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Ranibizumab vs. Aflibercept for Macular Edema due to Central Retinal Vein Occlusion
Reports Ranibizumab vs. Aflibercept for Macular Edema due to Central Retinal Vein Occlusion Central retinal vein occlusion (CRVO) is the second-most common retinal vascular disorder, following diabetic retinopathy, affecting mainly the adult population; it considered to be an important cause of visual loss.1 Ranibizumab (Lucentis, Novartis, Basel, Switzerland) was approved by the US Food and Drug Administration for the treatment of macular edema secondary to CRVO, showing resolution of macular edema and improvement in visual acuity (VA) in a long-term follow-up.2 Similarly, aflibercept (Eylea, Bayer Healthcare, Leverkusen, Germany) has been proven to be safe and effective in patients with CRVO in the large trials COPERNICUS and GALILEO.3,4 Real-life data based on protocols, which can be different from those used in clinical trials, also demonstrate significant anatomical and visual improvement in patients with CRVO who were treated with intravitreal ranibizumab or aflibercept in a variable follow-up period.5 However, there is, to our knowledge, no comparative study between the 2 approved antievascular endothelial growth factor (anti-VEGF) agents that evaluates VA, central subfield thickness (CST), as well as optical coherence tomography (OCT) characteristics in treatment-naïve patients with macular edema due to CRVO. In light of the above, the purpose of this pilot study was to compare the efficacy and safety of 2 anti-VEGF agents (i.e., ranibizumab and aflibercept) for the treatment of macular edema due to CRVO in a follow-up time of 12 months. Participants in the retrospective pilot study were 46 patients (46 eyes) with macular edema due to CRVO (CST >320 micrometers) who were treated either with 0.5 mg of ranibizumab intravitreally (n ¼ 25) or with 2.0 mg of aflibercept (n ¼ 21) and had a follow-up period of 12 months. A switch of treatment was not permitted during the follow-up period. Patients with age-related macular degeneration, diabetic retinopathy, history of vitrectomy, previous laser photocoagulation, previous anti-VEGF injection, uncontrolled glaucoma, uveitis, or dense cataract, as well as those lost to follow-up, were excluded from the study. The study adhered to the Declaration of Helsinki and was approved by the institutional review board of the participating hospitals. Written informed consent was obtained from all participants. All patients received 3 intravitreal injections of either 0.5 mg of ranibizumab or 2.0 mg of aflibercept to the affected eye and pro re nata thereafter, if a decrease in best-corrected VA (BCVA) 1 Snellen line, an increase in CST 50 micrometers, or presence of intraretinal/subretinal fluid in OCT was observed. If neovascularization was detected, scatter or panretinal photocoagulation was performed, as appropriate. All patients underwent clinic-based BCVA measurement at each visit. Spectral domain OCT and fluorescein angiography were performed at baseline using Spectralis equipment (Spectralis HRAOCT, Heidelberg Engineering, Heidelberg, Germany), whereas spectral domain OCT was done monthly thereafter. To assess the retinal ischemia, fluorescein angiography was done every 6 months or earlier, at a physician’s discretion. The total number of injections
was also recorded. Statistical analysis was performed using SPSS 22.0 statistical software (SPSS Inc, Chicago, IL). A P value of <0.05 was considered significant in cases other than those in which the Bonferroni correction was adopted. Table 1 shows the demographic and clinical characteristics of our study sample. At baseline, the mean BCVA was 54.89.1 Early Treatment Diabetic Retinopathy Study letters in ranibizumab group and 53.48.7 Early Treatment Diabetic Retinopathy Study letters in aflibercept group (P ¼ 0.478). The mean BCVA showed significant improvement from baseline at all time points in both groups (P < 0.0001 and P < 0.0001 for ranibizumab and aflibercept group respectively) and did not differ between the 2 groups at any time point, except for month 6, when ranibizumab presented slightly better mean BCVA (63.77.2 vs. 58.86.0 letters for ranibizumab and aflibercept group respectively, P ¼ 0.007). Figure 1A (available online at www.ophthalmologyretina.org) shows the mean BCVA in each group at various time points. At month 12, patients in the ranibizumab group had gained 8.4 letters, whereas those in the aflibercept group gained 8.0 letters (P ¼ 0.885 between the 2 groups). Figure 2 (available online at www.ophthalmologyretina.org) shows the percentage of patients who gained 5, 10, or 15 letters at month 12. The mean CST at baseline was 586.9141.3 micrometers in the ranibizumab group and 607.3105.3 micrometers in the aflibercept group (P ¼ 0.555). The mean CST showed significant reduction from baseline in both groups (P < 0.0001 regarding all comparisons). There was no statistically significant difference in CST
