Efficacy and Safety of Anti-Vascular Endothelial Growth Factor Drugs for Coats' Disease Treatment: A Systematic Review

Abstract

Purpose:

The efficacy and safety of anti-vascular endothelial growth factor (anti-VEGF) treatment for Coats' disease remains controversial. This study was designed to evaluate the efficacy and safety of anti-VEGF treatment for Coats' disease.

Methods:

PubMed, Embase, The Cochrane Library, Clinical Trials, CNKI, and WanFang databases were systematically searched for clinical efficacy and safety studies on anti-VEGF treatment for Coats' disease through June 2021. Study selection, data extraction, and quality assessment were independently performed by 2 reviewers. Quality assessments were performed using the Joanna Briggs Institute Critical Appraisal tools and GRADE-CERQual.

Results:

A total of 1,501 articles were retrieved and reviewed, of which 24 case series involving 378 patients (range: 3–67 patients each with 3–71 eyes) were included in the analysis. No randomized controlled trials, case-controlled studies, or cohort studies were available for analysis. Most patients were male (60.0%–92.9%), aged 1.35–42.3 years, with a median follow-up time ranging from 3 to 63 months. Among the 24 case series, 22 reported changes in the visual acuity (VA) after anti-VEGF treatment and 21 reported safety outcomes. The results showed that VA improved in 73 patients (37.63%), was stable in 89 (45.87%), and worsening VA was observed in 12 cases (6.19%). The most common adverse event was fibrotic changes (n = 35). Systemic complications were not observed.

Conclusions:

The results of this study indicate that anti-VEGF drugs provide an effective and relatively safe treatment strategy for Coats' disease. However, conducting well-designed, prospective, randomized clinical trials are necessary to confirm our findings.

Introduction

Coats' disease, also known as retinal telangiectasia, was first proposed by a Scottish ophthalmologist, George Coats in 1908, and is defined as a rare idiopathic retinal vascular disease.¹ Based on a prospective study conducted in the United Kingdom, the estimated incidence of Coats' disease is 0.09 per 100,000 individuals, and males are more commonly affected than females.² The main clinical features of Coats' disease are unilateral dilated retinal capillaries, retinal telangiectasia, and aneurysms with retinal exudation in eyes.^1,3 At present, Coats' disease is generally managed through cryotherapy or laser photocoagulation to reduce exudation by destroying abnormal blood vessels and ischemic retinal tissue. If extensive exudation or retinal detachment occurs, surgery is preferred.^4,5

However, even with conventional treatment, visual acuity (VA) may not improve. In a retrospective study conducted in the United States, the final VA was hand movement (HM) or worse in 50% of children after receiving traditional treatment methods.⁶ Given these poor VA outcomes, the best method to improve VA in patients with Coats' disease is a high clinical priority.

The pathogenesis of Coats' disease remains unclear. Vascular endothelial growth factor (VEGF) is believed to play a major role in the progression of Coats' disease.⁷ Multiple studies have demonstrated elevated VEGF levels in ocular fluids in Coats' disease.^7–9 The literature includes numerous studies on anti-VEGF used to treat Coats' disease. In addition to cryotherapy and laser photocoagulation, anti-VEGF medications are increasingly used to treat Coats' disease. At present, anti-VEGF treatment is considered an adjuvant treatment for Coats' disease. Despite its widespread use, there are no systematic reviews or meta-analyses on the efficacy and safety of anti-VEGF treatment for Coats' disease. Therefore, this study aimed to systematically review the clinical evidence on anti-VEGF treatment for Coats' disease, comprehensively evaluate its efficacy and safety, and provide a reference for clinical decisions.

Methods

A systematic review protocol was developed a priori and registered in PROSPERO (CRD42022302373).

Eligibility criteria

The population-intervention-comparator-outcomes-study design (PICOS) framework was used to identify eligible cases. The details of the criteria established a priori are as follows:

Population: Only human patients with Coats' disease, with no restrictions on age and staging of Coats' disease or other demographics.

Coats' disease is staged according to Shields' criteria.⁶ Stage 1 involves only retinal telangiectasia; stage 2 involves telangiectasia and exudation with stage 2A representing extrafoveal exudation and stage 2B representing exudation involving the macular fovea; stage 3 involves exudative retinal detachment, in which stage 3A1 does not involve the fovea, stage 3A2 involves the fovea, and stage 3B involves total retinal detachment; stage 4 involves total retinal detachment with glaucoma; and stage 5 involves severe end-stage disease.

Intervention: Anti-VEGF drugs or anti-VEGF drugs in combination with ablation (laser photocoagulation, cryotherapy) or surgical intervention (vitrectomy, subretinal fluid [SRF] drainage, etc.). Anti-VEGF drugs include bevacizumab, ranibizumab, conbercept, aflibercept, and brolucizumab.

Comparator: Only ablation treatment was used.

Outcomes:

Effective primary outcomes: VA or best-corrected VA (BCVA).

Effective secondary outcomes: central macular thickness (CMT), SRF absorption, retinal reattachment, and telangiectasia regression.

