# The management of neovascular age-related macular degeneration: A systematic literature review of patient-reported outcomes, patient mental health and caregiver burden

Richard Gale, Robert Finger, Bora Eldem, Tariq Aslam, Jane Barratt, Vincent Daien, Laurent Kodjikian, Anat Loewenstein, Mali Okada, Tien Yin Wong, et al.

► To cite this version:

Richard Gale, Robert Finger, Bora Eldem, Tariq Aslam, Jane Barratt, et al. The management of neovascular age-related macular degeneration: A systematic literature review of patient-reported outcomes, patient mental health and caregiver burden. Acta Ophthalmologica, 2022, 101 (1), pp.e26-e42. 10.1111/aos.15201. inserm-04957951

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REVIEW ARTICLE

Acta Ophthalmologica

# The management of neovascular age-related macular degeneration: A systematic literature review of patient-reported outcomes, patient mental health and caregiver burden

Richard P. Gale<fnref n="1" /> | Robert P. Finger<fnref n="2" /> | Bora Eldem<fnref n="3" /> | Tariq Aslam<fnref n="4" />,<fnref n="5" /> | Jane Barratt<fnref n="6" /> |
Vincent Daien<fnref n="7" /> | Laurent Kodjikian<fnref n="8" />,<fnref n="9" /> | Anat Loewenstein<fnref n="10" /> | Mali Okada<fnref n="11" /> |
Tien Yin Wong<fnref n="12" />,<fnref n="13" /> | Michelle Sylvanowicz<fnref n="14" /> | Francisco J. Rodríguez<fnref n="15" />

Correspondence

Richard P. Gale, York and Scarborough
Teaching Hospital NHS Foundation Trust,
York, UK.

Email: richard.gale@york.nhs.uk

Funding information

The systematic literature review was
funded by Bayer Consumer Care AG,
Pharmaceuticals, Switzerland, and
conducted by ApotheCom, United
Kingdom, under the direction of the
authors. Medical writing support, also
under the direction of the authors, was
provided by Sarah Feeny, BMedSci
(ApotheCom, UK) and funded by Bayer
Consumer Care AG, Pharmaceuticals,
Switzerland, in accordance with Good
Publication Practice (GPP3) guidance (*Ann
Intern Med* 2015;163:461–464).

Abstract

**Purpose:** The aim of this systematic literature review was to describe patient-reported outcomes, mental health and caregiver burden in patients with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) agents in routine clinical practice.

**Methods:** Electronic searches were conducted in Embase and MEDLINE according to pre-defined criteria.

**Results:** Of 856 records identified, 63 met inclusion criteria. Depression or depressive symptoms were reported in up to 42% of patients with nAMD. Of 25/63 (40%) studies evaluating quality of life (QoL) and using various tools, eight studies reported composite National Eye Institute Visual Functioning Questionnaire scores following anti-VEGF treatment. Of these, seven reported a statistically significant improvement at the earliest time point measured (Month 3–12) and approximately 50% reported sustained QoL benefits at 12 months. In studies comparing the attributed or different regimens, the most important factor from the patient's perspective was the likelihood that a particular regimen would maintain vision. There was a preference towards treat and extend, which was associated with a perceived reduction in patient and caregiver burden, compared to fixed dosing.

This is an open access article under the terms of the [Creative Commons Attribution-NonCommercial-NoDerivs License](https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

© 2022 The Authors. *Acta Ophthalmologica* published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.

<footnote n="1">¹York and Scarborough Teaching Hospital NHS Foundation Trust, York, UK</footnote>

<footnote n="2">²Department of Ophthalmology, University of Bonn, Bonn, Germany</footnote>

<footnote n="3">³Hacettepe University, Ankara, Turkey</footnote>

<footnote n="4">⁴Manchester Royal Eye Hospital, Manchester, UK</footnote>

<footnote n="5">⁵University of Manchester, Manchester, UK</footnote>

<footnote n="6">⁶International Federation on Ageing, Toronto, ON, Canada</footnote>

<footnote n="7">⁷Department of Ophthalmology, University Hospital of Montpellier, Montpellier, France</footnote>

<footnote n="8">⁸University of Lyon, Lyon, France</footnote>

<footnote n="9">⁹Croix-Rousse University Hospital, Lyon, France</footnote>

<footnote n="10">¹⁰Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel</footnote>

<footnote n="11">¹¹Royal Victorian Eye and Ear Hospital, Melbourne, Vic., Australia</footnote>

<footnote n="12">¹²Singapore National Eye Centre, Singapore Eye Research Institute, Singapore, Singapore</footnote>

<footnote n="13">¹³Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore</footnote>

<footnote n="14">¹⁴Bayer Consumer Care, Basel, Switzerland</footnote>

<footnote n="15">¹⁵Department of Ophthalmology, Fundación Oftalmológica Nacional and Universidad del Rosario School of Medicine, Bogotá, Colombia</footnote>
**Conclusions:** A coordinated holistic approach to patient care is key to optimizing patient well-being as well as visual outcomes. Further research regarding the patient-reported impact of nAMD management outside the trial setting (particularly international longitudinal studies) is warranted. Standardization of QoL studies would assist in establishing whether sustained QoL improvement, rather than prevention of QoL decline, should be a realistic expectation of treatment of nAMD in the longer term.

KEYWORDS

intravitreal injections, mental health, neovascular age-related macular degeneration, patient care, quality of life

# 1 | INTRODUCTION

Randomized controlled trials (RCTs) are the gold standard in establishing the efficacy of a clinical intervention; however, the associated protocols often necessitate more involved interactions between patients and clinical and administrative staff. This can impact the patient experience compared with the interactions that occur normally in routine clinical practice (Mattson et al., 1985; Tolmie et al., 2004). It is also well known that real-world studies explore the effectiveness of treatments in more diverse patient populations than are studied in RCTs (Talks et al., 2019) and different populations may have different perspectives of their disease and its management. Thus, experiences of patients and patient-reported outcomes (PROs) evaluated in non-interventional studies may be more similar to those in clinical practice than those reported in RCTs and a better reflection of real-world patient perspectives.

Randomized controlled trials have established the efficacy of anti-vascular endothelial growth factor (VEGF) agents in various retinal conditions, including neovascular age-related macular degeneration (nAMD), with an overwhelming improvement in the prognosis of patients affected by this chronic progressive disease (Schmidt-Erfurth et al., 2014). Differences have emerged between real-world evidence and RCTs regarding the magnitude of functional and anatomic improvements achieved with anti-VEGF agents. These have largely been attributed to undertreatment in routine clinical practice (Kim et al., 2016; Okada et al., 2020). The recommended standard is three initial monthly doses, followed either by monthly dosing until maximum visual acuity is achieved in the case of ranibizumab, or dosing every 2 months for intravitreal aflibercept. However, in the first year of treatment, >70% of treatment-naïve patients with nAMD received ≤6 injections of ranibizumab in the global LUMINOUS study (Holz et al., 2020) and approximately 70% of treatment-naïve patients with nAMD received <7 injections of intravitreal aflibercept in the German PERSEUS study (Framme et al., 2018).

While some RCTs have demonstrated that overall vision-related (VR) quality of life (QoL) improves more often in patients treated with an anti-VEGF agent than in control groups (Solomon et al., 2019), QoL is less

commonly assessed in non-interventional studies. In an earlier systematic literature review (SLR) of real-world studies (conducted prior to July 2018), only four real-world studies exploring the impact of anti-VEGF agents on patients' VRQoL were identified (Finger et al., 2020). The aim of this SLR was to expand upon, and update, the previous search criteria to specifically describe patient experiences regarding their perceived management of nAMD, including anti-VEGF therapy in routine clinical practice. This was assessed in terms of PRO measures associated with QoL, the psychosocial and psychological impact of disease, and treatment burden. We aimed to consolidate information regarding patient perspectives and sought to explore whether the improvement/maintenance of visual acuity achieved with anti-VEGF agents indirectly improves patients' QoL, depression and anxiety.

