RESUMO
BACKGROUND: To evaluate the impact of reimbursement criteria change on the utilization pattern of anti-vascular endothelial growth factor (anti-VEGF) among patients with wet age-related macular degeneration (wAMD) and diabetic macular edema (DME) separately in Taiwan. METHODS: An interrupted time series analysis (ITSA) was performed using Taiwan's National Health Insurance (NHI) database, and patients with wAMD or DME diagnosis at the first injection of anti-VEGF agents was identified from 2011 to 2019. The outcome of interest was treatment gaps between injections of anti-VEGF. This outcome was retrieved quarterly, and the study period was divided into three phases in wAMD (two criteria changed in August 2014 [intervention] and December 2016 [intervention]) and two phases in DME (three consecutive criteria changed in 2016 [intervention]). Segmented regression models adjusted for autocorrelation were used to estimate the change in level and the change in slope of the treatment gaps between each anti-VEGF injection. RESULTS: The treatment gaps between each anti-VEGF injection decreased from 2011 to 2019. The cancellation of the annual three needles limitation was associated with significantly shortened treatment gaps between the third and fourth needles (wAMD change in level: -228 days [95% CI -282, -173], DME change in level: -110 days [95% CI -141, -79]). The treatment gap between the fifth and sixth needles revealed a similar pattern but without significant change in DME patients. Other treatment gaps revealed considerable change in slopes in accordance with criteria changes. CONCLUSION: This is the first nationwide study using ITSA to demonstrate the impact of reimbursement policy on treatment gaps between each anti-VEGF injection. After canceling the annual limitation, we found that the treatment gaps significantly decreased among wAMD and DME patients. The shortened treatment gaps might further link to better visual outcomes according to previous studies. The different impacts from criteria changes can assist future policy shaping. Future studies were warranted to explore whether such changes are associated with the benefits of visual effects.
Assuntos
Inibidores da Angiogênese , Retinopatia Diabética , Análise de Séries Temporais Interrompida , Edema Macular , Fator A de Crescimento do Endotélio Vascular , Humanos , Edema Macular/tratamento farmacológico , Edema Macular/economia , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/economia , Masculino , Feminino , Inibidores da Angiogênese/economia , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/administração & dosagem , Taiwan , Idoso , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/economia , Injeções Intravítreas , Mecanismo de Reembolso , Pessoa de Meia-Idade , Programas Nacionais de Saúde/economia , Programas Nacionais de Saúde/estatística & dados numéricos , Ranibizumab/economia , Ranibizumab/uso terapêutico , Ranibizumab/administração & dosagem , Idoso de 80 Anos ou maisRESUMO
Purpose: To explore the long-term effect of diabetic retinopathy on response to anti-vascular endothelial growth factor (VEGF) treatment in age-related macular degeneration-associated type 1 macular neovascularization (MNV) using optical coherence tomography angiography (OCTA). Methods: A total of 45 eyes with exudative neovascular age-related macular degeneration (nAMD) with type 1 MNV were included in the analysis. Among them, 24 eyes of 24 patients had no history of diabetes mellitus (DM) in their anamnesis and were assigned to the Not Diabetic group; 21 eyes of 21 patients had mild diabetic retinopathy and were included in the Diabetic group. We considered the following outcome measures: (1) best-corrected visual acuity changes; (2) central macular thickness; (3) MNV lesion area; and (4) MNV flow area. The OCTA acquisitions were performed at the following time points: (1) baseline visit, which corresponded to the day before the first injection; (2) post-loading phase (LP), which was scheduled at 1 month after the last LP injection; and (3) 12-month follow-up visit. Results: All morphofunctional parameters showed a significant improvement after the LP and at the 12-month follow-up visit. Specifically, both the Diabetic group and the Not Diabetic group displayed a significant reduction of MNV lesion areas at both the post-LP assessment (P = 0.026 and P = 0.016, respectively) and the 12-month follow-up (P = 0.039 and P = 0.025, respectively). Similarly, the MNV flow area was significantly decreased in both the Diabetic group and the Not Diabetic group at the post-LP assessment (P < 0.001 and P = 0.012, respectively) and at the 12-month follow-up (P = 0.01 and P = 0.035, respectively) compared to baseline. A smaller reduction in the MNV lesion area was observed in the Diabetic group at both the post-LP evaluation (P = 0.015) and the 12-month follow-up (P = 0.032). No other significant differences were found between the groups for the other parameters (P > 0.05). Conclusions: Our results indicated that the Diabetic group exhibited a smaller reduction in MNV lesion area after 12 months of anti-VEGF treatment. This highlights the importance of considering diabetic retinopathy as a potential modifier of treatment outcomes in nAMD management, with DM serving as a crucial risk factor during anti-angiogenic treatment.
