Serious Adverse Events with Bevacizumab or Ranibizumab for Age-Related Macular Degeneration: Meta-analysis of Individual Patient Data

Abstract

A comparison between ranibizumab and bevacizumab of the incidence of systemic serious adverse events (SAEs) among patients with neovascular age-related macular degeneration (nAMD) who participated in a large-scale randomized trial. Use of individual patient data, rather than aggregate data, allowed adjustment for strong predictors of SAEs. Relative safety of ranibizumab and bevacizumab is important in choosing an anti-VEGF drug for the hundreds of thousands of patients with nAMD treated each year worldwide. Results of a Cochrane aggregate meta-analysis of the relative efficacy and safety of bevacizumab and ranibizumab that used searches of bibliographic databases and clinical trial registries as of March 14, 2014 and hand searching were reviewed to identify 6 large-scale, multicenter clinical trials. Individual patient data on SAEs, assigned drug and dosing regimen, and baseline prognostic factors were requested from the leaders of the 6 trials. A two-stage approach was used to estimate relative risks and 95% confidence intervals (CIs) from Cox proportional hazards models adjusting for baseline prognostic factors. The primary outcome measure was development of ≥1 SAE; secondary outcome measures were death, arteriothrombotic events, events associated with systemic anti-VEGF therapy, and events not associated with systemic anti-VEGF therapy. Individual patient data were received from 5 trials to provide information on 3052 patients. There were no large imbalances between drug groups on baseline factors. The adjusted relative risk (95% CI) for bevacizumab relative to ranibizumab was 1.06 [(0.84, 1.35); p=0.61] for ≥1 SAEs. For secondary outcomes, adjusted relative risks were 0.99 [ (0.69, 1.43); p=0.97] for death, 0.89 [ (0.62, 1.28); p=0.53] for arteriothrombotic events, 1.10 [ (0.81, 1.50); p=0.54] for events related to anti-VEGF treatment, and 1.11 [ (0.87, 1.40); p=0.40] for events not related to anti-VEGF treatment. Our findings support the absence of large differences in risk of systemic serious adverse events between these two anti-VEGF drugs; i.e., relative risks of ≥1.5 are unlikely. Because additional head-to-head trials are unlikely, any further investigation of differential risk between anti-VEGF agents will only be achieved though post-marketing surveillance or through the interrogation of healthcare databases.