and spectral-domain OCT (SD-OCT) results. The CNV lesion size, CNV thickness, and central retinal thickness (CRT) were measured from these images. RESULTS: Two staining patterns were identified on late-phase ICGA images, hypercyanescence (9/24, 37.5%) and non-hypercyanescence (15/24, 62.5%). There were no differences in baseline BCVA, CNV thickness, and CRT between ICGA pattern groups; however, the hypercyanescence group demonstrated a larger CNV lesion size (p = 0.035) and required more IVR injections than the non-hypercyanescence group (2.67 ± 1.58 vs 1.07 ± 0.27, p = 0.016), while the non-hypercyanescence group demonstrated better final BCVA improvement (p = 0.041). Hypercyanescence could be divided into two types, a uniform type and rim type. A pseudopodia-like protrusion of CNV enlargement with a rim-enhanced type hypercyanescence at the protrusion rim was predictive of required retreatment. CONCLUSIONS: Hypercyanescence on late-phase ICGA may assist in identifying more active mCNV requiring intensive treatment.

Assessment of conbercept therapy for high myopia macular neovascularization by optical coherence tomography angiography.

This study aimed to evaluate the efficacy and safety of the intravitreal injection of conbercept in the treatment of macular neovascularization (MNV) secondary to high myopia and to observe the application of optical coherence tomography angiography (OCTA) in the treatment follow-up. We reviewed the medical records of 20 patients (21 eyes) with MNV secondary to high myopia who were enrolled in the Department of Ophthalmology of the First Hospital of China Medical University between May 2018 and January 2020. Each patient received one or more intravitreal injections of conbercept (0.5 mg/0.05 mL). The treatment was conducted according to a 1 + PRN (pro re nata) regimen. The changes of best corrected visual acuity (BCVA), central macular thickness (CMT), and selected MNV and flow areas measured by OCTA were observed over a 6-month follow-up period. The mean logarithm of the minimum angle of resolution (logMAR) BCVA was 1.03 ± 0.61 before treatment and improved to 0.83 ± 0.59 (P = 0.007), 0.78 ± 0.62 (P = 0.001), 0.81 ± 0.73 (P = 0.027), and 0.79 ± 0.72 (P = 0.023) at 1 month, 2 months, 3 months, and 6 months after treatment, respectively. The mean CMT was 358.16 ± 206.11 µm before treatment and decreased to 295.38 ± 178.70 µm (P = 0.003), 288.34 ± 165.60 µm (P = 0.004), 284.36 ± 163.07 µm (P = 0.005), and 283.00 ± 160.32 µm (P = 0.004) at 1 month, 2 months, 3 months, and 6 months after treatment, respectively. Nineteen eyes (90.5%) had stable or improved vision at 6 months of follow-up. One month after conbercept injection, in OCTA images, the small-diameter blood vessels of the MNV decreased, the intertwined small blood vessels decreased or even disappeared, and the main or larger-diameter blood vessels were still present. The mean selected MNV and blood flow areas were 0.62 ± 0.81 and 0.22 ± 0.27 mm2, respectively, before treatment and decreased to 0.23 ± 0.33 and 0.07 ± 0.08 mm2 (P = 0.04 for both), respectively, 1 month after treatment. No drug-related systemic or ocular adverse effects were observed. Our results suggest that conbercept can effectively and safely improve BCVA and reduce CMT in patients with myopic MVN (mMNV). OCTA can be used to observe MNV area, blood flow area, and MNV morphological changes after treatment with conbercept, thus providing a reference for treatment follow-up.

Lifetime Outcomes of Anti-Vascular Endothelial Growth Factor Treatment for Neovascular Age-Related Macular Degeneration.

