Antiangiogenic therapy of neovascular age-related macular degeneration

Fayzrakhmanov R.R.; Voropaev V.Yu.; Sukhanova A.V.; Shatalova E.O.

doi:https://doi.org/10.17116/oftalma202113701183

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Abstract:

The problem associated with the prevalence of retinal diseases, and age-related macular degeneration (AMD) in particular, is undoubtedly relevant. This aspect is based on steadily growing statistics on morbidity, a high number of randomized controlled trials (RCT) and published real world data (RWD). The analysis of RCT results being published by researchers on 15.05.19 showed 2915 studies were registered on the subject of retinal diseases; that exceeds the number of studies on glaucoma by approximately 1.38 times (2118 studies) and conjunctival lesions by 2.37 times (1230 studies). AMD is one of the leading causes of irreversible vision loss and blindness; its neovascular form leads to blindness in 80—90% of all cases. Even though the topic of nAMD therapy is widely highlighted in modern ophthalmology, today there are many aspects that require targeted solutions. The main controversial issues that determine the complexity of therapy and patient management include discrepancies in determination of reference points (disease activity criteria) for implementation of anti-VEGF dosing regimens, patients’ compliance, prioritization issues in treatment, its continuity with potential for the increase of intervals between injections and monitoring visits.

Keywords:

age-related macular degeneration

neovascular AMD

ranibizumab

aflibercept

dosing regimen

T&E

treat-and-extend

Authors:

Fayzrakhmanov R.R.

Pirogov National Medical and Surgical Center

SPIN RSCI: 1620-0083
ORCID: 0000-0002-4341-3572

Voropaev V.Yu.

JSC Bayer

Sukhanova A.V.

Pirogov National Medical and Surgical Center

Shatalova E.O.

Clinics of doctor Shatalov

Received:

29.11.2020

Accepted:

24.12.2020

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References:

Li JQ, Welchowski T, Schmid M, Mauschitz MM, Holz FG, Finger RP. Prevalence and incidence of age-related macular degeneration in Europe: systematic review and meta-analysis. Br J Ophthalmol. 2020;104:1077-1084. https://doi.org/10.1136/bjophthalmol-2019-314422
Fayzrakhmanov RR. Anti-VEGF therapy of neovascular age-related macular degeneration: from randomized trials to routine clinical practice. Rossijskij oftal’mologicheskij journal. 2019;12(2):97-105. (In Russ.). https://doi.org/10.21516/2072-0076-2019-12-2-97-105
AlRyalat SA, Abukahel A, Elubous KA. Randomized controlled trials in ophthalmology: a bibliometric study. F1000Research. 2019;8:1718. https://doi.org/10.12688/f1000research.20673.1
Nov E, Moisseiev E. The Top 100 Most-Cited Papers on Intravitreal Injections: A Bibliographic Perspective. Clin Ophthalmol. 2020;14:2757-2772. https://doi.org/10.2147/OPTH.S267617
Baumal CR. Wet age-related macular degeneration: treatment advances to reduce the injection burden. Am J Manag Care. 2020;26:103-111. https://doi.org/10.37765/ajmc.2020.43435
Ambati J, Fowler BJ. Mechanisms of age-related macular degeneration. Neuron. 2012;75(1):26-39. https://doi.org/10.1016/j.neuron.2012.06.018
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431. https://doi.org/10.1056/NEJMoa054481
Schmidt-Erfurth U, Kaiser PK, Korobelnik J-F, Brown DM, Chong V, Nguyen QD, Ho AC, Ogura Y, Simader C, Jaffe GJ, Slakter JS, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Soo Y, Anderesi M, Sowade O, Zeitz O, Norenberg C, Sandbrink R, Heier JS. Intravitreal Aflibercept injection for neovascular age-related macular degeneration. Ninety-six weeks results of the VIEW studies. Ophthalmology. 2014;121:193-201. https://doi.org/10.1016/j.ophtha.2013.08.011
Fayzrakhmanov RR. Anti-VEGF dosing regimen for neovascular age-related macular degeneration treatment. Vestnik oftal’mologii. 2018;134(6):107-115. (In Russ.). https://doi.org/10.17116/oftalma2018134061107
Lanzetta P, Loewenstein A; The Vision Academy Steering Committee. Fundamental principles of an anti-VEGF treatment regimen: optimal application of intravitreal anti-vascular endothelial growth factor therapy of macular diseases. Graefes Arch Clin Exp Ophthalmol. 2017;255:1259-1273. https://doi.org/10.1007/s00417-017-3647-4
Fauser S, Muether PS. Clinical correlation to differences in ranibizumab and aflibercept vascular endothelial growth factor suppression times. Br J Ophthalmol. 2016;100:1494-1498. https://doi.org/10.1136/bjophthalmol-2015-308264
Steinle NC, Du W, Gibson A, Saroj N. Outcomes by Baseline Choroidal Neovascularization Features in Age-Related Macular Degeneration: A Post Hoc Analysis of the VIEW Studies. Ophthalmol Retina. 2020;S2468-6530(20)30281. https://doi.org/10.1016/j.oret.2020.07.003
Budzinskaya MV, Fursova AZh, Pedanova EK. Specific biomarkers of response to antiangiogenic therapy. Vestnik oftal’mologii. 2020;136(2):117-124. (In Russ.). https://doi.org/10.17116/oftalma2020136021117
Mantel I, Deli A, Iglesias K, Ambresin A. Prospective study evaluating the predictability of need for retreatment with intravitreal ranibizumab for age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2013;251: 697-704. https://doi.org/10.1007/s00417-012-2090-9
Ohji M, Takahashi K, Okada AA, Kobayashi M, Matsuda Y, Terano Y. Efficacy and Safety of Intravitreal Aflibercept Treat-and-Extend Regimens in Exudative Age-Related Macular Degeneration: 52- and 96-Week Findings from ALTAIR. Adv Ther. 2020;37(3):1173-1187. https://doi.org/10.1007/s12325-020-01236-x
Ichiyama Y, Sawada T, Sawada O, Ito Y, Kakinoki M, Obata S, Saishin Y, Ohji M. The correlation berween aqueous vascular endothelial growth factor level and clinical activity in neovascular age-related macular degeneration. Retina. 2021;41(1):111-117. https://doi.org/10.1097/IAE.0000000000002790
Spaide RF. Optical Coherence Tomography Angiography Signs of Vascular Abnormalization With Antiangiogenic Therapy for Choroidal Neovascularization. Am J Ophthalmol. 2015;160(1):6-16. https://doi.org/10.1016/j.ajo.2015.04.012
Coscas G, Lupidi M, Coscas F, Français C, Cagini C, Souied EH. Optical coherence tomography angiography during follow-up, qualitative and quantitative analysis of mixed type I and II choroidal neovascularization after vascular endothelial growth factor trap therapy. Ophthalm Res. 2015;54(2):57-63. https://doi.org/10.1159/000433547
Ross AH, Downey L, Devonport H, Gale RP, Kotagiri A, Mahmood S, Mehta H, Narendran N, Patel PJ, Parmar N, Jain N. Recommendations by a UK expert panel on an aflibercept treat-and-extend pathway for the treatment of neovascular age-related macular degeneration. Eye (Lond). 2020; 34(10):1825-1834. https://doi.org/10.1038/s41433-019-0747-x
