Article

Anti-VEGF in Retinopathy of Prematurity

New data since publication of BEAT ROP fail to answer remaining questions.

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The screening, treatment, and pathophysiologic understanding of retinopathy of prematurity (ROP) have dramatically evolved over the past 3 decades. Two landmark studies, ETROP and CRYO ROP, serve as the stepping stones for establishing treatment guidelines with respect to threshold and prethreshold type I ROP.1,2 Near confluent laser photoablation remains the current standard of care (SOC) for ROP with an estimated 9.1% structural recurrence rate.2

Most recently, however, intravitreal anti-VEGF agents for ROP have received much attention in the medical community as a potential alternative. Six years have passed since the publication of BEAT ROP, which suggested the superiority of intravitreal bevacizumab (IVB) over conventional laser in the treatment of zone I, stage 3+ ROP.3 However, several inconsistencies in the study design, follow-up duration, and overall higher failure rates of SOC laser compared to previous studies make interpretation and applicability of these results to high-risk neonatal care difficult and controversial.

While anti-VEGF treatment is advantageous with respect to ease of administration, availability of treatment, and potential role in aggressive posterior disease, questions remain 6 years later regarding the systemic safety, long-term anatomic and visual outcomes, and, most importantly, the superiority of this drug type to the current SOC with laser photoablation. Here we review the current evidence of anti-VEGF compared to conventional laser treatment and the ocular and systemic implications of anti-VEGF since the publication of BEAT ROP.

Prethy Rao, MD, is a vitreoretinal fellow at Associated Retina Consultants in Royal Oak, Michigan. Michael T. Trese, MD, is a vitreoretinal specialist with Associated Retina Consultants in Royal Oak, Michigan. The authors report no related disclosures.

RECURRENCE RATES FOR ANTI-VEGF VS CONVENTIONAL LASER

To date, 11 head-to-head studies (5 prospective, randomized; 6 retrospective, nonrandomized) have been published comparing intravitreal anti-VEGF to conventional laser photocoagulation for ROP in the English literature (Table 1). The results remain mixed with respect to dosing, drug type, study design, and sample size. However, most studies do not demonstrate meaningful structural regression rates that are superior to the current standard of care laser photoablation. A recent Cochrane review in 2014 concluded that there was insufficient evidence to provide a strong conclusion for the routine use of anti-VEGFs in clinical practice.4