Assuntos
Inibidores da Angiogênese , Retinopatia Diabética , Angiofluoresceinografia , Injeções Intravítreas , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular , Acuidade Visual , Degeneração Macular Exsudativa , Humanos , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/fisiopatologia , Masculino , Feminino , Inibidores da Angiogênese/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual/fisiologia , Idoso , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/fisiopatologia , Degeneração Macular Exsudativa/diagnóstico , Seguimentos , Pessoa de Meia-Idade , Ranibizumab/uso terapêutico , Ranibizumab/administração & dosagem , Bevacizumab/uso terapêutico , Estudos Retrospectivos , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Resultado do Tratamento , Fundo de Olho , Fatores de Tempo , Proteínas Recombinantes de FusãoRESUMO
Purpose: Retinal neovascularization is a significant feature of advanced age-related macular degeneration (AMD) and a major cause of blindness in patients with AMD. However, the underlying mechanism of this pathological neovascularization remains unknown. Iron metabolism has been implicated in various biological processes. This study was conducted to investigate the effects of iron metabolism on retinal neovascularization in neovascular AMD (nAMD). Methods: C57BL/6J and very low-density lipoprotein receptor (VLDLR) knockout (Vldlr-/-) mice, a murine model of nAMD, were used in this study. Bulk-RNA sequencing was used to identify differentially expressed genes. Western blot analysis was performed to test the expression of proteins. Iron chelator deferiprone (DFP) was administrated to the mice by oral gavage. Fundus fluorescein angiography was used to evaluate retinal vascular leakage. Immunofluorescence staining was used to detect macrophages and iron-related proteins. Results: RNA sequencing (RNA-seq) results showed altered transferrin expression in the retina and RPE of Vldlr-/- mice. Disrupted iron homeostasis was observed in the retina and RPE of Vldlr-/- mice. DFP mitigated iron overload and significantly reduced retinal neovascularization and vascular leakage. In addition, DFP suppressed the inflammation in Vldlr-/- retinas. The reduced signals of macrophages were observed at sites of neovascularization in the retina and RPE of Vldlr-/- mice after DFP treatment. Further, the IL-6/JAK2/STAT3 signaling pathway was activated in the retina and RPE of Vldlr-/- mice and reversed by DFP treatment. Conclusions: Disrupted iron metabolism may contribute to retinal neovascularization in nAMD. Restoring iron homeostasis by DFP could be a potential therapeutic approach for nAMD.
Assuntos
Deferiprona , Modelos Animais de Doenças , Homeostase , Quelantes de Ferro , Ferro , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Retiniana , Animais , Deferiprona/farmacologia , Deferiprona/uso terapêutico , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Camundongos , Ferro/metabolismo , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/tratamento farmacológico , Neovascularização Retiniana/etiologia , Neovascularização Retiniana/patologia , Angiofluoresceinografia , Receptores de LDL/genética , Receptores de LDL/metabolismo , Western Blotting , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/patologia , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/metabolismo , Fator de Transcrição STAT3/metabolismo , MasculinoRESUMO
BACKGROUND: Neovascular age-related macular degeneration (nAMD) is a common cause of visual impairment and blindness in the elderly with globally increasing prevalence. Vascular endothelial growth factor inhibitor (anti-VEGF) treatment has improved visual prognosis of nAMD, but continuous treatment may cause anxiety and stress, although increase in visual acuity (VA) may also have positive effects on patients' quality of life. The health care burden due to frequent treatment and monitoring is apparent, but the effect of anti-VEGF treatment on patients' quality of life is not fully understood. We evaluated the overall impact of nAMD and its treatment on newly diagnosed patients' health-related quality of life (HRQoL) in real-world setting. METHODS: The present prospective cohort study included newly diagnosed nAMD patients treated with anti-VEGF injections at Oulu University Hospital during 2019-2020. Data included parameters from comprehensive ophthalmic examination and fundus imaging, age at diagnosis, sex, comorbidities, visual acuity, and frequency of anti-VEGF injections. HRQoL was assessed by 15D questionnaire at diagnosis, 6 months, and 12 months. RESULTS: 95 nAMD patients were included. They were 78 ± 8 years old, 56 (59%) were female, and 74 (78%) had more than one comorbidity. The patients received 8 ± 3 anti-VEGF-injections. Visual acuity (VA) improved from 56 ± 18 to 61 ± 24 Early treatment diabetic retinopathy study (ETDRS) letters in 12 months. VA improved > 5 ETDRS letters in 45 (47%), remained stable in 30 (32%) and decreased > 5 letters in 17 (18%) eyes. The mean total 15D score reflecting overall HRQoL decreased from 0.850 ± 0.104 to 0.834 ± 0.103 in 12 months. Decreased HRQoL was associated with baseline best-corrected VA (BCVA) ≥ 70 ETDRS letters (p = 0.023) and more than one comorbidity (p = 0.034). HRQoL regarding visual function increased from 0.765 ± 0.194 to 0.789 ± 0.184 during the 12-month follow-up. CONCLUSIONS: In real world setting, HRQoL regarding visual function improved in anti-VEGF-treated nAMD patients during the first 12 months after the diagnosis and treatment initiation. Good baseline VA or several comorbidities were associated with decreased overall HRQoL during the follow-up. Despite the effectiveness of anti-VEGF treatment on visual function, several other aspects affecting elderly patients' everyday life should be considered when nAMD treatment is implemented.
