ABSTRACT

Choroidal neovascularization due to age-related macular degeneration (AMD) is currently treated successfully with anti-vascular endothelial growth factor (VEGF) intravitreal agents. Emerging evidence suggests that anti-VEGF treatment may potentially increase development of geographic atrophy. However, there is not yet direct proof of a causal relationship between geographic atrophy and use of anti-VEGF agents in neovaskuler AMD. The aim of this review is to discuss the evidence concerning the association between anti-VEGF therapy and progression of geographic atrophy.

Introduction

Intravitreal anti-vascular endothelial growth factor (VEGF) application has been the most effective treatment method in recent years for neovascular age-related macular degeneration (AMD).^1,2,3 The common feature of the multicenter studies conducted in this area with different agents and for different purposes is that they first determined the efficacy and safety of these agents. In the MARINA and ANCHOR trials, monthly ranibizumab injections preserved visual acuity and maintained vision level, and this finding has been clearly demonstrated in evidence-based, controlled comparative studies.^1,2 Two main points have recently been raised regarding the safety of anti-VEGFs. The first concern is local side effects such as endophthalmitis, vitreal hemorrhage, or retinal detachment, and the second is systemic side effects, especially cerebrovascular events. However, studies of these extremely rare adverse events showed that the use of these agents was not significantly associated with the likelihood of developing such complications.^1,2,3,4,5

Retrospective analyses of multicenter studies have provided new and interesting findings. One example is evidence from the CATT³ trial which suggests a relationship between long-term anti-VEGF therapy and the development of geographic atrophy. The IVAN⁴ and HARBOR⁶ trials were also retrospectively analyzed in terms of this possible relationship and reported suspicious findings similar to those found in the CATT trial.^3,4,5,6,7,8

Therefore, one of the most important questions of recent times is whether late geographic atrophy is really more prevalent in patients with long-term anti-VEGF use, and if so, what role the anti-VEGF agents play in the development of geographic atrophy.

Conclusion

In conclusion, retrospective analyses of the CATT^15,16, IVAN⁴, and HARBOR⁶ trials suggest that long-term intravitreal anti-VEGF therapies increase geographic atrophy in wet AMD patients. Even if this is the case, however, considering that 80% of these atrophic changes are extrafoveal and do not directly affect visual acuity, wet AMD patients should nevertheless be treated with adequate duration and frequency despite this possibility. As observed in the MARINA¹ and ANCHOR² trials, treatment yields visual gains of over 20 letters, compared to the loss of 14 letters in the sham group, which reflects the natural disease course. Even if atrophy does develop, the difference in letters gained between the patients with and without atrophy is 2.4 letters at 24 months. In light of these findings, it remains to be clarified whether the areas of geographic atrophy seen after anti-VEGF therapy in wet AMD are associated with the natural course of the disease or emerge as a result of the anti-VEGF molecules used in treatment. Regardless, considering the approximately 20-letter gain achieved over a 2-year period in these patients compared to the natural course, we believe these therapies are still indispensable for the treatment of wet AMD.