The impact of financial affordability on patient adherence to the dosing schedule of Anti-Vascular Endothelial Growth Factor in managing Diabetic Macular Edema.

doi:10.21203/rs.3.rs-4516212/v1

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The impact of financial affordability on patient adherence to the dosing schedule of Anti-Vascular Endothelial Growth Factor in managing Diabetic Macular Edema.

https://doi.org/10.21203/rs.3.rs-4516212/v1

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Purpose:

Regular maintenance dosing of Intravitreal anti-VEGF (anti-vascular endothelial growth factor) for Diabetic Macular edema (DME) poses a challenge for patients. We investigated whether financial affordability plays a role in influencing patients' adherence to the prescribed dosage schedule.

Methods:

In this prospective, interventional, comparative, cohort study of 12 months duration, naïve DME patients were enrolled in 3 groups. Group I: self-paying patients. Group II: patients with medical insurance. Group III: patients treated free of charge. The treatment regimen was 3 consecutive monthly injections followed by monthly visits and anti-VEGF injections as needed (pro re nata, PRN).Two indicators were measured. First, how many did not complete the loading dose phase and second, adherence to the PRN stage of the study over a period of 12 months.

Results:

264 patients were enrolled. Group I: 112 patients, Group II: 90 and Group 3: 60 patients. 230 patients (87%) adhered to the initial 3 monthly injection and 162 (61.3%) patients of initial cohort adhered to prn stage of the study. In the loading dose phase best compliance was seen in Group I; in the PRN stage best compliance was seen in Group II. Overall, best compliance was seen in Group III where 63.3% patients adhered to the full schedule though it was not statistically significant (p = 0.93226).

Conclusion:

Patient adherence and success rates of anti-VEGF therapy may be increased by analyzing various factors affecting patient compliance and raising awareness about DME. In our study, financial affordability was not a major reason for non-compliance.

Health sciences/Health care/Health care economics

Scientific community and society/Scientific community/Education

Diabetic eye disease, particularly diabetic retinopathy (DR) and diabetic macular edema (DME), can lead to severe visual impairment and is a major contributor to declining vision among individuals of working age. (1 2, 3) This condition is highly prevalent, with the Middle East and North Africa region (MENA) having the highest diabetes prevalence in 2019 at 12.2%. Alarmingly, it is projected that diabetes prevalence in this region will increase by 96% between 2019 and 2045, second only to the African region, which is expected to experience a staggering 143% rise. (4, 5, 7) The pathogenesis of diabetic macular edema (DME) is complex, involving various factors such as angiogenesis, inflammation, hypoxia, and hemodynamic processes. These processes contribute to the breakdown of the retinal barrier and the leakage of fluid within the retina. (8, 9, 10) Several studies have shown that vascular endothelial growth factor (VEGF), a powerful regulator of retinal vessel growth and permeability, plays a significant role in the disruption of the retinal barrier in diabetes.(11, 12) The efficacy of anti-VEGF injections in DME has been demonstrated in clinical trials as well as in real-world practice. (11, 12, 13, 14) Despite the proven efficacy, regular maintenance dosing is a tremendous burden for both patients and the healthcare system. As a result, various initiatives have been taken to formulate a flexible dosage plan that does not compromise the expected visual and anatomical benefits obtained from a fixed dose. Application of the treat-and-extend (T&E) and pro re nata (PRN; ‘as needed’) regimens for intravitreal anti-VEGF therapy has resulted in reduced injection burden on patients and increased cost effectiveness in managing macular edema. (15, 16) Non-adherence among patients undergoing anti-VEGF therapies refers to veering off their prescribed treatment routine. (17) Patient adherence is influenced by various factors, such as age, psychological well-being, treatment expectations, travel convenience, and cost implications, especially when patients bear a significant portion of the treatment expenses themselves.¹⁷ There is limited literature, particularly on the financial aspect of the treatment burden. Quantitative research did not address the problems associated with reimbursement and financial burden. In the realm of managing DME, adherence to the prescribed dosing schedule of Anti-VEGF treatments plays a crucial role. However, it is imperative to recognize the significant impact that financial affordability has on patient compliance. This study aims to explore the relationship between financial affordability and patient adherence to the Anti-VEGF dosing schedule in the management of DME.