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Inibidores da Angiogênese , Qualidade de Vida , Acuidade Visual , Humanos , Masculino , Feminino , Idoso , Estudos Prospectivos , Acuidade Visual/efeitos dos fármacos , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/efeitos adversos , Idoso de 80 Anos ou mais , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular/tratamento farmacológico , Degeneração Macular/fisiopatologia , Inquéritos e Questionários , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/fisiopatologia , Degeneração Macular Exsudativa/psicologia , Estudos de CoortesRESUMO
PURPOSE: To investigate the significance of intravitreal anti-vascular endothelial growth factor treatment in patients with neovascular age-related macular degeneration and poor visual acuity. METHODS: Retrospective study of patients with neovascular age-related macular degeneration with baseline best-corrected visual acuity of ≤20/200. Patients were divided into regular treatment and scarce treatment groups according to whether they underwent consecutive intravitreal anti-vascular endothelial growth factor treatments at intervals of ≤4 months or not. RESULTS: A total of 131 eyes were included: 87 and 44 eyes in the regular treatment and scarce treatment groups, respectively. The regular treatment group showed significantly improved preservation of lesion size at both Years 1 and 2, with significantly fewer incidences of new subretinal hemorrhage. Improvements in visual acuity, reduction in central subfield macular thickness, and maximal height of choroidal neovascularization were significantly favorable in the regular treatment group at Year 1, and central subfield macular thickness was significantly decreased at Year 2. Survival analysis revealed that the regular treatment group had significantly greater preservation of visual acuity and lesion size than that in the scarce treatment group. CONCLUSION: Maintaining intravitreal anti-vascular endothelial growth factor treatment for patients with neovascular age-related macular degeneration and poor vision showed significant advantages in visual acuity and lesion size stability and reduced the incidence of new subretinal hemorrhage, which suggests preservation of paracentral vision.
Assuntos
Inibidores da Angiogênese , Bevacizumab , Injeções Intravítreas , Ranibizumab , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular , Acuidade Visual , Degeneração Macular Exsudativa , Humanos , Acuidade Visual/fisiologia , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/uso terapêutico , Estudos Retrospectivos , Masculino , Feminino , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/fisiopatologia , Degeneração Macular Exsudativa/diagnóstico , Ranibizumab/administração & dosagem , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Bevacizumab/uso terapêutico , Angiofluoresceinografia , SeguimentosRESUMO
To investigate quantitative associations between AI-assessed disease activity and optical coherence tomography angiography (OCTA)-derived parameters in patients with neovascular age-related macular degeneration (nAMD) undergoing anti-VEGF therapy. OCTA and SD-OCT images obtained from multicenter, randomized study data were evaluated. A deep learning algorithm (RetInSight) was used to detect and quantify macular fluid on SD-OCT. Mixed effects models were applied to evaluate correlations between fluid volumes, macular neovascularization (MNV)-type and OCTA-derived MNV parameters; lesion size (LS) and vessel area (NVA). 230 patients were included. A significant positive correlation was observed between SRF and NVA (estimate = 199.8 nl/mm2, p = 0.023), while a non-significant but negative correlation was found between SRF and LS (estimate = - 71.3 nl/mm2, p = 0.126). The presence of Type I and Type II MNV was associated with significantly less intraretinal fluid (IRF) compared to Type III MNV (estimate type I:- 52.1 nl, p = 0.019; estimate type II:- 51.7 nl, p = 0.021). A significant correlation was observed between pigment epithelial detachment (PED) and the interaction between NVA and LS (estimate:28.97 nl/mm2; p = 0.012). Residual IRF at week 12 significantly correlated to baseline NVA (estimate:38.1 nl/mm2; p = 0.015) and LS (estimate:- 22.6 nl/mm2; p = 0.012). Fluid in different compartments demonstrated disparate associations with MNV OCTA features. While IRF at baseline was most pronounced in type III MNV, residual IRF was driven by neovascular MNV characteristics. Greater NVA in proportion to LS was associated with higher amounts of SRF and PED. The correlation between these parameters may represent MNV maturation and can be used as a biomarker for resolution of disease activity. AI-based OCT analysis allows for a deeper understanding of neovascular disease in AMD and the potential to adjust therapeutic strategies to optimize outcomes through precision medicine.
