Journal of Pediatric Ophthalmology and Strabismus

Original Article 

Comparison of the Efficacy Between Intravitreal Aflibercept and Laser Photocoagulation in the Treatment of Retinopathy of Prematurity

Dilbade Yildiz Ekinci, MD; Kiymet Çelik, MD

Abstract

Purpose:

To compare the efficacy of intravitreal aflibercept and laser photocoagulation in the treatment of retinopathy of prematurity (ROP).

Methods:

The files of patients who were diagnosed as having type 1 ROP or aggressive posterior ROP (APROP) and treated with laser photocoagulation and 1 mg/0.025 mL of intravitreal aflibercept were retrospectively analyzed. The patients' birth weight, gestational age, detection week of the disease, zone, stage, presence of plus disease and rubeosis, regression of ROP, re-treatments administered during the follow-up, and spherical equivalent values obtained at the corrected sixth month were recorded.

Results:

The study included 27 eyes of 15 patients who underwent laser photocoagulation and 24 eyes of 12 patients who received intravitreal aflibercept. Retinal vascularization was in zone II in all eyes in the laser photocoagulation group and zone 1 in 22 eyes (91.7%) in the intravitreal aflibercept group (P < .05). In the laser photocoagulation group, 25 eyes (92.6%) had stage 3 ROP and 2 eyes (7.4%) had stage 2 ROP. In the intravitreal aflibercept group, 14 eyes (58.3%) had stage 3 ROP and 10 eyes (41.7%) had APROP (P < .05). Treatment was established at a postmenstrual age of 37.6 ± 2.5 weeks in the laser photocoagulation group and 34.2 ± 2.4 weeks in the intravitreal aflibercept group (P < .05). The regression rates after treatment were 92.6% and 100%, respectively (P > .05). In the intravitreal aflibercept group, laser photocoagulation was performed on 10 eyes (41.6%) during follow-up visits. Spherical equivalents were measured as +1.10 ± 2.30 and +1.50 ± 2.41 diopters, respectively (P < .05) at the corrected sixth month.

Conclusions:

Intravitreal aflibercept is an effective treatment for ROP. However, it requires more additional treatments than laser photocoagulation during the follow-up visits.

[J Pediatr Ophthalmol Strabismus. 2020;57(1):54–60.]

Abstract

Purpose:

To compare the efficacy of intravitreal aflibercept and laser photocoagulation in the treatment of retinopathy of prematurity (ROP).

Methods:

The files of patients who were diagnosed as having type 1 ROP or aggressive posterior ROP (APROP) and treated with laser photocoagulation and 1 mg/0.025 mL of intravitreal aflibercept were retrospectively analyzed. The patients' birth weight, gestational age, detection week of the disease, zone, stage, presence of plus disease and rubeosis, regression of ROP, re-treatments administered during the follow-up, and spherical equivalent values obtained at the corrected sixth month were recorded.

Results:

The study included 27 eyes of 15 patients who underwent laser photocoagulation and 24 eyes of 12 patients who received intravitreal aflibercept. Retinal vascularization was in zone II in all eyes in the laser photocoagulation group and zone 1 in 22 eyes (91.7%) in the intravitreal aflibercept group (P < .05). In the laser photocoagulation group, 25 eyes (92.6%) had stage 3 ROP and 2 eyes (7.4%) had stage 2 ROP. In the intravitreal aflibercept group, 14 eyes (58.3%) had stage 3 ROP and 10 eyes (41.7%) had APROP (P < .05). Treatment was established at a postmenstrual age of 37.6 ± 2.5 weeks in the laser photocoagulation group and 34.2 ± 2.4 weeks in the intravitreal aflibercept group (P < .05). The regression rates after treatment were 92.6% and 100%, respectively (P > .05). In the intravitreal aflibercept group, laser photocoagulation was performed on 10 eyes (41.6%) during follow-up visits. Spherical equivalents were measured as +1.10 ± 2.30 and +1.50 ± 2.41 diopters, respectively (P < .05) at the corrected sixth month.