Safety outcomes: ocular complications, including fibrotic change, tractional retinal detachment (TRD), cataract formation, band keratopathy, neovascular glaucoma, vitreous hemorrhage, and systemic complications.

Study design: Randomized controlled trials, case–control studies, cohort studies, and case series published in full text were included.

Exclusion criteria

Single-case reports, reviews, conference abstracts, translations, and letters to the editor were excluded. Studies without related outcomes, Coats' disease complicated with other ocular diseases, anti-VEGF drugs combined with other drugs (intraocular medication or topical/periocular medication), and nonclinical studies were excluded.

Search strategies and information sources

A systematic search using search strategies, comprising MeSH items and free items (Supplementary Material, Appendix S1), was carried out in 6 databases, including PubMed, Embase, The Cochrane Library, Clinical Trials, CNKI, and WanFang. The final search was performed in June 2021.

Study selection

Search strategies were implemented by B.J. with initial results imported and merged into the reference management software ENDNOTE^® (version X7; Clarivate Analytics [formerly Thomson Reuters], Philadelphia, PA). After the removal of duplicates, the remaining titles and abstracts were assessed for inclusion. The full texts of relevant articles were retrieved and independently assessed by 2 author groups (B.J. and D.L.; L.G. and S.Z.). Conflicts were resolved by consensus, and consulting a third independent reviewer (Z.C.) if necessary.

Data extraction and quality assessment

Using standardized data extraction forms, data were extracted independently by the 2 author groups (as described previously) and compared. Discrepancies were discussed with Z.C. and S.Z. as adjudicators. Data extracted included the country of origin of the published cases, year of publication, patient demographics, number of cases, gender, age, research type, intervention measures, control measures, follow-up time, clinical outcomes, and adverse reactions.

Two reviewers (B.J. and L.G.) independently assessed the quality using the Joanna Briggs Institute Critical Appraisal tools for use in the JBI systematic review checklist for case series.¹⁰ The GRADE-CERQual was used to assess how much confidence to place in the key findings of this systematic review. Two reviewers (B.J. and L.G.) independently reviewed the findings according to the guidance for GRADE-CERQual parameters.¹¹

Strategy for data synthesis

Relative risk (RR) and its 95% confidence interval (95% CI) were calculated. When the research data could not be quantitatively synthesized, the results of the qualitative analysis were used.

Results

The initial database search identified 1,501 articles. There were no randomized controlled trials, case–control studies, or cohort studies. After the preliminary screening, 105 articles were included in the study. Of these, 81 articles were excluded for not meeting the inclusion criteria: 52 case reports, 14 articles without reported post-treatment outcomes, 5 letters to the editor regarding a single case, 5 research reviews, 3 with other ocular comorbidities, and 2 articles with dexamethasone intravitreal implants or triamcinolone acetonide intravitreal injection use. Finally, 24 articles were included,^12–35 all of which were case series, including 17 English articles and 7 Chinese articles, published between 2010 and 2021. Among the 24 case series, 20 were retrospective studies and 4 prospective studies. The study selection process is given in Fig. 1.

FIG. 1.

Flow diagram of the study selection process.

Characteristics of the included case series

A total of 378 patients with Coats' disease were included in 24 studies, with 3–67 cases in each study. Males accounted for 60.0%–92.9%, with an average age of 15.73 years, and median follow-up time was 18.8 months. The majority of patients were stage 2 (31.8%) and stage 3 (63.2%), patients with stage 4 (5.0%) were less, and there were no stage 1 or 5 patients. The characteristics of the 24 case series are given in Table 1.

Table 1.

Characteristics of 24 Included Case Series Studies

Studies	Cases (eyes)	Average age (years)	Gender (M/F, n)	Staging of Coats' disease (n)	Study design	Median follow-up times (months)
Cennamo et al.¹²	15 (15)	20.4	9/6	2A (10), 2B (5)	Retrospective study	3
Kang et al.¹³	67 (71)	25.8	50/17	2A (28), 2B (26), 3A1 (7), 3A2 (2), 3B (8)	Retrospective study	63
Nowara et al.¹⁴	16 (16)	5	11/5	2 (4), 3 (12)	Retrospective study	16
Jiang et al.¹⁵	8 (8)	36.1	7/1	2A (5), 2B (3)	Retrospective study	37.33
Liang et al.¹⁶	29	3.1	25/4	3B (29)	Retrospective study	44
Zhang et al.¹⁷	28 (28)	22.8	18/10	3A (21), 3B (7)	Retrospective study	24
Huang et al.¹⁸	13 (13)	10.5	7/6	3B (8), 4 (5)	Retrospective study	8–44
Jiang et al.¹⁹	6 (6)	34.1	5/1	—	Retrospective study	7.33
Li et al.²⁰	17	4.94	15/2	3A (10), 3B (7)	Retrospective study	22
Li et al.²¹	13 (13)	4.2	11/2	3B (13)	Retrospective study	18.5
Mao et al.²²	18 (18)	26.9	16/2	2A (7), 2B (8), 3A (3)	Retrospective study	18.8
Bhat et al.²³	7 (7)	2.8	5/2	3B (7)	Retrospective study	18
Park et al.²⁴	13 (13)	40.3	9/4	2B (7), 3A (6)	Retrospective study	21
Yang et al.²⁵	17	7.9	15/2	3A (6), 3B (11)	Prospective study	9
Chen et al.²⁶	14 (14)	9.6	13/1	3B (8), 4 (6)	Retrospective study	18.8
Wang and Song²⁷	9 (9)	13.5	8/1	—	Retrospective study	5–24
Gaillard et al.²⁸	9 (9)	1.35	7/2	3B (5), 4 (4)	Retrospective study	50
Villegas et al.²⁹	24	5.1	17/7	—	Retrospective study	22.4
Yang et al.³⁰	19 (19)	13.05	17/2	3A (13), 3B (6)	Retrospective study	19.11
Zheng and Jiang³¹	19 (19)	6.9/33.6	13/1; 4/1	2 (1), 3A (11), 3B (7)	Retrospective study	24
Ramasubramanian and Shields³²	8	7.3	5/3	2 (1), 3A (3), 3B (4)	Retrospective study	8.5
Goel et al.³³	3 (3)	42.3	2/1	2B (3)	Prospective study	9
Kaul et al.³⁴	3 (3)	8.3	2/1	3A (1), 4 (2)	Prospective study	6
Lin et al.³⁵	3 (3)	7.5	2/1	2B (1), 3A (1), 3B (1)	Prospective study	12

