Causes of Treatment Discontinuation in Retinal Diseases Treated with Intravitreal Injections

Abstract

Purpose To determine the most common reasons for treatment discontinuation in patients with retinal diseases undergoing intravitreal injections (IVI s).

Methods A retrospective study was conducted with all patients who underwent IVI therapy in our Department of Ophthalmology between January 2016 and January 2024. We investigated the reasons for therapy discontinuation, including non-persistence (declining therapy). Patients who declined therapy (non-persistence) were compared with the remaining patients to determine the potential factors responsible for their decision.

Results The mean age of the 2218 patients (1155 women, 1063 men) who took part in the study was 77.6 ± 12.0 years. A total of 1029 patients (46.4%) achieved a dry macula in both eyes at the time of the study. Treatment was discontinued in 865 patients (39%) due to poor prognosis (visual acuity < 1.3 logMAR) (188, 8.4%), change to another medical centre (175, 7.9%), comorbid systemic diseases (128, 5.7%), loss of contact (128, 5.7%), financial problems with health insurance (13, 0.5%) or death (59, 2.6%), while 174 patients (7.8%) declined IVI therapy (non-persistence). Compared to the other patients, non-persistence patients were significantly older (76.2 ± 12 vs. 81.2 ± 11, p < 0.001), had significantly worse visual acuity (logMAR) at the last visit (0.50 ± 0.5 vs. 0.29 ± 0.2, p = 0.001), received a significantly higher number of IVI s (10 ± 11 vs. 14 ± 15, p < 0.001) and had a significantly higher proportion following the pro re nata treatment protocol (59% vs. 72%, p = 0.001).

Conclusion The most common reason for treatment discontinuation was the poor prognosis, which related to the nature of macular diseases. Advanced age, higher number of injections, pro re nata protocol and reduced visual acuity during therapy were identified as factors that affected patient non-persistence to treatment.

Zusammenfassung

Zweck Es sollten die häufigsten Gründe für einen Behandlungsabbruch bei Patienten mit Netzhauterkrankungen ermittelt werden, die sich einer intravitrealen Injektion (IVI) unterziehen.

Methoden Es wurde eine retrospektive Studie mit allen Patienten durchgeführt, die sich zwischen Januar 2016 und Januar 2024 einer IVI-Therapie in unserer Klinik für Augenheilkunde unterzogen. Wir untersuchten die Gründe für den Therapieabbruch einschließlich der Nicht-Persistenz (Therapieabbruch). Anschließend wurden die Patienten, die eine Therapie ablehnten (Nicht-Persistenz), mit den übrigen Patienten verglichen, um die möglichen Faktoren zu ermitteln, die für ihre Entscheidung verantwortlich waren.

Ergebnisse Das Durchschnittsalter der 2218 Patienten (1155 Frauen, 1063 Männer), die an der Studie teilnahmen, betrug 77,6 ± 12,0 Jahre. Insgesamt 1029 Patienten (46,4%) wiesen zum Zeitpunkt der Studie eine trockene Makula in beiden Augen auf. Die Behandlung wurde bei 865 Patienten (39%) aufgrund einer schlechten Prognose (Sehschärfe < 1,3 logMAR) (188, 8,4%), eines Wechsels in ein anderes medizinisches Zentrum (175, 7,9%), komorbider Systemerkrankungen (128, 5,7%), eines Kontaktverlusts (128, 5,7%), finanzieller Probleme mit der Krankenversicherung (13, 0,5%) oder des Todes (59, 2,6%) abgebrochen, während 174 Patienten (7,8%) eine IVI-Therapie ablehnten (Nicht-Persistenz). Im Vergleich zu den anderen Patienten waren die Nicht-Persistenz-Patienten signifikant älter (76,2 ± 12 vs. 81,2 ± 11; p < 0,001), hatten eine signifikant schlechtere Sehschärfe (logMAR) bei der letzten Visite (0,50 ± 0,5 vs. 0,29 ± 0,2; p = 0,001), erhielten eine signifikant höhere Anzahl von IVI s (10 ± 11 vs. 14 ± 15; p < 0,001) und hatten einen signifikant höheren Anteil, der dem Pro-re-nata-Behandlungsprotokoll folgte (59% vs. 72%, p = 0,001).