Conclusions:

Intravitreal aflibercept is an effective treatment for ROP. However, it requires more additional treatments than laser photocoagulation during the follow-up visits.

[J Pediatr Ophthalmol Strabismus. 2020;57(1):54–60.]

Introduction

Retinopathy of prematurity (ROP) is a vasoproliferative retinal disease that may cause blindness, in which vascular endothelial growth factor (VEGF) plays a key role in the pathogenesis.1–3 Today, laser photocoagulation is still the gold standard in the treatment of ROP; peripheral avascular retina is ablated by laser photocoagulation, reducing the amount of VEGF and inducing the regression of the disease.3,4 Although the development of blindness is prevented by laser photocoagulation, a permanent peripheral visual field loss occurs due to ablation. This may lead to high refractive errors and poor visual outcomes, especially in cases of posterior disease.4–7

In ROP, anti-VEGF drugs (bevacizumab, ranibizumab, and aflibercept) that treat the disease by blocking VEGF in the vitreous have been widely used intravitreally.8–11 Anti-VEGF agents have higher anatomic success and produce less refractive error compared to laser photocoagulation, especially in cases of posterior disease.7 However, the disruption of vascularization by anti-VEGF treatment, late recurrences, and lack of clarity about the systemic side effects suggest that patients to be treated with these agents should be selected carefully.12–14 Our study aimed to compare the efficacy, recurrence rate, and requirement for additional treatment between laser photocoagulation and 1 mg/0.025 mL of intravitreal aflibercept in the treatment of ROP.

Patients and Methods

Before starting the study, the approval of the clinical research ethics committee of Gazi Yasargil Training and Research Hospital was obtained and the study was conducted in accordance with the ethical standards of the Declaration of Helsinki. The study was conducted by retrospectively analyzing the files of infants who were followed up and treated in the ROP Diagnosis and Treatment Center of Gazi Yasargil Training and Research Hospital between January and April 2018. Written consent was obtained from the families of all infants who participated in the study.

Patients who were lost to follow-up, died after treatment, were treated in another center for ROP, or had additional ocular disease were excluded from the study.

For the examination, mydriasis was achieved by administering 0.5% tropicamide (Tropamid; Bilim Ilaç, Istanbul, Turkey) and 2.5% phenylephrine (Mydfirin; Alcon Laboratories, Inc., Fort Worth, TX) to the eyes three times at 10-minute intervals after the discontinuation of oral feeding of the patients. Thirty minutes after the eye drops were instilled, topical anesthesia was administered with 0.5% proparacaine hydrochloride (Alcain; Alcon Laboratories, Inc.). The examinations were performed by an experienced ophthalmologist (DYE) using a 20-diopter (D) lens (Volk Optical Inc., Mentor, OH) with the help of Heine Video Omega 2c binocular indirect ophthalmoscope (Heine Optotechnik, Herrsching, Germany). The retinal images of the patients were recorded in the ArchiMED software (Digital Imaging S.r.l., Turin, Italy). The findings were evaluated according to the International Classification of Retinopathy of Prematurity.15

In eyes with ROP, treatment was administered to those diagnosed as having type 1 ROP or aggressive posterior ROP (APROP) according to the criteria of the Early Treatment for Retinopathy of Prematurity study.4 The treatment was administered within 72 hours after the families were informed about the possible risks of the treatment (laser photocoagulation/intravitreal injection) and signed an informed consent form.

Intravitreal aflibercept (1 mg/0.025 mL) was administered to the patients whose disease was zone I or zone II posterior, in whom adequate dilatation could not be achieved due to rubeosis and laser treatment could not be performed effectively due to vitreous hemorrhage, and whose general condition was not appropriate for laser photocoagulation. Laser photocoagulation was performed on the patients who did not meet these criteria and in whom the disease was in zone II periphery.

