Subconjunctival Bevacizumab Versus Mitomycin C Adjunctive to Trabeculectomy


To compare the outcome of trabeculectomy with subconjunctival bevacizumab with that of trabeculectomy with mitomycin C (MMC).


Prospective, randomized, comparative study.


Thirty-six eyes from 34 patients with uncontrolled glaucoma were enrolled. Eighteen eyes underwent trabeculectomy with subconjunctival bevacizumab injection (2.5 mg/0.1 mL), and 18 eyes underwent trabeculectomy with MMC (0.02% for 3 minutes). The outcome measures were the best-corrected visual acuity, intraocular pressure (IOP), number of IOP-lowering medications, complications, and bleb morphologic features (based on the Indiana Bleb Appearance Grading Scale).


The mean follow-up times for the MMC and bevacizumab groups were 7.8 ± 2.2 months and 7.4 ± 24 months, respectively ( P = .62). The mean preoperative IOP in the bevacizumab group improved from 21.9 ± 7.9 mm Hg with 2.7 ± 0.8 antiglaucoma medications to 13.6 ± 3.2 mm Hg with 0.2 ± 0.5 antiglaucoma medications at the last visit ( P < .001 and P < .001, respectively). The mean preoperative IOP in the MMC group improved from 23.3 ± 4.9 mm Hg with 2.6 ± 0.7 antiglaucoma medications to 9.6 ± 2.7 mm Hg with no antiglaucoma medications at the final visit ( P < .001 and P < .001, respectively). There was a statistically significant difference in the IOP between the 2 groups at the last visit ( P < .001). The cumulative probabilities of total success at the last follow-up according to Kaplan-Meier analysis were 100% and 94.4% in bevacizumab and MMC groups, respectively ( P = .32, log-rank test).


Adjunctive subconjunctival bevacizumab with trabeculectomy is effective in controlling the IOP profile; however, its effect is less prominent than that of MMC.

Glaucoma is the second leading cause of blindness globally. Although it is usually controlled with intraocular pressure (IOP)-lowering medications, surgical intervention becomes warranted in certain situations such as poor compliance with medications, progressive disease despite maximum medical therapy, or both. Trabeculectomy has been the most commonly performed surgical procedure in the management of uncontrolled glaucoma for more than 3 decades.

The main cause of failure in trabeculectomy is excessive postoperative conjunctival scarring at the site of the filtering bleb, which is related to the severity of conjunctival vascularization, the tortuosity of vessels, and fibroblast migration and proliferation. Deposition and contraction of dense collagen fibers after the proliferation of fibroblasts leads to the blockage of aqueous outflow by creating adhesions between conjunctiva and episclera as well as between the scleral flap and underlying tissues. To improve the outcome, several antifibrotic agents have been applied in combination with trabeculectomy. The most commonly used adjunctive agents are 5-fluorouracil and mitomycin C (MMC). Although the efficacy of these agents (particularly in high-risk patients) has been demonstrated in different studies, there are still concerns about potentially vision-threatening adverse effects such as hypotony with maculopathy, cystic thin avascular bleb, bleb infection, and endophthalmitis.

Vascular endothelial growth factor (VEGF), which is an endothelial cell-specific mitogen and an angiogenic inducer, has been found to be an important stimulus for wound healing. In addition to its antiangiogenic properties, there is histologic evidence indicating that VEGF induces fibroblast proliferation. Li and associates showed that VEGF increases in the aqueous humor of patients with glaucoma. They also demonstrated that fibroblast proliferation and scar formation have been decreased by administration of anti-VEGF agents at the site of the trabeculectomy.

One of the most commonly used anti-VEGF agents in the context of ocular disease with a vascular component is bevacizumab (Avastin; Genentech, San Francisco, California, USA). It is a humanized, nonselective monoclonal antibody against VEGF. There are few animal and human studies regarding the promising efficacy of anti-VEGF agents in trabeculectomy. In this study, we aimed to compare the outcome of trabeculectomy with adjunctive bevacizumab with that of trabeculectomy with adjunctive MMC.


Study Subjects

This prospective, randomized, comparative study was performed from April 2009 through July 2010 at Rassoul Akram Hospital, Tehran, Iran. The inclusion criteria were inadequately controlled glaucoma (IOP > 21 mm Hg with maximally tolerated medical therapy) or intolerance to antiglaucoma medications. The exclusion criteria were age younger than 18 years; being pregnant or currently breast feeding; past history of any ocular surgery; ocular surface infection over the previous 2 weeks; and systemic thromboembolic events. Thirty-six eyes from 34 patients with at least 6 months of postoperative follow-up were considered to participate in the study. The eyes were assigned randomly to 2 groups: the bevacizumab group consisted of 18 eyes (17 patients) that underwent trabeculectomy with adjunctive bevacizumab, and the MMC group consisted of 18 eyes (17 patients) that underwent trabeculectomy with MMC. Randomization was performed using the random block permutation method according to a computer-generated randomization list and was stratified based on age and sex. Neither patients nor investigators were masked to the study groups.