# 2 | METHODS

Searches were conducted using MEDLINE (PubMed) and Embase on 27 October 2020 for publications up to that date (no other date limit). The search strategy and associated terms were pre-defined (Appendix S1), based on inclusion/exclusion criteria for the patient population, interventions, outcomes and study design (PICOS; Table 1) as recommended by Cochrane (Higgins & Green, 2011). English full-text articles and non-English articles with an English abstract, where the full text could be translated with an online translation tool, were included. A manual review of proceedings from major ophthalmology conferences was also conducted (Appendix S1).

Results of all searches were compiled into a common Excel database, which was used to filter those papers that would be excluded as they did not meet the pre-specific inclusion criteria. Initially, titles and/or abstracts of retrieved articles were screened independently by two reviewers to identify those meeting inclusion criteria and the full texts of identified articles were then assessed in detail. Disagreement over a report's eligibility at either stage was resolved by discussion with a third reviewer. Results are reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (http://www.prisma-statement.org) reporting requirements where applicable.
<table><caption>TABLE 1 Population, intervention, comparison, outcomes and study (PICOS) framework</caption><thead><tr><th>Criteria</th><th>Inclusion criteria</th><th>Exclusion criteria</th></tr></thead><tbody><tr><td>Population</td><td>Adults<br>nAMD (including the subtype PCV)<br>Studies with mixed ophthalmology indications will only be included if results for nAMD patients are reported separately</td><td>Non-humans<br>No separately reported results for nAMD population<br>Specific subtypes of nAMD, such as RAP<br>Other ophthalmology indications</td></tr><tr><td>Intervention/ comparator</td><td>All anti-VEGF treatments, as a class, and individual treatments (intravitreal aflibercept, ranibizumab, bevacizumab and pegaptanib)</td><td>Absence of those treatments listed in the inclusion criteria</td></tr><tr><td>Outcomes</td><td>Outcomes of interest were impact of anti-VEGF therapy on: QoL of the patients (including general well-being, mental and physical health, patient-reported outcomes)<br>Psychosocial and psychological impact (e.g. depression, anxiety)<br>Qualitative outcomes</td><td>Absence of those outcomes listed in the inclusion criteria, e.g. only reporting other outcomes such as:<br>Impact of anti-VEGF treatment on visual acuity<br>Comparative effectiveness<br>Comparative costs<br>Cost-effectiveness</td></tr><tr><td>Study design</td><td>Observational studies<br>Non-interventional studies<br>Modelling- and simulation-based studies<br>Qualitative studies (e.g. patient surveys, interviews)<br>Letters to the editor</td><td>Randomized studies<br>Interventional studies<br>Systematic reviews<br>Meta-analyses<br>Editorials</td></tr></tbody></table>

Abbreviations: nAMD, neovascular age-related macular degeneration; PCV, polypoidal choroidal vasculopathy; QoL, quality of life; RAP, retinal angiomatous proliferation; VEGF, vascular endothelial growth factor.

## 3 | RESULTS

The search identified 856 records. After removing duplicates from PubMed/Embase searches, 810 titles and abstracts were examined and 134 articles were selected for full-text review. A further 76 records were excluded (per exclusion criteria) on evaluation of full text. Four conference abstracts from 2018 onwards were identified from Embase searches and supplemented with a further five conference abstracts identified through manual searches. Thus, this systematic review integrated the findings from a total of 54 full-text articles and nine conference abstracts (Figure 1; Table S1).

The articles mostly reported research from single-centre studies (>50%) and the majority of studies were conducted in Western Europe, North America, Australia or Japan. The majority of reports focused on either QoL (n = 25) or mental health (n = 13). Key PRO measures used are summarized briefly in Table S2. In addition, there were 12 articles (3 conference abstracts) reporting relevant patient perspectives that were not specifically focusing on our research topics of interest. They included, for example, reasons for non-persistence on therapy, which have been reviewed extensively elsewhere (Ehlken et al., 2020), and qualitative descriptive studies. The studies are cited in Table S1, but not discussed further.

### 3.1 | QoL and VRQoL

Of the 25 articles/abstracts evaluating QoL (Table S1), 10 did not report longitudinal data on the potential effects of anti-VEGF treatment on QoL (Casten et al., 2010; Muzyka-Wozniak et al., 2011; Matamoros et al., 2015; Wang et al., 2015; Bertelmann et al., 2016; Gohil et al., 2016; Pentek et al., 2017; Bobykin et al., 2018;

Dougherty et al., 2018; Spooner et al., 2018). Of the remaining 15 studies, only four (Finger et al., 2013; Finger et al., 2014; Inoue et al., 2014; Zhu et al., 2017) had been identified in the previous SLR (Finger et al., 2020).

### 3.2 | National Eye Institute VFQ-25

Of the 15 reports evaluating QoL before and after anti-VEGF treatment, 12 used the National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25), a 25-item questionnaire representing 11 vision-related subscales, plus an additional single-item general health rating question (Table S2). Two studies did not report change in composite NEI VFQ-25 score, and Schroeder et al only reported composite score change after >3 years' follow-up (Schroeder et al., 2017). For the other nine reports of eight study populations, all except one (Bian et al., 2020) described a statistically significant improvement in composite NEI VFQ-25 score at the earliest time point measured after baseline: 1 month (Finger et al., 2013); 3 months (Frennesson et al., 2010; Inoue et al., 2014; Jelin et al., 2018; Jelin et al., 2019) and 6 months (Rakic et al., 2013; Zhu et al., 2017; Gomi et al., 2019). In three studies, the early improvement in composite NEI VFQ-25 score was maintained during longer-term follow-up at 12 months (Inoue et al., 2014; Gomi et al., 2019; Jelin et al., 2019); in two other studies, it was not (Finger et al., 2013; Rakic et al., 2013).

Bian et al. found that both visual acuity in the treated eye and overall best-corrected visual acuity (BCVA) correlated significantly with the NEI VFQ-25 composite score at baseline, 1, 3, 6 and 12 months (Bian et al., 2020). This was consistent with previous, smaller studies, which reported better visual function scores associated with higher NEI VFQ-25 scores (Inoue et al., 2014; Wang et al., 2015; Zhu et al., 2017). In one of the larger
<figure><img src="image_2.png" /><figcaption>FIGURE 1 PRISMA flow diagram</figcaption></figure>

Japanese studies (N = 576), Gomi et al. showed no signif-
icant differences between subgroups in improvements in
NEI VFQ-25 scores according to male/female sex, lesion
subtype, unilateral/bilateral disease, disease duration or
treatment history (Gomi et al., 2019).

Inconsistent improvements in one or more of the NEI VFQ-25 subscales were reported across various studies (Table 2). Changes in the NEI VFQ-25 mental health subscale are included in the section ‘Effect of anti-VEGF treatment on anxiety and depression’. For the other subscales, no clear trends were observed.

3.3 | Other disease-specific and generic QoL measures

The Impact of Visual Impairment (IVI) and Macular
disease Dependent Quality of Life Questionnaire
(MacDQoL) also assessed QoL in patients with nAMD
treated with anti-VEGF agents (Table 3).

The IVI was evaluated in two studies (Finger et al., 2014;
Fenwick et al., 2018). Fenwick et al. showed a positive
effect of anti-VEGF treatment on the three subscales
of the measure (Reading and Accessing Information,
Mobility and Independence, and Emotional Well-being)
from baseline to 12 months (n = 116). Finger et al. did not
demonstrate a significant change from baseline at 6 or
12 months for the IVI subscales in their overall population

of treatment-naïve patients (n = 169); however, patients
who lost >2 lines reported significantly worse VRQoL at
12 months on the Accessing Information and Mobility
subscales and those who gained >2 lines reported signifi-
cantly better VRQoL on the Accessing Information and
Emotional Well-being subscales.

Macular disease Dependent Quality of Life Questionnaire score was evaluated in one study (Marakis et al., 2018). In this study, there was a significant increase in Macular Disease Treatment Satisfaction Questionnaire score after 12 months' anti-VEGF treatment, which showed significant correlations with the MacDQoL score, as well as the score of the generic health measure, the 12-Item Short Form Health Survey. A summary of the limited findings assessing QoL with other generic measures is included in the Appendix S1.

