Abstract
Purpose
To determine baseline predictors of visual acuity (VA) outcomes at 5 years after initiating treatment with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD).
Design
Secondary analysis of data from a cohort study.
Participants
Patients enrolled in the Comparison of AMD Treatments Trials (CATT) who completed a 5-year follow-up visit.
Methods
Participants were randomly assigned to ranibizumab or bevacizumab and to 1 of 3 dosing regimens. After two years, patients were released from the clinical trial protocol, and were recalled for examination at 5 years. Trained readers evaluated baseline lesion features, fluid and thickness. Baseline predictors were determined using univariate and multivariate regression analysis.
Main Outcome Measures
VA score and change from baseline, ≥3-line gain, and VA 20/200 or worse at 5 years.
Results
Among 647 patients with VA measured at 5 years, mean VA score in the study eye was 58.9 letters (≈20/63), mean decrease from baseline was 3.3 letters, 17.6% eyes gained ≥3 lines, and 19.9% had VA of 20/200 or worse. In multivariate analysis, worse baseline VA was associated with worse VA, more VA gain, higher percentage with ≥3-line gain, and higher percentage with 20/200 or worse at 5 years (all p<0.001). Larger baseline CNV lesion area was associated with worse VA, greater VA loss, and higher percentage with 20/200 or worse at 5 years (all p<0.05). Absence of baseline subretinal fluid was associated with worse VA (p=0.03) and more VA loss (p=0.03). Female gender, bevacizumab treatment in the first 2 years, and absence of RPE elevation were associated with higher percentage with ≥3-line gain. Cigarette smoking was associated with a higher percentage with 20/200 or worse. None of the 21 SNPs evaluated were associated with VA outcomes.
Conclusions
Five years after initiating treatment with ranibizumab or bevacizumab in CATT participants, worse baseline VA, larger baseline CNV lesion area, and presence of baseline RPE elevation remained independently associated with worse VA at 5 years. In addition, male gender, cigarette smoking, absence of subretinal fluid and treatment with ranibizumab in the first 2 years were independently associated with worse vision outcomes at 5 years.
Graphical Abstract
Five years after initiating treatment with ranibizumab or bevacizumab in CATT participants, cigarette smoking, more severe neovascularization and treatment with ranibizumab in the first 2 years were independently associated with worse vision outcomes at 5 years.
INTRODUCTION
Anti-vascular endothelial growth factor (anti-VEGF) agents are highly effective treatments for neovascular age-related macular degeneration (AMD), and clinical trials have demonstrated their efficacy are similar within 1 or 2-year follow-up.1–11 However, vision response to anti-VEGF treatment varies substantially among individual patients. Several studies have evaluated baseline demographic, clinical, genetic, or behavioral factors that may predict visual acuity (VA) outcomes.12–16,17–19 These studies have consistently found that patient age, baseline VA, and choroidal neovascularization (CNV) lesion size predict VA outcomes. However, almost all of these studies evaluated factors associated only with short-term treatment response (within 2 years after treatment). In spite of the good short-term VA response from anti-VEGF treatment for neovascular AMD, mean VA declines with longer follow-up.20–25 Factors that predict short-term VA changes may differ from those that predict long-term VA changes.
We recently completed 5-year follow-up of a well-defined cohort of patients who underwent treatment with ranibizuamb or bevacizumab during 2 years of a clinical trial followed by approximately 3.5 years of clinical care according to best medical judgment. Long-term (mean of 5.5 years) mean VA declined to 3 letters worse than at baseline and 11 letters worse than at 2 years.22 The aims of this paper are to evaluate baseline predictors for both long-term favorable VA outcomes and poor VA outcomes at 5 years among the participants of the Comparison of AMD Treatments Trials (CATT).
METHODS
Details on the study design and methods of the CATT have been reported in previous publications 7;8;22 and on ClinicalTrials.gov (NCT00593450). Only the major features related to this paper are described here.
Study Participants
The institutional review board associated with each clinical center approved the study protocol and informed consent was obtained from each patient. Between February 20, 2008, and December 9, 2009, patients were enrolled from 43 clinical centers in the United States and randomized to one of four treatment groups at baseline: (1) ranibizumab monthly; (2) bevacizumab monthly; (3) ranibizumab as needed (pro re nata, PRN); and (4) bevacizumab PRN. At the end of Year 1, patients initially assigned to monthly treatment retained their drug assignment but were reassigned randomly to either monthly or PRN treatment. Patients initially assigned to PRN treatment retained both their drug and regimen for Year 2.
The study enrollment criteria included age of 50 or older, the study eye (one eye per patient) having untreated active choroid neovascularization (CNV) due to AMD, and baseline study eye VA between 20/25 and 20/320 on electronic VA testing.
Study Procedures
During the initial visit, patients provided information on demographic characteristics and medical history. Certified photographers obtained stereoscopic, color fundus photographs, fluorescein angiograms and time-domain optical coherence tomography (OCT) images. Both photographic and OCT images were evaluated at reading centers using standardized protocols.26;27
At baseline and during follow-up visits every 4 weeks through 104 weeks, study eyes were treated following the CATT protocol. Certified VA examiners, masked to the treatment assignment, measured VA after refraction in both eyes using the Electronic Visual Acuity (EVA) Tester following the protocol used in the Diabetic Retinopathy Clinical Research Network.28
After the visit at 104 weeks, patients were released from their assigned treatment protocol, and all treatments were administered according to best medical judgment. At approximately 5.5 years (range 4.3 years to 7.1 years) after the date of treatment assignment in the clinical trial, patients were recalled for eye examination and VA measurement by study-certified personnel following the same protocol used during the clinical trial.
A subgroup of 835 CATT participants provided blood samples for genotyping including 7 single-nucleotide polymorphisms (SNPs) associated with risk of AMD: CFH Y402H (rs1061170), ARMS2 (also called LOC387715), A69S (rs10490924), HTRA1 (rs11200638), C3 R80G (rs2230199), LIPC (rs10468017), CFB (rs4151667), C2 (rs547154); 4 EPAS1 SNPs (rs6726454, rs7589621, rs9679290, rs12712973); 7 SNPs in VEGFA (rs699946, rs699947, rs833069, rs833070, rs1413711, rs2010963, and rs2146323) and 3 SNP in VEGFR2 (rs2071559, rs4576072, rs6828477). A custom made TaqMan OpenArray loaded with TaqMan SNP genotyping assays (Applied Biosystems) was used for genotyping.29–31
Statistical Analysis
We previously evaluated the baseline predictors for VA response at Year 1, and at Year 2 using univariate and multivariate regression models.14;15 Following a similar analysis approach, we evaluated the same candidate baseline predictors for 5-year VA outcomes.