Preoperative Assessments

Before surgery, all participants underwent a comprehensive ophthalmic examination, including slit-lamp biomicroscopy, best-corrected visual acuity (BCVA), IOP measurement by a calibrated applanation tonometer, dilated funduscopy with a 78-diopter lens, gonioscopy, and visual field perimetry (24-2 Swedish Interactive Threshold Algorithm Standard) using the Humphrey Field Analyzer 750 (Humphrey-Zeiss Instruments, Dublin, California, USA). The BCVA was measured using a Snellen chart (CP-690; Nidek Co, Ltd, Gamagori Aichi, Japan) calibrated for a 20-foot distance by the line assignment method; the figures were converted to logarithm of the minimal angle of resolution notation by the standard conversion table. The preoperative BCVA, IOP, and number of antiglaucoma medications were recorded separately for study analysis.

Surgical Procedure

All surgeries were carried out under either general or retrobulbar anesthesia by a single experienced surgeon (N.Ni.). Each patient underwent a fornix-based trabeculectomy involving the use of a half-thickness trapezoidal scleral flap (3 × 2 mm) in the supranasal quadrant. For all eyes in the MMC group, after creating the scleral flap, MMC 0.02% (0.2 mg/mL) was applied using multiple thin sponges under the scleral flap and between the sclera and Tenon capsule for 3 minutes. The sponges then were removed and the surgical field was irrigated with copious amounts of balanced salt solution. Sclerectomy was performed with a Kelly-Descemet punch, and peripheral iridectomy was performed with a Vannas scissors (Katena Products, Inc. Denville, New Jersey, USA). The scleral flap was closed with 2 10-0 nylon sutures using the releasable technique. At the end of surgery, the conjunctiva was closed with 10-0 nylon sutures. In the same fashion, trabeculectomy was performed in the bevacizumab group, but without applying MMC. After suturing the conjunctiva, 2.5 mg (0.1 mL) bevacizumab (Avastin) was injected subconjunctivally at the site of the scleral flap using a 30-gauge needle. The site of the needle entrance was at least 8 mm away from the site of injection to prevent any leakage. All patients were treated with ciprofloxacin eye drops (4 times daily for only 2 weeks) and betamethasone eye drops every 2 hours for 2 weeks that were tapered off slowly over 6 to 8 weeks. Releasable sutures were removed based on the IOP and assigned target pressure. After surgery, antiglaucoma medication was added if necessary based on the targeted IOP.

Postoperative Assessments

Patients returned for 7 postoperative follow-up visits within 6 months: days 1, 7, 14, 30, 60, 90, and 180. A window of ± 10 days was allowed for the 30-, 60-, and 90-day visits; a window of ± 14 days was permitted for the 180-day visit. After month 6, follow-up visits were continued every 2 to 3 months. Postoperative assessments included BCVA, IOP measurement, number of antiglaucoma medications, slit-lamp biomicroscopy results, bleb evaluation results, and funduscopy results. The IOP was considered the primary outcome measure. Bleb photographs were obtained at months 1 and 3 and at the last follow-up. Bleb photographs at the last follow-up were graded by a masked glaucoma specialist (N.Ni.) who compared the study photographs with standard photographs, according to the Indiana Bleb Appearance Grading Scale, which is based on extension, height, vascularization, and leakage.

Complete success was defined as an IOP of 21 mm Hg or less and at least 20% reduction in preoperative pressure, without any antiglaucoma medications. Qualified success was defined as the following: (1) IOP of 21mm Hg or less and at least 20% reduction in the preoperative IOP with antiglaucoma medications, where the number of antiglaucoma medications was less than that used before surgery; or (2) in eyes with preoperative IOP of 21 mm Hg or less, postoperative IOP equal to or less than preoperative IOP and a reduction of at least 2 medications. Total success was the sum of qualified and complete success rates. Failure of the treatment was defined as IOP of 5 mm Hg or less or more than 21 mm Hg on 2 consecutive visits after 3 months or needing further glaucoma surgery to control the IOP. Needling without the injection of antifibrotic agents and anterior chamber formation were not considered to be failures of surgery.