—, not mentioned; The listed follow-up time was average follow-up time in 9 studies owing to no specific follow-up data in these studies (Jiang et al.,¹⁵ Huang et al.,¹⁸ Jiang et al.,¹⁹ Li et al.,²¹ Mao et al.,²² Chen et al.,²⁶ Villegas et al.,²⁹ Yang et al.,³⁰ and Ramasubramanian and Shields³²).

Quality evaluation of included case series

According to the JBI systematic review checklist for case series, 14 (58.3%) studies clearly described the criteria for inclusion; 22 (91.7%) studies measured the condition in a standard, reliable way for all participants; 18 (75%) studies had consecutive inclusion of participants; 20 (83.3%) studies clearly reported the clinical information of the participants, and 24 studies (100%) clearly reported the outcomes or follow-up of cases. But none of the studies reported site(s)/clinic(s) demographic information. In general, the quality of the 24 included case series studies was high. The results of the quality evaluation are given in Supplementary Table S1.

Furthermore, we analyzed the confidence of our findings using the CERQual. Three key findings, including VA, retina reattachment, and adverse reaction, were analyzed. We found that the quality of studies supporting key findings was moderate, the concordance of results was high. The adequacy was moderate, low, and moderate for the 3 key findings. Owing to the above results and the nature of case series, the overall assessment of confidence was low, very low, and low for the 3 key findings, respectively. The results and detailed explanation of the confidence ratings are given in Supplementary Table S2.

Efficacy outcomes

The research outcomes are described in a qualitative analysis format. The dosing of conbercept and ranibizumab was 0.5 mg/0.05 mL, except one case initial dose was 0.03 mL in the study reported by Gaillard et al.²⁸ The dosing of bevacizumab was 1.25 mg/0.05 mL or 2.5 mg/0.1 mL.³⁵ The injection frequency was once a month and average number of injections was 2.23. The number of injections depended on the therapeutic outcomes, such as the SRF was completely reabsorbed or subretinal lipid significantly decreased in quantity. The primary outcome was the change in VA after anti-VEGF treatment, which was reported in 22 studies (91.7%), with 16 reporting specific changes in VA before and after treatment.^{12,14,15,17,19–22,24,26–28,30,33–35} A total of 194 cases were involved in the 16 case series, with 73 (37.63%) showing improvement in vision, 89 (45.87%) with stable vision, 12 (6.19%) with worsening vision, and 20 (10.31%) who were too young to complete formal VA testing.

Three studies did not demonstrate specific changes in VA; they only reported trends rather than numerical values.^18,25,31 Bhat et al.²³ reported that VA remained finger counting close to face or worse in all cases, although anatomical improvement was noted. Kang et al.¹³ found that more than third of all eyes (34%) experienced a 3-line decrease in vision compared with baseline, and no statistical differences in the incidence of complications or visual outcomes were observed in the laser only (n = 18) group compared with a combination of laser therapy and anti-VEGF injections (n = 16) group (all P > 0.05); however, although not statistically significant, a trend for superior final VA in eyes was observed in group treated with combination of laser and anti-VEGF (20/472 vs. 20/99, P = 0.066).

Ramasubramanian and Shields³² observed that the visual prognosis was poor in all patients. Liang et al.¹⁶ and Villegas et al.²⁹ showed that final anatomic success with retinal reattachment was achieved in 24 eyes (82.8%, total 29 eyes) and 24 eyes (100%, total 24 eyes), respectively, but the change in VA was not mentioned. The results are given in Table 2.

Table 2.