We analyzed baseline predictors for four clinically relevant VA outcomes in the study eye at 5 years including: VA score, change in VA score from baseline, ≥3-line (i.e., 15 letters) gain from baseline; and visual acuity 20/200 or worse at 5 years.
We evaluated baseline predictors including demographic, ocular characteristics and OCT findings. Each baseline predictor was first evaluated by univariate analysis (without adjustment for other covariates) using generalized linear models for continuous VA outcomes (i.e., VA score and change in VA score from baseline), and using the Fisher exact test for categorical VA outcomes (i.e., ≥3-line gain from baseline, VA 20/200 or worse). The baseline predictors with a p-value <0.20 in the univariate analysis were included in a multivariate analysis so that the independent effect of each predictor could be assessed. The final multivariate model was created by applying a backward selection procedure that retained only those predictors with a p-value ≤0.05. Adjusted means of VA score and VA score change from baseline were calculated based on the final multivariate linear regression models. The adjusted odds ratios (OR) and their 95% confidence intervals (95% CI) were calculated based on the final multivariate logistic regression models for categorical VA outcomes (≥3-line gain from baseline, VA 20/200 or worse). All data analyses were performed using SAS (v9.4, SAS Institute Inc., Cary, NC), and p<0.05 (without correction for multiple testing) was considered to be statistical significant.
In addition, we evaluated the association between SNPs and each VA outcome by using the linear regression model for continuous VA outcomes, and logistic regression for categorical VA outcomes. For each SNP, the genotype was summarized as the number of risk alleles present, and a linear trend test was performed to compare VA outcomes across the three genotype groups. Since we evaluated a total of 21 SNPs for their association with vision outcomes, p<0.002 was considered as statistically significant.
RESULTS
Among 914 living CATT participants, 647 (71%) patients completed the 5-year follow-up visit. The mean (SD) VA score in the study eye was 58.9 (24.1) letters, the mean loss from baseline was 3.3 (22.3) letters, 114 (17.6%) eyes gained ≥3 lines from baseline and 129 (19.9%) eyes had VA 20/200 or worse.22 The univariate analysis results for baseline predictors of each of VA outcomes are shown in Tables 1, 2 and 3 (online).
Table 1 (online).
Univariate analysis for association of baseline participant characteristics with visual acuity outcomes at 5 years
| # of subjects at 5 years (N=647) | VA score (letters) at 5 years | Change in VA score (letters) from baseline at 5 years | ≥ 3-line gain from baseline at 5 years | VA 20/200 or worse at 5 years | |||||
|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||
| Baseline Characteristics | n | Mean (SE) | P-value§ | Mean (SE) | P-value§ | n (%) | P-value┼ | n (%) | P-value┼ |
| Age (years) | 0.006 (0.003) | 0.40 (0.18) | 0.46 (0.54) | 0.32 | |||||
| 50–69 | 102 | 62.1 (2.4) | −1.3 (2.2) | 22 (21.6%) | 20 (19.6%) | ||||
| 70–79 | 260 | 61.4 (1.4) | −2.8 (1.3) | 42 (16.2%) | 45 (17.3%) | ||||
| ≥80 | 285 | 55.5 (1.5) | −4.5 (1.4) | 50 (17.5%) | 64 (22.5%) | ||||
| As continuous (per year increase) | 647 | −0.54 (0.13) | <0.001 | −0.32 (0.12) | 0.009 | −0.02 (0.01) | 0.13 | 0.02 (0.01) | 0.08 |
| Gender | 0.75 | 0.23 | 0.052 | 1.00 | |||||
| Female | 419 | 59.1 (1.2) | −2.5 (1.1) | 83 (19.8%) | 84 (20.0%) | ||||
| Male | 228 | 58.5 (1.6) | −4.7 (1.4) | 31 (13.6%) | 45 (19.7%) | ||||
| Cigarette Smoking | 0.28 | 0.50 | 0.93 | 0.03 | |||||
| Never | 274 | 60.4 (1.4) | −2.2 (1.3) | 48 (17.5%) | 47 (17.2%) | ||||
| Former | 315 | 58.3 (1.4) | −4.0 (1.3) | 57 (18.1%) | 63 (20.0%) | ||||
| Current | 58 | 55.2 (3.5) | −5.2 (3.1) | 9 (15.5%) | 19 (32.8%) | ||||
| Hypertension | 0.052 | 0.43 | 0.74 | 0.46 | |||||
| No | 209 | 61.6 (1.6) | −2.3 (1.4) | 35 (16.7%) | 38 (18.2%) | ||||
| Yes | 438 | 57.6 (1.2) | −3.8 (1.1) | 79 (18.0%) | 91 (20.8%) | ||||
| Diabetes | 0.50 | 0.57 | 0.78 | 1.00 | |||||
| No | 540 | 58.6 (1.0) | −3.5 (1.0) | 94 (17.4%) | 108 (20.0%) | ||||
| Yes | 107 | 60.3 (2.2) | −2.2 (2.2) | 20 (18.7%) | 21 (19.6%) | ||||
| Drug group in first 2 years | 0.19 | 0.17 | 0.08 | 0.28 | |||||
| Ranibizumab | 328 | 57.7 (1.3) | −4.5 (1.2) | 49 (14.9%) | 71 (21.6%) | ||||
| Bevacizumab | 319 | 60.2 (1.3) | −2.1 (1.3) | 65 (20.4%) | 58 (18.2%) | ||||
| Treatment regimen in first 2 years | 0.60 | 0.24 | 0.29 | 0.44 | |||||
| Monthly | 164 | 60.5 (1.8) | −0.8 (1.7) | 33 (20.1%) | 27 (16.5%) | ||||
| Switched | 157 | 58.6 (2.1) | −4.2 (2.0) | 31 (19.7%) | 33 (21.0%) | ||||
| PRN | 326 | 58.2 (1.3) | −4.2 (1.2) | 50 (15.3%) | 69 (21.2%) | ||||
From one way analysis of variance for comparing mean VA and VA change from baseline.
From Fisher exact test for comparing percent of gaining or losing of ≥3 lines.
P-value in the parenthesis is from the test of linear trend.
SE = standard error, VA = visual acuity.
Table 2 (online).
