Implementation studies of ranibizumab for neovascular age-related macular degeneration

The pathogenesis of AMD is associated with age changes plus pathological changes involving oxidative stress and an altered inflammatory response leading to injury of retinal pigment epithelial cells and the adjacent choroidea and photoreceptor cells. AMD is divided into early, intermediate and advanced AMD. The advanced form of AMD is further divided into non-neovascular AMD and neovascular AMD. The diagnosis of neovascular AMD is based on FA and clinical characteristics of the eyes. The CNV lesions are by their growth pattern divided into type 1 CNV lesions, which grow primarily beneath the RPE, and type 2 CNV lesions, which have penetrated the RPE and evolve within the subretinal space. The natural course of neovascular AMD leads to visual disability in a majority of cases within the first years after onset, primarily caused by the development of subfoveal fibrous tissue and atrophy of the RPE. The prognosis of visual acuity in neovascular AMD has been markedly improved by the introduction of an intravitreal administered VEGF inhibitor (ranibizumab) given on a monthly basis. Treatment with ranibizumab for neovascular AMD was introduced in Denmark in 2006 under a fully reimbursed national healthcare plan. Treatment with ranibizumab is given in a variable dosing regimen that varies from the monthly dosing regimen administered in the studies that led to the approval of ranibizumab for neovascular AMD in Europe. The main objectives of this PhD thesis were to evaluate and potentially improve treatment with ranibizumab in a variable OCT guided regimen for neovascular AMD. Another intension of this PhD thesis was to prepare the conditions for future research to further improve the visual prognosis in neovascular AMD treated with anti-VEGF agents. The first study revealed that vision was improved in eyes with active neovascular AMD treated for 1 year in a variable ranibizumab treatment regimen as compared to PDT and the natural course of the disease. We assumed by comparing our results with other pro re nata regimens based on a monthly reassessment of disease activity that our patients could gain substantial vision if we optimized our frequency of re-examinations. The analysis demonstrated that we could discontinue treatment in patients who had a poor visual acuity during the first 3 months of treatment and that visual outcome could be improved by minimizing the delay from diagnosis of neovascular AMD to first administered ranibizumab injection. This study led to changes in departmental treatment procedures. In the second study, we found that type 2 CNV lesions had a higher hazard ratio as compared to type 1 CNV lesions in developing subfoveal fibrosis. Prominent subfoveal fibrous tissue and fibrous tissue with retinal atrophy led to poorer visual performances in eyes with neovascular AMD after 2 years of treatment as compared with eyes without subfoveal fibrous tissue. In the development of randomized clinical trials designed to address how treatment with VEGF inhibitors can be improved by limiting the growth of subfoveal fibrous tissue or neuroretinal atrophy, it is important to define subgroups of eyes at risk of these pathological changes. The second PhD study has contributed to identify this subgroup of eyes. The third study included in this PhD thesis revealed that the annual incidence rate of AMD-related legally blind persons registered in Denmark has halved during the last decade, with the bulk of the reduction observed after the introduction of ranibizumab for neovascular AMD.