Anti-vascular endothelial growth factor (VEGF) drugs compared to laser photocoagulation for treatment of type 1 retinopathy of prematurity

Gonz�lez C., Ra�l; D�az C., Marcela; Garret�n C., Rodolfo

doi:DOI 10.5867/medwave.2022.01.8506

Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)

Medwave 2022;22(01):e8506 doi: DOI 10.5867/medwave.2022.01.8506

Anti-vascular endothelial growth factor (VEGF) drugs compared to laser photocoagulation for treatment of type 1 retinopathy of prematurity

Ra�l Gonz�lez C., Marcela D�az C., Rodolfo Garret�n C.

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Key Words: Retinopathy of prematurity (ROP), Anti-vascular endothelial growth factor (anti-VEGF), laser coagulation, Epistemonikos, GRADE.

Abstract

INTRODUCTION
Retinopathy of prematurity (ROP) is a condition that affects preterm infants, being the second leading cause of childhood blindness worldwide. The most commonly used treatments are cryotherapy or laser photocoagulation, but over the last few years, anti-vascular endothelial growth factor (anti-VEGF) drugs have gradually gained more adherents, mainly in the treatment of patients with type 1 retinopathy of prematurity (ET- ROP) Therefore, it is important to summarize the existing evidence to evaluate the efficacy and safety of anti-VEGF drugs in type 1 retinopathy of prematurity.

METHODS
We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.

RESULTS AND CONCLUSIONS
We identified six systematic reviews including 15 studies overall, of which five were randomized trials.
We conclude that the use of anti-VEGF compared to laser photocoagulation, probably reduces the risk of refractive errors. On the other hand, the use of anti-VEGF may result in little or no difference in the mortality at hospital discharge, lens or corneal opacity requiring surgery, and complete or partial retinal detachment, but the certainty of the evidence is low. Finally, it is not possible to clearly establish whether anti-VEGF compared with laser photocoagulation, increases the recurrence of retinopathy of prematurity, because the certainty of the existing evidence has been assessed as very low.

Problem

Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina that affects preterm newborns (PTNB) resulting in the second cause of childhood blindness in the world. Ablation of the avascular retina, with cryotherapy or laser photocoagulation has been considered useful and effective treatments for retinopathy of prematurity [1] [2].

The role and association of vascular endothelial growth factor (VEGF) in the pathogenesis of retinopathy of prematurity has been studied extensively. It has been found that the retinal neovascularization that causes the traction ultimately leading to retinal detachment is mainly due to the development and effect of vascular endothelial growth factor (VEGF) [3], [4], [5]. Given the above, the use of intravitreal anti-VEGF agents has gradually gained popularity, and has even been recommended by some ophthalmologists as first-line therapy to treat aggressive posterior retinopathy of prematurity and zone I disease. The objective of this summary is to evaluate the efficacy and safety of anti-VEGF drugs as monotherapy in preterm infants with type 1 retinopathy of prematurity compared to laser photocoagulation therapy.

Methods

We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information, we generated a structured summary denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos) using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies when it is possible, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

The use of anti-VEGF compared to laser photocoagulation therapy probably reduces the risk of refractive errors .
The use of anti-VEGF compared to laser photocoagulation therapy may make little or no difference in terms of treatment safety, whether in hospital discharge mortality, opacity of the lens or cornea that requires surgery and in partial or complete retinal detachment (certainty of low evidence).
We are uncertain whether anti-VEGF compared to laser photocoagulation therapy reduces the recurrence of retinopathy of prematurity, as the certainty of the evidence has been assessed as very low.

About the body of evidence for this question

What is the evidence. See the evidence matrix in Epistemonikos below.	The use of anti-VEGF compared to laser photocoagulation therapy probably reduces the risk of refractive errors .The use of anti-VEGF compared to laser photocoagulation therapy may make little or no difference in terms of treatment safety, whether in hospital discharge mortality, opacity of the lens or cornea that requires surgery and in partial or complete retinal detachment (certainty of low evidence).We are uncertain whether anti-VEGF compared to laser photocoagulation therapy reduces the recurrence of retinopathy of prematurity, as the certainty of the evidence has been assessed as very low.
What type of patients did the studies include? *	All trials included preterm infants with type 1 retinopathy of prematurity [13], [15], [19], [25], [29].
What type of interventions did the studies include? *	All trials compared anti-VEGF therapy versus laser photocoagulation therapy (standard treatment) [13], [15], [19], [25], [29].The anti-VEGF used were bevacizumab in four trials [13], [15], [25], [27] and ranibizumab in one trial [19].
What type of outcomes did they measure	The trials reported multiple outcomes, which were grouped by systematic reviews as follows: Recurrence of retinopathy of prematurity. Mortality at hospital discharge. Total or partial retinal detachment. Refractive error (myopia). Corneal opacity that requires corneal transplantation. Opacity of lens that requires removal of the cataract. Macular dragging.Epiretinal membrane. Exotropia. Retinal hemorrhage. The average follow-up of the trials was six months with a range between eight weeks and two years [13], [15], [19], [25], [29].

*Information on primary studies is extracted from the identified systematic reviews, not directly from the studies unless otherwise specified.

Summary of results

The information on the effects of anti-VEGF drugs is based on five randomized trials that include premature patients with type 1 retinopathy of prematurity [13], [15], [19], [25], [27]. Two trials measured the outcome recurrence of retinopathy of prematurity (193 patients) [13], [19]. Two trials measured the outcome mortality at hospital discharge (229 patients) [13], [27]. Four trials measured the outcome total or partial retinal detachment (393 patients) [13], [15], [19], [27]. Three trials measured the outcome opacity of the lens (cataract) that requires removal (544 patients) [13], [19], [27]. One trial evaluated the outcome corneal opacity requiring corneal transplantation (286 patients) [13]. One trial measured the outcome refractive error (myopia) (211 patients) [13].