Assuntos
Tomografia de Coerência Óptica , Humanos , Tomografia de Coerência Óptica/métodos , Feminino , Masculino , Idoso , Degeneração Macular/diagnóstico por imagem , Degeneração Macular/patologia , Idoso de 80 Anos ou mais , Inteligência Artificial , Fator A de Crescimento do Endotélio Vascular/metabolismo , Inibidores da Angiogênese/uso terapêutico , Angiofluoresceinografia/métodos , Neovascularização de Coroide/diagnóstico por imagem , Neovascularização de Coroide/patologia , Degeneração Macular Exsudativa/diagnóstico por imagem , Degeneração Macular Exsudativa/tratamento farmacológico , Aprendizado ProfundoRESUMO
Purpose: The purpose of this study was to investigate the molecular mechanisms underlying anti-vascular endothelial growth factor (anti-VEGF) efficacy and response variability in neovascular age-related macular degeneration (nAMD) using longitudinal proteomic and metabolomic analysis alongside three-dimensional lesion measurements. Methods: In this prospective study, 54 treatment-naive patients with nAMD underwent "3+ pro re nata" (3+PRN) anti-VEGF regimens followed for at least 12 weeks. Aqueous humors were collected pre- and post-treatment for proteomic and metabolomic analysis. Three-dimensional optical coherence tomography (OCT) and OCT angiography assessed different types of nAMD lesion volumes and areas. Results: There were 1350 proteins and 1268 metabolites that were identified in aqueous humors, with 301 proteins and 353 metabolites significantly altered during anti-VEGF treatment, enriched in pathways of angiogenesis, energy metabolism, signal transduction, and neurofunctional regulation. Sixty-seven changes of (Δ) molecules significantly correlated with at least one type of ΔnAMD lesion. Notably, proteins FGA, TALDO1, and ASPH significantly decreased during treatment, with their reductions correlating with greater lesion regression in at least two lesion types. Conversely, despite that YIPF3 also showed significant downregulation, its decrease was associated with poorer regression in total nAMD lesion and subretinal hyper-reflective material. Conclusions: This study identifies FGA, TALDO1, and ASPH as potential key molecules in the efficacy of anti-VEGF therapy, whereas YIPF3 may be a key factor in poor response. The integration of longitudinal three-dimensional lesion analysis with multi-omics provides valuable insights into the mechanisms and response variability of anti-VEGF treatment in nAMD.
Assuntos
Inibidores da Angiogênese , Angiofluoresceinografia , Injeções Intravítreas , Proteômica , Ranibizumab , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular , Degeneração Macular Exsudativa , Humanos , Tomografia de Coerência Óptica/métodos , Inibidores da Angiogênese/uso terapêutico , Estudos Prospectivos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo , Masculino , Feminino , Idoso , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/metabolismo , Degeneração Macular Exsudativa/diagnóstico , Angiofluoresceinografia/métodos , Ranibizumab/uso terapêutico , Idoso de 80 Anos ou mais , Humor Aquoso/metabolismo , Bevacizumab/uso terapêutico , Metabolômica/métodos , Acuidade Visual , Imageamento Tridimensional , MultiômicaRESUMO
PURPOSE: This study sought to provide an overview of the current research and further analyze publication trends in the field of vascular endothelial growth factor (VEGF) and anti-VEGF treatment for neovascular age-related macular degeneration (NVAMD). METHODS: We downloaded all related publications from 2001 to 2020 from the Web of Science Core Collection and conducted a bibliometric analysis using the bibiometrix package in R programming software. RESULTS: A total of 3717 publications were included in the analysis. The USA contributed the largest number of publications (1443), and achieved the highest number of citations (74,946) and H-index value (28). Johns Hopkins University, USA, was the top institution with the most publications, and Peter A. Campochiaro was the most productive professor at The Wilmer Eye Institute, USA. 9.60% of the total publications were from the Journal of Retinal and Vitreous Diseases. Trend analysis demonstrated that anti-VEGF therapy was introduced in early 2000 after steroids, and the last 2 decades have witnessed the blossom of several anti-VEGF agents. "Treat-and-extend" and "resistance" were two popular trend topics in recent years. CONCLUSIONS: The USA occupies a dominant position in the research field of VEGF and anti-VEGF treatments in NVAMD. Steroid administration, photodynamic therapy, and anti-VEGF therapy have been pivotal advances in the treatment of NVAMD patients over the past 2 decades. Limited acting period and resistance are potential investigation directions in future studies.
