Project description:Background: Antiangiogenic therapy with anti-vascular endothelial growth factor (VEGF) is commonly used to treat diabetic macular edema (DME), which can reduce edema, improve vision, and prevent further visual loss. There is little head-to-head trial data to guide the selection of an individual VEGF inhibitor. Therefore, we aimed to investigate the efficacy and safety of anti-VEGF for patients with DME and to assess the differences between clinically relevant options by using network meta-analysis (NMA). Methods: MEDLINE, Embase, the Cochrane Library, Web of Science, Chinese Biomedical Literature Database, Wanfang, China National Knowledge Infrastructure, and VIP databases were searched for published randomized controlled trials (RCTs) from their inception to November 2020. We included RCTs of anti-VEGF drugs (intravitreal aflibercept (IVT-AFL), intravitreal ranibizumab (IVR), and intravitreal conbercept (IVC)) treating adult patients who were diagnosed with DME, regardless of stage or duration of the disease. We estimated summary odds ratios (ORs) and mean differences (MDs) with 95% credible intervals (CrIs) using a Bayesian NMA. This study's registration number is CRD42021259335. Results: We identified 43 RCTs comprising 8,234 patients. Beneficial effects were observed in patients who used IVT-AFL compared with those who used other anti-VEGF therapies at 1-year follow-up on corrected visual acuity (BCVA) improvements (all patients: versus IVR: MD 2.83, 95% CrIs 1.64, 4.01, versus IVC: MD 2.41, 95% CrIs -0.52, 5.32; patients with worse baseline visual acuity (VA): versus IVR: MD 3.39, 95% CrIs 1.89, 4.9, versus IVC: MD 3.49, 95% CrIs 0.49, 6.44) and the proportion of patients with a gain of at least 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (all patients: versus IVR: OR 1.55, 95% CrIs 1.11, 2.17, versus IVC: OR 2.78, 95% CrIs 1.23, 6.04; patients with worse baseline VA: versus IVR: OR 2.05, 95% CrIs 1.18, 3.58, versus IVC: OR 2.85, 95% CrIs 1.24, 6.41). The effect of improvement in BCVA was identified for IVT-AFL compared to intravitreal bevacizumab. Based on the surface under the cumulative ranking curve (SUCRA), IVT-AFL had the highest probability of being the most effective option (99.9% and 99.5% in terms of the two primary outcomes, respectively). At the 2-year follow-up, numerical differences were identified favoring IVT-AFL; however, they did not reach statistical significance when comparing IVT-AFL to IVR. In the analysis of adverse events, IVT-AFL showed a lower risk of incidence of ocular adverse events compared to other anti-VEGF therapies at 1-year follow-up (versus IVR: OR 0.45, 95% CrIs 0.28, 0.7; versus IVC: OR 0.36, 95% CrIs 0.21, 0.63). Conclusion: IVT-AFL resulted in greater beneficial effects on BCVA and a higher proportion of patients with a gain of at least 15 ETDRS letters compared to IVR or IVC one year after treatment (especially in DME patients with worse baseline VA). In addition, fewer ocular adverse events occurred in the IVT-AFL group compared to the IVR or IVC groups. After two years, there was insufficient evidence to identify which anti-VEGF has superior efficacy or safety. Clinical Trial Registration: https://www.crd.york.ac.uk/prospero/, PROSPERO; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021259335, CRD42021259335.

Project description:Diabetes mellitus is a serious health problem that affects over 350 million individuals worldwide. Diabetic retinopathy (DR), which is the most common microvascular complication of diabetes, is the leading cause of new cases of blindness in working-aged adults. Diabetic macular edema (DME) is an advanced, vision-limiting complication of DR that affects nearly 30% of patients who have had diabetes for at least 20 years and is responsible for much of the vision loss due to DR. The historic standard of care for DME has been macular laser photocoagulation, which has been shown to stabilize vision and reduce the rate of further vision loss by 50%; however, macular laser leads to significant vision recovery in only 15% of treated patients. Mechanisms contributing to the microvascular damage in DR and DME include the direct toxic effects of hyperglycemia, sustained alterations in cell signaling pathways, and chronic microvascular inflammation with leukocyte-mediated injury. Chronic retinal microvascular damage results in elevation of intraocular levels of vascular endothelial growth factor A (VEGF), a potent, diffusible, endothelial-specific mitogen that mediates many important physiologic processes, including but not limited to the development and permeability of the vasculature. The identification of VEGF as an important pathophysiologic mediator of DME suggested that anti-VEGF therapy delivered to the eye might lead to improved visual outcomes in this disease. To date, four different inhibitors of VEGF, each administered by intraocular injection, have been tested in prospective, randomized phase II or phase III clinical trials in patients with DME. The results from these trials demonstrate that treatment with anti-VEGF agents results in substantially improved visual and anatomic outcomes compared with laser photocoagulation, and avoid the ocular side effects associated with laser treatment. Thus, anti-VEGF therapy has become the preferred treatment option for the management of DME in many patients.

