Introduction:Nowadays, anti-vascular endothelial growth factor (VEGF) therapy is widely used as first-line therapy for retinopathy of prematurity (ROP) with very good therapeutic and visual results.Aim:The aim of the present study is to compare the efficacy and safety outcomes between different anti-VEGF drugs.Materials and Methods:For the period January 2005–April 2023, in the available database (PubMed, Web of Science, Scopus), a systematic analysis of scientific publications examining the impact of anti-VEGF drugs on ROP was conducted.Results:Anti-VEGF drugs inhibit the second phase of pathogenesis of ROP, which is characterised by excessive production of VEGFs. In the last 15 years, many clinical trials comparing the efficacy of different concentraionts of the drugs, safety, ocular and systemic outcomes have been conducted.Conclusion:There are several advantages of anti-VEGF therapy, such as easier application, earlier regression of ROP, peripheral vascularisation of the retina, and lower risk of myopia

Manolova, Yana

Shangova, Kaloyana

English

Varna Medical University Press: Journals

Scripta Scientifi ca Medica, 2023; Online First                 ISSN 0582-3250 (Print)                     ISSN 1314-6408 (Online)REVIEWS© Th e Author(s) 2023. Th is is an open access article distributed under the Creative Commons Attribution License (CC BY), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.ANTI-VEGF THERAPY AND RETINOPATHY OF PREMATURITYKaloyana Shangova, Yana ManolovaDepartment of Ophthalmology and Visual Sciences, Faculty of Medicine, Medical University of Varna, BulgariaABSTRACTINTRODUCTION: Nowadays, anti-vascular endothelial growth factor (VEGF) therapy is widely used as first-line therapy for retinopathy of prematurity (ROP) with very good therapeutic and visual results.AIM: The aim of the present study is to compare the efficacy and safety outcomes between different anti-VEGF drugs.MATERIALS AND METHODS: For the period January 2005–April 2023, in the available database (PubMed, Web of Science, Scopus), a systematic analysis of scientific publications examining the impact of anti-VEGF drugs on ROP was conducted.RESULTS: Anti-VEGF drugs inhibit the second phase of pathogenesis of ROP, which is characterised by exces-sive production of VEGFs. In the last 15 years, many clinical trials comparing the efficacy of different concen-traionts of the drugs, safety, ocular and systemic outcomes have been conducted.CONCLUSION: There are several advantages of anti-VEGF therapy, such as easier application, earlier regres-sion of ROP, peripheral vascularisation of the retina, and lower risk of myopia.Keywords: anti-VEGF therapy, retinopathy of prematurity, outcomesAddress for correspondence: Kaloyana ShangovaFaculty of MedicineMedical University of Varna55 Marin Drinov St9002 Varna, Bulgariae-mail: kaloyana_shangova@abv.bgReceived: May 2, 2023Accepted: June 13, 2023INTRODUCTIONRetinopathy of prematurity (ROP) is vasopro-liferative multifactorial iatrogenic disease affecting the premature infants. It is the most important cause of treatable but irreversible blindness in premature children in both developed and developing coun-tries. Each year more than 20,000 neonates are diag-nosed with severe visual impairment and blindness due to ROP (1). The disease is characterised by reti-nal hypoxia and excessive production of vascular en-dothelial growth factor (VEGF), which cause retinal neovascularisation (RNV) in the severe stages. The main risk factors in the pathogenesis of the disorder are gestational age under 30 weeks, birth weight un-der 1500 g, and unregulated oxygen treatment. Ear-ly screening and treatment play a significant role in preventing the disease. Nowadays, anti-VEGF ther-apy is widely used as first-line therapy for ROP with very good therapeutic and visual results.AIMThe aim of the present study is to compare the efficacy and safety outcomes between different anti-VEGF drugs.MATERIALS AND METHODSFor the period January 2005–April 2023, in the available database (PubMed, Web of Science, Sco-pus), a systematic analysis of published results of tri-Scripta Scientifica Medica, 2023; Online FirstMedical University of VarnaAnti-VEGF Therapy and Retinopathy of Prematuritypreterm babies divided into 3 groups were enrolled in the study. The first group received 0.2 mg IVR, the second group – 0.1 mg IVR, and the third group un-derwent laser therapy. Success was achieved in 80% in the first group, 75% in the second group, and 66% in the third group (4).Marlow et al. published 2-year outcomes after ROP treatment with 0.2 mg ranibizumab. The study showed reduced risk of high myopia, strabismus and amblyopia, and better quality of life. After treatment with 0.2 mg IVR, high myopia was observed in 5% of the infants, while in the laser treatment group the frequency rate was 20% (5).CARE-ROP (Comparing Alternative Ranibi-zumab Dosages for Safety and Efficacy in Retinop-athy of Prematurity) is