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DOI: 10.1055/s-0042-101348
Das klinische Ergebnis eines Therapiewechsels von Ranibizumab und/oder Bevacizumab zu Aflibercept bei neovaskulärer altersabhängiger Makuladegeneration (AMD)
Switching Therapy from Ranibizumab and/or Bevacizumab to Aflibercept in Neovascular Age-Related Macular Degeneration (AMD): One-Year ResultsPublication History
eingereicht 01 August 2015
akzeptiert 07 January 2016
Publication Date:
28 April 2016 (online)
![](https://www.thieme-connect.de/media/klimo/201608/lookinside/thumbnails/10-1055-s-0042-101348_kl1461-1.jpg)
Zusammenfassung
Hintergrund: Bei der Studie handelt es sich um eine retrospektive Auswertung des klinischen Effekts eines Therapiewechsels zu Aflibercept in Patienten mit neovaskulärer altersabhängiger Makuladegeneration (AMD), welche zuvor mangelndes Ansprechen auf eine Therapie mit Ranibizumab und/oder Bevacizumab aufwiesen. Patienten und Methoden: In die Studie wurden 96 Augen mit neovaskulärer altersabhängiger Makuladegeneration (AMD) eingeschlossen, die mit Ranibizumab und/oder Bevacizumab (T&E, Treat and Extend) vorbehandelt wurden und ein mangelndes Ansprechen auf die Therapie zeigten. Als mangelndes Ansprechen wurde hierbei ein rezidivbedingtes Injektionsintervall von < 6 Wochen definiert oder dauerhaft persistierende intra- und/oder subretinale Flüssigkeit oder persistierende Pigmentepithelabhebungen (PED). Die Patienten wurden für 12 Monate nach Therapieumstellung nachverfolgt. Die Veränderung der zentralen Netzhautdicke (CRT) wurde als primärer Endpunkt definiert. Weitere Endpunkte waren die axiale Höhe von PEDs und das Injektionsintervall. Ergebnisse: Als primärer Endpunkt zeigte sich eine signifikante Abnahme der durchschnittlichen CRT 12 Monate nach Therapieumstellung auf Aflibercept (− 31,36 µm; SD ± 70,64 µm; p < 0,001; Wilcoxon-Nemenyi-McDonald-Thompson-post-hoc-Test). Als weiterer morphologischer Endpunkt zeigte sich eine signifikante Verringerung der durchschnittlichen axialen PED-Höhe (− 34,10 µm; SD ± 91,90 µm; p < 0,001) von 207,82 µm (SD ± 148,12 µm) auf 173,72 µm (SD ± 132,30 µm). Gleichzeitig verlängerte sich das durchschnittliche Injektionsintervall signifikant (p < 0,001; Friedman-Test) von 1,30 Monaten (SD ± 0,19 Monate) vor Therapiewechsel auf 1,67 Monate (SD ± 0,19 Monate) nach 12 Monaten. Der bestkorrigierte Visus (BCVA) als funktioneller Endpunkt hat sich hingegen durch die Therapieumstellung auf Aflibercept nach 12 Monaten (+ 0,36 ETDRS-Buchstaben; SD ± 16,94 ETDRS-Buchstaben; p = 0,0972) nicht signifikant verbessert. Schlussfolgerung: Bei Patienten mit neovaskulärer AMD, die zunächst ein ungenügendes Ansprechen auf Ranibizumab und/oder Bevacizumab aufweisen, zeigt sich ein klinischer Nutzen durch eine Therapieumstellung auf Aflibercept. Neben morphologischen Verbesserungen, wie der Abnahme der CRT und der Höhe von PEDs, ließ sich eine Verlängerung des durchschnittlichen Injektionsintervalls beobachten. Eine Verbesserung des Visus zeigt sich auch nach 1 Jahr hingegen nicht.