Project description:PURPOSE:To assess systemic vascular endothelial growth factor (VEGF)-A levels after treatment with intravitreous aflibercept, bevacizumab, or ranibizumab. DESIGN:Comparative-effectiveness trial with participants randomly assigned to 2 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab after a re-treatment algorithm. PARTICIPANTS:Participants with available plasma samples (N = 436). METHODS:Plasma samples were collected before injections at baseline and 4-week, 52-week, and 104-week visits. In a preplanned secondary analysis, systemic-free VEGF levels from an enzyme-linked immunosorbent assay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES:Changes in the natural log (ln) of plasma VEGF levels. RESULTS:Baseline free VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were -0.30±0.61 pg/ml, -0.31±0.54 pg/ml, and -0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted confidence interval [CI]; P value) were -0.01 (-0.12 to +0.10; P = 0.89), -0.31 (-0.44 to -0.18; P < 0.001), and -0.30 (-0.43 to -0.18; P < 0.001) for aflibercept-bevacizumab, aflibercept-ranibizumab, and bevacizumab-ranibizumab, respectively. At 52 weeks, a difference in mean VEGF changes between bevacizumab and ranibizumab persisted (-0.23 [-0.38 to -0.09]; P < 0.001); the difference between aflibercept and ranibizumab was -0.12 (P = 0.07) and between aflibercept and bevacizumab was +0.11 (P = 0.07). Treatment group differences at 2 years were similar to 1 year. No apparent treatment differences were detected at 52 or 104 weeks in the cohort of participants not receiving injections within 1 or 2 months before plasma collection. Participants with (N = 9) and without (N = 251) a heart attack or stroke had VEGF levels that appeared similar. CONCLUSIONS:These data suggest that decreases in plasma free-VEGF levels are greater after treatment with aflibercept or bevacizumab compared with ranibizumab at 4 weeks. At 52 and 104 weeks, a greater decrease was observed in bevacizumab versus ranibizumab. Results from 2 subgroups of participants who did not receive injections within at least 1 month and 2 months before collection suggest similar changes in VEGF levels after stopping injections. It is unknown whether VEGF levels return to normal as the drug is cleared from the system or whether the presence of the drug affects the assay's ability to accurately measure free VEGF. No significant associations between VEGF concentration and systemic factors were noted.

Project description:BackgroundThe comparative safety and efficacy between anti-vascular endothelial growth factor agents (anti-VEGFs) and between combined therapies for patients with neovascular age-related macular degeneration (nAMD) is unclear. We conducted a systematic review to examine the comparative safety and efficacy anti-VEGFs for adults with nAMD.MethodsStudies were identified through MEDLINE, EMBASE, and Cochrane CENTRAL (inception to June 3, 2019), grey literature, and scanning reference lists. Two reviewers independently screened citations and full-text articles to identify randomized controlled trials (RCTs), extracted data, and appraised risk of bias. Pairwise random-effects meta-analysis and Bayesian network meta-analysis (NMA) were conducted. The primary outcomes were the proportion of patients experiencing moderate vision gain (≥ 15 letters on the Early Treatment Diabetic Retinopathy Study chart) and the proportion of patients experiencing moderate vision loss (≤ 15 letters).ResultsAfter screening 3647 citations and 485 potentially relevant full-text articles, 92 RCTs with 24,717 patients were included. NMA (34 RCTs, 8809 patients, 12 treatments) showed small differences among anti-VEGFs in improving the proportion of patients with moderate vision gain, with the largest for conbercept versus broluczumab (OR 0.15, 95% CrI: 0.05-0.56), conbercept versus ranibizumab (OR 0.17, 95% CrI: 0.05-0.59), conbercept versus aflibercept (OR 0.19, 95% CrI: 0.06-0.65), and conbercept versus bevacizumab (OR 0.2, 95% CrI: 0.06-0.69). In NMA (36 RCTs, 9081 patients, 13 treatments) for the proportion of patients with moderate vision loss, small differences were observed among anti-VEGFs, with the largest being for conbercept versus aflibercept (OR 0.24, 95% CrI: 0-4.29), conbercept versus brolucizumab (OR 0.24, 95% CrI: 0-4.71), conbercept versus bevacizumab (OR 0.26, 95% CrI: 0-4.65), and conbercept versus ranibizumab (OR 0.27, 95% CrI: 0-4.67).ConclusionThe only observed differences were that ranibizumab, bevacizumab, aflibercept, and brolucizumab were statistically superior to conbercept in terms of the proportion of patients with nAMD who experienced moderate vision gain. However, this finding is based on indirect evidence through one small trial comparing conbercept with placebo. This does not account for drug-specific differences when assessing anatomic and functional treatment efficacy in variable dosing regimens.Systematic review registrationPROSPERO registration number CRD42015022041.

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Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis.

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