Long-term persistence to aflibercept therapy among treatment-naïve patients with exudative age-related macular degeneration in a universal health care system: A retrospective study

doi:10.21203/rs.3.rs-1981778/v1

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Research Article

Long-term persistence to aflibercept therapy among treatment-naïve patients with exudative age-related macular degeneration in a universal health care system: A retrospective study

https://doi.org/10.21203/rs.3.rs-1981778/v1

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Background

This study aimed to analyse the persistence rates of treatment-naïve patients with neovascular age-related macular degeneration (nAMD) that received intravitreal aflibercept therapy in a universal health care system.

Methods

In this single-centre retrospective cohort study, we audited data of 918 treatment-naïve patients that received exclusively intravitreal aflibercept therapy for nAMD between September 2015 and May 2021. Primary outcome measures were nonpersistence (gap of ophthalmological care > 6 months) and long-term nonpersistence (> 12 months) rates.

Results

The rates of nonpersistence and long-term nonpersistence were 12.3% and 3.4%, respectively, after one year and 22.4% and 9.5%, respectively, after two years; and increased to 38.3% and 19.3%, respectively, after five years. Logistic regression analysis revealed that older age (p = 0.045), male patients (p = 0.039), patients requiring caretakers or ambulance (p = 0.001), and patients with a low visual acuity of the study eye (p = 0.010) or fellow eye (p = 0.029) were independent risk factors for long-term nonpersistence. Patients aged > 80 and > 85 years (p = 0.013 and p = 0.022, respectively) had more than twice the risk for being nonpersistent to therapy within two years of follow-up. Male patients (p = 0.033), patients requiring caretaker (p = 0.038), and patients living > 60 km from the clinic (p = 0.029) had a two times higher risk of being persistently nonpersistent to therapy.

Conclusions

We found a lower nonpersistence rate in patients with nAMD treated with aflibercept compared to that of current literature. Multiple independent risk factors were correlated with long-term nonpersistence, early nonpersistence, or complete loss to follow-up. Considering the possible consequences of reduced compliance, further strategies are urgently needed for patients at risk of nonpersistence to therapy.

adherence

long-term effect of compliance

loss to follow-up

persistence

aflibercept

age-related macular degeneration

Despite the introduction of several anti-vascular endothelial growth factor (VEGF) therapies in the last few decades, exudative age-related macular degeneration (AMD) has been proven as a major contributor to vision impairment in elderly patients, accounting for 8.7% of all blindness worldwide [1,2]. Depending on the drug, the approved label, or different treatment protocols, monthly to three monthly injections are recommended after an initial loading dose of three injections for three consecutive months [3–6]. However, real-life studies have reported inconsistent numbers of injections and functional outcomes compared to the idealised setting and circumstances of randomised clinical trials [3,7–10]. The discrepancy in injection frequency and successful preservation of visual acuity in patients with neovascular AMD (nAMD) over a long period of time is most likely due to a lack of adherence to the rigorous treatment and examination regime. Considering the emphasis placed on frequent examinations and on timely administration of intravitreal injections, there is still a lack of awareness and knowledge of the obstacles that lead to reduced adherence of the treatment regime in the management of patients with nAMD. Recently, there have been reports of nonadherence or nonpersistence in 32% to 95% of these patients [7,11–13]. However, these studies have used either small samples, included other than treatment-naïve patients, or used various anti-VEGF agents in their study cohort. Additionally, according to a major review by Okada et al. [13], data on the compliance of aflibercept or regimens with longer treatment intervals in the management of nAMD is scarce. Moreover, previous studies have identified racial ethnicities and patient income as the main risk factors in a health system without general insurance [11]. Since the lack of health insurance was hypothesised as a reason for the underutilization of ophthalmological preventive care and treatment, the outcome of these studies might not be generalizable [14].

