Ranibizumab Treatment in Age-Related Macular Degeneration: A Meta-Analysis of One-Year Results

 

 Buy Article Permissions and Reprints

Abstract

Background: Although ranibizumab is widely used in age-related macular degeneration there is no systematic data available on the relation between treatment frequency and functional efficacy within the first 12 months of follow-up.

Material and Methods: A meta-analysis was performed on available MEDLINE literature. 47 relevant clinical studies (54 case series) could be identified covering 11 706 treated eyes. Non-linear and linear regressions were calculated for the relation between treatment frequency and functional outcome (average gain in visual acuity, % of eyes losing less than 15 letters of visual acuity, % of eyes gaining ≥ 15 letters) within the first year of care.

Results: Mean improvement of average visual gain was + 4.9 ± 3.6 (mean ± 1 standard deviation) letters (case-weighted: 3.3 letters). The average number of ranibizumab injections until month 12 was 6.3 ± 2.0 (case-weighted: 5.9). 92.4 ± 3.9 % of eyes (case-weighted: 91.9 %) lost less than three lines of visual acuity and 24.5 ± 8.2 % (case-weighted: 23.3) gained more than 3 lines within the first year. Analysis of the relation between the number of injections and functional improvement indicated best fit for non-linear equations. A nearly stepwise improvement of functional gain occurred between 6.8 and 7.2 injections/year. A saturation effect of treatment occurred at higher injection frequency.

Conclusions: The results of this meta-analysis clearly indicate a non-linear relation between the number of injections and functional gain of ranibizumab within the first 12 months of treatment. Treatment saturation seems to occur at a treatment frequency > 7.2 injections within the first 12 months.

Zusammenfassung

Hintergrund: Obschon die Behandlung der feuchten altersabhängigen Makuladegeneration mit Ranibizumab als weitverbreiteter Standard etabliert ist, sind bislang keine systematischen Analysen zur Relation von Injektionshäufigkeit und funktionellen Ergebnissen im 1. Betreuungsjahr verfügbar.

Material und Methoden: Es wurde eine Metaanalyse der in MEDLINE verfügbaren Literatur durchgeführt. 47 relevante klinische Studien (54 Fallserien) mit insgesamt 11 706 behandelten Augen konnten identifiziert werden. Nicht-lineare und lineare Regression wurden für die Relation zwischen Injektionshäufigkeit im Jahr 1 und funktionellen Ergebnissen (mittlerer Visusgewinn, % der Augen mit einem Verlust von weniger als 15 Buchstaben, % der Augen mit einem Gewinn von ≥ 15 Buchstaben) errechnet.

Ergebnisse: Der mittlere durchschnittliche Visusgewinn betrug 4,9 ± 3,6 (Mittelwert ± 1 Standardabweichung) Buchstaben. Im Mittel wurden im 1. Jahr 6,3 ± 2,0 Injektionen (fallzahlgewichtet: 5,9) appliziert. Bei 92,4 ± 3,9 % aller Augen (fallzahlgewichtet: 91,9 %) verringerte sich die Sehschärfe um weniger als 3 Linien; bei 24,5 ± 8,2 % (fallzahlgewichtet: 23,3) kam es zu einer Verbesserung um mehr als 3 Linien. Die Analyse der Relation von Injektionszahl und funktioneller Änderung ließ ein optimiertes Fitting nicht-linearer Modelle erkennen. Eine nahezu stufenförmige funktionelle Verbesserung zeigte sich bei einer Behandlungsfrequenz zwischen 6,8 und 7,2 Injektionen im 1. Jahr. Für eine höhere Behandlungsfrequenz war ein deutlicher Sättigungseffekt auszumachen.

Schlussfolgerungen: Die Ergebnisse dieser Analyse zeigen eine nicht-lineare Relation zwischen der Anzahl an Injektionen und dem funktionellen Gewinn innerhalb des 1. Behandlungsjahrs. Ein Sättigungseffekt der Behandlung scheint sich bei einer Injektionsfrequenz von > 7,2 Injektionen im 1. Jahr einzustellen.