Univariate analysis for association of baseline ocular and fundus characteristics with visual acuity outcomes at 5 years
| # of subjects at 5 years (N=647) | VA score (letters) at 5 years | Change in VA score (letters) from baseline at 5 years | ≥ 3-line gain from baseline at 5 years | VA 20/200 or worse at 5 years | |||||
|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||
| Baseline Ocular Characteristics | n | Mean (SE) | P-value§ | Mean (SE) | P-value§ | n (%) | P-value┼ | n (%) | P-value┼ |
| Baseline VA in study eye | <0.001 (<0.001) | 0.005 (<0.001) | <0.001 (<0.001) | <0.001 (<0.001) | |||||
| 20/25 – 20/40 | 268 | 67.7 (1.2) | −6.4 (1.2) | 6 (2.2%) | 27 (10.1%) | ||||
| 20/50 – 20/80 | 231 | 58.1 (1.5) | −2.8 (1.5) | 57 (24.7%) | 42 (18.2%) | ||||
| 20/100–20/160 | 110 | 47.3 (2.3) | 0.8 (2.3) | 40 (36.4%) | 41 (37.3%) | ||||
| 20/200–20/320 | 38 | 35.5 (3.7) | 3.6 (3.7) | 11 (28.9%) | 19 (50.0%) | ||||
| Baseline VA in fellow eye | 0.07 (0.02) | 0.23 (0.10) | 0.82 (0.56) | 0.29 (0.17) | |||||
| 20/20 or better | 229 | 61.6 (1.6) | −2.0 (1.4) | 42 (18.3%) | 38 (16.6%) | ||||
| 20/25–20/40 | 249 | 58.3 (1.6) | −2.9 (1.5) | 45 (18.1%) | 54 (21.7%) | ||||
| 20/50 or worse | 169 | 56.1 (1.8) | −5.7 (1.7) | 27 (16.0%) | 37 (21.9%) | ||||
| Baseline area of CNV (disc area) | 0.02 (0.002) | 0.01 (0.001) | 0.27 (0.14) | 0.10 (0.02) | |||||
| ≤1 | 277 | 63.0 (1.3) | −0.0 (1.2) | 56 (20.2%) | 42 (15.2%) | ||||
| >1 to ≤2 | 127 | 58.7 (2.2) | −3.6 (1.9) | 20 (15.7%) | 25 (19.7%) | ||||
| >2 to ≤4 | 116 | 57.3 (2.4) | −5.0 (2.4) | 22 (19.0%) | 24 (20.7%) | ||||
| >4 | 52 | 54.0 (3.7) | −9.9 (3.2) | 5 (9.6%) | 15 (28.8%) | ||||
| Baseline total area of CNV lesion (disc area) | <0.001 (<0.001) | 0.01 (0.001) | 0.10 (0.28) | 0.003 (<0.001) | |||||
| ≤1 | 222 | 63.5 (1.4) | −0.7 (1.3) | 39 (17.6%) | 32 (14.4%) | ||||
| >1 to ≤2 | 146 | 60.3 (1.9) | −1.7 (1.9) | 29 (19.9%) | 26 (17.8%) | ||||
| >2 to ≤4 | 148 | 56.2 (2.1) | −5.0 (2.1) | 31 (20.9%) | 34 (23.0%) | ||||
| >4 | 109 | 51.0 (2.6) | −8.7 (2.2) | 11 (10.1%) | 34 (31.2%) | ||||
| Location of lesion | 0.02 | 0.75 | 0.03 | 0.04 | |||||
| Not Subfoveal | 170 | 62.7 (1.6) | −2.8 (1.6) | 21 (12.4%) | 25 (14.7%) | ||||
| Subfoveal | 469 | 57.5 (1.2) | −3.4 (1.1) | 92 (19.6%) | 103 (22.0%) | ||||
| Lesion type | 0.11 | 0.10 | <0.001 | 0.053 | |||||
| Occult only | 392 | 60.1 (1.2) | −4.5 (1.1) | 50 (12.8%) | 69 (17.6%) | ||||
| Predominantly or Minimally classic | 242 | 56.9 (1.6) | −1.5 (1.5) | 62 (25.6%) | 58 (24.0%) | ||||
| RAP lesion | 0.51 | 0.21 | 0.16 | 0.74 | |||||
| No | 575 | 58.6 (1.0) | −3.6 (0.9) | 98 (17.0%) | 117 (20.3%) | ||||
| Yes | 62 | 60.7 (3.0) | 0.1 (2.9) | 15 (24.2%) | 11 (17.7%) | ||||
| Blocked fluorescence lesion | 0.39 | 0.10 | 0.08 | 0.57 | |||||
| No | 547 | 58.6 (1.0) | −3.8 (1.0) | 91 (16.6%) | 112 (20.5%) | ||||
| Yes | 93 | 60.9 (2.4) | 0.3 (2.2) | 23 (24.7%) | 16 (17.2%) | ||||
| Fibrotic or atrophic scar | 0.03 | 0.84 | 0.07 | 0.26 | |||||
| No | 620 | 59.3 (1.0) | −3.2 (0.9) | 107 (17.3%) | 122 (19.7%) | ||||
| Yes | 20 | 47.4 (6.0) | −4.3 (6.2) | 7 (35.0%) | 6 (30.0%) | ||||
| Hemorrhage associated with the lesion | 0.006 (0.004) | 0.26 (0.57) | <0.001 (0.01) | 0.02 (0.01) | |||||
| None | 249 | 61.2 (1.4) | −4.6 (1.4) | 27 (10.8%) | 42 (16.9%) | ||||
| ≤1 disc area | 330 | 58.7 (1.4) | −1.9 (1.3) | 77 (23.3%) | 66 (20.0%) | ||||
| >1 disc area | 60 | 50.2 (3.3) | −5.4 (2.7) | 9 (15.0%) | 20 (33.3%) | ||||
| Geographic atrophy | 0.13 | 0.81 | 0.55 | 0.57 | |||||
| None | 600 | 59.3 (1.0) | −3.3 (0.9) | 104 (17.3%) | 118 (19.7%) | ||||
| Present | 47 | 53.7 (3.6) | −4.1 (3.3) | 10 (21.3%) | 11 (23.4%) | ||||
| Intraocular pressure (mmHg) | 0.15 (0.06) | 0.65 (0.44) | 0.61 (0.34) | 0.58 (0.45) | |||||
| <10 | 10 | 62.9 (6.6) | −3.8 (6.8) | 2 (20.0%) | 2 (20.0%) | ||||
| 10–20 | 602 | 59.3 (1.0) | −3.1 (0.9) | 108 (17.9%) | 118 (19.6%) | ||||
| >20 | 35 | 51.4 (5.0) | −6.7 (4.4) | 4 (11.4%) | 9 (25.7%) | ||||
| Glaucoma | 0.52 | 0.51 | 0.24 | 0.52 | |||||
| No | 579 | 59.1 (1.0) | −3.1 (0.9) | 106 (18.3%) | 118 (20.4%) | ||||
| Yes | 68 | 57.1 (3.0) | −5.0 (2.8) | 8 (11.8%) | 11 (16.2%) | ||||
| CNV in fellow eye | 0.35 | 0.68 | 1.00 | 0.43 | |||||
| None | 460 | 58.5 (1.2) | −3.1 (1.1) | 80 (17.4%) | 95 (20.7%) | ||||
| Present | 170 | 60.5 (1.7) | −4.0 (1.6) | 30 (17.6%) | 30 (17.6%) | ||||
From one way analysis of variance for comparing mean VA and VA change from baseline.
