Effectiveness of anti-vascular endothelial growth factors in neovascular age-related macular degeneration and variables associated with visual acuity outcomes: Results from the EAGLE study

Giovanni Staurenghi; Francesco Bandello; Francesco Viola; Monica Varano; Giulia Barbati; Elena Peruzzi; Stefania Bassanini; Chiara Biancotto; Vito Fenicia; Claudio Furino; Maria Vadalà; Michele Reibaldi; Stela Vujosevic; Federico Ricci; on behalf of the EAGLE study investigators

doi:10.1371/journal.pone.0256461

. 2021 Sep 1;16(9):e0256461. doi: 10.1371/journal.pone.0256461

Effectiveness of anti-vascular endothelial growth factors in neovascular age-related macular degeneration and variables associated with visual acuity outcomes: Results from the EAGLE study

Giovanni Staurenghi ^1,^*, Francesco Bandello ², Francesco Viola ³, Monica Varano ⁴, Giulia Barbati ⁵, Elena Peruzzi ⁶, Stefania Bassanini ⁶, Chiara Biancotto ⁶, Vito Fenicia ⁷, Claudio Furino ⁸, Maria Vadalà ⁹, Michele Reibaldi ¹⁰, Stela Vujosevic ¹¹, Federico Ricci ¹²; on behalf of the EAGLE study investigators^¶

Editor: Vikas Khetan¹³

¹Department of Biomedical and Clinical Sciences “Luigi Sacco”, Luigi Sacco Hospital, University of Milan, Milan, Italy

²Department of Ophthalmology, IRCCS Ospedale San Raffaele, University Vita-Salute, Milan, Italy

³Foundation IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

⁴IRCCS-Fondazione Bietti, Rome, Italy

⁵Department of Medical Sciences, Biostatistics Unit, University of Trieste, Trieste, Italy

⁶Novartis Farma S.p.A., Origgio, VA, Italy

⁷Faculty of Medicine and Psychology, NESMOS Department, Ophthalmology Unit, S. Andrea Hospital, University of Rome "La Sapienza", Rome, Italy

⁸Department of Medical Science, Neuroscience and Sense Organs, Eye Clinic, Azienda Ospedaliero-Universitaria Policlinico Consorziale Bari, Bari, Italy

⁹Biomedicine, Neuroscience and Advanced Diagnostic Department, Unit of Ophthalmology, University of Palermo, Palermo, Italy

¹⁰Department of Surgical Sciences, University of Torino, Turin, Italy

¹¹Eye Clinic, IRCCS MultiMedica, Milan, Italy

¹²Department Experimental Medicine, Tor Vergata University, Viale Oxford, Roma, Italy

¹³Medical Research Foundation (Sankara Nethralaya), INDIA

Competing Interests: Giovanni Staurenghi: Heidelberg Engineering1,2,3, Optos2, Ocular Instruments4, Optovue2, Quantel Medical2, Centervue1,2, Carl Zeiss Meditec2, Nidek2,3, Apellis1, Allergan1, Astellas1, Bayer1,3, Boheringer1, Topcon2, Genentech1, Iveric1, Novartis1,3, Roche1,3, Chengdu Kanghong Biotechnology Co1, Kyoto Drug Discovery & Development Co1. 1 consultant/advisor, 2 grant support, 3 lecture fee, 4 patents/royalty Francesco Bandello: Advisory for Allergan, Bayer, Boehringer-Ingelheim, Fidia Sooft, Hofmann La Roche, Novartis, NTC Pharma, Sifi, Thrombogenics and Zeiss Francesco Viola: Advisor for Allergan, Bayer, Novartis Farma S.p.A., and Roche. Monica Varano: Advisory board participation for Allergan, Bayer, Biogen, and Novartis Farma S.p.A. Giulia Barbati: Statistical consultant and received funding from Novartis. Elena Peruzzi, Stefania Bassanini and Chiara Biancotto: Employees of Novartis Farma S.p.A., Origgio, Italy. Vito Fenicia: Nothing to declare Claudio Furino: Advisory board participation for Allergan and Bayer Maria Vadalà: Advisor for Allergan Italia S.p.A., Bayer Italia S.p.A., and Novartis Farma S.p.A. Michele Reibaldi: Advisor for Allergan, Bayer, Novartis and SIFI. Stela Vujosevic: Advisory Board participation for Allergan, Apellis, Bayer, and Novartis. Federico Ricci: Advisor for Allergan, Bayer, Biogen, Genetech, MS&D, Novartis, Regeneron, and Roche. This aforementioned disclosures/ commercial affiliations of the authors does not alter our adherence to PLOS ONE policies on sharing data and materials.

¶ The details of EAGLE study principal investigators is provided in Acknowledgments.

^✉

* E-mail: giovanni.staurenghi@unimi.it

Roles

Giovanni Staurenghi: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Writing – original draft, Writing – review & editing

Francesco Bandello: Investigation, Writing – original draft, Writing – review & editing

Francesco Viola: Investigation, Writing – original draft, Writing – review & editing

Monica Varano: Investigation, Writing – original draft, Writing – review & editing

Giulia Barbati: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Writing – original draft, Writing – review & editing

Elena Peruzzi: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Writing – original draft, Writing – review & editing

Stefania Bassanini: Conceptualization, Formal analysis, Methodology, Writing – original draft, Writing – review & editing

Chiara Biancotto: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Writing – original draft, Writing – review & editing

Vito Fenicia: Investigation, Writing – original draft, Writing – review & editing

Claudio Furino: Investigation, Writing – original draft, Writing – review & editing

Maria Vadalà: Investigation, Writing – original draft, Writing – review & editing

Michele Reibaldi: Investigation, Writing – original draft, Writing – review & editing

Stela Vujosevic: Investigation, Writing – original draft, Writing – review & editing

Federico Ricci: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Writing – original draft, Writing – review & editing

Vikas Khetan: Editor

PMCID: PMC8409622 PMID: 34469431

Abstract

Objective

To assess the overall effectiveness of anti-vascular endothelial growth factor (VEGF) therapy in treatment-naïve patients with neovascular age-related macular degeneration (nAMD) in a clinical practice setting.

Study design

EAGLE was a retrospective, 2-year, cohort observational, multicenter study conducted in Italy that analyzed secondary data of treatment-naïve patients with nAMD. The primary endpoint evaluated the mean annualized number of anti-VEGF injections at Years 1 and 2. The main secondary endpoints analyzed the mean change in visual acuity (VA) from baseline and variables associated with visual outcomes at Years 1 and 2.

Results

Of the 752 patients enrolled, 745 (99.07%) received the first dose of anti-VEGF in 2016. Overall, 429 (57.05%) and 335 (44.5%) patients completed the 1- and 2-year follow-ups, respectively. At baseline, mean (standard deviation, SD) age was 75.6 (8.8) years and the mean (SD) VA was 53.43 (22.8) letters. The mean (SD) number of injections performed over the 2 years was 8.2 (4.1) resulting in a mean (SD) change in VA of 2.45 (19.36) (P = 0.0005) letters at Year 1 and −1.34 (20.85) (P = 0.3984) letters at Year 2. Linear regression models showed that age, baseline VA, number of injections, and early fluid resolution were the variables independently associated with visual outcomes at Years 1 and 2.

Conclusions

The EAGLE study analyzed the routine clinical practice management of patients with nAMD in Italy. The study suggested that visual outcomes in clinical practice may be improved with earlier diagnosis, higher number of injections, and accurate fluid resolution targeting during treatment induction.

