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Observational outcomes in proliferative diabetic retinopathy patients following treatment with ranibizumab, panretinal laser photocoagulation or combination therapy - The non-interventional second year follow-up to the PRIDE study.
Lang, GE, Stahl, A, Voegeler, J, Quiering, C, Zaremba, L, Lorenz, K, Spital, G, Liakopoulos, S
Acta ophthalmologica. 2022;(2):e578-e587
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Abstract
PURPOSE Ranibizumab monotherapy showed stronger effects on area of retinal neovascularization (NV) reduction while offering better visual acuity (VA) results than panretinal laser photocoagulation (PRP) monotherapy during the first 12 months of the PRIDE study. The second year of PRIDE was an observational, non-interventional follow-up, performed to evaluate long-term anatomical and functional outcomes in proliferative diabetic retinopathy (PDR) patients under real-life conditions, prior to the approval of ranibizumab for PDR. METHODS Seventy-three PDR patients (28 from the ranibizumab group; 20 from the PRP group; 25 from the combination group) were included in the observational follow-up phase and treated at the investigators discretion. Visual acuity (VA) measurements and retinal imaging were performed at Months 12, 18 and 24. RESULTS Mean (± SD) NV area in the ranibizumab monotherapy and combination follow-up groups increased from 3.16 ± 4.30 mm2 and 1.13 ± 2.78 mm2 at Month 12 to 6.09 ± 10.79 mm2 and 2.14 ± 4.41 mm2 at Month 18 and 10.00 ± 17.63 mm2 and 3.26 ± 7.05 mm2 at Month 24, respectively. In the PRP follow-up group, NV area declined from 5.44 ± 14.55 mm2 at Month 12 to 1.22 ± 1.67 mm2 at Month 18, but increased again to 4.05 ± 11.66 mm2 at Month 24. During the observational phase, only 2 (6;8) patients in the ranibizumab (PRP;combination) follow-up group were treated with anti-VEGF medications, while 17 (6;10) patients received PRP laser therapy. CONCLUSION Discontinuation of ranibizumab treatment in PDR patients may result in an increase of NV area and VA loss. Tight monitoring of disease activity and continued treatment beyond the first year is needed to maintain disease control.
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Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration.
Holekamp, NM, Campochiaro, PA, Chang, MA, Miller, D, Pieramici, D, Adamis, AP, Brittain, C, Evans, E, Kaufman, D, Maass, KF, et al
Ophthalmology. 2022;(3):295-307
Abstract
PURPOSE To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD). DESIGN Phase 3, open-label, randomized, visual acuity assessor-masked noninferiority and equivalence trial. PARTICIPANTS Patients with nAMD diagnosed within 9 months of screening previously treated with and responsive to anti-vascular endothelial growth factor therapy. METHODS Patients were randomized 3:2 to treatment with the PDS with ranibizumab 100 mg/ml with fixed 24-week (Q24W) refill-exchanges (PDS Q24W) or intravitreal ranibizumab 0.5-mg injections every 4 weeks (monthly ranibizumab). MAIN OUTCOME MEASURES Primary end point was change in best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter (letters) score from baseline averaged over weeks 36 and 40 (noninferiority margin,-4.5 letters; equivalence margin, ±4.5 letters). RESULTS Archway enrolled 418 patients; 251 were randomized to and 248 received treatment with the PDS Q24W, and 167 were randomized to and received treatment with monthly ranibizumab. Baseline BCVA was 74.4 letters (PDS Q24W arm) and 75.5 letters (monthly ranibizumab arm; Snellen equivalent, 20/32). Adjusted mean change in BCVA score from baseline averaged over weeks 36 and 40 was +0.2 letters (standard error [SE], 0.5 letters) in the PDS Q24W arm and +0.5 letters (SE, 0.6 letters) in the monthly ranibizumab arm (difference, -0.3 letters; 95% confidence interval, -1.7 to 1.1 letters). PDS Q24W was both noninferior and equivalent to monthly ranibizumab. Of 246 PDS-treated patients assessed for supplemental ranibizumab treatment, 242 (98.4%) did not receive supplemental ranibizumab treatment before the first refill-exchange procedure, including 4 patients who discontinued treatment before the first refill-exchange procedure. Prespecified ocular adverse events of special interest were reported in 47 patients (19.0%) in the PDS Q24W arm and 10 patients (6.0%) in the monthly ranibizumab arm, which included, in the former arm, 4 (1.6%) endophthalmitis cases, 2 (0.8%) retinal detachments, 13 (5.2%) vitreous hemorrhages, 6 (2.4%) conjunctival erosions, and 5 (2.0%) conjunctival retractions. Most ocular adverse events in the PDS Q24W arm occurred within 1 month of implantation. CONCLUSIONS Archway met its primary objective and PDS Q24W demonstrated noninferior and equivalent efficacy to monthly ranibizumab, with 98.4% of PDS-treated patients not receiving supplemental treatment in the first 24-week interval.