In Austria, anti-VEGF therapy is covered by primary public insurance, but only in general hospitals with an ophthalmological department. These special circumstances provide the opportunity to assess risk factors for reduced long-term adherence without the potential bias of social status, income, or patients receiving therapy at a private practice. Thus, the present study sought to evaluate the intrinsic and extrinsic risk factors that lead to a reduced persistence to therapy among treatment-naive patients with nAMD treated on a pro re nata (PRN) regimen with intravitreal aflibercept at a fixed interval of 8 weeks following an initial loading dose of three injections every four weeks. Secondary outcome measures were the identification of risk factors leading to an early nonpersistence to therapy or to an complete loss to follow-up.

Study population

Data were retrieved from a structured electronic database used for patients receiving anti-VEGF therapy at the Department of Ophthalmology at the University Clinic Innsbruck, Innsbruck, Austria, from September 2015 to May 2021. The data were audited retrospectively, following a standardised protocol. Institutional Review Board approval was given before commencement of the research (Medical University Innsbruck, Innsbruck, Austria - No 1261/2020). The Review Board waived the requirement for an informed consent due to the retrospective nature of the study. All data were anonymized prior to the analysis. The study procedures were in accordance with the tenets of the Declaration of Helsinki.

The inclusion criteria were as follows: (1) patients with nAMD that were treatment naïve to anti-VEGF therapy who received exclusively aflibercept therapy during follow up and (2) patients that were started with a loading dose of three injections for three consecutive months and followed with a fixed therapy interval of aflibercept injections every 8 weeks in a PRN treatment regime.

The exclusion criteria were as follows: patients (1) with diabetes mellitus; (2) having a history of posterior uveitis, retinal vein occlusion; (3) history of treatment with other anti-VEGF agents, corticosteroids or photodynamic therapy; (4) having a clinically significant cataract or any other disease potentially threatening visual acuity; and (5) who had a follow-up examination at another clinic or private practice during the observation period. In Austria, intravitreal anti-VEGF therapy is covered only by primary public health insurance in hospitals with an ophthalmology department. Therefore, we also excluded patients who had their residences closer to another clinic with an ophthalmological department.

Clinical Assessment & Dataset

Neovascular AMD was diagnosed in all patients at baseline by retinal specialists using fundoscopic examination and fluorescent angiography or optical coherence tomography angiography (OCT-A; Heidelberg Spectralis® OCT, Heidelberg Engineering, Heidelberg, Germany). Patients who were treatment-naïve to anti-VEGF therapy and indicated for intravitreal aflibercept with an initial loading dose of three injections every 4 weeks, were included in the study. At follow-up examinations, further injections were indicated as triplets of aflibercept every 8 weeks on a pro re nata regime. Appointments for injection and follow-up examinations were routinely scheduled and documented at the end of every consultation.

We collected the following data: demographic data, best-corrected visual acuity (BCVA) at baseline and at every subsequent follow-up visit, number of aflibercept injections, number of follow-up examinations, bilateral or unilateral involvement at baseline, and duration of documented follow-up.

BCVA measurements were collected as the logarithm of the minimum angle of resolution (logMAR) units. We determined the “distance to the clinic” as the distance of the road required to travel between the patients’ residence and the clinic using Google Maps (Google Inc., Mountain View, USA).

The definition of nonpersistence

Patient persistence was assessed by analysing the occurrence of a gap of ophthalmological care during the given observation period. As described in the consensus by Okada et al[15] was defined by an interval without any visit or therapy of > 6 months and long-term nonpersistence by an interval without any visits or therapy of > 12 months. Early nonpersistence was defined as gap of ophthalmological care that occurred within two years of follow-up, late nonpersistence as a gap of ophthalmological care that occurred after two years of follow-up, and complete loss to follow-up was defined as failure to permanently return to treatment in the given observation period. Additionally, we documented the number of nonpersistence episodes and the duration of each nonpersistence episode. Patients who were rescheduled by the clinic/hospital or had themselves actively rescheduled their appointments beyond 6 follow-up months were not considered as nonpersistent.

