Comparing Intravitreal Aflibercept With Other DME Therapies
Comparing Intravitreal Aflibercept With Other DME Therapies
Severe retinopathy and presence of diabetic macular edema (DME) are associated with vision loss in patients with diabetes. Although focal laser photocoagulation has been the standard of care for DME it can only slow progression and its ability to reverse vision loss is low. Awareness of the role of vascular endothelial growth factors (VEGF and placental growth factor [PIGF]) and inflammatory mediators in stimulating retinal vasculogenesis and angiogenesis has led to the development and widespread use of anti-VEGF agents that can target these pathways.
Intravitreal aflibercept (IVT-AFL), which is composed of extracellular domains from human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin-G1 (IgG1), is a VEGF-A and PIGF inhibitor that blocks retinal cell migration and proliferation. Preclinical studies have shown that it has a longer duration of action than other anti-VEGF agents, and has 100-fold greater binding affinity to VEGF-A than intravitreal ranibizumab (IVR) (a recombinant humanized monoclonal antibody that inhibits VEGF-A). Clinical studies have demonstrated the efficacy and safety of these anti-VEGF agents compared with laser in DME patients. The IVT-AFL studies have supported its European license (i.e., five 2 mg injections every 4 weeks followed by 2 mg injections every 8 weeks [2q8]; with no requirement for monitoring between injections; after the first 12 months of treatment with IVT-AFL, the treatment interval may be extended based on visual and anatomic outcomes; the schedule for monitoring should be determined by the treating physician).
Meta-analyses have been undertaken to compare anti-VEGF agents, based on a lack of direct comparisons prior to the recent publication of the Protocol T study. However, some analyses have pooled IVR studies regardless of the posology or the nature of the comparator, and comparisons involving IVT-AFL have been based on only the DA VINCI study, which differs in design from the more recent phase III VIVID-DME and VISTA-DME studies in many aspects, including loading phase (DA VINCI included three initial loading doses in some arms compared with five in VIVID-DME and VISTA-DME). In addition, the meta-analysis by Virgili et al. contained a limited and exploratory indirect comparison of differences in efficacy among anti-VEGF agents (3-line gains only).
The aims of this study were to systematically identify and review studies informing the clinical effectiveness of IVT-AFL 2q8 in relation to comparator treatments and regimens licensed outside of the USA for the management of DME through mixed treatment and indirect comparison methods. The comparators of interest were: IVR 0.5 mg as needed (PRN), and implants of dexamethasone 0.7 mg or fluocinolone acetate 0.2 μg/day. Unlike the meta-analysis by Virgili et al., this study will consider a broader range of outcomes (including reporting of best-corrected visual acuity [BCVA] based on letters, which is used in most studies, rather than logarithm of the minimal angle of resolution) and will focus on a comparison of licensed anti-VEGF agents. The need for such an approach was supported by the limited outcome of the Virgili et al. meta-analysis.
Background
Severe retinopathy and presence of diabetic macular edema (DME) are associated with vision loss in patients with diabetes. Although focal laser photocoagulation has been the standard of care for DME it can only slow progression and its ability to reverse vision loss is low. Awareness of the role of vascular endothelial growth factors (VEGF and placental growth factor [PIGF]) and inflammatory mediators in stimulating retinal vasculogenesis and angiogenesis has led to the development and widespread use of anti-VEGF agents that can target these pathways.
Intravitreal aflibercept (IVT-AFL), which is composed of extracellular domains from human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin-G1 (IgG1), is a VEGF-A and PIGF inhibitor that blocks retinal cell migration and proliferation. Preclinical studies have shown that it has a longer duration of action than other anti-VEGF agents, and has 100-fold greater binding affinity to VEGF-A than intravitreal ranibizumab (IVR) (a recombinant humanized monoclonal antibody that inhibits VEGF-A). Clinical studies have demonstrated the efficacy and safety of these anti-VEGF agents compared with laser in DME patients. The IVT-AFL studies have supported its European license (i.e., five 2 mg injections every 4 weeks followed by 2 mg injections every 8 weeks [2q8]; with no requirement for monitoring between injections; after the first 12 months of treatment with IVT-AFL, the treatment interval may be extended based on visual and anatomic outcomes; the schedule for monitoring should be determined by the treating physician).
Meta-analyses have been undertaken to compare anti-VEGF agents, based on a lack of direct comparisons prior to the recent publication of the Protocol T study. However, some analyses have pooled IVR studies regardless of the posology or the nature of the comparator, and comparisons involving IVT-AFL have been based on only the DA VINCI study, which differs in design from the more recent phase III VIVID-DME and VISTA-DME studies in many aspects, including loading phase (DA VINCI included three initial loading doses in some arms compared with five in VIVID-DME and VISTA-DME). In addition, the meta-analysis by Virgili et al. contained a limited and exploratory indirect comparison of differences in efficacy among anti-VEGF agents (3-line gains only).
The aims of this study were to systematically identify and review studies informing the clinical effectiveness of IVT-AFL 2q8 in relation to comparator treatments and regimens licensed outside of the USA for the management of DME through mixed treatment and indirect comparison methods. The comparators of interest were: IVR 0.5 mg as needed (PRN), and implants of dexamethasone 0.7 mg or fluocinolone acetate 0.2 μg/day. Unlike the meta-analysis by Virgili et al., this study will consider a broader range of outcomes (including reporting of best-corrected visual acuity [BCVA] based on letters, which is used in most studies, rather than logarithm of the minimal angle of resolution) and will focus on a comparison of licensed anti-VEGF agents. The need for such an approach was supported by the limited outcome of the Virgili et al. meta-analysis.
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