Efficacy and safety of anti-vascular endothelial growth factor agents on corneal neovascularization: A meta-analysis

Table 1 Characteristics of included randomized controlled trials and non-randomized trials

Study	Inclusion criteria	Size (M/F), age by yr	Group: No.	F/U by month
Randomized controlled trials
Bhatti et al[15]	Undergoing high-risk corneal transplantation with CoNV	81 (62/19), 52.1 ± 5.5	Topi B: 40, Placebo: 41	7.1 (2-8)
Dohlman et al[16]	Age > 18 yr, undergoing high-risk PK, defined as CoNV in 1 or more quadrants ≥ 2 mm from the limbus, or extension of CoNV to the graft-host junction in a previously failed graft	92 (49/43), 62.55 ± 16.5	SC + Topi B: 48, Placebo: 44	12
Fasciani et al[17]	Age > 18 yr, scheduled for high-risk transplantation due to marked CN in post-herpetic leucoma and in re-grafting for repeated rejections	27 (16/11), 44.7 ± 14.5	SC B: 14, Placebo: 13	26.1 ± 5.7
Hamdan et al[18]	CoNV caused by ocular surface disorders including fungal keratitis and PK	7 (4/3), 69.7 ± 15.4	SC B: 2, PDT: 2, Combined: 3	6
Kim et al[19]	Chronic CoNV greater than 6 mo	16 (9/7), 51.1 ± 15.6	SC B: 8, SC R: 8	1
Li et al[20]	CoNV induced by PK after 3 mo	19 (12/7), 38	Placebo: 5, SC B: 5, SC B + TA: 5, SC TA: 5	36
Ozgurhan et al[21]	Age > 18 yr, undergoing recurrent pterygium excision with conjunctival autograft transplantation	44 (10/34), 49.5 ± 21.1	Topi B: 22, Placebo: 22	6
Petsoglou et al[22]	Age > 18 yr, presence of progressive CoNV, no epithelial defect. Progressive CoNV with a minimum radial ingrowth of vessels 2 mm from the limbus in the interval of 2 wk to 2 mo	30 (15/15), 45.7 ± 19.2	SC B: 15, Placebo: 15	3
You et al[23]	CoNV that did not improve after treatment with 1% prednisolone acetate eyedrops instilled QID for at least 1 mo	29 (18/11), 54.0 ± 12.4	SC B 1.25mg: 7, SC B 2.5 mg: 15, SC B 5 mg: 7	3
Non-randomized studies
Huang et al[24]	Age > 18 yr, with diffuse CoNV and opaque cornea due to chemical burns with a complete limbal deficiency; a minimal 6m interval from initial injury to surgery; a posterior cornea with at least 50 mm thickness with a normal reflectivity in an ultrasound biomicroscopy and a smooth endothelial surface in optical coherence tomography	39 (33/6), 29.4 ± 12.4	SC B: 26, Placebo: 13	14.3±2.2
Hurmeric et al[25]	Age > 18 yr, with pterygium recurrence less than 6m between the diagnosed recurrence and presentation	9 (7/2), 56 (39-69)	SC R ×1: 5, SC R ×3: 4	6
Trufanov et al[26]	Undergoing high-risk transplantation with corneal opacifications of various etiology complicated with CoNV	56 (NI/NI), 51.1 ± 13.6	SC A: 27, SC A + laser: 14, Placebo: 15	24.5 ± 4.9

A: Aflibercept; B: Bevacizumab; CoNV: Corneal neovascularization; F: Female; F/U: Follow-up period; M: Male; NI: No information; No.: Numbers; Pts: Patients; R: Ranibizumab; SC: Subconjunctival; PDT: Photodynamic therapy; PK: Penetrating keratoplasty; QID: Quater in die (four times per day); R: Ranibizumab; SC: Subconjunctival; TA: Triamcinolone acetonide; Topi: Topical.