Efficacy of Anti-Vascular Endothelial Growth Factor Drugs for Coats' Disease (Primary Outcomes)

Studies	Treatment regime	Evaluation criteria for results	VA
Cennamo et al.¹²	Ranibizumab (0.5 mg/0.05 mL, 3 monthly injections)	—	Baseline BCVA: 0.46 ± 0.11 logMAR, final visit BCVA: 0.47 ± 0.12 logMAR (P = 0.164)
Kang et al.¹³	Laser only (25%), laser + anti-VEGF (23%, single dose or monthly doses up to 4 times), cryotherapy (20%), vitrectomy or scleral buckle (16%), anti-VEGF (9%)	—	34% patients 3-line decrease in VA Final visit VA: laser only vs laser + anti-VEGF (20/472 vs. 20/99, P = 0.066)
Nowara et al.¹⁴	Ranibizumab [0.5 mg/0.05 mL, a median of 1 injection (range: 1–3)] + ablation therapy	—	Improved VA: 2 eyes (12.5%) Stable VA: 6 eyes (37.5%) Progression of disease: 1 eye (6.3%) Too young to assess: 7 eyes (43.8%)
Jiang et al.¹⁵	Conbercept (0.5 mg/0.05 mL, average number of injections: 1.37 ± 0.92) + laser photocoagulation	Improvement VA: increase ≥5 letters in EDTRS chart Stable VA: increase or decrease <5 letters in EDTRS chart Worsening VA: decrease ≥5 letters in EDTRS chart	Improved VA: 7 eyes (87.5%) Stable VA: 1 eye (12.5%)
Liang et al.¹⁶	SRF drainage + ranibizumab (0.5 mg/0.05 mL, average number of injections: 1.4) + laser photocoagulation	—	Anatomic success: 24 eyes (82.8%)
Zhang et al.¹⁷	Conbercept/ranibizumab (0.5 mg/0.05 mL, average number of injections: 2.82 ± 0.98) + laser photocoagulation	—	Baseline BCVA: 1.57 ± 0.73 logMAR Last visit BCVA: 1.33 ± 0.81 logMAR (P = 0.000)
Huang et al.¹⁸	Ranibizumab (number of injections: 1–7) + scleral drainage/laser Photocoagulation/membrane peeling/freezing/silicone oil filling	—	VA improved (P < 0.05), preoperative VA: 0.05 to 0.1 (0), 0.01 to <0.05 (0), CF(38%), LP (38%), HM(23%); final visit VA: 0.05 to 0.1 (23%), 0.01 to <0.05(23%), CF (38%), LP (15%), HM (0)
Jiang et al.¹⁹	Conbercept (0.5 mg/0.05 mL, average number of injections: 1.20 ± 0.52)+ laser photocoagulation	Improvement VA: increase ≥5 letters in EDTRS chart Stable VA: increase or decrease <5 letters in EDTRS chart Worsening VA: decrease ≥5 letters in EDTRS chart	Improved VA: 5 eyes (90%) Stable VA: 1 eye (10%)
Li et al.²⁰	Ranibizumab (0.5 mg/0.05 mL, average number of injections: 2.82 ± 0.95) only, ranibizumab + retinal photocoagulation/cryotherapy	For preoperative VA ≥0.1, VA changes ≥2 lines as improvement or worsening, VA changes <1 lines as stable For preoperative VA <0.1, VA changes ≥0.2 as improvement or worsening, VA changes <0.2 as stable	Improved VA: 7 eyes (41.2%) Stable VA: 7 eyes (41.2%) Too young to assess: 3 eyes (17.6%)
Li et al.²¹	Ranibizumab (0.5 mg/0.05 mL) + laser photocoagulation/cryotherapy	—	Improved VA: 2 eyes (15.4%) Stable VA: 8 eyes (61.5%) Too young to assess: 3 eyes (23.1%)
Mao et al.²²	Ranibizumab (0.5 mg/0.05 mL, average number of injections: 2.6) + laser photocoagulation	Improvement BCVA: improved >0.3 logMAR Worsening BCVA: decreased >0.3 logMAR Stable: other situations	Preoperative BCVA 0.81 ± 0.28 logMAR, final visit BCVA 0.76 ± 0.37 logMAR (P = 0.396)
Bhat et al.²³	Bevacizumab (1.25 mg/0.05 mL, single injection) + SRF drainage with cryopexy (5 eyes) SRF drainage with cryopexy only (2 eyes)	—	Anatomical improvement, VA remained CF or worse in all cases
Park et al.²⁴	Bevacizumab (1.25 mg/0.05 mL, average number of injections: 2.69) +laser photocoagulation	Improvement BCVA: increase ≥3 lines (≥0.3 logMAR) Stable BCVA: increase or decrease <3 lines (<0.3 logMAR) Worsening BCVA: decrease ≥3 lines (≥0.3 logMAR)	Improved BCVA: 3 eyes (23.1%) Stable BCVA: 7 eyes (53.8%) Worsening BCVA: 3 eyes (23.1%)
Yang et al.²⁵	Ranibizumab (0.5 mg, average number of injections: 3.9 ± 1.0) + laser photocoagulation/cryotherapy	—	Baseline BCVA: 1.4 ± 0.7 logMAR, final visit BCVA:1.1 ± 0.5 logMAR (P < 0.001)
Chen et al.²⁶	Ranibizumab/bevacizumab (average number of injections: 2.14) + SRF drainage/photocoagulation/vitrectomy	Stable VA: no change in VA Improvement/Worsening VA: improvement/decrease in VA	Improved VA: 2 eyes (14.3%) Stable VA: 8 eyes (57.1%) Worsening BCVA: 2 eyes (14.3%) Too young to assess: 2 eyes (14.3%)
Wang and Song²⁷	Ranibizumab (0.5 mg/0.05 mL, single injection) + posterior vitrectomy/SRF drainage/silicone oil/photocoagulation	—	Improved VA: 2 eyes (22.2%) Stable VA: 7 eyes (77.8%)
Gaillard et al.²⁸	Ranibizumab (0.5 mg/0.05 mL, average number of injections: 1.78) + laser photocoagulation	—	Improved VA: 4 eyes (44.4%) Stable VA: 3 eyes (33.3%) Optokinetic nystagmus present: 1 eye (11.1%) Eccentric fixation: 1 eye (11.1%)
Villegas et al.²⁹	Bevacizumab (1.25 mg, average number of injections: 4.6) + laser vascular ablation	—	Anatomic improvement: 24 eyes (100%)
Yang et al.³⁰	Ranibizumab (0.5 mg/0.05 mL) only, Ranibizumab + cryotherapy/cryotherapy and sclerotomy to drain subretinal fluid/vitrectomy	For preoperative VA ≥0.1, VA changes ≥2 lines as improvement or worsening, VA changes <1 lines as stable For preoperative VA <0.1, VA changes ≥0.2 as improvement or worsening, VA changes <0.2 as stable	Improved VA: 2 eye (14.3%) Stable VA: 13 eyes (68.4%) Worsening VA: 1 eye (5.3%) Too young to assess: 3 eyes (15.8%)
Zheng and Jiang³¹	Bevacizumab (1.25 mg/0.05 mL, average number of injections: 2.9 in the pediatric group and 2.0 in the adult group) + laser photocoagulation/cryotherapy	—	Pediatric group: baseline BCVA: 1.50 ± 0.55 logMAR Final visit BCVA: 1.13 ± 0.43 logMAR (P = 0.005) Adult group: Baseline BCVA:1.42 ± 0.71 logMAR, final visit BCVA: 1.25 ± 0.62 logMAR (P = 0.479)
Ramasubramanian and Shields³²	Bevacizumab (1.25 mg/0.05 mL, average number of injections: 1.25) + laser photocoagulation/cryotherapy	—	Visual prognosis was poor
Goel et al.³³	Bevacizumab (1.25 mg, single injection) + peripheral laser photocoagulation	—	Improved VA: 3 eyes (100%)
Kaul et al.³⁴	Pegaptanib sodium (0.3 mg/0.1 mL)/bevacizumab (1.25 mg/0.05 mL) + laser photocoagulation	—	Improved VA: 1 eye (33.3%) Stable VA: 1 eye (33.3%)
Lin et al.³⁵	Bevacizumab (2.5 mg/0.1 mL, average number of injections: 2.33) + laser photocoagulation/cryotherapy	—	Improved VA: 2 eyes (66.7%) Too young to assess: 1 eye (33.3%)