From Fisher exact test for comparing percent of gain or loss of ≥3 lines from baseline.
P-value in the parenthesis is from the test of linear trend.
Unknown status for a specific feature was excluded from the univariate analysis for this specific feature.
SE = standard error, VA = visual acuity, CNV = choroid neovascularization, RAP = retinal angiomatous proliferans.
Table 3 (online).
Univariate analysis for association of baseline OCT features with visual outcomes at 5 years
| # of subjects at 5 years (N=647) | VA score (letters) at 5 years | Change in VA score (letters) from baseline at 5 years | ≥ 3-line gain from baseline at 5 years | VA 20/200 or worse at 5 years | |||||
|---|---|---|---|---|---|---|---|---|---|
|
|
|||||||||
| Baseline OCT features | n | Mean (SE) | P-value | Mean (SE) | P-value | n (%) | P-Value | n (%) | P-Value |
| Retinal thickness (microns) | 0.02 (0.02) | 0.85 (0.65) | 0.46 (0.25) | 0.33 (0.20) | |||||
| <120 | 65 | 60.2 (3.5) | −4.8 (3.1) | 8 (12.3%) | 12 (18.5%) | ||||
| 120 to 212 | 351 | 61.0 (1.2) | −3.2 (1.1) | 62 (17.7%) | 64 (18.2%) | ||||
| >212 | 229 | 55.3 (1.6) | −3.0 (1.5) | 44 (19.2%) | 53 (23.1%) | ||||
| Subretinal fluid thickness (microns) | 0.10 (0.16) | 0.63 (0.84) | 0.83 (0.77) | 0.27 (0.26) | |||||
| 0 | 410 | 57.6 (1.2) | −3.6 (1.1) | 72 (17.6%) | 89 (21.7%) | ||||
| >0 to ≤25 | 54 | 64.6 (3.2) | −0.5 (2.8) | 8 (14.8%) | 7 (13.0%) | ||||
| >25 | 181 | 60.2 (1.8) | −3.4 (1.7) | 34 (18.8%) | 33 (18.2%) | ||||
| Subretinal tissue complex thickness (microns) by quartile | 0.04 (0.005) | 0.36 (0.63) | 0.06 (0.21) | 0.27 (0.06) | |||||
| 1st (>0 to ≤75) | 157 | 61.7 (1.8) | −5.4 (1.8) | 18 (11.5%) | 27 (17.2%) | ||||
| 2nd (>75 to ≤160) | 147 | 61.3 (1.9) | −2.0 (1.8) | 30 (20.4%) | 25 (17.0%) | ||||
| 3rd (>160 to ≤275) | 172 | 58.1 (1.9) | −1.6 (1.7) | 38 (22.1%) | 35 (20.3%) | ||||
| 4th (>275) | 169 | 54.9 (2.0) | −4.3 (1.8) | 28 (16.6%) | 42 (24.9%) | ||||
| Retinal + subretinal fluid thickness (microns) by quartiles | 0.02 (0.007) | 0.91 (0.91) | 0.46 (0.19) | 0.08 (0.10) | |||||
| 1st (≤160) | 156 | 61.2 (1.9) | −4.2 (1.7) | 23 (14.7%) | 29 (18.6%) | ||||
| 2nd (>160 to ≤225) | 164 | 60.4 (1.8) | −2.4 (1.7) | 30 (18.3%) | 30 (18.3%) | ||||
| 3rd (>225 to ≤320) | 171 | 60.1 (1.8) | −3.1 (1.6) | 28 (16.4%) | 28 (16.4%) | ||||
| 4th (>320) | 154 | 53.5 (2.1) | −3.6 (2.1) | 33 (21.4%) | 42 (27.3%) | ||||
| Total foveal thickness (microns) by quartile | <0.001 (<0.001) | 0.67 (0.90) | 0.01 (0.048) | <0.001 (<0.001) | |||||
| 1st (≤325) | 161 | 63.1 (1.6) | −4.3 (1.6) | 16 (9.9%) | 25 (15.5%) | ||||
| 2nd (>325 to ≤425) | 172 | 63.6 (1.7) | −1.5 (1.8) | 38 (22.1%) | 22 (12.8%) | ||||
| 3rd (>425 to ≤550) | 144 | 58.4 (2.1) | −3.5 (1.9) | 26 (18.1%) | 30 (20.8%) | ||||
| 4th (>550) | 168 | 50.5 (2.0) | −3.9 (1.8) | 34 (20.2%) | 52 (31.0%) | ||||
| Intra-retinal fluid | 0.003 | 0.43 | 0.03 | 0.06 | |||||
| No Fluid | 170 | 64.1 (1.7) | −3.2 (1.6) | 25 (14.7%) | 24 (14.1%) | ||||
| Fluid not in foveal center | 179 | 58.3 (1.9) | −5.2 (1.7) | 24 (13.4%) | 40 (22.3%) | ||||
| Fluid in foveal center | 285 | 56.1 (1.4) | −2.5 (1.3) | 63 (22.1%) | 64 (22.5%) | ||||
| Sub-retinal fluid | 0.009 | 0.19 | 0.95 | 0.046 | |||||
| No Fluid | 93 | 52.2 (2.8) | −7.2 (2.7) | 16 (17.2%) | 27 (29.0%) | ||||
| Fluid not in foveal center | 302 | 59.3 (1.3) | −2.5 (1.2) | 55 (18.2%) | 59 (19.5%) | ||||
| Fluid in foveal center | 245 | 61.2 (1.5) | −2.9 (1.5) | 42 (17.1%) | 41 (16.7%) | ||||
| Sub-RPE fluid | 0.15 | 0.10 | 0.10 | 0.44 | |||||
| No Fluid | 186 | 59.7 (1.7) | −3.3 (1.6) | 30 (16.1%) | 34 (18.3%) | ||||
| Fluid not in foveal center | 216 | 61.5 (1.6) | −0.9 (1.5) | 48 (22.2%) | 38 (17.6%) | ||||
| Fluid in foveal center | 206 | 57.0 (1.8) | −5.6 (1.6) | 30 (14.6%) | 46 (22.3%) | ||||
| RPE elevation | 0.03 | 0.04 | <0.001 | 0.47 | |||||
| No | 85 | 64.2 (2.5) | 1.2 (2.5) | 27 (31.8%) | 14 (16.5%) | ||||
| Yes | 551 | 58.1 (1.0) | −4.1 (0.9) | 84 (15.2%) | 112 (20.3%) | ||||
| RPEE maximum height (mm) by quartiles | 0.50 (0.36) | 0.45 (0.23) | 0.52 (0.79) | 0.62 (0.41) | |||||
| 1st (≤3.0) | 96 | 58.5 (2.4) | −3.6 (2.1) | 14 (14.6%) | 19 (19.8%) | ||||
| 2nd (>3.0 to ≤5.0) | 115 | 61.5 (2.2) | −1.7 (2.1) | 17 (14.8%) | 18 (15.7%) | ||||
| 3rd (>5.0 to ≤11.5) | 167 | 58.1 (1.9) | −3.6 (1.8) | 31 (18.6%) | 34 (20.4%) | ||||
| 4th (>11.5) | 159 | 57.2 (1.9) | −6.1 (1.7) | 20 (12.6%) | 35 (22.0%) | ||||
| RPEE maximum width (mm) by quartiles | 0.80 (0.41) | 0.38 (0.74) | 0.38 (0.97) | 0.97 (0.86) | |||||
| 1st (<=12.0) | 63 | 60.7 (3.0) | −4.4 (2.6) | 8 (12.7%) | 11 (17.5%) | ||||
| 2nd (>12.0 to ≤31.5) | 153 | 59.1 (2.0) | −3.5 (1.8) | 24 (15.7%) | 31 (20.3%) | ||||
| 3rd (>31.5 to ≤55.0) | 138 | 59.8 (1.8) | −0.9 (1.8) | 28 (20.3%) | 26 (18.8%) | ||||
| 4th (>55.0) | 157 | 57.5 (2.0) | −5.4 (1.9) | 21 (13.4%) | 31 (19.7%) | ||||
From one way analysis of variance for comparing mean VA and VA change from baseline.