The primary outcome measures included the prevalence and frequency of nonpersistence and long-term nonpersistence in patients with nAMD under intravitreal aflibercept therapy in a primary care centre for retinal diseases in the western region of Austria. Assessment and identification of risk factors that led to nonpersistence to intravitreal aflibercept therapy provided data that were considered as the secondary outcomes.

Statistical analysis

All statistical analyses were performed using SPSS Statistics version 25 (IBM, Armonk, NY, USA).

Demographic data are presented as the number of patients with percentages, normally distributed data as mean ± standard deviation (SD), and non-normally distributed variables are presented as median and interquartile range (IQR). The Kolmogorov–Smirnov and Saphiro-Wilk tests were used to determine all variables for normal distribution.

We used the chi-square test and Fisher’s exact test to compare categorical data, the unpaired sample t-test to assess normally distributed data, and the Mann-Whiney U test for non-normally distributed data. Potential risk factors for long-term nonpersistence, early nonpersistence, and complete LTFU were evaluated using a univariate binary logistic regression model. All demographic characteristics which were associated with long-term nonpersistence with a p-value < 0.1 were included for multivariate logistic regression to determine the main risk factors that lead to episodes of nonpersistence, early nonpersistence, and complete LTFU. Binary logistic regression was conducted to determine the odds ratio and 95% confidence interval (CI). Statistical significance was set at p-value of < 0.05.

Baseline characteristics and nonpersistence rates

A total of 918 treatment-naïve patients who were treated with intravitreal aflibercept therapy were eligible for analysis. The mean age was 79 ± 7.6 (SD) years, and the proportion of female patients in this study cohort was 65% (596/918). The median “distance to the clinic” was 13.6 (IQR, 2.7–38.1) km. While 490 (53%) of the patients were able to arrive independently for their therapy, 318 (35%) needed a caretaker and 110 (12%) arrived in an ambulance. Patients who adhered to their therapy received 10 (IQR, 6–16) injections during their follow-up and made a total of 13 (IQR, 7–22) visits, whereas patients who were nonpersistent to therapy received 7 (IQR, 4–11, p < 0.001, 99% CI 0.00–0.005) injections and made 9 (IQR, 6–16, p < 0.001, 99% CI–0.00-0.005) visits during their follow-up. After 5 years, 352 (38.3%) patients were nonpersistent for at least 6 months and 178 (19.4%) patients for more than 12 months (see Fig. 1). While the median follow-up of persistent patients was 31 (IQR, 19–48) months, the median follow-up until nonpersistence was 17 (IQR, 12–25) months for the group with nonpersistence and 15 (IQR, 8–25, p < 0.001; 99% CI 0.000–0.005) months for the group with long-term nonpersistence. Among the patients who were nonpersistent, 313 (88.9%) patients had one episode of nonpersistence, 33 (9.4%) had two episodes, and 6 (1.7%) had three episodes. Among the patients who were nonpersistent, there were 204 (58%) with nonpersistence and 44 (25%) with long-term nonpersistence, all of whom returned after a median time of 12 (IQR, 7–28) months for further examinations. Eighty-six patients (35%) were indicated for further therapy at their return visit. Details of the baseline characteristics of the aforementioned patients are presented in Table 1.

Table 1

Characteristics of patients with neovascular age-related macular degeneration persistent to therapy or with long-term nonpersistence
Baseline Characteristics	Persistent Group	Long-term nonpersistence Group (> 12m)	p-Value
N	741 (81)	177 (19)
Age
≤ 75	214 (29)	42 (24)	< 0.001
76–80	217 (29)	21 (12)
81–85	165 (22)	45 (25)
> 85	145 (20)	69 (39)
Sex
Male	251 (34)	71 (40)	0.070
Female	490 (66)	106 (60)	0.070
Distance to clinic, km
≤ 10	335 (45)	77 (43)	0.097
11–30	185 (25)	32 (18)
31–60	96 (13)	28 (16)
> 30	125 (17)	40 (23)
BCVA study eye at baseline, logMAR (SD)	0.62 (0.40)	0.79 (0.45)	< 0.001
BCVA fellow eye at baseline, logMAR (SD)	0.56 (0.50)	0.74 (0.56)	< 0.001
Eye involvement
bilateral	186 (25)	55 (31)	0.061
unilateral	555 (75)	122 (69)	0.061
Type of transport
independent arrival	428 (57)	61 (34)	< 0.001
arrival with caretaker	242 (33)	77 (44)
arrival with ambulance	71 (10)	39 (22)
^{N: number; km: kilometres; SD: standard deviation}