—, not mentioned; SRF, subretinal fluid; VA: visual acuity; BCVA: best corrected VA; HM, hand movement; CF, counting fingers; LP, light perception.

Data regarding VA changes in different stages of Coats' disease after anti-VEGF treatment in 11 studies,^{15,17,20–22,24,28,30,33–35} which contain the individual VA changes, are summarized in Fig. 2. Improved VA after anti-VEGF treatment was noted in 19 (55.9%, total 34 cases) stage 2, 34 (41.5%, total 82 cases) stage 3, and 2 (33.3%, total 6 cases) stage 4 patients. These results suggest that the visual prognosis may be related to disease severity.

FIG. 2.

VA changes after anti-VEGF treatment in 11 studies.^{15,17,20–22,24,28,30,33–35} VEGF, vascular endothelial growth factor.

The secondary outcomes reported included CMT, SRF absorption, and retinal reattachment. Mao et al.²² and Jiang et al.¹⁹ reported improved CMT, whereas Park et al.²⁴ reported improved mean central foveal thickness. However, Cennamo et al.¹² revealed no significant reduction in the CMT (P = 0.915). Eleven studies found different degrees (partial vs. complete) of SRF absorption in all patients, along with telangiectasia regression.^{15,17,20,25,26,29,31–35} Retinal reattachment was reported in 5 studies,^{18,26,27,30,34} 24 patients (42.11%) achieved complete retinal reattachment, 22 patients (38.60%) had partial retinal reattachment, and 11 patients (19.29%) failed to achieve retinal reattachment. Li et al.²⁰ found a statistically significant difference between the preoperative and postoperative retinal detachment heights (P = 0.000). The results are presented in Table 3.

Table 3.