Abstract
Background: The presented study is a retrospective evaluation of switching therapy from ranibizumab and/or bevacizumab to aflibercept in neovascular age-related macular degeneration in patients who had previously given an insufficient response to therapy with ranibizumab and/or bevacizumab. Patients and Methods: 96 eyes with neovascular age-related macular degeneration (AMD) were included, which had been pretreated with ranibizumab and/or bevacizumab (T&E), but had responded insufficiently. An injection interval of less than six weeks or permanently persisting intra- and/or subretinal fluid or persistent pigment epithelial detachments (PED) were defined as an insufficient response. The patients were followed for 12 months after switching therapy to aflibercept. The change in central retinal thickness (CRT) was defined as the primary endpoint. Other endpoints were the axial height of PEDs and the injection interval. Results: The primary endpoint, the average CRT, was significantly decreased twelve months after switching therapy to aflibercept (Wilcoxon Nemenyi-McDonald-Thompson post-hoc analysis − 31.36 µm; SD ± 70.64 µm; p < 0.001). Another morphological endpoint, the average axial height of PEDs, also decreased significantly (− 34.10 µm; SD ± 91.90 µm, p < 0.001) from 207.82 µm (SD ± 148.12 µm) at baseline to 173.72 µm (SD ± 132.30 µm) at month 12. Moreover, the average injection interval increased significantly (p < 0.001; Friedman test) from 1.30 months (SD ± 0.19 months) before switching therapy to 1.67 months (SD ± 0.19 months) at month 12 after switching therapy to aflibercept. However, the best corrected visual acuity (BCVA) as a functional endpoint did not significantly improve (+ 0.36 ETDRS letters = 0.0972 p; SD ± 16.94 ETDRS letters). Conclusion: In patients with neovascular AMD, who had initially exhibited an inadequate response to ranibizumab and/or bevacizumab, switching therapy to aflibercept improves clinical outcome measures. Besides morphological improvements, such as the decrease of the CRT and the axial height of PEDs, the average injection interval was prolonged. However, visual acuity did not improve.
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Literatur
- 1 Adamis AP, Miller JW, Bernal MT et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 1994; 118: 445-450
- 2 Aiello LP, Avery RL, Arrigg PG et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994; 331: 1480-1487
- 3 Rosenfeld PJ, Brown DM, Heier JS et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419-1431
- 4 Brown DM, Kaiser PK, Michels M et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1432-1444
- 5 Chakravarthy U, Harding SP, Rogers CA et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet 2013; 382: 1258-1267
- 6 Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Martin DF, Maguire MG et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 2012; 119: 1388-1398
- 7 Berg K, Pedersen TR, Sandvik L et al. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology 2015; 122: 146-152
- 8 Lux A, Llacer H, Heussen FM et al. Non-responders to bevacizumab (Avastin) therapy of choroidal neovascular lesions. Br J Ophthalmol 2007; 91: 1318-1322
- 9 Krebs I, Glittenberg C, Ansari-Shahrezaei S et al. Non-responders to treatment with antagonists of vascular endothelial growth factor in age-related macular degeneration. Br J Ophthalmol 2013; 97: 1443-1446
- 10 Eghøj MS, Sørensen TL. Tachyphylaxis during treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol 2012; 96: 21-23
- 11 Forooghian F, Chew EY, Meyerle CB et al. Investigation of the role of neutralizing antibodies against bevacizumab as mediators of tachyphylaxis. Acta Ophthalmol 2011; 89: e206-e207
- 12 Brown DM, Michels M, Kaiser PK et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 2009; 116: 57-65 e5
- 13 Ferrara N, Damico L, Shams N et al. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 2006; 26: 859-870