Gale RP, Mahmood S, Devonport H, Patel PJ, Ross AH, Walters G, Downey L, El-Sherbiny S, Freeman M, Berry S, Jain N. Action on neovascular age-related macular degeneration (nAMD): recommendations for management and service provision in the UK hospital eye service. Eye. 2019;33:1-21. https://doi.org/10.1038/s41433-018-0300-3
Schmidt-Erfurth U, Chong V, Loewenstein A, Larsen M, Souied E, Schlingemann R, Eldem B, Monés J, Richard G, Bandello F. Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA). Br J Ophthalmol. 2014; 98:1144-1167. https://doi.org/10.1136/bjophthalmol-2014-305702
Schmidt-Erfurth U, Waldstein SM. A paradigm shift in imaging biomarkers in neovascular age-related macular degeneration. Prog Retin Eye Res. 2016; 50:1-24. https://doi.org/10.1016/j.preteyeres.2015.07.007
Okada M, Mitchell P, Finger RP, Eldem B, Talks SJ, Hirst C, Paladini L, Barratt J, Wong TY, Loewenstein A. Non-adherence or non-persistence to intravitreal injection therapy for neovascular age-related macular degeneration: a mixed-methods systematic review. Ophthalmology. 2020;4: S0161-6420(20)30748-X. https://doi.org/10.1016/j.ophtha.2020.07.060.
Kamenskih TG. A differential approach to analysis of retinal fluid and assessment of its effect on anti-VEGF therapy of nAMD. Vestnik oftal’mologii. 2019;135(6):134-140 (In Russ.). https://doi.org/10.17116/oftalma2019135061134
German Society of Ophthalmology. Statement of the German Ophthalmological Society (DOG), the German Retina Society (GRS), and the Professional Association of German Ophthalmologists (BVA) on anti-VEGF treatment in neovascular age-related macular degeneration. Ophthalmologe. 2020;29. https://doi.org/10.1007/s00347-020-01188-1
Nair P, Aiello LP, Gardner TW, Jampol LM, Ferris FL. Report From the NEI/FDA Diabetic Retinopathy Clinical Trial Design and Endpoints Workshop. Invest Ophthalmol Vis Sci. 2016;57:5127-5142. https://doi.org/10.1167/iovs.16-20356
Guymer RH, Markey CM, McAllister IL, Gillies MC, Hunyor AP, Arnold JJ. Tolerating Subretinal Fluid in Neovascular Age-Related Macular Degeneration Treated with Ranibizumab Using a Treat-and-Extend Regimen. Ophthalmology. 2019;126:723-734. https://doi.org/10.1016/j.ophtha.2018.11.025
Guymer R., Wu Z. Age-related macular degeneration (AMD): More than meets the eye. The role of multimodal imaging in today’s management of AMD. Clin Exp Ophthalmol. 2020 Sep;48(7):983-995. Epub 2020 Sep 2. https://doi.org/10.1111/ceo.13837
Jaffe GJ, Ying G-S, Toth CA, Ebenezer D, Grunwald JE, Martin DF, Maguire MG. Macular Morphology and Visual Acuity in Year Five of the Comparison of Age-related Macular Degeneration Treatments Trials. Ophthalmology. 2019;126:252-260. https://doi.org/10.1016/j.ophtha.2018.08.035
Waldstein SM, Wright J, Warburton J, Margaron P, Simader C, Schmidt-Erfurth U. Predictive Value of Retinal Morphology for Visual Acuity Outcomes of Different Ranibizumab Treatment Regimens for Neovascular AMD. Ophthalmology. 2016;123:60-69. https://doi.org/10.1016/j.ophtha.2015.09.013
Melikhov OG. Klinicheskie issledovanija. 3e-izd., dop. M.: Atmosfera; 2013. (In Russ.).
Visual Acuity Outcomes Presentation from the 2019 Clinical Trials Workshop. DRCR.net — Public Web Site; 2019. Accessed September, 2020. https://public.jaeb.org/drcrnet/view/presentations
Medeiros FA. Biomarkers and Surrogate Endpoints: Lessons Learned From Glaucoma. Invest Ophthalmol Vis Sci. 2017;58:BIO20-BIO26. https://doi.org/10.1167/iovs.17-21987
Ciulla TA. How to Interpret Clinical Trial Outcomes. Review of Ophthalmology. 2017;8:52-59. https://www.reviewofophthalmology.com/CMSDocuments/2017/08/rp0817i.pdf
Fayzrakhmanov RR, Zainullin RM, Gilmanshin TR, Yarmukhametova AL. Mapping of the retinal foveolar zone with an idiopathic macular rupture. Vestnik Orenburgskogo gosudarstvennogo universiteta. 2014;13(173):322-324. (In Russ.).
Fayzrakhmanov RR, Yarmukhametova AL, Gilmanshin TR. Functional indicators of vision after removal of fibrovascular membranes. Vestnik Volgogradskogo gosudarstvennogo medicinskogo universiteta. 2013;48(4):171-173. (In Russ.).
Simader C, Ritter M, Bolz M, Deák GG, Mayr-Sponer U, Golbaz I, Kundi M, Schmidt-Erfurth UM. Morphologic Parameters Relevant for Visual Outcome During Anti-Angiogenic Therapy of Neovascular Age-Related Macular Degeneration. Ophthalmology. 2014;121:1237-1245. https://doi.org/10.1016/j.ophtha.2013.12.029
Yuzawa M, Fujita K, Tanaka E, Wang ECY. Assessing quality of life in the treatment of patients with age-related macular degeneration: clinical research findings and recommendations for clinical practice. Clin Ophthalmol. 2013;7: 1325-1332. https://doi.org/10.2147/OPTH.S45248
Joko T, Nagai Y, Mori R, Tanaka K, Oshima Y, Hikichi Y, Komori T, Carrasco J, Maculaitis MC, Will O, Beusterien K, Takahashi K. Patient Preferences for Anti-Vascular Endothelial Growth Factor Treatment for Wet Age-Related Macular Degeneration in Japan: A Discrete Choice Experiment. Patient Prefer Adherence. 2020;14:553-567. https://doi.org/10.2147/PPA.S228890