3.4 | Mental health

The systematic literature review identified eight pub-
lished articles reporting results of the mental health
subscale on the NEI VFQ-25 in patients receiving anti-
VEGF treatment. Thirteen published articles and four
conference abstracts evaluating mental health were as-
sessed using other tools or methods (Table 4). Most
studies were cross-sectional, reporting the prevalence
of anxiety and depression according to various tools/
<table><caption>TABLE 2 Prospective real-world studies reporting longitudinal NEI VFQ-25 data in patients receiving anti-VEGFs</caption><thead><tr><th>Citation</th><th>Study design, setting, population and treatment</th><th>Follow-up</th><th>Baseline mean NEI VFQ-25 composite score</th><th>Key findings</th></tr></thead><tbody><tr><td>(Finger et al. 2013)</td><td>Prospective observational Germany; multicentre Tx-naïve and prior anti-VEGF Ranibizumab PRN N = 3470</td><td>12 months</td><td>VFQ: 67.1</td><td><strong>Composite score:</strong> Significant improvement (p &lt;0.0001) from baseline to first follow-up after three initial monthly injections (mean±SD: +3.6±0.3 [median + 2.8] 95% CI 3.1–4.1). No change compared with baseline at 12 months.</td></tr><tr><td>(Gomi et al. 2019)</td><td>Prospective observational Japan; multicentre Tx-naïve AFlibercept according to Japanese PI N = 576</td><td>12 months</td><td>VFQ: 76.9</td><td><strong>Composite score:</strong> Significant improvement (p &lt;0.0001) from baseline at 6 months (mean±SD: +3.1±1.1). Significant improvement (p &lt;0.0001) from baseline at 12 months (mean±SD: +2.7±12.3).<br/><strong>Subscale scores:</strong> Mean change ≥4 (minimally important difference) from baseline for general vision, near vision and mental health at 6 months, and for general vision and mental health at 12 months (all p &lt;0.0001). Significant improvements (p &lt;0.05) for general health, distant vision, social functioning, role limitations, dependency on others and peripheral vision at 6 months. Significant improvements (p &lt;0.05) for general health, near vision, distant vision, social functioning, role limitations and dependency on others at 12 months. No significant differences in ocular pain, driving or colour vision at 12 months.</td></tr><tr><td>(Rakic et al. 2013)</td><td>Prospective observational Belgium; multicentre Tx-naïve and prior anti-VEGF Ranibizumab N = 267</td><td>24 months</td><td>VFQ: 67.0</td><td><strong>NEI VFQ associations:</strong> No significant differences between subgroups were found in terms of sex, lesion subtype, unilateral/bilateral disease, disease duration or treatment history.<br/><strong>Composite score:</strong> Significant improvement (p = 0.03) from baseline at 6 months (mean±SD: 71.0±20.2 vs. 67.0±20.9). Non-significant differences between baseline and 12 months (mean±SD: 68.9±22.3) and 24 months (mean±SD: 65.6±23.8). Clinical improvements maintained at 24 months in 38% of patients.<br/><strong>Subscale scores:</strong> Significant differences (all p &lt;0.0001) from baseline to 6 months, 12 months and 24 months for patient-appraised vision. No significant differences for the subscores of ocular pain, distance activities, vision-specific social functioning, vision-specific role difficulties, driving and peripheral vision. Significant improvements at 6 months but not at later time points for near activities (p = 0.02), vision-specific mental health (p &lt;0.0001) and vision-specific dependency (p &lt;0.0001). Unchanged from baseline to 6 months and 12 months, patient-reported general health (p = 0.03) and colour vision (p = 0.02) scores had declined by 24 months. The proportion of patients with clinically important improvements at 6 months, 12 months and 24 months was statistically similar for the composite score (43.2–45.3%), near activities (44.8–47.5%), distance activities (30.3–40.6%) and vision-specific dependency (25.7–28.9%).</td></tr><tr><td>(van Asten et al. 2015)</td><td>Prospective observational Netherlands; multicentre Tx-naïve and prior anti-VEGF Ranibizumab PRN N = 231</td><td>24 months</td><td>VFQ: Not reported</td><td><strong>Composite score:</strong> Change in composite NEI VFQ-25 score was not reported.<br/><strong>Subscale scores:</strong> Five of the 11 subscale scores demonstrated a significant difference between visits for change from baseline: general vision (p = 0.023; 56.20±17.95 at baseline, 59.77±17.35 at 6 months, 57.42±16.39 at 12 months and 55.42±19.11 at 24 months), ocular pain (p = 0.013; 86.41±19.31, 86.04±18.83, 82.82±20.85, 79.98±19.76 respectively), near activities (p = 0.043; 60.04±29.37, 61.14±29.81, 59.35±28.23, 56.53±30.06 respectively), distance activities (p = 0.014; 61.77±30.62, 62.55±30.58, 59.89±30.10, 56.78±31.45 respectively), social functioning (p = 0.021; 79.44±28.36, 80.19±29.17, 78.15±28.40, 75.21±27.40 respectively).</td></tr></tbody></table>
<table><caption>TABLE 2 (Continued)</caption><thead><tr><th>Citation</th><th>Study design, setting, population and treatment</th><th>Follow-up</th><th>Baseline mean NEI VFQ-25 composite score</th><th>Key findings</th></tr></thead><tbody><tr><td>(Jelin et al. 2019) and (Jelin et al. 2018)</td><td>Prospective observational Norway; single-centre Tx-naïve Anti-VEGF (97% bevacizumab) T&E N = 197</td><td>6 (Jelin et al. 2018) and 12 months (Jelin et al. 2019)</td><td>VFQ: 78.3</td><td><strong>Composite score:</strong> Significant improvement from baseline (78.3) to 82.2 at 3 months (p &lt; 0.001), 82.6 at 6 months (p &lt; 0.001) and 82.1 at 12 months (p &lt; 0.05) overall (71.0 to 76.9, 76.4 and 76.1, respectively, in patients with best-seeing eye treated, and from 83.0 to 84.2, 84.9 and 84.4, respectively, in patients with worst-seeing eye treated). At baseline, patients with best-seeing eye treated reported significantly worse NEI VFQ-25 scores than patients with worse-seeing eye treated.<br><br><strong>Subscale scores:</strong> Significant improvement from baseline to 12 months in general vision (+6.1), near vision (+3.3) and mental health (+5.83). Significant decrease from baseline to 12 months in general health (-4.0) and colour vision (-3.6).<br><br><strong>Composite score:</strong> NEI VFQ-25 score was 59.09 at baseline, 61.75 at 1 month, 62.34 at 3 months, 63.34 at 6 months (p &lt; 0.05 vs baseline) and 59.37 at 12 months.</td></tr><tr><td>(Bian et al. 2020)</td><td>Prospective observational China; single-centre Tx-naïve Ranibizumab N = 142</td><td>12 months</td><td>VFQ: 59.09</td><td><strong>Subscale scores:</strong> Statistically significant differences from baseline in: general vision, dependency and driving at 1-month follow-up; general health, general vision, near activities, role difficulties, dependency and driving at 3 months; general health, general vision, near activities, social functioning, role difficulties, driving, colour vision and peripheral vision at 6 months; general vision, distance activities, social functioning, role difficulties, dependency and driving at 12 months.<br><br><strong>NEI VFQ associations:</strong> Visual acuity in the treated eye and BCVA correlated significantly with the total score of NEI VFQ-25 at baseline, 1 month, 3 months, 6 months (BCVA only) and 12 months (p &lt; 0.01 for all).<br><br><strong>Composite score:</strong> Change in composite NEI VFQ-25 score was not reported.<br><br><strong>Subscale scores:</strong> Statistical improvements from baseline to 3 months (n = 66) in mental health (57 ± 30 to 63 ± 29 points; p = 0.014) and near activities (48 ± 24 to 56 ± 28; p = 0.002). No improvements observed at 37 months (n = 51). Statistically significant decreases from baseline to 37 months in general health (56 ± 26 to 46 ± 24; p = 0.004), ocular pain (83 ± 22 to 74 ± 29; p = 0.028), colour vision (81 ± 30 to 65 ± 30; p = 0.001), distance activities (57 ± 27 to 46 ± 31; p = 0.007), social functioning (74 ± 27 to 65 ± 30; p = 0.021) and role difficulties (67 ± 28 to 56 ± 32; p = 0.026).<br><br><strong>Composite score:</strong> Significant improvement from baseline (72.3) to 75.8 at 3 months (p = 0.006) and 78.5 at 12 months (p = 0.016).<br><br><strong>Subscale scores:</strong> Significant improvements from baseline to 3 months in general vision (from 55.2 to 66.1; p &lt; 0.001), near activities (56.5 to 62.7; p = 0.015) and mental health (68.4 to 77.2; p &lt; 0.001). Significant improvements from baseline to 12 months in general vision (to 67.3; p &lt; 0.001), near activities (to 65.6; p = 0.022), distance activities (from 70.5 to 76.7; p = 0.021), mental health (to 78.6; p = 0.009), colour vision (from 84.7 to 90.6; p = 0.038) and peripheral vision (from 64.6 to 71.4; p = 0.043).<br><br><strong>NEI VFQ associations:</strong> Better visual acuity at 12 months was associated with greater improvement of NEI VFQ-25 composite scores at 12 months (p &lt; 0.05).</td></tr><tr><td>(Rung & Lovestam-Adrian 2013)</td><td>Prospective observational Sweden, single-centre Tx-naïve Ranibizumab PRN N = 50</td><td>37 months</td><td>VFQ: Not reported</td><td></td></tr><tr><td>(Inoue et al. 2014)</td><td>Prospective observational Japan; single-centre Tx-naïve Ranibizumab PRN N = 54</td><td>12 months</td><td>VFQ: 72.3</td><td></td></tr></tbody></table>

