Effect of Intravitreal Aflibercept vs Laser Photocoagulation on Treatment Success of Retinopathy of Prematurity: The FIREFLEYE Randomized Clinical Trial

JAMA. 2022 Jul 26;328(4):348-359. doi: 10.1001/jama.2022.10564.


Importance: Laser photocoagulation, which is the standard treatment for retinopathy of prematurity (ROP), can have adverse events. Studies of anti-vascular endothelial growth factor injections have suggested efficacy in the treatment of ROP, but few studies have directly compared them with laser treatments.

Objective: To compare intravitreal aflibercept vs laser photocoagulation in infants with ROP requiring treatment.

Design, setting, and participants: This noninferiority, phase 3, 24-week, randomized clinical trial was conducted in 27 countries (64 hospital sites) throughout Asia, Europe, and South America. Overall, 118 infants (gestational age ≤32 weeks at birth or birth weight ≤1500 g) with ROP severity (zone I stage 1+ [stage 1 plus increased disease activity], zone I stage 2+, zone I stage 3, zone I stage 3+, zone II stage 2+, or zone II stage 3+) requiring treatment or with aggressive posterior ROP in at least 1 eye were enrolled between September 25, 2019, and August 28, 2020 (the last visit occurred on February 12, 2021).

Interventions: Infants were randomized 2:1 to receive a 0.4-mg dose of intravitreal aflibercept (n = 75) or laser photocoagulation (n = 43) at baseline. Additional treatment was allowed as prespecified.

Main outcomes and measures: The primary outcome was the proportion of infants without active ROP and unfavorable structural outcomes 24 weeks after starting treatment (assessed by investigators). The requirement for rescue treatment was considered treatment failure. Intravitreal aflibercept was deemed noninferior if the lower limit of the 1-sided 95% bayesian credible interval for the treatment difference was greater than -5%.

Results: Among 118 infants randomized, 113 were treated (mean gestational age, 26.3 [SD, 1.9] weeks; 53 [46.9%] were female; 16.8% had aggressive posterior ROP, 19.5% had zone I ROP, and 63.7% had zone II ROP) and 104 completed the study. Treatment (intravitreal aflibercept: n = 75; laser photocoagulation: n = 38) was mostly bilateral (92.9%), and 82.2% of eyes in the intravitreal aflibercept group received 1 injection per eye. Treatment success was 85.5% with intravitreal aflibercept vs 82.1% with laser photocoagulation (between-group difference, 3.4% [1-sided 95% credible interval, -8.0% to ∞]). Rescue treatment was required in 4.8% (95% CI, 1.9% to 9.6%) of eyes in the intravitreal aflibercept group vs 11.1% (95% CI, 4.9% to 20.7%) of eyes in the laser photocoagulation group. The serious adverse event rates were 13.3% (ocular) and 24.0% (systemic) in the intravitreal aflibercept group compared with 7.9% and 36.8%, respectively, in the laser photocoagulation group. Three deaths, which occurred 4 to 9 weeks after intravitreal aflibercept treatment, were considered unrelated to aflibercept by the investigators.

Conclusions and relevance: Among infants with ROP, intravitreal aflibercept compared with laser photocoagulation did not meet criteria for noninferiority with respect to the primary outcome of the proportion of infants achieving treatment success at week 24. Further data would be required for more definitive conclusions regarding the comparative effects of intravitreal aflibercept and laser photocoagulation in this population.

Trial registration: ClinicalTrials.gov Identifier: NCT04004208.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors* / administration & dosage
  • Angiogenesis Inhibitors* / adverse effects
  • Angiogenesis Inhibitors* / therapeutic use
  • Bevacizumab / therapeutic use
  • Female
  • Gestational Age
  • Humans
  • Infant
  • Infant, Newborn
  • Intravitreal Injections
  • Laser Coagulation* / adverse effects
  • Laser Coagulation* / methods
  • Male
  • Receptors, Vascular Endothelial Growth Factor* / administration & dosage
  • Receptors, Vascular Endothelial Growth Factor* / therapeutic use
  • Recombinant Fusion Proteins* / administration & dosage
  • Recombinant Fusion Proteins* / adverse effects
  • Recombinant Fusion Proteins* / therapeutic use
  • Retinopathy of Prematurity* / drug therapy
  • Retinopathy of Prematurity* / surgery
  • Treatment Outcome
  • Vascular Endothelial Growth Factor A


  • Angiogenesis Inhibitors
  • Recombinant Fusion Proteins
  • Vascular Endothelial Growth Factor A
  • aflibercept
  • Bevacizumab
  • Receptors, Vascular Endothelial Growth Factor

Associated data

  • ClinicalTrials.gov/NCT04004208