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Inibidores da Angiogênese , Bibliometria , Fator A de Crescimento do Endotélio Vascular , Degeneração Macular Exsudativa , Humanos , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/diagnóstico , Injeções IntravítreasRESUMO
PURPOSE: To understand factors affecting visual prognosis and the number of intravitreal antivascular endothelial growth factor (anti-VEGF) injections needed to stabilize wet age-related macular degeneration (AMD). METHODS: In this retrospective cohort, 119 treatment-naïve wet AMD patients were followed for two years. In patients with bilateral disease, the eye with worse best-corrected visual acuity (BCVA) or that received more intravitreal injections was recruited as the study eye. In all visits, BCVA was recorded, ophthalmological examination was performed including macular optical coherence tomography imaging. Twenty health status/lifestyle questions were asked to the patients via phone as potential risk factors. All patients received 3 loading doses of intravitreal bevacizumab injections and received repeat injections of aflibercept or ranibizumab when the eye had a new, active neovascular lesion. RESULTS: Patients who took regular micronutrition had similar visual outcome and injection numbers compared to the ones who did not. Patients with bilateral disease needed less intravitreal injections compared to unilateral AMD patients (p = 0.016) and women on hormone replacement therapy (HRT) required less injections compared to the women who were not (p = 0.024). Female patients had a mean gain of 2.7 letters while male patients lost 3.8 letters (p = 0.038). Wet AMD started at an earlier age in smokers (p = 0.002). Patients with a better education level presented earlier with better BCVA (p = 0.037). CONCLUSION: HRT and anti-VEGF injections to the fellow eye improved the prognosis of wet AMD, while male patients had slightly worse prognosis. Estrogen's protective effects and potential contribution in wet AMD needs further attention. Retrospectively registered: 2020/0622.
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Inibidores da Angiogênese , Bevacizumab , Injeções Intravítreas , Ranibizumab , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de Fusão , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular , Acuidade Visual , Degeneração Macular Exsudativa , Humanos , Masculino , Estudos Retrospectivos , Feminino , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/diagnóstico , Degeneração Macular Exsudativa/fisiopatologia , Inibidores da Angiogênese/administração & dosagem , Idoso , Ranibizumab/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Proteínas Recombinantes de Fusão/administração & dosagem , Bevacizumab/administração & dosagem , Tomografia de Coerência Óptica/métodos , Prognóstico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso de 80 Anos ou mais , Seguimentos , Pessoa de Meia-Idade , Angiofluoresceinografia/métodosRESUMO
Purpose: The purpose of this study was to evaluate the efficacy and safety of bevacizumab-awwb in the off-label treatment of neovascular age-related macular degeneration (n-AMD) and diabetic macular edema (DME). Methods: All patients with n-AMD and DME treated in the maintenance phase according to the "treat and extend" strategy, who underwent forced drug substitution from bevacizumab to bevacizumab-awwb from October 2022 to April 2023 at the Tor Vergata Polyclinic in Rome, were evaluated in a retrospective study. The primary outcome was changes in central retinal thickness (CRT) over time following drug substitution. The secondary outcomes were variations in drug durability, best corrected visual acuity (BCVA) and retinal fluid, and the incidence of drug-related local and systemic serious adverse events. Results: Of 80 eyes of 76 patients with n-AMD and 55 eyes of 44 patients with DME included, before and after drug substitution, the average CRT did not statistically differ; the proportion of patients within time intervals of q8, q12, and q16 was not different; and the mean BCVA remained constant. Of a cumulative 3496 bevacizumab-awwb treatments (2154 for patients with n-AMD and 1342 for patients with DME), no local severe complications were detected. Out of a total of 544 patients (342 affected by n-AMD and 202 affected by DME), no serious adverse events were reported. Conclusions: In our cohort of patients with n-AMD and DME in the maintenance phase, bevacizumab-awwb seems to represent a viable and cost-effective intravitreal therapy with comparable efficacy and safety to the originator. Translational Relevance: This study provides a preliminary assessment of the efficacy and safety of intravitreal bevacizumab-awwb, which is widely used off-label in retinal vascular diseases.