Long-term nonpersistence according to demographic risk factors

According to univariate analysis, age, type of transport, sex, distance to the clinic, and bilateral eye involvement (all p < 0.08) had a tendency to be associated with an increased long-term nonpersistence rate (Table 1). Therefore, these demographic characteristics were included in the multivariate analysis to rule out confounders and identify the key risk factors that lead to long-term nonpersistence. Binary logistic regression revealed that the odds of being nonpersistent to therapy were 64% higher for patients aged > 85 years than for patients aged ≤ 75 years (p = 0.045, see Table 2). Male patients had a 45% higher risk of being nonpersistent than female patients (p = 0.039). Additionally, patients requiring a caretaker or patients arriving in an ambulance had a two- and three-times higher chance of being nonpersistent for more than 12 months (p = 0.001 and p < 0.001, respectively).

Table 2

Findings of logistic regression analyses to determine the risk factors for long-term nonpersistence among patients with AMD
	Long-term nonpersistence (> 12m)	Univariate Model p-Value (odds ratio; 95% CI)	Multivariate Model⁺ p-Value (odds ratio; 95% CI)
N	177 (19.2)
Age
≤ 75	42 (16.4)	Reference	Reference
76–80	21 (8.8)	0.013* (2.02; 1.16–3.53	0.001* (2.56; 1.44–4.54)
81–85	45 (21.4)	0.167 (1.39; 0.87–2.22)	0.700 (1.10; 0.67–1.79)
> 85	69 (32.2)	< 0.001* (2.43; 1.56–3.76)	0.045* (1.64; 1.01–2.65)
Sex
Male	71 (22.0)	Reference	Reference
Female	106 (17.8)	0.119 (1.31; 0.55–1.07)	0.039* (1.45; 1.02–2.08)
Distance to clinic, km
≤ 10	77 (18.9)	Reference	Reference
11–30	32 (14.7)	0.188 (0.74; 0.47–1.16)	0.249 (1.32; 0.65–2.08)
31–60	28 (22.6)	0.377 (1.25; 0.76–2.03)	0.025* (2.04; 0.65–2.32)
> 60	40 (24.2)	0.158 (1.37; 0.87–2.11)	0.191 (1.36; 0.86–2.15)
Eye involvement
bilateral	55 (23.0)	Reference	Reference
unilateral	122 (18.1)	0.113 (1.352; 0.94–1.94)	0.536 (1.13; 0.77–1.65)
Type of transport
independent arrival	61 (34)	Reference	Reference
arrival with caretaker	77 (44)	< 0.001* (2.23; 1.54–3.23)	0.001* (1.99; 1.33–2.95)
arrival with ambulance	39 (22)	< 0.001* (3.83; 2.39–6.16)	< 0.001* (3.1; 1.84–5.25)
^{AMD: agel−related macular degeneration; m: month; CI: confidence interval; N: number; km: kilometres}
^{* indicates p−value <0.05}
^{+ binary logistic regression adjusted to age, sex and type of transport}

Long-term nonpersistence according to visual acuity

Binary logistic regression adjusted for age, sex, distance to the clinic, and type of transport revealed that patients with a low VA (> 1.0 logMAR) of the study eye at baseline had an 86% greater chance of being nonpersistent to therapy than patients with a good VA (< 0.4 logMAR) of the study eye at baseline (p = 0.010). Similarly, a low VA of the fellow eye at baseline correlated with a higher rate of nonpersistence than in patients with a good VA of the fellow eye at baseline (p = 0.029) (Table 3).

