© Borgis - Postępy Nauk Medycznych 3/2017, s. 112-116
Iwona Grabska-Liberek, *Barbara Terelak-Borys, Irmina Jankowska-Lech, Urszula Stachowska, Piotr Tesla
Comparative analysis of clinical and anatomic outcomes in the treatment of exudative age-related macular degeneration with intravitreal injections of vascular endothelial growth factor inhibitors
Analiza porównawcza klinicznych i anatomicznych wyników leczenia wysiękowej postaci zwyrodnienia plamki związanego z wiekiem przy pomocy doszklistkowych iniekcji inhibitorów śródbłonkowego czynnika wzrostu naczyń
Department of Ophthalmology, Centre of Postgraduate Medical Education, Prof. W. Orłowski Hospital, Warsaw
Head of Department: Professor Iwona Grabska-Liberek, MD, PhD
Wstęp. Zwyrodnienie plamki związane z wiekiem (ang. age-related macular degeneration – AMD) stanowi wiodącą przyczynę głębokiego upośledzenia ostrości wzroku u osób powyżej 50 roku życia.
Cel pracy. Celem pracy była analiza porównawcza wyników leczenia wysiękowej postaci AMD przy pomocy iniekcji doszklistkowych dwóch leków o charakterze inhibitorów śródbłonkowego czynnika wzrostu naczyń (ang. anti-vascular endothelial growth factor – anti-VEGF): ranibizumabu i bewacizumabu.
Materiał i metody. Do badania retrospektywnego włączono 55 pacjentów z wysiękową postacią AMD i najlepszą skorygowaną ostrością wzroku (ang. best corrected visual acuity – BCVA) równą lub lepszą niż 1,0 (logMAR). Grupa leczona ranibizumabem liczyła 31 osób (31 oczu), grupa leczona bewacizumabem – 24 osoby (27 oczu). Średni okres obserwacji wynosił 1 rok.
Wyniki. Po roku leczenia średnia BCVA nie uległa pogorszeniu w obu grupach (0,56 vs. 0,55 logMAR w grupie leczonej ranibizumabem i 0,62 vs. 0,60 logMAR w grupie leczonej bewacizumabem). Poprawa lub stabilizacja BCVA wystąpiła w 74,2% oczu leczonych ranibizumabem i 74,1% oczu leczonych bewacizumabem (różnica statystycznie nieistotna, p = 0,99). Brak płynu w siatkówce w badaniu OCT (optyczna koherentna tomografia) zanotowano w 45,2% oczu leczonych ranibizumabem i 59,8% oczu leczonych bewacizumabem (różnica statystycznie nieistotna, p = 0,28). Utrata o mniej niż 1 linię BCVA wystąpiła w 93,5% oczu leczonych ranibizumabem i 100% oczu leczonych bewacizumabem (różnica statystycznie nieistotna, p = 0,17).
Wnioski. Ranibizumab i bewacizumab wykazują podobną efektywność w zakresie stabilizacji ostrości wzroku oraz eliminacji płynu siatkówkowego u pacjentów z wysiękową postacią AMD po rocznym okresie leczenia.
Introduction. Age-related macular degeneration (AMD) is the leading cause of severe visual loss in people over 50 years of age.
Aim. The aim of the study was to compare the results of exudative AMD treatment with intravitreal injections of two anti-vascular endothelial growth factor (anti-VEGF) drugs: ranibizumab and bevacizumab.
Material and methods. We selected treatment results of 55 patients with neovascular AMD and best corrected visual acuity (BCVA) equal or better than 1.0 (logMAR) for the retrospective analysis. The patients were treated with ranibizumab – 31 persons (31 eyes) and with bevacizumab – 24 persons (27 eyes). Mean follow-up period was one year.
Results. The mean BCVA did not deteriorate in both groups after one year of treatment (0.56 vs. 0.55 logMAR in the ranibizumab group and 0.62 vs. 0.60 logMAR in the bevacizumab group). Visual acuity stabilization/improvement was seen in 74.2% of eyes in ranibizumab group and 74.1% of eyes in bevacizumab group (statistically insignificant, p = 0.99). Absence of retinal fluid in OCT (optical coherence tomography) examination was noted in 45.2% of eyes in ranibizumab group and in 59.8% of eyes in bevacizumab group (statistically insignificant, p = 0.28). Loss of less than 1 line in BCVA was noted in 93.5% of eyes treated with ranibizumab and in 100% of eyes treated with bevacizumab (statistically insignificant, p = 0.17).