Introduction

Age-related macular degeneration (AMD) is a progressive degenerative disease affecting the retina and is a leading cause of severe irreversible vision loss in the elderly, if left untreated. With its high prevalence and a progressively aging population, AMD is expected to affect 288 million by 2040 [1,2], leading to serious social consequences [3]. The neovascular form of AMD (nAMD/late-stage AMD) occurs mainly due to abnormally high expression of vascular endothelial growth factor (VEGF) [4–6] resulting in pathologic angiogenesis that determines the growth of blood vessels underneath the macula. The newly formed blood vessels are immature, and leak fluid (and sometimes blood) into the retina, disrupting its architecture, leading to progressive, severe, irreversible retinal damage [7].

Anti-VEGF therapies have revolutionized the treatment of nAMD [6,8,9]. Their efficacy in the maintenance of patient’s visual acuity (VA), owing to their mode of action in keeping the macula dry by inhibiting the recurrence of fluid, has been demonstrated in many pivotal trials [6,10–13]. Early detection, diagnosis, prompt therapeutic intervention, and continuous follow-up to assess fluid accumulation and other activity signs are critical to prevent irreversible vision loss; nonetheless, these are difficult to achieve in clinical practice, thus creating a gap between clinical trial and real-world results [8].

In Italian routine clinical practice, there is a need for a descriptive analysis to assess the effectiveness of anti-VEGF treatment in the broad patient population and to identify the variables of different responses to these drugs. The Evidence of Anti-VEGF use in real Life Experience (EAGLE) study described here presents the current Italian routine clinical practice scenario and investigates the major factors associated with VA outcomes and nAMD management to leverage them for future perspectives in therapy.

Materials and methods

Study design

EAGLE was a retrospective, 2-year, cohort observational, multicenter study conducted at 27 clinical sites across Italy. The study enrollment period was from 1^st January 2016 to 31^st December 2016. Secondary data retrieved from hospital charts were analyzed and the main variables were collected at the index date (date of the first injection in treatment-naïve patients), and during the 2-year follow-up period, whose end was set at 31^st December 2018.

The study protocol was reviewed and approved by Institutional Review Boards or Independent Ethics Committees. The complete list of investigational sites and related Ethics Committees are listed in S1 Table. All required local approvals from Ethics Committees were obtained before commencing data collection at each site.

Key eligibility criteria

EAGLE enrolled treatment-naïve patients with a confirmed nAMD diagnosis, who started on-label anti-VEGF therapy between 1^st January 2016 and 31^st December 2016. Patients provided written and signed informed consent for study inclusion and reviewing of charts.

Study objectives and endpoints

The primary objective was to evaluate anti-VEGF injections performed in clinical practice in patients with nAMD, treated for the first time with an anti-VEGF licensed for intraocular use, with respect to the mean (annualized) total number of anti-VEGF injections at Year 1, Year 2, and over 2 years.

The key secondary objectives were to (1) evaluate changes in VA from baseline at Years 1 and 2 in the treated eye, (2) evaluate factors associated with VA outcomes in the treated eye at Years 1 and 2 (age, gender, baseline VA, time from diagnosis to treatment, baseline type of macular neovascularization [MNV]; [14]), loading phase [LP], number of injections in the first year of treatment, and bilateral diagnosis), (3) evaluate factors associated with VA outcomes in the treated eye at Years 1 and 2 in the subgroup of patients who completed the LP, defined as patients receiving at least the first 3 injections in 90 days, and (4) estimate the median survival time of observation (overall exposure) from the index date to specific time points (6, 12, 18, and 24 months) stratified by baseline VA.

Assessments

Effectiveness assessments included annualized number of anti-VEGF injections to evaluate mean values and absolute changes in VA (Early Treatment Diabetic Retinopathy Study [ETDRS]) at Years 1 and 2 after the start of anti-VEGF therapy in the treated eye (compared with baseline). The association of variables such as age, gender, baseline VA, time from diagnosis to treatment, number of injections in the first year of treatment, LP, bilateral diagnosis and baseline type of MNV lesion on VA outcomes of the treated eye were assessed by means of linear regression models at Years 1 and 2 in the whole population and in the subgroup of patients who completed the LP. LP patients were classified as ‘wet’ or ‘dry’ based on the presence or absence of fluid in the treated eye at the corresponding optical coherence tomography (OCT) evaluation and by investigator’s judgment.

Statistical analysis

Owing to the descriptive nature of the study, the statistical analyses associated with the primary endpoint (number of injections) and the secondary endpoint (change in VA) are descriptive; therefore, no formal statistical hypotheses have been stated. Sample size calculations were estimated using MedCalc Statistical Software version 18.5 (MedCalc Software bvba, Ostend, Belgium) and all statistical analyses were performed using software R, version 3.6.3. Sample size calculations referred to the desired precision for the main outcome estimate (i.e., the average number of injections per year). The main secondary endpoint (i.e., the estimated mean change in VA) was also taken into account. With respect to the primary outcome, it was calculated that 668 patients were required to estimate the mean number of injections per year with a 99% probability of obtaining a confidence interval (CI) with a width of not more than 1, assuming a standard deviation (SD) of 5 for the mean number of injections. Regarding the main secondary endpoint, it was calculated that 668 patients were also required to estimate the mean change from a baseline score in VA based on letter count with a 99% probability of obtaining a CI with a width of not more than 2 letters, assuming a SD for the difference distribution of 10. Assuming that 10% of enrolled patients will have only one measure, at least 742 patients were expected to be enrolled. During the enrollment period, this size was respected considering a substantial loss because some patients refused to give their informed consent or due to difficulty in reaching them 3 years after the start of the therapy; thus, around 1300 patients’ charts were needed to be screened.

The primary endpoint of the study was estimated in terms of mean (annualized) total number of injections calculated at the end of the first year (Month 12), the second year (i.e., between Months 13 and 24), and overall, at Year 2 (Month 24) and reported with the corresponding 95% CI. The following analysis populations/groups were considered: Overall Exposed (OE, defined as all enrolled patients who received at least one dose of anti-VEGF treatment during the enrollment period i.e., from 1^st January to 31^st December 2016) and Efficacy Analysis (EA, defined as all patients in the OE who had a baseline and at least one post-baseline VA assessment) sets categorized by i) type of MNV lesion at baseline, ii) baseline VA and visual impairment classes for the treated eye, iii) LP versus no loading phase (NLP) sets and iv) ‘dry’ versus ‘wet’ patients after the LP.

To evaluate factors associated with VA outcomes, linear regression models were estimated at 1 and 2 years in the First-year Completer Analysis set (1stCA_EA) and Second-year Completer Analysis set (2ndCA_EA) populations, using the following covariates: age, gender, baseline VA, time from diagnosis to treatment, baseline type of MNV lesion, bilateral diagnosis, number of injections in the first year of treatment, and LP completed. Retinal fluid at the end of LP was evaluated as a covariate (instead of LP completed) in similar regression models on VA outcomes at 1 and 2 years in the groups of wet and dry patients with an available VA assessment at 1 and 2 years, respectively.

The subset of independent variables associated with the mean change in VA was estimated using a multivariable analysis approach, starting from a full model and retaining variables with P<0.05. As a supplementary analysis, to describe changes in VA during the follow-up using all available measurements per patient, a regression Linear Mixed Effects Model (LMM) with a random intercept for each patient was implemented using time as covariate (modeled as a restricted cubic spline).

