Clinical update: new treatments for age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of vision loss in the developed world. Until recently, this condition was believed to be largely untreatable, but developments in the past 2 years have challenged this view. A new class of drugs—based on suppression of vascular endothelial growth factor (VEGF)—has been introduced for the treatment of “wet” or neovascular AMD, the most visually disabling form (table 1). In 2006, results with an anti-VEGF agent, ranibizumab, showed that monthly intravitreal injections prevented vision loss and, in many cases, signifi cantly improved the visual acuity of patients with neovascular AMD. Somewhat less impressive, but still eff ective, fi ndings, were published 2 years earlier for another anti-VEGF agent, pegaptanib sodium. Both agents were recently approved for neovascular AMD by the US Food and Drug Administration (FDA) and have already been incorporated into European guidelines. A third agent, bevacizumab, is now increasingly used off -label for neovascular AMD. Bevacizumab was originally developed for systemic treatment of colon cancer (for which it is FDA-approved), and is related to the parent molecule of ranibizumab. Despite the lack of any randomised trial data, intravitreal injection of bevacizumab has become a popular treatment for neovascular AMD, mainly because its effi cacy is perceived to be similar to ranibizumab but it is much cheaper. Whilst these new treatments are appropriately seen as important breakthroughs in AMD management, the long-term systemic safety of intravitreal anti-VEGF drugs remains unclear. Several concerns have not yet been addressed. First, although the drugs are administered by injection through the sclera into the vitreous cavity, systemic absorption occurs with potential for systemic adverse eff ects (table 1). In particular, human data on the pharmacokinetics of intravitreal bevacizumab are scant. Second, because anti-VEGF treatment for AMD is given monthly or every 2 months and is potentially required for years, chronic VEGF inhibition may cause adverse eff ects that are not immediately apparent. VEGF has many essential functions, including the formation of collateral vessels crucial for the maintenance of perfusion to ischaemic tissues, such as the myocardium, after an infarction. With pegaptanib, the rate of arterial thromboembolic events in treatment and sham groups was similar (table 1) and a recent pharmacokinetics study detected no evidence of systemic VEGF suppression, although the lack of controls makes this fi nding diffi cult to interpret. The trials for ranibizumab reported a marginally higher rate of arterial thromboembolic events in the treatment arms, which was not statistically signifi cant. However, these trials were not powered to detect small diff erences in risk. The issue is further complicated by a recent reanalysis of systemic safety outcomes with ranibizumab, which showed a signifi cant increase in non-ocular haem orrhage in treated patients compared with controls (p=0·01), suggesting some impairment of