Conclusions. Ranibizumab and bevacizumab show similar effectiveness in stabilizing visual acuity and elimination of retinal fluid in patients with exudative AMD after one year of treatment.
Age-related macular degeneration (AMD) is the leading cause of severe visual loss in people over 50 years of age. Exudative form of this disease, which substance is the development of choroidal neovascularisation (CNV), leads to chorioretinal scar formation in the final stage. It occurs in 10-20% of patients affected but is responsible for 80-90% of cases of severe degeneration of visual acuity in the course of AMD (1).
Vascular endothelial growth factor (VEGF) is a protein mediator, stimulating angiogenesis primarily in hypoxic circumstances (1, 2). VEGF-A type is the primary signal for the development of CNV in the course of exudative AMD (3). The presence of VEGF-A has been observed in CNV membranes and its increased concentration has been discovered in the vitreous humour of patients with exudative AMD (1-3). It was found that the VEGF-A inhibitors administered intravitreally inhibit experimentally caused CNV in laboratory animals (4). Introduction of drugs blocking VEGF-A through intravitreal injections was a major advancement in the treatment of exudative AMD. Currently, among these drugs, two have the widest clinical use: ranibizumab (Lucentis, Novartis Pharma, Basel, Switzerland and Genentech, San Francisco, USA) and bevacizumab (Avastin, Genentech, San Francisco, USA). Ranibizumab is a Fab fragment (antibody binding fragment) of a recombinant, humanised, monoclonal antibody which blocks all isoforms of VEGF-A (1, 5, 6). This drug has been approved for use in treatment of exudative AMD (5, 6). Its high clinical efficacy, not only related to stabilising but also improving visual acuity in the treatment of all types of CNV membranes in the course of AMD, has been proved by multicentre, randomized clinical trials MARINA and ANCHOR (7, 8). Bevacizumab is a full, recombinant, humanised monoclonal antibody which also blocks all isoforms of VEGF-A (1, 5, 6). Because the Fab domain of both drugs differs only by 6 amino acids (1), there are presumptions that they can have a similar clinical efficacy in the treatment of AMD. Bevacizumab is not approved for treatment of exudative AMD, but it is often used as an off-label alternative treatment. The main reason for this is a high cost of ranibizumab in comparison with bevacizumab.
The aim of the study is to compare functional and structural outcomes of the treatment of exudative AMD with intravitreal injections of two anti-VEGF drugs: ranibizumab and bevacizumab, in 12 month follow-up period.
MATERIAL AND METHODS
The results of the treatment of exudative AMD with intravitreal injections of anti-VEGF drugs: ranibizumab and bevacizumab, in 55 patients of the Department of Ophthalmology, Medical Center of Postgraduate Education were analysed retrospectively. For the analysis, 31 eyes of 31 patients (20 women and 11 men) aged 64-94 (average age 76.77 ± 6.56) treated with ranibizumab, and 27 eyes of 24 patients (18 women and 6 men) aged 56-88 (average age 75.91 ± 5.84) treated with bevacizumab were selected, with best corrected visual acuity (BCVA) equal or better than 1.0 logMAR. The presence of exudative AMD was confirmed on the basis of fundus fluorescein angiography – FA (Heidelberg Engineering). All types of lesions which size did not exceed 12 areas of the optic disc, without dominant haemorrhage, without features of permanent, structural damage of fovea (scarring or geographic atrophy), not previously treated for AMD, were eligible for the therapy. Before the treatment an examination of the fundus periphery was performed to exclude lesions which could risk retinal detachment. Patients with uncontrolled glaucoma were not qualified for injections. General criteria for exclusion were: uncontrolled hypertension, uncontrolled diabetes, unstable coronary heart disease, history of thromboembolic diseases more than 6 months ago.
Possibility of the treatment with ranibizumab depended on availability of the drug, while the treatment of bevacizumab depended on patient’s agreement. The treatment with bevacizumab was possible as an experimental study, after receiving a permission from the Bioethical Commission of the Center. All patients have signed informed consent. After the complete approval for ranibizumab to treat exudative AMD by National Health Committee, patients from the bevacizumab group were switched to ranibizumab group. This, together with BCVA selection criterion, resulted in the small number of patients, enrolled in this study.
