Predictors of Visual Acuity After Treatment of Neovascular Age-Related Macular Degeneration – Current Perspectives

Figures & data

Table 1 Summary of Clinical Trials Investigating Predictors of Visual Outcomes in Anti-VEGF Treated Patients

Study	Treatment	Duration (Years)	Findings and Significant Factors	Non-Significant Factors
ANCHOR^Citation45	RBZ 0.3/0.5mg, q1m or PDT prn	1	● RBZ treated arms gained more VA than the PDT group ● Lower baseline VA, smaller baseline CNV lesion size and younger age associated with better VA gains	● Gender ● CNV type ● Duration between diagnosis and treatment
MARINA^Citation26	RBZ 0.3/0.5mg vs sham	2	● Lower baseline VA, smaller baseline CNV lesion size and younger age associated with better VA gains	● Gender ● CNV type ● Duration between diagnosis and treatment
MARINA & ANCHOR^Citation122	RBZ	1	● Fellow eye visual acuity was not predictive of study eye response	● Fellow eye visual acuity
PrONTO^Citation123	RBZ prn	2	● Larger reductions in CRT after 1 month associated with better VA gains	● # of injections
PIER^Citation124	RBZ 0.3/0.5mg q3m	2	● Lesion inactivity determined by FFA at 3 months associated with better 1 year VA gains ● Lesion inactivity on determined by OCT at 5 or 8 months associated with better 2 year VA gains	● RBZ dose
CATT^Citation46,Citation67	RBZ or BVZ, prn or q1m	1	● Factors associated with worse final VA were older age, worse baseline VA, larger CNV size, predominantly or minimally classic lesions, presence of GA, thicker foveal thickness and the presence of RPE elevation ● Factors associated with less VA gains were older age, better baseline VA (≥20/40), larger CNV size, absence of RAP lesions and presence of RPE elevation ● Factors associated with a decreased likelihood of VA gains ≥15 letters were better baseline VA, worse VA in the fellow eye, larger CNV size, absence of RAP lesions, thinner foveal thickness and the presence of RPE elevation ● PRN treatment group was less likely to gain ≥15 letters compared to fixed monthly dosing	● SNPs of CFH, ARMS2, HTRA1 & C3 ● No interactions between treatment groups and predictors
CATT^Citation40,Citation106	RBZ or BVZ, prn or q1m	2	● Older age, baseline VA of 20/40 or better, larger CNV area, presence of GA in the study eye, thicker (≥425 µm) or thinner (≤325 µm) CRT, and presence of RPE elevation were associated with less VA gain ● VA gains at 12 months (R^2=0.30) more predictive of 2 year VA gains than baseline VA (R^2=0.13) ● Baseline non-foveal GA (OR: 2.86), larger CNV area (OR: 3.91, 4 DA vs ≤1 DA), and BVZ treatment (OR: 1.83) were associated with a VA loss of 15 or more letters by weeks 88 and 104 ● Scars, GA, persistent IRF and SRHM were more common in eyes with VA loss	● Treatment group ● # of treatments or visits
CATT^Citation49	RBZ or BVZ, prn or q1m	5	● Better baseline VA associated with better final VA but less VA gains ● Smaller CNV lesion size presence of SRF associated with better final VA and better VA gains ● Absence of RPE elevation (OR: 3.85), female gender (OR: 1.79) and BVZ use during first 2 years of treatment (OR: 1.62) more likely to gain ≥3 lines ● Current (OR: 2.61) and former smokers (OR: 1.21) more likely to have final VA 20/200 or worse	● Various SNPs ● Hypertension, diabetes ● Treatment group ● IRF ● Various RT measures
HARBOR^Citation48	RBZ 0.5/2mg, prn or q1m	1	● Baseline predictors of better VA gains and/or percentage of 3-line gainers included lower VA, younger age, smaller CNV leakage area, smaller area of occult CNV, and presence of SRF ● Baseline predictors of final VA better than 20/40 included higher VA, smaller CNV leakage area, and presence of SRF	● Gender, ethnicity, smoking status ● Treatment regimen ● CNV type ● Other baseline morphologies
HARBOR^Citation125,Citation126	RBZ 0.5/2mg, prn or q1m	2	● Those in the lowest quartile for BCVA-LLVA gap at baseline (≤ 17 letters) gained more VA than those in the highest quartile (≥ 33 letters) and were more likely to gain ≥ 15 letters as well as lose ≥15 letters ● Patients who achieved peak BCVA after 6 months of treatment, had better VA gains and final VA than those who peaked during the first 6 months	● Treatment group ● Baseline morphology
VIEW^Citation47,Citation97	RBZ q4w, AFL q4w/q8w	1	● Younger age, lower VA and smaller CNV size more likely to have ≥15 letter VA gains ● Older age, larger CNV size and pre-dominantly classic CNV lesions likely to lose ≥1 and ≥15 letter VA ● Younger age, better baseline VA and smaller CNV size more likely to have final VA better than 20/40 ● Older age, lower baseline VA, larger CNV size and predominantly classic CNV lesions more likely to have final VA worse than 20/200 ● Higher baseline VA associated with less VA gain (−0.25 letters per letter increase) ● IRF and PED at baseline associated with less VA gains (−2.77 and −1.88 letters respectively) ● SRF at baseline associated with better VA gains (+2.11 letters)	● Gender ● Ethnicity ● Lesion location
EXCITE^Citation99	RBZ 0.3mg q1m or 0.3/0.5mg q3m	1	● Baseline IRF and infrequent treatment associated with less VA gains (−3.6 and −4.4 letters respectively) ● PVD and SRF at baseline associated with better VA gains (+3.5 and +2.8 letters respectively) ● Interaction between SRF, PVD and treatment frequency, where those without SRF and/or PVD at baseline requiring frequent dosing for better VA gains	● CRT, PED ● RBZ dose
OSPREY^Citation102	Brolucizumab or AFL	1	● Decreased SHRM correlated with better VA gains ● Improved ellipsoid zone integrity was associated with better VA gains	● Sub RPE volume
AREDS^Citation111	Any anti-VEGF	2	● Patients with final VA of 20/200 or worse were more likely to be non-White, have lower baseline VA, have macular atrophy or macular hemorrhage at baseline and fewer anti-VEGF injections in total	-