The Efficacy of Anti-Vascular Endothelial Growth Factor Drugs for Coats' Disease (Secondary Outcomes)

Studies	Intervention	Evaluation criteria for results	CMT	SRF absorption	Retina reattachment
Cennamo et al.¹²	Ranibizumab	—	Baseline CMT: 486.33 ± 93.37 μm; final visit CMT: 483.4 ± 80.97 μm> (P = 0.915)	—	—
Jiang et al.¹⁵	Conbercept + laser photocoagulation	—	—	SRF absorption of different degrees in 7 patients (87.5%)	—
Liang et al.¹⁶	SRF drainage + ranibizumab + laser photocoagulation	—	—	—	—
Zhang et al.¹⁷	Conbercept/ranibizumab + laser photocoagulation	—	—	SRF absorption: 15 eyes (88% of 17 SRF patients); regression of the telangiectasia: 28 eyes (100%)
Huang et al.¹⁸	Ranibizumab + scleral drainage/laserPhotocoagulation/membrane peeling/freezing/silicone oil filling	—	—	—	Complete retinal reattachment: 5 eyes (38%); Partial retinal reattachment: 3 eyes (23%); failed in retinal reattachment: 5 eyes (38%)
Jiang et al.¹⁹	Conbercept + laser photocoagulation	—	—	SRF absorption of different degrees in 5 patients (83.3%)	—
Li et al.²⁰	Ranibizumab only, ranibizumab + retinal photocoagulation/cryotherapy	—	—	SRF absorption of different degrees in 17 patients	Average retinal detachment height preoperative: 2363.88 μmFinal visit: 897.18 μm
Mao et al.²²	Ranibizumab + laser photocoagulation	—	Preoperative CMT: (341.11 ± 67.97) μm, final visit CMT: (277.83 ± 51.59) μm, (P = 0.030)	—	—
Park et al.²⁴	Bevacizumab + laser photocoagulation	—	Baseline CMT: 473 ± 223 μmFinal visit CMT: 288 ± 138 μm (P = 0.023)	—	—
Yang et al.²⁵	Ranibizumab + laser photocoagulation/cryotherapy	—	—	Telangiectasia regression in all patients	—
Chen et al.²⁶	Ranibizumab/bevacizumab + SRF drainage/photocoagulation/vitrectomy	Complete retinal reattachment: complete SRF absorption, partial retinal reattachment: partial SRF absorption, failed in retinal reattachment: no SRF absorption	—	SRF absorption of different degrees in all patients	Complete retinal reattachment: 5 eyes (35.7%); partial retinal reattachment: 3 eyes (21.4%); failed in retinal reattachment: 6 eyes (42.8%)
Wang and Song²⁷	Ranibizumab + posterior vitrectomy/SRF drainage/silicone oil/photocoagulation	—	—	—	Complete retinal reattachment: 9 eyes (100%)
Villegas et al.²⁹	Bevacizumab + laser vascular ablation	—	—	Resolution of exudative retinal detachment and ablation of vascular telangiectasia: 24 eyes (100%)	—
Yang et al.³⁰	Ranibizumab only, ranibizumab + cryotherapy/cryotherapy and sclerotomy to drain subretinal fluid/vitrectomy	Complete retinal reattachment: complete SRF absorption, partial retinal reattachment: partial SRF absorption, failed in retinal reattachment: no SRF absorption	—	—	Complete retinal reattachment: 3 eyes (15.8%); partial retinal reattachment: 16 eyes (84.2%)
Zheng and Jiang³¹	Bevacizumab + laser photocoagulation/cryotherapy	—	—	SRF absorption: 19 eyes (100%) regression of the telangiectasia: 19 eyes (100%)	—
Ramasubramanian and Shields³²	Bevacizumab + laser photocoagulation/cryotherapy	—	—	SRF absorption of different degrees in 8 patients	—
Goel et al.³³	Bevacizumab + peripheral laser photocoagulation	—	—	Reduction in the exudation at the macula and macular edema	—
Kaul et al.³⁴	Pegaptanib sodium/ranibizumab + laser photocoagulation	—	—	Regression of the telangiectasia: 3 eyes (100%)	Retinal reattachment: 2 eyes (66.7%)
Lin et al.³⁵	Bevacizumab + laser photocoagulation/cryotherapy	—	—	Resolution of exudation of different degrees in 3 patients	—

—, not mentioned; CMT, central macular thickness; SRF, subretinal fluid; different degrees: partial or complete.

Safety outcomes

Twenty-one studies reported the safety of anti-VEGF drugs for the treatment of Coats' disease. The most common adverse effects were vitreoretinal fibrosis (n = 17), subretinal fibrosis (n = 13), or combined vitreoretinal and subretinal fibrosis (n = 5). Fibrotic changes were observed in 5 studies,^{14,16,28,32,34} and the population was all pediatric. Other common adverse effects included cataract formation (n = 13), TRD (n = 12), band keratopathy (n = 2), neovascular glaucoma (n = 1), and vitreous hemorrhage (n = 1). No systemic adverse effects were observed. Although Kang et al.¹³ found that 23% of patients developed fibrotic changes, they were not distinguished by treatment group. Thus, the number of patients with fibrotic changes owing to anti-VEGF treatment was unclear and this article was excluded from this part of the safety analysis.