Results

Patient disposition, demographics, and baseline ocular characteristics

Patient disposition

Of the 1336 patients screened for study enrollment, 752 were deemed eligible and signed informed consent, and were therefore included as the Enrolled Population (EP). Of these, 745 (99.07%) were in the OE set and 617 (82.05%) were included in the EA set. In the EA set, 429 patients had an available follow-up evaluation of VA at least 1 year after the first injection and were categorized as First-year Completer Analysis set (1stCA_EA), while 335 had an available follow-up evaluation of VA at least 2 years after the first injection (2ndCA_EA). Furthermore, 452 patients from the EA set completed the LP (LP population). Of the 366 patients in the LP who had an available OCT performed between the end of LP and the 4^th injection, 191 were classified as ‘wet’ nAMD and 175 were classified as ‘dry’ nAMD as deemed by the investigator based on the presence or absence of fluid after the LP (Fig 1).

Fig 1 — Screened population (**SCR**): All patients who were screened, including those who did not give consent, but were contacted by the investigators; Enrolled population (EP): All screened patients who were eligible (i.e. fulfilled all inclusion and exclusion criteria) and who gave consent to participate in the study or were dead; Overall Exposed population (OE): All enrolled patients who received at least one dose of an anti-VEGF treatment during the enrollment period; Effectiveness Analysis set (EA): All patients in the OE who had a baseline and at least one post-baseline assessment of VA; **Excluded**: All patients included in the OE but not in the EA; Loading Phase population (LP): All patients in the EA who received at least 3 injections within 3 months (90 days) from the index date, with the date of the end of the LP for each patient being the date of the third injection in this time window; Not complete Loading Phase (**NLP**): All patients included in the EA but not in the LP; First-year Completer Analysis set (**1stCA _EA**): All patients in the EA with an available follow-up evaluation of VA at least 1 year after the first injection; Second-year Completer Analysis set (**2ndCA _EA**): All patients in the EA with an available follow-up evaluation of VA at least 2 years after the first injection; First-year OCT completer analysis set (**1stCA_OCT**): All patients in the LP with an available follow-up OCT assessment at least 1 year after the first injection; Second-year OCT completer analysis set (**2ndCA _OCT**): All patients in the LP with an available follow-up OCT assessment at least 2 years after the first injection. **Wet** and **Dry** classification (patients in the LP with an available OCT evaluation performed after the end of LP and before the date of the subsequent injection): A patient was classified as “dry” if at the corresponding OCT evaluation there was no presence of fluid in the treated eye based on investigator’s judgment, while if at the corresponding OCT evaluation there was presence of fluid in the treated eye based on investigator’s judgment, he/she was classified as “wet”.

Demographics and baseline ocular and disease characteristics

As shown in Table 1, the EA population was nearly all Caucasian (612 [99.19%]) and more than half were female (EA: 335 [54.29%]). The mean (SD) age at the index date was 75.5 (8.7) years. The baseline mean VA, central subfield retinal thickness (CSRT), and presence of fluid (as per investigators’ discretion) are also presented. Patients most frequently presented with type I (218 [35.33%]) and type II (167 [27.07%]) MNV lesions in the study eye (lesion type was classified using OCT or data entered into case report forms [CRFs]) (Table 1). Baseline characteristics observed in the EA set were comparable with those of the OE (S2 Table). In the OE and EA populations, 167 and 135 patients, respectively, were observed to have developed bilateral nAMD during the observation period. No significant difference in the type of MNV lesions in the treated eye was observed between patients with unilateral or bilateral nAMD. Overall exposure in the EA population was stratified by baseline VA categories (<58, ≥58, and <70, ≥70 Early Treatment Diabetic Retinopathy Study [ETDRS] letters). A statistically significant difference (P<0.02) was noted in the estimated survival curve of observation time between patients with baseline VA <58 compared with those with baseline VA≥70 ETDRS letters. Patients with better VA at baseline (≥70 ETDRS) had a longer observation period compared with patients with worse baseline VA (<58 ETDRS) (S1 Fig).

Table 1. Demographics and baseline ocular and disease characteristics.

Parameters	Effectiveness Analysis (EA) population (N = 617)
Mean (SD) age, years	75.5 (8.7)
Gender, Female, n (%)	335 (54.29)
Race, Caucasian, n (%)	612 (99.19)
Time from diagnosis to treatment (days)
n (%)	584 (94.65)
Median	16
Q1, Q3	7; 33
VA, ETDRS letters
Mean (SD)	53.43 (22.8)
Median (Q1; Q3)	60 (35–70)
MNV types (treated eye), n (%)
Classic (type II)	167 (27.07)
Mixed	52 (8.43)
ND	109 (17.67)
Occult (type I)	218 (35.33)
PCV	27 (4.38)
RAP	44 (7.13)
CSRT (μm)
n (%)	396 (64.18)
Mean (SD)	395.7 (143.1)
Median (Q1;Q3)	369.5 (300.0;463.0)
OCT variables
n (%)	481 (100)
Presence of fluid (investigators’ judgment)	436 (90.64)
Intra-retinal fluid	289 (60.08)
Sub-retinal fluid	314 (65.28)
RPE detachment	285 (59.25)
Atrophy	56 (11.64)
Fibrosis	73 (15.18)
Ocular disease history
n(%)	247 (40.03)
Cataract	38 (6.15)
Cataract surgery	0 (0)
Vitrectomy	0 (0)
RPE tear	0 (0)
Other	43 (6.96)

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OE population: All enrolled patients who had at least one anti-VEGF injection; EA set: All patients in the OE who had a baseline and at least one post-baseline assessment of VA.

CSRT, central sub-field retinal thickness; EA, effectiveness analysis; ETDRS, early treatment diabetic retinopathy study; LP, loading phase; MNV, macular neovascularization; N, total number of patients; n, number of patients; ND, not determined; OE, overall exposed; PCV; polypoidal choroidal vasculopathy; RAP, retinal angiomatous proliferation; RPE, retinal pigment epithelium; SD, standard deviation; VA, visual acuity; VEGF, vascular endothelial growth factor.

Annualized number of anti-VEGF injections

The mean (SD) number of anti-VEGF injections in the EA set was 5.6 (± 2.5) at Year 1, 3.0 (± 3.1) during Year 2 and 8.2 (± 4.1) during the overall 2-year study period (Fig 2). The median (Q1;Q3) time from diagnosis to treatment was 16 (7;33) days in the EA set (Table 1). The number of injections and time from diagnosis were comparable between the EA and OE sets (S2 Fig; S2 and S3 Tables). Patients in the LP population set had a statistically significant higher mean (SD) numbers of injections compared with patients in the NLP in Years 1 and 2 and over 2 years (S3A Fig). Moreover, at the end of Year 1, the mean (SD) number of injections was significantly higher in LP patients who had ‘wet’ status after the LP compared with ‘dry’ patients (S3B Fig).

The time interval between consecutive injections during Year 1, Year 2, and over 2 years is shown in Table 2.

Table 2. Time between consecutive injections.

Statistical parameters	EA population
Statistical parameters	Year 1 (n = 617)	Year 2 (n = 524)	Overall (n = 617)
n	597	310	602
Mean (SD) (days)	52 (23.5)	87.5 (56.2)	62.9 (50.8)
95% CI	50.2–53.9	83–91.9	58.9–66.9

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Interval in days were computed as: [date of j+1 injection]—[date of j injection] + 1.

CI, confidence interval; EA, effectiveness analysis; n, number of patients who had at least two injections; SD, standard deviation.

