Visual Acuity Change Linked to Anti-VEGF Dose Frequency in Neovascular AMD

MODEL RELEASED. Macular degeneration treatment. Doctor applying eyedrops to the eye of a 75-year-old female patient being prepped to receive an intra-ocular bevacizumab (Avastin) injection to treat macular degeneration and retinal vein thrombosis. Bevacizumab is an angiogenesis inhibitor, a drug that slows the growth of new blood vessels. It is usually used in chemotherapy to treat a number of cancers but here is being used to treat age-related eye conditions. Macular degeneration caused damage to the macula, the central area of the retina in the eye, which leads to a loss of vision in the central field of vision. Retinal vein thrombosis, or central retinal vein occlusion, is a blockage of the central retinal vein. As one of only two sources of blood supply to the eye, occlusion of the central retinal vein can lead to blindness.
Research shows that greater treatment frequency is associated with stronger visual acuity gains.

A “predictable, mathematically defined” relationship exist between dose frequency and 1-year visual acuity change in neovascular age-related macular degeneration (AMD) treated with anti-vascular endothelial growth factor agents (anti-VEGF) ranibizumab and aflibercept, according to research published in Retina. 

In a literature review, researchers sought to evaluate dose-response characteristics of ranibizumab and aflibercept in the treatment of neovascular AMD. Studies published between 2006 and 2018 were evaluated for inclusion, and data were extracted on treatment strategy, frequency, and year 1 visual acuity response. 

In total, investigators identified 96 articles with 120 data points. Treatment strategies within these studies were classified into 1 of 4 groups: fixed interval, PRN, treat and extend, and variable, where no specific strategy was listed. 

The fixed interval group included 21 studies (13 monthly); the PRN group included 59, the treat and extended group included 25, and the variable group included 16. 

Mean injections per year varied, from 3.5 to 13, with a highly significant difference in the number of injections in each treatment group. No difference was noted in terms of injection frequency between the variable and PRN groups. 

Visual acuity change, measured by Early Treatment Diabetic Retinopathy Study equivalent letters, ranged from -7.5 to +16.0. This change indicated a nonlinear response with injection frequency per year. Log transform of the dose frequency showed a linear relationship with visual acuity change — a highly significant result. 

After investigators controlled for the number of injections, the treatment strategy was not significant, nor was the drug used a significant predictor of change in visual acuity. 

Using a regression equation, expected acuity gain at each unit injection frequency can be calculated. Cost of treatment was calculated from pooled acquisition costs of ranibizumab and aflibercept, as well as the cost of an office visit, optical coherence tomography examination, and intravitreal injections. The lowest cost per letter gain was roughly 7 injections per year, although a “relatively flat” cost function per letter across 13 yearly injections. 

Study limitations include the heterogenous nature of the included publications in terms of design, size, and dosing frequency. 

“Trying to minimize treatment frequencies may not produce optimal outcomes,” the research shows. “The impact of AMD is often underestimated by physicians as compared with the patients themselves. The burdens inherent in the disease should be weighed against concept of treatment versions.”

“We have been using anti-VEGF agents for more than a decade for neovascular AMD but do not have any published dose-response data. This study seeks to provide [an] estimate of the dose-response curve for anti-VEGF treatment of neovascular AMD, one with a wide confidence interval,” according to the study. 

Disclosure: One study author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures. 


Spaide RF. Antivascular endothelial growth factor dosing and expected acuity outcome at 1 year. Retina. 2021;41(6):1153-1163. doi:10.1097/IAE.0000000000003116