Macular mystery

A post-hoc analysis of patients in the HARBOR study indicates that the development of macular atrophy in patients receiving intravitreal ranibizumab for neovascular age-related macular degeneration (AMD) does not appear to be influenced by the dosage regimen they receive and that the intravitreal agent continues to provide benefits in those who develop the condition, said Frank G Holz MD, University of Bonn, Germany, at the 15th EURETINA Congress in Nice, France.
Dr Holz noted that researchers have reported the development of macular atrophy among patients participating in several of the large clinical trials evaluating anti-vascular endothelial growth factor (anti-VEGF) agents in the treatment of neovascular AMD.
There are several possible explanations for this phenomenon, he said. Geographic atrophy may be a natural progression of macular degeneration, and neovascularisation may accelerate that progression through some sort of micro-mechanical stress on the retinal tissues. Alternatively, anti-VEGF treatment may interfere with the physiology of the eye.
To investigate the matter further, Dr Holz and his associates retrospectively analysed the findings from the phase III HARBOR study. The multicentre, double-masked, randomised controlled clinical trial involved 1,095 patients with neovascular AMD who received either 0.5mg or 2.0mg intravitreal ranibizumab, administered monthly or as needed (PRN) over a two-year period.
The HARBOR study investigators assessed the presence of macular atrophy based on fluorescein angiograms and colour fundus photographs. They defined the condition as the presence of well-defined areas of depigmentation, with increased choroidal vessel visibility with diameters of 250µm or more that corresponded to flat areas of well-demarcated staining on fluorescein angiography. They included all atrophy immediately within, adjacent to and non-adjacent to choroidal neovascular lesions, but excluded atrophy associated with retinal pigment epithelium tears.
In their retrospective analysis, Dr Holz and his associates found that 11.2 per cent of eyes had macular atrophy at baseline and an additional 29 per cent had developed the condition by month 24 of the study. By that time, the mean best visual acuity gains from baseline among those with and without macular atrophy at baseline were 6.7 letters and 9.7 letters, respectively. 

RISK FACTORS
The risk factors they identified for the development of macular atrophy included the presence of intraretinal cysts at baseline, which had a hazard ratio of 2.45, and the presence of macular atrophy at baseline, which had a hazard ratio of 2.02. Counter-intuitively, the presence of baseline subretinal fluid was associated with a lower incidence of macular atrophy, he said. Furthermore, at 24 months only 8.1 per cent of eyes with current subretinal fluid had macular atrophy, compared to 32.9 per cent of eyes without subretinal fluid.
Their findings did not seem to indicate that there was any dose-dependent effect of ranibizumab on the development of macular atrophy. For example, the condition did not occur any more frequently among those receiving the 2.0mg dosage than it did among those receiving the 0.5mg dosage, with a hazard ratio of 1.09.
And although there was a trend towards a higher incidence of macular atrophy occurring among those receiving a monthly regimen compared to those receiving a PRN regimen, greater frequency of injection in the study’s PRN arms did not significantly increase the incidence of macular atrophy. That is, among those receiving one to six PRN injections the macular atrophy incidence was 24 per cent in the 0.5mg group and 42 per cent in the 2.0mg group, and among those receiving more than 18 PRN injections the incidence was 21 per cent in the 0.5mg group and 19 per cent in the 2.0mg group. 
Dr Holz noted that the weaknesses of their study included its retrospective nature and the lack of a control group. He also pointed out that visual outcomes tend to be worse in non-treated eyes and that macular atrophy is the default outcome in AMD.
“Based on existing data, macular atrophy development does not appear to outweigh the benefits of ranibizumab therapy in neovascular AMD.”  
Frank G Holz: Frank.Holz@ukb.uni-bonn.de