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DOI: 10.1055/s-0043-125076
Kostenvergleich zugelassener intravitrealer Therapien bei nicht ausreichend auf primäre Therapie ansprechendem diabetischem Makulaödem mit fovealer Beteiligung in Deutschland
Cost Comparison of Licensed Intravitreal Therapies for Insufficiently Anti-VEGF Responding Fovea Involving Diabetic Macular Edema in GermanyPublication History
eingereicht 09 March 2017
akzeptiert 01 December 2017
Publication Date:
16 February 2018 (online)
![](https://www.thieme-connect.de/media/klimo/201902/lookinside/thumbnails/10-1055-s-0043-125076_kl1755-1.jpg)
Zusammenfassung
Hintergrund Bei der Behandlung eines diabetischen Makulaödems mit fovealer Beteiligung kann es trotz intensiver und konsequenter initialer Therapie mit einem Anti-VEGF-Medikament zu einem unzureichenden Ansprechen kommen. Für eine weitere Therapie stehen derzeit ein Wechsel des Anti-VEGF-Präparates oder die intravitreale Gabe der Steroidimplantate Fluocinolonacetonid oder Dexamethason zur Verfügung. Es soll zum einen systematisch untersucht werden, welche Studiendaten evidenzbasiert zur Wirksamkeit einer zugelassenen Therapie nach vorangegangener Anti-VEGF-Therapie vorliegen, und zum anderen, welche Ausgaben für die Krankenversicherungen mit einer weiteren intravitrealen Therapie verbunden sind.
Material und Methoden Es erfolgte eine systematische Literatursuche (SLR) zu randomisierten, kontrollierten Studien (RCT) in Medline und Embase. Ein Kurzzeitkostenmodell in MS Excel mit 3 Jahren Zeithorizont wurde erstellt, um die zugelassenen Optionen Ranibizumab (Lucentis®), Aflibercept (Eylea®), Fluocinolonacetonid-Implantat (Iluvien®) und Dexamethason-Implantat (Ozurdex®) zu vergleichen. Kostenkomponenten sind Arzneimittel- und Injektionskosten, optische Kohärenztomografie (OCT) und unerwünschte Ereignisse wie Endophthalmitis, den Augeninnendruck senkende Medikation bzw. Eingriffe oder Kataraktoperationen.
Ergebnisse Es wurden 42 Publikationen zu 20 RCTs identifiziert, wobei keine eine Population nach vorangegangener Anti-VEGF-Therapie hatte, sodass kein direkter Vergleich der Wirksamkeit möglich war. Im Kostenmodell ergaben sich Kosten von 17 542 € für Ranibizumab, 15 896 € für Aflibercept, 10 826 € für das Fluocinolonacetonid-Implantat und 12 365 € für das Dexamethason-Implantat. Bei allen Therapien sind die Medikamentenkosten die bestimmende Kostenkomponente. In der uni- und multivariaten Sensitivitätsanalyse zeigten sich die Ergebnisse als robust gegen Veränderungen des Inputs.
Schlussfolgerung Zusammenfassend konnte in einem Kostenvergleichsmodell über 3 Jahre gezeigt werden, dass die Steroidimplantate in der Therapie des diabetischen Makulaödems nach vorangegangener Anti-VEGF-Gabe erhebliche Kosteneinsparungen im Vergleich zu einer weiteren In-Label-Anti-VEGF-Therapie liefern können. Dabei stellt eine einmalige Gabe des Steroidimplantats Fluocinolonacetonid die kostengünstigste zulassungskonforme Alternative dar.
Abstract
Background In the treatment of center-involving diabetic macular edema, despite initial therapy with an anti-VEGF compound, an insufficient response may occur. Further therapy options include a switch of anti-VEGF products or to corticosteroid implants, such as Fluocinolone acetonide or Dexamethasone.
Objectives Firstly, to investigate systematically which evidence-based study data are available describing the efficacy of in-label treatments after primary anti-VEGF treatment, secondly, to investigate which costs go along for the healthcare provider.