Abbreviations: AFL, aflibercept; RBZ, ranibizumab; BVZ, bevacizumab; PRN, pro re nata; VA, visual acuity; BCVA, best-corrected visual acuity; LLVA, low-luminance visual acuity; PDT, photodynamic therapy; CNV, choroidal neovascularization; RT, retinal thickness CRT, central retinal thickness; FFA, fundus fluorescein angiography; OCT, optical coherence tomography; GA, geographic atrophy; RPE, retinal pigment epithelium; RAP, retinal anomalous proliferation; SNP, single nucleotide polymorphism; IRF, intraretinal fluid; SRF, subretinal fluid; SHRM, subretinal hyper-reflective material; PED, pigment epithelial detachment; PVD, posterior vitreous detachment.

Table 2 Summary from Major Real-World Studies Investigating Predictors of Visual Outcomes in Anti-VEGF Treated Patients

Author (Year)	Study	N (Eyes)	Treatment	Duration (Years)	Findings and Significant Factors	Non-Significant Factors
Holz (2016)^Citation50	AURA	1184	RBZ	2	● Higher baseline VA (−0.42 per letter) and older age (−0.28 per year) associated with less VA gains ● Higher # of ophthalmoscopies and OCT’s (+0.13 per observation) and higher total injections (+0.32 per injection) associated with better VA gains ● Age, baseline VA and # of ophthalmoscopies and OCT associated with VA maintenance (<15 letters) ● Age, baseline VA and # of injections associated with ≥15 letter gains	-
Fasler (2019)^Citation118	MEH	3357	AFL or RBZ	2	● Younger age, lower baseline VA and more injections were associated with higher VA gains	● Gender
Nguyen V (2019)^Citation39	FRB	2051	Any anti-VEGF	3	● Eyes with VA >70 letters by the 4^th injection were more likely to have final VA >70 letters (OR: 9.8) ● VA change at 4^th injection correlated more strongly with final VA (R^2=0.37) than baseline VA (R^2=0.20)	-
Nguyen CL (2019)^Citation37	FRB	856	Any anti-VEGF	5	● Older age (OR: 1.33, >80 vs ≤80 years), lower total number of injections (OR: 0.97 per injection) and a higher proportion of visits with active CNV (OR: 1.97 upper vs lower quartile) were associated with sustained ≥15 letter VA loss ● Older age (OR: 1.64, >80 vs ≤80 years), lower baseline VA (OR: 1.64, ≤70 vs > 70 letters), lower total number of injections (OR: 0.96 per injection) and a higher proportion of visits with active CNV (OR: 2.22 upper vs lower quartile) were associated with sustained ≥30 letter VA loss ● Eyes with sustained VA loss were more likely to have haemorrhage, RPE tears, GA and subretinal fibrosis	● Lesion type ● GLD
Fu (2020)^Citation28	MEH	7802	AFL or RBZ	~19 months	● Better baseline VA associated with an increased likelihood of achieving 20/40 (HR: 1.43 per 5 letters) ● Higher # of injections associated with an increased likelihood of achieving 20/40 (HR: 1.12 per injection) ● Older patients were less likely to achieve 20/40 (HR: 0.88 per 5 years) ● Baseline VA, injection # and age also associated with the ability to maintain 20/40 or better ● Those who had an incomplete loading phase less likely to achieve 20/40 (HR: 0.87) and more likely to have final VA 20/400 or worse ● Those on RBZ more likely to have final VA 20/400 or worse	● Drug choice (for good visual outcomes) ● Sex ● Ethnicity