(Continues)
<table><caption>TABLE 2 (Continued)</caption><thead><tr><th>Citation</th><th>Study design, setting, population and treatment</th><th>Follow-up</th><th>Baseline mean NEI VFQ-25 composite score</th><th>Key findings</th></tr></thead><tbody><tr><td>(Schroeder et al. 2017)</td><td>Prospective observational Sweden; single-centre Tx-naïve Ranibizumab PRN N = 50 (cohort 1) and N = 26 (cohort 2)</td><td>37 months (cohort 1) 45 months (cohort 2)</td><td>VFQ: 64</td><td><strong>Composite score:</strong> The mean composite score change from baseline to follow-up decreased in cohort 1 from 64±21 to 59±25 scores (p = 0.04), but increased in cohort 2 from 64±28 to 67±23 scores (p = 0.38).<br><strong>Subscale scores:</strong> See (Rung & Lovestam-Adrian 2013) for cohort 1 results; for cohort 2, some of the subscale scores increased at follow-up, but without reaching significant levels.<br><strong>NEI VFQ associations:</strong> In both cohorts, patients with an increase of ≥15 letters showed a trend to gain the largest mean increase in NEI VFQ-25 score. Patients with a loss of ≥15 letters showed the greatest decrease in the NEI VFQ-25 scores.</td></tr><tr><td>(Zhu et al. 2017)</td><td>Prospective observational Australia; single-centre Prior anti-VEGF Aflibercept fixed dosing N = 49</td><td>48 weeks</td><td>VFQ: 70.0</td><td><strong>Composite score:</strong> Significant improvements from baseline (70.0±20.1) by 4.5±9.2 points (p = 0.002) at Week 24 and 4.4±11.8 points (p = 0.012) at Week 48.<br><strong>Subscale scores:</strong> Significant improvements (all p <0.05) from baseline at Week 24 and Week 48 in general vision and near and distance activities (from 58.8, 56.4 and 64.1, respectively, at baseline by +6.4, +6.4 and +7.2, respectively, at Week 24 and by +5.8, +8.7 and +7.7, respectively, at Week 48). Mental health subscale improved from 67.5 by +6.2 at Week 24 (p <0.05) and +4.3 (p = 0.056) at Week 48.<br><strong>NEI VFQ associations:</strong> Improvements in the NEI VFQ-25 composite score was significantly associated with increased BCVA at Week 48 (p = 0.029), but not with change in CMT (p = 0.631). There was no association between NEI VFQ-25 changes and better-seeing eye or worse-seeing eye.</td></tr><tr><td>(Frennesson et al. 2010)</td><td>Prospective observational Sweden; single-centre Tx-naïve Ranibizumab PRN N = 30</td><td>3 months</td><td>VFQ: Not reported</td><td><strong>Composite score:</strong> At 3 months, the mean change in NEI VFQ-25 score per patient for all questions (excluding general health and driving) overall was +8±7 points.<br><strong>Subscale scores:</strong> VRQoL improved significantly more (p = 0.024) for near activities (from 49±26 to 63±26 points [29%]; p <0.0001) than for distance activities, which also improved (from 54±28 to 63±28 points [17%]; p <0.0001).</td></tr></tbody></table>

Abbreviations: BCVA, best-corrected visual acuity; CI, confidence interval; CMT, central macular thickness; NEI VFQ-25, National Eye Institute Visual Function Questionnaire 25; PI, prescribing information; PRN, pro re nata; SD, standard deviation; T&E, treat-and-extend; Tx, treatment; VEGF, vascular endothelial growth factor; VRQoL, vision-related quality of life.
<table><caption>TABLE 3 Real-world studies evaluating VRQoL measures other than NEI VFQ-25 in patients receiving anti-VEGF treatment</caption><thead><tr><th>Citation</th><th>Study design, setting and population</th><th>Treatment</th><th>Follow-up</th><th>Key findings</th></tr></thead><tbody><tr><td>(Rakic et al. 2013)</td><td>Prospective observational<br>Belgium; multicentre<br>Tx-naïve and prior anti-VEGF<br>N = 267</td><td>Ranibizumab</td><td>24 months</td><td><strong>HUI3:</strong> Significant improvements from baseline in mean composite HUI3 scores at 6 months (0.63±0.31 vs 0.58±0.34; p = 0.02), but not at 12 months (0.60±0.35) and 24 months (0.57±0.34). Clinical improvements in the HUI3 were maintained at 24 months in 24% of patients.<br>Significant improvements in the vision subscore at 6 months (p = 0.03) and 12 months (p = 0.02), but not 24 months.</td></tr><tr><td>(van Asten et al. 2015)</td><td>Prospective observational<br>Netherlands; multicentre<br>Tx-naïve and prior anti-VEGF<br>N = 231</td><td>Ranibizumab PRN</td><td>24 months</td><td>Significant improvements in the emotion subscore at 6 months (p = 0.01), but not at 12 months and 24 months.<br>The pain subscore was unchanged at 6 and 12 months, but significantly worse at 24 months (p = 0.03).<br><strong>EQ-5D and EQ-VAS:</strong> Significant improvements in the EQ-VAS score at 24 months (from 53.7±32.6 at baseline to 70.9±16.7; p &lt; 0.001).<br>No significant changes from baseline in the EQ-5D index scores at 24 months.</td></tr><tr><td>(Jelin et al. 2019)<br>and (Jelin et al. 2018)</td><td>Prospective observational<br>Norway; single-centre<br>Tx-naïve<br>N = 197</td><td>Anti-VEGF (97% bevacizumab)<br>T&E</td><td>6 and 12 months</td><td><strong>PASS and EQ-5D:</strong> Significant improvement in PASS at 12 months compared with baseline; improved from 'under acceptable' to 'over acceptable': 3.30 (baseline) to 2.82 and 2.70 at 3 and 6 months (p &lt; 0.001 for both).<br>No significant changes from baseline in the EQ-5D index scores at 6 months.</td></tr><tr><td>(Marakis et al. 2018)</td><td>Prospective observational<br>Greece; single-centre<br>Prior anti-VEGF<br>N = 176</td><td>Mostly ranibizumab PRN</td><td>12 months</td><td><strong>Greek MacTSQ, MacDQoL and SF-12:</strong> Significant correlations between the SF-12 Health Survey and the Greek MacDQoL scores<br>Statistically significant improvements from baseline to 1 year (n = 83) in mean MacTSQ score (from 59.06±10.63 to 62.60±6.78; p = 0.007).</td></tr><tr><td>(Finger et al. 2014)</td><td>Prospective observational<br>Australia; single-centre<br>Tx-naïve<br>N = 169</td><td>Ranibizumab fixed dosing or T&E</td><td>12 months</td><td><strong>IVI questionnaire:</strong> No significant change from baseline at 6 or 12 months for the IVI subscales.<br>Patients who lost >2 lines (n = 13, 11%) reported worse VRQoL at 12 months on the Accessing Information and Mobility subscales (p = 0.007 and p = 0.050 respectively).<br>Patients who gained >2 lines (n = 29, 24%) reported better VRQoL on the Accessing Information and Emotional Well-being subscales (p = 0.009 and p = 0.008 respectively).</td></tr><tr><td>(Fenwick et al. 2018)</td><td>Prospective observational<br>Singapore, single-centre<br>Tx-naïve<br>N = 116</td><td>Anti-VEGF not specified</td><td>12 months</td><td><strong>IVI questionnaire:</strong> Statistically significant improvements from baseline to 12 months in Reading and Accessing Information (mean±SD: 0.43±1.73; p = 0.005), Mobility and Independence (0.45±1.54; p &lt; 0.001), and Emotional Well-being subscales (0.66±1.6; p &lt; 0.001) respectively.<br>In multivariable models, a ≥2-line improvement in BCVA was independently associated with a 47% (CI 0.01–0.39) increase in Reading Scores, but not Mobility or Emotional scores.<br>Mean final BCVA was not independently associated with changes in any of the VRQoL outcomes. Better baseline VRQoL was negatively associated with change in all three VRQoL outcomes at follow-up (p &lt; 0.001).</td></tr></tbody></table>