Schlussfolgerung Der häufigste Grund für den Abbruch der Behandlung war die schlechte Prognose, die mit der Art der Makulaerkrankung zusammenhing. Fortgeschrittenes Alter, eine höhere Anzahl von Injektionen, das Pro-re-nata-Protokoll und eine reduzierte Sehschärfe während der Therapie wurden als Faktoren identifiziert, die sich auf die Nicht-Persistenz der Behandlung auswirkten.

Keywords

anti-VEGF therapy - retinal diseases - persistence - adherence - intravitreal injection

Schlüsselwörter

Anti-VEGF-Therapie - Netzhauterkrankungen - Persistenz - Adhärenz - intravitreale Injektion

Introduction

Over the past two decades, the injection of various medications into the vitreous cavity has been the most important and effective option for treating a variety of vitreoretinal diseases.

Currently, intravitreal injection (IVI) has become the most common intraocular outpatient procedure in Germany [1], [2].

Consequently, IVI of anti-VEGF agents and steroids are currently recognized as the gold standard for the treatment of macular edema in various diseases. Currently, five anti-VEGF agents and two steroid agents are approved in Europe and the USA for the treatment of macular diseases: ranibiziumab, aflibercept 2 mg/8 mg, faricimab, ranibizumab biosimilar, brolucizumab, dexamethasone and fluocinolone. In addition, bevacizumab and triamcinolone are used “off-label” worldwide.

Despite the huge development of this treatment in the last few years, there are still some serious challenges related to the chronic nature of macular diseases, which requires regular monitoring and long-term therapy with high frequency of injections. This may be burdensome in the real world and will therefore make IVI therapy highly dependent on the adherence of patients [3].

As defined by the World Health Organization (WHO), adherence to long-term therapy is the extent to which an individualʼs behaviour – taking medication, following a diet and/or making lifestyle changes – is consistent with agreed recommendations from health care providers [4]. However, it is important to distinguish between “adherence” and “persistence” [5].

In other words, non-adherence means failing to follow recommended therapeutic regimens, such as “missed appointments” or “irregular attendance”, whereas non-persistence refers to patients deciding to stop treatment against the prescriberʼs recommendation [3].

In this context, there are many factors that lead to treatment discontinuation. First, the medical or healthcare system, represented by the availability of appointments, then socio-economic issues such as cost and reimbursement problems, difficulties in visiting the doctorʼs office, not to mention the patientʼs general health and co-morbidities. The nature of the disease can also play a role, in case of lack of success or hope, besides the anxiety of the therapy or its side effects [6].

In response to these difficulties and in order to improve the service provided to IVI patients, a separate centre for IVI was established at our department in 2016 [2].

This special outpatient center treats patients with neovascular age-related macular degeneration (nAMD), macular edema (ME) in diabetes mellitus (DME), retinal vein occlusion (RVO) and uveitis (UME), myopic choroidal neovascularization (mCNV), proliferative diabetic retinopathy (PDR) and CNV caused by rare diseases (rCNV). Our (IVI) treatment is carried out by a specialized team of doctors strictly in accordance with the scientific guidelines of the German Society of Ophthalmology (DOG), the Retinological Society and the German Association of Ophthalmologists (BVA).

After a few years, this designated centre proved to be an extremely useful and beneficial one-stop centre (IVI carousel) for patients requiring IVI and macular consultations. It offered a shorter route for the often elderly or disabled patients, less time for treatment and an improved patient-doctor relationship [2]. Moreover, this center was enlarged in 2023 due to the increase in IVI patients, which required an additional larger working area, in particular a second operating theatre. However, issues of adherence and persistence to treatment are still considered a reliable challenge in our centre.

In this study, we aimed to identify the most common reasons for treatment discontinuation in patients with retinal diseases undergoing IVI treatment and then focus on one of these reasons, namely non-persistence, and try to identify factors that influence it.

Methods

In this retrospective study we reviewed the medical records of all patients, who underwent IVI therapy in our Depatrment of Ophthalmology between January 2016 and January 2024.

At baseline, all eyes underwent a general eye examination, including a decimal best corrected visual acuity (BCVA) test, dilated funduscopy, colour fundus photography, fluorescein angiography (FA) (HRA-2; Heidelberg Engineering, Inc, Heidelberg, Germany) and Spectralis optical coherence tomography (SD-OCT; Heidelberg Engineering, Heidelberg, Germany). At each visit in follow up, a BCVA test, funduscopy and SD-OCT were performed in all patients.