Importance: Neovascular age-related macular degeneration (nAMD), the largest single cause of irreversible severe vision loss in high-income countries, can now be treated with vascular endothelial growth factor (VEGF) inhibitors, but to our knowledge, no data on lifetime outcomes are available. Objective: To determine visual acuity (VA) outcomes of anti-VEGF treatment for nAMD in both eyes for patients' remaining lifetime. Design, Setting, and Participants: Multistate modeling using real-world cohort data of 3192 patients with nAMD (>67 000 visits) treated in routine eye clinics in Australia, New Zealand, and Switzerland. Data were analyzed between 2007 and 2015. Exposures: Intravitreal anti-VEGF treatment at the treating physician's discretion and prospective data collection in standardized registry. Main Outcomes and Measures: Visual acuity in both eyes over the remaining lifetime. Results: For the mean remaining lifetime of 11 years, an estimated 12% (n = 371; 95% CI, 345-400) of the sample retained driving VA and an estimated 15% (n = 463; 95% CI, 434-495) reading VA in at least 1 eye. At that time, an estimated 82% of the sample (n = 2629; 95% CI, 2590-2660) had dropped out. Younger age at baseline and more injections during the first year of treatment were associated with better long-term outcomes. Conclusions and Relevance: Anti-VEGF treatment was associated with preserved useful visual acuity in almost 20% of patients over their average remaining lifetime. More than 80% of patients will cease treatment over that time, having likely experienced a deterioration of vision beforehand. This is a remarkable outcome compared with outcomes without intervention, which lead to legal blindness within 3 years of disease onset in 80% of those affected. These findings underline the public health necessity of providing anti-VEGF treatment to persons in need.

Eliminating Visual Acuity and Dilated Fundus Examinations Improves Cost Efficiency of Performing Optical Coherence Tomogrpahy-Guided Intravitreal Injections.

PURPOSE: The clinic efficiency and cost savings achieved by eliminating formal visual acuity (VA) and dilated fundus examinations (DFEs) were assessed for established patients receiving optical coherence tomography (OCT)-guided intravitreal injections. DESIGN: Comparative cost analysis. METHODS: Two different treatment models were evaluated. The first model included patients undergoing routine VA assessment, DFEs, OCT imaging, and intravitreal injections. The second model eliminated the routine VA assessment and DFE while using OCT imaging through an undilated pupil followed by the intravitreal injection. The 2 models incorporated both bevacizumab and aflibercept. The number of patients per clinic day, the cost per visit, and the daily revenues were compared between the 2 models. RESULTS: Optimized schedules with and without VA assessments and DFEs allowed for 48 and 96 patients to be injected per day, respectively. Excluding drug costs, the cost per encounter for the visits with and without a DFE were $39.33 and $22.63, respectively. Including the drug costs, the costs per encounter for the visits with and without a DFE were $85.55 and $68.85 for bevacizumab and $1787.58 and $17770.88 for aflibercept, respectively. Once the reimbursements for each visit type were included, the clinics that eliminated the VA and DFEs were more cost efficient. CONCLUSION: Eliminating both VA assessments and DFEs for patients undergoing OCT-guided retreatment with intravitreal injections resulted in decreased exposure times between patients and clinic staff, decreased cost per encounter, and increased patient volumes per clinic day, resulting in improved clinic efficiency and safety while seeing more patients in a clinic day.

Cost-Utility Analysis of VEGF Inhibitors for Treating Neovascular Age-Related Macular Degeneration.