a multicenter, randomised, double-blind trial conducted from September 2014 to August 2016 in Germany. In the survey participat-ed 20 infants with ROP zone I, stage 1 and 2 with plus disease, or stage 3 with or without plus disease, or ROP zone II stage 3 with plus disease, or aggres-sive ROP, who received different concentrations of ranibizumab (0.12 mg and 0.20 mg). The study dem-onstrates that the lower dose of the drug is as effec-tive as the higher dose  and better peripheral vascu-larisation is observed (4).Long-term two-year follow-up of ophthalmo-logic status (first year) and neurodevelopment (sec-ond year) was performed in 16 of the preterm infants. Disease reactivation was found in only one of the children. Normal fixation and motility and mild my-opia were observed in 15 of the preterm infants. At long-term follow-up, no negative impact on the over-all development of the children was established. Due to the results of the study, ranibizumab is considered a safe medication for ROP treatment (4).АfliberceptAflibercept (Eylea) is an ultra-purified and iso-osmotic drug product that has been developed specif-ically for intravitreal injection for use in the treatment of various ophthalmological conditions. Aflibercept (VEGF-Trap), a recombinant human synthetic pro-tein, acts as a soluble receptor that blocks a larger number of vascular endothelial factors.In contrast to bevacizumab and ranibizum-ab, aflibercept binds not only to VEGF-A but also to VEGF-B and placental growth factor (PIGF), dem-als about the effect of anti-VEGF drugs in managing ROP was conducted.RESULTS AND DISCUSSIONThe increasing use of anti-VEGF agents has revolutionised the approach to the disease manage-ment by reducing RNV, choroidal neovasculariza-tion (CNV), and vascular permeability. Nowadays, the main drugs used in ophthalmology are afliber-cept, bevacizumab, pegaptanib, ranibizumab, con-bercept, brolucizumab, and faricimab.Bevacizumab Bevacizumab is a recombinant, humanized monoclonal antibody (148 kDa) that binds all iso-forms of VEGF-A, and first has been approved for the treatment of metastatic colorectal cancer in 2004 (2). Тhe first prospective multicentral randomised trial BEAT-ROP (Bevacizumab Eliminates the An-giogenic Threat of Retinopathy of Prematurity), which compared the effect of intravitreal adminis-tration of bevacizumab (0.625 mg in 0.025 mL of so-lution) versus laser therapy for ROP zone I or zone II posterior stage 3+ (stage 3 with plus disease), was conducted in 2011. In the trial were enrolled 150 in-fants. Recurrence of the disease was observed in 4 ne-onates in the intravitreal bevacizumab (IVB) group and in 19 neonates in the laser treatment group. Sta-tistical significance was found only for ROP zone I (P = 0.003). In contrast to laser therapy, which coag-ulates the peripheral retina, intravitreal administra-tion of bevacizumab allows further vascularisation of the entire retina (3).Ranibizumab Ranibizumab is a 48 kDa recombinant human-ized monoclonal antibody with affinity towards all isotypes of VEGF-A. The lack of a fragment crystal-lizable (Fc) domain and its small molecule size might expand its affinity for more isoforms of VEGF-A (VEGF165, VEGF121, and VEGF110) and increase its diffusion within the retina and choroid (4).The Ranibizumab Compared With Laser for the Treatment of Infants Born Prematurely With Retinopathy of Prematurity (RAINBOW) is the first randomised prospective clinical trial which com-pares the efficacy of intravitreal ranibizumab (IVR) (0.2 mg and 0.1 mg) and laser therapy. A total of 225 Scripta Scientifica Medica, 2023; Online FirstMedical University of VarnaKaloyana Shangova, Yana Manolovaonstrating higher affinity for VEGF-A isoforms. As a result, more rapid blockage of VEGF-A- and PIGF-induced activation of VEGFR1 and VEGFR2 is ob-served  as well as inhibition of endothelial cell mi-gration (6-8).In February 2023, aflibercept was officially ap-proved by the FDA to treat ROP, following the pub-lication of results from two global randomised trials: FIREFLEYE and BUTTERFLEYE, which compared the effect of intravitreal administration of 0.4 mg aflibercept and conventional laser therapy in ROP premature babies.FIREFLEYE was the first global randomised open-label controlled phase 3 clinical trial, which compared the efficacy and safety profile of 0.4 mg intravitreal aflibercept (IVA) against laser therapy among 118 infants. They were diagnosed with ROP zone 1 stages 1 +, stage 2 and 3, stage 3+, ROP zone 2 stages 2+, 3+, and aggressive ROP. Treatment success was 85.5% in the IVA group compared with 82.1% in the laser-treatment group. Additional treatment was required in fewer num-ber of cases after IVA (4.8% vs 11.1%). Adverse oc-ular side effects were found in 13.3% of the cases in the IVA group compared to 7.9% in laser-treatment group. Systemic adverse reaction rate was 24.0% in IVA group and 36.8% in laser-treatment group (4,9).Pegaptanib