Introduction: The aim of the study was to assess the outcome of long treat-and-extend (TE) anti-VEGF intravitreal injection (IVI) intervals (≥every 12 weeks [Q12W]) in neovascular age-related macular degeneration (nAMD). The aims of this retrospective study were to determine the proportion of nAMD eyes treated ≥ Q12W, to analyze their longitudinal, functional, and anatomical outcomes, and to compare functional and anatomical outcomes between eyes that rapidly versus slowly reached a Q12W regimen and between eyes directly treated with versus initiating lately the TE regimen. Methods: All patients receiving IVIs for nAMD were screened. The longitudinal, functional, and anatomical characteristics of Q12W-treated eyes were reported at different timepoints. Results: Ninety-one eyes were included (38% of our total nAMD cohort). The mean TE regimen time to reach a Q12W interval was 20.1 ± 16.2 months. During this time, a mean number of 12.1 ± 9.3 IVIs were needed. The mean best-corrected visual acuity was 68 letters at the time of diagnosis and was maintained (p > 0.05). Eyes that rapidly reached a Q12W interval had a shorter follow-up before TE regimen initiation (p = 0.04) and received fewer IVIs (p = 0.02) than eyes that slowly reached a Q12W interval. Eyes directly treated with the TE regimen reached a Q12W interval more rapidly than eyes with late TE initiation. The neovascularization subtype was not a predictor of outcome in TE-treated eyes. Conclusion: ≥Q12W eyes represent an important part of the nAMD population in our real-life study. No baseline anatomical characteristics were associated with the outcome under a TE regimen, although early TE regimen initiation allowed extending more rapidly the IVI interval.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. About 2.7 million Europeans had late AMD in 2013, and this number might increase to 4.8 million in 2040 [1]. Neovascular AMD (nAMD), resulting from the growth of abnormal vessels under or through the retina, leads to visual loss [2]. Vascular endothelial growth factor (VEGF), being known as the main biological cytokine involved in choroidal neovessel growth, has become the main target of pharmaceutical products to treat nAMD [3].

Aflibercept and ranibizumab, two anti-VEGF drugs given by intravitreal injections (IVIs), allow safely limiting the neovascularization process and its complications [4, 5]. These medications have proven their efficacies on the three neovessel subtypes [6]. The administration schemes were initially based on monthly fixed injections, and have evolved to reactive treatment such as Pro re Nata (PRN) regimens [7]. To reduce the therapeutic burden, clinicians have rapidly oriented their routine practice toward a proactive protocol, the treat-and-extend (TE) regimen [8, 9]. The TE regimen is personalized and allows reducing the number of consultations and medical costs [10, 11]. While the maximum interval between two injections was initially limited to 12 weeks (Q12W) [12‒14], some studies have shown the efficacy of a Q16W interval [4, 15]. However, the profile of AMD patients who could benefit from a longer interval has not yet been defined. The aims of this study were to determine the proportion of patients injected at intervals ≥Q12W in the overall nAMD population in a real-life context, and to describe their longitudinal, functional, and anatomical characteristics.

This monocentric retrospective study was conducted in December 2022 in a cohort of patients treated at intervals of ≥Q12W identified between December 2021 and April 2022 (photography within 5 months). These patients were followed in the ophthalmology department of the Academic Desgenettes Military Hospital in Lyon, France, for nAMD and treated with IVIs according to a TE regimen. Figure 1 shows the study flowchart. One or both eyes of a patient could be included. Patients with diabetic maculopathy or any other macular disease, patients who received an intravitreal treatment other than aflibercept or ranibizumab or treated with photodynamic therapy, and patients with discontinuous treatment were excluded. It should be noted that all patients are treated using a TE regimen in our center since aflibercept and ranibizumab have been granted an authorization for such a protocol in France (2015 for ranibizumab and 2018 for aflibercept). All patients received an anti-VEGF loading dose (LD) consisting in three monthly ranibizumab or aflibercept IVIs. At the clinician’s discretion, a first PRN regimen was used, especially in patients with the longest follow-up (i.e., followed for more than 4 years). After aflibercept or ranibizumab LD, patients were possibly switched to the other therapy if they were unresponsive or if the response was incomplete to treatment with no improvement or deterioration in visual acuity, stable or increasing subretinal fluid (SRF), intraretinal fluid, or pigment epithelial detachment (PED). After a variable time, all patients were switched to a TE regimen, using first short intervals and progressive enlargement. Disease activity was assessed by optical coherence tomography (OCT) and/or based on a decline in best-corrected visual acuity (BCVA; loss ≥5 Early Treatment Diabetes Retinopathy Study [ETDRS] letters). Anatomical criteria for shortening the IVI interval were the occurrence of retinal hemorrhage, the presence of new or persistent fluid on OCT, an increase in retinal PED by ≥50 μm, and an increase in central retinal thickness (CRT) by ≥50 μm. If any sign of disease activity was observed, the interval was reduced by 2 weeks until resolution.

Fig. 1.

Study flowchart for data collection. LD, loading dose; PRN, pro re nata protocol; TE, treat-and-extend protocol; Q12W, first visit 12 weeks after the last injection; M6-8, 6–8 months after the first Q12W visit.

Fig. 1.

Study flowchart for data collection. LD, loading dose; PRN, pro re nata protocol; TE, treat-and-extend protocol; Q12W, first visit 12 weeks after the last injection; M6-8, 6–8 months after the first Q12W visit.

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Study Objectives

The primary objective was to determine the proportion of patients treated with a ≥Q12W interval for nAMD in our real-life setting. The secondary objectives were to describe the general, longitudinal, anatomical, and functional characteristics of these patients. Data were collected at 4 different timepoints: at the time of diagnosis (T1), at the time of TE regimen initiation (T2), at time of the first Q12W visit (T3), and once 2 IVIs were received after the first Q12W visit (T4, i.e., 6–8 months after T3). T4 data were recorded until the end of December 2022 to gather information on all eyes that received 2 IVIs after T3 (Fig. 1). Two subgroups analyzes were also performed: (1) a comparison between slow- and fast-Q12W treatment interval eyes (with a data cutoff at 12 months.) and (2) a comparison between eyes directly treated with the TE regimen (naive eyes) versus eyes treated lately with the TE regimen. The subgroup directly treated with the TE regimen included the eyes that were directly switched to a TE protocol after their LD. Finally, patients were asked to answer two questions about anxiety: they had to grade anxiety felt during the IVI visits from 0 (no anxiety) to 10 (maximum anxiety), and they had to indicate if they felt reassured or worried about extending the IVI interval, and if they were worried, to indicate the reason.

Data Collection

Demographics, including the age, gender, phakic status, anti-VEGF medication and potential switches, and subtype of choroidal neovascularization (CNV), were recorded at baseline. Polypoidal choroidal vasculopathy was considered type 1 CNV and retinal angiomatous proliferation as type 3 CNV.

The BCVA using the ETDRS scale was reported at each visit, as well as OCT measurements (Spectralis®, Heidelberg Engineering Inc., Germany), OCT-angiography (OCT-A Angioplex™ platform of the Cirrus 5,000™, Carl Zeiss Meditec AG, Germany), and fluorescein and indocyanine-green angiography (Spectralis®, Heidelberg Engineering Inc., Germany) findings, when available. All available multimodal imaging were analyzed by two different retinal specialists (P.L. and E.A.). In case of discrepancies between the reviews, a senior retinal specialist (C.D.) has a last evaluation. OCT measures and OCT-angiography and fluorescein angiography neovascular network areas were measured manually using area devices provided by the viewer. PED and SRF heights were measured at their thickest points.

Retinal pigment epithelium (RPE) atrophy was defined as an impaired RPE layer associated with choroidal hypertransmission on OCT defined as the c-RORA by the Classification of Atrophy Report 3 [16]. CNV subtypes were assessed by multimodal imaging according to the last consensus nomenclature on AMD [17].