PURPOSE: To perform 11- and 2-year health care sector (ophthalmic) and societal cost perspective reference case, cost-utility analyses comparing bevacizumab, ranibizumab, and aflibercept monotherapies for neovascular age-related macular degeneration (NVAMD). DESIGN: Cost-utility analysis. METHODS: The authors performed 11-year and 2-year ophthalmic and societal cost perspective, cost-utility analyses comparing bevacizumab, ranibizumab, and aflibercept monotherapies for neovascular age-related macular degeneration (NVAMD). We employed patient utilities, bilateral outcomes, 2018 U.S. dollars, vision-related mortality, a Medicare fee schedule, and CATT (Comparison of Age-Related Macular Degeneration Treatments) study and VIEW (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD) trial. Cochrane data were also used. SETTING: Center for Value-Based Medicine. Patient/study population: patients with NVAMD. INTERVENTION: Cost-utility analyses using published data. Data-modeled 10-year vision outcomes were modeled forward to year 11. MAIN OUTCOME MEASUREMENT: These included cost-utility ratios (CURs), costs, and quality-adjusted life-years (QALYs) gained. $100,00/QALY was considered the US cost-effectiveness upper limit. RESULTS: Bevacizumab and ranibizumab each conferred an 11-year, 1.339 QALY gain versus observation. Aflibercept conferred a 1.380 QALY gain. Aflibercept conferred greater QALY gain for less cost than ranibizumab but was not cost-effective compared to bevacizumab ($1,151,451/QALY incremental CUR). The average ophthalmic cost perspective CUR for bevacizumab was $11,033/QALY, $79,600/QALY for ranibizumab, and $44,801/QALY for aflibercept. Eleven-year therapies saved a 1.0 year-of-life loss without treatment from the 11.0-year life expectancy. Early treatment was 138%-149% more cost-effective than late treatment. Two-year therapy prevented a 1-month-of-life loss, and revealed bevacizumab, ranibizumab, and aflibercept conferred 0.141, 0.141, and 0.164 QALY gains, respectively, with corresponding average CURs of $40,371/QALY, $335,726/QALY, and $168,006/QALY, respectively. CONCLUSIONS: From an ophthalmic (medical) cost perspective, bevacizumab, ranibizumab, and aflibercept NVAMD monotherapies were all cost-effective over 11 years, with bevacizumab 6.21× more cost-effective than ranibizumab and 3.06× more cost-effective than aflibercept. Two-year modeling revealed bevacizumab was cost-effective, whereas ranibizumab and aflibercept were not. Early treatment was critical for obtaining optimal vision and cost-effectiveness, as is long-term follow-up and adherence to treatment.

Definition of indicators of appropriateness in the management of neovascular age-related macular degeneration: An expert opinion.

Wet age-related macular degeneration is a chronic condition culminating, in most cases, in blindness. The introduction of anti-angiogenic agents in 2006 has represented a major breakthrough in the treatment of the disease, but timely and effective treatment with regular follow-up and monitoring is mandatory to stabilize and preserve visual acuity. In clinical practice, however, appropriate therapy provision is frequently challenged by economic and organizational issues that result in suboptimal visual outcomes and increased incidence of legal blindness. International Guidelines have defined a diagnostic and therapeutic pathway to ensure the best practice in wet age-related macular degeneration management, but reference parameters to evaluate and compare the performance of Retina Centers are lacking. To address the appropriateness of wet age-related macular degeneration management in Italy, a multidisciplinary panel of ten experts gathered in three meetings. They defined three sets of indicators and relative benchmark values that each Center should comply with to ensure patients optimal care already from the first access: (a) clinical intervention indicators, to determine the possible Center's deviation from the diagnostic and therapeutic pathway; (b) outcome indicator, to evaluate the socioeconomic impact of the healthcare systems' performance; (c) management indicators, to test the size of the gap between the Center's supply and demand. Once the indicators have been analyzed, healthcare systems can plan actions to improve appropriateness and monitor their effects. However, to put this in practice, a concerted effort by all parts involved in healthcare provision is required, together with adequate systems to analyze clinical and administrative documentation.

ORCA study: real-world versus reading centre assessment of disease activity of neovascular age-related macular degeneration (nAMD).