From Fisher exact test for comparing percent of gaining or loss of ≥3 lines.
OCT= Optical coherence tomography, RPE= retinal pigment epithelium, RPEE=RPE elevation.
P-value in the parenthesis is from the test of linear trend.
Unknown status for a specific feature was excluded from the univariate analysis for this specific feature.
In the multivariate analysis (Table 4), the statistically significant baseline predictors for worse VA score at 5 years were: worse baseline VA in study eye (p<0.0001), larger baseline total area of CNV lesion (p=0.001) and absence of subretinal fluid (p=0.03). The statistically significant baseline predictors for more VA loss from baseline at 5 years were: better baseline VA in study eye (p<0.001), larger baseline total area of CNV lesion (p=0.002), and absence of subretinal fluid (p=0.03) (Table 4).
Table 4.
Multivariate analysis for baseline predictors of VA score and VA score change from baseline at 5 years
| VA score at 5 years | VA score change from baseline at 5 years | ||||
|---|---|---|---|---|---|
| Baseline Characteristics | N* | Adjusted Mean (SE)§ | P-value | Adjusted Mean (SE) § | P-value |
| Baseline VA in study eye | <0.001 | <0.001 | |||
| 20/25 – 20/40 | 267 | 66.9 (1.4) | −7.2 (1.4) | ||
| 20/50 – 20/80 | 229 | 58.4 (1.5) | −2.6 (1.5) | ||
| 20/100–20/160 | 107 | 48.6 (2.1) | 2.0 (2.1) | ||
| 20/200–20/320 | 37 | 36.7 (3.6) | 4.6 (3.6) | ||
| Baseline total area of CNV lesion (disc area) | 0.001 | 0.002 | |||
| ≤1 | 218 | 62.7 (1.5) | 0.3 (1.5) | ||
| >1 to ≤2 | 145 | 60.8 (1.8) | −1.8 (1.8) | ||
| >2 to ≤4 | 147 | 56.8 (1.8) | −5.4 (1.8) | ||
| >4 | 108 | 52.2 (2.1) | −10.1 (2.1) | ||
| Unknown | 22 | 59.1 (4.7) | −1.4 (4.7) | ||
| Baseline subretinal fluid | 0.03 | 0.03 | |||
| No Fluid | 93 | 53.2 (2.3) | −9.1 (2.3) | ||
| Fluid not in foveal center | 302 | 59.8 (1.3) | −2.4 (1.3) | ||
| Fluid in foveal center | 245 | 60.3 (1.4) | −2.2 (1.4) | ||
7 eyes with ungradeable subretinal fluid were excluded.
SE = standard error, VA = visual acuity, CNV = choroid neovascularization.
From the multivariate model that included baseline visual acuity in study eye, baseline total area of CNV lesion, and baseline subretinal fluid.
In the multivariate analysis (Table 5), the statistically significant baseline predictors of a ≥3-line gain from baseline at 5 years were: female gender (OR=1.79, p=0.03), drug treatment in the first two years (OR=1.62 for bevacizumab as compared to ranibizumab, p=0.04), baseline VA in study eye (OR=33.9 for VA 20/100 to 20/160 vs 20/40 or better, p<0.001), and absence of RPE elevation (OR=3.85, p<0.001).
Table 5.
Multivariate analysis for baseline predictors of 3-line gain, and 20/200 or worse in VA at 5 Years
| ≥3-line gain from baseline at 5 years | VA 20/200 or worse at 5 years | ||||
|---|---|---|---|---|---|
| Baseline Characteristics | N | n (%) | Adjusted OR (95% CI)* | n (%) | Adjusted OR (95% CI)§ |
| Gender | P=0.03 | ||||
| Female | 419 | 81 (19.6%) | 1.0 | ||
| Male | 228 | 30 (13.5%) | 0.56 (0.34, 0.93) | ||
| Cigarette smoking | P=0.02 | ||||
| Never | 274 | 47 (17.2%) | 1.0 | ||
| Quit | 315 | 63 (20.0%) | 1.21 (0.78, 1.88) | ||
| Current | 58 | 19 (32.8%) | 2.61 (1.32, 5.15) | ||
| Drug group in first 2 years | P=0.04 | ||||
| Ranibizumab | 328 | 46 (14.2%) | 1.0 | ||
| Bevacizumab | 319 | 65 (20.8%) | 1.62 (1.01, 2.58) | ||
| Baseline VA in study eye | P<0.001 | P<0.001 | |||
| 68–82 letters, 20/25 – 20/40 | 268 | 6 (2.3%) | 1.0 | 6 (2.2%) | 1.0 |
| 53–67 letters, 20/50 – 20/80 | 231 | 55 (24.0%) | 13.5 (5.6, 32.5) | 57 (24.7%) | 1.95 (1.15, 3.31) |
| 38–52 letters, 20/100–20/160 | 110 | 40 (37.4%) | 33.9 (13.4, 85.7) | 40 (36.4%) | 5.16 (2.93, 9.09) |
| 23–37 letters, 20/200–20/320 | 38 | 10 (27.8%) | 17.0 (5.6, 51.9) | 11 (28.9%) | 8.03 (3.73, 17.3) |
| Baseline total area of CNV lesion (disc area) | P=0.045 | ||||
| ≤1 | 222 | 32 (14.4%) | 1.0 | ||
| >1 to ≤2 | 146 | 26 (17.8%) | 1.15 (0.63, 2.08) | ||
| >2 to ≤4 | 148 | 34 (23.0%) | 1.60 (0.91, 2.83) | ||
| >4 | 109 | 34 (31.2%) | 2.35 (1.31, 4.21) | ||
| Unknown | 22 | 3 (13.6%) | 1.02 (0.27, 3.79) | ||
| RPE elevation | P<0.001 | ||||
| No | 85 | 27 (31.8%) | 1.0 | ||
| Yes | 551 | 84 (15.2%) | 0.26 (0.14, 0.48) | ||
OR=odds ratio, CI=confidence interval, SE = standard error, VA = visual acuity, CNV = choroid neovascularization, RPE= retinal pigment epithelium.
