Short summary

The overall goal of I-OPTA is to investigate the challenges and barriers patients in treatment for neovascular age-related macular degeneration (nAMD) face. We want to do this from a patient perspective using e.g. patient panel, interview and questionnaire survey. In addition, we aim to investigate in a registry based cohort study whether there is an increased mortality and morbidity associated with the treatment for nAMD with intravitreal anti-VEGF injection.

Rationale

Background: The introduction of intravitreal angiostatic therapy has revolutionized the treatment of neovascular age- related macular degeneration (nAMD) and halved the number of newly blind people over 50 years of age. In Denmark, around 14000 patients receive treatment for nAMD every 4 to 12 week. Barrier associated with nAMD treatment has previously been reported as the injection therapy itself and one Danish study found that up to 20% of patients in injection therapy opted out within the first two years for non-medical reasons. One Danish study on cardiac rehabilitation participation demonstrated that long commute, comorbidity, marital status, and socioeconomic position are barriers that contribute to non- participation. However, treatment adherence patterns from one disease cannot necessarily be extrapolated to another. Thus, we do not know if the same barriers exist among patients with nAMD, but we hypothesize that this, at least to a certain degree, may also apply to patients with nAMD. There is a need for an in-depth exploration of the nAMD patient group and the barriers they experience to be able to identify patients at risk of not seeking consultations at the hospital and to target individual courses of the treatment to achieve the optimal outcome for the patient and prevent loss of vision.

Aim: Our main objective is to fill this crucial gap of knowledge by examining how we can prevent patients with nAMD from interrupting their recommended therapy and, thereby, reduce the risk of loss of visual acuity. Further, we aim to examine the treatment-induced risk of systemic morbidity and mortality and explore whether this may influence the approach of the patients to the treatment.

Methods: This PhD-project is a 36 months mixed method study including qualitative methods, a survey and register-based analyses from Danish national registers. We have planned two work packages (WP1 and WP2) to examine potential patient-reported barriers of following the recommended treatment regimen for nAMD and to accept potential risks of treatment-induced side effects. Each of the work packages includes two phases (A and B). We aim to bridge qualitative and quantitative information using mixed methods to obtain a more qualified knowledge of patients with nAMD and to create a broader understanding of their experienced barriers and health literacy in order to engage in the management of their disease. We already work closely together with our advisory board including five patients receiving intravitreal angiostatic therapy for nAMD and private ophthalmologists. We will continue this collaboration throughout the entire study period.

The study population: The study population includes Danish-speaking patients at age ≥ 70, diagnosed with nAMD who had received at least one intravitreal injection. The intention is to collect qualitative and quantitative data from patients with nAMD in at least one eye to compare the results according to progression of nAMD. In the register-based study, we will compare nAMD patients with a matched control group of individuals not diagnosed with nAMD to estimate the risk of systemic morbidity and mortality due to intravitreal angiostatic injections.

Recruitment: WP1-A and WP2-B: Patients from Departments of Ophthalmology at Odense University Hospital and Zealand University Hospital in Roskilde will be invited to participate in an interview (n=30) when they visit one of the two departments for scheduled eye examinations or intravitreal treatment for nAMD. WP1-B: From the Danish National Patient register, we will identify all patients with nAMD in Denmark and invite them to participate in a questionnaire (n=14000). Patients with nAMD and any known severe mental disorder or dementia will be excluded as eligible patients. Written information materials and audio files to patients with low visual acuity will introduce the project.

WP1: Exploratory sequential mixed method study

Aim: To explore patient-reported barriers of seeking and receiving recommended therapy for nAMD.

Rationale: Although we know that some patients do not adhere to the recommended treatment regime for nAMD, it is undefined if they stop or omit the treatment for a longer period due to barriers like lack of knowledge of the disease, delayed diagnosis, the treatment itself, distance from home to hospital or the commute to the many visits at the hospital. Thus, it is essential to examine the barriers and if they are modifiable and whether individual, treatment courses can be developed to prevent patients from interrupting their recommended treatment and, thereby, prevent a negatively affected long-term outcome in nAMD patients.

WP1-A: Qualitative study We plan to conduct a qualitative study using semi-structured interviews, where the interview guide will be developed in collaboration with the PPI. The intention is to involve 30 patients with nAMD in an open-ended interview to report their experiences and barriers to be diagnosed and receive treatment. The interviews will be used to develop WP1-B, as the patient-reported barriers identified in interviews will be used to build and refine the questionnaire.