BACKGROUND/AIMS: The prospective, non-interventional ORCA module of the OCEAN study (Observation of Treatment Patterns with Lucentis in Approved Indications) evaluated the qualiy of spectral domain-optical coherence tomography (SD-OCT) image interpretation and treatment decisions by clinicians in Germany and the impact on visual outcomes over 24 months in patients with neovascular age-related macular degeneration (nAMD). METHODS: 2286 SD-OCT scans of 205 eyes were independently evaluated by clinicians and reading centres (RCs) regarding signs of choroidal neovascularisation (CNV) activity, including presence of intraretinal fluid, subretinal fluid, and/or increase in pigment epithelial detachments. Agreement between clinicians and RCs was calculated. Treatment decisions by clinicians and the impact on treatment outcomes were evaluated. RESULTS: CNV activity was detected by RCs on 1578 scans (69.0%) and by clinicians on 1392 scans (60.9%), with agreement in 74.9% of cases. Of the 1578 scans with RC detected CNV activity, anti-vascular endothelial growth factor injections were performed by clinicians in only 35.5% (560/1578). In 19.7% of cases (311/1578), lack of treatment was justified by patients request, termination criteria or chronic cystoid spaces without other signs for CNV activity. In 44.8% of cases (707/1578) with RC detected CNV activity, clinicians claimed no treatment was necessary despite having correctly detected CNV activity in about 2/3 of these cases. In 34% of cases with presumed undertreatment, visual acuity declined in the following visit. CONCLUSION: Although broad agreement on CNV activity parameters was observed between clinicians and RCs, correct identification of CNV activity did not always lead to the initiation of (re-)treatment. To preserve vision over time, correct interpretation of SD-OCT scans and careful retreatment decisions are required. TRIAL REGISTRATION NUMBER: NCT02194803.

Cost-effectiveness of Intravitreal Ranibizumab With Verteporfin Photodynamic Therapy Compared With Ranibizumab Monotherapy for Patients With Polypoidal Choroidal Vasculopathy.

Importance: The EVEREST II trial showed that for patients with polypoidal choroidal vasculopathy (PCV), intravitreal ranibizumab in combination with verteporfin photodynamic therapy improves visual acuity relative to ranibizumab monotherapy. However, whether combination therapy is incrementally cost-effective relative to monotherapy during a lifetime is unclear. Objective: To assess the incremental cost-effectiveness of combination therapy compared with ranibizumab monotherapy in patients with PCV. Design, Setting, and Participants: This model-based, economic evaluation used 2018 unit cost data from a tertiary eye hospital in Singapore, first- and second-year outcomes and resource use data from a multicenter trial across various Asian countries (EVEREST II) to model a hypothetical cohort of patients with symptomatic PCV. Scenario analyses and deterministic and probabilistic sensitivity analyses were performed to examine uncertainty. Data were collected from October 2018 through April 2019 and analyzed from March through October 2019. Interventions: This model used data from the EVEREST II trial, in which all participants were given 0.5 mg of intravitreal ranibizumab once every 4 weeks for the first 3 months. Subsequent administration occurred as needed. For participants receiving combination therapy, standard fluence (50 J/cm3) photodynamic therapy with 6-mg/m2 verteporfin was administered once during the first 3 months and thereafter as needed. Main Outcomes and Measures: Incremental cost per quality-adjusted life-year (QALY) gained for combination therapy relative to monotherapy for patients with PCV. Results: In this model based on a cohort of 1000 patients aged 68 years, a patient with PCV incurred a total cost in Singapore dollars (SGD) of 92 327 (US $67 399) with combination therapy and SGD 92 371 (US $67 431) with monotherapy during a lifetime horizon, generating a modest cost savings of SGD 44 (US $32) per patient undergoing combination therapy. Lifetime QALYs were estimated to be 7.87 for combination therapy and 7.85 for monotherapy, for an incremental gain of 0.02 QALYs. Combination therapy remained cost-saving or cost-effective in all lifetime scenarios modeled, but during shorter time horizons and at lower monotherapy costs, it may not be cost-effective. Conclusions and Relevance: This study found combination therapy to be a dominant (more effective and less costly) strategy, being similar in costs and slightly more effective than ranibizumab monotherapy during a lifetime horizon. However, decreasing the time horizon to less than 10 years and/or reductions in the cost of monotherapy may result in combination therapy no longer being cost-effective.

Economic Value of Anti-Vascular Endothelial Growth Factor Treatment for Patients With Wet Age-Related Macular Degeneration in the United States.