This was a prospective, interventional, comparative, cohort study. Naïve DME patients who needed anti VEGF injections were enrolled in the study. This study was conducted at a tertiary care eye center, as per the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Institutional ethics board (KSEC EC vide letter reference IRB/024/2021) approval was obtained for this study. Written informed consent was obtained from all participants included in the study. The treatment regimen was 3 consecutive monthly injections followed by monthly as needed (pro re nata, PRN). Duration of study was 12 months. Patients were divided in 3 groups. Group I were patients who were paying for the treatment themselves. Group II were patients whose treatment was reimbursed by insurance company. Group III were cases which whose treatment cost was reimbursed by local charitable organizations. Demographic and ocular characteristics were recorded. Two indicators were measured. The main predefined non-compliance end points of this 12-month-study were: (1) patients who did not completed the loading dose phase and (2) patient who showed non-adherence to the PRN dosage schedule over a period of 1 year and the reason for that. The patients who did not adhere to the study protocol were called on phone and were asked questions specified in a set. Demographic and ocular characteristics were recorded. Clinical data, including vision, diagnosis, number of clinic appointments, dates of injections and OCTs, and VA before first treatment and after 12 months (or at last examination before 12 months), were recorded. Only one eye per patient was chosen as study eye. If both eyes fulfilled the aforementioned criteria, the right eye was included. Non adherence was defines as missing two consecutive scheduled outpatient visits. Standard statistical analysis was performed using MedCalc Statistical Software version 18.5 (MedCalc Software bvba, Ostend, Belgium; descriptive statistics [mean (standard deviation)] and percentages were used as needed. The paired sample t-test was used for intragroup comparisons of the parameters that were normally distributed. The significance level was set at P < 0.05.

A total of 264 patients were enrolled in the study. There were 160 male and 154 female patients with mean age of 56.27+/-9.67. Their demographic profile and baseline characteristics are enumerated in Table 1. Mean number of visits over a period of 12 months was 9.5 (+/-3.52) in Group I, 9.03(+/-4.03) in Group II and 9.5 (+/-3.61) in Group III. The difference was not statistically significant p 0.719. The mean number of injections was 5.38(+/- 1.65) in Group I, 5.46(+/- 1.85) in Group II and 5.71(+/-1.90) in Group III this was also not statistically significant with p 0.259. Table 2 compares treatment adherence in different patient groups. Overall, out of 246 patients, 162(61.3%) adhered to the treatment protocol throughout the 12 months of study duration. 219(83% of initial cohort of 246) patients adhered to the 3 monthly injections loading dose schedule. 162 (73.9% of the 219 patients who completed the loading dose phase), adhered to the PRN stage of the study. In individual groups, in Group I where patients were paying for their treatment, 100(89.2%) completed the loading dose stage and out of these 100, 69(69%) continued in the PRN stage till 12 months. In Group II, where patients were covered by their insurance for their treatment, 66(71.7%) completed the loading dose stage and out of these 66, 55(83.3%) patients continued in the PRN stage. In Group III where patients were not charged for the treatment (helped by local charity organizations), 53(88.3%) completed the loading dose stage and out of 53, 38(71.6%) continued in the PRN stage. Table 3 enumerates the reason for the drop out or non-adherence both during the 3-injection loading dose as well as PRN stage of the treatment. Upon analyzing the reasons for non-adherence during this phase, we identified 45 patients (17%) dropped out in the 3-injection loading dose phase. Among these patients, the majority belonged to the insured group, with 15 patients (33.3%) failing to complete the three required loading dose injections due to reimbursement issues. Additionally, 11 patients (24.4%) did not complete the three-monthly injections due to no perceived visual changes. 8 patients did not adhered to 3 injection-loading dose due to change of residence or no answer, 5 patients due to other medical comorbidities affecting the appointments, and 2 due to direct financial reason of inability to afford further injections. In PRN stage of our study we noted that 57 patients (21.5% of initial cohort; 35.1% of patients who continued after 3-injection loading dose) did not adhere to treatment schedule over a period of 12 years. Out of these 57 patients, 31 (54.3%) were self-paying, 11 (19.2%) belonged to the insured group, and 15 (26.3%) were part of the free treatment group. Upon analyzing the reasons for non-adherence in PRN stage of the study, we discovered that 24 (42%) of the dropouts were unable to complete the PRN stage due to the burden of multiple visits to different hospitals caused by co-morbidities. Additionally, 18 (31.5%) patients discontinued this stage of the treatment protocol due to a perceived lack of improvement in their vision during subsequent visits. Furthermore, 9 (15.1%) patients did not respond to our phone questionnaire, 2 (3.5%) exceeded their insurance coverage limit, and 4 (7%) changed hospitals for their treatment.

