Patient Perspectives on Intravitreal Anti-Vascular Endothelial Growth Factor Therapy for Neovascular Age-Related Macular Degeneration

Introduction
Neovascular age-related macular degeneration (nAMD) is the primary cause of irreversible vision impairment and blindness among the elderly in developed countries. While the introduction of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy in 2007 has significantly improved the prognosis for nAMD, our recent findings show that the aging population is projected to increase the number of intravitreal anti-VEGF injections by 50% from 2022 to 2027. Long-term treatment with anti-VEGF injections is considered safe. However, the consistently demanding nature of this regimen, requiring hospital visits every 4-12 weeks, can present challenges for elderly and visually impaired patients.

The objective of this dissertation was to explore patient perspectives on intravitreal therapy for nAMD, with the aim of understanding how the treatment regimen and the disease itself affect the physical, mental, and social well-being of patients with nAMD. This was achieved by investigating barriers to treatment as experienced by patients (Paper I), developing a questionnaire and subsequent recruiting a representative samples of patients with nAMD (Paper II), and exploring the association between different factors and the impacts of nAMD on quality of life (QoL) (Paper III).

Methods
Paper I was conducted as a qualitative exploratory study comprising semi-structured individual and dyadic interviews. Guided by Gadamer’s hermeneutics, we employed maximum variation sampling to capture a wide range of patient experiences. Patients were recruited from Odense University Hospital (OUH) and Zealand University Hospital in Roskilde, and the interviews were analyzed using thematic analysis.

In Paper II, we described in detail the development of a survey targeting patients with nAMD, as well as the recruitment process of eligible participants. The survey comprised various sections, including self-developed background questions to characterize patients, along with previously validated instruments such as the National Eye Institute Visual Function Questionnaire-25, developed in 2001 and the Macular-dependent quality of life (MacDQoL) questionnaire developed by Mitchel and Bradley in 2004. Recruitment methods included the Department of Ophthalmology at OUH, patient registries at OUH, and social media, with respondents completing the survey electronically or via telephone interview. The validation of the survey included a face validity assessment and cognitive interviews with seven patients as part of the pilot testing.

In Paper III, we used questionnaire data from patients receiving intravitreal anti-VEGF injections for nAMD and analyzed associations between nAMD-related QoL and patient characteristics, as well as treatment-related factors. The impact of nAMD on QoL was evaluated based on the MacDQoL questionnaire, which consist of 22 domains. Each domain gives an impact score between -9 (greatest impact of nAMD on QoL) to +3 (least impact of nAMD on QoL). An average weighted impact (AWI) score was calculated as an average across all domains. The relationship between AWI scores and various factors was analyzed using linear regression with bootstrapping. Results were presented as β-coefficients with 95% confidence intervals (CI) in a crude analysis and an analysis adjusted for sex, age, and best-corrected visual acuity (BCVA).

Patient and public involvement was utilized as an overarching method throughout the studies, consisting of five patients receiving nAMD treatment, three relatives, and three ophthalmologist. Their insights served a dual purpose: democratizing research by allowing affected individuals to influence it and enhancing research quality and relevance.

Results
Paper I: Among 21 patients affected by nAMD (median age 79 years) the analysis identified five themes that reveal patient-reported barriers to treatment: 1) Good compliance with the intravitreal treatment, describing good patient compliance to recommended treatment despite numerous patient-reported barriers; 2) The dual role of relative’s, illustrating that the relatives played a dual role where some posed a facilitator and others a barrier for attending treatment; 3) Treatment commute, describing how the commute to the hospital could pose a hindrance for some patients but was perceived as unproblematic by others, and even enriching through conversations with taxi drivers.; 4) Hospital barriers, illustrating that the organization of treatment in hospitals can create a barrier that significantly impacts the sense of safety and involvement among patients throughout the treatment process; 5) Preventive health literacy, revealed that several patients were unaware of the pathological mechanisms underlying nAMD and the preventive measures they themselves could take to prevent disease progression.

Paper II: We electronically distributed 713 invitations to participate in the survey and received 494 responses (69.3%). Among patient exempt from receiving electronic mail from public hospitals, 52 patients and 5 patients answered the questionnaire by phone interview and e-mail, respectively. Of the 551 responses collected, 16 were excluded due to no treatment or uncertainty about treatment with anti-VEGF, leaving 535 valid responses. Among these, 359 patients were currently undergoing treatment, while 176 had previously received treatment.

Paper III: We included 348 patients who had completed the MacDQoL questionnaire and were currently undergoing treatment for nAMD to evaluate the impact of nAMD on QoL. The overall median age was 79.2 years (IQR 75.0; 84.0), of which 58.3% were women. The patients experienced that nAMD had the greatest negative impact on how they enjoyed their leisure and hobbies (-2.07, 95% CI -2.35; -1.79), their thoughts about the future (-1.95, 95% CI -2.23; -1.68), and their independents including ability to manage daily activities without assistance (-1.87, 95% CI -2.16; -1.57). Conversely, nAMD had the least negative effect on their physical appearance regarding aspects such as clothing (-0.56, 95% CI - 0.72; -0.40), how patients perceive others' reactions toward them (-0.52, 95% CI -0.67; -0.36), and their financial situation (-0.16, 95% CI -0.25; -0.07).

In the adjusted linear regression, a higher average AWI score indicating a lower impact of nAMD on QoL was associated with BCVA in the better-seeing eye ≥0.5 (β: 1.75, 95% CI: 1.13; 2.37), preserved driving ability (β: 1.62, 95% CI: 1.10; 2.13), and perceiving a treatment effect (β: 0.71, 95% CI: 0.16; 1.27). In the crude analysis, men scored significantly higher than women (β: 0.36 95% CI: 0.15; 0.70), which was not significant in the adjusted linear regression (β: 0.30, 95% CI: -0.04; 0.64). Bilateral treatment was linked to a significantly lower AWI score, indicating a greater impact of nAMD on QoL (β: -0.44, 95% CI -0.79; -0.09). No significant correlations were found between age, duration of treatment, marital status, living situation, retirement status, or home-to-treatment travel time and the impact of nAMD on QoL.

Conclusion
Patients with nAMD undergoing anti-VEGF therapy demonstrate high adherence to treatment despite the demanding treatment process and few patients discontinue treatment against their doctor's advice. Many patients also express a willingness to participate in research.

Maintaining independence is crucial for patients, which is further reflected in the correlation between continued driving and higher nAMD-related QoL. Additionally, the lack of perceived treatment effect warrants further exploration for clinical applications. While some patients face commuting challenges, others find it unproblematic or even enriching. These findings align with our observations that travel time to hospital did not have a significant impact on how nAMD affected QoL. This provides important perspectives on the organization of the healthcare system, where recent debates have focused on whether certain aspects of nAMD treatment should be shifted to peripheral treatment centres, such as private ophthalmologists or decentralized hospital-operated treatment clinics. Future studies, including those based on these collected data, may help ensure that patients' perspectives remain central to the treatment process, maintaining low dropout rates even as direct interactions between patients and healthcare providers is gradually reduced.