Table 3

Long-term nonpersistence according to the visual acuity among patients with AMD
	Long-term nonpersistence (> 12m)	Univariate Model p-Value (odds ratio; 95% CI)	Multivariate Model⁺ p-Value (odds ratio; 95% CI)
Visual Acuity, logMAR
Study eye at baseline
≤ 0.4	32 (14.5)	Reference	Reference
0.4–1.0	64 (15.8)	0.561 (1.15; 0.72–1.82)	0.972 (1.01; 0.63–1.62)
> 1.0	81 (27.9)	< 0.001* (2.36; .1.49–3.74)	0.010* (1.86; 1.16–2.99)
Fellow eye at baseline
≤ 0.4	61 (15.2)	Reference	Reference
0.4–1.0	38 (17.9)	0.379 (1.22; 0.78–1.90)	0.025 (1.57; 1.05–2.33)
> 1.0	78 (26.4)	< 0.001* (2.01; .1.38–2.93)	0.029* (1.65; 1.05–2.58)
Stud eye before episode of nonpersistence
≤ 0.4	37 (15.7)	Reference	Reference
0.4–1.0	45 (7.2)	0.934 (1.02; 0.64–1.64)	0.176 (0.74; 0.47–1.15)
> 1.0	95 (22.7)	0.015* (1.68; 1.11–2.56)	0.08 (0.70; 0.46–1.04)
Fellow eye before episode of nonpersistence
≤ 0.4	47 (29.2)	Reference	Reference
0.4–1.0	45 (8.4)	0.084 (1.49; 0.95–2.33)	0.406 (1.21; 076–1.93)
> 1.0	85 (40.1)	0.003* (1.81; 1.22–2.68)	0.069 (1.46; 0.97–2.2)
Study eye - change of visual acuity until episode of nonpersistence
≤ -0.2	69 (19.1)	Reference	Reference
− 0.2 to 0.2	61 (20.1)	0.792 (1.05; 0.72–1.55)	0.992 (1.00; 0.67–1.50)
> 0.2	47 (19.3)	0.931 (1.01; 0.67–1.54)	0.919 (0.98; 0.64–1.50)
^{AMD: agel−realted macular degeneration; m: month; CI: confidence interval; logMAR: logarithm of minimum angle of resolution}
^{+ binary logistic regression adjusted to age, sex and type of transport}
^{* indicates p−value <0.05}

Characterization of early nonpersistence and patients returning for therapy

To analyse the risk factors for early nonpersistence, we divided patients into two subgroups—the early nonpersistence group, within two years of follow-up and the late nonpersistence group, after two years of follow-up. Binary logistic regression analysis between these groups revealed that people aged 81–85 and people aged > 85 years had more than twice the risk of developing nonpersistence within two years of follow-up (p = 0.013 and p = 0.022, respectively) (see Table 4). Patients with either a moderate VA (0.4–1.0 logMAR; p = 0.364 and p = 0.255, respectively) or a low VA (p = 0.352 and p = 0.070, respectively) of their study or fellow eye did not show a higher rate of early nonpersistence compared to patients with a good VA.