Importance: Anti-vascular endothelial growth factor (anti-VEGF) is a breakthrough treatment for wet age-related macular degeneration (wAMD), the most common cause of blindness in western countries. Anti-VEGF treatment prevents vision loss and has been shown to produce vision gains lasting as long as 5 years. Although this treatment is costly, the benefits associated with vision gains are large. Objective: To estimate the economic value of benefits, costs for patients with wAMD, and societal value in the United States generated from vision improvement associated with anti-VEGF treatment. Design, Setting, and Participants: This economic evaluation study used data from the published literature to simulate vision outcomes for a cohort of 168 820 patients with wAMD aged 65 years or older and to translate them into economic variables. Data were collected and analyzed from March 2018 to November 2018. Main Outcomes and Measures: Main outcomes included patient benefits, costs, and societal value. Each outcome was estimated for a newly diagnosed cohort and the full population across 5 years, with a focus on year 3 as the primary outcome because data beyond that point may be less representative of the general population. Drug costs were the weighted mean across anti-VEGF therapies. Two current treatment scenarios were considered: less frequent injections (mean [SD], 8.2 [1.6] injections annually) and more frequent injections (mean [range], 10.5 [6.8-13.1] injections annually). The 2 treatment innovation scenarios, improved adherence and best case, had the same vision outcomes as the current treatment scenarios had but included more patients treated from higher initiation and lower discontinuation. Results: The study population included 168 820 patients aged 65 years at the time of diagnosis with wAMD. The underlying clinical trials that were used to parameterize the model did not stratify visual acuity outcomes or treatment frequency by sex; therefore, the model parameters could not be stratified by sex. The current treatment scenario of less frequent injections generated $1.1 billion for the full population in year 1 and $5.1 billion in year 3, whereas the scenario of more frequent injections generated $1.6 billion (year 1) and $8.2 billion (year 3). Three-year benefits ranged from $7.3 billion to $11.4 billion in the improved adherence scenario and from $9.7 billion to $15.0 billion if 100% of the patients initiated anti-VEGF treatment and the discontinuation rates were 6% per year or equivalent to clinical trial discontinuation (best-case scenario). Societal value (patient benefits net of treatment cost) ranged from $0.9 billion to $3.0 billion across 3 years in the current treatment scenarios and from $0.9 billion to $4.3 billion in the treatment innovation scenarios. Conclusions and Relevance: This study's findings suggest that improved vision associated with anti-VEGF treatment may provide economic value to patients and society if the outcomes match published outcomes data used in these analyses; however, future innovations that increase treatment utilization may result in added economic benefit.

Intravitreal Ranibizumab for the Treatment of Visual Impairment Due to Choroidal Neovascularization Associated with Rare Diseases: Cost-Effectiveness in the UK.

INTRODUCTION: This study sought to determine the cost-effectiveness of intravitreal ranibizumab compared with best supportive care (BSC; considered to be no active treatment) for the treatment of visual impairment due to choroidal neovascularization (CNV) associated with causes other than neovascular age-related macular degeneration (nAMD) and pathologic myopia (PM) in a UK setting. METHODS: An individual patient-level simulation model was developed to estimate the lifetime costs and quality-adjusted life years (QALYs) of ranibizumab vs. BSC. Regression analyses, performed on patient-level data collected within the pivotal phase III MINERVA trial, modelled visual acuity (VA) progression while patients remained on treatment. Patient utilities were modelled as a function of VA in both eyes and resource use estimates were based on trial data or the literature. Costs were evaluated from the perspective of the UK National Health Service and personal social services, with future costs and health outcomes discounted at 3.5% per annum. Sensitivity and scenario analyses were conducted. RESULTS: The incremental cost-effectiveness ratio for intravitreal ranibizumab was £1363 per QALY compared to BSC and was associated with an incremental benefit of 1.06 QALYs and an incremental cost of £1444 per patient. Drug and administration costs of intravitreal ranibizumab were offset by the prevention of the development of blindness and its associated costs, while the increase in benefits was driven by a reduction in mortality risk and an improved health-related quality of life attributed to an improvement in VA. The findings were robust to a range of sensitivity analyses and ranibizumab consistently remained cost-effective at a willingness-to-pay threshold of £20,000-30,000 per QALY gained for all sensitivity analyses. CONCLUSION: Intravitreal ranibizumab is a highly cost-effective intervention for the treatment of CNV due to causes other than nAMD and PM as it delivers substantial QALY gains to patients while making cost savings vs. BSC. FUNDING: Novartis Pharmaceuticals UK Ltd.

