Ranibizumab or Aibercept for Neovascular Age-Related Macular Degeneration, Twelve-Month Outcomes of Therapeutic Program in Non-Tertiary Institution: A Comparative Study.

Purpose: This single center study aimed to compare the 12-month treatment outcomes of ranibizumab with that of aibercept in routine clinical practice. Methods: Cohort of patients diagnosed with treatment-naïve neovascular AMD, treated using either ranibizumab (n = 33 eyes) or aibercept (n = 44 eyes) monotherapy over a 12-month follow-up period was analyzed. Anonymous data were extracted from the electronic database dedicated to the drug program. Results: In the ranibizumab group, there were not statistically signicant changes in BCVA (ETRDS letters) and CRT (µm), between baseline (67.9 ± 8.6 & 384.9 ± 97.9) and at 12 months (67.9 ± 12.1 & 398.9 ± 127.1; P = 0.372 & P = 0.884, respectively). In the aibercept, there was an improvement in BCVA and reduction in CRT between baseline (64.2 ± 8.1 & 414.3 ± 97.8) and at 12 months (70.7 ± 7.4 & 342.3 ± 71.6; P <.001 & P <.001, respectively). There was no difference in BCVA between the two groups at either diagnosis (P= 0.101) or 12 months (P= 0.917). Mean number of injections in the ranibizumab group was signicantly lower (4.9 ± 1.5) than in the aibercept group (6.7 ± 1; P<.001). Conclusions: One initial injection of ranibizumab and then PRN regimen resulted in stabilization of disease progression. Drug selection and treatment scheme could inuence twelve-months outcomes. In the aibercept group, three initial monthly injections and then every two months provided both signicant BCVA improvement and CRT reduction at 12 months of treatment.


Introduction
Age-related macular degeneration (AMD) is a chronic disease that affects around 50-70 million people worldwide and is the leading cause of blindness in developed countries, including Poland. 1 The treatment of choice for wet AMD is intravitreal injection of vascular endothelial growth factors inhibitors (VEGF). 2,3 Although anti-VEGF therapy is focused at treating symptoms, it has revolutionized the treatment of exudative AMD. 4 Since November 2015, treatment of patients with wet AMD in Poland has been nanced by the National Health Found (NHF). Two drugs, a ibercept or ranibizumab are administrated as part of the Polish National Treatment Program. 5 The authors aimed to compare effectiveness of ranibizumab and a ibercept, in non-tertiary institution.

Study design
This was a non-randomized, retrospective, observational single center study of treatment-naïve eyes for wet-AMD. Anonymous data were collected from the drug program dedicated electronic database. Records from December 2015 to December 2020 were analyzed.
Data included the assessment of the following: the best corrected visual acuity (BCVA) on a decimal scale made on the basis of a Snellen chart, macular morphology with automatic measurement of the central retina thickness (CRT) from the central sub eld of the optical coherence tomography (OCT); percentage share of active area in degenerative lesion, size of degenerative lesion (DA). Type of neovascularization was determined with uorescein angiography (FA). All OCT scans were performed on certi ed spectral domain OCT (Spectralis OCT, Heidelberg Engineering, Germany). In addition, possible prior treatment with VEGF inhibitors, disease activity de ned as the presence of sub-or intra-retinal uid in OCT or a new hemorrhage were reported.
Demographic factors extracted from the database were age (years), gender, eye (right/left), date of diagnosis, dates and number of injections with VEGF inhibitors.

Treatment program
The following inclusion criteria were applied in the treatment program: 1) presence of active (primary degeneration, not secondary) occult (type 1), classic (type 2) or mixed (other than pure classic or occult, including retinal angiomatous proliferation -type 3) Subretinal choroidal neovascularization (CNV) occupying more than 50% of the lesion; 2) age ≥ 45 years 3) total size of degenerative lesion less than 12 optic disc area (DA); 3) BCVA in the treated eye of 0.1-0.8 (from 2015 to 2017); 0.2-0.8 (from 2017 to present), determined on a decimal scale according to the Snellen chart; 4) absence of dominant geographic atrophy or hemorrhage in the whole lesion (more than 50% of the lesion); 6) informed consent of the patient to undergo intravitreal injections. Patients with scarring or atrophy of the fovea were not eligible for the treatment.
BCVA deterioration to ≤ 0.05 according to Snellen's chart lasting longer than 2 months excluded patient from the program. In addition, physician could remove the patient from the program according to the exclusion criteria contained in summary of product characteristics.
A ibercept or ranibizumab were chosen by the physician at the time of the rst injection. Ranibizumab was mainly administrated in cases which were expected to improve rapidly, allowing for a prompt withdrawal from the therapeutic program. All eyes were treated with xed regimen, according to the "Treatment of neovascular form of age-related macular degeneration" National Health Found program guidelines. 6 Three monthly intravitreal injections of a ibercept (2.0 mg/0.05mL) were administrated and then drug was injected every 2 months.
After the rst 12 months of a ibercept treatment, a pro re nata (PRN) regimen was in force. In patients treated with ranibizumab, after administering the initial dose (0.5 mg/0.05mL) the PRN scheme was applied. Patients received injections monthly until the disease was no active and functional stability was achieved. Then, patients were followed-up for 4-8 weeks. Ranibizumab was given again, when active neovascularization recurred, and functional parameters worsened. Physician could switch drug if the patient met both of the following criteria: 1) BCVA after 7 injections of ranibizumab or a ibercept (since inclusion to the program) was worse than BCVA at baseline; 2) patient still met the inclusion criteria for therapeutic program. Switch from ranibizumab to a ibercept and vice versa was permitted. However, patients which drug was switched during the therapy were excluded from the analysis.
Clinical examinations, OCT and measurement of BCVA were performed at each follow-up visit and recorded in the electronic database.
Patients with follow-up period cript > 12 months were excluded from the analysis. Only, patients with treatment-naïve wet AMD eyes and complete medical records were included in the study.
Changes after 12-month treatment.
The baseline BCVA and CRT were compared with those at 12 months within each treatment group.
Comparisons between the ranibizumab group and a ibercept group.
Eyes were divided into two groups: the ranibizumab (n = 33) and a ibercept groups (n = 44). These were compared in terms of baseline characteristics (BCVA, CRT, percentage share of active area in degenerative lesion, size of degenerative lesion, neovascularization type, age and sex). In addition, the BCVA, CRT and number of injections after 12 months of treatment were compared between groups.
To investigate difference between good visual outcome and poor visual outcome, eyes were divided into two groups on the basis of BCVA at 12 months. These with BCVA ≥ 20/50 were assigned to the "good visual outcome" group. Patients with BCVA cript > 20/50 were included in the "poor visual outcome" group. Within each treatment group, the visual outcomes were compared in terms of baseline characteristics (mentioned above) and number of injections.
The patients were divided into two groups, according to the number of injections received within 12-month treatment period. Mean number of injections were calculated for ranibizumab and a ibercept groups. Patients, whose number of injections was ≥ than mean in their drug group were compared against these, whose number of injections was cript > than mean in their drug group. The BCVA and CRT at baseline and at 12 months were compared between these groups.
For the purpose of the study, visual acuity was calculated from the Snellen decimal scale to the number of ETRDS letters. 7 The CRT values were reported in µm.