The following treatment schedule was applied: three consecutive injections of ranibizumab in a 0.5 mg dose every 4 weeks or bevacizumab in a 1.25 mg dose every 6 weeks, both in a 0.05 ml of solution (so-called initial phase: 2 months for treatment with ranibizumab and 3 months for treatment with bevacizumab). Because the half-life of bevacizumab is assumed 150% of the half-life of ranibizumab in the vitreous humour (in rabbits: the half-life is 2.88 days for 0.5 mg of ranibizumab and 4.32 days for 1.25 mg of bevacizumab) (9, 10), and the recommended protocol for ranibizumab is every 4 weeks injection, some authors apply bevacizumab every 6 weeks. After the initial phase, subsequent injections in 4 or 6 week intervals respectively for each given drug were performed, depending on the need dictated by current outcomes of treatment. This schedule was applied on the basis on PrONTO and SUSTAIN trials which suggests elastic approach to the treatment i.e. continuation of the anti-VEGF drug injections (in the case of these studies – ranibizumab) after the initial phase, depending on the outcomes of the treatment, it allows maintaining proper therapeutic effects while minimising the number of injections (11). Monitoring the outcomes of treatments and qualification for next injection were carried out by means of visual acuity evaluation and optical coherence tomography OCT 3D (Topcon), performed every 4 or 6 weeks, in a week period before the prospective date of next injection. In selected cases, FA was performed to confirm the presence of active CNV. Qualification for the next injection was carried out on the basis of criteria applied in the PrONTO and SUSTAIN trials, and on the concept of “active change” (11). Those were: decrease of BCVA more than 1 line depending on active CNV, persistent accumulation of fluid in the lesion detected by OCT, dye leakage in FA, enlargement of the lesion detected by FA, new or persistent haemorrhage.
Injections of the drugs were administered in operating room conditions, with aseptic procedures adopted. Topical anaesthesia of conjunctival sac was used. Prior to injection, a 5% povidone solution was administered to the conjunctival sac for 1.5 minutes. Both drugs were administered via tuberculin syringe in 0.05 ml volume, in 3.5 mm distance from the corneal limbus. In the pre-surgery period (3 days) and in the post-surgery period (4 days) a patient was given antibiotic drops (ofloxacin) administered locally 4 times a day. On the day of injection, in the morning, patients received 2 tablets of acetazolamide (500 mg) per os to prevent a potential increase of intraocular pressure related to the treatment. The intraocular pressure was measured 30 minutes after the treatment with a pneumotonometer. Follow-up visits took place 1-2 days and 7 days after the treatment.
Comparison of the treatment outcomes between the two groups was performed after the initial phase (2 and 3 months of treatment respectively for the ranibizumab group and the bevacizumab group) and after 1 year of treatment on average (10-14 months). Chi-square test was used for statistical analysis and p values of less than 0.05 was considered statistically significant.
Mean BCVA (logMAR) before the treatment was 0.56 (± 0.34 SD) in the group treated with ranibizumab and 0.62 (± 0.32 SD) in the group treated with bevacizumab. After the initial phase, BCVA was 0.53 (± 0.34 SD) in the ranibizumab group and 0.59 (± 0.33 SD). After 1 year of therapy, BCVA remained on the before-treatment level in both groups, and amounted to 0.55 (± 0.36 SD) for the ranibizumab treated group and to 0.60 (± 34 SD) in the bevacizumab treated group.
Considering the natural course and prognosis of untreated exudative AMD, which is an average loss of approximately 3 lines in VA after 1 year of the duration of the disease (12) we have determined the percentage of eyes with loss of less than 3 lines after 1 year of treatment. In both groups it was very high and amounted to 93.5% in the ranibizumab treated group and 100% in the bevacizumab treated group (statistically insignificant difference, p = 0.17, chi-square test). In both groups we also calculated the percentage of eyes which did not lose even a single line (stabilization and improvement of the VA) after 3 injections and 1 year of treatment, what means, in the case of qualification for treatment criteria adopted, that they maintained BCVA ≤ 1.0 (logMAR). This was also a very high and comparable percentage of eyes: after 3 injections it amounted to 80.6% in the ranibizumab treated group and 81.5% in the bevacizumab treated group (statistically insignificant difference, p = 0.93, chi-square test), and after 1 year of treatment: 74.2 and 74.1% respectively (statistically insignificant difference, p = 0.99, chi-square test). Absence of fluid in the area of lesion in OCT after 3 injections was very well correlated with the stabilization/improvement of VA in the ranibizumab treated group (no indication of fluid in 80.6% of eyes), whereas to a lesser degree in the bevacizumab treated group (no indication of fluid in 63% of eyes) (statistically insignificant difference, p = 0.13, chi-square test). After 1 year of treatment, absence of fluid was observed in a lesser percentage of eyes: 45.2% in the ranibizumab treated group and in 59.8% in the bevacizumab treated group (statistically insignificant difference, p = 0.28, chi-square test).
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