WP1-B: Quantitative study

We plan to invite all patients in treatment for nAMD in Denmark to participate in a survey through E-boks. The questionnaire's content will partly emerge from themes from the interviews as well as barriers earlier found in the literature. Where possible, we will include already validated measuring instruments to measure relevant factors such as understanding and using health information (health literacy), the emotional impact of nAMD, depression, anxiety, and disease severity.

WP2: Explanatory sequential mixed method study

Aim: To identify potential long-term systemic risks in treating nAMD with injection therapy and explore patient views of potential systemic risks along with patient's health literacy to understand to what extend health literacy may act as potential barriers to the injection therapy.

Rationale: While studies have indicated that optimized visual outcomes are found in patients treated continuously with short injection intervals, concerns have been raised as to whether intensified intravitreal treatment of nAMD with vascular endothelial growth factor (VEGF) inhibitors may result in systemic morbidity and mortality among vulnerable patients. While there have not been any definite safety concerns in registration trials, these are seldom powered to detect subtle signals. Patients in such trials are generally healthier than average population with nAMD, which is often frail and of high age. While the eye is often regarded as an isolated immune privileged system, systemic exposure can be detected after intravitreal injection. In Denmark, aflibercept and ranibizumab are the two major VEGF inhibitors used to treat nAMD. In particular, aflibercept leads to a high systemic exposure (up to 37-fold higher than ranibizumab), with measurable suppressions of plasma free VEGF for more than seven days. As VEGF is a necessary signaling molecule that affects the body's vascularizing functions, continuous suppression in intensively treated patients may lead to systemic disease. Clinical proof-of-concept for this theory has been provided in diabetic macular edema, which is another retinal disease treated by intravitreal VEGF-inhibitors. In a systematic review, Avery et al demonstrated a 3-fold higher risk of mortality in patients intensively treated with aflibercept or ranibizumab. However, we do not know, if these findings translate into patients with nAMD, and if they are representative for Danish patients. Likewise, it would be important for future guidelines to know if the potential risk of mortality and systemic morbidity is dose-response dependent, and if it differs between aflibercept and ranibizumab, as could be expected given the notable differences in systemic exposure for these two agents

WP2-A Register-based study

The register-based study will be completed as a matched cohort study, where we will use data from national registers to identify cases, outcome and covariates. We will use data from the Danish National Patient registers to identify cases. Cases will be defined as patients in Denmark who have been diagnosed with nAMD and have received intravitreal therapy for nAMD between 2010 and 2020. Index date will be defined as the date of the first intravitreal angiostatic therapy. Cases will be matched 1:10 by sex and birth year with controls. Outcome measures will be defined as death, cerebrovascular infarction, myocardial infarct, retinal artery and venous occlusion.

WP2-B Qualitative study The findings from the register-based study in WP2-A, will guide the development of the interview guide for the planned qualitative study in WP2-B. If our register-based study indicates potential side effects because of the injection therapy, we will examine which side effect that the patients perceive as acceptable to maintain their recommended treatment and prevent loss of visual acuity. We expect to invite 30 patients with nAMD to participate in the semi-structured interviews

Mixed methods: This study uses two sequential mixed methods designs. In WP1, we will use an exploratory sequential mixed methods design where the findings from interviews (WP1-A) will guide the questions included in the questionnaire (WP1-B). For WP2, we will use an explanatory sequential mixed method design where the findings from the register-based study (WP2-A) will guide the question that we ask the participants (WP2- B). Analyses of the qualitative and quantitative data will be performed separately and integrated into mixed method analyses at the end of each WP. We will match up, merge and weave data together in joint displays (i.e. visual displays integrating qualitative and quantitative findings), 'data-fit' between qualitative and quantitative findings will be assessed as confirmation, expansion or discordance and meta-inferences concluded.

Description of the cohort

Interviews: Patients in treatment with anti-VEGF for nAMD From Odense University Hospital or New Zealand University Hospital. Questionnaire survey: Every patient with nAMD in Denmark.

Collaborating researchers and departments

Department of Ophthalmology, Rigshospitalet, University of Copenhagen

• Professor Morten Dornonville de la Cour
• Phd Yousif Subhi

Department of Ophthalmology, Zealand University Hospital, Roskilde

• Professor Torben Lykke Sørensen

Department of Ophthalmology, OUH

• Head of Department Gerda Møller
• Professor Jakob Grauslund

University College Copenhagen

• Associate professor Maria Kjøller Pedersen

OPEN, OUH & Department of Clinical Research, SDU

• Associate professor Lonny Stokholm
• Associate professor Lars Morsø
• Associate professor Søren Møller