• References

• 1 Rosenfeld PJ, Brown DM, Heier JS et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419-1431
  CrossrefPubMedGoogle Scholar
• 2 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
  CrossrefPubMedGoogle Scholar
• 3 Boyer DS, Heier JS, Brown DM et al. A phase III b study to evaluate the safety of ranibizumab in subjects with neovascular age-related macular degeneration. Ophthalmology 2009; 116: 1731-1739
  CrossrefPubMedGoogle Scholar
• 4 Regillo CD, Brown DM, Abraham P et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study Year 1. Am J Ophthalmol 2008; 145: 239-248
  CrossrefPubMedGoogle Scholar
• 5 Schmidt-Erfurth U, Eldem B, Guymer R et al. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related degeneration: The EXCITE study. Ophthalmology 2011; 118: 831-839
  CrossrefPubMedGoogle Scholar
• 6 Fung AE, Lalwani GA, Rosenfeld PJ et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol 2007; 143: 566-583
  CrossrefPubMedGoogle Scholar
• 7 Holz FG, Amoaku W, Donate J et al. Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: The SUSTAIN study. Ophthalmology 2011; 118: 663-671
  CrossrefPubMedGoogle Scholar
• 8 The CATT Research Group. Ranibizumab and Bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011; 364: 1897-1908
  CrossrefPubMedGoogle Scholar
• 9 Bandukwala T, Muni RH, Schwartz C et al. Effectiveness of intravitreal ranibizumab for the treatment of neovascular age-related macular degeneration in a Canadian retina practice: a retrospective review. Can J Ophthalmol 2010; 45: 590-595
  CrossrefPubMedGoogle Scholar
• 10 Bloch SB, la Cour M, Sander B et al. Predictors of 1-year visual outcome in neovascular age-related macular degeneration following intravitreal ranibizumab treatment. Acta Ophthalmol 2013; 91: 42-47
  CrossrefPubMedGoogle Scholar
• 11 Busbee BG, Ho AC, Brown DM et al. Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology 2013; 120: 1046-1056
  CrossrefPubMedGoogle Scholar
• 12 Carneiro AM, Mendonça LS, Falcão MS et al. Comparative study of 1+PRN ranibizumab versus bevacizumab in the clinical setting. Clin Ophthalmol 2012; 6: 1149-1157
  PubMedGoogle Scholar
• 13 Cohen SY, Dubois L, Tadayoni R et al. Results of one-yearʼs treatment with ranibizumab for exudative age-related macular degeneration in a clinical setting. Am J Ophthalmol 2009; 148: 409-413
  CrossrefPubMedGoogle Scholar
• 14 Cohen SY, Mimoun G, Qubraham H et al. Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE Study. Retina 2013; 33: 474-481
  CrossrefPubMedGoogle Scholar
• 15 Cohen SY, Dubois L, Ayrault S et al. Ranibizumab for exudative AMD in a clinical setting: differences between 2007 and 2010. Graefes Arch Clin Exp Ophthalmol 2013; 251: 2499-2503
  CrossrefPubMedGoogle Scholar
• 16 Dadgostar H, Ventura AA, Chung JY et al. Evaluation of injection frequency and visual outcomes for ranibizumab monotherapy in exudative age-related macular degeneration. Ophthalmology 2009; 116: 1740-1747
  CrossrefPubMedGoogle Scholar
• 17 Finger RP, Wiedemann P, Blumenhagen F et al. Treatment patterns, visual acuity and quality-of-life outcomes of the WAVE study – A noninterventional study of ranibizumab treatment for age-related macular degeneration in Germany. Acta Ophthalmol 2013; 91: 540-546
  CrossrefPubMedGoogle Scholar
• 18 Fong DS, Custis P, Howes J et al. Intravitreal bevacizumab and ranibizumab for age-related macular degeneration. Ophthalmology 2010; 117: 298-302
  CrossrefPubMedGoogle Scholar
• 19 Frennesson CI, Nilsson SEG. A three-year follow-up of ranibizumab treatment of exudative AMD: impact on the outcome of carrying forward the last acuity observation in drop-outs. Acta Ophthalmol 2013; DOI: 10.1111/aos.12091.