Annualized number of injections based on baseline ocular characteristics

Number of injections based on MNV lesion type at baseline

A statistically significant difference in the mean total annualized number of anti-VEGF injections among MNV lesion types was seen in Year 2 (P = 0.0049) and over 2 years (P = 0.0255) but not in Year 1. The mean total annualized number of injections appeared to be higher in patients with polypoidal choroidal vasculopathy and lower in those with classic lesions (S4A Fig).

Number of injections based on baseline VA

The annualized number of anti-VEGF injections was stratified by baseline VA categories (<58, ≥58 and <70, ≥70 and <79, and ≥79 ETDRS letters) as well as by visual impairment categories identified by The International Classification of Diseases 11 (2018) (see Supplementary data, S4C Fig). The mean (SD) total number of injections was statistically different among VA disjoint classes at Year 1 (P = 0.0038), between Years 1 and 2 (P<0.0001), and over 2 years (P<0.0001) in the EA population. Patients with better VA received a higher mean number of injections compared with those with lower baseline VA (S4B Fig).

VA outcomes over time after anti-VEGF therapy

At Year 1, the mean (SD) VA increased by 2.45 (±19.36) letters compared with baseline; the change was statistically significant (P = 0.0005). Patients who were kept on treatment throughout the observation period maintained their VA with a mean (SD) VA change at Year 2 from baseline that was –1.34 (±20.85) letters with P = 0.3984 (S4 Table).

Furthermore, to describe changes in VA through follow-up using all available measurements per patient, a LMM regression model with a random intercept for each patient was implemented using time as a covariate (modelled as a restricted cubic spline). As shown in Fig 3, when using all available VA measures per patient, a significant positive time effect was detected followed by a decrease in VA after the first 200 days post-baseline VA assessment.

Fig 3 — Letter count trend in the treated eye during the study period is depicted as a function of time from baseline VA. The mean number of assessments per patient in the overall study period was 8.95. EA set: All patients in the OE who had a baseline and at least one post-baseline assessment of VA; EA, effectiveness analysis; OE, overall exposed; VA, visual acuity.

To evaluate factors associated with VA outcomes, linear regression models were estimated at Years 1 and 2 in the 1stCA_EA and 2ndCA_EA populations, using the following covariates: age, gender, baseline VA, time from diagnosis to treatment, baseline type of MNV lesion, number of injections during the first year, bilateral diagnosis, and loading phase completion. The subset of independent factors associated with VA outcomes at 1 and 2 years were age (P = 0.0276 [Year 1]; P = 0.0043 [Year 2]), baseline VA (P<0.0001 [Years 1 and 2]), and the number of injections during the first year (P<0.0001 [Year1]; P = 0.0394 [Year2)] (Table 3).

Table 3. Multivariable regression model results for ETDRS change after the 1st and 2nd year excluding patients with ND lesion type (EA set, 1stCA and 2ndCA).

	ETDRS change after Year 1				ETDRS change after Year 2
Variable	Estimate	SE	t value	Pr(>\|t\|)	Estimate	SE	t value	Pr(>\|t\|)
Intercept	27.2041	9.4969	2.8645	0.0044	42.3832	11.4797	3.6920	0.0003
Age (1-year increase)	−0.2365	0.1069	−2.2120	0.0276	−0.3989	0.1384	−2.8817	0.0043
Gender: male vs female	1.3970	1.7916	0.7797	0.4361	0.3504	2.2320	0.1570	0.8754
Baseline VA (ETDRS)	0.6336	0.0436	14.5254	0.0000	0.6125	0.0540	11.3456	0.0000
Time to treatment (1-day increase)	−0.0011	0.0112	−0.0944	0.9248	−0.0166	0.0269	−0.6177	0.5373
Lesion type: mixed vs classic	−2.5713	3.0990	−0.8297	0.4073	−0.5398	3.9204	−0.1377	0.8906
Lesion type: occult vs classic	−1.1198	2.0889	−0.5361	0.5923	3.6140	2.6664	1.3554	0.1765
Lesion type: PCV vs classic	0.0608	4.2996	0.0142	0.9887	9.7109	5.0502	1.9229	0.0556
Lesion type: RAP vs classic	−0.0890	3.3535	−0.0265	0.9788	−4.8802	4.0313	−1.2106	0.2271
Number of injections in the first year (1-unit increase)	2.5666	0.5266	4.8744	0.0000	0.6873	0.3320	2.0704	0.0394
Loading phase completed: no vs yes	2.1128	2.1982	0.9612	0.3371	2.7693	2.7403	1.0106	0.3131
Bilateral diagnosis: yes vs no	0.6254	2.0628	0.3032	0.7619	3.6440	2.5898	1.4070	0.1606

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*Adjusted R² for the model is 0.44, **Patients with complete data were 354 for Year 1.

*Adjusted R² for the model is 0.39, **Patients with complete data were 275 for Year 2.

IstCA, first-year completer analysis set; 2ndCA, second-year completer analysis set; ETDRS, early treatment diabetic retinopathy study ND, not determined; PCV, polypoidal choroidal vasculopathy; RAP, retinal angiomatous proliferation; SE, standard error; VA, visual acuity.

The persistence of retinal fluid at the end of the LP was also evaluated as a covariate in similar regression analysis on VA outcomes in the subgroup of LP patients with available VA assessments at 1 and 2 years. Results indicated that the presence of retinal fluid after the LP was significantly associated with VA outcomes: VA at Years 1 and 2 decreased on average by 4.7143 (P = 0.0364) and 5.0244 (P = 0.0536) letters, respectively, for patients with persistent fluid compared with patients with ‘dry’ retina (Table 4).

Table 4. Multivariable regression model results for VA changes between baseline, 1st year and 2nd years excluding patients with ND lesion type (wet vs dry set, 1stCA, 2ndCA).

	VA change after Year 1				VA change after Year 2
Variable	Estimate	SE	t value	Pr (>\|t\|)	Estimate	SE	t value	Pr (>\|t\|)
Intercept	36.6528	11.3307	3.2348	0.0014	45.6233	13.5096	3.3771	0.0009
Age (1 year increase)	−0.3347	0.1244	−2.6899	0.0077	−0.3982	0.1583	−2.5152	0.0128
Gender: male vs female	2.2303	2.1679	1.0288	0.3047	0.1000	2.5592	0.0391	0.9689
Baseline VA (ETDRS)	0.5946	0.0538	11.0539	0.0000	0.5724	0.0596	9.6021	0.0000
Time to treatment (1 day increase)	0.0003	0.0118	0.0288	0.9771	0.0188	0.0377	0.4970	0.6199
Lesion type: Mixed vs classic	−3.1347	3.5904	−0.8731	0.3836	0.9366	4.4350	0.2112	0.8330
Lesion type: occult vs classic	0.1421	2.5443	0.0558	0.9555	5.2651	3.0005	1.7547	0.0811
Lesion type: PCV vs classic	1.3318	5.6620	0.2352	0.8143	11.8228	6.0292	1.9609	0.0516
Lesion type: RAP vs classic	0.5021	3.7943	0.1323	0.8948	−5.3562	4.2839	−1.2503	0.2129
Number of injections in the first year (1-unit increase)	3.0740	0.6276	4.8978	0.0000	0.8718	0.3812	2.2872	0.0234
Presence of fluid end LP: yes vs no	−4.7143	2.2393	–2.1052	0.0364	−5.0244	2.5849	−1.9438	0.0536
Bilateral diagnosis: yes vs no	2.7481	2.4866	1.1051	0.2703	3.3126	2.8576	1.1592	0.2480

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*Adjusted R² for the model is 0.45, **Patients with complete data were 225 for year 1.