Table 2 Assessment of risk of bias

RoB 2.0 for randomized controlled trials
			D1	D2	D3	D4	D5	All
Bhatti et al[15]			H1	SC3	H5	L	H7	H
Dohlman et al[16]			L	L	L	L	L	L
Fasciani et al[17]			SC2	SC3	SC6	L	L	H
Hamdan et al[18]			SC2	L	L	L	L	SC
Kim et al[19]			SC2	L	L	L	L	SC
Li et al[20]			H1	L	SC6	L	L	H
Ozgurhan et al[21]			SC2	SC4	L	L	L	SC
Petsoglou et al[22]			L	L	L	L	L	L
You et al[23]			SC2	L	L	L	L	SC
D1: Bias arising from the randomization process
D2: Bias due to deviations from intended interventions
D3: Bias due to missing outcome data
D4: Bias in measurement of the outcome
D5: Bias in selection of the reported result
ROBINS-I for non-randomized studies
	D1	D2	D3	D4	D5	D6	D7	All
Huang et al[24]	L	L	L	L	M6	L	L	M
Hurmeric et al[25]	M8	L	L	L	L	L	S9	S
Trufanov et al[26]	M8	L	L	L	M6	L	S9	S
D1: Bias due to confounding
D2: Bias in selection of participants into the study
D3: Bias in classification of interventions
D4: Bias due to deviations from intended interventions
D5: Bias due to missing data
D6: Bias in measurement of outcomes
D7: Bias in selection of the reported result

¹Allocation sequence not concealed.

²Imbalance baseline or no information on allocation sequences.

³Open-labeled without information on deviation.

⁴No information on blinding or deviation.

⁵Missing data without descriptions.

⁶No information on missing data.

⁷Incomplete results.

⁸Apropriate analysis not conducted to control for confounding.

⁹Statistical analysis not conducted

H: High; S: Serious; SC: Some concerns; M: Moderate; L: Low.

Table 3 Summary of all results

Trial/Study	Target	Comparison	Brief conclusion	Overall RoB
Efficacy of reducing CoNV
Hamdan et al[18]	All pathologies	SC B vs PDT vs combined	B = PDT = combined	SC
Ozgurhan et al[21]	Pterygium	Topi B vs placebo	B > placebo	SC
Bhatti et al[15]	Transplant	Topi B vs placebo	B > placebo	H
Dohlman et al[16]	Transplant	SC + Topi B vs placebo	B > placebo	L
Li et al[20]	Transplant	Placebo vs SC B vs SC B + TA vs SC TA	B = combined > TA = placebo	H
Petsoglou et al[22]	All pathologies	SC B vs placebo	B > placebo	L
Kim et al[19]	All pathologies	SC B vs SC R	B > R	SC
You et al[23]	All pathologies	SC B 1.25 mg vs SC B 2.5 mg vs SC B 5 mg	1.25 mg < 2.5 mg = 5 mg	SC
Hurmeric et al[25]	Pterygium	SC R ×1 vs SC R ×3	R ×1 = R ×3 (Statistical analysis not conducted)	S
Pooled results of three trials[16,20,22] showed B > placebo on reducing CoNV
Efficacy of improving BCVA/VA
Li et al[20]	Transplant	Placebo vs SC B vs SC B + TA vs SC TA	B > pre-treatment (No statistical detail)	H
Bhatti et al[15]	Transplant	Topi B vs placebo	B > placebo	H
Dohlman et al[16]	Transplant	SC + Topi B vs placebo	B = placebo	L
Huang et al[24]	Transplant	SC B vs placebo	B > placebo	M
Petsoglou et al[22]	All pathologies	SC B vs placebo	B = placebo	L
Kim et al[19]	All pathologies	SC B vs SC R	B = R = pre-treatment	SC
You et al[23]	All pathologies	SC B 1.25 mg vs 2.5 mg vs 5 mg	1.25 mg = 2.5 mg = 5 mg = pre-treatment	SC
Pooled results of two trials[22,24] showed B > placebo on improving VA
Efficacy of reducing graft rejection/failure
Li et al[20]	Transplant	Placebo vs SC B vs SC B + TA vs SC TA	B, C > pre-treatment (No statistical detail)	H
Dohlman et al[16]	Transplant	SC + Topi B vs placebo	B = placebo	L
Fasciani et al[17]	Transplant	SC B vs placebo	B > placebo	H
Huang et al[24]	Transplant	SC B vs placebo	B > placebo	M
Trufanov et al[26]	Transplant	SC A vs SC A + laser vs placebo	A = A + laser > placebo (statistical analysis not conducted)	S
Pooled results of four trials[16,17,24,26] showed B > placebo on reducing rejection/failure risks

A: Aflibercept; B: Bevacizumab; BCVA: Best-corrected visual acuity; CoNV: Corneal neovascularization; PDT: Photodynamic therapy; R: Ranibizumab; RoB: Risk of bias (RoB judgment: H: High; S: Serious; SC: Some concerns; M: Moderate; L: Low); SC: Subconjunctival; TA: Triamcinolone acetonide; Topi: Topical; VA: Visual acuity.