Table 4

Distribution and findings of logistic regression analyses to determine the risk factors of early nonpersistence among patients with AMD
	Early nonpersistence	Late nonpersistence	Univariate Model p-Value (odds ratio; 95% CI)	Multivariate Model⁺ p-Value (odds ratio; 95% CI)
N	219	133
Age
≤ 75	43 (12)	45 (13)	Reference	Reference
76–80	41 (12)	26 (7)	0.128 (1.65; 0.87–3.14)	0.227 (1.51; 0.77–2.93)
81–85	60 (17)	27 (8)	0.007* (2.32; 1.25–4.31)	0.013* (2.27; 1.20–4.34)
> 85	75 (21)	35 (10)	0.006* (2.24; 1.25–4.00)	0.022* (2.07; 1.12–3.86)
Sex
Male	85 (24)	43 (12)	Reference	Reference
Female	134 (38)	90 (26)	0.221 (0.75; 0.478–1.19)	0.118 (0.68; 0.42–1.10)
Distance to clinic, km
≤ 10	96 (27)	61 (17)	Reference	Reference
11–30	50 (14)	22 (6)	0.214 (1.46; 0.80–2.64)	0.183 (1.52; 0.82–2.79)
31–60	30 (9)	27 (8)	0.279 (0.71; 0.39–1.31)	0.284 (0.71; 0.38–1.33)
> 60	43 (12)	23 (7)	0.550 (1.20; 0.66–2.19)	0.522 (1.23; 0.65–2.30)
Type of transport
independent arrival	92 (26)	65 (18)	Reference	Reference
arrival with caretaker	83 (24)	55 (16)	0.787 (1.07; 0.67–1.70)	0.739 (0.92; 0.56–1.51)
arrival with ambulance	44 (12)	13 (4)	0.014* (2.39; 1.19–4.79)	0.061 (2.05; 0.97–4.33)
^{AMD: age−related macular degeneration; m: month CI: Confidence Interval; N: number; km: kilometres}
^{+ binary logistic regression adjusted to age and type of transport}
^{* indicates p−value <0.05}

Similarly, we subdivided patients that were nonpersistent into a return group and a complete LTFU group. Multivariate analysis adjusted for age, sex, distance to the clinic, and type of transport showed that male patients had a 67% higher chance of being completely LTFU than female patients (p = 0.033). Additionally, patients staying at a distance of > 60 km from the clinic and patients in need of an ambulance to arrive at the clinic had a two times higher risk of being completley LTFU compared to patients in proximity to the clinic (p = 0.029 and p = 0.038, respectively) (see Table 5). Moderate (p = 0.671) or low VA (p = 0.150) of the study eye did not correlate with higher return rates after being nonpersistent to therapy. In contrast, patients with a low VA of the fellow eye had a 216% higher chance of being completley LTFU compared to patients with a good VA of the fellow eye (p = 0.003, 95% CI 1.30–3.62).

Table 5

Distribution and findings of logistic regression analyses to determine the risk factors for complete loss to follow-up among patients with AMD
	complete LTFU	return after nonpersistence	Univariate Model p-Value (odds ratio; 95% CI)	Multivariate Model⁺ p-Value (odds ratio; 95% CI)
N	148	204
Age
≤ 75	34 (10)	54 (15)	Reference	Reference
76–80	18 (5)	49 (14)	0.126 (1.71; 0.86–3.42)	0.068 (1.96; 0.95–4.02)
81–85	40 (11)	47 (14)	0.326 (0.74; 0.41–1.35)	0.486 (0.798; 0.42–1.50)
> 85	56 (16)	54 (15)	0.086 (0.61; 0.344–1.07)	0.281 (0.71; 0.38–1.32)
Sex
Male	61 (17)	67 (19)	Reference	Reference
Female	87 (25)	137 (39)	0.108 (1.43; 0.925–2.23)	0.033* (1.66; 1.04–2.64)
Distance to clinic, km
≤ 10	59 (17)	98 (28)	Reference	Reference
11–30	26 (7)	46 (13)	0.804 (1.08; 0.60–1.92)	0.859 (1.05; 0.58–1.92)
31–60	27 (8)	30 (8.5)	0.210 (0.68; 0.37–1.25)	0.155 (0.63; 0.33–1.91)
> 60	36 (10)	30 (8.5)	0.022* (0.51; 0.28–0.91)	0.029* (1.98; 1.07–3.64)
Type of transport
independent arrival	53 (15)	104 (30)	Reference	Reference
arrival with caretaker	64 (18)	74 (21)	0.028* (1.69; 1.06–2.72)	0.164 (0.70; 0.42–1.16)
arrival with ambulance	31 (9)	26 (7)	0.014* (2.34; 1.26–4.32)	0.038* (2.05; 1.03–4.04)
^{AMD: age−related macular degeneration; m: month CI: Confidence Interval; N: number; km: kilometres}
^{+ binary logistic regression adjusted to distance and type of transport}
^{* indicates p−value <0.05}