Statistical Analysis

Categorical variables are reported as numbers and percentages and continuous variables as means and standard deviations. For categorical variables, comparisons between groups were performed using the χ2 test or the Fisher’s exact test as appropriate. For continuous variables, comparisons between groups were performed using the t test in case of normal distribution and sample size >30 in each group or using the nonparametric Mann-Whitney U test otherwise. Normality was tested using the Shapiro-Wilk test. For comparisons of paired continuous data, a Wilcoxon signed-rank test was used. For paired categorical variables, the McNemar test was used. The correlation analysis was performed using the Pearson correlation test. A value of p < 0.05 was considered statistically significant. All analyzes were performed using R software version 3.5.3 (R Foundation for Statistical Computing, Austria).

Primary Outcome

Between December 2021 and April 2022, 240 eyes of 182 patients with nAMD were treated with either aflibercept or ranibizumab and included in this study (Fig. 2). Among these eyes, 91 eyes (37.9%) of 76 patients (41.8%) were treated with a ≥Q12W TE regimen, and 31 eyes (12.9%) of 27 patients (14.8%) were treated with a ≥Q16W TE regimen. These data are summarized in Table 1.

Fig. 2.

Study flowchart for patients’ inclusion. nAMD, neovascular age-related macular degeneration; Q12W, treatment every 12 weeks.

Fig. 2.

Study flowchart for patients’ inclusion. nAMD, neovascular age-related macular degeneration; Q12W, treatment every 12 weeks.

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Table 1.

Number and distribution of patients treated every 12 weeks (Q12W) or less often than Q12W (≥Q12W)

Total cohort: 240 eyesTotal cohort: 182 patients
eyes, n (%)patients, n (%)
IVI-treatment interval, weeks  
 ≥12 91 (37.9) 76 (41.8) 
 ≥16 31 (12.9) 27 (14.8) 
IVI interval ≥12 weeks details, weeks n = 91 eyes 
 12 46 (19.2) 
 14 14 (5.8) 
 16 20 (8.3) 
 18 2 (0.8) 
 20 9 (3.8) 
Total cohort: 240 eyesTotal cohort: 182 patients
eyes, n (%)patients, n (%)
IVI-treatment interval, weeks  
 ≥12 91 (37.9) 76 (41.8) 
 ≥16 31 (12.9) 27 (14.8) 
IVI interval ≥12 weeks details, weeks n = 91 eyes 
 12 46 (19.2) 
 14 14 (5.8) 
 16 20 (8.3) 
 18 2 (0.8) 
 20 9 (3.8) 

IVI, intravitreal injection.

Population

Patients’ mean age was 80.5 ± 6.5 years. 52% were women and 84.6% were pseudophakic. The diagnosis was made and the first IVI was given between 2010 and 2021, with a mean time between the diagnosis and the first IVI of 57.4 ± 39.7 months. Patients’ longitudinal characteristics are described in Table 2. The baseline functional and anatomical characteristics are summarized in Table 3.

Table 2.

Patients’ characteristics and demographics at baseline, full analysis set

Characteristicsn = 91 eyes
Age at diagnosis, mean±SD, years 80.5±6.5 
Sex, n (%), women 47 (51.7) 
Pseudophakic, n (%) 77 (84.6) 
Type of CNV, n (%) 
 Type 1 57 (62.6) 
  Including PCV alone 3 (3.3) 
 Type 2 10 (11.0) 
 Both types 1 and 2 7 (7.7) 
 Type 3 17 (18.7) 
Medication used for the first Q12 visit, n (%) 
 Aflibercept 69 (75.8) 
 Ranibizumab 22 (24.2) 
Eyes with therapy switch during follow-up, n (%) 16 (17.6) 
 Before TE, n (%) 17a (89.5b
 During TE, n (%) 2a (10.5b
Total follow-up duration, mean±SD, months 57.4±39.7 
Follow-up duration before TE, mean±SD, months 20.7±24.9 
Follow-up duration under TE to reach a Q12W visit, mean±SD, months 20.1±16.2 
Exudation-free at the first Q12W visit, n (%) 70 (76.9) 
 Exudation signs at the first Q12W visit, n (%) 21 (23.1) 
 Back to q12 later in the follow-up after a first exudating Q12W visit, n (%) 15/21 (71.4*) 
Q interval, mean±SD [range], weeks 14.1±2.6 [12–20] 
Characteristicsn = 91 eyes
Age at diagnosis, mean±SD, years 80.5±6.5 
Sex, n (%), women 47 (51.7) 
Pseudophakic, n (%) 77 (84.6) 
Type of CNV, n (%) 
 Type 1 57 (62.6) 
  Including PCV alone 3 (3.3) 
 Type 2 10 (11.0) 
 Both types 1 and 2 7 (7.7) 
 Type 3 17 (18.7) 
Medication used for the first Q12 visit, n (%) 
 Aflibercept 69 (75.8) 
 Ranibizumab 22 (24.2) 
Eyes with therapy switch during follow-up, n (%) 16 (17.6) 
 Before TE, n (%) 17a (89.5b
 During TE, n (%) 2a (10.5b
Total follow-up duration, mean±SD, months 57.4±39.7 
Follow-up duration before TE, mean±SD, months 20.7±24.9 
Follow-up duration under TE to reach a Q12W visit, mean±SD, months 20.1±16.2 
Exudation-free at the first Q12W visit, n (%) 70 (76.9) 
 Exudation signs at the first Q12W visit, n (%) 21 (23.1) 
 Back to q12 later in the follow-up after a first exudating Q12W visit, n (%) 15/21 (71.4*) 
Q interval, mean±SD [range], weeks 14.1±2.6 [12–20] 

SD, standard deviation; CNV, choroidal neovascularization; PCV, polypoidal choroidal vasculopathy; TE, treat-and-extend regimen; IVI, intravitreal injections.

aThree eyes were switched back.

bPercentages among the overall 19 switches observed in our cohort.

*Among eyes with exudation at the first Q12W visit.

Table 3.

Functional and anatomical characteristics at the time of diagnosis (T1), at the time of TE regimen initiation (T2), at time of the first Q12W visit (T3), and once 2 IVIs were received after the first Q12W visit (6–8 months) (T4), full analysis set