All eyes with macular edema caused by nAMD, DME, RVO, mCNV and rCNV and PDR were treated initially with intravitreal anti-VEGF injections. Eyes with UME were initially treated with intravitreal steroids. Retreatment was then carried out depending on reactivity following a Pro re nata (PRN) or Treat and Extend (T&E) regimen. In case of non-response, therapy was switched to other agents. Using the search engine integrated program in the electronic documentation system FIDUS (Arztservice Wente GmbH, Darmstadt) [7], [8], we extracted from the electronic medical records the data of all patients who received IVI therapy in our Department of Ophthalmology between January 2016 and January 2024. These included:

• Patient demographics and ocular characteristics, including age, gender, occupation, type of insurance, home address, diagnosis, switch in therapy, intravitreal agents administered, number of IVI s per eye and BCVA (logMAR) at first and last visit

• Current treatment status, which categorized patients into 3 main groups

  • Treatment success including patients who had achieved a dry macula in both eyes over 6 months at the time of the study.

  • Ongoing therapy

  • Discontinuation of treatment

• The reasons of treatment discontinuation, including

  • poor prognosis due to extremely reduced BCVA (< 1.3 logMAR)

  • change to another medical center

  • comorbid systemic diseases (non-adherence)

  • financial problems with health insurance

  • death

  • non-persistence in treatment (deciding against the doctorʼs recommendation to discontinue treatment).

All patients who experienced a ‘loss to follow-up’ were contacted by telephone to determine the reason.

The demographic and ocular characteristics of patients who declined treatment (non-persistence) were then compared with those of the remaining patients to determine the factors responsible for their decision.

Statistical analysis

Data was collected using Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA, USA). IBM SPSS version 27 was used for statistical analysis. Continuous data are presented as mean±standard deviation. Categorical data were summarized as frequencies and percentages. Comparisons between demographic and ocular characteristics were performed by independent Studentʼs t, Mann–Whitney rank sum, Fisherʼs exact, or χ2 tests, where appropriate. Results were considered statistically significant if the P value was < 0.05.

Informed consent statement

For this type of retrospective study, formal consent is not required. However, all patients were informed in detail about this therapy and signed a written consent form, which also included the right to refuse the use of their data for scientific purposes in general.

Results

Demographics and ocular characteristics

A total of 2750 eyes of 2218 patients were included in the present study. The average age of the patients was 77.6 ± 12.0 years. 52% of the patients (n = 1155) were female. Most patients (1902, 85%) were retired. A therapy switching was required in 777 eyes (35%). The most common first intravitreal agent administered was bevacizumab in 1791 (63%). On average, 13.3 ± 14.0 IVI s were administered per eye. The BCVA in logMAR was 0.54 ± 0.4 at the first visit and 0.64 ± 0.5 at the last visit. The baseline characteristics of all patients are summarized in [Table 1].

Table 1 Demographic and ocular characteristics for all patients, who underwent intravitreal injections (IVI s) therapy in our designated center for intravitreal injections between January 2016 and January 2024.

2 750 eye from 2 218 patients	Number	Percent %
IVI: intravitreal injection, IVB: intravitreal bevacizumab, IVR: intravitreal ranibizumab, IVA: intravitreal aflibercept, IVD intravitreal dexamethasone, BCVA: best corrected visual acuity
Bilateral therapy	532	19.3
Unilateral therapy	2 218	80.7
Male : Female	1 063 : 1 155	48 : 52
Age (years)	77.6 ± 12
Job	1 902 retired	85
Therapy switching	777	35
First applied medications (IVB : IVR : IVA : IVD)	1 791 : 605 : 312 : 101	63 : 21 : 11 : 4
IVI number per eye	13.3 ± 14
BCVA (logMAR) before → after treatment	0.54 ± 0.4 → 0.64 ± 0.5

The most common diagnosis was nAMD (1100 eyes, 50%), followed by ME due to RVO (521 eyes, 23%), then DME (395 eyes, 18%), mCNV (76 eyes, 3%), UME (57 eyes, 3%), rCNV (40 eyes, 2%) and PDR (29 eyes, 1%; [Table 2]).