Methods A systematic literature review (SLR) for randomized controlled trials (RCT) was performed in Medline and Embase. A short-term cost-cost model was built in MS Excel with a 3 year time horizon to compare in-label intravitreal options Ranibizumab (Lucentis®), Aflibercept (Eylea®), Fluocinolone acetonide implant (Iluvien®), and Dexamethasone implant (Ozurdex®). Cost components comprised of drug and injection costs, optical coherence tomography (OCT) procedures, and adverse events such as endophthalmitis, IOP-lowering drugs and surgery and cataract surgery.
Results A total of 42 publications of 20 RCTs were identified. No study had a clearly defined population after first line anti-VEGF treatment, thus no direct efficacy comparison was possible. In the short-term cost-cost model total costs were 17,542 € for Ranibizumab, 15,896 € for Aflibercept, 10,826 € for Fluocinolone acetonide implant and 12,365 € for Dexamethasone implant. For all treatment regimens, drug costs were the predominant cost component, followed by injection costs (with variations dependent on the specific drug) and OCT costs. In the uni- and multivariate sensitivity analyses, the results obtained were robust to changes of model inputs.
Conclusions In summary, the short-term cost-cost comparison demonstrates that steroid implants can provide significant cost savings versus in-label anti-VEGF treatment for center-involving diabetic macular edema. Single application of the long-lasting Fluocinolone acetonide implant is the most cost-efficient in-label treatment option.
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Literatur
- 1 Mitchell P, Bandello F, Schmidt-Erfurth U. et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011; 118: 615-625
- 2 Schmidt-Erfurth U, Lang GE, Holz FG. et al. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. Ophthalmology 2014; 121: 1045-1053
- 3 Do DV, Schmidt-Erfurth U, Gonzalez VH. et al. The DA VINCI Study: phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema. Ophthalmology 2011; 118: 1819-1826
- 4 Korobelnik JF, Do DV, Schmidt-Erfurth U. et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology 2014; 121: 2247-2254
- 5 Deutsche Ophthalmologische Gesellschaft (DOG), Retinologische Gesellschaft (RG), Berufsverband der Augenärzte Deutschlands (BVA). Therapie der diabetischen Makulopathie. 2013 Im Internet: http://www.dog.org/?cat=7 Stand: 27.10.2017
- 6 Diabetic Retinopathy Clinical Research Network. Wells JA, Glassman AR. et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 2015; 372: 1193-1203
- 7 Diabetic Retinopathy Clinical Research Network. Elman MJ, Aiello LP. et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010; 117: 1064-1077.e35
- 8 Hanhart J, Chowers I. Evaluation of the response to ranibizumab therapy following bevacizumab treatment failure in eyes with diabetic macular edema. Case Rep Ophthalmol 2015; 6: 44-50
- 9 Katz G, Moisseiev E, Goldenberg D. et al. Ranibizumab for persistent diabetic macular edema after bevacizumab treatment. Eur J Ophthalmol 2016; 27: 210-214 doi:10.5301/ejo.5000838
- 10 Rahimy E, Shahlaee A, Khan MA. et al. Conversion to aflibercept after prior anti-VEGF therapy for persistent diabetic macular edema. Am J Ophthalmol 2016; 164: 118-127.e2
- 11 Totan Y, Guler E, Guragac FB. Dexamethasone intravitreal implant for chronic diabetic macular edema resistant to intravitreal bevacizumab treatment. Curr Eye Res 2016; 41: 107-113
- 12 Escobar-Barranco JJ, Pina-Marin B, Fernandez-Bonet M. Dexamethasone implants in patients with naive or refractory diffuse diabetic macular edema. Ophthalmologica 2015; 233: 176-185