Assuntos
Inibidores da Angiogênese , Bevacizumab , Injeções Intravítreas , Edema Macular , Uso Off-Label , Acuidade Visual , Humanos , Masculino , Bevacizumab/uso terapêutico , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Feminino , Estudos Retrospectivos , Idoso , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/administração & dosagem , Acuidade Visual/efeitos dos fármacos , Edema Macular/tratamento farmacológico , Idoso de 80 Anos ou mais , Retinopatia Diabética/tratamento farmacológico , Pessoa de Meia-Idade , Degeneração Macular Exsudativa/tratamento farmacológico , Substituição de Medicamentos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tomografia de Coerência Óptica , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the efficacy and safety of faricimab compared with other anti-vascular endothelial growth factor (anti-VEGF) agents in treating neovascular age-related macular degeneration (nAMD) patients. METHODS AND ANALYSIS: A systematic review (SR) was conducted up to January 2023. Network meta-analyses (NMA) were performed, including sensitivity and subgroup analyses for naïve population. Outcomes included changes in visual acuity (Early Treatment of Diabetic Retinopathy Study [ETDRS] letters), anatomical changes, frequency of injections and adverse events. The Cochrane Collaboration guidelines and the Confidence in Network Meta-Analysis framework were used for the SR and the certainty of evidence, respectively. RESULTS: From 4128 identified records through electronic databases and complementary searches, 63 randomised controlled trials (RCTs) met the eligibility criteria, with 42 included in the NMA. Faricimab showed a significant reduction in the number of annual injections compared with most fixed and flexible anti-VEGF treatment regimens, while showing no statistically significant differences in visual acuity through ETDRS letter gain, demonstrating a comparable efficacy. Retinal thickness results showed comparable efficacy to other anti-VEGF agents, and inferior only to brolucizumab. Results also showed that more patients treated with faricimab were free from post-treatment retinal fluid compared with aflibercept every 8 weeks, and both ranibizumab and bevacizumab, in the fixed and pro re nata (PRN) assessed schedules. Faricimab showed a comparable safety profile regarding the risk of ocular adverse events and serious ocular adverse events (SOAE), except for the comparison with brolucizumab quarterly, in which faricimab showed a significant reduction for SOAE risk. CONCLUSION: Faricimab showed a comparable clinical benefit in efficacy and safety outcomes, with a reduction in annual injections compared with fixed and flexible anti-VEGF drug regimens, representing a valuable treatment option for nAMD patients. PROSPERO REGISTRATION NUMBER: CRD42023394226.
Assuntos
Inibidores da Angiogênese , Injeções Intravítreas , Metanálise em Rede , Fator A de Crescimento do Endotélio Vascular , Acuidade Visual , Degeneração Macular Exsudativa , Humanos , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/administração & dosagem , Acuidade Visual/efeitos dos fármacos , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Resultado do Tratamento , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagemRESUMO
Purpose: This analysis investigated potential associations between gene variants and clinical end points in the VIEW 1 and 2 randomized clinical trials of intravitreal aflibercept and ranibizumab in neovascular age-related macular degeneration (AMD). Methods: A genome-wide association analysis was conducted in a subgroup of patients from VIEW 1 and 2 consenting to the optional pharmacogenetic analysis. Results: Data were pooled from 780 samples from patients representative of the overall VIEW 1 and 2 populations. After Bonferroni correction for multiplicity and statistical adjustment for baseline risk factors, no significant associations were found between previously identified prognostic AMD gene variants and treatment response according to key prespecified VIEW 1 and 2 end points. Genome-wide, there were no significant genetic associations in patients experiencing gains of ≥15 Early Treatment of Diabetic Retinopathy Study letters after 1 or 2 years of treatment. A cluster of variants in ANO2 (encoding anoctamin 2, a calcium-activated chloride channel expressed on photoreceptor cells) on chromosome 12 reached the level of significance for loss of ≥5 letters after 1 year of treatment (P < 5 × 10-8), with the ANO2 rs2110166 SNP demonstrating highly significant association (P = 1.99 × 10-8). Carriers of the ANO2 rs2110166 TT genotype showed a robust increase in visual acuity versus baseline compared with a small decrease in those with the TC genotype. Conclusions: None of the potential prognostic candidate genes were associated with the clinical end points for treated patients. Preliminary analyses suggest an association of ANO2 with retinal function, with a potential impact on vision of approximately one line over at least the first year. Further investigation of the function of ANO2 in retinal pathophysiology is merited.
Assuntos
Inibidores da Angiogênese , Anoctaminas , Estudo de Associação Genômica Ampla , Injeções Intravítreas , Polimorfismo de Nucleotídeo Único , Ranibizumab , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de Fusão , Fator A de Crescimento do Endotélio Vascular , Acuidade Visual , Humanos , Masculino , Feminino , Inibidores da Angiogênese/uso terapêutico , Idoso , Acuidade Visual/fisiologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ranibizumab/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Anoctaminas/genética , Degeneração Macular Exsudativa/genética , Degeneração Macular Exsudativa/tratamento farmacológico , Idoso de 80 Anos ou mais , Genótipo , Resultado do Tratamento , Farmacogenética , Testes FarmacogenômicosRESUMO
This Viewpoint highlights the discrepancy between dosing and patient assessment schedules in clinical trials for 2 new intravitreal agents, faricimab, 6 mg, and aflibercept, 8 mg, to treat neovascular age-related macular degeneration.
