Purpose
To investigate outcomes after trabeculectomy using intraoperative intravitreal ranibizumab and topical mitomycin C (MMC) vs MMC alone.
Design
Prospective randomized single-site pilot study.
Methods
Patients diagnosed with primary open-angle glaucoma were randomized 1:1 to either combination intravitreal ranibizumab 0.5 mg and topically applied MMC (0.4 mg/mL for 2 min) or MMC (0.4 mg/mL for 2 min) therapy alone at time of trabeculectomy surgery. The primary endpoint measured was bleb morphology and vascularity using the Moorfields Bleb Grading System. Unqualified success was defined as postoperative intraocular pressure (IOP) of >5 and <22 mm Hg and a 30% decrease from baseline without use of postoperative hypotensive drops. Qualified success was defined as postoperative IOP of >5 and <22 mm Hg and a 30% decrease from baseline with use of postoperative hypotensive drops.
Results
Ten patients were randomized to either standard trabeculectomy with MMC (Group A) or trabeculectomy with intravitreal ranibizumab and MMC (Group B). All patients completed the study and were classified as unqualified successes. There were statistically significant differences in peripheral bleb area ( P = .02), peripheral bleb vascularity ( P = .02), and non-bleb-related peripheral conjunctiva vascularity ( P = .0003), with Group B exhibiting more diffuse blebs with a lower degree of vascularity.
Conclusions
Combination intravitreal ranibizumab and topical MMC at time of trabeculectomy resulted in more diffuse blebs with less vascularity when compared to use of topical MMC alone. Further studies are planned to better understand the utility of anti–vascular endothelial growth factor agents as modulators of wound healing post trabeculectomy.
Trabeculectomy is the current gold-standard surgery for decreasing intraocular pressure (IOP) in glaucoma patients with disease refractory to medical and/or laser intervention. The introduction of mitomycin C (MMC) and 5-fluorouracil (5-FU) as antifibrotic adjuncts to standard trabeculectomy increased IOP-lowering efficacy of the procedure while also increasing the rate of complications such as thin cystic blebs, leaking blebs, and endophthalmitis. Many other agents have been studied in the past but none have replaced MMC and 5-FU in common practice. Recently, the use of anti–vascular endothelial growth factor (VEGF) agents for neovascular diseases of the retina and choroid has become common. Reports have also been published on the utility of these agents in treating neovascular glaucoma. While mainly thought of as having anti-angiogenic characteristics, anti-VEGF agents also inhibit vascular permeability and possess antiproliferative and antimetabolic effects on various cell lines.
A previous report indicated that bevacizumab, a humanized VEGF-A-inhibiting monoclonal antibody that is approved by the United States Food and Drug Administration (USFDA) for treating colorectal cancer, may have a role in preventing excessive scar formation in patients post bleb needle revision. Grewal and associates recently reported favorable results after using bevacizumab as a wound modulator at time of trabeculectomy with 6 months of follow-up. Both of these reports involved the use of anti-VEGF therapy alone and it is unclear if there would be any synergistic effect if a combination approach were utilized. We hypothesize that anti-VEGF agents may have utility as an adjunct to trabeculectomy surgery with MMC at time of surgery. This pilot study investigates the safety and efficacy of intravitreal injection of ranibizumab, a Fab fragment of a recombinant humanized IgG1 kappa isotype murine monoclonal antibody, at time of trabeculectomy with topical MMC compared to standard trabeculectomy with MMC alone. Ranibizumab was chosen over bevacizumab because the former is approved by the USFDA, is formulated for intraocular injection, and has long-term clinical trial data demonstrating safety. The intravitreal method for delivery of ranibizumab was chosen to achieve a sustained release of medication over a longer period of time than would occur with an intracameral or sub-Tenon’s injection.
Methods
This is a prospective, open-label, Phase I/II pilot study of 10 patients diagnosed with primary open-angle glaucoma undergoing trabeculectomy surgery with 6-month follow-up. All patients were judged by the author to be on maximal tolerated medical therapy and required trabeculectomy surgery because of 1) advancing visual field loss and/or optic nerve head changes and/or 2) IOP above a predetermined goal pressure that was set based on optic nerve status, visual field status, and/or baseline IOP.
The patients were randomized 1:1 to either combination intravitreal ranibizumab 0.5 mg and topically applied MMC (0.4 mg/mL for 2 min) or MMC (0.4 mg/mL for 2 min) therapy alone. Inclusion criteria for the study included ability to provide written informed consent and to comply with study assessments for the full duration of the study. Patients recruited were over 21 years of age and were considered candidates for primary trabeculectomy procedure. Exclusion criteria included pregnancy, history of active ocular inflammatory diseases, history of ocular surface disease, cataract surgery in the 6 months prior to enrollment, history of retinal disease, and those considered noncandidates for 2 minutes of therapy with MMC. The primary endpoints measured were bleb morphology/vascularity and IOP differences between groups. Secondary endpoints included bleb-related complications (leaks), endothelial cell count (using specular microscopy), and change in logMAR vision. Postoperative follow-up visits took place on day 1, at week 1, and at 1, 2, 3, and 6 months. Outcome measures were specifically tabulated at baseline and 6-month visits. Unqualified success was defined as postoperative IOP of >5 and <22 mm Hg and a 30% decrease from baseline without use of postoperative hypotensive drops. Qualified success was defined as postoperative IOP of >5 and <22 mm Hg and a 30% decrease from baseline with use of postoperative hypotensive drops.