*Adjusted R² for the model is 0.43, **Patients with complete data were 178 for year 2.

IstCA, first-year completer analysis set; 2ndCA, second-year completer analysis set; ETDRS, early treatment diabetic retinopathy study; LP, loading phase; PCV, polypoidal choroidal vasculopathy; RAP, retinal angiomatous proliferation; SE, standard error; VA, visual acuity.

Safety outcomes

No systemic safety data were collected owing to the retrospective nature of the study.

Discussion

EAGLE was a 2-year, cohort observational, retrospective, multicenter study in Italy that evaluated the effectiveness of anti-VEGF therapy conducted on secondary data retrieved directly from hospital charts. It is also the first study in Italy to provide insights about the management of treatment-naïve patients with nAMD in clinical practice and to evaluate factors affecting responses to anti-VEGF treatment after 1 and 2 years.

The mean number of anti-VEGF injections in the EAGLE study at Year 1 was 5.6, an improvement on the previous routine clinical practice study, AURA (5.2 in 2 years for Italy) [15]. Despite this improvement, the mean number of injections clearly shows that patients in the EAGLE study were undertreated with respect to pivotal randomized controlled trials [10–12,16] and other routine clinical practice studies, particularly those adopting a proactive and customized treatment approach, with the goal of preventing disease recurrence [17,18].

The completion of a loading scheme was important for receiving anti-VEGF injections at a higher frequency during both the first and second year of follow-up, as well as overall (overall period: LP, 8.7; NLP, 6.7; P<0.0001) and data demonstrates that more injections correlates with better VA outcomes. Other than completion of the LP, a better VA at baseline was the factor associated with a higher number of injections. In particular, data suggests that patients with better baseline VA were able to follow more appropriate treatment in terms of number of injections and treatment persistence. The reasons for this could be two-fold; lower baseline VA could be associated with increased fibrosis and disorganization of neurosensory layers at baseline and thus, a more rapid evolution of scar. Furthermore, physician might be reluctant to treat patients with a lower chance of improving VA based on the risk-benefit ratio assessment and the way patients with better baseline VA might be more motivated to continue therapy [19]. Although the reasons that confer a lower baseline VA at diagnosis may be multiple (such as age, other ocular pathologies, presence of geographic atrophy), data suggest the need for earlier diagnosis, earlier treatment, and better awareness on disease chronicity [20], the improvement of which might contribute to reduction in the high number of patients lost to follow-up in the first year of therapy (~43% (n = 323)).

With respect to functional results, mean VA increased during Year 1 of treatment (2.45 letters; P = 0.0005) and was maintained in Year 2 (–1.34 letters; P = 0.398). In line with reports in other real-world evidence studies, the extent of VA gain and its maintenance over time is associated with injection frequency [21–23]; receiving <7 injections in the first year does not guarantee a significant gain in letters with current available therapies [15,24]. A possible explanation for such an observation in clinical practice is the application of a flexible pro re nata regimen of treatment based on disease reactivation. This therapeutic scheme does not allow disease activity to be promptly detected and treated because monthly monitoring is challenging in clinical practice, resulting in the recurrence of exudative changes which culminate in unsatisfactory clinical outcomes [25]. In contrast, patients receiving proactive regimens (such as treat-and-extend or fixed dosing) are more likely to receive an adequate number of injections allowing VA gains in the first year that are maintained during follow-up years [22]. Apart from number of injections, the literature indicates that older age and a higher proportion of follow-up visits with active MNV lesions are associated with poor VA outcomes in patients with nAMD [26].

To better understand the variables associated with VA outcomes in Italian clinical practice, a multiple regression analysis was conducted in this study. As mentioned previously, the number of injections given in Year 1 was one of the principal factors determining a better VA at Years 1 and 2. In addition, the analysis revealed that age and baseline VA are the variables that had the most impact on visual gains supporting available evidences. In EAGLE, the completion of the LP per se had no significant effect on VA gains at 1 and 2 years compared with NLP subgroup; bigger real-world studies, such as AURA [15] and LUMINOUS [24], reported a tendency but did not demonstrate a strong association. These data suggest that in routine clinical practice, patients might take longer than the mandated number of days to complete the LP (3 injections) which could possibly result in milder VA outcomes [27]. Remarkably, EAGLE data showed that ~52% (191 out of 366) of patients who were assessed for fluid status after the LP, have unresolved fluid (wet) indicating this as one of the hurdles for better visual outcomes in current clinical practice, of which inappropriate LP might be one of the potential contributors.

Multivariable analysis in patients who completed the LP at Years 1 and 2, revealed that the presence of retinal fluid at the end of LP correlated with worse VA outcomes at Years 1 and 2. This even more highlights the importance of achieving an early dry condition to maintain a better VA in the long term. This observation from a clinical practice setting further confirmed what has already been demonstrated in post hoc analyses of pivotal studies [28,29], where early fluid control determined successful management of patients with nAMD, thereby decreasing the burden associated with number of injections. Thus, achieving a ‘dry’ retina is deemed to be more important for achieving better or desired long-term VA outcomes.

The results of EAGLE are representative of patients enrolled in an observational real-life setting and may not necessarily apply to all patients with nAMD. This study was subject to the limitations inherent to medical chart reviews. Moreover, this observational, retrospective study presented some methodological limitations, such as different clinical centers using different OCT machines and different retreatment criteria, which were not standardized. Estimations of VA measurements are possible owing to conversions (decimals to ETDRS). MNV lesion type was classified based on the data entered into CRFs from different centers or OCT assessments. Furthermore, the study might have unmeasured confounders (i.e., latent characteristics not taken into account in the regression models such as reactive or proactive individualized strategy).

To conclude, EAGLE represents a comprehensive database of nAMD patients, showing a reliable picture of management with approved anti-VEGF drugs in Italy from 2016–2018. As observed in other routine clinical practices, the present analysis showed a reduced number of injections and a great loss of patients at follow-up, suggesting that treatment centers could deliver a limited number of injections that are carried out for a limited period and varied from one patient to another. The data analyzed from this chart review confirmed that absolute VA gains were always higher in patients with better VA at baseline, strengthening the need of prompt treatment with anti-VEGF drugs following diagnosis of nAMD. Patients with lower baseline VA (<58 letters) are usually lost early to follow-up and received an average of one less injection in the first year and 2 fewer injections in the second year compared with the rest of the study population. Moreover, the study demonstrated that in the clinical practice setting, early fluid resolution is a critical factor for achieving a better functional outcome. This study identified that in Italy, like many other countries, there is a critical unmet medical need linked to under-treatment of patients. More effective therapies targeting retinal fluid along with individualized proactive treatment strategies and stricter follow-ups are needed to achieve appropriate patient treatment in terms of efficacy, despite the limited treatment capability of the Italian healthcare system.

Supporting information

S1 Fig. Overall exposure by VA at baseline (EA population).

EA set: All patients in the OE who had a baseline and at least one post-baseline assessment of VA. At Month 12, 94% of patients with baseline VA ≥70 ETDRS letters, 87% of patients with baseline VA ≥58 and <70 ETDRS and 79% of patients with baseline VA <58 were under observation. At Month 24, 61%, 50% and 41% of patients with baseline VA ≥70, ≥58 and <70 ETDRS and <58 ETDRS letters, respectively, were still under observation. EA, effectiveness analysis; ETDRS, early treatment diabetic retinopathy study; VA, visual acuity. According to the application of Bonferroni correction due to multiple comparisons the threshold of significance was set at 0.02.

