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Comment & Response
March 12, 2020

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

Author Affiliations
  • 1Fundación Oftalmológica 2020, Iberoamerican Cochrane Network, Santiago, Chile
  • 2Andrés Bello University, School of Nursing, Santiago, Chile
JAMA Ophthalmol. Published online March 12, 2020. doi:10.1001/jamaophthalmol.2020.0286

To the Editor We present some complementary frequentist meta-analysis to an article published.1 The authors only used articles published in the English language. Although with the Peters and Egger test, they did not find a publication bias (P = .44; P = .19), when analyzing the funnel plot graph, an asymmetry is evidenced. This may reflect a selection bias by language; there is a lack of small articles that should have a result in the direction of a higher risk of mortality, so the presence of this bias may favor statistical nonsignificance and must be taken into account when interpreting the results.

When performing a cumulative meta-analysis ordered by the year of publication of the articles, a clear trend toward statistical significance is appreciated. At the end of 2012, in the accumulated meta-analysis using a random-effects method, an odds ratio of 1.22 (95% CI, 0.71-2.11) is obtained. From 2015 onward, the odds ratios obtained are always greater than 1.30 as each new study is added and the total number of patients accumulated increases. The confidence intervals gradually narrow, positioning the result of the cumulative meta-analysis in favor of an increase in mortality, requiring more and more studies with negative results to reverse this result in the future.

When making a forest plot stratified by the follow-up time, the subgroups are group 1 (with 6 months of follow-up), group 2 (follow-up of 11-12 months), and group 3 (follow-up of 23-24 months). When evaluating the results according to the follow-up period, there is a clear association between the follow-up period and the number of events. In group 1, the odds ratio is 0.65 (95% CI, 0.16-2.66); in group 2, the odds ratio is 1.02 (95% CI, 0.54-1.92); and in group 3, there is a greater occurrence of events, with an odds ratio of 1.89 (95% CI, 1.06-3.36). It should be taken into account that patients with greater follow-up have a mean of almost 1 monthly injection; that is, the longer the study is, the greater exposure it has for a greater amount of cumulative injections and also a longer follow-up time, which allows the detection of death.

We believe that there is a clear tendency to a higher mortality rate in the group of patients receiving an anti–vascular endothelial growth factor intravitreal injection for prolonged periods, we agree that a better analysis is required to establish the subgroups with the highest risk and evaluate their association with the amount of injections used. However, since this type of treatment is very frequently used in clinical practice, it is necessary to establish an alert about its use, given the evidence currently available.

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Article Information

Corresponding Author: Christian Fau, MD, MSc, Fundación Oftalmológica 2020, Avd Presidente Riesgo 5157, Dep 212, Las Condes, Santiago, Metropolitana 7560854, Chile (chfauf@gmail.com; cfau@fundacion2020.org).

Published Online: March 12, 2020. doi:10.1001/jamaophthalmol.2020.0286

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
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