Table 1. Demographic and Clinical Characteristics of Our Study Sample at Baseline Ranibizumab (n [ 25)
Aflibercept (n [ 21)
Mean SD Age. yrs Best-corrected visual acuity, letters Central subfield thickness, micrometers
P value
62.37.1 54.89.1
65.16.1 53.48.7
0.108 0.478
586.9141.3
607.3105.3
0.555
n (%) Gender Male Female Open-angle glaucoma Hypertension Diabetes mellitus Hyperlipidemia Ischemic type Duration <3 mos Type of macular edema Cystoid Diffuse
14 11 9 17 3 15 7 17
(56) (44) (36) (68) (12) (60) (28) (68)
20 (80) 5 (20)
11 10 6 15 2 13 5 16
(52.4) (47.6) (28.6) (71.4) (9.5) (61.9) (23.8) (76.2)
17 (81) 4 (19)
0.817 0.078 0.213 0.175 0.777 0.082 0.079 0.913
SD ¼ standard deviation.
1
Ophthalmology Retina Volume -, Number -, Month 2016 between the 2 groups at any time point, although at month 6, the ranibizumab group presented a greater decrease in CST, which did not reach significance (P ¼ 0.087). Figure 1B (available online at www.ophthalmologyretina.org) shows the mean CST in each group over time. The mean change in CST was 260 micrometers in the ranibizumab group and 234 micrometers in the aflibercept group at month 12, and it did not differ significantly between the 2 groups (P ¼ 0.147). At month 12, 13 out of 25 patients (52%) in the ranibizumab group and 10 out of 21 patients (47.6%) in the aflibercept group presented total resolution of macular edema. The mean numbers of injections were 5.11.1 and 4.62.3 in the ranibizumab and aflibercept groups, respectively (P ¼ 0.137). No serious adverse ocular or systemic side effects were reported from any of the patients in the study. In our study, the change in BCVA at month 12 compared with baseline was þ8.4 letters in the ranibizumab group and þ8.0 letters in the aflibercept group, which was inferior to the results reported by the pivotal CRUISE, COPERNICUS, and GALILEO studies.2e4 This observation could be partially explained by the fact that in our study, 28% and 23.8% of patients in the ranibizumab and aflibercept groups, respectively, had ischemic CRVO, a percentage that is higher than that in either the COPERNICUS or GALILEO study, whereas the CRUISE study did not include ischemic cases at all.2,4,5 The superiority of the outcomes in clinical trials compared with those of real-life data could also be attributed to the different treatment regimen (i.e., fixed dose regimen of 6 monthly injections and pro re nata thereafter in clinical trials compared with 3 monthly injections and pro re nata in our study). Another possible explanation of the discrepancy in the outcomes between clinical trials and real-life data studies could be the fact that the patients in clinical trials were selected based on strict and specific criteria, whereas patients in daily practice did not meet these restrictions. In conclusion, our study showed similar efficacy of a similar number of injections of ranibizumab and aflibercept with regards to visual and anatomical outcomes in treatment-naïve patients with macular edema due to CRVO at the 12-month follow-up. However, this is a pilot study with a relatively small sample size; therefore, further studies examining the noninferiority of aflibercept compared with ranibizumab with a large sample size are needed to validate our results.
IRINI CHATZIRALLI, MD, PHD1 GEORGE THEODOSSIADIS, MD, PHD2 MARILITA M. MOSCHOS, MD, PHD3
2
PANAGIOTIS MITROPOULOS, MD4 PANAGIOTIS THEODOSSIADIS, MD, PHD1 1 Second Department of Ophthalmology, Attikon Hospital, University of Athens, Athens, Greece; 2Second Department of Ophthalmology, Henry Dunant Hospital, Athens, Greece; 3First Department of Ophthalmology, University of Athens, Athens, Greece; 4Second Department of Ophthalmology, Ophthalmiatrion Athinon, Athens, Greece
Financial support: None. Conflict of interest: The authors declare no conflict of interest. Author Contributions: Research design: Chatziralli Data analysis and/or interpretation: Chatziralli, G. Theodossiadis Data acquisition and/or research execution: Chatziralli, G. Theodossiadis, Moschos, Mitropoulos, P. Theodossiadis Manuscript preparation: Chatziralli, G. Theodossiadis Abbreviations and Acronyms: BCVA ¼ best-corrected visual acuity; CRV ¼ central retinal vein occlusion; CST ¼ central subfield thickness; OCT ¼ optical coherence tomography; VA ¼ visual acuity. Correspondence: Irini Chatziralli, MD, MSc, PhD, FEBO, 28, Papanastasiou Street, Agios Dimitrios, 17342, Athens, Greece. E-mail: [email protected].
