Suppression of Neovascularization by Topical and Subconjunctival Bevacizumab After High-Risk Corneal Transplantation

Abstract

Purpose: To assess the effectiveness of topical and subconjunctival bevacizumab in suppressing vascularization in graft and host bed after high-risk corneal transplantation.

Design: Secondary analysis of prospective, randomized, double-blind, placebo-controlled multicentric clinical trial.

Participants: The study includes patients aged > 18 years who underwent high-risk penetrating keratoplasty, which was defined as corneal vascularization in ≥ 1 quadrants of the corneal graft and host bed, excluding the limbus.

Methods: Patients were randomized to treatment and control groups. The patients in the treatment group received subconjunctival injection of bevacizumab (2.5 mg/0.1 ml) on the day of the procedure, followed by topical bevacizumab (10 mg/ml) 4 times per day for 4 weeks. The patients in control group received injection of vehicle (0.9% sodium chloride) on the day of procedure, followed by topical vehicle (carboxymethylcellulose sodium 1%) 4 times a day for 4 weeks.

Main outcome measures: Vessel and invasion area of vessels in the corneal graft and host beds.

Results: This study included 56 eyes of 56 patients who underwent high-risk corneal transplantation, with equal numbers in the bevacizumab and vehicle (control) treatment groups. The mean age of patients who received bevacizumab was 61.2 ± 15.9 years, and the mean age of those treated with vehicle was 60.0 ± 16.1 years. The vessel area at baseline was comparable in the bevacizumab (16.72% ± 3.19%) and control groups (15.48% ± 3.12%; P = 0.72). Similarly, the invasion areas were also similar in the treatment (35.60% ± 2.47%) and control (34.23% ± 2.64%; P = 0.9) groups at baseline. The reduction in vessel area was significantly higher in the bevacizumab-treated group (83.7%) over a period of 52 weeks compared with the control group (61.5%; P < 0.0001). In the bevacizumab-treated group, invasion area was reduced by 75.8% as compared with 46.5% in the control group. The vessel area was similar at 52 weeks postprocedure in cases of first (3.54% ± 1.21%) and repeat (3.80% ± 0.40%) corneal transplantation in patients who received bevacizumab treatment. In the vehicle-treated patients, the vessel area was significantly higher in repeat (9.76% ± 0.32%) compared with first (8.06% ± 1.02%; P < 0.0001) penetrating keratoplasty. In the bevacizumab treatment group, invasion areas at week 52 were comparable in first (11.70% ± 3.38%) and repeat (11.64% ± 1.74%) procedures, whereas invasion area was significantly higher in repeat (27.87% ± 2.57%) as compared with first (24.11% ± 2.17%) penetrating keratoplasty in vehicle-treated patients.

Conclusions: In patients undergoing vascularized high-risk corneal transplantation, bevacizumab is efficacious in reducing vascularization of corneal graft and host bed, thereby reducing the risk of corneal graft rejection in vascularized host beds.

Financial disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Keywords: Bevacizumab; Corneal transplantation; Neovascularization; Penetrating keratoplasty; Vascular endothelial growth factor.

Figure 1

Methodology for assessing vessel and invasion areas in transplanted cornea and host beds. The total vessel and invasion areas were traced in 2 separate layers in Adobe Photoshop. The total vessel area was demarcated as the area of vessels assessed using length and girth on the transplanted corneal tissue. The total invasion area was demarcated as the area of the transplanted graft and host beds with vessels and was demarcated starting from the peak of the longest vessel and connecting the vessel peaks unless the gap between the vessels was > 2 clock hours.

Figure 2

Representative images of vessel area in the grafted tissue and host beds in vehicle and bevacizumab-treated patients.

Figure 3

Representative images of invasion area in the grafted tissue and host beds in vehicle and bevacizumab-treated patients.

Figure 4

A, Vessel and (B) invasion areas in the grafted tissue and host beds in vehicle and bevacizumab-treated patients. ∗∗∗∗P < 0.0001; ∗∗P < 0.01.

Figure 5

A, Vessel and (B) invasion area areas in the grafted tissue and host beds of patients undergoing first or repeat corneal transplantation. ∗∗∗∗P < 0.0001, ∗∗∗P < 0.001.