  PubMedGoogle Scholar
• 20 Gerding H, Loukopoulos V, Riese J et al. Results of flexible ranibizumab treatment in age-related macular degeneration and search for parameters with impact on outcome. Graefes Arch Clin Exp Ophthalmol 2011; 249: 653-662
  CrossrefPubMedGoogle Scholar
• 21 Gupta OP, Shienbaum G, Patel AH et al. A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration. Ophthalmology 2010; 117: 2134-2140
  CrossrefPubMedGoogle Scholar
• 22 Gupta B, Adewoyin T, Patel SK et al. Comparision of two intravitreal ranibizumab treatment schedules for neovascular age-related macular degenerations. Br J Ophthalmol 2011; 95: 386-390
  CrossrefPubMedGoogle Scholar
• 23 Heimes B, Lommatzsch A, Zeimer M et al. Long-term visual course after anti-VEGF therapy for exsudative AMD in clinical practice evaluation of the German reinjection scheme. Graefes Arch Clin Exp Ophthalmol 2011; 249: 639-644
  CrossrefPubMedGoogle Scholar
• 24 Hjelmqvist L, Lindberg C, Kanulf P et al. One-year outcomes using ranibizumab for neovascular age-related macular degeneration: Results of a prospective and retrospective observational multicenter study. J Ophthalmol 2011; 2011: 405724
  PubMedGoogle Scholar
• 25 Holz FG, Bandello F, Gillies M et al. Safety of ranibizumab in routine clinical practice: 1-year retrospective pooled analysis of four European neovascular AMD registries within the LUMINOUS programme. Br J Ophthalmol 2013; 97: 1161-1167
  CrossrefPubMedGoogle Scholar
• 26 Kaiser PK, Boyer DS, Cruess AF et al. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month results of the DENALI study. Ophthalmology 2012; 119: 1001-1010
  CrossrefPubMedGoogle Scholar
• 27 Kang S, Roh YJ. One-year results of intravitreal ranibizumab for neovascular age-related macular degeneration and clinical responses of various subgroups. Jpn J Ophthalmol 2009; 53: 389-395
  CrossrefPubMedGoogle Scholar
• 28 Kodjikian L, Souied EH, Mimoun G et al. Ranibizumab versus bevacizumab for neovascular age related macular degeneration: Results from the GEFAL noninferiority randomized trial. Ophthalmology 2013; 120: 2300-2309
  CrossrefPubMedGoogle Scholar
• 29 Krebs I, Marlovits VV, Bodenstorfer J et al. Comparison of ranibizumab monotherapy versus combination of ranibizumab with photodynamic therapy with neovascular age-related macular degeneration. Acta Ophthalmol 2013; 91: 178-183
  CrossrefPubMedGoogle Scholar
• 30 Krebs I, Schmetterer L, Boltz A et al. A randomized double-masked trial comparing the visual outcome after treatment with ranibizumab or bevacizumab in patients with neovascular age-related macular degeneration. Br J Ophthalmol 2013; 97: 266-271
  CrossrefPubMedGoogle Scholar
• 31 Kumar A, Sahni JN, Stangos AN et al. Effectiveness of ranibizumab for neovascular age-related macular degeneration using clinician-determined retreatment strategy. Br J Ophthalmol 2011; 95: 530-533
  CrossrefPubMedGoogle Scholar
• 32 Kwon OW, Lee FL, Chung H et al. EXTEND III: Efficacy and safety of ranibizumab in south Korean and Taiwanese patients with subfoveal CNV secondary to AMD. Graefes Arch Clin Exp Ophthalmol 2012; 250: 1467-1476
  CrossrefPubMedGoogle Scholar
• 33 Lala C, Framme C, Wolf-Schurrbusch UE et al. Three-year results of visual outcome with disease activity-guided ranibizumab algorithm for the treatment of exudative age-related macular degeneration. Acta Ophthalmol 2013; 91: 526-530
  CrossrefPubMedGoogle Scholar