CharacteristicsT1, n = 79 eyesT2, n = 91 eyesT3, n = 91 eyesT4, n = 91 eyesp value
Follow-up duration, mean±SD, months  20.7±24.9 40.9±31.3 47.1±30.4   
Number of IVI, mean±SD, n  9.3±11.1 21.4±15.7 23.4±15.6   
Follow-up duration since last collection, mean±SD, months  20.7±24.9 20.1±16.2 6.2±0.9   
Number of IVI since last collection, mean±SD, n  9.3±11.1 12.1±9.3 2.0±0.0   
Q-interval at T4, n (%)       
 ≥Q12W 75 (82.4) 
 Q10W 7 (7.7) 
 Q8W 8 (8.8) 
 Q6W 1 (1.1) 
BCVA EDTRS score, mean±SD 68.3±16.9 66.4±20.3 68.1±19.5 67.5±20.0 ①versus②: 0.63 ①versus④: 0.25 
①versus③: 0.18 ②versus④: 0.44 
②versus③: 0.24 ③versus④: 0.32 
 BCVA >70 ETDRS letters, n (%) 42 (53.2) 48 (52.7) 52 (57.1) 53 (58.4) ①versus②: 0.25 ①versus④: 0.15 
①versus③: 0.15 ②versus④: 0.36 
②versus③: 0.42 ③versus④: 1 
CRT, mean±SD, μm 398.7±123.4 343.4±109.3 275.4±61.7 278.6±65.6 ①versus②: <0.001 ①versus④: <0.001 
①versus③: <0.001 ②versus④: <0.001 
②versus③: <0.001 ③versus④: 0.79 
 CRT variation from diagnosis, mean±SD, μm  −47.2±77.1 −121.7±121.5 −121.1±124.8 ②versus③: <0.001 ②versus④: <0.001 
③versus④: 0.88 
 CRT variation from the last studied time, mean±SD, μm  −47.2±77.1 −67.8±107.8 3.3±34.5 ②versus③: 0.26 ②versus④: <0.001 
③versus④: <0.001 
Macular hemorrhage, n (%) 21 (26.6) 11 (12.1) 0 (0) 0 (0) ①versus②: 0.16 ①versus④: <0.001 
①versus③: <0.001 ②versus④: <0.001 
②versus③: <0.001 ③versus④: 1 
Exudative patterns 
 IRF, n (%) 52 (65.8) 55 (60.4) 12 (13.2) 13 (14.3) ①versus②: 0.30 ①versus④: <0.001 
①versus③: <0.001 ②versus④: <0.001 
②versus③: <0.001 ③versus④: 1 
 SRF, n (%) 62 (78.5) 50 (55.0) 15 (16.5) 12 (13.2) ①versus②: 0.002 ①versus④: <0.001 
①versus③: <0.001 ②versus④: <0.001 
②versus③: <0.001 ③versus④: 0.65 
  SRF height, mean±SD, μm 129.4±106.5 105.6±90.8 46.7±34.8 41.4±22.2 ①versus②: 0.20 ①versus④: 0.08 
①versus③: 0.005 ②versus④: 0.04 
②versus③: 0.01 ③versus④: 0.63 
 Dry macula (no IRF and/or SRF), n (%) 4 (5.1) 32 (35.2) 70 (76.9) 62 (68.9) ①versus②: <0.001 ①versus④: <0.001 
①versus③: <0.001 ②versus④: <0.001 
②versus③: <0.001 ③versus④: 0.23 
 PED, n (%) 77 (97.5) 89 (97.8) 87 (95.6) 87 (95.6) ①versus②: 1 ①versus④: 0.62 
①versus③: 0.62 ②versus④: 0.62 
②versus③: 0.62 ③versus④: 1 
  PED height, mean±SD, μm 196.9±131.3 181.1±133.1 135.0±94.1 132.1±92.0 ①versus②: 0.003 ①versus④: <0.001 
①versus③: <0.001 ②versus④: <0.001 
②versus③: <0.001 ③versus④: 0.03 
Nonexudative patterns 
 Atrophy, n (%) 13 (16.5) 51 (56.0) 72 (79.1) 78 (85.7) ①versus②: <0.001 ①versus④: <0.001 
①versus③: <0.001 ②versus④: <0.001 
②versus③: <0.001 ③versus④: 0.02 
 Subretinal fibrosis, n (%) 4 (5.1) 6 (6.6) 9 (9.9) 9 (9.9) ①versus②: 1 ①versus④: 0.19 
①versus③: 0.37 ②versus④: 1 
②versus③: 0.25 ③versus④: 1 
 Intraretinal apoptotic cysts, n (%) 2 (2.5) 4 (4.4) 11 (12.1) 12 (13.2) ①versus②: 1 ①versus④: 0.01 
①versus③: 0.04 ②versus④: 0.04 
②versus③: 0.10 ③versus④: 1 
 PRD, n (%) 13 (16.5) 15 (16.5) 15 (16.5) 15 (16.5) ①versus②: 1 ①versus④: 1 
①versus③: 0.90 ②versus④: 1 
②versus③: 1 ③versus④: 1 
Neovascular network area, mean (SD), mm2 
 FA/ICGA 1.7±2.7 (n = 57 eyes)      
 OCT-Aa 1.5±1.8 (n = 22 eyes) 1.7±1.9 (n = 22 eyes)   ①versus②: <0.001  
CharacteristicsT1, n = 79 eyesT2, n = 91 eyesT3, n = 91 eyesT4, n = 91 eyesp value
Follow-up duration, mean±SD, months  20.7±24.9 40.9±31.3 47.1±30.4   
Number of IVI, mean±SD, n  9.3±11.1 21.4±15.7 23.4±15.6   
Follow-up duration since last collection, mean±SD, months  20.7±24.9 20.1±16.2 6.2±0.9   
Number of IVI since last collection, mean±SD, n  9.3±11.1 12.1±9.3 2.0±0.0   
Q-interval at T4, n (%)       
 ≥Q12W 75 (82.4) 
 Q10W 7 (7.7) 
 Q8W 8 (8.8) 
 Q6W 1 (1.1) 
BCVA EDTRS score, mean±SD 68.3±16.9 66.4±20.3 68.1±19.5 67.5±20.0 ①versus②: 0.63 ①versus④: 0.25 
①versus③: 0.18 ②versus④: 0.44 
②versus③: 0.24 ③versus④: 0.32 
 BCVA >70 ETDRS letters, n (%) 42 (53.2) 48 (52.7) 52 (57.1) 53 (58.4) ①versus②: 0.25 ①versus④: 0.15 
①versus③: 0.15 ②versus④: 0.36 
②versus③: 0.42 ③versus④: 1 
CRT, mean±SD, μm 398.7±123.4 343.4±109.3 275.4±61.7 278.6±65.6 ①versus②: <0.001 ①versus④: <0.001 
①versus③: <0.001 ②versus④: <0.001 
②versus③: <0.001 ③versus④: 0.79 
 CRT variation from diagnosis, mean±SD, μm  −47.2±77.1 −121.7±121.5 −121.1±124.8 ②versus③: <0.001 ②versus④: <0.001 
③versus④: 0.88 
 CRT variation from the last studied time, mean±SD, μm  −47.2±77.1 −67.8±107.8 3.3±34.5 ②versus③: 0.26 ②versus④: <0.001 
③versus④: <0.001 
Macular hemorrhage, n (%) 21 (26.6) 11 (12.1) 0 (0) 0 (0) ①versus②: 0.16 ①versus④: <0.001 
①versus③: <0.001 ②versus④: <0.001 
②versus③: <0.001 ③versus④: 1 
Exudative patterns 
 IRF, n (%) 52 (65.8) 55 (60.4) 12 (13.2) 13 (14.3) ①versus②: 0.30 ①versus④: <0.001 
①versus③: <0.001 ②versus④: <0.001 
②versus③: <0.001 ③versus④: 1 
 SRF, n (%) 62 (78.5) 50 (55.0) 15 (16.5) 12 (13.2) ①versus②: 0.002 ①versus④: <0.001 
①versus③: <0.001 ②versus④: <0.001 
②versus③: <0.001 ③versus④: 0.65 
  SRF height, mean±SD, μm 129.4±106.5 105.6±90.8 46.7±34.8 41.4±22.2 ①versus②: 0.20 ①versus④: 0.08 
①versus③: 0.005 ②versus④: 0.04 
②versus③: 0.01 ③versus④: 0.63 
 Dry macula (no IRF and/or SRF), n (%) 4 (5.1) 32 (35.2) 70 (76.9) 62 (68.9) ①versus②: <0.001 ①versus④: <0.001 
①versus③: <0.001 ②versus④: <0.001 
②versus③: <0.001 ③versus④: 0.23 
 PED, n (%) 77 (97.5) 89 (97.8) 87 (95.6) 87 (95.6) ①versus②: 1 ①versus④: 0.62 
①versus③: 0.62 ②versus④: 0.62 
②versus③: 0.62 ③versus④: 1 
  PED height, mean±SD, μm 196.9±131.3 181.1±133.1 135.0±94.1 132.1±92.0 ①versus②: 0.003 ①versus④: <0.001 
①versus③: <0.001 ②versus④: <0.001 
②versus③: <0.001 ③versus④: 0.03 
Nonexudative patterns 
 Atrophy, n (%) 13 (16.5) 51 (56.0) 72 (79.1) 78 (85.7) ①versus②: <0.001 ①versus④: <0.001 
①versus③: <0.001 ②versus④: <0.001 
②versus③: <0.001 ③versus④: 0.02 
 Subretinal fibrosis, n (%) 4 (5.1) 6 (6.6) 9 (9.9) 9 (9.9) ①versus②: 1 ①versus④: 0.19 
①versus③: 0.37 ②versus④: 1 
②versus③: 0.25 ③versus④: 1 
 Intraretinal apoptotic cysts, n (%) 2 (2.5) 4 (4.4) 11 (12.1) 12 (13.2) ①versus②: 1 ①versus④: 0.01 
①versus③: 0.04 ②versus④: 0.04 
②versus③: 0.10 ③versus④: 1 
 PRD, n (%) 13 (16.5) 15 (16.5) 15 (16.5) 15 (16.5) ①versus②: 1 ①versus④: 1 
①versus③: 0.90 ②versus④: 1 
②versus③: 1 ③versus④: 1 
Neovascular network area, mean (SD), mm2 
 FA/ICGA 1.7±2.7 (n = 57 eyes)      
 OCT-Aa 1.5±1.8 (n = 22 eyes) 1.7±1.9 (n = 22 eyes)   ①versus②: <0.001  