(TIF)

Click here for additional data file.^{(91.7KB, tif)}

S2 Fig. Mean (SD) annualized anti-VEGF injections in OE study population.

OE population: All enrolled patients who had at least one anti-VEGF injection; Mean (SD) number of anti-VEGF injections received by OE populations during Year 1 (until Month 12), Year 2 (Months 13–24) and overall period are presented. n, number of patients; OE, overall exposed; SD, standard deviation.

(TIF)

Click here for additional data file.^{(55.4KB, tif)}

S3 Fig. Mean (SD) annualized number of injections based on loading phase and in patients’ classified wet vs dry.

Mean (SD) number of injections in patients during Year 1, 2 and overall period are presented based on (A) those completing LP or NLP; and (B) in patients classified as wet or dry based on investigators discretion at the end of LP. LP, loading phase; NLP, no loading phase; SD, standard deviation.

(TIF)

Click here for additional data file.^{(165.3KB, tif)}

S4 Fig. Mean (SD) annualized anti-VEGF injections based on baseline ocular characteristics in the EA population.

Mean (SD) annualized anti-VEGF injections in EA population during the Year 1, 2 and overall period were evaluated based on baseline ocular characteristics (A) type of lesion, (B) baseline VA, and (C) visual impairment in the treated eye. EA, effectiveness analysis; SD, standard deviation; VEGF, vascular endothelial growth factor.

(TIF)

Click here for additional data file.^{(483.6KB, tif)}

S1 Table. List of EAGLE study investigational sites and ethics committees.

(DOCX)

Click here for additional data file.^{(30.4KB, docx)}

S2 Table. Demographics and baseline ocular and disease characteristics in OE population.

(DOCX)

Click here for additional data file.^{(22KB, docx)}

S3 Table. Median (annualized) anti-VEGF injections in OE and EA study population

(DOCX)

Click here for additional data file.^{(21.7KB, docx)}

S4 Table. Summary statistics of VA (ETDRS letters) and change from baseline in ETDRS at 1 year and 2 years (EA population) as per available measures.

(DOCX)

Click here for additional data file.^{(21.8KB, docx)}

S5 Table. List of EAGLE study investigators and affiliation.

(DOCX)

Click here for additional data file.^{(24.7KB, docx)}

S1 Appendix. Statistical analysis.

(DOCX)

Click here for additional data file.^{(22.2KB, docx)}

Acknowledgments

The authors thank all the EAGLE study investigators: Cristiana Laculli, Nicolò Massimo, Marco Nardi, Paolo Lanzetta, Leonardo Mastropasqua, Gianni Virgili, Francesco Boscia, Rosalia Giustolisi, Michele Coppola, Carlo Cagini, Vincenzo Pucci, Luca Migliavacca, Antonio Laborante, Enrico Peiretti, Tommaso Micelli Ferrari, Cesare Mariotti, Giuseppe Romeo for their valuable contribution towards this study. The membership/affiliation of EAGLE study investigators is provided in S5 Table. The authors also thank Swapna Ganduri (Senior Scientific Writer I, Medical and Clinical Solutions, NBS CONEXTS, Novartis Healthcare Pvt. Ltd., Hyderabad, India) for medical writing and editorial assistance towards the development of this article.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

This study was funded by Novartis Farma S.p.A, Origgio, Italy. Elena Peruzzi (EP), Stefania Bassanini (SB) and Chiara Biancotto (CB) are employees of Novartis Farma S.p.A., Origgio, Italy. The funder provided support in the form of salaries for authors [CB,EP,SB]. The sponsor had a role in the study design, study conduction, data collection, data analysis, data interpretation and manuscript preparation. Additionally, Novartis Farma S.p.A was responsible for the conduct of the study and oversight of the collection and management of data. The specific roles of the authors employed by Novartis Farma are articulated in the ‘author contributions’ section.

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PLoS One. doi: 10.1371/journal.pone.0256461.r001

Decision Letter 0

Vikas Khetan

17 Jun 2021

PONE-D-21-16791

Effectiveness of anti-vascular endothelial growth factors in neovascular age-related macular degeneration and variables associated with visual acuity outcomes: Results from the EAGLE study

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Giovanni Staurenghi: Heidelberg Engineering1,2.3, Optos2, Ocular Instruments4, Optovue2, Quantel Medical 2, Centervue1,2, Carl Zeiss Meditec2, Nidek2,3, Apellis1, Allergan1, Astellas1, Bayer1,3, Boheringer1, Topcon2, Genentech1, Iveric1, Novartis1,3, Roche1,3, Chengdu Kanghong Biotechnology Co1 Kyoto Drug Discovery & Development Co1 1 consultant/advisor, 2 grant support, 3 lecture fee, 4 patents/royalty

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Reviewer #2: Yes

**********

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Reviewer #1: No

Reviewer #2: I Don't Know

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Reviewer #1: Dear author,

I had the opportunity to review this manuscript and I am glad to share my viewpoints.

The study is undoubtedly good and sound. However, I have major concerns, and I would like to share these with you.

1. What is the exact message that this study convey that has not been conveyed by other studies, so far, including the study by Holz et al in 2015? The reports suggesting the number of injections, the visual gains, and the anatomic results in eyes with nAMD treated with AntiVEGF injections have already shown the real world data. How is it different from the Italian data that you are trying to present?

2. There is mention of the number of loading injections in your study, which is lass than the average number of injections in other studies. Understandably, there will be differences in various countries, following different protocols, and even clinician based variations. However, studies comparing between loading dose and PRN dose have reported minimal differences in visual acuity gains and anatomical results. However, the difference erupts in the ability to detect the amount of fibrosis/ atrophy at the presentation, which, in retrospective studies is a major confounding factor.

3. Studies have already proven the fact that the better visual acuity at baseline is correlated with overall better final visual acuity.

4. P16, Line 326: This statement may be over-exaggerated here. Retrospective chart analysis may not be able to define the exact type of fluid which was noted, and may miss important aspects such as RPE atrophy underlying some intraretinal fluid spaces suggesting poor outcomes.

5. P17, Line 336: This statement may not hold true in real world, especially when recent studies have reported no difference between "some fluid" versus "no fluid". Again, this is very subjective, and differs between subRPE fluid, subretinal fluid above the lesion, or subretinal fluid adjacent to a high RPED.

6. I have major concerns regarding the clinical implications of this study in real world situation.

7. Methodology gets the reader confused. Maybe, you can depict this in a line diagram format when this is being revised further.

8. How many patients had significant cataract/ cataract surgery/ any intravitreal procedures/ diabetic retinopathy/ atrophy at presentation etc. All these are extremely important confounders to the results of this study.

9. How many patients had IRF without SRF? How many of them had RPE atrophy underlying the fluid?

10. Was FFA done in all the patients to qualify for classic/ occult varieties? Most of the classic patterns on FFA would account for type 2 CNV, but this cannot be 100% true. Also, was ICGA done in all the patients especially when diagnosing conditions like PCV and RAP lesions?

11. There are plenty of grammatical and editing errors which need to be rectified.

Thank youy

Best regards

Reviewer #2: I wanted to know if the presence of retinal fluid at the end of LP included both intraretinal and subretinal fluid? In the discussion it is mentioned as remnant retinal fluid at the end of LP as one of the possible factors for reduced vision gain at the end of the study period.

Tolerable Subretinal fluid at the end of LP in the T and E regimens have shown comparable VA outcomes: referring to the FLUID study.