Assuntos
Inibidores da Angiogênese , Injeções Intravítreas , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de Fusão , Fator A de Crescimento do Endotélio Vascular , Humanos , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Proteínas Recombinantes de Fusão/administração & dosagem , Inibidores da Angiogênese/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual/fisiologia , Esquema de Medicação , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Degeneração Macular Exsudativa/tratamento farmacológico , MasculinoRESUMO
PURPOSE: Wet age-related macular degeneration (AMD) is a blinding retinal disease. Monthly intravitreal anti-VEGF antibody injections of bevacizumab (off-label) and ranibizumab (FDA approved) are the standard of care. Antibody aggregation may interfere with ocular absorption/distribution. This study assessed topical delivery of dilute antibodies to the posterior segment of rabbit eyes using a novel anti-aggregation formula (AAF). METHODS: Bevacizumab, or biosimilar ranibizumab was diluted to 5 mg/ml in AAF. All rabbits were dosed twice daily. Substudy 1 rabbits (bevacizumab, 100 µl eye drops): Group 1 (bevacizumab/AAF, n = 6); Group 2 (bevacizumab/PBS, n = 7) and Vehicle control (AAF, n = 1). Substudy 2 rabbits (ranibizumab biosimilar/AAF, 50 µl eye drops): (ranibizumab biosimilar/AAF, n = 8). At 14.5 days, serum was drawn from rabbits. Aqueous, vitreous and retina samples were recovered from eyes and placed into AAF aliquots. Tissue analyzed using AAF as diluent. RESULTS: Bevacizumab in AAF permeated/accumulated in rabbit aqueous, vitreous and retina 10 times more, than when diluted in PBS. AAF/0.1% hyaluronic acid eye drops, dosed twice daily, provided mean tissue concentrations (ng/g) in retina (29.50), aqueous (12.34), vitreous (3.46), and serum (0.28 ng/ml). Additionally, the highest concentration (ng/g) of ranibizumab biosimilar was present in the retina (18.0), followed by aqueous (7.82) and vitreous (1.47). Serum concentration was negligible (< 0.04 ng/ml). No irritation was observed throughout the studies. CONCLUSIONS: Bevacizumab and ranibizumab, in an AAF diluent eye drop, can be delivered to the retina, by the twice daily dosing of a low concentration mAb formulation. This may prove to be an adjunct to intravitreal injections.
Assuntos
Bevacizumab , Soluções Oftálmicas , Ranibizumab , Retina , Animais , Ranibizumab/administração & dosagem , Ranibizumab/farmacocinética , Coelhos , Bevacizumab/administração & dosagem , Bevacizumab/farmacocinética , Soluções Oftálmicas/administração & dosagem , Retina/metabolismo , Retina/efeitos dos fármacos , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacocinética , Corpo Vítreo/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Injeções Intravítreas , Medicamentos Biossimilares/administração & dosagem , Medicamentos Biossimilares/farmacocinética , Degeneração Macular Exsudativa/tratamento farmacológicoRESUMO
PURPOSE: To evaluate the predictive factors of neovascular age-related macular degeneration (nAMD) with poor response to three loading doses of intravitreal bevacizumab (IVB). METHODS: A retrospective cohort study was performed on nAMD patients three loading IVB initial treatment. The patients were divided into two groups, without residual fluid on optical coherence tomography (OCT) images (Group 1) and with residual fluid (Group 2). Demographic data, OCT findings, and morphological features of macular neovascularization (MNV) in optical coherence tomography angiography (OCTA) were recorded. RESULTS: The study included one hundred thirty-six eyes of 120 patients (Group 1: n = 66 eyes, Group 2: n = 70 eyes). Central macular thickness, presence of intraretinal fluid, subretinal fluid, hyperreflective foci-band, pigment epithelial detachment (PED), and prechoroidal cleft were similar between the two groups. Pre-injection central choroidal thickness (CCT) was 214.17 ± 50.28 µm in Group 1 and 247.40 ± 60.55 µm in Group 2 (p = 0.021). PED width (p = 0.028) and PED area (p = 0.042) were statistically significantly higher in Group 1. When the morphology of MNV in OCTA was examined, branching (p = 0.736), loops (p = 0.442), peripheral arcade (p = 0.600), hypointense halo (p = 0.779), sea fan (p = 0.250), medusa (p = 0.255), pruned vascular tree pattern (p = 0.148), capillary fringe (p = 0.683) were similar in both groups. The presence of a closed circuit pattern was significantly higher in Group 2 (p = 0.028). CONCLUSION: Initial CCT and closed circuit pattern MNV were higher in IVB-resistant cases. It was observed that PEDs with large bases and areas responded significantly better to loading therapy. The presence of a closed-circuit pattern was an independent risk factor for poor response to loading therapy. Retrospectively registered. REGISTRATION NUMBER: 2011-KAEK-25 2023/05-08.