Table 1: Comparative Studies Between Anti-VEGF and Laser in ROP
STUDY DESIGN PARTICIPANTS INTERVENTION OUTCOMES
Autrata et al, Eur J Ophthalmology, 20125 Prospective, nonrandomized
  • 152 infants
  • Zone I or II stage 3+
  • Duration: 19.3-21.5 months
Group 1: Pegaptanib (0.3 mg) + diode laser (68 eyes) Group 2: diode laser (84 eyes) Regression of ROP (89.7% in group 1 and 60.8% in group 2)
Lepore et al, Ophthalmology, 20146 Randomized controlled trial
  • 13 infants (23 eyes)
  • Type I ROP
  • Duration: 9 months
Bevacizumab (0.5 mg, 12 eyes) vs fellow eye laser (11 eyes)
  • Recurrence rate: 2/11 eyes with laser (18.1%)
  • No recurrence in bevacizumab group only
  • Fluorescein angiographic features: abnormal vascular tangles, avascular retina, and arteriovenous shunt vessels (91.7%) in bevacizumab vs laser (9.1%)
  • More macular abnormalities in bevacizumab group (75% vs 36.4%, P<.05)
Isaac et al, J AAPOS, 201510 Retrospective comparative study
  • 13 infants (23 eyes)
  • Type I ROP
  • Duration: 9 months
Bevacizumab (0.625 mg/0.025 mL), 23 eyes vs laser (22 eyes)
  • None developed unfavorable structural outcomes
  • 1 eye in laser group had persistent neovascularization in a skip area that required retreatment
  • No difference in vision or refraction
  • More frequent follow up in bevacizumab group (median 16 vs 6)
Hwang et al, Ophthalmology, 201512 Retrospective comparative study
  • 28 infants (54 eyes)
  • Type I ROP
  • Duration: 6 months
Bevacizumab (0.625 mg/0.025 mL, 22 eyes) vs laser (32 eyes)
  • No difference in recurrence rates (3/16 (19%) zone I ROP for laser vs 1/5 (20%) for bevacizumab (P=1.0)
  • No difference in spherical equivalent between groups for zone I eyes; greater myopic spherical equivalent with laser in zone II eyes
O’Keeffe et al, Ir Med J, 20167 Randomized controlled trial
  • 15 infants (15 eyes)
  • Zone I or posterior zone II, stage 3+
  • Duration: 12 months
Bevacizumab (1.25 mg/0.05 mL) vs laser in fellow eye
  • 3/15 (20%) eyes with recurrence in bevacizumab group vs 1/15 eyes (6.7%) in laser group
  • No difference in refractive error between groups at 1 year; laser group more myopic at 5 years post treatment
  • No difference in neuroimaging with MRI at 1 year
Nicoara et al, Med Sci Monit, 201615 Retrospective comparative study
  • 23 infants (46 eyes)
  • APROP
  • Duration: 60 weeks (laser), 80 weeks (anti-VEGF)
Bevacizumab (34 eyes) vs laser (12 eyes) Recurrence rate: 3/12 eyes (25%) with laser vs 5/34 (14.7%) with bevacizumab
Mueller et al, Br J Ophthalmology, 201613 Retrospective comparative study
  • 54 infants
  • Type I ROP
  • Duration: 12-15 months
Bevacizumab (37 infants) vs laser (17 infants)
  • Faster regression rates in bevacizumab vs laser (12 days vs 57 days, P<.01)
  • Recurrence rate: 7/37 (12%) in bevacizumab and no recurrence in laser group
Karkhaneh et al, Acta Ophthalmol, 20168 Randomized controlled trial
  • 79 infants (158 eyes)
  • Zone II/stage 2 or 3
  • Duration: 90 weeks/22.5 months
Bevacizumab (0.625 mg/0.025 mL, 86 eyes) vs laser (72 eyes) Recurrence rate: 9/86 (10.5%) vs 1/72 (1.4%) P=.018
Kabatas et al, Curr Eye Res, 201711 Retrospective comparative study
  • 128 infants
  • Type I ROP
  • Duration: 18 months
Bevacizumab (24 eyes) vs ranibizumab (12 eyes) vs laser (72 eyes) Recurrence rate: 2/24 (8.3%) bevacizumab, 2/12 (16.7%) ranibizumab, 10/72 (13.4%) laser
Gunay et al, Curr Eye Res, 201714 Retrospective comparative study
  • 134 (264 eyes)
  • Type I ROP and APROP
  • Duration: 17.6-22.5 months
Bevacizumab (0.625 mg/0.025 mL) vs ranibizumab (0.25 mg/0.025 mL) vs laser
  • Recurrence rate: 3 infants (5.5%) bevacizumab, 3 (50%) ranibizumab, 1 (1.8%) laser
  • Recurrence requiring further treatment: 3 (5.5%) bevacizumab, 3 (13.6%), 0 (0%) laser
Zhang et al, Retina, 20179 Randomized controlled trial
  • 100 eyes
  • Zone II, stage 2 or 3+
  • Duration: 6 months
Ranibizumab (0.3 mg/0.03mL, 50 eyes) vs laser (50 eyes) Recurrent rate: 26/50 eyes (52%) in ranibizumab group vs 2/50 (4%) in laser group

Five clinical trials from 2014 to 2017 have compared conventional laser to 3 different anti-VEGF drugs (1 pegaptanib, 3 bevacizumab, and 1 ranibizumab). In 2014, Autrata et al demonstrated higher recurrence rates with diode laser only (38%) compared to pegaptinib + laser (11.7%, P=.0274) in 152 infants with zone I or II, stage 3+ disease.5 Curiously, the laser recurrence rates were higher than those reported in ETROP, and drug monotherapy was not directly compared.