Nonpersistence and nonadherence to anti-VEGF therapy is one of the biggest challenges in the management of patients with nAMD. It represents a major contributing factor that displays its effect via the rather sobering results of real-life studies compared to the outcomes of the major clinical trials [3, 7–10]. The complexity and multifactorial reasons that might lead to non-adherence and reduced compliance in the treatment of patients with nAMD were explored in a major review by Okada et al. [13], which revealed that non-adherence varied from 32–95%, depending on the definition criteria of the studies.

In our study, we analysed the non-adherence to intravitreal aflibercept therapy in treatment-naïve patients with nAMD. We found the rate of nonpersistence for periods of 6 and 12 months to be 12.3% and 3.4%, respectively, after one year and 22.4% and 9.5%, respectively, after two years. In contrast, a cohort study, conducted in the tristate area of Pennsylvania, New Jersey, and Delaware by Obeid et al [11], revealed a LTFU of 12 months in 22% of cases at a median follow up time of 2.4 years. As opposed to the primarily public healthcare system in Austria, the United States does not provide a universal healthcare program; consequently, anti-VEGF therapy is not covered. The impact of the insurance status is perfectly reflected in the report by Obeid et al. [11] who identified patient’s income and ethnicity as major contributors for a reduced compliance. Another retrospective study of 201 patients receiving ranibizumab at an 4-weeks interval, which was conducted in France under universal health care, reported LTFU episodes of at least 6 months in 26% of the cases after one year, and in 38% of the cases after two years, and in more than 50% within four years [7]. In contrast, the results of our study revealed a weighted nonpersistence of 6 months of 38% in exclusively treatment-naïve patients on an 8-weeks treatment interval of aflibercept after 5 years.

Particularly, in a phone survey, the burden of follow-up visits has been attributed to non-adherence to intravitreal therapy in one of four cases [7]. The same survey assessed the distance to the clinic as the main reason for therapy break-off in every second patient. Similarly, patients who had to travel more than 30 km from their residence to clinic were predisposed to be nonpersistent to therapy and patients traveling more than 60 km had twice the risk to be completley LTFU and not return for a follow-up. Besides the distance to clinic, increasing age was correlated as a major contributor for non-adherence being responsible for an increased risk for long-term nonpersistence or early nonpersistence by a factor of 1.5–2.0. Additionally, compared to female patients, we observed higher long-term nonpersistence rates and a higher proportion of complete LTFU in male patients. It should be considered that comorbidities and morbidity increase with age, and these impede their ability to operate independently [16] along with the greater distances to the clinic. Patients in need of anti-VEGF therapy must adhere to numerous follow-ups and treatment schedules, and such dependence can be devastating. The impact of the ability to operate independently is highlighted by the finding that the proportion of patients with long-term nonpersistence increased up to 36% in the group of patients in need of a caretaker or an ambulance. This is significantly higher than those who were able to travel independently. The proportion of patients who returned after being nonpersistent was significantly higher in the group that travelled independently compared to those requiring an ambulance. A lack of mobility was considered an independent risk factor and it doubled or tripled the odds of long-term nonpersistence and complete LTFU.

A notable finding of the study was the correlation between poor VA of the study/fellow eye at baseline and an increased rate of long-term nonpersistence. Furthermore, our results suggest that patients had twice the risk of being completley LTFU, if the fellow eye had a poor VA at baseline. Given the equivocal results of previous studies regarding the association of non-compliance with VA, it seems that the role of vision has yet not been sufficiently explored. The VA of the fellow eye, which was taken into account in this study, seems to be an important factor. However, in most of these studies, bilateral VA was not documented, and it is unclear whether the patients were treatment-naïve or not [7, 11, 12].