Injection Technique

Intravitreal aflibercept injection was administered in the operating room under local anesthesia with monitoring by an anesthetist. After the eye was stained with 10% betadine (Poviiodeks; Tip Kim San, Istanbul, Turkey), a sterile eyelid speculum was applied and the eye was washed with 5% povidone-iodine. Using a 30-gauge, 4-mm microneedle, 1 mg/0.025 mL (20% of adult dose) of aflibercept (Eylea; Regeneron Pharmaceuticals Inc., Tarrytown, NY) was administered from the upper temporal area at a distance of 1.5 mm to the limbus. The pulsation of the central retinal artery was evaluated immediately after the injection. Topical antibiotic eye drops were used four times daily for 1 week after the injection. After the injection, the patients were examined at postoperative 1 day, 1 week, and then weekly until the disease completely regressed.

Laser Photocoagulation Technique

Laser photocoagulation was performed in the operating room under general anesthesia with a 810-nm diode laser (Iridex; Oculight Sl, Mountainview, CA) in the near confluent pattern. Topical steroid and antibiotic eye drops were used for 1 week after the procedure. After laser photocoagulation, the follow-up visits were performed at postoperative 1 day, 1 week, and then weekly until the disease completely regressed.

Unresponsiveness to the first treatment was evaluated as the absence of any regression in the stage and the plus disease in the first postoperative week. Recurrence was accepted as the presence of a demarcation line or neovascularization in the retinal vascular termination region during the follow-up visits with or without plus disease after complete regression of the disease. Laser photocoagulation was performed if the patients who developed recurrence met the type 1 ROP criteria.

The presence of any of the following in the study was considered an unfavorable anatomic outcome: dragging of the disc, localized tractional or non-tractional membranes at the posterior pole or in the retinal periphery, and total or partial retinal detachment.

The patients' sex, birth weight (BW) and gestational age (GA), diagnosis of ROP, presence of plus disease, rubeosis and vitreous hemorrhage, regression status of plus disease and ROP in the postoperative follow-up visits, requirement for additional treatment and recurrence status, and anatomic success rate during the postoperative visit were recorded. The success rates were compared in the eyes treated with intravitreal aflibercept or laser photocoagulation.

Statistical Analysis

Mean, standard deviation, median, minimum, maximum, frequency, and rate values were used for the descriptive statistics of the data. The distribution of the variables was measured by the Kolmogorov–Smirnov test. The Mann–Whitney U test was used to analyze the quantitative independent variables. The chi-square test was used to analyze the qualitative independent data, and the Fisher's exact test was used when the conditions for the chi-square test were not met. SPSS software (version 22.0; SPSS, Inc., Chicago, IL) was used in the analyses.

Results

A total of 27 infants (51 eyes) who completed the follow-up period after laser photocoagulation or intravitreal aflibercept treatments were enrolled in the study. There were 27 eyes of 15 infants (55.6%) in the laser photocoagulation group and 24 eyes of 12 infants (44.6%) in the intravitreal aflibercept group. The demographic and clinical characteristics of the study groups are shown in Table 1. In the laser photocoagulation group, stage 3 ROP was detected in 25 eyes (92.6%) and stage 2 ROP in 2 eyes (7.4%). In the intravitreal aflibercept group, stage 3 ROP was detected in 14 eyes (58.3%) and APROP in 10 eyes (41.7%) (P < .05).

Demographic and Clinical Characteristics

Table 1:

Demographic and Clinical Characteristics

No treatment-related ocular or systemic complication was observed in both groups. The regression rates after treatment were 92.6% and 100%, respectively (P > .05). Figures 12 show the treatment response to laser photocoagulation and intravitreal aflibercept in ROP. In the laser photocoagulation group, rescue therapy with intravitreal aflibercept was administered to the 2 eyes unresponsive to treatment in the first week after the first treatment and the disease was brought under control. As a result of both treatment modalities, no recurrence was observed in the first group after the disease completely regressed. However, recurrence occurred in 8 eyes (30%) in the intravitreal aflibercept group (P < .05). During the follow-up visits, the disease spontaneously regressed in the 2 eyes that developed recurrence. Progression to stage 3 along with plus disease was detected in 6 eyes (25%); these eyes were treated with laser photocoagulation and the disease completely regressed. The mean PMA for recurrence development was 48.2 weeks and treatment was administered at PMA of 52.4 weeks. Of these eyes, 4 were zone I APROP and 2 were zone I stage 3. In the intravitreal aflibercept group, the mean GA of the patients who underwent laser photocoagulation due to recurrence was 25.6 ± 0.5 weeks (range: 25 to 26 weeks) and the mean BW was 745 ± 54.4 g (range: 650 to 810 g). The GA and BW of the patients who developed recurrence and were treated were significantly lower than those who did not develop recurrence (P < .05).