T1, time of diagnosis; T2, time of TE regimen initiation; T3, time of the first Q12W visit; T4, once 2 IVIs were received after T3; SD, standard deviation; IVI, intravitreal injection; BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; CRT, central retinal thickness; IRF, intraretinal fluid; SRF, subretinal fluid; PED, pigment epithelium detachment; PRD, pseudoreticular drusen; FA/ICGA, fluorescein and indocyanine-green angiography; OCT-A, optical coherence tomography angiography.

aData presented only for eyes that were examined twice (at T1 and T2).

Regarding CNV subtypes, 57 eyes (62.6%) had type 1 CNV (including 3 eyes [3.3%] with polypoidal choroidal vasculopathy), 10 eyes (11%) had type 2 CNV, 7 eyes (7.7%) had mixed CNV (types 1 and 2), and 17 eyes (18.7%) had type 3 CNV. Medications and switches are summarized in Table 2. The mean follow-up duration before TE regimen initiation was 20.7 ± 24.9 months (with a mean number of 9.3 ± 11.1 IVIs received). The mean TE regimen duration to reach the first Q12W visit was 20.1 ± 16.2 months (with a mean number of 12.1 ± 9.3 IVIs received). The TE regimen was directly initiated after the LD in 42.9% of eyes. The total follow-up duration was 35.9 ± 21.1 months and 83.9 ± 38.0 months, respectively, in eyes that directly initiated the TE regimen and in those that initiated it later (p < 0.001). In the whole cohort, three quarters of the eyes (76.9%) did not show any sign of exudation at the first Q12W visit. Among the 21 eyes (23.1%) with exudation, about two-thirds (71.4%, n = 15) reached a Q12W interval later. The mean TE regimen interval was 14.1 ± 2.6 weeks (12–20 weeks). At T4, a long interval (≥Q12W) was maintained in 82.4% of eyes.

Secondary Outcomes

Anatomical and Functional Characteristics

The BCVA was stable: 68.3 ± 16.9, 66.4 ± 20.3, 68.1 ± 19.5, and 67.5 ± 20.0 ETDRS letters, respectively, at T1, T2, T3, and T4 (mean follow-up of 47.1 ± 30.4 months) (p > 0.05 for all comparisons). The CRT was significantly reduced over time: 398.7 ± 123.4 μm, 343.4 ± 109.3 μm, and 275.4 ± 61.7 μm, respectively, at T1, T2, and T3 (p < 0.001 for all comparisons) and then remained stable at T4 (278.6 ± 65.6 μm, p = 0.79). This thinning was more marked during the TE protocol (−67.8 ± 107.8 μm) than during the PRN protocol (mean difference in CRT of −47.2 ± 77.1 μm), but this difference did not reach significance (p = 0.26).

It should be noted that the rate of eyes with RPE atrophy significantly increased over time from 16.5% at T1 to 85.7% at T4 (p < 0.001). The rate of eyes with fibrosis remained limited to around 10% with no significant change. Nevertheless, the BCVA remained stable. The OCT-A findings of patients who underwent 2 examinations at T1 and T2 (n = 22 eyes) were compared. The size of the neovascular area increased from 1.5 ± 1.8 mm2 to 1.7 ± 1.9 mm2 between T1 and T2 (p < 0.001). Other anatomical data are shown in Table 3. A positive correlation was found between the baseline CNV area at T1 and the time needed to reach a Q12W interval (r = 0.357, p = 0.006) (Fig. 3).

Fig. 3.

Analysis of the correlation between the neovascular network area at the time of diagnosis and the time to reach the first Q12W visit.

Fig. 3.

Analysis of the correlation between the neovascular network area at the time of diagnosis and the time to reach the first Q12W visit.

Close modal

Comparison between Slow- and Fast-Q12W Treatment Interval Eyes

The data of patients were compared according to their time to reach a Q12W TE regimen interval. These eyes were divided into 2 subgroups: those reaching rapidly a Q12W treatment interval (within 12 months) and those reaching slowly a Q12W treatment interval (after 12 months) (Table 4).

Table 4.

Comparison of the demographic, functional, and anatomical outcomes between slow- and fast-Q12W treatment interval eyes at the time of TE initiation (T2), at the time of the first Q12W visit (T3), and once 2 IVIs were received after the first Q12W visit (6–8 months) (T4), full analysis set

