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
|Autrata et al, Eur J Ophthalmology, 20125||Prospective, nonrandomized||
||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||
||Bevacizumab (0.5 mg, 12 eyes) vs fellow eye laser (11 eyes)||
|Isaac et al, J AAPOS, 201510||Retrospective comparative study||
||Bevacizumab (0.625 mg/0.025 mL), 23 eyes vs laser (22 eyes)||
|Hwang et al, Ophthalmology, 201512||Retrospective comparative study||
||Bevacizumab (0.625 mg/0.025 mL, 22 eyes) vs laser (32 eyes)||
|O’Keeffe et al, Ir Med J, 20167||Randomized controlled trial||
||Bevacizumab (1.25 mg/0.05 mL) vs laser in fellow eye||
|Nicoara et al, Med Sci Monit, 201615||Retrospective comparative study||
||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||
||Bevacizumab (37 infants) vs laser (17 infants)||
|Karkhaneh et al, Acta Ophthalmol, 20168||Randomized controlled trial||
||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||
||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||
||Bevacizumab (0.625 mg/0.025 mL) vs ranibizumab (0.25 mg/0.025 mL) vs laser||
|Zhang et al, Retina, 20179||Randomized controlled trial||
||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
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
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
- Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol. 1988;106:471-479.
- Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol. 2003;12(12):1684-1694.
- Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364(7):603-615.
- Sankar MJ, Sankar J, Mehta M, Bhat V, Srinivas R. Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity. Cochrane Database Syst Rev. 2016;2.
- Autrata R, Kreicirova I, Senkova K, Holousova M, Dolezel Z, Borek I. Intravitreal pegaptanib combined with diode laser therapy for stage 3+ retinopathy of prematurity in zone I and posterior zone II. Eur J Ophthalmol. 2012;22(5):687-694.
- Lepore D, Quinn GE, Molle F, et al. Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings. Ophthalmology. 2014;121(11):2212-2219.
- O’Keeffe N, Murphy J, O’Keefe M, Lanigan B. Bevacizumab compared with diode laser in stage 3 posterior retinopathy of prematurity: A 5 year follow up. Ir Med J. 2016;109(2):355.
- Karkhaneh R, Khodabande A, Riazi-Eafahani M, et al. Efficacy of intravitreal bevacizumab for zone-II retinopathy of prematurity. Acta Ophthalmol. 2016;94(6):e417-e420.
- Zhang G, Yang M, Zeng J, et al; Shenzhen Screening for Retinopathy of Prematurity Cooperative Group. Comparison of intravitreal injection of ranibizumab versus laser therapy for zone II treatment-requiring retinopathy of prematurity. Retina. 2017;37(4):710-717.
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- Kabatas EU, Kurtul BE, Altiaylik O, Kabatas N. Comparison of intravitreal bevacizumab, intravitreal ranibizumab and laser photocoagulation for treatment of type 1 retinopathy of prematurity in Turkish preterm children. Curr Eye Res. 2017;42(7):1054-1058.
- Hwang CK, Hubbard GB, Hutchinson AK, Lambert SR. Outcomes after intravitreal bevacizumab versus laser photocoagulation for retinopathy of prematurity: a 5-year retrospective analysis. Ophthalmology. 2015;122(5):1008-1015.
- Mueller B, Salchow DJ, Waffenschmidt E, et al. Treatment of type I ROP with intravitreal bevacizumab or laser photocoagulation according to retinal zone. Br J Ophthalmol. 2016. [Epub ahead of print]
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- Geloneck MM, Chuang AZ, Clark WL, et al; BEAT-ROP Cooperative Group. Refractive outcomes following bevacizumab monotherapy compared with conventional laser treatment: a randomized clinical trial. JAMA Ophthalmol. 2014;132(11):1327-1333.
- Pandya HK, Faia LJ, Robinson J, Drenser KA. Macular development in aggressive posterior retinopathy of prematurity. Biomed Res Int. 2015;2015:808639.
- Kim J, Kim SJ, Chang YS, Park WS. Combined intravitreal bevacizumab injection and zone I sparing laser photocoagulation in patients with zone I retinopathy of prematurity. Retina. 2014;34(1):77-82.
- Yoon JM, Shin DH, Kim SJ, et al. Outcomes after laser versus combined laser and bevacizumab treatment for type 1 retinopathy of prematurity in zone I. Retina. 2017;37(1):88-96.
- Hu J, Blair MP, Shapiro MJ, Lichtenstein SJ, Galasso JM, Kapur R. Reactivation of retinopathy of prematurity after bevacizumab injection. Arch Ophthalmol. 2012;130(8):1000-1006.
- Yonekawa Y, Wu WC, Nitulescu CE, et al. Progressive retinal detachment in infants with retinopathy of prematurity treated with intravitreal bevacizumab or ranibizumab. Retina. 2017 May 3. [Epub ahead of print]
- Larrañaga-Fragoso P, Peralta J, Bravo-Ljubetic L, Pastora N, Abelairas-Gómez J. Intravitreal bevacizumab for zone II retinopathy of prematurity. J Pediatr Ophthalmol Strabismus. 2016;53(6):375-382.
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- Hong YR, Kim YH, Kim SY, Nam GY, Cheon HJ, Lee SJ. Plasma concentrations of vascular endothelial growth factor in retinopathy of prematurity after intravitreal bevacizumab injection. Retina. 2015;35(9):1772-1777.
- Lien R, Yu MH, Hsu KH, et al. Neurodevelopmental outcomes of infants with retinopathy of prematurity and bevacizumab treatment. PLoS One. 2016;11(1):e0148019.
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- Fernandez MP, Berrocal AM, Goff TC, et al. Histopathologic characterization of the expression of vascular endothelial growth factor in a case of retinopathy of prematurity treated with ranibizumab. Am J Ophthalmol. 2017;176:134-140.
- Khodabande A, Niyousha MR, Roohipoor R. A lower dose of intravitreal bevacizumab effectively treats retinopathy of prematurity. J AAPOS. 2016 Dec;20(6):490-492.
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- Mireskandari K, Collins ME, Tehrani N. Intravitreal bevacizumab for retinopathy of prematurity: considerations for informed consent. Can J Ophthalmol. 2015;50(6):409-412.
- Patel SN, Klufas MA, Ryan MC, et al. Color fundus photography versus fluorescein angiography in identification of the macular center and zone in retinopathy of prematurity. Am J Ophthalmol. 2015;159(5):950-957.