Survey of Intravitreal Injection Preferences for the Treatment of Age-Related Macular Degeneration and Macular Edema Among Members of the Turkish Ophthalmological Association

V. Levent Karabaş; Ecem Önder Tokuç; Figen Şermet

doi:10.4274/tjo.galenos.2021.37075

ABSTRACT

Objectives:

To analyze the current preferences of ophthalmologists for the treatment of macular edema and age-related macular degeneration (AMD) and to evaluate off-label use of bevacizumab in Turkey.

Materials and Methods:

All members of the Turkish Ophthalmological Association were contacted by e-mail to complete an anonymous, 47-question internet-based survey. The second part of the survey (questions 36-47) was evaluated.

Results:

When current legal regulations were considered, ophthalmologists used bevacizumab as the first-line agent in patients with diabetic macular edema (DME), AMD, and retinal vein occlusion (RVO) (58.25%, 55.89%, and 52.29%, respectively). When economic and legal constraints were disregarded, the participants’ preference for bevacizumab in the treatment of DME, AMD, and RVO decreased (11.64%, 10.58%, and 10.93%, respectively). Approximately three-quarters (75.75%) of ophthalmologists stated that dispensing multiple syringes from a single bevacizumab bottle could increase the risk of endophthalmitis. Most participants (93.68%) did not feel legally safe from harm caused by off-label bevacizumab use. However, 66.43% of ophthalmologists stated that bevacizumab is as effective as other anti-vascular endothelial growth factor (anti-VEGF) drugs.

Conclusion:

Bevacizumab is widely used as a first-line treatment for all indications of anti-VEGF use in the current reimbursement conditions, which preclude the right of ophthalmologists to treat according to their own preferences.

Keywords:

Anti-VEGF, bevacizumab, aflibercept, ranibizumab, off-label, diabetic macular edema, age-related macular degeneration, retinal vein occlusion

Introduction

The treatment of neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), and retinal vein occlusion (RVO) is evolving as new research results become available. Ophthalmologists widely use intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents such as ranibizumab, aflibercept, and bevacizumab in the treatment of these conditions.^1,2,3,4 Aflibercept and ranibizumab were approved by the United States Food and Drug Administration (FDA) for the treatment of AMD, RVO, and DME. However, bevacizumab does not have FDA approval for ophthalmic use and is thus “off-label,” despite being widely used.⁵ Bevacizumab is also not approved for ophthalmologic use in Turkey. The ophthalmic off-label use of bevacizumab has caused great controversy due to the ethical, legal, economic, and political issues surrounding its use.⁶

As a global health issue, the substantial cost variation, the risk of endophthalmitis, the legal restriction of off-label use, the cost of obtaining medications, and reimbursements contribute to a controversial health policy and an ethical dilemma in regard to anti-VEGF agents. In Turkey, reimbursement regulations suggest three consecutive monthly injections of bevacizumab for the treatment of DME, AMD, and RVO. The aim of this study was to describe the preferences of ophthalmologists regarding anti-VEGF drugs and evaluate the off-label use of bevacizumab.

Materials and Methods

All members of the Turkish Ophthalmological Association were contacted via e-mail in May 2020 to complete a 47-question online survey conducted using SurveyMonkey (www.surveymonkey.com; SurveyMonkey, San Mateo, CA). Three reminder e-mails were sent to participants who had not completed the survey yet. Data collection was concluded on June 4, 2020. Results from the first part of the survey (questions 1-35) evaluating intravitreal injection techniques were published previously.⁷ The second part of the survey (questions 36-47) evaluated ophthalmologists’ approaches to bevacizumab and other FDA-approved anti-VEGF drugs for patients with DME, AMD, and RVO. The participants were divided into subgroups as representatives of private hospitals, private offices, public hospitals, city hospitals, university hospitals, training and research hospitals, and foundation universities. The research protocol was approved by the Institutional Ethics Committee and Review Board of Kocaeli University (number: KAEK 2020/219).

Results

In total, 892 ophthalmologists answered the questionnaire, and 660 participants who were actively performing intravitreal injections were included in the study. The institutions of the participants are presented in Table 1.

Considering the current reimbursement restrictions, 58.3% (332/570) of the participants used bevacizumab as a first-line agent in patients with DME (Figure 1). The participants’ preference for bevacizumab varied between institutions (Table 2). Participants working in private offices were more likely to use aflibercept than bevacizumab (51.9%, 14/27 vs. 22.2%, 6/27).

