A systematic review and meta-analysis of the effect of intravitreal VEGF inhibitors on cardiorenal outcomes

Background: Vascular endothelial growth factor inhibitors (VEGFi) have transformed the treatment of many retinal diseases, including diabetic maculopathy. Increasing evidence supports systemic absorption of intravitreal VEGFi and development of significant cardiorenal side effects. Methods: Systematic review and meta-analysis (PROSPERO: CRD42020189037) of randomised controlled trials of intravitreal VEGFi treatments (bevacizumab, ranibizumab and aflibercept) for any eye disease. Outcomes of interest were cardiorenal side effects (hypertension, proteinuria, kidney function decline and heart failure). Fixed-effects meta-analyses were conducted where possible. Results: There were 78 trials (81 comparisons; 13 175 participants) that met criteria for inclusion: 47% were trials in diabetic eye disease. Hypertension (29 trials; 8570 participants) was equally common in VEGFi and control groups (7.3 versus 5.4%; RR 1.08 [0.91; 1.28]). New or worsening heart failure (10 trials; 3384 participants) had similar incidence in VEGFi and control groups (RR 1.03 [0.70; 1.51]). Proteinuria (5 trials; 1902 participants) was detectable in some VEGFi-treated participants (0.2%) but not controls (0.0%; RR 4.43 [0.49; 40.0]). Kidney function decline (9 trials; 3471 participants) was similar in VEGFi and control groups. In participants with diabetic eye disease, risk of all-cause mortality was higher in VEGFi-treated participants (RR 1.62 [1.04; 2.46]). Conclusion: In trials of intravitreal VEGFi, we did not identify an increased risk of cardiorenal outcomes, though these outcomes were reported in only a minority of cases. There was an increased risk of death in VEGFi-treated participants with diabetic eye disease. Additional scrutiny of post-licensing observational data may improve recognition of safety concerns in VEGFi-treated patients