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.
Diabetic Macular Edema
In Turkey, ophthalmologists utilize anti-VEGF injections as first-line therapy to treat DME. Due to the current reimbursement restrictions, 58.3% of ophthalmologists stated that they use bevacizumab as a first-line therapy in DME. However, participants working in private offices preferred aflibercept (51.9%). This may be related to the better socioeconomic level of the patients who receive service from private offices and the higher compliance of ophthalmologists with their drug preference. Nearly half (49.8%) of all the participants would prefer aflibercept if there was no reimbursement limitation.
In the 2019 American Society of Retina Specialists (ASRS) global trends survey, most of the participants (Africa/Middle East: 74.0%; Asia/Pacific: 33.7%; and United States: 65.8%) used bevacizumab for initial treatment of DME based on the Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol T 2-year results.8 However, in the same survey, European participants (39.8%) and Central and South American participants (33.6%) preferred aflibercept for patients with DME. The use of off-label drugs, cost effectiveness, and changing reimbursement policies of states may be the reasons for this difference. In the United States, 65.8% of ASRS participants preferred bevacizumab as a first-line agent for patients with DME. However, in the 2020 ASRS global trends survey, 57.8% of retina specialists in the United States chose aflibercept (pre-filled syringe [PFS]) for their own center-involving DME.9 Similarly, in Europe, the preference of aflibercept increased from 39.8% for patients with DME in 2019 to 47.6%+20.7% (PFS+vial) for retina specialists’ own center-involving DME in 2020.
In addition, 49.4% of the ophthalmologists in our study preferred aflibercept for the treatment of DME when reimbursement restrictions are not considered. This may be due to the doctors’ desire to reduce the treatment burden (number of injections) with aflibercept. However, unlike in other institutions, participants in public hospitals (43.8%) preferred ranibizumab for the treatment of DME. The higher preference for ranibizumab may be due to the use of PFSs to reduce the risk of endophthalmitis. The use of a PFS eliminates most of the steps in injection preparation (aseptic), thereby reducing the risk of contamination.10,11 The participants in public hospitals may prefer to use PFSs due to the lack of equipment and the lack of retina specialists to manage endophthalmitis complications that may occur after intravitreal injection.
Age-related Macular Degeneration
Anti-VEGF therapy is the current treatment for AMD. Under current reimbursement policies, bevacizumab was preferred for AMD treatment in all institutions except private offices and foundation universities. When restrictions were not considered, 61.7% of the participants stated that they would use aflibercept as the first-line therapy for AMD. In the 2020 ASRS global trends survey, 60.6% of American retina specialists stated that aflibercept delivers the most effective fluid resolution in wet AMD.9 The participants may have thought that aflibercept is more effective for the treatment of standard AMD patients. The eight-week dosing regimen of aflibercept represents reduced treatment requirements in comparison with monthly dosing regimens and thus has the potential to reduce the treatment burden and risks associated with frequent injections.
In European countries, the usage of off-label bevacizumab for the treatment of AMD and associated cost vary from country to country.12 The intravitreal administration of bevacizumab has also been a matter of legal dispute in European countries. Moreover, the specific factors influencing medication choice appear to go beyond clinical considerations. The controversy over the ophthalmic off-label use of bevacizumab remains remarkably unresolved within the world’s largest single market. In the United States, 70.2% of American retina specialists use bevacizumab as the first-line anti-VEGF.13
Retinal Vein Occlusion
In this survey, no consensus among ophthalmologists was observed for the treatment of RVO when economic and reimbursement restrictions were ignored. According to the 2019 Euretina RVO guideline, intravitreal anti-VEGF therapy has become the standard of care for treating this disease.14 According to the guideline, corticosteroids are important in the armamentarium of drugs for treating patients with RVO, but largely as a second choice. In the 2015 ASRS global trends survey, retina specialists primarily used anti-VEGF agents for the treatment of RVO.15
Use of Bevacizumab
Of the total participants, 93.7% stated that they did not feel that it was legally safe to use off-label bevacizumab. The legal safety of off-label bevacizumab use is also unclear in European countries.12 Considering the current reimbursement restrictions in Turkey, it can be understood why the participants do not feel that it is safe. According to the Off-Label Drug Use guideline, “In our country, off-label drug use is not allowed for diseases that can be treated with medication within an approved indication. However, if there are treatment options that provide significant advantages according to scientific data, the request for off-label drug use is evaluated by the Institution.”16 However, the requirement of three doses of bevacizumab for reimbursement before the use of approved anti-VEGF drugs leaves ophthalmologists in a dilemma.
No large-scale prospective randomized clinical trial has been conducted showing that bevacizumab is superior to the approved anti-VEGF drugs (aflibercept and ranibizumab). The Protocol T study was the only randomized controlled clinical trial that compared bevacizumab with other approved anti-VEGFs for the treatment of DME. In the Protocol T study, aflibercept had superior 2-year visual acuity outcomes compared with bevacizumab among eyes with baseline visual acuity of 20/50 to 20/320, and bevacizumab was not superior to aflibercept and ranibizumab under any circumstances.17 The superiority of aflibercept over ranibizumab has also not been verified.
Moreover, 75.8% of participants believed that dispensing multiple syringes from a single bevacizumab vial could increase the risk of endophthalmitis and 35.6% felt pressured to use a single bevacizumab bottle for more than one patient, although the reimbursement restrictions are not clear regarding dispensing multiple syringes from a single bevacizumab bottle. The multiple use of bevacizumab from a single bottle remains a matter of debate. Ng et al.18 reused vials for a maximum of 10 consecutive injections in their trial and concluded that as long as proper sterile techniques are implemented, using the same vial does not increase the risk of endophthalmitis from intravitreal injections. Das et al.19 stated that bevacizumab does not lose stability when stored at 4°C and may be used for a week by direct withdrawal from the vial without fear of infection or inflammation if all standard precautions related to intravitreal injection are adhered to. Ornek et al.20 stated that the storage and reuse of bevacizumab do not seem to result in microbial contamination, and multiple doses of bevacizumab from a single-use vial could be used within 2 weeks. However, an endophthalmitis outbreak in a university hospital was caused by dividing the same single-use bevacizumab into multiple doses. In fact, several endophthalmitis cases have been reported in association with splitting bevacizumab from a single bottle.21
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.
Acknowledgements: The authors express their appreciation to the Turkish Ophthalmological Association for their support. The authors would like to thank Dr. İzzet Can for his support.
Ethics
Ethics Committee Approval: The research protocol was approved by the Institutional Ethics Committee and Review Board of Kocaeli University (number: KAEK 2020/219).
Informed Consent: Obtained.
Peer-review: Externally peer reviewed.
Authorship Contributions
Surgical and Medical Practices: V.L.K., E.Ö.T., Concept: V.L.K., E.Ö.T., Design: V.L.K., E.Ö.T., Data Collection or Processing: V.L.K., E.Ö.T., Analysis or Interpretation: V.L.K., E.Ö.T., F.Ş., Literature Search: V.L.K., E.Ö.T., Writing: V.L.K., E.Ö.T., F.Ş.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.