References 1. Cugati S, Wang JJ, Rochtchina E, Mitchell P. Ten-year incidence of retinal vein occlusion in an older population: the Blue Mountains Eye Study. Arch Ophthalmol. 2006;124(5):726e732. 2. Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118(10):2041e2049. 3. Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study. Ophthalmology. 2014;121(7):1414e1420. 4. Ogura Y, Roider J, Korobelnik JF, et al. Intravitreal aflibercept for macular edema secondary to central retinal vein occlusion: 18-month results of the phase 3 GALILEO study. Am J Ophthalmol. 2014;158(5):1032e1038. 5. Farinha C, Marques JP, Almeida E, et al. Treatment of retinal vein occlusion with ranibizumab in clinical practice: longerterm results and predictive factors of functional outcome. Ophthalmic Res. 2015;55(1):10e18.
was also recorded. Statistical analysis was performed using SPSS 22.0 statistical software (SPSS Inc, Chicago, IL). A P value of <0.05 was considered significant in cases other than those in which the Bonferroni correction was adopted. Table 1 shows the demographic and clinical characteristics of our study sample. At baseline, the mean BCVA was 54.89.1 Early Treatment Diabetic Retinopathy Study letters in ranibizumab group and 53.48.7 Early Treatment Diabetic Retinopathy Study letters in aflibercept group (P ¼ 0.478). The mean BCVA showed significant improvement from baseline at all time points in both groups (P < 0.0001 and P < 0.0001 for ranibizumab and aflibercept group respectively) and did not differ between the 2 groups at any time point, except for month 6, when ranibizumab presented slightly better mean BCVA (63.77.2 vs. 58.86.0 letters for ranibizumab and aflibercept group respectively, P ¼ 0.007). Figure 1A (available online at www.ophthalmologyretina.org) shows the mean BCVA in each group at various time points. At month 12, patients in the ranibizumab group had gained 8.4 letters, whereas those in the aflibercept group gained 8.0 letters (P ¼ 0.885 between the 2 groups). Figure 2 (available online at www.ophthalmologyretina.org) shows the percentage of patients who gained 5, 10, or 15 letters at month 12. The mean CST at baseline was 586.9141.3 micrometers in the ranibizumab group and 607.3105.3 micrometers in the aflibercept group (P ¼ 0.555). The mean CST showed significant reduction from baseline in both groups (P < 0.0001 regarding all comparisons). There was no statistically significant difference in CST
Table 1. Demographic and Clinical Characteristics of Our Study Sample at Baseline Ranibizumab (n [ 25)
Aflibercept (n [ 21)
Mean SD Age. yrs Best-corrected visual acuity, letters Central subfield thickness, micrometers
P value
62.37.1 54.89.1
65.16.1 53.48.7
0.108 0.478
586.9141.3
607.3105.3
0.555
n (%) Gender Male Female Open-angle glaucoma Hypertension Diabetes mellitus Hyperlipidemia Ischemic type Duration <3 mos Type of macular edema Cystoid Diffuse
14 11 9 17 3 15 7 17
(56) (44) (36) (68) (12) (60) (28) (68)
20 (80) 5 (20)
11 10 6 15 2 13 5 16
(52.4) (47.6) (28.6) (71.4) (9.5) (61.9) (23.8) (76.2)
17 (81) 4 (19)
0.817 0.078 0.213 0.175 0.777 0.082 0.079 0.913
SD ¼ standard deviation.