Note: See Table S2 for a description of the tools/measures and the associated scoring.

Abbreviations: BCVA, best-corrected visual acuity; EQ-5D, EuroQol 5 Dimension; EQ-VAS, EuroQol visual analogue scale; HUI3, Health Utilities Index Mark 3; IVI, Impact of Visual Impairment; MacDQoL, Macular disease Dependent Quality of Life Questionnaire; MacTSQ, Macular Disease Treatment Satisfaction Questionnaire; NEI VFQ-25, National Eye Institute Visual Function Questionnaire 25; PASS, Patient Acceptable Symptom Status; PRN, pro re nata; SD, standard deviation; SF-12, 12-Item Short Form Health Survey; T&E, treat-and-extend; Tx, treatment; VEGF, vascular endothelial growth factor; VRQoL, vision-related quality of life.
measures, and the association between anxiety/depression and other patient/disease characteristics.

## 3.5 | Prevalence of anxiety and depression in nAMD

In a recent large (n = 547) Australian multicentre study of patients with nAMD receiving anti-VEGF agents, 42% of individuals had depressive symptoms, as assessed by the Centre of Epidemiological Studies Depression 10-point scale and 32% had depressive symptoms as assessed by the Mental Health Index component of the 36-item Short Form Survey (Vu et al., 2021). Furthermore, data from Jaffe et al. show wide variation in the prevalence of self-reported anxiety and depression in the European Union (15% and 8% respectively) compared with the United States (26% and 18% respectively) (Jaffe et al., 2018). These two studies highlight the importance of the assessment tool being used and that incidence data are likely impacted by regional and cultural influences, respectively, indicating that anxiety and depression prevalence data should not be compared across studies in different regions or using different tools/measures.

The prevalence of depression assessed using the Geriatric Depression scale was 26% in patients with nAMD receiving anti-VEGF treatment in Korea (Lee et al., 2013); 20% of patients in the United States had clinically significant depressive symptoms according to the Patient Health Questionnaire 9, which combines scores for each of the nine Diagnostic and Statistical Manual of Mental Disorders criteria (Casten et al., 2010); and, in the United Kingdom, 17% and 12% of patients showed clinical levels of anxiety and depression, respectively, as evaluated using the Hospital Anxiety and Depression Scale (HADS) (Senra et al., 2017).

## 3.6 | Anxiety and depression risk factors in nAMD

While there was a lack of consistent evidence as to whether depression was a predictor of NEI VFQ-25 total scores (Casten et al., 2010; Bian et al., 2020), positive correlations between depression scores on the Geriatric Depression Scale and age, visual acuity of either the treated or better eye, duration of nAMD and the number of previous treatments for nAMD have been found (Lee et al., 2013). In several studies, the major sources of anxiety for patients with nAMD were related to fear of losing eyesight because of disease activity and/or prognosis, or concerns about the effectiveness of treatment (Droege et al., 2013; Senra et al., 2017; Giocanti-Auregan et al., 2018; Yiallouridou et al., 2020). In a German study, >60% of patients were anxious about examination results regarding disease activity (Droege et al., 2013) and in a UK study, 30–40% of patients reported fears relating to disease progression and/or vision worsening (Senra et al., 2017). When evaluated, anxiety scores did not seem to be affected by employment status (Kayikcioglu et al., 2017); however, conflicting results have been seen for the impact of sex on anxiety (Segal et al., 2016;

Kayikcioglu et al., 2017). Kayikcioglu et al. did not find a difference between the state and trait anxiety scores of men and women with nAMD in Turkey, whereas Segal et al. found that, in Israel, women were statistically more anxious than men, as evaluated using a visual analogue scale.

In some studies, a minority of patients—<10% (Muller et al., 2017), 16% (Casten et al., 2010) and 19% (Droege et al., 2013)—reported some anxiety or stress related to the injection, and in others, there were higher rates (~50%) of anxiety reported (Kandula et al., 2010; Senra et al., 2017). When evaluated, the level of anxiety appeared to be linked to intravitreal injection pain (Segal et al., 2016; Mbekeani et al., 2020) and disturbed sleep associated with injections has also recently been suggested as affecting some patients (Yiallouridou et al., 2020). A survey of ophthalmologists proposed that treat-and-extend (T&E) dosing may allow the patient to better prepare mentally for injection appointments, versus pro re nata (PRN) regimens (Iida & Ishii, 2016), as their injection schedule is determined months ahead.

Despite the interventional nature of an intravitreal injection, qualitative studies report that patients expressed willingness to continue treatment and recognized injections as their only option to preserve eyesight (Yiallouridou et al., 2020). Chua et al. evaluated patient perceptions immediately before and 2 weeks after anti-VEGF therapy, reporting that patients found intravitreal injections less fearful than they expected and >90% were not anxious having had their first injection (Chua et al., 2009). However, other studies have shown that anxiety levels were generally similar between treatment-naïve and previously treated patients (Segal et al., 2016; Kayikcioglu et al., 2017).

## 3.7 | Effect of anti-VEGF treatment on anxiety and depression

There was a paucity of data that specifically evaluated whether treatment with anti-VEGF agents had any indirect impact on the aspects of mental health. Data were, however, reported for the mental health subscale of the NEI VFQ-25 (Table 2) in eight studies (Rakic et al., 2013; Rung & Lovestam-Adrian, 2013; Inoue et al., 2014; van Asten et al., 2015; Zhu et al., 2017; Gomi et al., 2019; Jelin et al., 2019; Bian et al., 2020). Two of these studies (van Asten et al., 2015; Bian et al., 2020), one of which reported a stabilization of BCVA, but not statistically significant improvement (van Asten et al., 2015), did not show a positive improvement in the mental health subscale. All other studies showed a statistically significant improvement, as early as Month 3 (Rung & Lovestam-Adrian, 2013; Inoue et al., 2014), at Month 6 (Rakic et al., 2013; Zhu et al., 2017; Gomi et al., 2019) and/or Month 12 (Inoue et al., 2014; Gomi et al., 2019; Jelin et al., 2019).

