The WHO has defined non-adherence as a major potential threat in the care of chronic diseases [
10]. However, eye diseases have not been specifically included in the current WHO analyses. This systematic review discusses factors involved in non-adherence and non-persistence in the treatment with intravitreal injections under real-life conditions. In the extracted publications, definitions of non-adherence and non-persistence differ depending on the study design, and similar endpoints may be called non-adherence or non-persistence in different publications. However, the high proportion of non-adherent and non-persistent patients with intravitreal injection therapy is a major limitation of this therapeutic option under real-life conditions, leading to inferior results in visual function [
9,
17,
56]. Thus, identification of risk factors for non-adherence is pertinent, and knowledge of these factors may contribute to an improvement in the care of patients in need of IVT therapy. While awareness of modifiable factors that can be addressed in daily clinical work may be of special importance, knowledge of unmodifiable factors may also be valuable to better advise the individual patient.
Unrealistic expectations may precipitate non-adherence
In this review, factors were grouped according to the five dimensions of adherence according to the WHO. Most evidence was found for the dimension “condition,” showing that
worse visual acuity at baseline and
unfavorable development of visual acuity were associated with non-adherence. Evidence for the factor “unfavorable development of visual acuity” was found in both the quantitative and qualitative analysis. This is intriguing since non-adherence itself may lead to inferior VA results and thus further precipitate non-adherence. Furthermore, the high rate of disappointment regarding the development of VA may be caused by unrealistic expectations, e.g., illustrated by the results of the interviews in the PONS study [
20,
48]: Although many patients were aware of the need for repeated examinations and treatments, the majority was not aware of the chronic nature of nAMD and hoped to gain visual acuity during the course of the treatment. This emphasizes the need to establish realistic expectations, and it underlines the importance of a sensible education by the care providers (physicians and nurses).
Differences between qualitative and quantitative analysis
There was no consistent association with
comorbidities, and the disparity between quantitative analysis (association only in one study [
55] and no association in two studies) and qualitative analysis (mentioned in 7 studies, Tab.
3) is noticeable. Non-adherent patients repeatedly listed comorbidity as a major contributing factor. The design of the majority of the studies was retrospective, and thus the disparity between them may be attributable to reporting bias or insufficient documentation, as well as differences in the definition. Reduced mobility, for example, with ensuing difficulties in attending regular appointments, may be regarded as an independent factor as well as the consequence of systemic comorbidity.
Considerable evidence was found for the dimension “socio-economy”: Higher age was associated with lower adherence, and financial burden was reported in several qualitative studies as a cause of non-adherence. Parameters of the “health system” (availability of and accessibility to medication and treatment capacity, relationship between attending physician and patient, availability of information) were repeatedly described in the qualitative analysis. Descriptive analysis of quantitative studies only showed limited evidence in the dimensions “therapy” (e.g., treatment protocols) and “patient” (e.g., patient knowledge of disease and treatment). In qualitative studies, high follow-up burden and high treatment burden were repeatedly cited as factors for non-adherence.
Particular barriers in intravitreal therapy compared with other chronic diseases
Although the included studies identified a variety of factors affecting non-adherence, only few of them are modifiable. In addition, some obvious factors encountered in clinical everyday life, such as patient accompaniment to therapy, were not addressed in studies at all. These factors are not directly conferrable to identified risk factors for low therapy adherence in other chronic diseases such as arterial hypertension [
63] or dyslipidemia [
64]. Due to the particular nature of the treatment, which includes repetitive surgical injections into the eye, it may be rather compared with treatments such as subcutaneous depot injection, although the psychological tension experienced by the patients and the organizational requirements (i.e., operating theater in some countries) are different and presumably cause greater strain. In this analysis, pain and discomfort have not been proven to be relevant risk factors, but studies focusing on pain and possible approaches to prevent discomfort during the injection procedure were not specifically included. While multiple studies concerning pain and discomfort have been published, these rarely address its effect on adherence (see Suppl.
2) [
65‐
67].
Addressing modifiable and unmodifiable risk factors in everyday practice
The literature research identified both modifiable and unmodifiable risk factors for non-adherence. Modifiable factors were in the “health system” dimension (such as center-dependent risk factors, including organization, availability of short-term appointments, or phone service) and the “patient” dimension (such as anxiety or fear, patient knowledge, and motivation). Addressing modifiable factors seems a feasible approach to improve adherence. Improving organizational processes may considerably reduce center-associated barriers. However, this may require considerable effort and reallocation of resources for the treatment center. For example, establishing a better level of accessibility via telephone may require additional personnel and thus may be limited by financial considerations.