CharacteristicsT2, n = 91 eyesT3, n = 91 eyesT4, n = 91 eyes
Slow Q12, n = 48 eyesFast Q12, n = 43 eyesp valueSlow Q12, n = 48 eyesFast Q12, n = 43 eyesp valueSlow Q12, n = 48 eyesFast Q12, n = 43 eyesp value
Age at diagnosis, mean±SD, years 80.3±6.9 80.6±6.0 0.85       
Sex, n (%), women 19 (39.6) 28 (65.1) 0.02       
Total follow-up duration, mean±SD, months 73.8±39.5 51.8±37.0 0.002       
Follow-up duration, mean±SD, months 24.7±25.2 16.3±24.1 0.04 53.8±32.1 26.4±23.3 <0.001 60.1±32.2 32.9±23.3 <0.001 
Number of IVI, mean±SD, n 12.0±13.6 6.4±6.3 0.02 29.1±17.7 12.8±5.8 <0.001 31.1±18.0 14.7±5.7 <0.001 
Naive-TE, n (%) 15 (31.3) 24 (55.8) 0.02       
Time to reach a Q12W visit under TE, mean±SD, months    29.2±17.8 10.1±2.8 <0.001    
IVI needed to reach a Q12W visit under TE, mean±SD, n    17.1±10.3 6.4±1.8 <0.001    
Q interval at T4, mean±SD, weeks       12.7±2.8 12.9±2.5 0.68 
Type of CNV, n (%) 
 Type 1 30 (62.5) 27 (62.8) 0.98       
  Including PCV alone 1 (2.1) 2 (4.7) 0.60       
 Type 2 6 (12.5) 4 (9.3) 0.74       
 Both types 1 and 2 3 (6.2) 4 (9.3) 0.70       
 Type 3 9 (18.8) 8 (18.6) 0.99       
Medication use for the first Q12W visit, n (%) 
 Aflibercept    37 (77.1) 32 (74.4) 0.77    
 Ranibizumab   11 (22.9) 11 (25.6)    
Medication switch, n (%) 12 (25.0) 4 (9.3)* 0.05       
BCVA EDTRS score, mean±SD 63.1±22.4 70.1±17.2 0.14 65.7±20.1 70.8±18.6 0.08 64.8±21.2 70.5±18.4 0.14 
 BCVA for type 1 CNV only (n = 57 eyes) 61.9±22.7 (n = 30) 73.9±14.1 (n = 27) 0.04 66.2±18.3 (n = 30) 73.2±16.5 (n = 27) 0.07 65.2±17.9 (n = 30) 72.0±17.2 (n = 27) 0.06 
CRT, mean±SD, μm 347.8±100.7 338.4±119.5 0.43 280.7±61.5 269.5±62.3 0.26 278.0±60.8 279.3±71.3 0.96 
 CRT variation from TE entry, mean±SD, μm    −67.2±94.7 −68.4±122.3 0.76 −70.0±98.2 −58.6±134.0 0.51 
Macular hemorrhage, n (%) 5 (10.4) 6 (14.0) 0.19       
Exudative patterns 
 IRF, n (%) 29 (60.4) 26 (60.5) 0.99 7 (14.6) 5 (11.6) 0.68 8 (16.7) 5 (11.6) 0.49 
 SRF, n (%) 24 (50.0) 26 (60.5) 0.32 7 (14.6) 8 (18.6) 0.61 5 (10.4) 7 (16.3) 0.41 
  SRF height, mean±SD, μm 102.7±80.5 108.5±101.8 0.97 56.3±39.2 38.4±30.5 0.27 53.5±30.5 34.3±14.1 0.30 
 Dry macula (no IRF and/or SRF), n (%) 19 (39.6) 13 (30.2) 0.35 37 (77.1) 33 (76.7) 0.97 36 (75.0) 30 (69.8) 0.31 
 PED, n (%) 46 (95.8) 43 (100) 0.50 45 (93.8) 42 (97.7) 0.62 45 (93.8) 42 (97.7) 0.62 
  PED height, mean±SD, μm 186.6±132.5 174.4±135.1 0.71 144.9±97.3 123.4±90.0 0.38 138.7±86.0 125.0±98.7 0.25 
Nonexudative patterns 
 Atrophy, n (%) 29 (60.4) 22 (51.2) 0.37 39 (81.2) 33 (76.7) 0.60 43 (89.6) 35 (81.4) 0.27 
 Subretinal fibrosis, n (%) 4 (8.3) 2 (4.7) 0.68 5 (10.4) 4 (9.3) 5 (10.4) 4 (9.3) 
 Intraretinal apoptotic cysts, n (%) 3 (6.2) 1 (2.3) 0.62 9 (18.8) 2 (4.7) 0.04 7 (14.6) 5 (11.6) 0.68 
 PRD, n (%) 10 (20.8) 5 (11.6) 0.24 10 (20.8) 5 (11.6) 0.24 10 (20.8) 5 (11.6) 0.24 
Neovascular network area, mean±SD, mm2 
 OCT-Aa 1.7±1.6 (n = 9 eyes) 1.7±2.2 (n = 13 eyes) 0.64       
CharacteristicsT2, n = 91 eyesT3, n = 91 eyesT4, n = 91 eyes
Slow Q12, n = 48 eyesFast Q12, n = 43 eyesp valueSlow Q12, n = 48 eyesFast Q12, n = 43 eyesp valueSlow Q12, n = 48 eyesFast Q12, n = 43 eyesp value
Age at diagnosis, mean±SD, years 80.3±6.9 80.6±6.0 0.85       
Sex, n (%), women 19 (39.6) 28 (65.1) 0.02       
Total follow-up duration, mean±SD, months 73.8±39.5 51.8±37.0 0.002       
Follow-up duration, mean±SD, months 24.7±25.2 16.3±24.1 0.04 53.8±32.1 26.4±23.3 <0.001 60.1±32.2 32.9±23.3 <0.001 
Number of IVI, mean±SD, n 12.0±13.6 6.4±6.3 0.02 29.1±17.7 12.8±5.8 <0.001 31.1±18.0 14.7±5.7 <0.001 
Naive-TE, n (%) 15 (31.3) 24 (55.8) 0.02       
Time to reach a Q12W visit under TE, mean±SD, months    29.2±17.8 10.1±2.8 <0.001    
IVI needed to reach a Q12W visit under TE, mean±SD, n    17.1±10.3 6.4±1.8 <0.001    
Q interval at T4, mean±SD, weeks       12.7±2.8 12.9±2.5 0.68 
Type of CNV, n (%) 
 Type 1 30 (62.5) 27 (62.8) 0.98       
  Including PCV alone 1 (2.1) 2 (4.7) 0.60       
 Type 2 6 (12.5) 4 (9.3) 0.74       
 Both types 1 and 2 3 (6.2) 4 (9.3) 0.70       
 Type 3 9 (18.8) 8 (18.6) 0.99       
Medication use for the first Q12W visit, n (%) 
 Aflibercept    37 (77.1) 32 (74.4) 0.77    
 Ranibizumab   11 (22.9) 11 (25.6)    
Medication switch, n (%) 12 (25.0) 4 (9.3)* 0.05       
BCVA EDTRS score, mean±SD 63.1±22.4 70.1±17.2 0.14 65.7±20.1 70.8±18.6 0.08 64.8±21.2 70.5±18.4 0.14 
 BCVA for type 1 CNV only (n = 57 eyes) 61.9±22.7 (n = 30) 73.9±14.1 (n = 27) 0.04 66.2±18.3 (n = 30) 73.2±16.5 (n = 27) 0.07 65.2±17.9 (n = 30) 72.0±17.2 (n = 27) 0.06 
CRT, mean±SD, μm 347.8±100.7 338.4±119.5 0.43 280.7±61.5 269.5±62.3 0.26 278.0±60.8 279.3±71.3 0.96 
 CRT variation from TE entry, mean±SD, μm    −67.2±94.7 −68.4±122.3 0.76 −70.0±98.2 −58.6±134.0 0.51 
Macular hemorrhage, n (%) 5 (10.4) 6 (14.0) 0.19       
Exudative patterns 
 IRF, n (%) 29 (60.4) 26 (60.5) 0.99 7 (14.6) 5 (11.6) 0.68 8 (16.7) 5 (11.6) 0.49 
 SRF, n (%) 24 (50.0) 26 (60.5) 0.32 7 (14.6) 8 (18.6) 0.61 5 (10.4) 7 (16.3) 0.41 
  SRF height, mean±SD, μm 102.7±80.5 108.5±101.8 0.97 56.3±39.2 38.4±30.5 0.27 53.5±30.5 34.3±14.1 0.30 
 Dry macula (no IRF and/or SRF), n (%) 19 (39.6) 13 (30.2) 0.35 37 (77.1) 33 (76.7) 0.97 36 (75.0) 30 (69.8) 0.31 
 PED, n (%) 46 (95.8) 43 (100) 0.50 45 (93.8) 42 (97.7) 0.62 45 (93.8) 42 (97.7) 0.62 
  PED height, mean±SD, μm 186.6±132.5 174.4±135.1 0.71 144.9±97.3 123.4±90.0 0.38 138.7±86.0 125.0±98.7 0.25 
Nonexudative patterns 
 Atrophy, n (%) 29 (60.4) 22 (51.2) 0.37 39 (81.2) 33 (76.7) 0.60 43 (89.6) 35 (81.4) 0.27 
 Subretinal fibrosis, n (%) 4 (8.3) 2 (4.7) 0.68 5 (10.4) 4 (9.3) 5 (10.4) 4 (9.3) 
 Intraretinal apoptotic cysts, n (%) 3 (6.2) 1 (2.3) 0.62 9 (18.8) 2 (4.7) 0.04 7 (14.6) 5 (11.6) 0.68 
 PRD, n (%) 10 (20.8) 5 (11.6) 0.24 10 (20.8) 5 (11.6) 0.24 10 (20.8) 5 (11.6) 0.24 
Neovascular network area, mean±SD, mm2 
 OCT-Aa 1.7±1.6 (n = 9 eyes) 1.7±2.2 (n = 13 eyes) 0.64       

SD, standard deviation; T2, time of TE regimen initiation; T3, time of the first Q12W visit; T4, once 2 IVIs were received after T3; IVI, intravitreal injections; TE, treat-and-extend regimen; PCV, polypal choroidal vasculopathy; CNV, choroidal neovascularization; BCVA, best-corrected visual acuity; ETDRS, Early treatment diabetic retinopathy study; CRT, central retinal thickness; IRF, intraretinal fluid; SRF, subretinal fluid; PED, pigment epithelium detachment; PRD, pseudo-reticular drusen; OCT-A, optical coherence tomography angiography.