The second randomized trial after BEAT ROP published by Lepore et al in Italy demonstrated a 18.2% ROP recurrence rate in laser-treated eyes (2/11 eyes) compared to no recurrence in 12 IVB eyes for zone I or II, stage 3+ disease.6 However, the sample size was small and most eyes that received IVB exhibited persistent arteriovenous shunt vessels (11/12 eyes) and macular abnormalities (absence of foveal avascular zone, hyperfluorescent lesions in the posterior pole; 75% vs 36.4% P<.05). The implications of these angiographic features remain unclear.

In contrast, a subsequent randomized trial by O’Keeffe in 2016 reported a higher recurrence rate in 1.25 mg IVB treated eyes (3/15, 20%) compared to fellow eyes treated with diode laser only (1/15; 6.7%) in those with zone I or II, stage 3+ disease.7 However, the role of systemic anti-VEGF crossover effects is not well established. Similarly, Karkhaneh et al demonstrated a higher recurrence rate in IVB-treated eyes (10.5%) compared to 1.4% in laser-only eyes with type I, zone II ROP.8 Most recently, a Chinese prospective randomized trial of 100 eyes with zone II, stage 2 or 3+ disease exhibited a higher recurrence rate of 52% with the biologically smaller ranibizumab molecule (IVR, 0.3 mg/0.03 mL) compared to diode alone (4%).9

Six retrospective series have been published between 2015 and 2017. Two studies exhibited no difference between IVB and conventional laser10,11 while 3 studies demonstrated superiority of laser over bevacizumab monotherapy.12-14 In contrast, a retrospective Romanian study of 11 eyes demonstrated statistically higher recurrence rates with laser (25%) compared to IVB monotherapy (14.7%).15 Of note, this study exclusively included aggressive posterior retinopathy of prematurity (APROP) eyes compared to prior reports. Therefore, these results may need to be interpreted with caution against other comparative studies that use more typical prethreshold and threshold ROP criteria.

ADVANTAGES OF ANTI-VEGF VS LASER

The biological plausibility of VEGF-mediated ROP progression makes anti-VEGF use a logical option. Arguably the most consistent evidenced-based advantage of anti-VEGF over laser is the lower rate of myopic shifts.12,14,16 Other technical advantages include (1) the ease and expediency of administration, especially in the setting of a hazy ocular media from the cornea or tunica vasculosa lentis that is typical of a premature newborn, (2) the ability to perform the injection without sedation or intubation for higher risk infants, and (3) ready availability of anti-VEGF agents in clinical practice. Anatomically, anti-VEGF use is associated with more rapid resolution of ROP within 48 hours compared to laser13 and may be beneficial in sparing foveal destruction in patients with posterior Type I ROP or APROP involving the fovea. However, we have demonstrated that normal foveal development continues with transverse and anterior-posterior eye wall growth, even in the setting of very posterior laser.17

Current randomized trials for combined anti-VEGF and laser in posterior disease compared to laser or anti-VEGF monotherapy remain scant. In a retrospective review by Kim et al in 2014, combined IVB (0.25 mg) and laser anterior to zone I in 18 type I ROP infants resulted in a 100% regression rate with theoretical advantages that include lower anti-VEGF dosing and visual field preservation.18 Most recently, a retrospective review by Yoon et al demonstrated no recurrence in 51 infants with type I ROP and zone I disease who underwent concomitant laser and IVB treatment compared to laser only (22.7%).19 However, larger, randomized studies may be needed to further elucidate this mode of therapy.

