Meta-Analysis Finds No Increased Mortality for Patients Treated With Intravitreal Anti-VEGFs

Intravitreal injection with anti–vascular endothelial growth factor (anti-VEGF) drugs has represented a major step forward for patients with retinal diseases, and the upcoming biosimilars market for these drugs—including aflibercept and ranibizumab, as well as off-label bevacizumab—is beginning to take shape. However, there have been some lingering concerns about the safety of these drugs, as increased mortality has been reported after anti-VEGF treatment in the general population.
Kelly Davio
December 30, 2019
Intravitreal injection with anti–vascular endothelial growth factor (anti-VEGF) drugs has represented a major step forward for patients with retinal diseases, and the upcoming biosimilars market for these drugs—including aflibercept and ranibizumab, as well as off-label bevacizumab—is beginning to take shape.

However, there have been some lingering concerns about the safety of these drugs, as increased mortality has been reported after anti-VEGF treatment in the general population as well as in patients who have additional risk factors. Some have suggested that even small doses of anti-VEGF could have systemic effects, particularly for patients at elevated risk for events like stroke.

In November, researchers reported the results of a meta-analysis that found, however, that there was no difference in mortality rate for patients treated with intravitreal anti-VEFGs and control groups.

The researchers derived data from sources including PubMed and MEDLINE, among others, for studies from inception through May of 2019. They arrived at 34 unique studies with 8887 participants. These studies were conducted in patients with diabetic macular edema, retinal vein occlusion, and age-related macular degeneration, and they included treatment with aflibercept, ranibizumab, bevacizumab, and pegaptanib sodium. Follow-up in the studies ranged from 6 months to 24 months.

In the 34 studies, all-cause death was recorded in 91 (1.6%) of 5724 patients who received anti-VEGF therapy, and 37 (1.2%) of 3163 controls. In the 18 studies in which there was at least 1 death in each study arm, the corresponding percentages were 2.1% and 1.6%, respectively.

A frequentist pooled estimate yielded similar fixed- and random-effects odds ratios (ORs) of 1.34 (95% CI, 0.95-2.07; P = .9) and 1.34 (95% CI, 0.89-2.01; P = .17), respectively. A primary Bayesian meta-analysis yielded an OR of 1.34 (95% credible interval, 0.79-2.34) and a probability of 0.13 that the OR was 1.00 or less.

However, a subgroup analysis did reveal a difference in mortality when pooling data from the 5 studies that had a follow-up of 24 months. In these studies, there was a 2.5-fold increase in mortality when compared with studies that had a 6-month follow-up. It was not possible to determine whether this increased risk of death suggested in the studies with 24 months of follow-up was associated with a larger number of injections or with longer follow-up time.

Overall, say the authors, no difference in mortality rate was observed between the anti-VEGF treatment group and the control group, and going forward, nonrandomized comparative studies that use real-world data and that adjust for confounders would be useful to further clarify this issue.

Reference
Reibaldi M, Fallico M, Avitabile T, et al. Risk of death associated with intravitreal anti–vascular endothelial growth factor therapy: a systematic review and meta-analysis [published online November 1, 2019]. JAMA Opthalmol. doi: 10.1001/jamaophthalmol.2019.4636.

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