From the multivariate model that included gender, drug group in first 2 years, baseline visual acuity in study eye, and baseline RPE elevation.
From the multivariate model that included cigarette smoking, baseline visual acuity in study eye, and baseline total area of CNV lesion.
In the multivariate analysis (Table 5), the statistically significant baseline predictors for VA 20/200 or worse at 5 years were: current smoking (OR=2.61, p=0.02), worse baseline VA in study eye (OR=8.0 for VA 20/200 or worse vs 20/40 or better, p<0.001), and larger baseline total area of CNV lesion (OR=2.35 for total lesion area >4 vs. ≤1 disc area, p=0.045).
The associations of 21 SNPs in 6 genes related to the risk of AMD and 3 genes that regulate VEGFA expression with VA outcomes are shown in Table 6 (online). Among 539 CATT participants who had genetic data and completed the 5-year follow-up visit, none of the SNPs were significantly associated with VA outcomes.
Table 6 (online).
Univariate analysis for association of genotype with VA outcomes
| # of Subjects at Year 5 (N=539) | VA score (letters) at year 5 | Change in VA score (letters) from baseline at year 5 | >= 3-line gain from baseline at year 5 | VA 20/200 or worse at year 5 | |||||
|---|---|---|---|---|---|---|---|---|---|
| SNP and genotype | n | Mean (SE) | P-value | Mean (SE) | P-value | n (%) | P-Value | n (%) | P-value |
| 7 SNPs related to AMD | |||||||||
| CFH, rs1061170 | 0.88 | 0.62 | 0.56 | 0.92 | |||||
| TT | 102 | 61.2 (2.4) | −2.0 (2.2) | 15 (14.7%) | 19 (18.6%) | ||||
| TC | 260 | 57.9 (1.5) | −3.5 (1.4) | 51 (19.6%) | 50 (19.2%) | ||||
| CC | 177 | 60.1 (1.7) | −3.5 (1.6) | 24 (13.6%) | 34 (19.2%) | ||||
| ARMS2, rs10490924 | 0.88 | 0.51 | 0.92 | 0.66 | |||||
| GG | 180 | 59.6 (1.8) | −3.8 (1.7) | 32 (17.8%) | 36 (20.0%) | ||||
| GT | 253 | 59.0 (1.5) | −3.3 (1.4) | 39 (15.4%) | 48 (19.0%) | ||||
| TT | 106 | 59.3 (2.1) | −2.0 (2.0) | 19 (17.9%) | 19 (17.9%) | ||||
| HTRA1, rs11200638 | 0.78 | 0.69 | 0.98 | 0.74 | |||||
| GG | 184 | 59.8 (1.8) | −3.4 (1.7) | 33 (17.9%) | 36 (19.6%) | ||||
| AG | 254 | 58.9 (1.5) | −3.5 (1.4) | 38 (15.0%) | 49 (19.3%) | ||||
| AA | 101 | 59.2 (2.2) | −2.1 (2.1) | 19 (18.8%) | 18 (17.8%) | ||||
| C3, rs2230199 | 0.46 | 0.75 | 0.70 | 0.86 | |||||
| CC | 291 | 58.8 (1.4) | −3.2 (1.3) | 51 (17.5%) | 54 (18.6%) | ||||
| CG | 208 | 59.2 (1.6) | −3.8 (1.6) | 32 (15.4%) | 44 (21.2%) | ||||
| GG | 40 | 62.6 (3.1) | −0.5 (2.6) | 7 (17.5%) | 5 (12.5%) | ||||
| LIPC, rs10468017 | 0.25 | 0.20 | 0.91 | 0.18 | |||||
| TT | 32 | 55.4 (4.4) | −9.3 (3.6) | 2 (6.3%) | 7 (21.9%) | ||||
| CT | 220 | 62.1 (1.4) | 0.3 (1.3) | 44 (20.0%) | 33 (15.0%) | ||||
| CC | 287 | 57.5 (1.5) | −5.3 (1.4) | 44 (15.3%) | 63 (22.0%) | ||||
| CFB, rs4151667 | 0.28 | 0.38 | 0.31 | 0.58 | |||||
| AA | 2 | 38.5 (36.5) | −16.5 (14.5) | 0 (0.0%) | 1 (50.0%) | ||||
| AT | 26 | 56.8 (4.5) | −5.3 (4.1) | 3 (11.5%) | 5 (19.2%) | ||||
| TT | 511 | 59.5 (1.0) | −3.0 (1.0) | 87 (17.0%) | 97 (19.0%) | ||||
| C2, rs547154 | 0.37 | 0.95 | 0.79 | 0.79 | |||||
| TT | 2 | 55.5 (4.5) | −10.0 (13.0) | 0 (0.0%) | 0 (0.0%) | ||||
| GT | 92 | 57.5 (2.5) | −2.9 (2.3) | 17 (18.5%) | 19 (20.7%) | ||||
| GG | 443 | 59.8 (1.1) | −3.0 (1.0) | 73 (16.5%) | 82 (18.5%) | ||||
| 4 EPAS1 SNPs | |||||||||
| rs6726454 | 0.51 | 0.24 | 0.02 | 0.50 | |||||
| AA | 138 | 57.4 (2.1) | −5.0 (1.8) | 16 (11.6%) | 25 (18.1%) | ||||
| AG | 265 | 60.2 (1.4) | −3.0 (1.4) | 44 (16.6%) | 49 (18.5%) | ||||
| GG | 136 | 59.3 (2.1) | −1.8 (1.9) | 30 (22.1%) | 29 (21.3%) | ||||
| rs7589621 | 0.69 | 0.93 | 0.19 | 0.12 | |||||
| GG | 280 | 59.4 (1.4) | −3.4 (1.3) | 41 (14.6%) | 49 (17.5%) | ||||
| AG | 215 | 59.7 (1.6) | −2.9 (1.6) | 40 (18.6%) | 41 (19.1%) | ||||
| AA | 44 | 56.7 (3.8) | −3.6 (3.5) | 9 (20.5%) | 13 (29.5%) | ||||
| rs9679290 | 0.76 | 0.42 | 0.10 | 0.60 | |||||
| GG | 162 | 57.9 (1.9) | −5.0 (1.7) | 20 (12.3%) | 31 (19.1%) | ||||