Fundus photographs of an infant with zone II stage 3 retinopathy of prematurity (ROP). (A and B) Plus disease and stage 3 ROP are clearly observed. (C and D) The response to treatment is seen 1 week following laser photocoagulation with regression of plus disease and ridge.

Figure 1.

Fundus photographs of an infant with zone II stage 3 retinopathy of prematurity (ROP). (A and B) Plus disease and stage 3 ROP are clearly observed. (C and D) The response to treatment is seen 1 week following laser photocoagulation with regression of plus disease and ridge.

Fundus photographs of an infant with zone II posterior retinopathy of prematurity (ROP). (A and B) Plus disease and stage 3 ROP are clearly observed. (C and D) The response to treatment is seen 1 month following laser photocoagulation with regression of plus disease and ridge.

Figure 2.

Fundus photographs of an infant with zone II posterior retinopathy of prematurity (ROP). (A and B) Plus disease and stage 3 ROP are clearly observed. (C and D) The response to treatment is seen 1 month following laser photocoagulation with regression of plus disease and ridge.

In the intravitreal aflibercept group, prophylactic laser photocoagulation was performed on the 4 eyes (16.6%) with non-progressive vascularization at the corrected sixth month. At the end of the follow-up period, the rate of additional treatment was higher in the intravitreal aflibercept group than in the laser photocoagulation group (P < .05).

A fibrotic band and dragging of the optic disc developed in one eye of a patient who received intravitreal aflibercept with the diagnosis of aggressive posterior ROP and underwent laser photocoagulation due to recurrence (zone II stage 3 ROP, plus disease) during the follow-up visits. No additional fibrotic band–related complication was observed during the follow-up visits.

In the refraction measurements at the corrected sixth month, the spherical equivalent was +1.10 ± 2.30 D in the laser photocoagulation group and +1.50 ± 2.41 D in the intravitreal aflibercept group (P > .05). Myopia of greater than 6.00 D was detected in 1 eye (3.7%) in the laser photocoagulation group and 2 eyes (8.3%) in the intravitreal aflibercept group (P > .05). One patient had esotropia in the laser photocoagulation group, whereas one patient had exotropia and one patient had esotropia in the intravitreal aflibercept group (P > .05).

Discussion

Laser ablation of the peripheral retina is still the gold standard in the treatment of ROP.4,5,16 Especially in cases of zone I disease and previously failed laser photocoagulation, the disease can be successfully treated with anti-VEGF agents.7,8 In the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) study, it was reported that intravitreal bevacizumab treatment was more successful than laser photocoagulation in patients with zone 1 ROP and had a lower recurrence rate.8 In addition, it was shown that intravitreal bevacizumab, intravitreal aflibercept, and intravitreal ranibizumab were effective in the treatment of ROP in patients with zone II disease and retinal vascularization continued after the treatment, unlike laser photocoagulation.11,17,18 In our study, the first study comparing the efficacy of intravitreal aflibercept and laser photocoagulation in the treatment of ROP, both treatment modalities were found to have similar efficacy. According to our results, intravitreal aflibercept provides a high rate of anatomical success in patients with zone I ROP. This result demonstrates that intravitreal aflibercept is an alternative treatment modality in such cases where laser photocoagulation is likely to have a poor prognosis.