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EFFECT OF RETINAL THICKNESS VARIABILITY ON VISUAL OUTCOMES AND FLUID PERSISTENCE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Post Hoc Analysis of the HAWK and HARRIER Studies.
Dugel, PU, Jhaveri, CD, Chakravarthy, U, Wykoff, CC, Singh, RP, Hamilton, R, Weissgerber, G, Mulyukov, Z, Holz, FG
Retina (Philadelphia, Pa.). 2022;(3):511-518
Abstract
PURPOSE To determine the association between central subfield thickness (CST) variability and visual outcomes in eyes with neovascular age-related macular degeneration treated with anti-vascular endothelial growth factor therapies. METHODS In this post hoc, treatment-agnostic analysis, patients (N = 1,752) were grouped into quartiles of increasing CST variation. The association between CST variability and best-corrected visual acuity was measured from baseline, or from the end of the loading phase, until the end of the study using a multilevel modeling for repeated-measures model. The association between CST variability and the presence of retinal fluid was also assessed. RESULTS Increased CST variability was associated with worse best-corrected visual acuity outcomes at the end of study, with a least-square mean difference in best-corrected visual acuity of 8.9 Early Treatment Diabetic Retinopathy Study letters between the quartiles with the lowest and highest CST variability at the final visit. Increased variability was also associated with a higher mean fraction of visits with the presence of fluid. CONCLUSION More stable CST was associated with better visual outcomes at the end of treatment suggesting that CST variability may provide a more reliable prognostic marker of visual outcomes than the presence of fluid alone, with the potential to enhance the clinical care of neovascular age-related macular degeneration patients.
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Intravitreal anti-VEGF use in France: a cross-sectional and longitudinal Nationwide observational study.
Billioti de Gage, S, Bertrand, M, Grimaldi, S, Zureik, M
Acta ophthalmologica. 2022;(2):e502-e511
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Abstract
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.
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NEW BIOMARKER QUANTIFYING THE EFFECT OF ANTI-VEGF THERAPY IN EYES WITH PROLIFERATIVE DIABETIC RETINOPATHY ON ULTRAWIDE FIELD FLUORESCEIN ANGIOGRAPHY: RECOVERY Study.
Fan, W, Nittala, MG, Wykoff, CC, Brown, DM, Uji, A, Hemert, JV, Fleming, A, Robertson, G, Sadda, SR, Ip, M
Retina (Philadelphia, Pa.). 2022;(3):426-433
Abstract
PURPOSE To quantify changes of the retinal vascular bed area (RVBA) in mm2 on stereographically projected ultrawide field fluorescein angiography images in eyes with proliferative diabetic retinopathy after antivascular endothelial growth factor injection. METHODS This is a prospective, observational study. The early-phase ultrawide field fluorescein angiography images (Optos 200Tx) of 40 eyes with proliferative diabetic retinopathy and significant nonperfusion obtained at baseline and after six months (NCT02863354) were stereographically projected by correcting peripheral distortion. The global retinal vasculature on ultrawide field fluorescein angiography was extracted for calculating RVBA by summing the real size (mm2) of all the pixels automatically. RESULTS For the entire cohort, the global RVBA for the entire retina decreased from 67.1 ± 15.5 to 43.6 ± 18.8 mm2 after anti-VEGF treatment at six months (P < 0.001). In the subgroup receiving monthly anti-VEGF injections, the global RVBA decreased from 68.7 ± 16.2 to 33.9 ± 13.3 mm2 (P < 0.001). In the subgroup receiving anti-VEGF every three months, the global RVBA decreased from 65.6 ± 15.1 to 50.8 ± 19.3 mm2 (P = 0.004). CONCLUSION RVBA seems to be a new biomarker to indicate efficiency of retinal vascular changes after anti-VEGF injection. Eyes with proliferative diabetic retinopathy and significant nonperfusion demonstrate reduced RVBA after anti-VEGF treatment.
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Intravitreal Pharmacotherapies for Diabetic Macular Edema: A Report by the American Academy of Ophthalmology.
Ehlers, JP, Yeh, S, Maguire, MG, Smith, JR, Mruthyunjaya, P, Jain, N, Kim, LA, Weng, CY, Flaxel, CJ, Schoenberger, SD, et al
Ophthalmology. 2022;(1):88-99
Abstract
PURPOSE To review the evidence on the safety and efficacy of current anti-vascular endothelial growth factor (VEGF) and intravitreal corticosteroid pharmacotherapies for the treatment of diabetic macular edema (DME). METHODS Literature searches were last conducted on May 13, 2020, in the PubMed database with no date restrictions and limited to articles published in English. The combined searches yielded 230 citations, of which 108 were reviewed in full text. Of these, 31 were deemed appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist. RESULTS Only the 21 articles with level I evidence were included in this assessment. Seventeen articles provided level I evidence for 1 or more anti-VEGF pharmacotherapies, including ranibizumab (14), aflibercept (5), and bevacizumab (2) alone or in combination with other treatments for DME. Level I evidence was identified in 7 articles on intravitreal corticosteroid therapy for treatment of DME: triamcinolone (1), dexamethasone (4), and fluocinolone acetonide (2). CONCLUSIONS Review of the available literature indicates that intravitreal injections of anti-VEGF agents and corticosteroids are efficacious treatments for DME. Elevated intraocular pressure and cataract progression are important potential complications of corticosteroid therapy. Further evidence is required to assess the comparative efficacy of these therapies. Given the limited high-quality comparative efficacy data, choice of therapy must be individualized for each patient and broad therapeutic access for patients is critical to maximize outcomes.