*All 4 switches occurred before the initiation of the TE regimen.

aData presented for eyes were only examined twice (at the time of diagnosis and at T2).

The proportion of women was significantly higher in eyes who reached rapidly a Q12W treatment interval with a rate of 65.1% compared to 39.6% in eyes who reached slowly a Q12W treatment interval (p = 0.02), while the sex ratio was well balanced in the whole cohort (51.7% of women). The follow-up duration and the number of IVIs at T2 were significantly reduced in eyes who reached rapidly a Q12W treatment interval: 16.3 ± 24.1 months versus 24.7 ± 25.2 months (p = 0.04) and 6.4 ± 6.3 IVIs received versus 12.0 ± 13.6 IVIs received (p = 0.02). The number of eyes directly treated with the TE regimen was higher in eyes who reached rapidly a Q12W treatment interval (55.8% vs. 31.3%, p = 0.02). Regarding the CNV subtypes, no anatomical factors predictive of a rapid or slow extent of the IVI interval was identified. A higher number of eyes had a treatment switch before initiating the TE regimen in eyes who reached slowly a Q12W treatment interval (25% vs. 9.3% in eyes who reached rapidly a Q12W treatment interval, p = 0.05). At each timepoint, the BCVA tended to differ between both subgroups but without reaching significance (63.1 ± 22.4 ETDRS letters vs. 70.1 ± 17.2 ETDRS letters at T2, p = 0.14; 65.7 ± 20.1 ETDRS letters vs. 70.8 ± 18.6 ETDRS letters at T3, p = 0.08; and 64.8 ± 21.2 ETDRS letters vs. 70.5 ± 18.4 ETDRS letters at T4, p = 0.14). However, regarding type 1 CNV, the BCVA was significantly better at T2 in eyes who reached rapidly a Q12W treatment interval (61.9 ± 22.7 ETDRS letters vs. 73.9 ± 14.1 ETDRS letters, p = 0.04), and this difference persisted but did not remain significant at T3 and T4. Exudative patterns as well as the change in CRT were distributed equally between both subgroups. The rate of RPE atrophy was not different between both subgroups. Although the time to reach the first Q12W visit was longer in eyes who reached slowly a Q12W treatment interval, the same proportion of successful first Q12W visit in the absence of the exudation sign was reached in both subgroups (77.1% vs. 76.7%, p = 0.97).

Comparison between Naive-TE and Delayed-TE Eyes

Logically, the mean follow-up was shorter in the naive-TE group (35.9 ± 21.1 months vs. 83.9 ± 38.0 months in eyes initiating lately the TE regimen, p < 0.005). These eyes reached more rapidly the T3 timepoint (12.5 ± 9.9 months vs. 20.3 ± 19.2 months in eyes initiating lately the TE regimen, p = 0.02) and the proportion of eyes that reached the Q12W treatment interval within the first year was also higher (61.5% vs. 36.5%, respectively, in naive-TE and delayed-TE eyes, p = 0.02). There was no difference in BCVA between both subgroups at each timepoint, including when eyes with type 1 CNV were considered alone (Table 5).

Table 5.

Comparison of the demographic, functional and anatomical outcomes between naive- and delayed-TE at TE entry visit (T2), at the time of the first Q12W visit (T3) and once 2 IVIs were received after the first Q12W visit (6–8 months) (T4), full analysis set