Safety and Efficacy of Anti-Vascular Endothelial Growth Factor Therapies for Neovascular Age-Related Macular Degeneration: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the evidence on the safety and efficacy of anti-vascular endothelial growth factor (VEGF) therapies for the treatment of neovascular age-related macular degeneration (AMD). METHODS: A literature search of the PubMed and Cochrane Library databases was last conducted in February 2017; there were no date restrictions, and the search was limited to studies published in English. The combined searches yielded 191 citations, 28 of which were selected because they were clinical trials and were deemed clinically relevant for the Ophthalmic Technology Assessment Committee Retina/Vitreous Panel to review in full. The panel methodologist then assigned a level of evidence rating to each study. RESULTS: Sixteen of the 28 citations provided level I evidence supporting the use of anti-VEGF agents for neovascular AMD, including intravitreal ranibizumab, aflibercept, and bevacizumab. Eight studies reviewed provided level II evidence, and 4 studies provided level III evidence, but only the level I studies are included in this assessment. There are long-term follow-up data on the efficacy of ranibizumab and bevacizumab (≥5 years), but these data are subject to the bias of incomplete follow-up. CONCLUSIONS: Review of the literature indicates that intravitreal injection of anti-VEGF therapy is safe and effective for neovascular AMD over 2 years, the period for which data are available. Further research is needed to evaluate the long-term safety and comparative efficacy of these agents.

Real-world use of ranibizumab for neovascular age-related macular degeneration in Taiwan.

This study investigated the "real-world" use of ranibizumab for neovascular age-related macular degeneration (nAMD) in Taiwan and assessed the visual outcome. We reviewed the medical records at National Cheng Kung University Hospital, Taiwan, during 2012-2014 for 264 consecutive eyes of 229 patients with nAMD, who applied for ranibizumab covered by national health insurance. A total of 194 eyes (73.5%) in 179 patients (65.5% men; mean ± standard deviation age 69.4 ± 10.7 years) were pre-approved for treatment. Applications for treatment increased year by year, but approval rates decreased during this time. The major causes of rejection for funding were diseases mimicking nAMD, including macular pucker/epiretinal membrane, macular scarring, dry-type AMD, and possible polypoidal choroidal vasculopathy. After completion of three injections in 147 eyes, visual acuity significantly improved, gaining ≥1 line in 51.8% of eyes and stabilising in 38.3% of 141 eyes in which visual acuity was measured. The 114 eyes approved with only one application had a better visual outcome than the 27 eyes approved after the second or third applications. In conclusion, ranibizumab is effective for nAMD; however, approval after the second or third application for national health insurance cover is a less favourable predictor of visual outcome.

Intravitreal Ziv-Aflibercept: Clinical Effects and Economic Impact.