Assuntos
Inibidores da Angiogênese , Bevacizumab , Angiofluoresceinografia , Injeções Intravítreas , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular , Acuidade Visual , Degeneração Macular Exsudativa , Humanos , Estudos Retrospectivos , Masculino , Inibidores da Angiogênese/administração & dosagem , Feminino , Tomografia de Coerência Óptica/métodos , Bevacizumab/administração & dosagem , Idoso , Angiofluoresceinografia/métodos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/diagnóstico , Fundo de Olho , Idoso de 80 Anos ou mais , Macula Lutea/patologia , Macula Lutea/diagnóstico por imagem , Seguimentos , Pessoa de Meia-IdadeAssuntos
Inibidores da Angiogênese , Degeneração Macular , Fator A de Crescimento do Endotélio Vascular , Humanos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/uso terapêutico , Degeneração Macular/tratamento farmacológico , Degeneração Macular/radioterapia , Injeções Intravítreas , Ranibizumab/administração & dosagem , Ranibizumab/uso terapêutico , Degeneração Macular Exsudativa/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagemRESUMO
Background: To evaluate the efficacy and safety of Brolucizumab for neovascular age-related macular degeneration (n-AMD) through a systematic review and meta-analysis. Materials and Methods: Cochrane, PubMed, Embase, and Web of Science databases were comprehensively searched for relevant studies. Stata and RevMan5.4 were applied for meta-analysis and risk of bias assessment. Data on the best-corrected visual acuity (BCVA), central subfield thickness (CSFT), presence of intraretinal fluid (IRF) and/or subretinal fluid (SRF), participants with ≥1 serious adverse events, and participants with ≥1 adverse events were analyzed. Results: Six studies were finally included. Meta-analysis showed statistical differences in BCVA [SMD = -0.65, 95% CI [-0.17 to -0.23], P < 0.05], the presence of IRF and/or SRF [RR = 0.67, 95% CI [0.56-0.79], P < 0.05], and the safety of participants with ≥1 serious adverse events [RR = 0.57, 95% CI [0.39-0.84], P < 0.05] between the experimental group and the control group. However, no statistical differences were observed in CSFT [SMD = -1.16, 95% CI [-2.79 to 0.47], P > 0.05] or the safety of participants with ≥1 adverse events [RR = 1.07, 95% CI [0.97-1.17], P > 0.05]. Conclusions: Compared to other anti-VEGF drugs such as Aflibercept and Ranibizumab, intravitreal injection of 6 mg Brolucizumab is more effective and safer for n-AMD, especially in the presence of IRF and/or SRF, and for participants with ≥1 serious adverse events.
Assuntos
Inibidores da Angiogênese , Anticorpos Monoclonais Humanizados , Degeneração Macular , Humanos , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Injeções Intravítreas , Degeneração Macular/tratamento farmacológico , Resultado do Tratamento , Acuidade Visual/efeitos dos fármacos , Degeneração Macular Exsudativa/tratamento farmacológicoRESUMO
Wet age-related macular degeneration (wet AMD) is a primary contributor to visual impairment and severe vision loss globally, but the prevailing treatments are often unsatisfactory. The development of conventional treatment strategies has largely been based on the understanding that the angiogenic switch of endothelial cells (ECs) is mainly dictated by angiogenic growth factors. Even though treatments targeting vascular endothelial growth factor (VEGF), like ranibizumab, are widely administered, more than half of patients still exhibit inadequate or null responses, suggesting the involvement of other pathogenic mechanisms. With advances in research in recent years, it has become well recognized that EC metabolic regulation plays an active rather than merely passive responsive role in angiogenesis. Disturbances of these metabolic pathways may lead to excessive neovascularization in angiogenic diseases such as wet AMD, therefore targeted modulation of EC metabolism represents a promising therapeutic strategy for wet AMD. In this review, we comprehensively discuss the potential applications of EC metabolic regulation in wet AMD treatment from multiple perspectives, including the involvement of ECs in wet AMD pathogenesis, the major endothelial metabolic pathways, and novel therapeutic approaches targeting metabolism for wet AMD.
Assuntos
Células Endoteliais , Degeneração Macular Exsudativa , Humanos , Células Endoteliais/metabolismo , Degeneração Macular Exsudativa/metabolismo , Degeneração Macular Exsudativa/tratamento farmacológico , Animais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ranibizumab/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/farmacologia , Redes e Vias Metabólicas , Neovascularização Patológica/metabolismoRESUMO
Age-related macular degeneration (AMD) is the leading cause of vision loss in senior adults. The disease can be categorized into two types: wet AMD and dry AMD. Wet AMD, also known as exudative or neovascular AMD, is less common but more severe than dry AMD and is responsible for 90% of the visual impairment caused by AMD and affects 20 million people worldwide. Current treatment options mainly involve biologics that inhibit the vascular endothelial growth factor or complement pathways. However, these treatments have limitations such as high cost, injection-related risks, and limited efficacy. Therefore, new therapeutic targets and strategies have been explored to improve the outcomes of patients with AMD. A promising approach is the use of small-molecule drugs that modulate different factors involved in AMD pathogenesis, such as tyrosine kinases and integrins. Small-molecule drugs offer advantages, such as oral administration, low cost, good penetration, and increased specificity for the treatment of wet and dry AMD. This review summarizes the current status and prospects of small-molecule drugs for the treatment of wet AMD. These advances are expected to support the development of effective and targeted treatments for patients with AMD.