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

Abstract

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.

Effect of intravitreal anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration on renal function

“…There are concerns about nephropathy after intravitreal anti-vascular endothelial growth factor (VEGF) treatment, which is commonly used in ophthalmic clinical practice for diseases such as age-related macular degeneration (nAMD) and diabetic macular oedema (DMO). 1,2 A recent systematic review and meta-analysis in this journal found trials of these drugs do not often report renal side effects, yet there is increasing evidence that systemic absorption of anti-VEGF drugs can cause renal dysfunction, due to systemic VEGF downregulation or direct drug-kidney interactions. 1,3 Cases reporting nephropathy tend to fall into one of two categories; those with underlying renal disease, who have accelerated disease progression following treatment; and those with new-onset kidney disease attributed to reduced systemic VEGF levels or allergic reactions (e.g.…”

“…1,2 A recent systematic review and meta-analysis in this journal found trials of these drugs do not often report renal side effects, yet there is increasing evidence that systemic absorption of anti-VEGF drugs can cause renal dysfunction, due to systemic VEGF downregulation or direct drug-kidney interactions. 1,3 Cases reporting nephropathy tend to fall into one of two categories; those with underlying renal disease, who have accelerated disease progression following treatment; and those with new-onset kidney disease attributed to reduced systemic VEGF levels or allergic reactions (e.g. thrombotic microangiopathy and acute interstitial nephritis).…”

Should patient enrollment criteria for anti‐VEGF phase III trials be reconsidered

“…[4][5][6] After the reports of increased mortality rates from several registration trials, patients who had experienced a cardiovascular or cerebrovascular event were excluded from studies for intravitreal anti-VEGF injection trials for DR. 5,7,8 In addition, for agerelated macular degeneration, registration trials with anti-VEGF agents specifically excluded patients with DR. [9][10][11][12][13] Unlike patients reported in registration and other randomized clinical trials, patients with DR in the clinical practice setting are possibly at greater risk of serious adverse effects. [14][15][16][17][18][19][20] Those patients are presumably at risk of adverse effects that might remain undetectable should the design of registration trials not consider the results of large clinical practice setting studies. DR patients who reflect real-world cohorts should, then, be included in phase III trials for better information on the risks of severe adverse effects of anti-VEGF use.…”

“…Unlike patients reported in registration and other randomized clinical trials, patients with DR in the clinical practice setting are possibly at greater risk of serious adverse effects. 14 , 15 , 16 , 17 , 18 , 19 , 20 Those patients are presumably at risk of adverse effects that might remain undetectable should the design of registration trials not consider the results of large clinical practice setting studies. DR patients who reflect real‐world cohorts should, then, be included in phase III trials for better information on the risks of severe adverse effects of anti‐VEGF use.…”