Of the participants, 49.4% stated that they would prefer aflibercept as a first-line agent in patients with DME if there were no economic and reimbursement restrictions (Figure 2). Preferences for aflibercept were similar among institutions except in public hospitals (Table 3). Participants working in public hospitals preferred ranibizumab for patients with DME (43.8%, 21/48).

Considering the current reimbursement restrictions, over half of the participants (55.9%, 318/569) used bevacizumab as a first-line agent in patients with AMD (Figure 3). Bevacizumab was used in most institutions (Table 4). However, participants from private offices and foundation universities reported greater use of aflibercept for patients with AMD (51.9%, 14/27 and 59.4%, 19/32, respectively).

Most of the participants (61.7%, 350/567) stated that they would prefer aflibercept as first-line treatment for AMD if there were no economic and reimbursement restrictions (Figure 4). Under these circumstances, aflibercept was preferred for patients with AMD in all institutions (Table 5).

Over half the participants (52.3%, 297/568) used bevacizumab initially for patients with RVO under the current reimbursement restrictions. Participants in city hospitals (73.1%, 19/26), university hospitals (53.1%, 94/177), training and research hospitals (61.8%, 81/131), and private hospitals (53.2%, 84/158) mostly used bevacizumab, while the participants at foundation universities (31.3%, 10/32) and private offices (37.0%, 10/27) used aflibercept. However, participants in public hospitals preferred ranibizumab.

Overall, 35.5% of participants would prefer aflibercept as first-line therapy in patients with RVO if there were no economic and reimbursement restrictions. Participants in private hospitals (44.9%, 71/158), private offices (40.7%, 11/27), foundation universities (43.8%, 14/32), and training and research hospitals (38.9%, 51/131) mostly preferred aflibercept as a first-line agent. Participants in public hospitals mostly preferred ranibizumab (40.4%, 19/47), while dexamethasone implants were preferred as first-line treatment by those in city hospitals (53.9%, 14/26) and university hospitals (33.0%, 58/176).

Most of the participants (75.8%, 431/569) stated that dispensing multiple syringes from a single bevacizumab bottle could increase the risk of endophthalmitis (private hospitals: 59.5% [94/158]; private offices: 73.1% [19/26], public hospitals: 80.9% [38/47], city hospitals: 80.8% [21/26], university hospitals: 81.5% [145/178], training and research hospitals: 84.1% [111/132], and foundation universities: 78.1% [25/32]). However, 47.1% of the participants reported that they dispense multiple syringes from a single bevacizumab bottle (Table 6).

In addition, less than half (48.2%) of the participants stated that they did not feel under pressure to use a single bevacizumab bottle for more than one patient. The percentages of participants who felt pressure to use a single bevacizumab bottle on several patients are presented in Tablo 7. Unlike participants in other institutions, those in training and research hospitals were under greater pressure to use a single bevacizumab bottle for more than one patient (47.7%, 63/132). However, 16.2% of the participants did not use bevacizumab.

Some participants (25.6%) noted that they did not use bevacizumab while an approved anti-VEGF drug was available for that indication. Most of the participants (93.7%, 534/570) stated that they did not feel legally safe from harm caused by off-label bevacizumab use.

Overall, 66.4% (376/566) of participants stated that bevacizumab is as effective as other anti-VEGF drugs. In contrast, 60.6% of the participants stated that they think aflibercept is more effective and safer than other anti-VEGF agents (bevacizumab and ranibizumab) in patients with AMD, RVO, and DME (Table 8). However, participants in public hospitals stated that they think ranibizumab is more effective and safer than other anti-VEGFs (38.3%, 18/47).

Discussion

Due to the necessity of using bevacizumab for the first three loading doses under the current reimbursement restrictions in our country, most ophthalmologists prefer bevacizumab as first-line therapy in patients with DME, RVO, and AMD. However, when reimbursement restrictions were not considered, ophthalmologists’ drug preferences differed. Many participants working in private offices and foundation universities did not prefer bevacizumab as first-line therapy.

Conclusion

Bevacizumab is widely used as a first-line treatment for all indications of anti-VEGF, and reimbursement conditions preclude ophthalmologists’ right to treat patients according to their own preferences. Given the current reimbursement situation, it is not possible for doctors to freely choose a patient-specific treatment.

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