Statistical Analysis

Data analysis was performed using SPSS software version 15 (SPSS, Inc., Chicago, Illinois, USA). Statistical independent and paired t tests were used to evaluate between- and within-group differences, respectively. An estimation of sample size was performed considering the study power of at least 80% with an α error of 0.05, aiming to detect a difference of 1 mm Hg between the 2 groups in the mean IOP after surgery. Based on this estimation, a total of 16 eyes were deemed adequate, and considering a total of 10% assumed dropout during the follow-up, recruitment of 18 eyes was targeted for each group. The cumulative probability of success was calculated by Kaplan- Meier analysis. The bleb classification data were considered as nonparametric variables, and statistical analysis was performed using the Mann–Whitney U test. P values less than .05 were considered statistically significant.


Table 1 depicts patient baseline characteristics in both groups. The mean follow-up time was 7.8 ± 2.2 months and 7.4 ± 2.4 months in the MMC and bevacizumab groups, respectively. There was no statistically significant difference between groups in the preoperative mean age, gender, IOP, BCVA, or the number of antiglaucoma medications. Figure 1 depicts the mean IOP measurements at each visit in both groups. Table 2 demonstrates the postoperative outcome measures in both groups at month 6 and at the last follow-up. Mean postoperative BCVA was 0.62 ± 0.53 and 0.67 ± 0.93 at month 6 and 0.65 ± 0.75 and 0.96 ± 0.94 at the last follow-up in the bevacizumab and MMC groups, respectively. No significant difference was detected between the preoperative and postoperative BCVA at month 6 or the last visit in either group ( P > .1 for all). The preoperative IOP improved significantly from 21.9 ± 7.9 mm Hg to 12.8 ± 3.1 mm Hg at month 6 ( P < .001) and to 13.6 ± 3.2 mm Hg at the last follow-up ( P < .001) in the bevacizumab group, and from 23.3 ± 4.9 mm Hg to 9.72 ± 2.4 mm Hg at month 6 ( P < .001) and to 9.6 ± 2.7 mm Hg at the last follow-up ( P < .001) in the MMC group. The number of antiglaucoma medications dropped significantly from 2.7 ± 0.8 medications before surgery to no medication at month 6 ( P < .001) and 0.2 ± 0.5 medications ( P < .001) at the last follow-up in the bevacizumab group and from 2.6 ± 0.7 medications to no medication at both month 6 and the last follow-up in the MMC group ( P < .001).


Demographic and Baseline Characteristics of Study Subjects in the Groups Receiving Mitomycin C versus Bevacizumab Adjunctive to Trabeculectomy

MMC Group (n = 18) Bevacizumab Group (n = 18) P Value
No. of patients 17 17
Mean age ± SD (y) 58.6 ± 12.1 60.7 ± 8.9 .58 a
Male/female 11/6 11/6 1.0 b
Right/left (n) 8/10 6/12 .49 b
Mean BCVA ± SD (logMAR) 0.96 ± 0.90 0.77 ± 0.75 .50 a
Mean IOP ± SD (mm Hg) 23.3 ± 4.9 21.9 ± 7.9 .53 a
Mean no. of glaucoma medications ± SD 2.6 ± 0.7 2.7 ± 0.8 .66 a
Type of glaucoma
Primary open angle 12 10
Pseudoexfoliative 6 8

BCVA = best-corrected visual acuity; IOP = intraocular pressure; logMAR = logarithm of minimal angle of resolution; MMC = mitomycin C; SD = standard deviation; y = years.

a Based on independent t test.

b Based on chi-square test.


Graph showing mean and P values of the intraocular pressure (IOP) at each follow-up visit in groups treated with mitomycin C (MMC) compared with bevacizumab adjunctive to trabeculectomy.


Comparison of Postoperative Measures in the Groups Receiving Mitomycin C versus Bevacizumab Adjunctive to Trabeculectomy

MMC Group (n = 18) Bevacizumab Group (n = 18) P Value a
Follow-up time ± SD (range), mos 7.8 ± 2.2 (6 to 12) 7.4 ± 2.4 (6 to 14) .62
Mean BCVA at the last visit, logMAR 0.96 ± 0.94 0.65 ± 0.59 .24
Mean IOP ± SD at month 6, mm Hg 9.72 ± 2.4 12.78 ± 3.07 .002
Mean IOP ± SD at the last visit, mm Hg 9.61 ± 2.7 13.56 ± 3.2 <.001
Mean no. of medications at month 6 ± SD 0 0.16 ± 0.51 .18
Mean no. of medications at the last visit ± SD 0 0.22 ± 0.54 .09
Complete success at month 6 (%) 88.8 77.7
Total success at month 6 (%) 94.4 100
Complete success at the last visit (%) 88.8 61.1
Total success at the last visit (%) 94.4 100

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Jan 12, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Subconjunctival Bevacizumab Versus Mitomycin C Adjunctive to Trabeculectomy
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