- 13 Scaramuzzi M, Querques G, Spina CL. et al. Repeated intravitreal dexamethasone implant (ozurdex) for diabetic macular edema. Retina 2015; 35: 1216-1222
- 14 Zhioua I, Semoun O, Lalloum F. et al. Intravitreal dexamethasone implant in patients with ranibizumab persistent diabetic macular edema. Retina 2015; 35: 1429-1435
- 15 Nentwich MM, Ulbig MW. The therapeutic potential of intraocular depot steroid systems: developments aimed at prolonging duration of efficacy. Dtsch Arztebl Int 2012; 109: 584-590
- 16 European Medicines Agency (EMA). Assessment report Dexamtehasone, Procedure No. EMEA/H/C/001140/II/0015. 2014 Im Internet: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/001140/WC500173294.pdf Stand: 27.10.2017
- 17 Alimera Sciences. Zusammenfassung der Merkmale des Arzneimittels – Iluvien 190 Mikrogramm intravitreales Implantat im Applikator. 01/2016 Im Internet: http://www.fachinfo.de Stand: 27.10.2017
- 18 Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG). Allgemeines Methoden. Version 5.0. 2017 Im Internet: https://www.iqwig.de/download/Allgemeine-Methoden_Version-5-0.pdf Stand: 27.10.2017
- 19 (G-BA) Gemeinsamer Bundesausschuss. Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie (AM-RL): Anlage XII – Beschlüsse über die Nutzenbewertung von Arzneimitteln mit neuen Wirkstoffen nach § 35a SGB V – Aflibercept (neues Anwendungsgebiet). 2015 Im Internet: https://www.g-ba.de/downloads/39-261-2202/2015-03-05_AM-RL-XII_Aflibercept_nAWG_2014-09-15-D-137_BAnz.pdf Stand: 27.10.2017
- 20 Sivaprasad S, Crosby-Nwaobi R, Heng LZ. et al. Injection frequency and response to bevacizumab monotherapy for diabetic macular oedema (BOLT Report 5). Br J Ophthalmol 2013; 97: 1177-1180
- 21 Klein R, Klein BE, Moss SE. et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XV. The long-term incidence of macular edema. Ophthalmology 1995; 102: 7-16
- 22 National Institute for Health and Care Excellence (NICE). Fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy (rapid review of technology appraisal guidance 271). 2013 Im Internet: http://www.nice.org.uk/guidance/ta301/resources/diabetic-macular-oedema-fluocinolone-acetonide-intravitreal-implant-rapid-review-of-ta271-final-appraisal-determination-document2 Stand: 27.10.2017
- 23 Neubauer AS, Holz FG, Schrader W. et al. Was darf Lebensqualität kosten? – Kosten-Nutzwertanalyse von Ranibizumab (Lucentis®) bei altersabhängiger Makuladegeneration. Klin Monatsbl Augenheilkd 2007; 224: 727-732
- 24 AOK Bayern BDOC, BDOC Plus AG. Vertrag zur besonderen ambulanten augenchirurgischen Versorgung nach § 73c SGB V. Im Internet: https://www.aok-gesundheitspartner.de/by/arztundpraxis/vertraege/index_13367.html 2015. Stand: 27.10.2017
- 25 Cunha-Vaz J, Ashton P, Iezzi R. et al. Sustained delivery fluocinolone acetonide vitreous implants: long-term benefit in patients with chronic diabetic macular edema. Ophthalmology 2014; 121: 1892-1903
- 26 Deutsche Ophthalmologische Gesellschaft (DOG), Retinologische Gesellschaft, Berufsverband der Augenärzte Deutschlands (BVA). Endophthalmitis-Prophylaxe bei intravitrealer operativer Medikamenteneingabe (IVOM). 2013 Im Internet: http://www.dog.org/wp-content/uploads/2013/03/Stand-Sep-2013-IVOM-topische-Antibiose.pdf Stand: 27.10.2017
- 27 (G-BA) Gemeinsamer Bundesausschuss. Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie (AM-RL): Anlage XII – Beschlüsse über die Nutzenbewertung von Arzneimitteln mit neuen Wirkstoffen nach § 35a SGB V – Tafluprost/Timolol 2015. Im Internet: https://www.g-ba.de/downloads/39-261-2261/2015-06-18_AM-RL-XII_Tafluprost_Timolol_2015-01-01-D-144_BAnz.pdf Stand: 27.10.2017