INTRAOCULAR ADVERSE EVENTS AND IMPLICATIONS

Anatomically, the biggest concerns for anti-VEGF use are persistent avascular zones,2 late reactivation of disease,20 and the “crunch phenomenon” with fibrovascular contraction and tractional RD.21,22 Functionally, visual field preservation from subsequent complete vascularization is an additional advantage over laser.22 However, persistent avascular zones have been noted in larger trials,2 and the long-term implications remain largely unknown. We have previously reported persistent avascular zones in older premature infants despite ROP regression.23

The higher overall risk of retinal tears/detachments in premature infants, and associations between late-onset neovascularization in peripheral ischemia in the setting of nonaccidental trauma and other familial vitreoretinal diseases suggest that persistent avascular zones may have long-term consequences that may not be fully understood.23,24 While there is a predictable course of RD that occurs after laser (ie, if not present by 50 weeks post menstrual age, it is very unlikely to happen), the late reactivation of ROP up to 69 weeks+ after anti-VEGF may require longer-term follow-up.20 However, the exact frequency and follow-up duration to detect reactivation may vary and is not yet well established.

SYSTEMIC ADVERSE ASSOCIATIONS

Arguably, the biggest controversy of anti-VEGF agents is the systemic implication for organ development in high-risk infants. Hong et al demonstrated that IVB lowers VEGF plasma concentrations outside of the eye up to 7 weeks after intraocular administration.25 Two large randomized trials in 2016 demonstrated higher incidence rates of mental/psychomotor impairment and neurodevelopmental disabilities in IVB + laser26 and IVB only treated groups,27 respectively. Most recently, hypotension-related reports28 and histopathologically proven new or reactivation of bronchopulmonary dysplasia have been noted after anti-VEGF administration.29 Of note, the bronchopulmonary dysplastic findings were based on autopsy. The alveoli appear to be the most susceptible organ to small amounts of VEGF blockage.

Optimal dosing to achieve ROP regression and minimize systemic effects is not established; however, recent studies are promising. Khodabande et al evaluated the efficacy of lower-dose IVB (0.25 mg/0.01 mL) and observed complete regression and no systemic adverse events in all 49 eyes.30 Wallace et al most recently reported similar regression rates with lower IVB doses (0.031 mg) compared to higher dosages (0.125 mg or 0.063 mg) in a multicentered phase 1 dosing trial.31

INFORMED CONSENT

The use of anti-VEGF drugs to treat ROP is still off label from the standpoint of the age of the patient, the indication for use, and the dose for a premature infant. This must be discussed with parents and legal guardians to obtain a legal informed consent. Reactivation and/or contraction phenomenon, systemic implications for organ development, longer follow-up duration, and unknown long-term outcomes should be addressed during the informed consent process as well.32

SUMMARY

Several randomized trials and retrospective studies have been published since BEAT ROP comparing anti-VEGF and laser head-to-head. However, variations in study design as well as different drug type and dosing regimens make interpretation of these results difficult. Regardless of drug type, most studies fail to demonstrate a consistent superiority of anti-VEGF agents to the current gold standard (near confluent laser photoablation) with respect to regression rates. Although anti-VEGF has unique advantages because it has lower rates of myopic refractive errors, it has faster regression in larger trials compared to laser, and overall it is less time intensive, the current literature to date regarding the local and systemic adverse effects (peripheral avascular zones, reactivation, contraction, organ development) suggests that the role of anti-VEGF for primary use in routine clinical practice remains controversial. There may be a role in select cases, such as poor visualization from media opacities, progressive APROP cases despite laser, or very posterior ROP involving the fovea.

It was hoped that the RAINBOW study (a Randomized, Controlled Study Evaluating the Efficacy and Safety of RAnibizumab Compared With Laser Therapy for the Treatment of INfants BOrn Prematurely With Retinopathy of Prematurity; Clinicaltrials.gov identifier NCT02375971) would clarify these issues using photographic determination of actual zone 1 disease, being certain that laser treatment is applied in an accurate pattern, and studying the proper dose. These considerations are important because physicians are not good at determining zone 1 on clinical exam but are quite good at determining zone 1 on photographs.33 As demonstrated by several other laser-vs-drug studies, the failure rates of laser studies like the BEAT ROP study were much higher than others. Unfortunately, the investigators of the RAINBOW study have had to compromise their original design, will not be doing total photographic screening, and may not be able to draw the conclusive evidence we had hoped for. Anti-VEGF for ROP remains off label and as such requires appropriate informed consent until such labeling is achieved. RP

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