CharacteristicsT2, n = 91 eyesT3, n = 91 eyesT4, n = 91 eyes
Naive-TE, n = 39 eyesDelayed-TE, n = 52 eyesp valueNaive-TE, n = 39 eyesDelayed-TE, n = 52 eyesp valueNaive-TE, n = 39 eyesDelayed-TE, n = 52 eyesp value
Age at diagnosis, mean±SD, years 80.9±5.5 80.1±7.1 0.49       
Sex, n (%), women 22 (56.4) 25 (48.1) 0.43       
Total follow-up duration, mean±SD, months 35.9±21.1 83.9±38.0 <0.005       
Follow-up duration, mean±SD, months 3.41±0.5 33.7±26.4 <0.005 15.9±10.0 54.0±32.2 <0.001 22.4±10.2 60.3±32.3 <0.001 
IVI, mean±SD, n 3.0±0.3 14.1±12.8 <0.005 10.4±5.4 25.3±18.4 <0.001 12.2±5.5 27.3±18.5 <0.001 
Time to reach a Q12W visit under TE, mean±SD, months    12.5±9.9 20.3±19.2 0.02    
 First Q12W visit within the first year under TE, n (%)    24 (61.5) 19 (36.5) 0.02    
 IVI needed to reach a Q12W visit under TE, mean±SD, n    7.3±5.4 11.2±11.3 0.08    
Q interval at T4, mean±SD, weeks       13.2±2.3 12.5±2.9 0.19 
Type of CNV, n (%) 
 Type 1 24 (61.5) 33 (63.5) 0.85       
  Including PCV alone 1 (2.6) 2 (3.8)       
 Type 2 4 (10.3) 6 (11.5)       
 Both types 1 and 2 2 (5.1) 5 (9.6) 0.69       
 Type 3 9 (23.1) 8 (15.4) 0.35       
Medication use for first Q12W visit, n (%) 
 Aflibercept    33 (84.6) 36 (69.2) 0,09    
 Ranibizumab   6 (15.4) 16 (30.8)    
Medication switch, n (%) 0 (0) 16 (30.8)* <0.001       
BCVA EDTRS score, mean±SD 67.3±18.1 65.8±22.0 0.88 71.1±17.5 65.9±20.8 0.28 68.3±19.0 66.9±20.9 0.89 
BCVA for type 1 CNV only (n = 57 eyes) 66.0±22.2 69.8±16.4 0.85 68.1±18.7 71.5±16.4 0.55 67.5±18.7 n = 24 eyes 69.0±17.3 n = 33 eyes 0.79 
CRT, mean±SD, μm 356.8±128.9 333.2±91.6 0.68 268.8±65.4 280.3±58.9 0.26 272.3±72.0 283.4±60.6 0.20 
 CRT variation from TE entry. mean±SD, μm    −88.0±133.3 −52.3±81.3 0.18 −84.5±138.4 −49.4±93.4 0.18 
Macular hemorrhage, n (%) 5 (12.8) 6 (11.5)       
Exudative patterns 
 IRF, n (%) 23 (59.0) 32 (61.5) 0.80 4 (10.3) 8 (15.4) 0.47 6 (15.4) 7 (13.5) 0.76 
 SRF, n (%) 24 (61.5) 26 (50.0) 0.27 8 (20.5) 7 (13.5) 0.37 4 (10.3) 8 (15.4) 0.47 
  SRF height, mean±SD, μm 127.5±89.4 83.7±88.6 0.03 36.6±31.9 58.3±36.7 0.13 41.3±16.5 41.4±26.1 0.92 
 Dry macula (no IRF and/or SRF), n (%) 12 (30.8) 20 (38.5) 0.45 29 (74.4) 41 (78.8) 0.62 29 (74.4) 37 (71.2) 0.33 
 PED, n (%) 38 (97.4) 51 (98.1) 36 (92.3) 51 (98.1) 0.31 36 (92.3) 51 (98.1) 0.31 
  PED height, mean±SD, μm 171.5±138.9 188.7±129.1 0.53 108.7±95.1 155.5±89.0 0.004 109.47±98.7 148.7±83.9 0.007 
Nonexudative patterns 
 Atrophy, n (%) 20 (51.3) 31 (59.6) 0.42 29 (74.4) 43 (82.7) 0.33 31 (79.5) 47 (90.4) 0.15 
 Subretinal fibrosis, n (%) 1 (2.6) 5 (9.6) 0.23 2 (5.1) 7 (13.5) 0.29 2 (5.1) 7 (13.5) 0.29 
 Intraretinal apoptotic cysts, n (%) 1 (2.6) 3 (5.8) 0.63 4 (10.3) 7 (13.5) 0.75 5 (12.8) 7 (13.5) 0.93 
 PRD, n (%) 7 (17.9) 8 (15.4) 0.74 7 (17.9) 8 (15.4) 0.74 7 (17.9) 8 (15.4) 0.74 
Neovascular network area, mean±SD, mm2 
 OCT-Aa 1.44±1.5 (n = 17 eyes) 2.1±2.6 (n = 15 eyes) 0.95       
CharacteristicsT2, n = 91 eyesT3, n = 91 eyesT4, n = 91 eyes
Naive-TE, n = 39 eyesDelayed-TE, n = 52 eyesp valueNaive-TE, n = 39 eyesDelayed-TE, n = 52 eyesp valueNaive-TE, n = 39 eyesDelayed-TE, n = 52 eyesp value
Age at diagnosis, mean±SD, years 80.9±5.5 80.1±7.1 0.49       
Sex, n (%), women 22 (56.4) 25 (48.1) 0.43       
Total follow-up duration, mean±SD, months 35.9±21.1 83.9±38.0 <0.005       
Follow-up duration, mean±SD, months 3.41±0.5 33.7±26.4 <0.005 15.9±10.0 54.0±32.2 <0.001 22.4±10.2 60.3±32.3 <0.001 
IVI, mean±SD, n 3.0±0.3 14.1±12.8 <0.005 10.4±5.4 25.3±18.4 <0.001 12.2±5.5 27.3±18.5 <0.001 
Time to reach a Q12W visit under TE, mean±SD, months    12.5±9.9 20.3±19.2 0.02    
 First Q12W visit within the first year under TE, n (%)    24 (61.5) 19 (36.5) 0.02    
 IVI needed to reach a Q12W visit under TE, mean±SD, n    7.3±5.4 11.2±11.3 0.08    
Q interval at T4, mean±SD, weeks       13.2±2.3 12.5±2.9 0.19 
Type of CNV, n (%) 
 Type 1 24 (61.5) 33 (63.5) 0.85       
  Including PCV alone 1 (2.6) 2 (3.8)       
 Type 2 4 (10.3) 6 (11.5)       
 Both types 1 and 2 2 (5.1) 5 (9.6) 0.69       
 Type 3 9 (23.1) 8 (15.4) 0.35       
Medication use for first Q12W visit, n (%) 
 Aflibercept    33 (84.6) 36 (69.2) 0,09    
 Ranibizumab   6 (15.4) 16 (30.8)    
Medication switch, n (%) 0 (0) 16 (30.8)* <0.001       
BCVA EDTRS score, mean±SD 67.3±18.1 65.8±22.0 0.88 71.1±17.5 65.9±20.8 0.28 68.3±19.0 66.9±20.9 0.89 
BCVA for type 1 CNV only (n = 57 eyes) 66.0±22.2 69.8±16.4 0.85 68.1±18.7 71.5±16.4 0.55 67.5±18.7 n = 24 eyes 69.0±17.3 n = 33 eyes 0.79 
CRT, mean±SD, μm 356.8±128.9 333.2±91.6 0.68 268.8±65.4 280.3±58.9 0.26 272.3±72.0 283.4±60.6 0.20 
 CRT variation from TE entry. mean±SD, μm    −88.0±133.3 −52.3±81.3 0.18 −84.5±138.4 −49.4±93.4 0.18 
Macular hemorrhage, n (%) 5 (12.8) 6 (11.5)       
Exudative patterns 
 IRF, n (%) 23 (59.0) 32 (61.5) 0.80 4 (10.3) 8 (15.4) 0.47 6 (15.4) 7 (13.5) 0.76 
 SRF, n (%) 24 (61.5) 26 (50.0) 0.27 8 (20.5) 7 (13.5) 0.37 4 (10.3) 8 (15.4) 0.47 
  SRF height, mean±SD, μm 127.5±89.4 83.7±88.6 0.03 36.6±31.9 58.3±36.7 0.13 41.3±16.5 41.4±26.1 0.92 
 Dry macula (no IRF and/or SRF), n (%) 12 (30.8) 20 (38.5) 0.45 29 (74.4) 41 (78.8) 0.62 29 (74.4) 37 (71.2) 0.33 
 PED, n (%) 38 (97.4) 51 (98.1) 36 (92.3) 51 (98.1) 0.31 36 (92.3) 51 (98.1) 0.31 
  PED height, mean±SD, μm 171.5±138.9 188.7±129.1 0.53 108.7±95.1 155.5±89.0 0.004 109.47±98.7 148.7±83.9 0.007 
Nonexudative patterns 
 Atrophy, n (%) 20 (51.3) 31 (59.6) 0.42 29 (74.4) 43 (82.7) 0.33 31 (79.5) 47 (90.4) 0.15 
 Subretinal fibrosis, n (%) 1 (2.6) 5 (9.6) 0.23 2 (5.1) 7 (13.5) 0.29 2 (5.1) 7 (13.5) 0.29 
 Intraretinal apoptotic cysts, n (%) 1 (2.6) 3 (5.8) 0.63 4 (10.3) 7 (13.5) 0.75 5 (12.8) 7 (13.5) 0.93 
 PRD, n (%) 7 (17.9) 8 (15.4) 0.74 7 (17.9) 8 (15.4) 0.74 7 (17.9) 8 (15.4) 0.74 
Neovascular network area, mean±SD, mm2 
 OCT-Aa 1.44±1.5 (n = 17 eyes) 2.1±2.6 (n = 15 eyes) 0.95       

SD, standard deviation; T2, time of TE regimen initiation; T3, time of the first Q12W visit; T4, once 2 IVIs were received after T3; IVI, intravitreal injections; TE, Treat-and-Extend regimen; PCV, polypoidal choroidal vasculopathy; CNV, choroidal neovascularization; BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; CRT, central retinal thickness; IRF, intraretinal fluid; SRF, subretinal fluid; PED, pigment epithelium detachment; PRD, pseudoreticular drusen; OCT-A, optical coherence tomography angiography.

*All 16 switches occurred before the initiation of the TE regimen.

aData presented for eyes were only examined twice (at the time of diagnosis and at T2).

Regarding the anatomical characteristics, the presence of SRF was not significantly different between T3 and T4. Nevertheless, the PED height was significantly lower in eyes at T3 and T4 (108.7 ± 95.1 μm vs. 155.5 ± 89.0 μm, p = 0.004 at T3 and 109.47 ± 98.7 μm vs. 148.7 ± 83.9 μm, p = 0.007 at T4). The presence of RPE atrophy was not different between both subgroups throughout the study, as well as the neovascular network area on OCT-A at T2 (p = 0.95).

Anxiety Questionnaire

Among the 76 patients included in our cohort, 55 completed the anxiety questionnaire. The mean anxiety score associated with IVIs reported by the patients during the visits was 3.5 ± 2.8 on a 10-point scale (range 0–10), and the anxiety score was ≥5 in 38.2% of patients. Most patients (89%) found that extending the interval between the IVIs was reassuring, while 11% found it worrying. The reason for worrying was always the fear of an undiagnosed recurrence between two visits (the maximum interval reached between two visits was Q20W in our cohort).

Ocular Safety

Over the course of the study, no serious adverse events, including endophthalmitis, sterile intraocular inflammation, or retinal detachment, occurred. No new intraocular hemorrhage or other hemorrhagic complications were observed.