- 28 Do DV, Nguyen QD, Vitti R. et al. Intravitreal aflibercept injection in diabetic macular edema patients with and without prior anti-vascular endothelial growth factor treatment: outcomes from the phase 3 program. Ophthalmology 2016; 123: 850-857
- 29 Fechter C, Frazier H, Marcus WB. et al. Ranibizumab 0.3 mg for persistent diabetic macular edema after recent, frequent, and chronic bevacizumab: the ROTATE trial. Ophthalmic Surg Lasers Imaging Retina 2016; 47: 1-18
- 30 Boyer DS, Yoon YH, Belfort jr. R. et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014; 121: 1904-1914
- 31 Gillies MC, Lim LL, Campain A. et al. A randomized clinical trial of intravitreal bevacizumab versus intravitreal dexamethasone for diabetic macular edema: the BEVORDEX study. Ophthalmology 2014; 121: 2473-2481
- 32 Fraser-Bell S, Lim LL, Campain A. et al. Bevacizumab or dexamethasone implants for DME: 2-year results (the BEVORDEX study). Ophthalmology 2016; 123: 1399-1401
- 33 Campochiaro PA, Brown DM, Pearson A. et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology 2012; 119: 2125-2132
- 34 Hermann C, Pfaff A. Arzneimittelsteuerung am Beispiel der intravitrealen operativen Medikamenteneingabe in Baden-Württemberg. Monitor Versorgungsforschung 2015; 8: 39-42
- 35 Bressler SB, Glassman AR, Almukhtar T. et al. Five-year outcomes of ranibizumab with prompt or deferred laser versus laser or triamcinolone plus deferred ranibizumab for diabetic macular edema. Am J Ophthalmol 2016; 164: 57-68
- 36 Bressler SB, Liu D, Glassman AR. et al. Change in diabetic retinopathy through 2 years: secondary analysis of a randomized clinical trial comparing aflibercept, bevacizumab, and ranibizumab. JAMA Ophthalmol 2017; 135: 558-568
- 37 Cai S, Bressler NM. Aflibercept, bevacizumab or ranibizumab for diabetic macular oedema: recent clinically relevant findings from DRCR.net Protocol T. Curr Opin Ophthalmol 2017; 28: 636-643
- 38 Jampol LM, Glassman AR, Bressler NM. et al. Anti-vascular endothelial growth factor comparative effectiveness trial for diabetic macular edema: additional efficacy post hoc analyses of a randomized clinical trial. JAMA Ophthalmol 2016; DOI: 10.1001/jamaophthalmol.2016.3698.
- 39 Wells JA, Glassman AR, Ayala AR. et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology 2016; 123: 1351-1359
- 40 Wells JA, Glassman AR, Jampol LM. et al. Association of baseline visual acuity and retinal thickness with 1-year efficacy of aflibercept, bevacizumab, and ranibizumab for diabetic macular edema. JAMA Ophthalmol 2016; 134: 127-134 [Erratum in: JAMA Ophthalmol 2016; 134: 469]
- 41 Fouda SM, Bahgat AM. Intravitreal aflibercept versus intravitreal ranibizumab for the treatment of diabetic macular edema. Clin Ophthalmol 2017; 11: 567-571
- 42 Brown DM, Nguyen QD, Marcus DM. et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology 2013; 120: 2013-2022
- 43 Nguyen QD, Brown DM, Marcus DM. et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012; 119: 789-801
- 44 Pieramici DJ, Wang PW, Ding B. et al. Visual and anatomic outcomes in patients with diabetic macular edema with limited initial anatomic response to ranibizumab in RIDE and RISE. Ophthalmology 2016; 123: 1345-1350
- 45 Wykoff CC, Elman MJ, Regillo CD. et al. Predictors of diabetic macular edema treatment frequency with ranibizumab during the open-label extension of the RIDE and RISE Trials. Ophthalmology 2016; 123: 1716-1721
- 46 Massin P, Bandello F, Garweg JG. et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care 2010; 33: 2399-2405
- 47 Nguyen QD, Shah SM, Heier JS. et al. Primary end point (six months) results of the ranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology 2009; 116: 2175-2181.e1