• 34 Larsen M, Schmidt-Erfurth U, Lanzetta P et al. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration. Twelve-month MONT BLANC study results. Ophthalmology 2012; 119: 992-1000
  CrossrefPubMedGoogle Scholar
• 35 Mantel I, Deli A, Iglesias K et al. 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
  CrossrefPubMedGoogle Scholar
• 36 Marques IP, Fonseca P, Luz Cachulo M et al. Treatment of exudative age-related macular degeneration with intravitreal ranibizumab in clinical practice: a 3-year follow-up. Ophthalmologica 2013; 229: 158-167
  CrossrefPubMedGoogle Scholar
• 37 Martinez-de-la-Casa JM, Ruiz-Calvo A, Saenz-Frances F et al. Retinal nerve fibre layer thickness changes in patients with age-related macular degeneration treated with intravitreal ranibizumab. Invest Ophthalmol Vis Sci 2012; 53: 6214-6218
  CrossrefPubMedGoogle Scholar
• 38 Muether PS, Hoerster R, Hermann MM et al. Long-term effects of ranibizumab treatment delay in neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2013; 251: 453-458
  CrossrefPubMedGoogle Scholar
• 39 Muniraju R, Ramu J, Sivaprasad S. Three-year visual outcome and injection frequency of intravitreal ranibizumab therapy for neovascular age-related macular degeneration. Ophthalmologica 2013; 230: 27-33
  CrossrefPubMedGoogle Scholar
• 40 Oubraham H, Cohen SY, Samimi S et al. Inject and extend dosing versus dosing as needed: a comparative retrospective study of ranibizumab in exudative age-related macular degeneration. Retina 2011; 31: 26-30
  CrossrefPubMedGoogle Scholar
• 41 Pushpoth S, Sykakis E, Merchant K et al. Measuring the benefit of 4 years of intravitreal ranibizumab treatment for neovascular age-related macular degeneration. Br J Ophthalmol 2012; 96: 1469-1473
  CrossrefPubMedGoogle Scholar
• 42 Querques G, Azrya S, Martinelli D et al. Ranibizumab for exudative age-related macular degeneration: 24-month outcome from a single-centre institutional setting. Br J Ophthalmol 2010; 94: 292-296
  CrossrefPubMedGoogle Scholar
• 43 Ross AH, Donachie PHJ, Sallam A et al. Which visual acuity measurements define high-quality care for patients with neovascular age-related macular degeneration treated with ranibizumab?. Eye (Lond) 2013; 27: 56-64
  CrossrefPubMedGoogle Scholar
• 44 Rothenbuehler SP, Waeber D, Brinkmann CK et al. Effects of ranibizumab in patients with subfoveal choroidal neovascularization attributable to age-related macular degeneration. Am J Ophthalmol 2009; 147: 831-837
  CrossrefPubMedGoogle Scholar
• 45 Tan SZ, Laude A, Aspinall PA et al. Decisional answer tree analysis of exudative age-related macular degeneration treatment outcomes. Int Ophthalmol 2013; 33: 467-474
  CrossrefPubMedGoogle Scholar
• 46 Tano Y, Ohji M. Extend-1: Safety and efficacy of ranibizumab in Japanese patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration. Acta Ophthalmol 2010; 88: 309-316
  CrossrefPubMedGoogle Scholar
• 47 Toalster N, Russel M, Ng P. A 12-month prospective trial of inject and extend regimen for ranibizumab treatment of age-related macular degeneration. Retina 2013; 33: 13518
  PubMedGoogle Scholar
• 48 Holz FG, Korobelnik JF, Lanzetta P et al. The effects of a flexible visual acuity-driven ranibizumab treatment regimen in age-related macular degeneration: Outcomes of a drug and disease model. Invest Ophthalmol Vis Sci 2010; 51: 405-411
  CrossrefPubMedGoogle Scholar
• 49 Heier JS, Brown DM, Chong V et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012; 119: 2537-2548
  CrossrefPubMedGoogle Scholar
• 50 IVAN Study Investigators. Chakravarthy U, Harding SP et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology 2012; 119: 1399-1411
  CrossrefPubMedGoogle Scholar