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Comment & Response
March 12, 2020

Frequentist Analysis of Death Associated With Intravitreal Anti–Vascular Endothelial Growth Factor Therapy—Reply

Author Affiliations
  • 1Department of Ophthalmology, University of Catania, Catania, Italy
  • 2Eye Unit, Southampton University Hospital, Southampton, United Kingdom
  • 3Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze, Florence, Italy
  • 4Azienda Ospedaliero Universitaria Careggi, Florence, Italy
JAMA Ophthalmol. Published online March 12, 2020. doi:10.1001/jamaophthalmol.2020.0289

In Reply We are grateful to Fau et al for conducting and providing further analyses on our data set,1 which reinforced our interpretation and the need for further investigation regarding long-term, intensive intravitreal anti–vascular endothelial growth factor (anti-VEGF) treatment. Specifically, the authors remarked on our finding of a potential increase in overall mortality in the subgroup with monthly injections for up to 24 months (odds ratio, 1.89 [95% CI, 1.06-3.36]), which is a key finding of our study.1 However, we have been conservative in drawing conclusions, because despite a relatively large sample size (8887 trial participants), the number of deaths was only 128 (1.44%). Unsurprisingly, a contrast comparing the 6-month follow-up subgroup and the 24-month follow-up subgroup was not significant in the frequentist meta-analysis. This result was confirmed by bayesian methods.1

We also acknowledge that the restriction of our search to articles published in English is a limitation of our review. On the other hand, we suggest that larger studies are unlikely to have been published in other languages.

We disagree with the authors that the funnel plot is suggestive of publication bias (Figure). While we decided not to submit this funnel plot for publication, a contour-enhanced funnel plot2 shows that 4 trials with a significant increase of mortality were in fact among the largest studies. We suggest that these studies are characterized by longer-term follow-up and more intensive treatment and cannot be thought of as a subset of similar, smaller studies that remained unpublished because of nonsignificant results. Moreover, no study included in this review primarily aimed to assess the risk of death with anti-VEGF injections, and nonsignificant findings regarding mortality must not have been a reason for selection in the editorial and peer-review process.

Figure.  Contour-Enhanced Funnel Plot
Contour-Enhanced Funnel Plot

Contour-enhanced funnel plot showing odds ratios of mortality (x-axis) vs its standard error (y-axis) for graphical inspection of small study bias. Four studies in the external light-gray shaded area show a statistically significant increase in mortality.

Overall, we agree with the authors of this comment1 that there is a warning signal of higher mortality for patients receiving intense and prolonged anti-VEGF intravitreal treatment, especially patients who are frail and at high risk. Further studies are warranted to better clarify this issue. We think that such studies can only by conducted using large real-world databases, for which the challenge is to manage selection and other biases, which are common in observational research.

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Article Information

Corresponding Author: Michele Reibaldi, MD, PhD, Department of Ophthalmology, University of Catania, Via Santa Sofia 78, Catania, Italy (mreibaldi@libero.it).

Published Online: March 12, 2020. doi:10.1001/jamaophthalmol.2020.0289

Conflict of Interest Disclosures: None reported.

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.  JAMA Ophthalmol. 2019;138(1):50-57. doi:10.1001/jamaophthalmol.2019.4636PubMedGoogle ScholarCrossref
Langan  D, Higgins  JP, Gregory  W, Sutton  AJ.  Graphical augmentations to the funnel plot assess the impact of additional evidence on a meta-analysis.  J Clin Epidemiol. 2012;65(5):511-519. doi:10.1016/j.jclinepi.2011.10.009PubMedGoogle ScholarCrossref
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