| Summary: | <p><strong>Topic:</strong> To compare bevacizumab, ranibizumab, aflibercept and laser as primary therapies for retinopathy of prematurity (ROP) in terms of retreatment rate.</p>
<p><strong>Clinical relevance:</strong> Anti-VEGF agents are increasingly used as primary treatment for ROP and may provide superior outcomes compared with laser in posterior disease. Head-to-head comparisons between different anti-VEGFs are lacking.</p>
<p><strong>Methods:</strong> We searched CENTRAL, EMBASE, MEDLINE and CINAHL for randomised controlled trials and non-randomised comparative studies as of March 2022. We included studies that used bevacizumab, ranibizumab, aflibercept and laser for ROP with comparable cohorts and treatment criteria. Studies were evaluated by the GRADE framework and those with biased case selection, non-randomised case-control, or lack of control group were excluded. Frequentist meta-analyses of proportions were performed to determine the absolute primary retreatment rate of each modality followed by Bayesian network meta-analyses to compare pairs of treatments in Type 1 and Zone I ROP.</p>
<p><strong>Results:</strong> 30 studies (4686 eyes) were included in the network meta-analyses. For Type 1 ROP, single treatment success rates (i.e. likelihood of needing no further treatment) were 89.3% (95% CI: 83.8-93.8; n=1552) for laser, 87.0% (78.6-93.8; n=2081) for bevacizumab, 80.7% (62.0-94.4; n=326) for aflibercept, and 74.0% (62.7-84.1; n=727) for ranibizumab. Bayesian network meta-analysis indicates that laser is associated with a significant 62% (95% CrI: 16-83) reduction in retreatment risk compared with ranibizumab, while no significant differences were found between other pair-wise comparisons. The mean time to secondary treatment following primary aflibercept (12.96 weeks ±0.47 SEM) and bevacizumab (11.36±0.54) were significantly longer than primary ranibizumab (9.29±0.43) therapy (p=7E-07 and p=9E-03 respectively). For Zone I ROP, single treatment success rates were 91.2% (83.6-96.9; n=231) for bevacizumab, 78.3% (61.4-91.9; n=100) for ranibizumab, and 65.9% (41.4-87.2; n=158) for laser. In this case, Bayesian network meta-analysis suggests that primary bevacizumab is associated with a significant 67% (10-90) reduction in retreatment risk compared with laser. No moderating effects were found to arise from gestational age, birth weight, or post-menstrual age at treatment when considering each modality in isolation using a frequentist approach.</p>
<p><strong>Conclusions:</strong> Laser was associated with a lower rate of retreatment than ranibizumab in Type 1 ROP (Zones I and II combined), while bevacizumab was associated with lower rate of retreatment than laser in Zone I ROP. Aflibercept and bevacizumab demonstrate longer duration of action than ranibizumab for ROP.</p>
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