Comparative Safety of Bevacizumab, Ranibizumab, and Aflibercept for Treatment of Neovascular Age-Related Macular Degeneration (AMD): A Systematic Review and Network Meta-Analysis of Direct Comparative Studies
Abstract
:1. Introduction
2. Materials and Methods
2.1. Search Strategy
2.2. Selection of Studies
2.3. Inclusion and Exclusion Criteria
- (P) Study population: patients diagnosed with neovascular AMD
- (I) Interventions of interest: intravitreal BVZ, RBZ or AFB
- (C) Treatment comparisons: BVZ, RBZ and AFB
- (O) Outcomes of interest: any safety data reported (death, systemic and ocular serious adverse events)
- (T) Minimal follow-up period: 1 year
- (S) Studies were designed as RCTs. Studies published in English were eligible for inclusion in the review. Only studies that provided sufficient data of safety outcomes with at least 1-year follow-up and compared the safety of the following interventions: 1.25 mg BVZ or 0.5 mg RBZ monthly, as needed (pro re nata) or a treat-and-extend regimen, 2 mg AFB every 2 months or treat-and-extend regimen after 3 initial monthly doses (2q8), were included for network meta-analysis (NMA).
2.4. Data Extraction
2.5. Outcomes of Interest
2.6. Risk of Bias Assessment
2.7. Statistical Analysis
2.8. Sensitivity Analysis
3. Results
3.1. Characteristics of Included Studies and Quality Assessment
3.2. Risk of Bias Assessment
3.3. Safety Analysis
3.3.1. BVZ vs. RBZ
3.3.2. AFB vs. RBZ
3.3.3. AFB vs. BVZ
3.3.4. Synthetic Comparison of Three Options
4. Discussion
4.1. Limitations
4.2. Strengths
5. Conclusions
Supplementary Materials
Author Contributions
Acknowledgments
Conflicts of Interest
References
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Bevacizumab (BVZ) | Ranibizumab (RBZ) | Aflibercept (AFB) | |
---|---|---|---|
Manufacturer | Avastin; Genetech, South San Francisco, CA, USA | Lucentis; Genetech, South San Francisco, CA, USA | Eylea; Regeneron Pharmaceuticals, Tarrytown, NY, USA |
Type of molecule | Full-size recombinant humanized IgG1 kappa monoclonal antibody | Fab fragment of a recombinant humanized IgG1 kappa isotype murine monoclonal antibody | Fusion protein of the second Ig domain of human vascular endothelial growth factor receptor 1 (VEGFR-1) and the third Ig-binding domain of human VEGFR-2 with the constant fragment crystallizable portion of the human IgG1 |
Molecular weight | 149 kDa | 48 kDa | 115 kDa |
Picture | |||
Comments | N-glycosylated in its Fc region | Not glycosylated | NA |
Production | Mammalian cell lines CHO DP-12 | Escherichia coli cells, recombinant DNA technology | Hamster ovary cells |
Receptor-ligand interaction | Against all isoforms of VEGF-A | Against all isoforms of VEGF-A | Binds to all isoforms of VEGF-A (higher affinity than BVZ and RBZ); also binding to VEGF-B and Placental Growth Factor (PIGF). |
Authorization in the USA | FDA in 2005, colorectal and breast cancers, used in AMD off-label | FDA in 2006, AMD | FDA—2011, AMD |
Reason for Exclusion | Number of Articles Excluded |
---|---|
All references identified | 4043 |
Duplicates | 2975 |
Unique references | 1068 |
Excluded unique references | |
Reviews | 22 |
Brachytherapy | 5 |
Combined anti-VEGF treatment | 8 |
Central retinal vein occlusion (CRVO) | 15 |
Diabetes macular edema | 61 |
Less than one-year follow-up | 31 |
Mixed diagnosis AMD and macular degeneration (MD) caused diabetic macular edema (DME)/ Polypoidal choroidal vasculopathy (PCV) | 7 |
Photodynamic therapy(PDT) | 5 |
Switch | 28 |
Other reasons for exclusion (no direct comparison, secondary analysis, observational studies, etc.) | 747 |
Not published as a full manuscript (no safety data available) | 13 |