**********

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Reviewer #2: Yes: Chetan Rao

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PLoS One. 2021 Sep 1;16(9):e0256461. doi: 10.1371/journal.pone.0256461.r002

Author response to Decision Letter 0

23 Jul 2021

We thank the reviewers for their critical review and insightful comments on the manuscript. Following are our point-by-point responses to the reviewers’ queries and any changes in the manuscript arising out of the potential revisions.

Reviewer 1:

1. What is the exact message that this study convey that has not been conveyed by other studies, so far, including the study by Holz et al in 2015? The reports suggesting the number of injections, the visual gains, and the anatomic results in eyes with nAMD treated with Anti-VEGF injections have already shown the real world data. How is it different from the Italian data that you are trying to present?

Response: We thank the reviewer for the critical review of the manuscript.

We agree that consistent with other real-world (RW) studies, EAGLE demonstrates the relative

under-treatment of patients with neovascular age-related degeneration (nAMD) receiving lower numbers of anti-vascular endothelial growth factor (VEGF) injections [in the second year specifically].

EAGLE study provides important insights about the real-life management of treatment-naïve patients with nAMD in Italy, as well as the determinants of the response to treatment after 1 and 2 years.

Multivariable analysis in patients, who completed the loading phase (LP; three consecutive injections in 90 days) at Years 1 and 2, revealed that the presence of retinal fluid at the end of the LP correlated with worse visual acuity (VA) outcomes at Years 1 and 2. (lines 284-289; lines 356-363 in track change version of the manuscript). Thus, a dry condition (i.e. absence of retinal fluid in the treated eye based on investigator’s judgment) along with an early diagnosis were found to be important prognostic factors for achieving and maintaining a better VA and a dry condition in the long-term.

To our knowledge, no previous study has investigated the association between visual outcomes and the presence/absence of retinal fluid after the LP based on the investigator’s opinion in a RW study.

Furthermore, compared with the AURA study, EAGLE made it possible to update the data on the current scenario following the introduction to the market of aflibercept and it characterizes the Italian situation in detail. In fact, the number of Italian patients included in AURA was insufficient to assess subgroup-significant results.

2. There is mention of the number of loading injections in your study, which is less than the average number of injections in other studies. Understandably, there will be differences in various countries, following different protocols, and even clinician based variations. However, studies comparing between loading dose and PRN dose have reported minimal differences in visual acuity gains and anatomical results. However, the difference erupts in the ability to detect the amount of fibrosis/ atrophy at the presentation, which, in retrospective studies is a major confounding factor.

Response: The EAGLE study used secondary data from the primary clinical records of treatment-naïve patients with nAMD. We agree with the reviewer on the limitations associated with such retrospective chart review studies.

In clinical practice, the study highlights that achieving a dry retina after the LP is critical for better VA outcomes at 1 and 2 years, despite confounding factors (such as treatment regimens).

Moreover, the study was able to obtain optical coherane tomography ( OCT) variables at baseline, end of LP, and Years 1 and 2 from the clinical charts of these patients. Hence, we do have details of the number of patients who presented with fibrosis/atrophy at these time points. We have included the details of the number of patients with atrophy and fibrosis at baseline in revised Table 1 (Pg:9-10, track changes).

This is descriptive piece of data and it mentions in the Discussion section (lines 316-321; track changes version) that, “lower baseline VA could be associated with increased fibrosis and disorganization of neurosensory layers at baseline and thus, a more rapid evolution of scar,’ but such a claim needs to be warranted and validated by further research.

Although these aspects are intriguing, this primary manuscript will address the primary and main secondary protocol endpoints. The contribution of fibrosis/atrophy to VA outcomes might be considered for future post hoc analyses in a secondary manuscript.

Changes in the manuscript: Pg:9-10; Revised Table 1 (track changes)

3. Studies have already proven the fact that the better visual acuity at baseline is correlated with overall better final visual acuity

Response: We agree with the reviewer. The EAGLE study, like any other real-world observational study, further demonstrates that higher/better baseline VA correlates with overall better final VA outcomes. In the present study, we tried to evaluate the reasons associated with this.

In fact, mean annualized anti-VEGF injections at Years 1 and 2 assessed based on baseline ocular characteristics and number of injections based on baseline VA reiterated the fact that patients with better VA received higher mean number of injections compared with those with lower baseline VA (prior Fig S5B, now Fig S4B in revised manuscript). Moreover, as described in prior Fig S2 (now Fig S1 in revised manuscript), patients with better VA at baseline (�70 Early Treatment Diabetic Retinopathy Study [ETDRS] letters) had a longer observation period compared with those with worse baseline VA (�58 ETDRS). These aspects are elaborated on in the Discussion section (lines 313-321; track changes version).It was possible to correlate better baseline VA with an early dry condition, leading to better VA outcomes.

The EAGLE study data thus suggests the need for earlier diagnosis, earlier treatment, and better awareness on disease chronicity, the improvement of which might contribute to a reduction in the high number of patients lost to follow-up in the first year of therapy.

Strikingly, in the multivariate analysis, which considers all associated variables, baseline VA is one of the most important factors that should be considered to improve the unmet need in wAMD. Locally strengthening this data is very important because it highlights a strong unmet medical need that is underestimated compared with other chronic diseases for which greater prevention is made.

Response: The identification of the presence of fluid in the patients was based on investigator’s judgment at the corresponding OCT evaluation.

We understand the limitations associated with retrospective medical chart reviews and associated methodological limitations have been emphasized (lines 364-373; track changes version). As pointed by the reviewer, we have now revised the statement (track changes: line 354)

Changes made in the manuscript: Pg 18; revised line 354, in track changes

Response: We thank the reviewer for pointing this out.

The recent study referred by you is the FLUID study, a randomized clinical trial (RCT), with inclusion/exclusion criteria where patients in both the intensive (who had subretinal fluid [SRF] resolution) and relaxed (who had some SRF) treatment groups received numerically higher number of injections during Year 1, compared to the total number of injections received by EAGLE study participants in 2 years.

RCT’s are more controlled in terms of the time taken by the patients to complete the loading dose versus the RWE study that is described here. These could have attributed to non-inferior results seen with the ‘some SRF’ group compared with the ‘no SRF’ group.

In FLUID, SRF tolerance during treatment proved to be non-inferior compared with intensive treatment only when using a treat and extend approach; In EAGLE, treatment strategies (and under-treatment) could widely differ among the involved centers and hence it was not possible to assess if residual fluid was due to investigators’ intention to tolerate SRF.

The relative under-treatment seen in Italian clinical practice reprises the need for achieving a dry retina early for better VA outcomes.

6. I have major concerns regarding the clinical implications of this study in real world situation.

Response: The study, in addition to describing the updated scenario of clinical practice in Italy for the treatment of wAMD, identifies critical factors to be improved in the management of patients suffering of wAMD in Italy: the study emphasizes the need for early diagnosis and, importantly, demonstrates the need for early fluid resolution in achieving better functional outcomes in a clinical practice setting.

Locally strengthening this piece of data is important because it highlights a strong unmet medical need that is underestimated compared with other chronic diseases for which greater prevention is made.

7.Methodology gets the reader confused. Maybe, you can depict this in a line diagram format when this is being revised further

Response: Please refer to previous Fig S1 (now Fig 1), a schematic describing the disposition of patients screened and enrolled for study analysis that clearly depicts the number of patients in the Efficacy analysis (EA) set who had LP vs NLP (no loading phase) and the subsequent OCT assessments available to categorize them as ‘Wet’ or ‘Dry’. The prior Fig S1 is included in the main figures section (new Figure 1).