Statistics
Statistical analyses were performed with open-source software JASP, version 0.14.1, https://jasp-stats.org. Data were collected with use of Microsoft Excel software, version 16.46, (Microsoft Corporation, Redmond, WA, USA). The normality of data was examined with Shapiro -Wilk test. Differences between two time points were analyzed using the Wilcoxon signed -rank test. To analyze differences involving parametric values between two groups, either the independent t test or the Mann -Whitney U test were utilized. These that concerned non-parametric values were analyzed using the chi-square test. P values < .05 were considered signi cant. Data were presented as mean ± standard deviation (SD), where applicable.

Results
During the analyzed period, 67 patients (77 eyes) met the eligibility criteria. Both eyes of 10 patients (14,9%) were enrolled in the study. The mean age was 80.3 ± 7.4 years. The ranibizumab group consisted of 33 eyes and the a ibercept included 44 eyes. Table. 1.

Discussion
In the present study, one initial injection of ranibizumab and then PRN regimen resulted in stabilization of neovascular AMD progression.
The twelve month outcomes of treatment with ranibizumab were different than revealed in other studies. 8-10 Retrospective, observational studies 8-10 reported both signi cant improvement in BCVA and reduction in CRT at 12 months. Eyes treated with ≥ 5 number of injections had similar results as eyes, that received < 5 injections. Observed outcomes could be associated with administration of ranibizumab to eyes with better prognosis at baseline. This might result in lower BCVA improvement and CRT reduction at 12 months. In addition, these eyes might receive less injections. According to recommendations of the drug programme, 6 ranibizumab was administered in PRN scheme. None of the analyzed patients received initial 3 monthly injections. This could also explain different outcomes than in cited studies.
A ibercept was found to be effective in treating patients with the neovascular AMD. There was statistically signi cant visual acuity improvement and CRT reduction. At 12 months patients gained 4.9 ± 8.5 ETRDS letters and CRT was reduced by 72 ± 90 µm, form the baseline. Similar results were revealed in other retrospective, observational studies with 12-months follow up. [11][12][13][14][15] Less than 7 injections resulted in non-signi cant change in BCVA and CRT. This coincides with other authors ndings. Treatment-naïve wet AMD eyes receiving fewer than 7 intravitreal a ibercept injections in the rst year of treatment had worse visual outcomes. [16][17][18] In the present study, good baseline BCVA was associated with visual acuity of 20/50 or better at 12 months in both the ranibizumab and a ibercept groups. Previous studies showed that type 1 neovascularization was associated with a better long term visual outcome than other subtypes of neovascularization. 15,19 In ranibizumab group, the proportion of cases involving type 1 neovascularization was greater in the good visual outcome than in the poor visual outcome group. This trend was not revealed in the a ibercept group. The difference in the ranibizumab group, could be potentially due to the small sample size. However, this was statistically signi cant.
The main limitation of this study was its retrospective, single center nature. There were a relatively small number of patients and short follow-up period. The authors aimed to evaluate effectiveness of anti-VEGF therapy in the setting of regional hospital.
To conclude, 3 monthly intravitreal injections of a ibercept (2.0 mg/0.05mL) and then every 2 months was an effective treatment regimen of naïve wet AMD eyes. This resulted in signi cant BCVA improvement and CRT reduction at 12 months of therapy. One initial monthly injection of ranibizumab (0.5 mg/0.05mL) and then PRN regimen resulted in stabilization of the disease progression, for 12 months follow-up period in naïve wet AMD eyes.
Declarations Figure 1 Changes in BCVA in patients treated with ranibizumab or a ibercept.

Figure 2
Changes in CRT (µm) in patients treated with ranibizumab or a ibercept.