Included unique references | |
RCT | 33 (12 unique studies) |
Author Study | Treatment Groups | Regimen Doses | Following Months | Number of Patients: BVZ/RBZ or AFB/RBZ | Age, Years |
---|---|---|---|---|---|
CATT 1 (2011) | BVZ OR RBZ | 0.50 mg/in 0.05 mL RBZ or 1.25 mg/0.05 mL BVZ cont/discont | 12 m | 586/599 | 79.7/78.8 |
CATT 2 | BVZ OR RBZ | 0.50 mg/in 0.05 mL RBZ or 1.25 mg/0.05 mL BVZ cont/discont | 24 m | 586/599 | 79.7/78.8 |
IVAN 2012 | BVZ OR RBZ | 1.1.1.1 cont/discont regimen BRZ (0.5 mg) or BVZ (1.25 mg) | 12 m | 296/314 | 77.8/77.7 |
IVAN 2013 | BVZ OR RBZ | 1.1.1.1 cont/discont regimen BRZ (0.5 mg) or BVZ (1.25 mg) | 24 m | 296/314 | 77.8/77.7 |
GEFAL 2013 | BVZ OR RBZ | BVZ 1.25 mg or RBZ 0.50 mg in 0.05 mL of solution following treat-and-extend protocol | 12 m | 191/183 | 79.6/78.7 |
BRAMD 2016 | BVZ OR RBZ | Monthly 1.25 mg BVZ or 0.5 mg RBZ | 12 m | 161/166 | 79/78 |
LUCAS 2015 | BVZ OR RBZ | RBZ 0.5 mg or BVZ 1.25 mg following a treat-and-extend protocol | 24 m | 213/218 | 62/78 |
MANTA 2013 | BVZ OR RBZ | RBZ 0.5 mg or BVZ 1.25 mg following a treat-and-extend protocol | 12 m | 154/163 | 76.7/77.6 |
Biswas 2011 | BVZ OR RBZ | RBZ 0.5 mg or BVZ 1.25 mg monthly | 18 m | 50/54 | 64.4/63.5 |
VIEW 1 | AFB OR RBZ | AFB 0.5 mg monthly (0.5q4), 2 mg monthly (2q4), 2 mg every 2 months after 3 initial monthly doses (2q8), or RBZ 0.5 mg monthly (Rq4) | 24 m | 911/304 | 78/78 |
VIEW 2 | 24 m | 913/291 | 74/73 | ||
RIVAL | AFB OR RBZ | AFB 2.0 mg OR 0.5 mg RBZ in a treat-and-extend regimen | 24 m | 139/142 | 76.6/78.7 |
CATT 2 | IVAN2 | Gefal | BRAMD | LUCAS2 | MANTA | Biswas | VIEW12 | RIVAL2 | |
---|---|---|---|---|---|---|---|---|---|
patients dead | Y | Y | Y | Y | Y | Y | Y | Y | Y |
patients with ≥ 1 systemic SAE | Y | Y | Y | N | Y | Y | Y | Y | Y |
patients dead from cardiovascular (CV) event | Y | Y | Y | N | Y | N | Y | Y | Y |
patients with ≥ 1 venous thrombotic events | Y | Y | Y | N | Y | Y | Y | N | N/av |
patients with ≥ 1 atherotrombotic events | Y | Y | Y | N | Y | Y | Y | Y | Y |
patients with ≥1 ocular SAE | CATT1 only | Y | Y | N | N | Y | Y | Y | N/av |
endophtalmitis | Y | N | Y | N | Y | Y | Y | Y | Y |
pseudoendophtalmitis | Y | N | N | N | Y | Y | Y | N | N/av |
patients with retinal pigment epithelium tear | CATT1 only | Y | N | N | Y | Y | Y | Y | N/av |
new macular atrophy | Y | Y | N | N | N | N | N | Y | Y |
dropout rate | Y | Y | Y | Y | Y | Y | Y | Y | Y |
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Plyukhova, A.A.; Budzinskaya, M.V.; Starostin, K.M.; Rejdak, R.; Bucolo, C.; Reibaldi, M.; Toro, M.D. Comparative Safety of Bevacizumab, Ranibizumab, and Aflibercept for Treatment of Neovascular Age-Related Macular Degeneration (AMD): A Systematic Review and Network Meta-Analysis of Direct Comparative Studies. J. Clin. Med. 2020, 9, 1522. https://doi.org/10.3390/jcm9051522
Plyukhova AA, Budzinskaya MV, Starostin KM, Rejdak R, Bucolo C, Reibaldi M, Toro MD. Comparative Safety of Bevacizumab, Ranibizumab, and Aflibercept for Treatment of Neovascular Age-Related Macular Degeneration (AMD): A Systematic Review and Network Meta-Analysis of Direct Comparative Studies. Journal of Clinical Medicine. 2020; 9(5):1522. https://doi.org/10.3390/jcm9051522
Chicago/Turabian StylePlyukhova, Anna A., Maria V. Budzinskaya, Kirill M. Starostin, Robert Rejdak, Claudio Bucolo, Michele Reibaldi, and Mario D. Toro. 2020. "Comparative Safety of Bevacizumab, Ranibizumab, and Aflibercept for Treatment of Neovascular Age-Related Macular Degeneration (AMD): A Systematic Review and Network Meta-Analysis of Direct Comparative Studies" Journal of Clinical Medicine 9, no. 5: 1522. https://doi.org/10.3390/jcm9051522