Table 1

Demographic profile of the study population
	Group I N = 112	Group II N = 92	Group II N = 60	P value
Age	56.21+/-8.71	57.08+/-10.47	55.13+/-10.84	0.809
Type I DM^@	28	21	15	0.936
Type II DM	84	71	45	0.936
Duration of DM	16.07 (5.18)	15.79 (5.31)	16.73 (4.19)	0.579
HbA1C^#	9.40 (0.96)	9.39 (1.24)	9.63 (1.31)	0.687
Baseline Vision	0.721 (+/-0.378)	0.638 (+/-0.354)	0.766 (+/-0.406)	0.596
Number of visits*	9.5 (+/-3.52)	9.03 (+/-4.03)	9.5 (+/-3.61)	0.719
Number of Injections*	5.38 (+/- 1.65)	5.46 (+/- 1.85)	5.71 (+/- 1.90)	0.259
^@DM - Diabetes mellitus
^# HbAIC - glycated haemoglobin
*At the end of 12 months

Table 2

Comparing Treatment Adherence in Different Patient Groups
	Group I (Self-payment)	Group II Insured	Group III (Free treatment)	Total	p-value
Number	112	92	60	264 (100%)
Pts completed 3 loading dose stage	100 (89.2%)	66 (71.7%)	53 (88.3%)	219/264 (83%)
Pts not adhering to loading dose	12 (10.8%)	26 (28.3%)	07 (11.7%)	45 (17%)	0.0699
Pts who continued in the study	100	66	53	219 (83%)
Pts who did not adhere to PRN stage	31 (31%)	11 (16.6%)	15 (28.3%)	57 (26%)	0.2798
Pts who completed study at 12 months	69 (61.6%) (69%)	55 (59.7%) (83.3%)	38 (63.3%) (71.6%)	162/264 (61.3%) 162/219 (73.9%) of pts after loading phase	0 .9322

Table 3

Reason for non-compliance
	Group I Self-paying N = 112	Group II Insured N = 92	Group III Free treatment N = 60
Loading Dose stage	Non-compliance 12(10.8%)	Non-compliance 26(28.3%)	Non-compliance 7(11.7%)
Reasons for non-compliance	7 – No change in vision 3- Other medical issues 2 – Financial issue	4- No change in vision 15- problems with reimbursements 4- changed care to another hospital 3- Lost to follow-up/No reply	5- Changed country of residence 2- other medical issues
*PRN Stage**	Non- compliance 31(31%) out of 100 who continued after Loading dose phase. 31(27.61%) of the initial cohort of 112 patients.	Non- compliance 11(16.6%) out of 66 who continued after the loading dose phase. 11(1.06%) of the initial cohort of 92 patients.	Non- compliance 15(28.3%) out of 53 who continued after the loading dose phase. 15(25%) of the initial cohort of 60 patients.
Reasons for non-compliance	17 – Too many visits including other medical issues/visits 10 – Feel no improvement 4- Lost to follow up/no reply	5- Too many visits including other medical issues/visits 3- No improvement 2- Exceed limit 1 – Lost to follow-up/No reply	2- Too many visits including other medical issues/visits 5- No improvement 4- Changed the residence 4- Lost to follow-up/no reply.
*PRN - pro re nata

In this study, we found that financial affordability was not a major reason for non-compliance.