It is worth mentioning that Bhat et al.²³ retrospectively analyzed 7 Coats' disease cases, of which 5 patients received bevacizumab combined with SRF drainage, 2 patients received only SRF drainage, and the results showed that 75% of patients receiving bevacizumab developed TRD, and 2 patients received only SRF drainage without any traction. The results are presented in Table 4.

Table 4.

Safety Outcomes of Anti-Vascular Endothelial Growth Factor Drugs for Coats' Disease

Studies	Intervention	Ocular complications				Systemic complications
Studies	Intervention	TRD	Vitreoretinal fibrosis	Cataract formation	Other	Systemic complications
Cennamo et al.¹²	Ranibizumab	—	—	—	Retinal and choriocapillaris vascular impairment persisted	—
Nowara et al.¹⁴	Ranibizumab + ablation therapy	0	3	0	0	0
Jiang et al.¹⁵	Conbercept + laser photocoagulation	0	0	0	0	0
Liang et al.¹⁶	SRF drainage + ranibizumab + laser photocoagulation	3	Subretinal fibrosis 13, vitreoretinal fibrosis 4, both types of fibrosis 5	6	Increasing ERD 6, band keratopathy 2	0
Zhang et al.¹⁷	Conbercept/ranibizumab + laser photocoagulation	0	0	0	0	0
Jiang et al.¹⁹	Conbercept + laser photocoagulation	0	0	0	0	0
Li et al.²⁰	Ranibizumab only, ranibizumab + retinal photocoagulation/cryotherapy	0	0	0	0	0
Li et al.²¹	Ranibizumab + laser photocoagulation/cryotherapy	0	0	0	0	0
Mao et al.²²	Ranibizumab + laser photocoagulation	0	0	0	0	0
Bhat et al.²³	Bevacizumab + SRF drainage with cryopexy (5 eyes)SRF drainage with cryopexy only (2 eyes)	Combination group: 3Only SRF drainage group: 0	0	0	0	0
Park et al.²⁴	Bevacizumab + laser photocoagulation	0	0	0	0	0
Yang et al.²⁵	Ranibizumab + laser photocoagulation/cryotherapy	1	0	1	0	0
Chen et al.²⁶	Ranibizumab/bevacizumab + SRF drainage/photocoagulation/vitrectomy	0	0	2	0	0
Gaillard et al.²⁷	Ranibizumab + laser photocoagulation	1	5	4	0	0
Villegas et al.²⁹	Bevacizumab + laser vascular ablation	0	0	0	0	0
Yang et al.³⁰	Ranibizumab only, ranibizumab + cryotherapy/cryotherapy and sclerotomy to drain subretinal fluid/vitrectomy	0	0	0	Neovascular glaucoma 1Vitreous hemorrhage 1	0
Ramasubramanian and Shields³²	Bevacizumab + laser photocoagulation/cryotherapy	3	4	—	—	—
Goel et al.³³	Bevacizumab + peripheral laser photocoagulation	0	0	0	0	0
Kaul et al.³⁴	Pegaptanib sodium/ranibizumab + laser photocoagulation	0	1	0	0	0
Lin et al.³⁵	Bevacizumab + laser photocoagulation/cryotherapy	0	0	0	0	0

—, not mentioned; SRF, subretinal fluid; TRD, tractional retinal detachment; ERD, exudative retinal detachment.

Discussion

Coats' disease is a retinopathy characterized by idiopathic vascular abnormalities in the retinal periphery, including extensive intraretinal and subretinal exudation.²⁵ Common presenting features include vision loss, strabismus, and xanthocoria, of which xanthocoria can mimic leukocoria of retinoblastoma.^6,36 VA can vary from 20/20 to no perception of light, with most patients suffering from severe visual loss.⁴ Coats' disease is classified into 5 stages of increasing disease severity, ranging from asymptomatic retinal telangiectasia (stage 1) to telangiectasia with exudation (stage 2), subtotal exudative retinal detachment (stage 3), total retinal detachment with secondary glaucoma (stage 4), and end-stage disease (stage 5).^6,36 The gold standard for diagnosis of Coats' disease is examination of the fundus by indirect ophthalmoscopy, and retinal telangiectasia is found in all cases.⁴

Treatment of Coats' disease depends on the disease stage. Mild cases can be observed.⁶ Stage 5 is an advanced end-stage disease, phthisis bulbi, representing an ocular end-stage disease characterized by shrinkage and disorganization of the eye. This may explain the absence of stage 1 and 5 patients in the included studies.

At present, there are no standard treatment guidelines for Coats' disease. The present therapeutic options are used to obliterate abnormal vessels and minimize exudation. However, these conventional ablation treatments have not achieved satisfactory VA.⁶ Recently, the most important development in the treatment of Coats' disease was the introduction of intravitreal injection of anti-VEGF agents. Although the pathogenesis of Coats' disease is not clear, previous studies have suggested that elevated levels of VEGF in Coats' disease are speculated to result in an increased vascular permeability and formation of peripheral telangiectasias.³⁷ Numerous clinical investigations have found that intravitreal injection of anti-VEGF drugs can reduce exudation and edema, hence improving VA in patients with Coats' disease.^7,38, In this study, 73 patients (37.63%) achieved improvement in vision, 89 (45.87%) had stable vision after anti-VEGF treatment in 16 case series. This may be owing to the rapid absorption of exudation under the macular area and reduction in macular thickness.