Pegaptanib is an aptamer that selectively binds to and neutralises VEGF-A165 and was the first anti-VEGF therapy approved for the treatment of the exu-dative form of macular degeneration. Several articles have been published for the effect of IVP for treat-ment of ROP.Autrata et al. reported a positive effect of the in-travitreal administration of pegaptanib (IVP) in pre-mature infants with ROP stage 3 with plus disease (10).Conbercept Conbercept is also a VEGF-Trap recombinant DNA protein with high affinity for all VEGFs and PIGF, which is approved for treatment of the exu-dative form of age-related macular degeneration (ARMD) (11).SAFERThe increasing use of anti-VEGF drugs necessi-tates the publication of a practical guideline for prop-er administration and adequate follow-up of these patients. In order to optimize the safety of anti-VEGF treatment, a practical protocol, the so-called SAFER algorithm, has been published (12): S (short needle) – the needle should be 32-gaugeА (antiseptics/antibiotics) – betadine 10 % or 5%, before and after injectionF (follow-up) – examination after 48 to 72 hours to check for ocular infectionЕ (extra attention to detail) – intravitreal injec-tion should be performed at a precise distance from the limbus and under completely sterile conditions R (re-check) – follow-up in 1–2 weeks until complete vascularisation of the peripheral retinaCONCLUSIONAnti-VEGF therapy provides several advantag-es and long-term benefits, such as easier application, earlier regression of ROP, peripheral vascularisation of the retina, and lower risk of myopia (13).REFERENCES1. Blencowe H, Lawn JE, Vazquez T, Fielder A, Gilbert C. Preterm-associated visual impairment and esti-mates of retinopathy of prematurity at regional and global levels for 2010. Pediatr Res. 2013;74(S1):35-49. doi:10.1038/pr.2013.205.2. Mintz-Hittner HA. Avastin as monotherapy for retinopathy of prematurity. J Am Assoc Pe-diatr Ophthalmol Strabismus. 2010;14(1):2-3. doi:10.1016/j.jaapos.2009.12.002.3. Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364(7):603-15. doi:10.1056/NEJMoa1007374.4. Stahl A, Krohne TU, Eter N, Oberacher-Velten I, Guthoff R, Meltendorf S, et al. Comparing alterna-tive ranibizumab dosages for safety and efficacy in retinopathy of prematurity: A randomized clinical trial. JAMA Pediatr. 2018;172(3):278. doi:10.1001/jamapediatrics.2017.4838.5. Marlow N, Stahl A, Lepore D, Fielder A, Reynolds JD, Zhu Q, et al. 2-year outcomes of ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematu-rity (RAINBOW extension study): prospective fol-low-up of an open label, randomised controlled tri-al. Lancet Child Adolesc Health. 2021;5(10):698-707. doi:10.1016/S2352-4642(21)00195-4.Scripta Scientifica Medica, 2023; Online FirstMedical University of VarnaAnti-VEGF Therapy and Retinopathy of Prematurity6. Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E, et al. Binding and neutraliza-tion of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15(2):171-85. doi:10.1007/s10456-011-9249-6.7. Stewart MW, Rosenfeld PJ. Predicted biological ac-tivity of intravitreal VEGF Trap. Br J Ophthalmol. 2008;92(5):667-8. doi:10.1136/bjo.2007.134874.8. Huang CY, Lien R, Wang NK, Chao AN, Chen KJ, Chen TL, et al. Changes in systemic vascular en-dothelial growth factor levels after intravitreal in-jection of aflibercept in infants with retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol. 2018;256(3):479-87. doi:10.1007/s00417-017-3878-4.9. Stahl A, Sukgen EA, Wu WC, Lepore D, Nakani-shi H, Mazela J, et al. Effect of intravitreal afliber-cept vs laser photocoagulation on treatment success of retinopathy of prematurity: The FIREFLEYE randomized clinical trial. JAMA. 2022;328(4):348. doi:10.1001/jama.2022.10564.10. Autrata R, Krejčířová I, Šenková K, Holoušová M, Doležel Z, Borek I. Intravitreal pegaptanib com-bined with diode laser therapy for stage 3+ retinop-athy of prematurity in zone I and posterior zone II. Eur J Ophthalmol. 2012;22(5):687-94. doi:10.5301/ejo.5000166.11. Wu Z, Zhao J, Lam W, Yang M, Chen L, Huang X, et al. Comparison of clinical out-comes of conbercept versus ranibizumab treat-ment for retinopathy of prematurity: a multicen-tral prospective randomised controlled trial. Br J Ophthalmol. 2022;106(7):975-9. doi:10.1136/bjophthalmol-2020-318026.12. Beck KD, Rahman EZ, Ells A, Mireskan-dari K, Berrocal AM, Harper CA. SAFER-ROP: updated protocol for anti-VEGF Injec-tions for retinopathy of prematurity. Ophthal-mic Surg Lasers Imaging Retina. 2020;51(7):402-6. doi:10.3928/23258160-20200702-05.13. Tran KD, Cernichiaro-Espinosa LA, Berrocal AM. Management of Retinopathy of Prematuri-ty--Use of Anti-VEGF Therapy. Asia Pac J Oph-thalmol (Phila). 2018;7(1):56-62. doi: 10.22608/APO.2017436.

Anti-VEGF therapy and retinopathy of prematurity

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Anti-VEGF therapy and retinopathy of prematurity

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