Response: The most frequently reported ocular conditions at baseline were prior/ongoing cataract or prior cataract surgery. Revised Table 1 includes ocular disease history.

In the EA population, 247 (40.03%) concomitant ocular conditions were reported, of which 81 were ongoing during anti-VEGF treatment; 38 (6.15%) of these conditions were cataract, while none reported prior cataract surgery, retinal pigment epithelium (RPE) tear, or vitrectomy. Other ocular conditions were reported in 43 (6.96%) cases.

Changes made in the manuscript: Pg:9-10; Revised Table 1 (track changes)

9. How many patients had IRF without SRF? How many of them had RPE atrophy underlying the fluid?

Response: Details on the number of patients with intraretinal fluid (IRF), SRF, RPE detachment, atrophy, and fibrosis are presented in revised Table 1. These data are descriptive as the association between atrophy and baseline fluid type was not defined as a study endpoint. We acknowledge the reviewer for this suggestion and this might be considered for future post hoc analysis.

Response: Lesion type was classified using OCT or data entered into CRFs (described in lines 199-201, lines 369-370 track changes version).In fact, overall, during the 24-month follow-up, patients had an average of 8.8±4.9 non-injection visits, 5.8±4.6 OCT assessments, but <1 evaluation of Fluorescein angiography (FAG), Indocyanine green angiography (ICGA) and Fundus autofluorescence (FAF).

11. There are plenty of grammatical and editing errors which need to be rectified.

Response: We have addressed this point and the revised manuscript is now copy edited for language.

Changes made in the manuscript: Editorial changes for language throughout the manuscript (in track)

Reviewer 2:

1. I wanted to know if the presence of retinal fluid at the end of LP included both intraretinal and subretinal fluid? In the discussion it is mentioned as remnant retinal fluid at the end of LP as one of the possible factors for reduced vision gain at the end of the study period.

Tolerable Subretinal fluid at the end of LP in the T and E regimens have shown comparable VA outcomes: referring to the FLUID study.

Response: Presence of fluid at the end of the LP (based on investigators judgment) refers to both IRF and SRF.

In the EAGLE study, the multi-variable regression analysis carried out indicated that the persistence of retinal fluid at the end of the LP was significantly associated with VA outcomes (Table 4). VA at Years 1 and 2 decreased on average by 4.7143 (P=0.0364) and 5.0244 (P=0.0536) letters, respectively, for patients with persistent fluid compared with patients with ‘dry’ retina. In addition, the manuscript has references supporting the fact that early dryness is associated with better visual outcomes and less treatment burden.

We agree that FLUID study (interventional RCT) demonstrated non-inferiority in VA gains between patient groups with some SRF fluid vs those with none. We feel that any comparison between a controlled interventional trial and a RW study should be done with some caution due to differences in study design, eligibility criteria, follow-up management, and treatment schedules. Moreover, in FLUID, both groups received a higher number of injections compared with RW studies and in FLUID study re-treatment criteria were pre-defined in the protocol.

In a RWE study, patients are often lost to follow-up early and also may take longer times to complete the loading dose than the mandatory days. Such factors might contribute to suboptimal results in a RW setting. This has been elaborated in lines 342-359 (track changes version).

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PLoS One. doi: 10.1371/journal.pone.0256461.r003

Decision Letter 1

Vikas Khetan

9 Aug 2021

Effectiveness of anti-vascular endothelial growth factors in neovascular age-related macular degeneration and variables associated with visual acuity outcomes: Results from the EAGLE study

PONE-D-21-16791R1

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: Thank you for revising the manuscript extensively. All the data that was missing in the first document is now available, and I am glad that the manuscript meets a publication criteria. These results are extremely important to asses the adequate treatment of AMD in real world, although geographical and interpersonal differences may exist. I have no further comments

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Chetan Rao

PLoS One. doi: 10.1371/journal.pone.0256461.r004

Acceptance letter

Vikas Khetan

23 Aug 2021

PONE-D-21-16791R1

Effectiveness of anti-vascular endothelial growth factors in neovascular age-related macular degeneration and variables associated with visual acuity outcomes: Results from the EAGLE study

Dear Dr. Staurenghi:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. Overall exposure by VA at baseline (EA population).

(TIF)

Click here for additional data file.^{(91.7KB, tif)}

S2 Fig. Mean (SD) annualized anti-VEGF injections in OE study population.

(TIF)

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S3 Fig. Mean (SD) annualized number of injections based on loading phase and in patients’ classified wet vs dry.

(TIF)

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S4 Fig. Mean (SD) annualized anti-VEGF injections based on baseline ocular characteristics in the EA population.

(TIF)

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S1 Table. List of EAGLE study investigational sites and ethics committees.

(DOCX)

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S2 Table. Demographics and baseline ocular and disease characteristics in OE population.

(DOCX)

Click here for additional data file.^{(22KB, docx)}

S3 Table. Median (annualized) anti-VEGF injections in OE and EA study population

(DOCX)

Click here for additional data file.^{(21.7KB, docx)}

S4 Table. Summary statistics of VA (ETDRS letters) and change from baseline in ETDRS at 1 year and 2 years (EA population) as per available measures.

(DOCX)

Click here for additional data file.^{(21.8KB, docx)}

S5 Table. List of EAGLE study investigators and affiliation.

(DOCX)

Click here for additional data file.^{(24.7KB, docx)}

S1 Appendix. Statistical analysis.

(DOCX)

Click here for additional data file.^{(22.2KB, docx)}

Attachment

Submitted filename: Point-wise response to reviewers comments_FINAL.docx

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Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Effectiveness of anti-vascular endothelial growth factors in neovascular age-related macular degeneration and variables associated with visual acuity outcomes: Results from the EAGLE study

Giovanni Staurenghi

Francesco Bandello

Francesco Viola

Monica Varano

Giulia Barbati

Elena Peruzzi

Stefania Bassanini

Chiara Biancotto

Vito Fenicia

Claudio Furino

Maria Vadalà

Michele Reibaldi

Stela Vujosevic

Federico Ricci

Roles

Abstract

Objective

Study design

Results

Conclusions

Introduction

Materials and methods

Study design

Key eligibility criteria

Study objectives and endpoints

Assessments

Statistical analysis

Results

Patient disposition, demographics, and baseline ocular characteristics

Patient disposition

Fig 1. Disposition of patients screened and enrolled in the study analysis.

Demographics and baseline ocular and disease characteristics

Table 1. Demographics and baseline ocular and disease characteristics.

Annualized number of anti-VEGF injections

Fig 2. Mean (SD) annualized anti-VEGF injections in EA study population.

Table 2. Time between consecutive injections.

Annualized number of injections based on baseline ocular characteristics

Number of injections based on MNV lesion type at baseline

Number of injections based on baseline VA

VA outcomes over time after anti-VEGF therapy

Fig 3. Estimated letter count trend for the EA population during the study period.

Table 3. Multivariable regression model results for ETDRS change after the 1st and 2nd year excluding patients with ND lesion type (EA set, 1stCA and 2ndCA).

Table 4. Multivariable regression model results for VA changes between baseline, 1st year and 2nd years excluding patients with ND lesion type (wet vs dry set, 1stCA, 2ndCA).

Safety outcomes

Discussion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Vikas Khetan

Roles

Author response to Decision Letter 0

Decision Letter 1

Vikas Khetan

Roles

Acceptance letter

Vikas Khetan

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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