Abstract
Objective
Summarize and compare the available evidence on the reactivation times in patients with age-related macular degeneration treated with Ranibizumab (RNB).
Method
Systematic review of studies that reported the reactivation time of patients (direct method) or the number of injections received in a certain period of follow-up (indirect method).
Results
Only 18 of 89 selected studies reported the average reactivation time of patients in a manifest form, without the need of any calculation. The average calculated, weighted reactivation time was 101.8 days with the direct method and 99.8 days in the indirect method (84 studies included). With both methods, it was found that the average reactivation time of the RCTs was between 2 and 3 weeks less than the average time identified in the observational studies. These differences are also reflected in the clinical results, there being a correlation between the number of doses received and the change in BCVA. The analysis of 11 comparative studies showed a difference in reactivation times between patients treated with RNB or Bevacizumab (BVZ).
Conclusion
There are few direct studies of reactivation time, but calculation from the PRN dose number turns out to be a good approximation for retrospective study of the variable. The use of the PRN, with criteria not based on optical coherence tomography scans, delays the application of doses between 2 or 3 weeks, and patients suffer loss of clinical benefits. RNB enables patients to receive less injections than BVZ throughout treatment.
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References
Resnikoff S, Pascolini D, Etya'ale D, Kocur I, Pararajasegaram R, Pokharel GP, Mariotti SP (2004) Global data on visual impairment in the year 2002. Bull World Health Organ 82(11):844–851
Gohdes DM, Balamurugan A, Larsen BA, Maylahn C (2005) Age-related eye diseases: an emerging challenge for public health professionals. Prev Chronic Dis 2(3):A17
Wong TY, Chakravarthy U, Klein R, Mitchell P, Zlateva G, Buggage R, Fahrbach K, Probst C, Sledge I (2008) The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis. Ophthalmology 115(1):116–126
MARINA Study Group, Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355(14):1419–1431
ANCHOR Study Group; Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Lanchulev T (2006) Ranibizumab versus Verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 116(1):57–65
Smiddy WE (2009) Economic implications of current age-related macular degeneration treatments. Ophthalmology 116(3):481–487
Real JP, Tártara I, Allemandi D, Granero G, Palma SD (2011) Tratamiento de la degeneración macular asociada a la edad (DMAE). Atención Farmacéutica. (European Journal of Clinical Pharmacy) Barcelona: rasgo editorial. 13(3):160–171
Stewart MW (2015) Individualized treatment of neovascular age-related macular degeneration: what are patients gaining? Or losing? J Clin Med 4:1079–1101
Monés J, Biarnés M, Trindade F, Casaroli-Marano R (2012) FUSION regimen: ranibizumab in treatment-naïve patients with exudative age-related macular degeneration and relatively good baseline visual acuity. Graefes Arch Clin Exp Ophthalmol 250(12):1737–1744
Zhang Y, Yao Z, Kaila N, Kuebler P, Visich J, Maia M, Tuomi L, Ehrlich JS, Rubio RG, Campochiaro PA (2014) Pharmacokinetics of ranibizumab after intravitreal administration in patients with retinal vein occlusion or diabetic macular edema. Ophthalmology 21(11):2237–2246
Holz FG, Amoaku W, Donate J, Guymer RH, Kellner U, Schlingemann RO, Weichselberger A, Staurenghi G (2011) Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study. Ophthalmology 118(4):663–671
Rebasa P (2005) Basic concepts in survival analysis. Cirugía Española 78(4):222–230
Moraleda A, Villalba CM (2013) Modelado y Simulación de Eventos Discretos (ebook), 1ra edicion edn. Uned. Universidad Nacional de Educacion a Distancia, España
ARRIBALZAGA EB (2007) Interpretación de las curvas de supervivencia. Rev Chil Cir 59(1):75–83. https://doi.org/10.4067/S0718-40262007000100013
Cox C, Chu H, Schneider MF, Muñoz A (2007) Parametric survival analysis and taxonomy of hazard functions for the generalized gamma distribution. Stat Med 26(23):4352–4374
Arroyo I, Bravo LC, Llinas H, Munoz FL (2014) Distribuciones Poisson y Gamma: Una Discreta y Continua Relación. Prospect. [online], 12(1):99–107. http://www.scielo.org.co/pdf/prosp/v12n1/v12n1a12.pdf
Higgins J, Green S (2011) Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration; http://handbook-5-1.cochrane.org. Accessed 6 Jul 2015
Berg K, Hadzalic E, Gjertsen I, Forsaa V, Berger LH, Kinge B, Henschien H, Fossen K, Markovic S, Pedersen TR, Sandvik L, Bragadóttir R (2015) Ranibizumab or Bevacizumab for neovascular age-related macular degeneration according to the Lucentis compared to Avastin study treat-and-extend protocol: two-year results. Ophthalmology 123(1):51–59
IVAN study investigators [IVAN], Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Culliford LA, Reeves BC (2013) Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet 382(9900):1258–1267
Hörster R, Ristau T, Sadda SR, Liakopoulos S (2011) Individual recurrence intervals after anti-VEGF therapy for age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 249(5):645–652
Mantel I, Deli A, Iglesias K, Ambresin A (2013) Prospective study evaluating the predictability of need for retreatment with intravitreal ranibizumab for age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 251(3):697–704
Muether PS, Hermann MM, Viebahn U, Kirchhof B, Fauser S (2012) Vascular endothelial growth factor in patients with exudative age-related macular degeneration treated with ranibizumab. Ophthalmology 10:2082–2086
Cohen SY, Dubois L, Tadayoni R et al (2009) Results of one-year’s treatment with ranibizumab for exudative age-related macular degeneration in a clinical setting. Am J Ophthalmol 148:409–413
Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ (2011) Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 364(20):1897–1908
Real JP, Granero GE, De Santis MO, Juarez CP, Palma SD, Kelly SP, Luna JD (2015) Rate of vision loss in neovascular age-related macular degeneration explored. Graefes Arch Clin Exp Ophthalmol 253(11):1859–1865
Barquet A, Monés J (2012) New treatment protocols and follow-up in patients with exudative age-related macular degeneration. Arch Soc Esp Oftalmol 87(Suppl 1):10–17
Gupta OP, Shienbaum G, Patel AH, Fecarotta C, Kaiser RS, Regillo CD (2010) A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration clinical and economic impact. Ophthalmology 17(11):2134–2140
Oubraham H, Cohen SY, Samimi S, Marotte D, Bouzaher I, Bonicel P, Fajnkuchen F, Tadayoni R (2011) Inject and extend dosing versus dosing as needed: a comparative retrospective study of Ranibizumab in exudative age-related macular degeneration. Retina 3:26–30
Abraham P, Yue H, Wilson L (2010) Randomized, double-masked, sham-controlled trial of Ranibizumab for neovascular age-related macular degeneration: PIER study year 2. Am J Ophthalmol 150(3):315–324
Magdelaine-Beuzelin C, Pinault C, Paintaud G, Watier H (2010) Therapeutic antibodies in ophthalmology: old is new again. MAbs 2(2):176–180
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Real, J.P., Luna, J.D. & Palma, S.D. The reactivation time in the treatment of AMD: a forgotten key parameter?. Graefes Arch Clin Exp Ophthalmol 256, 1079–1087 (2018). https://doi.org/10.1007/s00417-018-3974-0
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DOI: https://doi.org/10.1007/s00417-018-3974-0