The summary of the results is as follows:

The use of anti-VEGF drugs compared to laser photocoagulation therapy may make little or no difference in total or partial retinal detachment (low certainty evidence).
The use of anti-VEGF drugs compared to laser photocoagulation therapy probably reduces the risk of refractive errors.
The use of anti-VEGF drugs compared to laser photocoagulation therapy may make little or no difference in mortality at hospital discharge (low certainty evidence).
We are uncertain whether anti-VEGF drugs compared to laser photocoagulation therapy reduces the recurrence of retinopathy of prematurity, as the certainty of the evidence has been assessed as very low.
The use of anti-VEGF drugs compared to laser photocoagulation therapy may make little or no difference in the generation of corneal opacities that require corneal transplantation (low certainty evidence).
The use of anti-VEGF drugs compared to laser photocoagulation therapy may make little or no difference in the generation of lens opacities that require cataract removal (low certainty evidence).

Follow the link to access the interactive version of this table (Interactive Summary of Findings - iSoF)

Other considerations for decision-making

To whom this evidence applies and to whom it does not apply.

The evidence presented in this summary applies to premature newborns with type 1 retinopathy of prematurity.
This evidence does not apply to premature patients with more advanced retinopathy of prematurity or for the use of anti-VEGF as an adjuvant together with or after laser therapy.

About the outcomes included in this summary

The outcomes included in the summary table are those considered critical for decision making by the authors of this article, and generally coincide with those used by systematic reviews.
The outcome "need for a second procedure with another type of anti-VEGF” or “indication surgery (vitrectomy or conventional surgery)”, were not considered relevant by the authors of this summary.
The outcome endophthalmitis, a severe infectious complication is considered critical for decision making. However, it was not reported in any study. This may be a consequence of the limited number of patients included in the studies.

Harm/benefit balance and certainty in evidence

The body of evidence shows a probable benefit of the use of anti-VEGF in reducing the risk of refractive errors compared to laser photocoagulation.
On the other hand, the use of anti-VEGF could result in little or no difference in the mortality at hospital discharge, lens opacity that require removal of cataract, corneal opacity that require corneal transplantation, and complete or partial retinal detachment, but the certainty of the evidence is low.
Finally, it is not possible to clearly establish whether anti-VEGF compared with laser photocoagulation, increases the recurrence of retinopathy of prematurity, because the certainty of the existing evidence has been assessed as very low.
Considering the above, it is not possible to make an adequate balance between benefits and risks, due to the existing uncertainty.

Resource considerations

The administration of anti-VEGF compared to laser photocoagulation therapy is technically simpler and does not require general anesthesia or the services of an expert retina surgeon. Therefore, laser photocoagulation therapy would be associated at a higher cost, due to the need for treatment specialists.
While there may be some benefits, it is not possible to balance these and costs due to uncertainty about the outcomes.

What would patients and their doctors think about this intervention

Currently, despite the fact that the use of anti-VEGF has increased in recent times, the usual treatment in this scenario continues to be laser photocoagulation.
Faced with the evidence presented in this summary, doctors and patients are expected to be in favor of laser therapy, due to the existing uncertainty regarding anti-VEGF.

Differences between this summary and other sources

The conclusions of this summary are similar to those of the systematic reviews identified in clinical and anatomical terms. The results obtained in this summary are largely consistent with those reported worldwide.
The clinical guidelines of the American Academy of Ophthalmology of the United States of America [29] and of the Ministry of Health of Chile [30] affirm that the current routine treatment in this setting is laser photocoagulation, and although anti-VEGF have shown favorable evidence, more information is necessary.
On the other hand, the Spanish Association of Pediatrics [31] is also in favor of the use of laser photocoagulation, without providing more detail about anti-VEGF. The above is probably because of the year of publication of the mentioned guide.

Could this information change in the future?

The probability of future evidence changing the conclusions of this summary is high, due to the existing uncertainty.There are currently no other ongoing systematic reviews in the PROSPERO International prospective register of systematic reviews database that compare both interventions.
We did not find ongoing randomized trials comparing the use of anti-VEGF with laser photocoagulation in the International Clinical Trials Registry Platform of the World Health Organization.

How we conducted this summary

We collected all the relevant evidence for this question and presented it in an evidence matrix using automated and collaborative methods.

Follow the link to access the interactive version: Anti-VEGF compared to laser photocoagulation for type 1 retinopathy of prematurity

Notes

If new systematic reviews on this topic are published after the publication of this abstract, a "new evidence" notification will be displayed at the top of the matrix. While the project provides regular updates of these abstracts, users are invited to comment on the Medwave website or contact the authors by e-mail if they believe evidence warrants an earlier update.

After creating an Epistemonikos account, by saving the matrices, you will receive automatic notifications whenever there is new evidence that potentially answers this question.

This article is part of the Epistemonikos evidence synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and an internal peer review process. Each of these articles corresponds to a summary, called FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence of a specific question, in a friendly manner for physicians. The main resources are based on the Epistemonikos evidence matrix and the analysis of the result is based on the GRADE methodology. Further details of this FRISBEE elaboration method are described here.

The Epistemonikos Foundation is an organization that seeks to bring information closer to health decision-makers through the use of technologies. Its main source is the Epistemonikos database (www.epistemonikos.org).

Competing interest

The authors declare no competing interest.

This work is licensed under a Creative Commons Attribution 4.0 International License.