| CG | 269 | 60.5 (1.4) | −2.1 (1.3) | 49 (18.2%) | 48 (17.8%) | ||||
| CC | 108 | 58.3 (2.5) | −3.3 (2.2) | 21 (19.4%) | 24 (22.2%) | ||||
| rs12712973 | 1.00 | 0.74 | 0.10 | 0.25 | |||||
| CC | 145 | 58.3 (2.1) | −2.8 (1.9) | 30 (20.7%) | 33 (22.8%) | ||||
| AC | 273 | 60.3 (1.4) | −3.2 (1.3) | 44 (16.1%) | 49 (17.9%) | ||||
| AA | 121 | 58.1 (2.2) | −3.7 (1.9) | 16 (13.2%) | 21 (17.4%) | ||||
| 7 SNPs in VEGFA | |||||||||
| rs699946 | 0.17 | 0.43 | 0.72 | 0.09 | |||||
| GG | 21 | 62.8 (4.2) | −4.6 (4.4) | 5 (23.8%) | 2 (9.5%) | ||||
| AG | 175 | 60.8 (1.7) | −1.6 (1.5) | 28 (16.0%) | 29 (16.6%) | ||||
| AA | 343 | 58.2 (1.3) | −4.0 (1.2) | 57 (16.6%) | 72 (21.0%) | ||||
| rs699947 | 0.88 | 0.91 | 0.98 | 0.64 | |||||
| CC | 155 | 59.7 (1.8) | −3.0 (1.6) | 23 (14.8%) | 27 (17.4%) | ||||
| AC | 266 | 58.9 (1.5) | −3.3 (1.4) | 50 (18.8%) | 53 (19.9%) | ||||
| AA | 118 | 59.4 (2.3) | −3.2 (2.0) | 17 (14.4%) | 23 (19.5%) | ||||
| rs833069 | 0.23 | 0.20 | 0.20 | 0.14 | |||||
| TT | 237 | 58.0 (1.7) | −4.5 (1.6) | 36 (15.2%) | 51 (21.5%) | ||||
| TC | 231 | 59.9 (1.5) | −2.5 (1.4) | 38 (16.5%) | 42 (18.2%) | ||||
| CC | 71 | 61.4 (2.5) | −1.1 (2.3) | 16 (22.5%) | 10 (14.1%) | ||||
| rs833070 | 0.95 | 0.84 | 0.71 | 0.82 | |||||
| TT | 122 | 59.7 (2.2) | −3.6 (1.9) | 16 (13.1%) | 23 (18.9%) | ||||
| CT | 261 | 59.0 (1.5) | −3.1 (1.4) | 50 (19.2%) | 52 (19.9%) | ||||
| CC | 156 | 59.4 (1.8) | −3.1 (1.6) | 24 (15.4%) | 28 (17.9%) | ||||
| rs1413711 | 0.91 | 0.91 | 0.83 | 0.82 | |||||
| TT | 124 | 59.8 (2.2) | −3.4 (1.9) | 17 (13.7%) | 23 (18.5%) | ||||
| CT | 257 | 58.9 (1.5) | −3.2 (1.5) | 49 (19.1%) | 52 (20.2%) | ||||
| CC | 158 | 59.4 (1.8) | −3.1 (1.6) | 24 (15.2%) | 28 (17.7%) | ||||
| rs2010963 | 0.22 | 0.19 | 0.16 | 0.17 | |||||
| CC | 68 | 61.3 (2.6) | −1.1 (2.4) | 16 (23.5%) | 10 (14.7%) | ||||
| CG | 233 | 60.1 (1.5) | −2.5 (1.3) | 38 (16.3%) | 42 (18.0%) | ||||
| GG | 238 | 57.9 (1.7) | −4.5 (1.6) | 36 (15.1%) | 51 (21.4%) | ||||
| rs2071559 | 0.78 | 0.72 | 0.11 | 0.71 | |||||
| GG | 143 | 60.5 (1.8) | −2.2 (1.7) | 19 (13.3%) | 22 (15.4%) | ||||
| AG | 281 | 57.6 (1.5) | −4.7 (1.3) | 47 (16.7%) | 62 (22.1%) | ||||
| AA | 115 | 61.7 (2.1) | −0.9 (2.1) | 24 (20.9%) | 19 (16.5%) | ||||
| 3 SNPs in VEGFR2 | |||||||||
| rs2146323 | 0.52 | 0.66 | 0.89 | 0.92 | |||||
| CC | 240 | 58.4 (1.5) | −4.0 (1.4) | 38 (15.8%) | 46 (19.2%) | ||||
| AC | 240 | 59.9 (1.6) | −2.3 (1.4) | 45 (18.8%) | 45 (18.8%) | ||||
| AA | 59 | 59.9 (3.2) | −3.7 (2.7) | 7 (11.9%) | 12 (20.3%) | ||||
| rs4576072 | 0.21 | 0.41 | 0.73 | 0.42 | |||||
| TT | 376 | 58.7 (1.3) | −3.6 (1.1) | 65 (17.3%) | 74 (19.7%) | ||||
| CT | 149 | 59.7 (1.8) | −2.8 (1.7) | 22 (14.8%) | 28 (18.8%) | ||||
| CC | 14 | 69.9 (3.7) | 2.4 (5.4) | 3 (21.4%) | 1 (7.1%) | ||||
| rs6828477 | 0.70 | 0.37 | 0.31 | 0.45 | |||||
| TT | 155 | 58.9 (1.9) | −4.3 (1.7) | 22 (14.2%) | 30 (19.4%) | ||||
| CT | 294 | 59.2 (1.4) | −3.1 (1.3) | 51 (17.3%) | 60 (20.4%) | ||||
| CC | 90 | 60.1 (2.5) | −1.7 (2.5) | 17 (18.9%) | 13 (14.4%) | ||||
SNP = Single-nucleotide polymorphism, AMD=age-related macular degeneration, VA=visual acuity, SE= standard error. P-value is for the test of linear trend.
DISCUSSION
This study evaluated baseline predictors for long-term VA outcomes among the CATT participants who were treated with ranibizumab or bevacizumab in the 2-year clinical trial, and followed-up for an additional 3 years after exiting from the clinical trial. We found that worse baseline VA, larger baseline total area of CNV lesion and presence of baseline RPE elevation, which were associated with 1- or 2-year VA outcomes, remained independently associated with worse VA at 5 years. In addition, we found that male gender, cigarette smoking, absence of subretinal fluid, and treatment with ranibizumab in the first 2 years were independently associated with worse vision outcomes at 5 years.