We noted good adherence in the loading phase of the anti-VEGF treatment protocol in all the three groups. Out of initial cohort of 264 patients; 45 did not adhere to the treatment protocol; 15 patients (33.3%) did not complete 3 loading dose injections due to reimbursement issues, 11(24.4%) did not complete 3 monthly injections due to no perceived visual change. Out of these 11 patients; 7 were in self-paying group and 4 in insured group. There were 2 non-adherent patients due to direct financial affordability and 15 due to indirect financial reasons for treatment drop-outs at this stage due to insurance reimbursement. The unique reimbursement rules and need for approval in different countries can influence access and persistence to treatment/dosage schedule. However, even in countries where the cost of the drug itself may be funded, patients reported some financial stress related to indirect costs for treatment, such as the cost of parking and productivity losses, with the caregiver needing to take time off work to accompany patients for treatment. (18) In PRN stage of our study it was observed that 57 patients did not complete this stage of study over a period of 12 months. Out of these 57 patients; it was noted that 24(42%) dropouts could not complete the PRN stage due to burden of multiple visits to different hospital due to co-morbidities. 18 (31.5%) did not continue this stage of treatment protocol due to no perceived improvement in vision on subsequent visits, 9 (15.1%) did not reply to our phone questionnaire, 2(3.5%) exceeded limit on insurance coverage and 4(7%) changed the hospital for treatment. In PRN stage of our study only 2 patients (3.5%) dropped out of the treatment protocol due to financial reasons directly. Even when treatment was provided free (cost of injection as well as OCT & administrative charges include) 15 patients (26.3%) from free treatment Group III dropped out of the treatment protocol. In the loading dose phase best compliance was seen in Group I; in the PRN stage best compliance was seen in Group II. Overall, best compliance was seen in Group III where 63.3% patients adhered to the full schedule though it was not statistically significant when compared to other groups.

The cost of anti-VEGF treatment can be substantial, often requiring multiple injections over an extended period. For many patients, the financial burden associated with these treatments can be overwhelming, leading to non-adherence or treatment discontinuation. In order to ensure optimal outcomes, it is crucial that every treatment is customized to meet the unique needs of each patient and their specific disease. While certain treatments may prove effective in clinical trials, their success in everyday clinical practice may be compromised due to low patient acceptance, primarily resulting from inadequate patient adherence. (12, 13) This issue becomes particularly evident in cases like DME, where lifelong treatment is necessary. Patient acceptance is influenced by various factors, including their treatment expectations, affordability of treatment, past experiences, and the effectiveness of communication between physicians and patients. (14, 15) Therefore, it is imperative to gather reliable and valid data on the perceptions and preferences of patients with DME. This holds true regardless of the specific IVT regimen employed, be it fixed injections, PRN, treat-and-extend, or observe-and-plan, as the success of all these approaches hinges on patients' willingness and ability to adhere to them. (16) Recent preference analyses have shown that DME patients are not willing to accept suboptimal visual acuity (VA) development, even if associated with a lower treatment burden. (11, 15) Studies have shown that non-adherence rates remain consistent between studies lasting 12 months and those extending beyond that timeframe. This suggests that once patients complete a year-long course of intravitreal injections, they are less likely to discontinue treatment in the near future. (16) Consequently, the majority of non-persistence cases occur within the first year of initiating treatment, highlighting that decisions to discontinue, driven by patient-led factors, are often made early on in the treatment process. (16) The World Health Organization defines "adherence" as the degree to which a person's actions align with the recommendations provided by their healthcare provider. It is crucial to address these challenges and improve patient adherence and persistence to treatment in order to mitigate the risk of vision loss. (17)