1
Ophthalmology Retina Volume -, Number -, Month 2016 between the 2 groups at any time point, although at month 6, the ranibizumab group presented a greater decrease in CST, which did not reach significance (P ¼ 0.087). Figure 1B (available online at www.ophthalmologyretina.org) shows the mean CST in each group over time. The mean change in CST was 260 micrometers in the ranibizumab group and 234 micrometers in the aflibercept group at month 12, and it did not differ significantly between the 2 groups (P ¼ 0.147). At month 12, 13 out of 25 patients (52%) in the ranibizumab group and 10 out of 21 patients (47.6%) in the aflibercept group presented total resolution of macular edema. The mean numbers of injections were 5.11.1 and 4.62.3 in the ranibizumab and aflibercept groups, respectively (P ¼ 0.137). No serious adverse ocular or systemic side effects were reported from any of the patients in the study. In our study, the change in BCVA at month 12 compared with baseline was þ8.4 letters in the ranibizumab group and þ8.0 letters in the aflibercept group, which was inferior to the results reported by the pivotal CRUISE, COPERNICUS, and GALILEO studies.2e4 This observation could be partially explained by the fact that in our study, 28% and 23.8% of patients in the ranibizumab and aflibercept groups, respectively, had ischemic CRVO, a percentage that is higher than that in either the COPERNICUS or GALILEO study, whereas the CRUISE study did not include ischemic cases at all.2,4,5 The superiority of the outcomes in clinical trials compared with those of real-life data could also be attributed to the different treatment regimen (i.e., fixed dose regimen of 6 monthly injections and pro re nata thereafter in clinical trials compared with 3 monthly injections and pro re nata in our study). Another possible explanation of the discrepancy in the outcomes between clinical trials and real-life data studies could be the fact that the patients in clinical trials were selected based on strict and specific criteria, whereas patients in daily practice did not meet these restrictions. In conclusion, our study showed similar efficacy of a similar number of injections of ranibizumab and aflibercept with regards to visual and anatomical outcomes in treatment-naïve patients with macular edema due to CRVO at the 12-month follow-up. However, this is a pilot study with a relatively small sample size; therefore, further studies examining the noninferiority of aflibercept compared with ranibizumab with a large sample size are needed to validate our results.
IRINI CHATZIRALLI, MD, PHD1 GEORGE THEODOSSIADIS, MD, PHD2 MARILITA M. MOSCHOS, MD, PHD3
2
PANAGIOTIS MITROPOULOS, MD4 PANAGIOTIS THEODOSSIADIS, MD, PHD1 1 Second Department of Ophthalmology, Attikon Hospital, University of Athens, Athens, Greece; 2Second Department of Ophthalmology, Henry Dunant Hospital, Athens, Greece; 3First Department of Ophthalmology, University of Athens, Athens, Greece; 4Second Department of Ophthalmology, Ophthalmiatrion Athinon, Athens, Greece
Financial support: None. Conflict of interest: The authors declare no conflict of interest. Author Contributions: Research design: Chatziralli Data analysis and/or interpretation: Chatziralli, G. Theodossiadis Data acquisition and/or research execution: Chatziralli, G. Theodossiadis, Moschos, Mitropoulos, P. Theodossiadis Manuscript preparation: Chatziralli, G. Theodossiadis Abbreviations and Acronyms: BCVA ¼ best-corrected visual acuity; CRV ¼ central retinal vein occlusion; CST ¼ central subfield thickness; OCT ¼ optical coherence tomography; VA ¼ visual acuity. Correspondence: Irini Chatziralli, MD, MSc, PhD, FEBO, 28, Papanastasiou Street, Agios Dimitrios, 17342, Athens, Greece. E-mail: [email protected].
References 1. Cugati S, Wang JJ, Rochtchina E, Mitchell P. Ten-year incidence of retinal vein occlusion in an older population: the Blue Mountains Eye Study. Arch Ophthalmol. 2006;124(5):726e732. 2. Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118(10):2041e2049. 3. Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study. Ophthalmology. 2014;121(7):1414e1420. 4. Ogura Y, Roider J, Korobelnik JF, et al. Intravitreal aflibercept for macular edema secondary to central retinal vein occlusion: 18-month results of the phase 3 GALILEO study. Am J Ophthalmol. 2014;158(5):1032e1038. 5. Farinha C, Marques JP, Almeida E, et al. Treatment of retinal vein occlusion with ranibizumab in clinical practice: longerterm results and predictive factors of functional outcome. Ophthalmic Res. 2015;55(1):10e18.