Despite the reduced sample size and substantial variation in treatment pattern after exiting from the 2-year CATT clinical trial,22 some of the baseline predictors for Year 1 and Year 2 VA outcomes remained, including baseline VA in the study eye, baseline total area of CNV lesion, and RPE elevation. Worse baseline VA and larger CNV lesion have been consistently demonstrated to be significantly associated with worse VA outcomes at one and two years.32–34 Consistent with our study findings, the results from the HORIZON study of 388 patients who completed 4 years of follow-up beyond their 2-year clinical trial showed that younger age, worse baseline VA and smaller area of CNV lesion were associated with a gain of ≥3 lines from baseline.25 Early detection of CNV and timely treatment before substantial loss of VA and lesion growth are important to maximize the patient’s visual acuity.35–38
At 5-years, we found eyes treated with ranibizumab in the first 2 years had a lower percentage with ≥3-line gain from baseline than patients treated with bevacizumab (20.4% vs. 14.9%, p=0.08), and the difference was statistically significant (adjusted OR=1.62, p=0.04) in the multivariate analysis after accounting for gender, study eye baseline VA score and RPE elevation at baseline. During the clinical trial, there was no difference between bevacizumab and ranibizumab in the percentage with ≥3-line gain from baseline at 1 year (29.7% vs. 29.5%, p=0.94) or at 2 years (28.8% vs. 30.6%, p=0.53).7,8 The interpretation of this finding should be cautious, because two-thirds of these eyes received treatment with either bevacizumab or aflibercept during the 3 years after the clinical trial.22 The difference in VA improvement at 5-years may be attributable to morphological differences at 5-years between the two drugs, as CATT eyes treated with ranibizumab in the first 2 years tended to have larger lesion area (mean 13.9 vs. 11.9 mm2, p=0.06),22 and a higher rate of GA growth (0.38 vs. 0.28 mm/year, p=0.009).39
Although current cigarette smoking at enrollment was uncommon (9%) in CATT participants, current cigarette smoking at baseline was independently associated with a 2.6 times higher risk of VA 20/200 or worse in the study eye at 5 years, while smoking in the past was not associated with increased risk of worse VA (VA 20/200 or worse 33%, 20%, 17% in current, former, and non-smokers respectively). Current smokers had only a slightly higher proportion with VA 20/200 or worse at Year 1 (8.5%, 6.3% and 7.2% in current, former, and non-smokers respectively, p=0.70) or at Year 2 (9.2%, 7.3% and 7.5% in current, former, and non-smokers respectively, p=0.82). The association between smoking and worse long-term VA outcome could be due to the fact that cigarette smoking increases oxidative stress, promotes angiogenesis, damages choroidal vessels and diminishes choroidal blood flow, and reduces choroidal thickness.40–44 The Macular Photocoagulation Study found that cigarette smoking was associated with a higher recurrence rate of CNV after laser photocoagulation.45 Cigarette smoking may also affect the response to treatment with anti-VEGF agents. Lee et al found that current smoking was independently associated with poor VA improvement (OR=7.3) after 3 months of treatment with ranibizumab for neovascular AMD as compared to non-smokers.41 Piermarocchi et al also found that smoking was independently associated with worse VA outcomes after 1 year of treatment with ranibizumab. 46 However, others studies have not found a significant association of smoking with treatment response.12;47 Overall, these findings provide further support for encouraging patients to quit smoking.
We found that presence of subretinal fluid at baseline was associated with better VA score at 5 years and less VA loss from baseline. In our previous cross-sectional analysis, we also found that presence of subretinal fluid was associated with better VA at Year 1 and Year 2.48;49 Possible explanations for these effects include that subretinal fluid may protect the photoreceptors from toxicity related to direct contact with underlying diseased RPE, or that subretinal fluid may contain neuroprotective substances. We have previously found that in eyes with subretinal fluid there was a lower risk of developing GA than in those eyes without subretinal fluid (adjusted hazard ratio 0.52).50 Because of the association between subretinal fluid and good VA, a a clinical trial is ongoing to evaluate whether tolerating subretinal fluid results in similar visual acuity as compared to treatment for complete resolution of both intra-retinal fluid and subretinal fluid when treating with ranibizuamb 0.5 mg.51
We have previously evaluated baseline predictors for VA score change from baseline at years 1 and 2, VA score and ≥3-lines gain from baseline at year 1.14;15 However, we did not evaluate the baseline predictors for worse VA outcomes because of the small number of eyes with worse VA outcome at Years 1 or 2 during the clinical trial. With more eyes losing vision by 5 years, we evaluated VA 20/200 or worse in the study eye. We found that current smoking, worse baseline VA and larger CNV lesion area were independently associated with higher risk of VA 20/200 or worse at 5 years.
The role of single-nucleotide polymorphisms on the response to anti-VEGF treatment for neovascular AMD has been evaluated in many studies, including genes related to incidence of AMD, genes associated with VEGF, and EPAS1 genes. However, the findings from these studies are inconsistent.12 In CATT, we have previously evaluated these genetic associations with the morphological or vision outcomes at year 1 or at year 2, and did not find any significant associations. 29–31 Consistent with our previous findings, we found that none of these genetic factors were significantly associated with vision outcomes at Year 5.
The results of this study are limited by the fact that only 71% of living patients from the original clinical trial population returned for VA measurement, and patients who did not return had a mean age 2 years older and mean baseline VA 3 letters worse than patients who returned.22 This may limit the generalizability of our study findings. However, our sensitivity analysis among 518 participants who underwent in-clinic visual acuity measurements at centers with in-clinic visit rate of at least 50% provided very similar results. The study is also limited by the multiple testing of four-related VA outcomes, as false positive findings can occur with multiple testing.
In conclusion, similar to the previous findings for the predictors of VA outcomes at 1 or 2 years in CATT, worse baseline VA and larger CNV lesion size were strongly associated with worse long-term VA, and none of the studied genetic factors were associated VA outcomes at 5-years. Current smoking was not associated with VA outcomes at 1 or 2 years but was associated with a higher risk of VA 20/200 or worse at 5-years. Early detection and treatment of neovascular AMD and quitting smoking may improve their long-term VA outcomes from anti-VEGF treatment.
Supplementary Material
Acknowledgments
Supported by cooperative agreements U10 EY017823, U10 EY017825, U10 EY017826, and U10 EY017828 from the National Eye Institute, National Institutes of Health, Department of Health and Human Services.
Footnotes
This article contains online-only material. The following should appear online-only: Tables 1, 2, 3, 6.
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