We appreciate the comments of Drs Brijesh and Shorya on our report, which examined the cohort of patients with exudative age-related macular degeneration (AMD) who were subjects in the original phase 3 trials of intravitreal ranibizumab therapy. Visual and anatomic outcomes collected at 7-year follow-up indicated that macular atrophy and its progression were significant factors in long-term vision outcomes in patients undergoing anti–vascular endothelial growth factor (VEGF) treatment for exudative AMD.
The discussants raise 3 points, the first on the risk of error in spectral-domain optical coherence tomography (SD-OCT) measurements of macular thickness that can arise from indistinct borders of retinal pigment epithelium (RPE) vs underlying fibrosis or neovascular tissue, a difficulty circumvented in our analysis by the use of manual delineation to measure “neurosensory retina only,” which excluded subretinal and RPE layers. Moreover, the surprising finding that active macular edema did not correlate with long-term vision outcomes was buttressed by a similar lack of correlation for the presence or absence of intra- and subretinal fluid, which are also detected independently of the RPE and deeper layers. Swept-source OCT, which was predated by these studies, promises improved resolution and segmentation in future studies of macular anatomic outcomes.
A second point suggests performing an assessment of macular atrophy growth within several time frames, specifically from baseline to year 2 in order to look for any disproportionate early progression that could reasonably be associated with monthly ranibizumab injections, as compared to later periods during which progression would more likely be attributable to the disease process itself. We agree this would be of great interest, but had determined that accurate quantification of macular atrophy area at baseline was precluded in too many cases by active exudative processes (overlying submacular hemorrhage and exudates, active choroidal neovascularization leakage, etc), and so we selected the period from years 2 to 7 to perform analysis of macular atrophy progression. Perhaps the question of any direct relationship of VEGF inhibition and macular atrophy formation is at least partially addressed by our finding that macular atrophy progressed significantly over this 5-year span of quite low frequency of anti-VEGF treatments overall.
Finally, it is proposed that treatment with the Age-related Eye Disease Study (AREDS) vitamin formulation might have a benefit against macular atrophy progression, which was found to be ubiquitous in this group of treated AMD patients. This hypothesis would seem to be testable through a database analysis of the AREDS trials themselves (for the subpopulation who developed exudative AMD during up to 10 years of follow-up), using a nested case-control design to comparatively assess macular atrophy incidence and progression. We also agree that macular atrophy occurring in the setting of exudative AMD management presents an intriguing therapeutic target for future investigations, not only for micronutrient supplementation but also for different anti-VEGF treatment frequency regimens, as well as for novel adjunctive therapies, such as neuroprotective agents or inhibitors of complement-mediated retinal cell death. Once again, the attention of our colleagues to this report is both helpful and gratifying.