In the “therapy” dimension, the design and complexity of therapy protocols were commonly raised by patients. For the average patient, treatment protocols with a better ability to plan appointments and reduce examination or control visits (such as fixed or TAE protocols) may be advantageous compared to PRN. However, individual patients may prefer different treatment regimes, and this places additional burdens on the organizational endeavors of the treatment centers. Treatment in one treatment center (as opposed to a referral system) is preferred by patients, and patients preferred a “one-stop clinic” (examination and injection on the same day) over a referral system [
57]. Treatment at one center was associated with less non-adherence in a German study [
48]. However, treatment networks offering the possibility of direct data exchange and a cooperative approach may provide a high level of patient satisfaction and good clinical results [
68,
69].
Many of the identified risk factors, such as age, involvement of the fellow eye, comorbidity, general education, or visual acuity at baseline, are unmodifiable, and a direct approach for improvement is not palpable. However, knowledge of these factors as potential barriers is crucial. Addressing and verbalizing them, together with clarifying the need for therapy to stabilize or improve visual function, may help to establish realistic expectations and thus improve adherence. Nevertheless, to date there are no outcome research studies exploring potential interventions to improve adherence in intravitreal therapy and thus therapeutic results. Interdisciplinary medical care, as typically carried out in diabetes care, may lead to improved results, when all care providers are aware of the necessary repetitive injections [
70]. In addition, it appears that repetitive patient education is necessary. A recent analysis showed that after a few weeks, patients do not remember important details about their disease, the treatment, and possible complications despite thorough information having been provided and informed consent having been obtained [
71]. This underlines the importance of repeatedly and regularly educating the patient, even during the course of the therapy.
Limitations and the need for systematic research
There are limitations of our study. The analysis of factors associated with non-adherence has the inherent difficulty of being biased. Data may not be available at the point when non-adherence occurs, and in chronic (chorio-)retinal diseases, reasons for non-adherence may change or develop during the course of treatment. It is possible that practitioners do not allow insights that might make them appear in an unfavorable light. Hidden or insufficiently researched factors are not and cannot be found even in a meta-analysis. In this review, we analyzed studies with quantitative data, e.g., statistical calculations and association analysis, as well as studies with qualitative data, e.g., from patient interviews. Factors from all dimensions as defined by the WHO were identified in quantitative or qualitative analysis. For some factors, such as higher age, development of visual acuity, or greater distance to the treatment center, there was consistent and quantitative evidence in multiple studies. Some factors, however, were only identified in qualitative analysis, such as fear of adverse events or pain, or treatment burden.
Most of the studies analyzed patients with age-related macular degeneration, while only a few studies included patients with diabetic macular edema (DME) or retinal vein occlusion as subgroups. Although patients with DME seem to be more prone to become non-adherent, there is insufficient quantitative data to identify significant attributable factors [
16,
17]. One study found that the reasons for non-adherence between patients with DME and nAMD were similar, although a significantly higher proportion of patients with DME gave “no explanation” at all for non-adherence in a telephone interview [
16]. As patients with DME are younger in average than nAMD patients, conflicts with work or other appointments may present a greater barrier in this population. In addition, the minority of the overall healthcare visits (mean of 29 visit days per year) were due to eye care-related visit days, indicating the complex comorbidity profile and their care in diabetic patients with DME [
72].
The majority of the included studies were retrospective, and the study designs varied with regard to the time of data extraction, time and mode of interviews, or even definition of non-adherence (see Table
1). Until now there has been no uniform definition of non-adherence or non-persistence which has contributed further to divergent findings. The most identified publications were from Europe, especially from Germany; thus, results are not directly transferable to other healthcare systems. Healthcare systems themselves differ considerably from one other, and this may have led to different treatment adherence [
7], i.e., between European countries, or to different selection of patients receiving therapy. This can be seen in data from the AURA study: In the UK, patients are followed by a strict control and treatment regime, while treatment in other European countries, such as Germany, followed more individual and variable treatment plans. This, however, resulted in a significant lower number of OCT scans and IVT treatments in Germany, and clinical results were inferior to those in the UK [
7]. Endeavors have been made to establish methods for the early detection of potential barriers, e.g., by early implementation of questionnaires in the management protocol [
73]. However, it still remains to be evaluated whether this knowledge can be transferred into daily care and improve adherence and clinical results under everyday conditions.
The field of non-persistence seems to be a subject that is still completely underexposed. Of course, it is a very special problem to assess patients and their parameters which do not even appear in the routine. The deceased can no longer be interviewed; others with non-persistence may also be more critical of scientific surveys. Nevertheless, the knowledge of the poor outcome in the spontaneous course of the disease gives an idea of how important it is to avoid the termination of a necessary therapy as the maximum form of undertreatment.