In a study conducted by Obeid et al, the role of cost as a risk factor was found to be less consistent than anticipated in age related macular degeneration (AMD) patients, where like in DME, long term anti-VEGF injection treatment is needed. Financial barriers were found to account for only 2–30% of the causes of non-persistence. This lack of consistency may be attributed to the inclusion of various countries in the review. (19) To illustrate, in Taiwan, AMD patients can be reimbursed for 3 to 7 doses of ranibizumab or aflibercept in each eye over a 2-year period, as prescribed by an approved ophthalmologist. Moreover, switching between intravitreal agents is restricted, necessitating the decision on the type of anti-VEGF treatment to be made at the initial application, regardless of treatment outcomes. (20) This highlights the multifaceted nature of factors that influence individuals' commitment to their treatment plans. In our study, patients were exclusively administered a single type of anti-VEGF medication, without the provision of alternative options for switching. A study conducted by Habib et al, (21) revealed that approximately 21% of patients with DME were found to be noncompliant in terms of follow-up and treatment with anti-VEGFs. The authors attributed this noncompliance to several key factors, including the cost of the injected drug, the patient's medical insurance coverage, the psychological burden associated with repeated intraocular injections, and the level of patient satisfaction. By addressing the financial burden, providing adequate insurance coverage, and offering psychological support to patients, healthcare professionals can help alleviate some of the barriers that contribute to noncompliance. Furthermore, educating patients about the importance of regular follow-up and treatment, as well as addressing their concerns and fears regarding repeated injections, can significantly enhance patient satisfaction and overall compliance. In a study conducted by Best et al. (22) it was observed that a quarter of patients with DME were noncompliant. This finding highlights the challenges faced by patients with diabetes who have to attend multiple medical consultations, often with different specialists. The burden of these repeated consultations can be a barrier to regular follow-up. Similarly, Weiss et al (23) conducted a study where only 35% of patients were found to be compliant. The study also shed light on the reasons behind noncompliance. The most common reason reported by patients for abstaining from treatment was the presence of other comorbidities. Additionally, many patients were found to have limited understanding of their disease. Kelkar et al (24) evaluated the rate of compliance and the reasons for loss to follow‑up in Indian patients with DME, AMD, and retinal vein occlusion (RVO) being treated with anti-VEGF therapy. They reported that the most frequently cited reason for loss to follow-up was "non-affordability" (n = 120; 41.1%), followed by "no improvement in vision" (n = 83; 28.4%), "treatment elsewhere" (n = 27; 9.2%), and "shift of residence" (n = 24; 8.2%). Conversely, "non-affordability" was slightly higher among patients with DME (37.5%). In another comprehensive study conducted by Sobolewska et al. (25) the most prevalent barrier in anti-VEGF therapy in AMD patients was the time commitment associated with treatment, affecting a substantial 68.5% of patients. Additionally, 57.4% of individuals reported challenges in arranging for a companion to accompany them to doctors' appointments. The burden placed on family members was also a significant concern, impacting 50.0% of patients. Other notable barriers included the travel and opportunity costs associated with treatment (46.3%), the financial burden of therapy (42.6%), and the presence of comorbidities (24.1%). Additional barriers identified included discomfort experienced in the doctors' office (14.8%), side effects of the therapy (13.0%), and insufficient knowledge about the treatment (13%). Trust in the physician (11.1%) and lack of support (11.1%) were also cited as contributing factors.

Strengths of the study include being first of its kind in Middle East, large sample size, and pre-defined outcomes. Our study has some limitations. One key limitation in our financial affordability study is that this study is done in Kuwait. The economy of Kuwait is a wealthy petroleum-based economy. According to the World Bank, Kuwait is the fifth richest country in the world by gross national income per capita. Hence, financial affordability can differ in different social status. However, our data indicates that even when treatment is provided free of charge, there is not a significant difference in adherence compared to patients who pay for their treatment. Another limitation of our study was the use of only one type of anti-VEGF treatment, Aflibercept. In the event that a patient did not respond well to this particular molecule, there was no option to switch to another anti-VEGF drug or change the class of the intravitreal injection drug, such as a steroid. This restriction may have impacted the overall effectiveness of the treatment. Additionally, other potential limitation of our study was the use of a PRN (as needed) protocol instead of a treat and extend or tailor-made protocol for each patient. The decision to employ the PRN protocol was made in order to maintain homogeneity of the data and follow-up visits. Furthermore, our study had a relatively short duration of one year. Anti-VEGF treatment can often continue for several years, and the financial burden associated with such treatment may vary over a longer duration.

In conclusion, this study illustrates the intricate issue of patient noncompliance in DME treatment, highlighting the complex interplay among various factors. To address this challenge and improve patient compliance, it is crucial that healthcare providers and policymakers collaborate effectively. Further research in diverse socio-economic parameters is needed to gain a deeper understanding of these factors and devise strategies to mitigate their impact on patient outcomes. By implementing various strategies, such as expanding insurance coverage, establishing patient assistance programs, and initiating cost reduction initiatives, the financial burden on patients may be alleviated. Ultimately, this will enhance the likelihood of patients adhering to their prescribed protocols, thereby improving their overall visual outcome and quality of life.

Conflict of Interest: None

Financial disclosure: None

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You are reading this latest preprint version

The impact of financial affordability on patient adherence to the dosing schedule of Anti-Vascular Endothelial Growth Factor in managing Diabetic Macular Edema.

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