Table 2 The distribution of the initial diagnoses: neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), macular edema (ME) in retinal vein occlusion (RVO) and uveitis (UME), myopic choroidal neovascularization (mCNV), CNV caused by rare diseases (rCNV) and proliferative diabetic retinopathy (PDR).

Diagnoses	Number of eyes	%
nAMD	1 100	50
DME	395	18
RVO	521	23
UME	57	3
rCNV	40	2
mCNV	76	3
PDR	29	1

In general, 66.7% of patients lived within 15 km of the IVI centre, while 16% of patients had to travel more than 45 km for each visit ([Table 3]).

Table 3 Proximity of patientsʼ place of residence to our designated center for intravitreal injections.

Zone	Patientsʼ place of residence	Number	Percent %
1	Central 5 km	556	25.1
2	5 – 15 km	922	41.6
3	15 – 25 km	240	10.8
4	25 – 45 km	137	6.2
5	More than 45 km	363	16.4
	Total	2 218	100.0

Therapy follow-up ([Fig. 1])

Fig. 1 Summary of the study results.

• Therapy success: a total of 1029 patients (46.4%) achieved a dry macula in both eyes over 6 months at the time of the study and required no further IVI therapy,

• Ongoing therapy: 323 patients (14.6%) are currently still undergoing therapy.

• Discontinuation of treatment: 865 patients (39%) discontinued therapy due to:

  • poor prognosis by extremely reduced BCVA (< 1.3 logMAR; 188, 8.4%)

  • change to another medical center (175, 7.9%)

  • comorbid systemic diseases (non-adherence; 128, 5.7%)

  • loss of contact (128, 5.7%)

  • financial problems with health insurance (13, 0.5%)

  • death (59, 2.6%)

  • non-persistence to treatment (174, 7.8%) (they decided to discontinue treatment against the doctorʼs recommendation).

Compared to the other patients, non-persistence patients (n = 174, 7.8%) were significantly older (76.2 ± 12 vs. 81.2 ± 11, p < 0.001), had significantly worse visual acuity (logMAR) at the last visit (0.50 ± 0.5 vs. 0.29 ± 0.2, p = 0.001), received a significantly higher number of IVI s (10 ± 11 vs. 14 ± 15, p < 0.001) and had a significantly higher proportion following the pro re nata treatment protocol (59% vs. 72%, p = 0.001; [Table 4]).

Table 4 The demographic and ocular characteristics of patients who declined treatment (non-persistence) compared to the remaining patients

	Remaining patients	Non-persistence	p-value
Place of residence zone (1: central 5 km, 2: 5 – 15 km, 3: 15 – 25 km, 4: 25 – 45 km, 5: more than 45 km), nAMD: neovascular age-related macular degeneration, DME: diabetic macular edema, RVO: retinal vein occlusion, IVI: intravitreal injection, PRN: pro re nata, T&E: treat and extend, BCVA: best corrected visual acuity
Number of patients	2 044 (92.2%)	174 (7.8%)
Place of residence zone (1 : 2 : 3 : 4 : 5)	514 : 803 : 213 : 125 : 359 (25 : 39 : 10 : 6 : 20%)	42 : 84 : 27 : 12 : 9 (24 : 48 : 16 : 7 : 5%)	0.11
Male : Female	981 : 1 062 (48 : 52%)	71 : 103 (41 : 59%)	0.05
Age (years)	76 ± 12	81 ± 11	< 0.001
Diagnosis (nAMD : RVO : DME : Other)	1 020 : 412 : 408 : 204 (49 : 21 : 20 : 10%)	94 : 34 : 30 : 14 (54 : 20 : 18 : 8%)	0.51
Therapy switching	450 (22%)	49 (28%)	0.07
Duration of treatment (years)	2.3 ± 2.3	2.2 ± 2.3	0.76
IVI s number per eye	10 ± 11	14 ± 15	< 0.001
Treatment protocol (PRN : T&E)	1 224 : 820 (59 : 41%)	125 : 49 (72 : 28%)	0.001
BCVA (logMAR) before therapy	0.40 ± 0.5	0.40 ± 0.2	0.84
Last BCVA (logMAR)	0.50 ± 0.5	0.71 ± 0.2	< 0.001

The reasons for treatment discontinuation were analyzed depending on the pathology (“initial therapy diagnosis”). The percentage of patients diagnosed with RVO and PDR was significantly higher in the group of patients who discontinued treatment due to poor prognosis. The percentage of patients with DME was significantly higher in patients who discontinued treatment due to comorbid systemic disease or loss of contact. The initial diagnosis had no significant impact on other reasons for treatment discontinuation including non-persistence ([Table 5]).