Ho (2020)^Citation32	IRIS	162,902	Any anti-VEGF	2	● Eyes with worse baseline VA had larger VA gains but worse final VA	-
Schroeder (2020)^Citation127	SMR	6142	Any anti-VEGF	2	● Those with worse baseline VA, worse-seeing eye treated, older age, larger CNV lesion size at baseline and treated by RBZ or BVZ monotherapy were more likely to have final VA of ≤ 35 letters	● Sex ● Lesion type and location ● Symptom duration

Abbreviations: AFL, aflibercept; RBZ, ranibizumab; BVZ, bevacizumab; VEGF, vascular endothelial growth factor; CNV, choroidal neovascularization; OCT, optical coherence tomography; GLD, greatest linear dimension; RPE, retinal pigment epithelium; GA, geographic atrophy; VA, visual acuity.

Table 3 Summary of Predictive Factors, Their Effects on Visual Outcomes Following Anti-VEGF Treatment and the Level of Supporting Evidence Within the Literature

Baseline Factors	Level of Evidence (Strong, Insufficient or Mixed)	Relationship with VA After Anti-VEGF Treatment
Functional
Visual acuity	Strong	● Patients presenting with lower VA gain more VA during treatment but are more likely to respond poorly ● Those with good initial VA are more likely to maintain good final VA in both the short and long term
Demographic
Gender	Insufficient	-
Age	Strong	● Older age is associated with worse visual outcomes
Ethnicity	Insufficient	-
Systemic disease	Insufficient	-
Social habits	Mixed	● Current and previous smoking status may be associated with worse visual outcomes
Genetics	Mixed	● The presence of certain AMD risk alleles (CFH & ARMS2) and VEGF polymorphisms may influence visual response
Anatomic
CNV lesion type	Mixed	● Classic & pre-dominantly classic lesions may be associated with worse visual outcomes due to worse presenting VA.
CNV lesion size	Strong	● A larger lesion size is associated with lower VA gains
Retinal thickness	Mixed	● Markedly thinner or thicker retinas associated with worse VA gain ● Fluctuations in thickness are associated with less VA gain and higher risk of atrophy
Retinal exudation	Mixed	● IRF (particularly sub-foveal) associated with worse visual outcomes ● SRF at baseline associated with better VA gains, residual SRF associated with poorer outcomes
Pigment epithelial detachments	Mixed	● Presence of PED at baseline associated with worse visual outcomes ● Response of PED not associated with VA gain
Atrophy	Mixed	● Presence of macular atrophy associated with worse long-term VA gain
Hemorrhage	Mixed	● Sub-retinal hemorrhage may lead to worse visual outcomes through scar formation

Abbreviations: AMD, age-related macular degeneration; VA, visual acuity; VEGF, vascular endothelial growth factor; IRF, intraretinal fluid; SRF, subretinal fluid; PED, pigment epithelial detachment.

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