- 14 Leveziel N, Pelat T, Watier H et al. Detection of antiranibizumab antibodies among patients with exudative age-related macular degeneration. Ophthalmologica 2014; 232: 53-56
- 15 Moja L, Lucenteforte E, Kwag KH et al. Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration. Cochrane Database Syst Rev 2014; (9) CD011230
- 16 Fassnacht-Riederle H, Becker M, Graf N et al. Effect of aflibercept in insufficient responders to prior anti-VEGF therapy in neovascular AMD. Graefes Arch Clin Exp Ophthalmol 2014; 252: 1705-1709
- 17 Gasperini JL, Fawzi AA, Khondkaryan A et al. Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation. Br J Ophthalmol 2012; 96: 14-20
- 18 Meyer CH, Krohne TU, Holz FG. Intraocular pharmacokinetics after a single intravitreal injection of 1.5 mg versus 3.0 mg of bevacizumab in humans. Retina 2011; 31: 1877-1884
- 19 Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 2008; 92: 667-668
- 20 Yang LP, McKeage K. Intravitreal aflibercept (Eylea(®)): a review of its use in patients with macular oedema secondary to central retinal vein occlusion. Drugs Aging 2014; 31: 395-404
- 21 Zhang F, Tang Z, Hou X et al. VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. Proc Natl Acad Sci USA 2009; 106: 6152-6157
- 22 Rakic JM, Lambert V, Devy L et al. Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest Ophthalmol Vis Sci 2003; 44: 3186-3193
- 23 Stewart MW. Predicted biologic activity of intravitreal bevacizumab. Retina 2007; 27: 1196-1200
- 24 Spaide RF. The as-needed treatment strategy for choroidal neovascularization: a feedback-based treatment system. Am J Ophthalmol 2009; 148: 1-3
- 25 Toalster N, Russell M, Ng P. A 12-month prospective trial of inject and extend regimen for ranibizumab treatment of age-related macular degeneration. Retina 2013; 33: 1351-1358
- 26 Lalwani GA, Rosenfeld PJ, Fung AE et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009; 148: 43-58 e41
- 27 Engelbert M, Zweifel SA, Freund KB. „Treat and extend“ dosing of intravitreal antivascular endothelial growth factor therapy for type 3 neovascularization/retinal angiomatous proliferation. Retina 2009; 29: 1424-1431
- 28 Gregori NZ, Feuer W, Rosenfeld PJ. Novel method for analyzing snellen visual acuity measurements. Retina 2010; 30: 1046-1050
- 29 Spaide RF, Curcio CA. Anatomical correlates to the bands seen in the outer retina by optical coherence tomography: literature review and model. Retina 2011; 31: 1609-1619
- 30 Fassnacht-Riederle H, Becker M, Graf N et al. Effect of aflibercept in insufficient responders to prior anti-VEGF therapy in neovascular AMD. Graefes Arch Clin Exp Ophthalmol 2014; 252: 1705-1709
- 31 Heussen FM, Shao Q, Ouyang Y et al. Clinical outcomes after switching treatment from intravitreal ranibizumab to aflibercept in neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2014; 252: 909-915
- 32 Kumar N, Marsiglia M, Mrejen S et al. Visual and anatomical outcomes of intravitreal aflibercept in eyes with persistent subfoveal fluid despite previous treatments with ranibizumab in patients with neovascular age-related macular degeneration. Retina 2013; 33: 1605-1612
- 33 Broadhead GK, Hong T, Zhu M et al. Response of pigment epithelial detachments to intravitreal aflibercept among patients with treatment-resistant neovascular age-related macular degeneration. Retina 2015; 35: 975-981
- 34 Mazaraki K, Fassnacht-Riederle H, Blum R et al. Change in choroidal thickness after intravitreal aflibercept in pretreated and treatment-naive eyes for neovascular age-related macular degeneration. Br J Ophthalmol 2015; 99: 1341-1344
- 35 Grunwald JE, Daniel E, Huang J et al. Risk of geographic atrophy in the comparison of age-related macular degeneration treatments trials. Ophthalmology 2014; 121: 150-161
- 36 Ho AC, Busbee BG, Regillo CD et al. Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology 2014; 121: 2181-2192
- 37 Heier JS, Brown DM, Chong V et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012; 119: 2537-2548