Each patient underwent standard fornix-based trabeculectomy with intraoperative use of 0.4 mg/mL of MMC for 2 minutes. MMC is also known to target endothelial cells that can influence vascularity of the bleb. For this reason, we used an identical concentration and exposure time for MMC in both groups to better evaluate the distinctive effects of ranibizumab on vascularity in Group B. All procedures were performed by the same surgeon (M.Y.K.). Five of the 10 patients also received intravitreal injection of 0.05 mL of 10 mg/mL (0.5 mg) ranibizumab performed in the infratemporal quadrant 3.5 to 4.0 mm away from the limbus at the conclusion of the surgery. There was an option to reinject the same dose of ranibizumab 1 month postoperatively at the discretion of the physician if excessive vascularization was noted in those patients who received the ranibizumab injection at the time of surgery. All patients received prednisolone acetate 1% 6 times per day for 1 month with slow taper for 3 months postoperatively. A fourth-generation fluoroquinolone was also used 4 times per day for the first week after surgery. Laser suture lysis was performed at the discretion of the treating physician and none of the patients required postoperative use of cycloplegic agents.
We used the Moorfields Bleb Grading System to evaluate bleb morphology and vascularity using the method described on www.blebs.net . In brief, the Moorfields Bleb Grading System requires that photos be taken with the patient looking down to provide a clear view of the superior conjunctiva canthus to canthus. The grading is done under magnification and the evaluator is asked to make judgments based on comparisons to standard photographs. Evaluated parameters include central and peripheral bleb area, bleb height, and bleb vascularity in central and peripheral regions of the bleb as well as the non-bleb peripheral conjunctiva. A masked glaucoma specialist, who had prior experience with the Moorfields Bleb Grading System, completed bleb analyses by viewing photos that were de-identified and saved in individual digital files. One-way analysis of variance was used to compare data between groups.
Results
Between August 1, 2007 and December 30, 2007, 10 patients were recruited, all of whom completed the 6-month follow-up. Five patients were randomized to either standard trabeculectomy with MMC alone (Group A) or trabeculectomy with intravitreal ranibizumab and MMC (Group B). The average age of those enrolled was 64.2 ± 10.06 years in Group A and 70.6 ± 4.72 years in Group B. Medication use prior to trabeculectomy was similar between groups, with Group A using 2.60 ± 0.55 medications and Group B using 2.80 ± 0.85 medications ( P = .67). The results of the baseline and 6-month evaluations are found in Tables 1 and 2 . All patients completed the study with no adverse side effects noted. There were no cases of leaking blebs, dehisced wounds, hyphema, or significant subconjunctival hemorrhages postoperatively. None of the patients underwent laser suture lysis postoperatively. Vision decreased slightly in both groups between baseline and the 6-month follow-up (Group A: logMAR 0.10 to 0.11; Group B: logMAR 0.11 to 0.15). The decrease in vision was attributed to advancing cataracts within the follow-up clinic notes; however, no formal cataract analyses were performed in this study to verify this as the cause for visual acuity changes. There were no other processes noted on careful examination that would explain this slight decrease in vision.
| Group | Age | IOP | Endothelial Cell Number | Bleb Area 1a | Bleb Area 1b | Bleb Height | Vascularity 3a | Vascularity 3b | Vascularity 3c |
|---|---|---|---|---|---|---|---|---|---|
| Group A: trabeculectomy with MMC | 64.20 ± 10.06 | 20.00 ± 8.60 | 2425.20 ± 170.75 | 2.80 ± 0.84 | 3.80 ± 0.45 | 1.80 ± 0.45 | 3.20 ± 0.45 | 3.00 ± 0.71 | 2.80 ± 0.84 |
| Group B: trabeculectomy with MMC + ranibizumab | 70.60 ± 4.72 | 17.00 ± 3.08 | 2441.40 ± 240.50 | 2.60 ± 0.55 | 4.20 ± 0.45 | 2.20 ± 0.45 | 3.00 ± 0.71 | 3.20 ± 0.45 | 3.00 ± 1.00 |
| P value | .23 | .48 | .90 | .67 | .20 | .20 | .61 | .61 | .74 |
a Baseline Moorfields Bleb Grading System scores took place at day 1 postoperatively.
| Group | IOP | Endothelial Cell Number | Bleb Area 1a | Bleb Area 1b | Bleb Height | Vascularity 3a | Vascularity 3b | Vascularity 3c |
|---|---|---|---|---|---|---|---|---|
| Group A: MMC | 9.00 ± 1.22 | 2542.20 ± 471.75 | 2.00 ± 0.71 | 3.40 ± 0.55 | 1.60 ± 0.55 | 1.60 ± 0.55 | 3.40 ± 0.55 | 3.20 ± 0.45 |
| Group B: MMC + ranibizumab | 10.80 ± 2.17 | 2523.60 ± 310.19 | 2.60 ± 0.55 | 4.40 ± 0.55 | 2.00 ± 0.71 | 1.40 ± 0.55 | 2.40 ± 0.55 | 2.00 ± 0.00 |
| P value | .14 | .94 | .17 | .02 | .35 | .58 | .02 | .0003 |
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