- 48 Nguyen QD, Shah SM, Khwaja AA. et al. Two-year outcomes of the ranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology 2010; 117: 2146-2151 [Erratum in: Ophthalmology 2011; 118: 1016]
- 49 Diabetic Retinopathy Clinical Research Network. Elman MJ, Aiello LP. et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010; 117: 1064-1077.e35
- 50 Diabetic Retinopathy Clinical Research Network. Elman MJ, Qin H. et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology 2012; 119: 2312-2318 [Erratum in: Ophthalmology 2014; 121: 805]
- 51 Elman MJ, Ayala A, Bressler NM. et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology 2015; 122: 375-381
- 52 Elman MJ, Bressler NM, Qin H. et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2011; 118: 609-614
- 53 Ishibashi T, Li X, Koh A. et al. The REVEAL study: ranibizumab monotherapy or combined with laser versus laser monotherapy in Asian patients with diabetic macular edema. Ophthalmology 2015; 122: 1402-1415
- 54 Do DV, Nguyen QD, Khwaja AA. et al. Ranibizumab for edema of the macula in diabetes study: 3-year outcomes and the need for prolonged frequent treatment. JAMA Ophthalmol 2013; 131: 139-145
- 55 Dhoot DS, Baker K, Saroj N. et al. Baseline factors affecting changes in diabetic retinopathy severity scale score after intravitreal aflibercept or laser for diabetic macular edema. Post hoc analyses from VISTA and VIVID. Ophthalmology 2018; 125: 51-56
- 56 Heier JS, Korobelnik JF, Brown DM. et al. Intravitreal aflibercept for diabetic macular edema: 148-week results from the VISTA and VIVID studies. Ophthalmology 2016; 123: 2376-2385
- 57 Wykoff CC, Le RT, Khurana RN. et al. Outcomes with as-needed aflibercept and macular laser following the phase III VISTA DME trial: ENDURANCE 12-month extension study. Am J Ophthalmol 2017; 173: 56-63
- 58 Wykoff CC, Marcus DM, Midena E. et al. Intravitreal aflibercept injection in eyes with substantial vision loss after laser photocoagulation for diabetic macular edema subanalysis of the vista and vivid randomized clinical trials. JAMA Ophthalmol 2017; 135: 107-114
- 59 Campochiaro PA, Brown DM, Pearson A. et al. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology 2011; 118: 626-635.e2
- 60 Campochiaro PA, Hafiz G, Shah SM. et al. Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert. Ophthalmology 2010; 117: 1393-1399.e3
- 61 Maturi RK, Pollack A, Uy HS. et al. Intraocular pressure in patients with diabetic macular edema treated with dexamethasone intravitreal implant in the 3-year mead study. Retina 2016; 36: 1143-1152
- 62 Aroney C, Fraser-Bell S, Lamoureux EL. et al. Vision-related quality of life outcomes in the BEVORDEX study: A clinical trial comparing ozurdex sustained release dexamethasone intravitreal implant and bevacizumab treatment for diabetic macular edema. Invest Ophthalmol Vis Sci 2016; 57: 5541-5546
- 63 Fraser-Bell S, Lim LL, Campain A. et al. Bevacizumab or dexamethasone implants for DME: 2-year results (the BEVORDEX study). Ophthalmology 2016; 123: 1399-1401
- 64 Callanan DG, Gupta S, Boyer DS. et al. Dexamethasone intravitreal implant in combination with laser photocoagulation for the treatment of diffuse diabetic macular edema. Ophthalmology 2013; 120: 1843-1851
- 65 Haller JA, Kuppermann BD, Blumenkranz MS. et al. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol 2010; 128: 289-296
- 66 Callanan DG, Loewenstein A, Patel SS. et al. A multicenter, 12-month randomized study comparing dexamethasone intravitreal implant with ranibizumab in patients with diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 2017; 255: 463-473