This study has some limitations. First, due to its retrospective nature, we could not obtain information regarding person-specific reasons for being nonpersistent to thearpy. Therefore, we were unable to address individual patient needs to improve their adherence to therapy. A larger-scale retrospective phone survey stratified for the person-specific reasons of nonpersistence and treatment quality are needed to assess patients’ special needs in the management of nAMD. It has to be mentioned that approximately 18% of the nonpersistence of 6 months took place during the Corona Virus Disease 2019 (COVID-19) pandemic. This may be of great concern, considering that a potentially irreversible deterioration of macular function can develop relatively quickly in untreated nAMD patients [17]. The impact of COVID-19 pandemic-related restrictions on the outcomes of nAMD patients has been displayed in a report of our study team. [18]

The strengths of the present study are its considerably large number of treatment-naïve nAMD patients that received exclusively intravitreal aflibercept at one tertiary centre. In Austria, as aforementioned, anti-VEGF therapy is only covered by general insurance in public hospitals with an ophthalmological department; consequently, we were able to rule out the bias of patient income and the potential bias of patients receiving therapy from other ophthalmologists, which is a unique feature of the present study. Furthermore, we were able to characterise patients who returned for therapy, providing new insights into the inter-related phenomena of non-adherence to anti-VEGF therapy in the real world.

Although there are novel anti-VEGF drugs with a longer durability approaching, other strategies, such as reminder software or teaching programs, may be needed to ensure better adherence to the rigid therapy programs that are currently in place for nAMD, thereby reducing the episodes of nonpersistence [18]. However, this might be difficult to apply for older patients, and alternative routes in the growing field of telemedicine and artificial intelligence might be a viable option [19–22]. Additionally, strategies that reduce the number of visits might be beneficial in times of pandemic situations.

Our findings revealed a lower nonpersistence rate in patients with nAMD treated with intravitreal aflibercept compared to the current literature describing nonadherence to other anti-VEGF agents. A lack of mobility was identified to double or triple the risk for long-term nonpersistence and complete LTFU. Further key risk factors for early nonpersistence, long-term nonpersistence, or complete LTFU were older age, male sex, long distances to the clinic, and low visual acuity at baseline. The higher nonpersistence rates of patients with longer distances to the clinic and patients requiring a caretaker or ambulance could indicate a structural problem in the quality of care for patients with nAMD. Further strategies to preserve the visual function of patients at risk of nonpersistence are urgently needed.

anti-vascular endothelial growth factor, VEGF; age-related macular degeneration, AMD; neovascular AMD, nAMD; loss to follow-up, LTFU; pro re nata, PRN; optical coherence tomography angiography, OCT-A; best-corrected visual acuity, BCVA; logarithm of the minimum angle of resolution, logMAR; standard deviation, SD; interquartile range, IQR; confidence interval, CI; Corona Virus Disease 2019, COVID-19

Ethics approval: This study was approved by the Institutional Review Board of the Medical University Innsbruck (Innsbruck, Austria - No 1261/2020). All data were anonymized prior to the analysis. The study procedures were in accordance with the tenets of the Declaration of Helsinki.

Consent to participate: The requirement for informed consent was waived by the Institutional Review Board of the Medical University Innsbruck, Innsbruck Austria owing to the retrospective nature of the study.

Consent for publication: Not applicable.

Availability of data and material: The data of this research will be available on reasonable request from the corresponding author.

Competing interests: The authors declare that they have no competing interests.

Funding: Not applicable.

Authors' contributions: All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by RA, AF, KF and VS. The first draft of the manuscript was written by RA and CZ and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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No competing interests reported.

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Editorial decision: Major revision
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Long-term persistence to aflibercept therapy among treatment-naïve patients with exudative age-related macular degeneration in a universal health care system: A retrospective study

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