Kiss S, Campbell J, Almony A, Shih V, Serbin M, LaPrise A, Wykoff CC. Management and Outcomes for Neovascular Age-Related Macular Degeneration: Analysis of United States Electronic Health Records. Ophthalmology. 2020;127:1179-1188. https://doi.org/10.1016/j.ophtha.2020.02.027
Droege KM, Muether PS, Hermann MM, Caramoy A, Viebahn U, Kirchhof B, Fauser S. Adherence to ranibizumab treatment for neovascular age-related macular degeneration in real life. Graefes Arch Clin Exp Ophthalmol. 2013;251(5):1281-1284. https://doi.org/10.1007/s00417-012-2177-3
Bhagat D, Kirby B, Bhatt H, Jager R, George M, Sheth V. Patient Preferences Associated with Anti-Vascular Endothelial Growth Factor Therapies for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema. Clin Ophthalmol. 2020;14:2975-2982. https://doi.org/10.2147/OPTH.S273564
Hanemoto T, Hikichi Y, Kikuchi N, Kozawa T. The impact of different anti-vascular endothelial growth factor treatment regimens on reducing burden for caregivers and patients with wet AMD in a single-center real-world Japanese setting. PLoS One. 2017;12(12):0189035. https://doi.org/10.1371/journal.pone.0189035
Ye L, Jiaqi Z, Jianchao W, Zhaohui F, Liang Y, Xiaohui Z. Comparative efficacy and safety of antivascular endothelial growth factor regimens for neovascular age-related macular degeneration: systematic review, and Bayesian network meta-analysis. Ther Adv Chronic Dis. 2020;11:2040622320953349. https://doi.org/10.1177/2040622320953349
Muether PS, Hoerster R, Hermann MM, Kirchhof B, Fauser S. Long-term effects of ranibizumab treatment delay in neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2013;251(2):453-458. https://doi.org/10.1007/s00417-012-2038-0.
Budzinskaya MV, Plyukhova AA, Toropigyn SG. Modern view on the treatment of wet-AMD patients. Vestnik oftal’mologii. 2019;135(5):107-115. (In Russ.). https://doi.org/10.17116/oftalma2019135051107
Garweg JG. Twelve-week dosing with Aflibercept in the treatment of neovascular age-related macular degeneration. Clin Ophthalmol. 2019;13:1289-1295. https://doi.org/10.2147/OPTH.S185756
Maruko I, Ogasawara M, Yamamoto A, Itagaki K, Hasegawa T, Arakawa H, Nakayama M, Koizumi H, Okada AA, Sekiryu T, Iida T. Two-Year Outcomes of Treat-and-Extend Intravitreal Aflibercept for Exudative Age-related Macular Degeneration: A Prospective Study. Ophthalmol Retina. 2020; 4(8):767-776. https://doi.org/10.1016/j.oret.2020.03.010.
Wachtlin J, Eter N, Hasanbasic Z, Keramas G, Rech C, Sachs H, Schilling H, Wiedemann P, Framme C. Importance of continuous treatment with intravitreal aflibercept injections in patients with neovascular age-related macular degeneration, 12-month post hoc analysis of the PERSEUS real-world evidence study. Graefes Arch Clin Exp Ophthalmol. 2020. https://doi.org/10.1007/s00417-020-04803-8
Ohji M, Lanzetta P, Korobelnik J-F, Wojciechowski P, Taieb V, Deschaseaux C, Janer D, Tuckmantel C. Efficacy and Treatment Burden of Intravitreal Aflibercept vs Intravitreal Ranibizumab Treat-and-Extend Regimens at 2 Years: Network Meta-Analysis, Incorporating Individual Patient Data Meta-Regression and Matching-Adjusted Indirect Comparison. Adv Ther. 2020;37(5):2184-2198. https://doi.org/10.1007/s12325-020-01298-x
Wykoff CC, Rusakevich AM, Moshfeghi DM. Re: Adrean SD, Chaili S, Ramkumar H, Pirouz A, Grant S. Consistent long-term therapy of neovascular AMD managed by 50 or more anti-VEGF injections using a treat-extend stop protocol. Ophthalmology. Correspondence. 2018;18-19.
Nguyen V, Vaze A, Fraser-Bell S, Arnold J, Essex RW, Barthelmes D, Gillies MC. Outcomes of Suspending VEGF Inhibitors for Neovascular Age-Related Macular Degeneration When Lesions Have Been Inactive for 3 Months. Ophthalmol Retina. 2019;3:623-628. https://doi.org/10.1016/j.oret.2019.05.013
Adrean SD, Chaili S, Grant S, Pirouz A. Recurrence Rate of Choroidal Neovascularization in Neovascular Age-Related Macular Degeneration Managed with a Treat-Extend-Stop Protocol. Ophthalmol Retina. 2018;2:225-230. https://doi.org/10.1016/j.oret.2017.07.009
Vaze A, Fraser-Bell S, Gillies M. Consequences of long-term discontinuation of vascular endothelial growth factor inhibitor therapy in the patients with neovascular age-related macular degeneration. Acta Ophth. 2014;92(8): e697-8. https://doi.org/10.1111/aos.12417
Wakazono T, Yamashiro K, Oishi A, Ooto S, Tamura H, Akagi-Kurashige Y, Hata M, Takahashi A, Tsujikawa A, Yoshimura N. Recurrence of choroidal neovascularization lesion activity after aflibercept treatment for age-related macular degeneration. Retina. 2017;37(11):2062-2068. https://doi.org/10.1097/IAE.0000000000001451