Only two other studies (Kato et al., 2018; Kuwayama et al., 2019; Bian et al., 2020) assessed whether treatment with anti-VEGF agents had any indirect impact on symptoms of anxiety and depression using instruments other than the NEI VFQ subscale (both used HADS; Table 4). The Japanese study data, reported in two conference
<table><caption>TABLE 4 Real-world studies evaluating aspects of mental health (other than the NEI VFQ-25 mental health domain) in patients receiving anti-VEGF treatment</caption><thead><tr><th>Citation</th><th>Study design and setting</th><th>No. of patients</th><th>Anti-VEGF treatment</th><th>Key findings</th></tr></thead><tbody><tr><td>(Vu et al. 2021)</td><td>Cross-sectional patient questionnaire/ interview/survey Australia; multicentre</td><td>547</td><td>Not specified</td><td><strong>CES-D-10 and MHI:</strong> Prevalence of depressive symptoms was 42% and 32% per the CES-D-10 and MHI scales respectively.<br>Poor self-rated health was associated with increased odds of depressive symptoms (multivariable-adjusted OR: 3.00 [95% CI 1.90–4.73] for CES-D-10; OR: 2.67 [95% CI 1.67–4.28] for MHI).<br>Impaired activities of daily living (multivariable-adjusted OR: 2.62 [95% CI 1.56–4.38] for CES-D-10; OR: 3.59 [95% CI 2.10–6.15] for MHI) and a visual function score within the two lowest quartiles were also associated with increased odds of depressive symptoms using both scales.</td></tr><tr><td>(Senra et al. 2017)</td><td>Cross-sectional patient questionnaire/ interview/survey UK; single-centre</td><td>300 patients, 100 caregivers</td><td>Not specified</td><td><strong>HADS:</strong> Prevalence of clinical levels of anxiety and depression were 17% and 12%, respectively, per the HADS.<br>Depression levels, but not anxiety, were significantly higher in patients who received up to three injections compared with patients who received between four and 12 injections (p = 0.027) and compared with patients who received more than 12 injections (p &lt; 0.001).<br>Patients' main concerns and sources of anxiety related to anti-VEGF treatment were: fear of the injection/needle causing damage (39%), fear of disease/vision getting worse (37%), anxiety waiting in the clinic prior to the appointment (35%) and fear of the unknown in relation to treatment outcomes and disease progression (30%). Anxiety regarding injection pain was infrequently raised (3%).</td></tr><tr><td>(Droege et al. 2014)</td><td>Cross-sectional patient questionnaire/ interview/survey Germany; multicentre</td><td>200</td><td>Ranibizumab PRN</td><td>&lt;10% of patients definitely agreed with the statement 'I am afraid of intravitreal injections' or 'I am afraid of the risk of infection due to intravitreal injections'; ~30% of patients definitely agreed with the statement 'I was afraid of examination results regarding disease activity'.</td></tr><tr><td>(Dougherty et al. 2017)</td><td>Prospective observational USA; single-centre</td><td>137</td><td>Not specified</td><td><strong>PSS:</strong> A nine-item form of the Perceived Stress Scale demonstrated acceptable psychometric properties in patients.</td></tr><tr><td>(Dougherty et al. 2018)</td><td>Prospective observational USA; single-centre</td><td>159</td><td>Not specified</td><td><strong>CES-D, PSS and IVI:</strong> IVI score was associated with both perceived stress and depression. There was no significant relationship between the total number of injections and either stress or depression.</td></tr><tr><td>(Segal et al. 2016)</td><td>Prospective observational Israel; single-centre</td><td>148</td><td>Bevacizumab</td><td><strong>VASA:</strong> In 25% of patients, VASA anxiety levels were ≥6 (on a scale of 0 to 10 [highest anxiety score]) and in 8.4%, pain visual analogue scores were ≥6.<br>Women were more anxious than men (p = 0.04).</td></tr><tr><td>(Bian et al. 2020)</td><td>Prospective observational China; single-centre</td><td>142</td><td>Ranibizumab</td><td><strong>CES-D, HAD, SCSQ, PSSS and GSES:</strong> Mean scores of CES-D, HAD, SCSQ, PSSS and GSES are reported at baseline, and Months 1, 3, 6 and 12, but clear trends are not seen.</td></tr><tr><td>(Jaffe et al. 2018)</td><td>Retrospective cross-sectional USA; France; Germany; Italy; Spain; UK</td><td>142</td><td>Not specified</td><td>Self-reported prevalences of anxiety and depression were 15% and 8%, respectively, in the European Union, and 26% and 18%, respectively, in the United States.</td></tr></tbody></table>

(Continues)

(Continues)
<table><caption>TABLE 4 (Continued)</caption><thead><tr><td>Citation</td><td>Study design and setting</td><td>No. of patients</td><td>Anti-VEGF treatment</td><td>Key findings</td></tr></thead><tbody><tr><td>(Mbekeani et al. 2020)</td><td>Prospective observational USA; multi-centre</td><td>140</td><td>Ranibizumab</td><td>GAD-7 and PSQI: Mean (SD) anxiety score was 4.9 (5.6), PSQI, 6.3 (4.1) and IVA pain, 3.69 (2.64). Anxiety was significantly correlated with IVA pain.</td></tr><tr><td>(Kayikcioglu et al. 2017)</td><td>Prospective observational Turkey; single-centre</td><td>113</td><td>Ranibizumab/ bevacizumab</td><td>STAI: Mean state anxiety scores were 45 in previously treated patients and 43 in treatment-naïve patients (mean trait anxiety scores were 50 and 49 respectively), where moderate anxiety is 33–44 and high anxiety is 45–80. There was no statistically significant difference in the state and trait anxiety scores between males and females, and employed and retired patients.</td></tr><tr><td>(Lee et al. 2013)</td><td>Cross-sectional patient questionnaire/ interview/survey South Korea; single centre</td><td>107</td><td>Ranibizumab</td><td>GDS: The prevalence of depression was 26% in patients treated with intravitreal ranibizumab. Positive correlations were observed between Korean GDS and age, visual acuity of the injected eye and the better eye, duration of AMD and the number of previous treatments for AMD.</td></tr><tr><td>(Chua et al. 2009)</td><td>Prospective observational UK; single-centre</td><td>100</td><td>Ranibizumab</td><td>53% of patients reported that intravitreal injection was a less fearful experience than they expected. Those who had previously received anti-VEGF injections reported no change in fear or anxiety compared with their previous injection procedure. Overall, 93% of patients were neither anxious nor fearful after the first injection.</td></tr><tr><td>(Droege et al. 2013)</td><td>Cross-sectional patient questionnaire/ interview/survey Germany; single-centre</td><td>95</td><td>Ranibizumab PRN</td><td>17% of patients definitely agreed with the statement ‘I was afraid of the first intravitreal injections’, 5% ‘I was afraid of subsequent intravitreal injections’ and 41% ‘My fear of intravitreal injections decreased in the further course of treatment’. ~30% of patients definitely agreed with the statement ‘I was afraid of examination results regarding disease activity’. Experience of injection pain was infrequent (3%).</td></tr><tr><td>(Kandula et al. 2010)</td><td>Cross-sectional patient questionnaire/ interview/survey USA; single-centre</td><td>83</td><td>Not specified</td><td>51% of patients were ‘somewhat afraid’ and 10% were ‘very afraid’ about getting their first injection. No patients reported missing appointments because of concern of receiving intravitreal injections. Most patients (75%) had a better-than-expected experience when receiving their first injection. Over 66% of patients also reported that they were less afraid before going in for their second injection.</td></tr><tr><td>(Casten et al. 2010)</td><td>Prospective observational USA; single-centre</td><td>51</td><td>Not specified</td><td>PHQ-9: At 3 months following initiation of anti-VEGF treatment, 10 subjects (20%) had clinically significant depressive symptoms (mean PHQ-9 score, 6.8). Compared with non-depressed subjects, depressed subjects had a greater decline in vision over 3 months. Depression was unrelated to changes in NEI VFQ-25 scores.</td></tr><tr><td>(Kato et al. 2018)</td><td>Prospective observational Japan; multicentre</td><td>40</td><td>Ranibizumab T&E</td><td>HADS: At 1 year (n = 40), the mean HADS anxiety score and mean HADS depression score were decreased from 5.0 to 3.8 and from 4.5 to 3.6 points respectively (p &lt; 0.05). Eight patients had anxiety at baseline, four of whom became free from anxiety at Week 52. Nine patients had depression at baseline, six of whom became free from depression by Week 52 and two additional patients developed depression during the same timeframe.</td></tr></tbody></table>
<table><caption>TABLE 4 (Continued)</caption><thead><tr><td>Citation</td><td>Study design and setting</td><td>No. of patients</td><td>Anti-VEGF treatment</td><td>Key findings</td></tr></thead><tbody><tr><td>(Kuwayama et al. 2019)</td><td>Prospective observational Japan; multicentre</td><td>25</td><td>Ranibizumab T&amp;E</td><td>HADS: At 2 years (n = 25), the mean HADS anxiety score significantly decreased from 5.4 at baseline to 3.2 points at Week 104 (p &lt; 0.01); the depression score decreased slightly from 3.9 at baseline to 3.4 points at Week 104 (no significant difference).</td></tr></tbody></table>