During the past decade, drugs that inhibit the actions of vascular endothelial growth factor (VEGF) have become standard-of-care treatment for a variety of chorioretinal vascular conditions. The off-label, intravitreal use of ziv-aflibercept (Zaltrap) has provided clinicians with an additional cost-effective drug. The commercial preparation of ziv-aflibercept contains the same aflibercept (VEGF-trap) molecule as Eylea but has a much higher osmolarity (1000 mOsm/kg vs 300 mOsm/kg). Initial concerns regarding cytotoxicity and long-term safety of intravitreal ziv-aflibercept have been largely negated after a series of publications failed to identify adverse ocular and systemic side effects. Both treatment-naive and anti-VEGF‒resistant cases of neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), retinal vein occlusion (RVO), and choroidal neovascular membrane (CNVM) may respond as well to ziv-aflibercept as to aflibercept. A higher dose of ziv-aflibercept (2 mg in 0.08 mL) does not cause any adverse effects during short-term follow-up period (1 month). Data from various sources suggest that ziv-aflibercept may be as cost effective as bevacizumab, thereby making it an attractive treatment option in low- and middle-income countries. However, problems with off-label use, compounding, and counterfeiting limit its availability in many countries. Data from prospective, randomized, multicenter clinical trials are still required to convince physicians and regulatory bodies of its clinical efficacy and potential as early therapy.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY ASSESSMENT OF VASCULAR EFFECTS OCCURRING AFTER AFLIBERCEPT INTRAVITREAL INJECTIONS IN TREATMENT-NAIVE PATIENTS WITH WET AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate vessel changes occurring after aflibercept injections in treatment-naive exudative age-related macular degeneration patients. METHODS: Fifteen eyes of 15 patients affected by wet age-related macular degeneration were enrolled in the study. All the patients had a diagnosis of Type 1 choroidal neovascularization and were treated with 3 monthly aflibercept intravitreal injections (IVI). Subjects were evaluated by means of optical coherence tomography angiography at baseline, the day after the first injection and one month after both the first and the second IVI. At last, all the patients were followed up to 2 months after the third IVI. RESULTS: Foveal superficial vascular plexus flow density was 29.01% (21.13-37.32%) at baseline and was significantly reduced as soon as 1 month after the first IVI (median: 20.78%; interquartile range: 14.75-23.13%; P = 0.017). Parafoveal superficial vascular plexus flow density was 47.09% (44.91-51.72%) at baseline and significantly decreased as soon as 1 month after the second IVI (median: 44.40%; interquartile range: 41.59-49.29%; P = 0.034). Choroidal neovascularization lesion area remained stable throughout the follow-up. Nevertheless, interestingly, choroidal neovascularization flow area was significantly reduced as soon as the next day the first IVI (median: 0.37 mm and interquartile range: 0.27-0.72 mm at baseline; median: 0.30 mm and interquartile range: 0.24-0.64 mm at 1 day after the first IVI; P = 0.047). CONCLUSION: Intravitreal aflibercept injections are associated with a significant change in native retinal and choroidal vasculature. Moreover, the treatment did not cause a reduction in lesion area, but rather reduced the flow in the choroidal neovascularization.

Preliminary in vitro and in vivo assessment of a new targeted inhibitor for choroidal neovascularization in age-related macular degeneration.

Choroidal neovascularization (CNV) in age-related macular degeneration usually causes blindness. We established a novel targeted inhibitor for CNV in age-related macular degeneration. The inhibitor CR2-sFlt 1 comprises a CR2-targeting fragment and an anti-vascular endothelial growth factor (VEGF) domain (sFlt 1). The targeting of CR2-sFlt 1 was studied using the transwell assay in vitro and frozen sections in vivo using green fluorescent labeling. Transwell assay results showed that CR2-sFlt 1 migrated to the interface of complement activation products and was present in the retinal tissue of the CR2-sFlt 1-treated CNV mice. Treatment effects were assessed by investigating the VEGF concentration in retinal pigmented epithelial cell medium and the thickness of the CNV complex in the mice treated with CR2-sFlt 1. CR2-sFlt 1 significantly reduced the VEGF secretion from retinal pigmented epithelial cells in vitro and retarded CNV progress in a mouse model. Expression analysis of VEGF and VEGFRs after CR2-sFlt 1 intervention indicated the existence of feedback mechanisms in exogenous CR2-sFlt 1, endogenous VEGF, and VEGFR interaction. In summary, we demonstrated for the first time that using CR2-sFlt 1 could inhibit CNV with clear targeting and high selectivity.