Table 5 Reasons of treatment discontinuation according to initial therapy diagnoses.

	nAMD	DME	RVO	UME	rCNV	mCNV	PDR	p-value	Total
The initial diagnoses: neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), macular edema (ME) in retinal vein occlusion (RVO) and uveitis (UME), myopic choroidal neovascularization (mCNV), CNV caused by rare diseases (rCNV) and proliferative diabetic retinopathy (PDR); p-value refers to the difference between the initial diagnoses
Death	40	8	11	0	0	0	0	0.08	59
	9.1%	5.3%	5.3%	0.0%	0.0%	0.0%	0.0%		6.8%
Poor prognosis	95	19	52	8	2	6	6	0.001	188
	21.7%	12.5%	24.9%	40.0%	14.3%	35.3%	40.0%		21.7%
Non-persistence	96	29	34	5	3	3	4	0.11	174
	21.9%	19.1%	16.3%	25.0%	21.4%	17.6%	26.7%		20.1%
Comorbid systemic diseases	68	33	23	1	0	3	0	0.02	128
	15.5%	21.7%	11.0%	5.0%	0.0%	17.6%	0.0%		14.8%
Loss of contact	51	33	31	2	4	4	3	0.002	128
	11.6%	21.7%	14.8%	10.0%	28.6%	23.5%	20.0%		14.8%
Finacial problems	6	5	1	1	0	0	0	0.18	13
	1.4%	3.3%	0.5%	5.0%	0.0%	0.0%	0.0%		1.5%
Change to another center	82	25	57	3	5	1	2	0.05	175
	18.0%	14.5%	26.3%	15.0%	28.6%	5.9%	6.7%		19.1%
Total	438	152	209	20	14	17	15		865

The reasons for treatment discontinuation were analyzed depending on the time period. The most common reason for therapy discontinuation before 2020 was non-persistence, and after 2020 was changing to another center ([Table 6]).

Table 6 Reasons for treatment discontinuation before and after 2020.

%	Death	Poor prognosis	Non-persistence	Comorbid systemic diseases	Loss of contact	Financial problems	Change to another center
Before 2020	13	22	23	13	14	1	14
After 2020	6	18	18	19	13	1	25

Discussion

In this study, 865 patients (39%) discontinued treatment. Extremely poor prognosis was the most common reason. On the other hand, one of the commen reases was non-persistance to treatment, which was influenced by many factors such as older age and lower visual acuity during IVI therapy.

In this context, recent systematic reviews have examined non-adherence and non-persistence to anti-VEGF treatment regimens specifically in nAMD and DME [9], [10]. All of them indicated the necessity to explore the reasons for treatment discontinuation and non-persistence and to define strategies to overcome these challenges.

To date, discontinuation of IVI therapy has not been clearly identified, with a range of factors such as patient preference, economic issues, social and clinical problems being cited.

Due to the different concepts of non-adherence, there was also a wide variation in non-adherence rates in the literature, ranging from 15% to 95% [3], [11], [12].

On the other hand, non-persistence rates were less variable in the literature (3% to 34%). This could be due to the fact that non-persistence could be more clearly defined as a primary patient decision. Many factors affecting non-persistence have been reported in the literature, such as dissatisfaction with treatment, advanced age, difficulty in making appointments, lack of improvement, fear of injections, greater distance to clinic, unilateral eye disease, loss of motivation, lack of hope due to extremely reduced visual acuity beside personal factors [3], [13]. This may be consistent with our study, which reported a non-persistence rate of 7.8%, in which the patient was the primary decision-maker to cease treatment, and found also advanced age, increased number of IVI s, following PRN protocol and loss of visual acuity during treatment as main factors for non-persistence.