Note: See Table S2 for a description of the tools/measures and the associated scoring.

Abbreviations: AMD, age-related macular degeneration; CES-D, Centre for Epidemiologic Studies' depression; CI, confidence interval; GAD, Generalized Anxiety Disorder; GDS, Geriatric Depression Scale; GSES, General Self-Efficacy Scale; HADS, Hospital Anxiety and Depression Scale; IVI, Impact of Visual Impairment; MHI, Mental Health Index; NEI VFQ-25, National Eye Institute Visual Function Questionnaire 25; OR, odds ratio; PHQ, Patient Health Questionnaire; PRN, pro re nata; PSQI, Pittsburgh Sleep Quality Index; PSS, Perceived Stress Scale; PSSS, Perceived Social Support Scale; SCSQ, Simplified Coping Style Questionnaire; STAI, Spielberg's State-Trait Anxiety Inventory; T&E, treat-and-extend; Tx, treatment; VASA, visual analogue scale for anxiety; VEGF, vascular endothelial growth factor.

abstracts (Kato et al., 2018; Kuwayama et al., 2019), suggested positive effects on symptoms of anxiety and depression in patients treated with anti-VEGF agents followed for 2 years (n = 40 at Year 1 and n = 25 at Year 2). The data from the Chinese study (Bian et al., 2020) appeared to show no consistent effects of anti-VEGF treatment on anxiety and depression according to HADS.

## 3.8 | Impact of different regimens on patients' experiences

Three studies (one each from Germany, Japan and the United States) reported patients' perspectives of different regimens (Droege et al., 2014; Bhagat et al., 2020; Joko et al., 2020), one Japanese study reported the physicians' understanding of patient perspectives (Iida & Ishii 2016) and another Japanese study reported caregivers' perspectives (Hanemoto et al., 2017).

The earliest study was conducted in 2014 and identified two separate groups of patients; one that preferred dosing PRN and the other that preferred fixed monthly dosing (Droege et al., 2014). The preference for a regimen was not correlated with parameters investigated (number of injections, therapy duration, age or sex). More recently, in a discrete-choice experiments, most patients preferred T&E because of its higher chance of 2-year maintenance of visual acuity (Joko et al., 2020). Indeed, while patients preferred a less frequent injection schedule (Bhagat et al., 2020; Joko et al., 2020) some patients were willing to accept less desirable treatment attributes, such as increased cost (Bhagat et al., 2020) and/or injection frequency (Bhagat et al., 2020; Joko et al., 2020) in order to achieve superior vision outcomes.

Iida and Ishii assessed ophthalmologists' perspectives of T&E vs PRN dosing for the patient (Iida & Ishii, 2016). Concerns regarding T&E regimens were increased financial burden (when number of injections increases) and worry about complications (risk of infections). Benefits of T&E compared with PRN from the patient/caregiver perspective, as understood by the treating ophthalmologist, were ability to tangibly experience treatment efficacy through injection interval, decreases in emotional burden associated with receiving intraocular injections and decreases in patient/caregiver time.

## 3.9 | Caregiver burden

Seven studies reported disease-associated burden directly from the caregivers themselves (Gohil et al., 2015; Varano et al., 2015; Varano et al., 2016; Hanemoto et al., 2017; Muller et al., 2017; Senra et al., 2017; Spooner et al., 2018; Gopinath et al., 2019) and two studies reporting caregiver burden from the perspectives of patients (Varano et al., 2015; Joko et al., 2020). However, none of the studies provided insight into caregiver burden before, compared with during or after, anti-VEGF treatment.

The largest study identified was the international wet AMD Patient and Caregiver Survey conducted in nine countries (Australia, Brazil, Canada, France, Germany, Italy, Japan, Spain and the United Kingdom) (Varano et al., 2015; Varano et al., 2016). This cross-sectional survey included 910 patients with an existing nAMD diagnosis who received current or prior anti-VEGF injections, and 890 caregivers (mainly child/grandchild [47%] or partner [23%] of the patient) and used a 29-item, self-administered questionnaire to assess the impact of caregiving on several domains, including psychological well-being, social activities and retirement plans. Most caregivers always attended appointments (>60%) and were involved in discussions about treatment (>80%); many caregivers (>30%) were able to reduce the level of domestic assistance provided after the patient started treatment; however, up to 30% of caregivers reported that frequent appointments were inconvenient (Varano et al., 2015). Although the study reported on the impact of the disease, rather than any impact (positive or negative) of anti-VEGF treatment, it does highlight the variation in burden of disease which will invariably impact the need for caregiver support. For example: depending on the population, patients who could not drive anymore ranged from ~10% to ~50%; patients who reported difficulties in reading ranged from ~40% to ~80%; and the need for help with reading (directly from the caregiver perspective) ranged from ~25% to ~80% (Varano et al., 2016).

Other insights are gained from smaller studies. In one study in the United Kingdom (n = 250), burden evaluated on the Caregiver Reaction Assessment Scale was similar to individuals caring for patients with atrial fibrillation who require regular hospital monitoring
of thromboprophylaxis (Gohil et al., 2015). In another (n = 100 caregivers), approximately 75% of caregivers reported little or no burden associated with supporting patients with nAMD, as evaluated on the Burden Assessment Scale (Senra et al., 2017). Patient's visual acuity in the better eye was identified as impacting caregiver burden (Gohil et al., 2015); however, as ~50% of the patients in this study had visual acuity of 74 letters (Snellen 6/12) or better in the better-seeing eye, the authors suggested that either visual acuity score is not an accurate measure of visual morbidity, or that visual acuity is not the most significant factor in determining caregiver burden.

The need to attend hospital appointments was identified in various studies as an important contributor to caregiver burden (Gohil et al., 2015; Varano et al., 2015; Spooner et al., 2018). Approximately two-thirds of patients required an accompanying person for travel to/from the clinic (Droege et al., 2013; Varano et al., 2015; Muller et al., 2017). A caregiver's inability to accompany the patient to an appointment was also reported to be a contributor to non-adherence (Varano et al., 2015). Compared with PRN dosing, a T&E regimen was associated with a reduction in caregiver burden, in part due to the time and costs associated with fewer hospital visits (Hanemoto et al., 2017).

## 4 | DISCUSSION

The importance of patient-focussed research has become increasingly recognized in recent years; however, previous research has shown that, in RCTs in patients with nAMD, investigators rarely measure and report patient perspectives such as the effects of anti-VEGF agents on QoL or other patient-reported outcome measures (Solomon et al., 2019). The findings of this extensive literature review in non-interventional studies are consistent with this; patient perspectives are poorly represented in the published literature on nAMD studies. We therefore highlight the ongoing paucity of evidence in this important area and encourage further initiatives to address the research gaps identified.