However, not all patients had positive outcomes. The VA in 12 patients (6.19%) worsened after anti-VEGF treatment. Li et al.²⁰ found that the VA in patients without exudation of cholesterol crystals under the macular area improved after anti-VEGF treatment, whereas the VA in patients with cholesterol crystals deposited in the macular area did not significantly improve. This may serve as an adjunctive decision to administer anti-VEGF treatment. Another effect of anti-VEGF treatment for Coats' disease is regression of dilated abnormal vessels. In our study, SRF absorption and telangiectasia regression of different degrees were observed in all patients at the final follow-up in 11 case series. Yang et al.²⁵ also found that mesh-like or vasoproliferative retinal tumor-like abnormal retinal vessels responded best to anti-VEGF drugs, and the abnormal vessels seemed to regress quickly, whereas the aneurysm-like abnormal vessels responded poorly to anti-VEGF drugs.

Three studies reported anatomical improvement, but VA remained unchanged or worse at follow-up.^16,23,29 This discrepancy between anatomical and functional improvement may result from foveal configuration at the final visit. To elaborate, significantly decreased central foveal thickness after treatment may in turn be associated with decreased submacular fluid and cystoid changes. However, the same patient showed decreased VA with subfoveal hard exudates, which resulted in outer retinal damage even after treatment.²⁴

The main concern of anti-VEGF treatment is fibrotic change, which was also the most common adverse effect in our study, accounting for 54.7% of all adverse reactions. We found that in the 5 case series, the population with fibrotic changes was all pediatric, aged 1.35–8.3 years, and most of them were in the late stage (stages 3 and 4). No fibrotic changes were found in the adult patients. The pathogenesis of fibrosis in Coats' disease is not clear, but it has been proposed that vitreoretinal fibrosis is a natural part of the course of Coats' disease.⁶ Moreover, other studies have reported the occurrence of fibrosis in patients without anti-VEGF treatment.³⁹ Meanwhile, fibrosis was observed to occur relatively late in Coats' disease process, usually months or even years,^39,40 which might be less associated with anti-VEGF drugs owing to their transient effect in the eye.⁴¹

Whether anti-VEGF treatment can accelerate fibrosis remains controversial. In our opinion, the occurrence of fibrotic changes in patients may be more related to the severity of Coats' disease than to the use of anti-VEGF drugs. It is worth mentioning that Bhat et al.²³ found that 75% of patients receiving bevacizumab developed TRD, but the injection of bevacizumab was administered after SRF drainage; therefore, they recommended initiating the anti-VEGF drugs treatment in advanced Coats' disease followed by surgery, cryotherapy, or laser after exudation decreases. Furthermore, considering that telangiectatic lesions are more localized in adult-onset Coats' disease than in pediatric disease, and that the symptoms are less severe, we propose that anti-VEGF drugs are relatively safe for the treatment of adult-onset Coats' disease.

Although literature gives a gloomy prognosis for eyes in advanced stage 4 Coats' disease, with only 22% globe preservation,⁴² in our study, the treatment with intravitreal anti-VEGF drugs in combination with conventional ablations showed considerably higher efficacy in terms of globe preservation (100%) in patients with stage 4 Coats' disease at long-term follow-up in 4 case series.^18,26,28,34 These results increase the efficacy evidences of anti-VEGF treatment in advanced Coats' disease.

This study has several limitations. First, this was a systematic review of case series reports, which cannot be quantitatively analyzed. There have been no randomized clinical trials, probably owing to the rare nature of Coats' disease. Second, different outcome definitions in different case series may have caused bias in the final conclusion. Third, most of the included studies had a retrospective design; hence, the results may be prone to information or selection bias. In future, well-designed prospective, multicenter, randomized clinical trials on the anti-VEGF treatment for Coats' disease are needed to confirm our findings and establish whether anti-VEGF treatment is a useful adjunct therapy for Coats' disease.

In conclusion, to the best of our knowledge, this is the first study to systematically review the efficacy and safety of anti-VEGF treatment for Coats' disease. Although anti-VEGF treatment may not cure Coats' disease, the absorption of SRF offers the opportunity to perform other effective ablative therapies, and combination therapy may have a long-term effect on keeping the disease under control.

Footnotes

Acknowledgment

The authors thank for the help from the staffs in Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University.

Authors' Contributions

Conceptualization: B.J., L.G., and Z.C.; methodology: B.J., and S.Z.; investigation: B.J.; data curation: B.J., S.Z., L.G., and D.L.; writing—original draft preparation: B.J., and L.G.; writing—review and editing: D.L., S.Z., and Z.C.; supervision: S.Z., and Z.C. All authors have read and agreed to the published version of the article.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Supplementary Material

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