As nAMD is a challenging pathology for clinicians, minimizing the therapeutic burden without altering the visual outcomes is essential in our daily practice [8]. To do so, the TE regimen has emerged as a safe and effective option [18, 19]. However, only a few studies have reported the proportion of eyes with long intervals between the IVIs in a real-life cohort. In this cohort, we showed that these eyes accounted for about 38% of nAMD eyes treated with IVIs. Many pivotal prospective studies have reported higher rates of eyes treated Q12W from 42 to 60% in the ARIES ALTAIR and VIEW studies [4, 20, 21]. Our results are closer to the rates of 32–37% reported in the recent real-life studies with a shorter follow-up [22‒24]. However, our study being cross-sectional, our cohort included all eyes injected during a fixed period regardless of the protocol initially used (directly and lately treated with the TE regimen). To our knowledge, this is the first cross-sectional study with such a long follow-up (47 months) to report the proportion of eyes treated ≥Q12W in a real-life population and its impact on our department organization.

Regarding the secondary outcomes, we found that a higher number of IVIs (over a longer time) was needed to reach a Q12W TE treatment interval compared to other studies [20, 22]. Indeed, our total cohort included naive- and delayed-TE protocols, and the mean follow-up duration before initiating the TE protocol was long (about 21 months). We hypothesized that this long pre-TE regimen period allowed a change in the neovessel behavior under the TE regimen, extending the time needed to reach a Q12W visit. This time could be explained by the use of other treatment-monitoring methods before the approval of the TE regimen (in 2018 and 2015 for aflibercept and ranibizumab, respectively). In contrast, the eyes that were treated directly with the TE regimen reached more rapidly a Q12W visit, despite the same baseline distribution of the CNV subtypes.

Other studies have shown different distributions of the CNV subtypes, with subtype 1 found in 34–61% of eyes and subtype 3 in 2–40% of eyes [22, 25‒27]. The predominance of type 1 CNV in our study is in accordance with the recent publications by Mathis et al. [28, 29]. These eyes might need a higher number of injections [30, 31]. Conversely, type 3 CNV requires fewer injections and most eyes do not show any sign of exudative activity after the LD [32]. For such a CNV type, in our center, the TE regimen is initiated in case of recurrence and not as a first line. Thus, our rate of type 3 CNV (19%) could have been lowered compared to other studies.

Regarding the baseline BCVA, our mean BCVA of 68 ETDRS letters is higher than in many other studies [33, 34]. This could explain why no VA gain was perceptible. The high baseline BCVA observed in our study could be due to good public information and screening, allowing early detection and management of AMD in the past few years, as shown by Keenan et al. [35] and in other French studies [22, 35]. On the other hand, the baseline BCVA was maintained in our cohort after a long follow-up (47 months), which was remarkable despite an increased RPE atrophy rate. This BCVA stability in patients with a good baseline visual acuity has previously been reported in the RAINBOW and LUMINOUS studies with aflibercept and ranibizumab, respectively, with a lower follow-up [36, 37].

Regarding the CRT, the mean values are highly variable from one study to another, ranging from 300 μm to 380 μm in the VIEW [38] and ALTAIR [4] studies, respectively. In our study, the baseline CRT (398 μm) was in line with the values reported in other observational studies [22‒24]. At the first Q12W visit, the CRT was significantly decreased (275 μm) and 76.9% of the macula was dry. This long interval is then most often maintained or improved in 82% of eyes as reported in other studies [4, 39, 40].

Retinal pigment atrophy (present or absent) increased over time from 16.5% at baseline to 85% after 4 years of follow-up. It is well known that the frequency and extent of atrophy increase over time in nAMD [41]. Other studies have reported different rates depending on the time and the RPE atrophy detection methods: between 37% and 70% at 2 years, 40% at 5 years in the CATT post hoc analysis, and 98% in the SEVEN-UP study at 7 years [22, 42‒44]. However, it should be noted that our population maintained a good visual acuity throughout the follow-up. It could be assumed that even if it progressed, atrophy could be located outside the center of the visual axis.

Another interesting point was our low rate of fibrosis that could be explained by the small number of eyes with type 2 CNV that are most likely to present fibrosis. Fibrosis and macular atrophy have previously been described as the main restricting features for long-term visual ability [44, 45], and limiting their occurrence represents a challenge for future therapies.

The comparison of eyes reaching slowly and rapidly a Q12W interval showed some differences. Eyes that rapidly reached the Q12W interval required less intensive treatment with a lower number of IVIs before initiating the TE regimen and a lower number of switches. The analysis of type 1 CNV eyes showed a better baseline BCVA in eyes that rapidly reached the Q12W interval (p = 0.04). Moreover, we found a positive correlation between the size of CNV and the time to reach the first Q12W visit. We could therefore assume that eyes that were more difficult to manage before initiating the TE regimen presented with a more aggressive disease and then did not reach the first Q12W visit as early as the others. However, both subgroups showed good outcomes with more than three quarters of the eyes with no sign of exudation at the first Q12W visit. We could therefore draw the profile of patients who rapidly reached the Q12W interval: women with a good baseline BCVA (>70 ETDRS letters), a small CNV area, in whom a TE regimen was rapidly initiated.

The second subgroup analysis between naive- and delayed-TE is interesting too. We observed that naive-TE permits to achieve a Q12-interval faster, with a higher proportion of patients reaching the Q12W interval within the first year (61.5% vs. 36.5%), and with a lower number of injections needed. Nevertheless, no difference in functional outcomes was found as reported in the ARIES study between patients who benefited from early and late TE protocols [21]. Again, the baseline visual acuity was high in our cohort, and could explain this finding. Although naive-TE eyes do not have an improved functional prognosis, their therapeutic burden was significantly reduced.

Finally, the mean anxiety was rated as moderate, but for one-third of our patients who felt more anxious, our practice should be improved with the use of innovant strategies. Most patients appreciated the extended intervals, but some of them (11%) reported the fear of an undiagnosed recurrence, and home OCT monitoring could be used to reduce these fears in the future.

Our study has some limitations, including its retrospective design and its small sample size. A larger cohort of patients is needed to confirm our findings in Q12W eyes. More than half of the eyes were initially followed using a PRN regimen for about 20 months. This could obviously change the outcome during the subsequent use of a TE regimen. Nevertheless, this was a real-life study including patients who were followed in our department for many years and in whom the TE regimen used as a second line allowed maintaining their high BCVA after 4 years. The strengths of our study include the long follow-up of our cohort, the analysis according to the CNV subtype with a larger proportion of type 1 CNV. Unfortunately, we were not able to identify any anatomical predictor. This could be explained by the small size of the type 2 CNV subgroup and the well-known complexity of nAMD. Moreover, the comparison between two profiles, patients who slowly and rapidly reached a Q12W interval under a TE regimen, was an original way to analyze the limited population of eyes treated with IVIs beyond the time to initiate the TE regimen.

To conclude, we showed that eyes treated ≥Q12W with a TE regimen accounted for about 40% of our nAMD population in our center. In this population, the baseline BCVA was good and maintained after 4 years of treatment. Early TE regimen initiation allowed more rapidly reaching a long interval without any impact on the visual outcomes and finally reducing treatment burden. No anatomical biomarkers could predict the future course of the disease under the TE regimen except the CNV size. Larger studies are needed to confirm our results.

This study was conducted in accordance with the principles outlined in the Declaration of Helsinki. It was approved by the Ethics Committee of the French Society of Ophthalmology (IRB 00008855 Société Française d’Ophtalmologie (IRB#1). All patients received oral and written information and gave their written informed consent prior to collecting the data.

The authors have no conflict of interest to declare.

There is no funding source to declare.

P.L., E.A., J.B., A.L., H.B., Y.B., and I.D. collected the data. P.L., E.A., and C.D. analyzed and interpreted the data. P.L. drafted the manuscript. P.P. revised the data. C.D., as the supervisor, conceived the idea, analyzed and interpreted the data, and critically revised the manuscript. All authors read and approved the final version of the manuscript.

All data generated or analyzed during this study are included in this article. For any inquiry, please contact the corresponding author.

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