Artificial Intelligence-Based Predictions in Neovascular Age-Related Macular Degeneration

Daniela Ferrara; Elizabeth M. Newton; Aaron Y. Lee


Curr Opin Ophthalmol. 2021;32(5):389-396. 

In This Article


Anti-VEGF therapy, notably aflibercept (Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA), ranibizumab (Genentech, Inc., South San Francisco, California, USA), and off-label use of bevacizumab (Genentech, Inc.), became standard-of-care treatments for nAMD,[3] following demonstration that dosing on a fixed treatment regimen provided significant vision gains, on average, from baseline in pivotal phase 3 clinical trials.[1,4,5] However, achieving these optimal outcomes involved frequent intravitreal injections; in clinical trials, mean vision gains from baseline of approximately seven to 11 letters at 1 year were achieved with approximately 7.5–12 total anti-VEGF injections.[4–8]

In contrast, patients in real-world clinical practice are not, on average, achieving these vision outcomes (Figure 1).[9,10] This has been attributed to several factors, particularly differences between real-world and clinical trial patient populations and differences in treatment frequency.[11] Notably, several studies, including large real-world studies[9–14] and a recent systematic review,[15] found that dose frequency is a consistent indicator of vision outcomes, with real-world studies reporting average vision gains of zero to three letters with approximately five to seven injections in the first year of treatment.

Figure 1.

Mean change in visual acuity score from baseline over time for all patients by country: (a) Germany, France, United Kingdom, Italy, and the Netherlands, and (b) Canada, Ireland, and Venezuela in the AURA retrospective, observational, multicenter study of patients with neovascular age-related macular degeneration who started treatment with ranibizumab between January 1, 2009 and August 31, 2009 [10]. Data based on effectiveness analysis set using a last observation carried forward (LOCF) approach. The mean number of injections received in 2 full years was: United Kingdom, 9.0; the Netherlands, 8.7; France, 6.3; Germany, 5.6; Italy, 5.2; Ireland, 11.0; Canada, 9.9; Venezuela, 3.2. Figure reprinted from Ref [10].

This gap highlights the overall unmet need to balance anti-VEGF injection frequency and burden in clinical practice. To date, efforts to address this have focused on understanding which baseline characteristics are associated with treatment response and exploring different regimens, particularly as-needed (PRN) and treat-and-extend.

Several studies have identified baseline visual acuity as a consistent predictor of long-term visual outcomes;[16–19] however, it is thought to correlate indirectly with disease severity and anatomical changes of the neurosensory retina. Baseline anatomical features, including larger choroidal neovascularization (CNV) lesion size, ellipsoid zone disruption, external limiting membrane interruption, intraretinal fluid (IRF) presence, subretinal fluid (SRF) absence, and increased choroidal thickness have been associated with worse vision outcomes.[16,19] In a study of treatment frequency, patients with occult CNV, presence of retinal fluid, and fluorescein leakage after 1 year of fixed monthly/bimonthly dosing were less likely to achieve every-12-week dosing in year 2.[20]

In the clinic, physicians make treatment decisions for individual patients, while treatment paradigms are traditionally based on average treatment response of a cohort. A key unsolved challenge is identifying the optimal treatment regimen for each individual, with the least burden and maximum visual gains, particularly because need for frequent treatment[20–22] and anti-VEGF treatment response under real-world conditions (Figure 2; Supplemental Movie, vary greatly. For example, in the HARBOR clinical trial, treatment required by patients on a PRN regimen ranged from 3 to 24 injections over 2 years, with a nearly flat distribution.[22] In year 2 of the VIEW clinical trial, about half of patients had PRN treatment intervals of at least every 12 weeks, with similar vision outcomes as patients requiring more frequent treatment.[20] Although informative on a population level, these traditional analyses based on standard imaging evaluations have not greatly influenced individual treatment decisions.

Figure 2.

Illustration of individual responses to anti-vascular endothelial growth factor therapy for patients with neovascular age-related macular degeneration, stratified by baseline VA from a real-world large electronic medical records-extracted database [47]. Each faint line represents the VA (Early Treatment Diabetic Retinopathy Study [ETDRS] letter score) from one patient (one eye) over 5 years of time, with one line, representing one patient, bolded for illustration in each panel. Black lines represent the mean. See also Supplementary Movie, VA, visual acuity.