In cases of zone I ROP, it is known that the disease is detected at a lower PMA and progresses faster than the cases of zone II ROP.19 Moreover, it has been shown that patients with zone I disease have poorer GA, BW, and anatomical and visual outcomes than those with zone II disease.4,5,20–23 In our study, most of the patients in the intravitreal aflibercept group had zone I disease and, although not statistically significant, had lower BW and GA than the laser photocoagulation group. Contrary to the literature data, this result can be explained by the small sample size in both groups.

In our study, patients who received intravitreal aflibercept were treated at an earlier PMA compared to those who underwent laser photocoagulation. The requirement for treatment at an earlier PMA in the intravitreal aflibercept group, the detection of rubeosis in the majority of eyes at the time of diagnosis, and retinal vascularization in zone 1 in almost all patients demonstrate that the disease was more severe in this group compared to the other group. Treatment of all eyes in the laser photocoagulation group with a 100% success rate using the intravitreal aflibercept mono-therapy demonstrates that aflibercept is an anti-VEGF agent that can be used as an alternative to intravitreal bevacizumab and laser photocoagulation.7–9,12

Laser photocoagulation may cause a progression in ROP leading to a temporary increase in VEGF levels in the vitreous.24 It is known that intravitreal bevacizumab is successfully used as a rescue therapy in patients who fail with laser photocoagulation.25,26 In our study, response to treatment could not be obtained in 2 eyes of 1 patient as a result of laser photocoagulation applied without leaving avascular space. In the postoperative first week, intravitreal aflibercept was administered to the 2 eyes of the patient and the disease completely regressed. The successful outcome of rescue therapy with intravitreal aflibercept was reported for the first time in the literature and demonstrated that intravitreal aflibercept can be used safely after failed laser photocoagulation treatment such as intravitreal bevacizumab.

It is known that patients who receive anti-VEGF agents due to ROP develop recurrence in the late period and blindness may develop due to these recurrences.8,12,14,17,27 Recurrence after treatment with anti-VEGF agents is more common in infants who are treated for APROP, hospitalized for a long time, and have a low BW and GA.14 In addition, eyes with slow progression of retinal vascularization are considered at risk in terms of recurrence.14 It is emphasized that patients with these risk factors should be followed up at more frequent intervals and for a longer period of time. Especially for patients treated with intravitreal bevacizumab, a PMA between 45 and 55 weeks is considered a window in terms of recurrence and it is recommended to increase the frequency of follow-up visits in this period.14

In addition to these risk factors, an anti-VEGF agent administered was also found to be effective in recurrence. In a study comparing intravitreal bevacizumab and intravitreal ranibizumab, eyes treated with intravitreal ranibizumab developed recurrence more frequently. This was attributed to the fact that the half-life of ranibizumab was shorter than that of bevacizumab.12 In a study comparing intravitreal ranibizumab and intravitreal aflibercept, eyes treated with intravitreal ranibizumab again developed recurrence more frequently and at an earlier period.28 In the same study, the recurrence rate was 13.9% in the intravitreal aflibercept group. In another study evaluating the efficacy of intravitreal aflibercept, the recurrence rate was 7.7% and the eyes that developed recurrence were treated with a second dose of intravitreal aflibercept.

In our study, the recurrence rate was 30% in the intravitreal aflibercept group throughout the follow-up and 25% of all eyes were treated for recurrence. We found that the BW and GA of the patients who developed recurrence were lower than those who did not develop recurrence, supporting the view that very low BW and GA are risk factors for recurrence. However, because the other two studies conducted with intravitreal aflibercept did not evaluate BW and GA of the patients who developed recurrence, it could not be clarified whether these two factors had an effect on our high recurrence rate compared to the others. PMA at which the second treatment was administered for recurrence was similar in all three studies. Our higher recurrence rate compared to the other two studies may be due to the initial disease being zone I in almost all of our patients in contrast to the other two studies.