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A New Era in Reducing Treatment Burden in Retinal Disease.
Retina (Philadelphia, Pa.). 2021;(Suppl 1):S1-S12
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Medication Trends for Age-Related Macular Degeneration.
Cho, YK, Park, DH, Jeon, IC
International journal of molecular sciences. 2021;(21)
Abstract
Age-related macular degeneration (AMD) is central vision loss with aging, was the fourth main cause of blindness in 2015, and has many risk factors, such as cataract surgery, cigarette smoking, family history, hypertension, obesity, long-term smart device usage, etc. AMD is classified into three categories: normal AMD, early AMD, and late AMD, based on angiogenesis in the retina, and can be determined by bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E)-epoxides from the reaction of A2E and blue light. During the reaction of A2E and blue light, reactive oxygen species (ROS) are synthesized, which gather inflammatory factors, induce carbonyl stress, and finally stimulate the death of retinal pigment epitheliums (RPEs). There are several medications for AMD, such as device-based therapy, anti-inflammatory drugs, anti-VEGFs, and natural products. For device-based therapy, two methods are used: prophylactic laser therapy (photocoagulation laser therapy) and photodynamic therapy. Anti-inflammatory drugs consist of corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs). Anti-VEGFs are classified antibodies for VEGF, aptamer, soluble receptor, VEGF receptor-1 and -2 antibody, and VEGF receptor tyrosine kinase inhibitor. Finally, additional AMD drug candidates are derived from natural products. For each medication, there are several and severe adverse effects, but natural products have a potency as AMD drugs, as they have been used as culinary materials and/or traditional medicines for a long time. Their major application route is oral administration, and they can be combined with device-based therapy, anti-inflammatory drugs, and anti-VEGFs. In general, AMD drug candidates from natural products are more effective at treating early and intermediate AMD. However, further study is needed to evaluate their efficacy and to investigate their therapeutic mechanisms.
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Patient profiles as an aim to optimize selection in the second line setting: the role of aflibercept.
González Astorga, B, Salvà Ballabrera, F, Aranda Aguilar, E, Élez Fernández, E, García-Alfonso, P, González Flores, E, Vera García, R, Fernández Montes, A, López Muñoz, AM, Salud Salvia, A
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2021;(8):1520-1528
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Abstract
Colorectal cancer is the second leading cause of cancer-related death worldwide. For metastatic colorectal cancer (mCRC) patients, it is recommended, as first-line treatment, chemotherapy (CT) based on doublet cytotoxic combinations of fluorouracil, leucovorin, and irinotecan (FOLFIRI) and fluorouracil, leucovorin, and oxaliplatin (FOLFOX). In addition to CT, biological (targeted agents) are indicated in the first-line treatment, unless contraindicated. In this context, most of mCRC patients are likely to progress and to change from first line to second line treatment when they develop resistance to first-line treatment options. It is in this second line setting where Aflibercept offers an alternative and effective therapeutic option, thought its specific mechanism of action for different patient's profile: RAS mutant, RAS wild-type (wt), BRAF mutant, potentially resectable and elderly patients. In this paper, a panel of experienced oncologists specialized in the management of mCRC experts have reviewed and selected scientific evidence focused on Aflibercept as an alternative treatment.
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Anti-vascular endothelial growth factor therapy in breast cancer: Molecular pathway, potential targets, and current treatment strategies.
Zhang, M, Liu, J, Liu, G, Xing, Z, Jia, Z, Li, J, Wang, W, Wang, J, Qin, L, Wang, X, et al
Cancer letters. 2021;:422-433
Abstract
As the highest incidence of female malignancy, breast cancer is likewise the leading cause of cancer-related deaths. The development of cancer relies on neo-vascularization, which provides sufficient nutrition and oxygen, and supplies a pathway for distant metastasis. Angiogenesis represents the formation of new blood vessels, and is a principal pathogenetic action in breast cancer. Vascular endothelial growth factor (VEGF) is a major angiogenesis regulator that modulates the maintenance and function of mature vascular networks. Therefore, the VEGF pathway is a promising oncotherapeutic target. This review elaborates an update on the prognostic value of VEGF in breast cancer, summarizes clinical experience and lessons of anti-VEGF therapeutics, meanwhile, provides an overview of biomarkers that predict the effectiveness of anti-angiogenic treatment.