In this study, it was remarkable that patients with non-persistence underwent significantly more IVI s (14 vs. 10) in the same period (approx. 2 years) of treatment, but had a significantly worse BCVA (0.4 vs. 0.7) at the end of the treatment. This clarifies why poorer visual acuity during treatment was associated with non-persistence.

Depending on the chronic nature of retinal diseases such as nAMD, most studies showed that an average gain in visual acuity could only be achieved during the loading phase, but this could not be maintained over time, while multiple treatments with anti-VEGF-IVI were often required to achieve no deterioration in visual acuity [14], [15], [16], [17], [18], [19]. This may lead to unrealistic expectations for patients and ultimately to dissatisfaction and non-persistence to treatment [20], [21].

This emphasizes the importance of the initial visit, which should be used to provide patients with realistic expectations. Therefore, the chronicity of the disease, complications during treatment, the possible lifelong duration of treatment and burdens of consistent therapy should be explained openly and clearly.Furthermore, it is advisable to keep the patient informed throughout the treatment and discuss the individual course of the disease with the patient and involve him/her in the treatment steps and decisions, like an extension of the treatment interval or a switch to a different medication. Good patient education before, during and after treatment can facilitate treatment management. For example, it is useful to explain that the achievement of stabilization of visual acuity is a therapeutic success [6], [22].

The reported treatment success rate of 46% appears higher than that of other published cohorts, which typically report rates of 20 – 35%, depending on the diagnosis and treatment agent [23]. This discrepancy may be due to differences in patient selection, treatment protocols, or definitions of “treatment success.” In this study, success was defined as achieving macular dryness in both eyes over a 6-month period at the time of evaluation.

Compared to the other patients, non-persistence patients had a significantly higher proportion following the pro-re-nata treatment protocol (59% vs. 72%, p = 0.001). This could be explained by the fact that the targeted reduction in the number of intravitreal injections in the PRN protocol was not associated with a reduction in visits. Monthly examinations with monthly OCTs are still needed. Thus, this study may support the reported advantages of the T&E protocol over other treatment protocols, such as better disease stability, better patient adherence, and better management of the surgical schedule [24].

Although the difference in proximity of patientsʼ residence to our center for intravitreal injections between the two study groups was not significant, this was cited in the literature as one of the most common factors for non-persistence [3], [25]. This could be related to the fact that just 16% of our patients live further than 45 km from our treatment center, in addition to the high density of centers performing IVI s in our region.

An important reason for treatment discontinuation is the financial burden. This is probably more common (up to 40%) in other countries where patients are expected to contribute to the cost of treatment [26], [27]. In our study, this was extremely rare (only 0.5%), as in other European studies, e.g. in Austria (2.9%) [28], where the healthcare systems are still able to provide comprehensive healthcare.

As already mentioned, some patients experienced a “loss to follow-up”. All of these patients were contacted by telephone to determine the reason. Nevertheless, we were unable to reach 128 of them (5.7%) who were categorized under “loss of contact” as a cause of treatment discontinuation and to avoid any confounding, we did not classify them as non-persistence.

The main potential limitations of our study were the retrospective nature of the work, a population from a single medical center, making its results regional, and they cannot be generalized to the general population, besides the fact that a relatively short time period was taken. Therefore, studies with a much larger sample size and a longer time period are needed for a better understanding of these real-world challenges.

Conclusions

The most common reason for treatment discontinuation was the poor prognosis, which related to the nature of macular diseases. Advanced age, higher number of injections, pro re nata protocol and reduced visual acuity during therapy were identified as factors that negatively affected patient persistence to treatment.

Conclusion Box

Already known:

• Discontinuation of treatment with intravitreal injections is still a major challenge in daily practice.

Newly described:

• The poor prognosis (visual acuity < 1.3 logMAR) was the most common reason for treatment discontinuation.

• Non-persistence to treatment (declining therapy) is not an uncommon reason for treatment discontinuation.

• Many factors have an impact on patient non-persistence to treatment, including advanced age, higher number of injections, following pro re nata protocol and reduced visual acuity during treatment.

Conflict of Interest

Financial interests: Abdin AD has received speaker honoraria from Novartis and Bayer Companies. Other authors declare they have no financial interests. Non-financial interests: none.

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Publication History

Received: 12 February 2025

Accepted: 05 August 2025

Article published online:
01 September 2025