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Perioperative Bevacizumab May Be Beneficial in High-Risk Corneal Transplantation

Key findings

  • This multicenter, placebo-controlled, randomized pilot trial examined the safety and efficacy of topical bevacizumab in 86 patients undergoing corneal transplantation who were at high risk of graft failure because of vascularized and inflamed corneas
  • At 52 weeks, the endothelial rejection rate was 10% in the bevacizumab group vs. 19% in the control group (HR, 0.46; P=0.21), and the all-cause graft failure rate was 15% vs. 26% (HR, 0.50; P=0.17)
  • 59 of the 86 participants were followed beyond the trial period (median 207 weeks for the bevacizumab group and 176 weeks for the control group), and the endothelial rejection rates were 3% and 38%, respectively (P=0.003)
  • On post hoc Cox regression analysis, bevacizumab treatment was significantly associated with decreased risk of endothelial rejection (HR, 0.15; P=0.01) and overall graft failure (HR, 0.15; P=0.003)
  • Efficacy might be greater with more intensive dosing or an alternative route of delivery of bevacizumab or use of a vascular endothelial growth factor–A inhibitor more capable of penetrating intact corneal epithelium

The presence of corneal neovascularization (NV) in a transplant recipient is one of the strongest predictors of immune rejection and graft failure. A key promoter of NV is vascular endothelial growth factor–A (VEGF-A), which supports the survival, proliferation, and migration of vascular endothelial cells.

Thomas H. Dohlman, MD, an assistant scientist and cornea surgeon at Mass Eye and Ear, and colleagues recently conducted the first prospective, double-masked, randomized clinical trial to evaluate the effect of anti-VEGF therapy on high-risk corneal graft survival.

They selected bevacizumab because it's readily available, relatively inexpensive, and already used off-label to treat certain retinal conditions. In Ophthalmology, they present evidence that this VEGF-A inhibitor has a beneficial—although not statistically significant—effect on immune rejection and corneal transplant survival.


At three centers, patients scheduled for high-risk corneal transplantation were enrolled between January 2010 and March 2018. High risk was defined as corneal NV in one or more quadrants or extension of corneal NV to the graft–host junction in a previously failed graft. To aid patient enrollment, an additional study site was added in August 2014 followed by another in October 2017.

92 patients were randomized and 86 underwent surgery (43 in each treatment arm). They received a subconjunctival injection of 2.5% bevacizumab or placebo (Refresh Liquigel) after surgery. They then instilled topical bevacizumab (1% solution) or placebo four times per day for four weeks in addition to standard topical corticosteroid and antibiotic therapy.

One-Year Efficacy

At 52 weeks the results were:

  • Endothelial rejection rate (primary outcome)—10% in the bevacizumab group and 19% in the control group (HR, 0.46; P=0.21)
  • Overall graft failure rate (edema and opacity due to any cause)—15% and 26% (HR, 0.50; P=0.17)

Post Hoc Analyses

Cox regression analyses showed:

  • Baseline corneal NV length was significantly associated with endothelial rejection (HR, 1.56; P=0.002) and overall graft failure (HR, 1.55; P<0.005)
  • Bevacizumab treatment was significantly associated with decreased risk of endothelial rejection (HR, 0.15; P=0.01) and overall graft failure (HR, 0.15; P=0.003)

A linear regression analysis showed bevacizumab use predicted decreased corneal NV extent (P=0.01) and length (P=0.03).


The most frequent treatment-related adverse event was foreign body sensation. One patient assigned to bevacizumab developed a serious adverse event (atrial fibrillation), which was judged to be unrelated to treatment.

Delayed corneal epithelial healing has been reported with bevacizumab, and the presence of an epithelial defect at postoperative day 7 was a prespecified endpoint. The number of cases of delayed epithelial healing did not differ between treatment arms and, in fact, was greater in the control group (16% vs. 5% with bevacizumab, P=0.16).

Long-term Efficacy

59 of the 86 participants were treated at Mass Eye and Ear. They were followed for an extended period beyond the trial period (median 207 weeks for the bevacizumab group and 176 weeks for control):

  • Endothelial rejection rate—3% with bevacizumab and 38% with control (P=0.003)
  • Overall graft failure—34% and 39% (P=0.55)

Regimen May Warrant Adjustment

A number of different bevacizumab regimens for corneal neovascular pathologies have been reported, and penetration of topical bevacizumab through intact corneal epithelium is limited. Although the drug inhibited corneal NV in this study, there may be a greater benefit with more intensive dosing or a different delivery method. The use of an anti-VEGF agent with a lower molecular weight may also be more successful.

less risk of endothelial rejection with bevacizumab on post hoc analysis

less risk of all-cause graft failure with bevacizumab on post hoc analysis

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