In terms of VRQoL, this systematic review expands on that published in 2020, which included four studies (Finger et al., 2020) and includes the findings of a further 14 reports. The manner in which data related to patient-relevant outcomes were collected and reported was highly heterogenous. Various tools were used and, in most cases, these tools have not been specifically validated for use in patients with nAMD. The most apparent finding was that QoL, as measured by the NEI VFQ-25, appeared to improve from baseline early in patients treated with anti-VEGF agents and that better visual acuity was associated with higher NEI VFQ-25 total scores. Longer-term gains compared with baseline were not consistently observed, but data interpretation is complicated by the lack of a control group.

Here, we identified the primary challenge when attempting to assess the effect of a treatment intervention on QoL in routine clinical practice: in non-interventional studies, the comparison for our treatment arm can only

come from other published studies of similar populations without the treatment of interest. Historical controls from MARINA with sham injections show that QoL decreases over a 2-year period (Bressler et al., 2010), and so it could be argued that, beyond Year 1, maintenance of baseline QoL levels (rather than sustained improvements in QoL) may be a more appropriate anti-VEGF treatment goal for patients with nAMD.

One of the major challenges when investigating quality of life in any condition is how well the tool being used performs in the population of interest. Generic measures may not focus sufficiently on the aspects of the disease that are impacting the patient and specifically the performance of the EQ-5D health-related assessment instrument has been shown to be poor in patients with nAMD (Tosh et al., 2012). In terms of therapy-area specific tools, the NEI VFQ-25 was developed over 20 years ago and is generally considered the best validated of the tools for use in ophthalmic conditions (Finger et al., 2008). However, Marella et al have suggested that the NEI VFQ-25 questionnaire items may actually be measuring two different underlying constructs, one related to visual functioning and another to socio-emotional status (Marella et al., 2010). This is important, as it would suggest that the single composite score is not reliable and larger subscales or summated subscales should be used. It was hoped that disease-specific QoL instruments might better describe important dimensions of VRQoL in nAMD. However, developing such tools is not without its complications and, like the NEI VFQ-25, the MacDQoL questionnaire is also undesirably multidimensional (Finger et al., 2012).

Optimal patient management, in any condition, should take a holistic approach. However, there is relatively scarce information as to what this should comprise specifically in an individual with nAMD. There is little in the medical literature advocating a multidisciplinary approach despite evidence that >80% of patients have five or more comorbidities (Zlateva et al., 2007). Communication and co-created treatment goal-setting is obviously key, but can be complicated by hearing and/or cognitive impairment in this elderly population. Additionally, while several recent studies have investigated the effect of the COVID-19 pandemic on treatment regimens and vision in nAMD (Arruabarrena et al., 2021; Bulut et al., 2021; Weng et al., 2021), we should also remember the impact of the recent pandemic on the mental health of our patients and our ability to provide the required level of physician-patient interaction.

There is increasing acceptance that, despite new pharmacologic treatments, depression and anxiety are common in patients with nAMD. However, from the published data, there is no clear or strong evidence of positive or negative changes in the extent of depression or anxiety in patients with nAMD treated with anti-VEGF agents. It could be proposed that positive effects of anti-VEGF treatment on visual acuity would result in indirect, positive effects on depressive symptoms. However, the data do not consistently support this, possibly because of various confounding factors impacting patients' mental health. One of the major factors impacting a patient's mental health appears to be the emotional
burden associated with the chronic, progressive nature of the disease and chronic nature of the treatment. This is exemplified by a German study (Droege et al., 2013), where >60% of patients were anxious about examination results regarding disease activity, whereas <20% were afraid of intravitreal injections. Although patients would prefer not to have intravitreal injections, the impression from the data is that this is a burden that patients are willing to accept to optimize visual outcomes. As long as vision is maintained with anti-VEGF treatment, studies indicate that patients prefer a T&E regimen due to the reduced burden and increase in the certainty of the injection schedule.

The perception of caregiver burden appears to be influenced by cultural/geographic 'norms' though there are no data measuring the effects of anti-VEGF treatment on caregiver burden over time. This lack of longitudinal data, therefore, means that the findings described show only a point-in-time assessment. Additionally, we did not find any studies comparing the perspectives of the patient with either those of their carer or physician. Since a disconnect between patient and physician perspectives has been identified in various other therapy areas (such as neurology, respiratory medicine and rheumatology [Husni et al., 2018; Maher et al., 2018; Hermanowicz et al., 2019]), it would be interesting for research efforts to investigate this topic further in ophthalmology.

The main strength of this literature review is its comprehensiveness, driven by broad search terms, without a limit on dates. Despite this, many of the evaluated studies did not meet the search criteria, demonstrating the paucity of data to address the specific research questions. Consequently, all studies were included, without eligibility criteria based on study size, or an assessment of quality of controls for biases. Thus, one of the limitations of our review is that the findings are based mostly on single-centre studies, which were often relatively small (<100 patients). Also, evidence was geographically limited—mainly to North America and Western Europe, with some studies from Australia and Asia (primarily Japan). Indeed, data on patient perspectives from observational studies in countries, such as those in Africa, Central/Eastern Europe and South America, are particularly needed. It is highly likely that patient experiences regarding the management of nAMD in lower-income countries are likely to be impacted by additional factors related to access to treatment, healthcare organization and general infrastructure considerations.

In conclusion, we find that the heterogeneity of how QoL and other patient-relevant concepts were evaluated highlights the need for a standardized approach if evidence is to be consolidated and results from individual studies in patients with nAMD are to be more easily compared. There is relatively consistent evidence suggesting that intravitreal anti-VEGF injections result in improved QoL following treatment in clinical practice of patients with nAMD. Some QoL improvements are sustained at 1 year; however, it remains to be established whether sustained improvement in QoL should be a realistic expectation of anti-VEGF treatment, particularly

in the longer term. In nAMD, it appears that depression and anxiety have complex and nuanced origins, rather than being simply related to anti-VEGF injections or poor vision alone. Overall, more robust research in each of these areas is warranted and a coordinated, holistic approach to patient care and patient/physician dialogue is key to optimizing the likelihood of patient well-being, as well as improvements in visual outcome.

## DISCLOSURES

RPG: Consultant/advisory boards: Novartis, Bayer, Allergan, Alimera, Santen; Educational travel grants: Novartis, Bayer, Allergan, Heidelberg; Research grants: Allergan, Bayer, Novartis, Roche. RPF: Grant: Novartis, CentreVue, Heidelberg Engineering, Zeiss; Consultant: Novartis, Bayer, Roche/Genentech, Ellex, Alimera, Allergan, Santhera, Inositec, Opthea; Support for travel: Novartis. BE: Consultant: Bayer, Novartis, Allergan. TA: Consultant: Novartis, Bayer, Laboratoires, Théa Pharmaceuticals, Bausch & Lomb, Oraya. JB: Nothing to disclose. VD: Consultant: Bayer, Horus Pharma, Novartis, Théa. LK: Consultant: AbbVie, Alcon, Allergan, Bayer, Krystal Biotech, Novartis, Regeneron, Théa. AL: Consultant: Allergan, Bayer, Beyeonics, Forsight Labs, Notal Vision, Novartis, Roche. MO: Travel support: Bayer; Honorarium for lectures: Bayer, Allergan. TYW: Clinical trial grants: Allergan, Bayer, Boehringer-Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics), Roche, Samsung Bioepis, NMRC Singapore, Novartis Singapore; Consulting fees/travel support/review fees/consultant fees: Allergan, Bayer, Boehringer-Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics), Roche, Samsung Bioepis; Stock: Plano, EyRIS. MS: Employee: Bayer Consumer Care AG. FJR: Consultant: Bayer, Novartis, Roche; Speaker: Bayer, Novartis, Roche; Research funds: Novartis.

## ACKNOWLEDGEMENTS

Open access funding enabled and organized by ProjektDEAL.

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## SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

**How to cite this article:** Gale, R.P., Finger, R.P., Eldem, B., Aslam, T., Barratt, J. & Daien, V. et al. (2023) The management of neovascular age-related macular degeneration: A systematic literature review of patient-reported outcomes, patient mental health and caregiver burden. *Acta Ophthalmologica*, 101, e26–e42. Available from: https://doi.org/10.1111/ aos.15201