The disruption of vascular development after intravitreal bevacizumab, intravitreal aflibercept, and intravitreal ranibizumab treatments has been ophthalmoscopically and angiographically demonstrated.11,13,28,29 Prophylactic laser photocoagulation is recommended to prevent recurrence-related blindness in cases of avascular areas detected by fundus fluorescein angiography during the follow-up of patients receiving VEGF monotherapy.29,30 Considering that we were unable to evaluate patients using fundus fluorescein angiography in our clinic and that our patients had risk factors in terms of recurrence, prophylactic laser photocoagulation was performed on 4 eyes (16.6%) with ophthalmoscopically residual avascular areas at the corrected sixth month.

In the BEAT-ROP study, the rate of recurrence after laser photocoagulation was higher in patients with zone 1 compared to those treated with intravitreal bevacizumab and similar in zone 2 posterior cases.8 Moreover, the rate of anatomic success was lower in patients treated with laser photocoagulation than in those treated with intravitreal bevacizumab in the zone 1 group. In our study, no recurrence was observed in the eyes treated with laser photocoagulation after the disease completely regressed. The anatomic success rate during the last visit was similar in both groups. This difference between the two studies in terms of recurrence and anatomical success may be due to the fact that we preferred intravitreal aflibercept instead of laser photocoagulation for patients with zone 2 posterior ROP and left avascular areas that might cause VEGF production by applying laser spots in the near-confluent pattern.

When the effects of intravitreal bevacizumab and laser photocoagulation on refraction were evaluated, it was found that the eyes with zone 1 disease developed less myopia in the intravitreal bevacizumab group than in the laser group.8 In a study in which zone 1 and zone 2 distribution was more equal, myopia and mean spherical equivalent were similar in patients treated with intravitreal bevacizumab and laser photocoagulation.31 In the refraction tests of the patients treated with intravitreal aflibercept at the age of 1 year, myopia of greater than 5.00 D was detected only in 1 patient (3.8%); the disease located in zone 1 and a low PMA at which the treatment was administered were determined to be risk factors for the development of high myopia. Posterior location of the disease and low BW and GA, especially in the eyes treated with laser photocoagulation, are risk factors for myopia development.17 In our study, there was no difference between the groups in terms of spherical equivalent. Lower refractive error compared to the other studies, especially in the laser photocoagulation group, may be due to the preference for intravitreal aflibercept instead of laser photocoagulation in patients with zone 1 ROP.

Intravitreal aflibercept treatment provides successful anatomical and refractive outcomes in cases of posterior disease and allows the retinal vascularization to progress. However, the recurrence rate and requirement for additional treatment compared to laser photocoagulation suggest that patients receiving this treatment should be followed up more frequently.

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Demographic and Clinical Characteristics

CharacteristicLPC GroupIVA GroupP
Sex (M/F) (no., %)9 (33, 3%)/18 (66, 7%)10 (41, 7%)/14 (58, 3%).539a
GA, mean ± SD (95% CI), weeks28.7 ± 3.027.3 ± 2.8.068b
BW, mean ± SD (95% CI), g1,281 ± 4381,095 ± 442.12b
Treatment (PMA), mean ± SD (95% CI), weeks37.6 ± 2.534.2 ± 2.4.000b
Follow-up, mean ± SD (95% CI), weeks47.0 ± 10.145.2 ± 11.1.636b
Zone I/zone II (no., %)0 (0%)/27 (100%)22 (91, 7%)/2 (8, 3%).05a
Rubeosis iridis (−)/(+)27 (100, 0%)/0 (0, 0%)6 (25, 0%)/18 (75, 0%).05a
Authors

From the Departments of Ophthalmology (DYE) and Neonatology (KC), Diyarbakir, Gazi Yasargil Training and Research Hospital, Diyarbakir, Turkey.

The authors have no financial or proprietary interest in the materials presented herein.

Correspondence: Dilbade Yildiz Ekinci, MD, Department of Ophthalmology, Diyarbakir, Gazi Yasargil Training and Research Hospital, Diyarbakir, Turkey. E-mail: dilbadeekinci@gmail.com

Received: August 12, 2019
Accepted: October 03, 2019

10.3928/01913913-20191104-01

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