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Keywords:

  • Ahmed valve;
  • glaucoma;
  • ranibizumab;
  • VEGF;
  • wound healing

Abstract

  1. Top of page
  2. A
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background:  To determine the safety and efficacy of intravitreal ranibizumab therapy before and after Ahmed tube insertion for open-angle glaucoma as a means of optimizing postoperative intraocular pressure control.

Design:  Randomized, controlled trial.

Participants:  Open-angle glaucoma patients scheduled for Ahmed tube insertion, randomized to ranibizumab or control groups.

Methods:  Ranibizumab (0.5 mg in 0.05 mL) was administered intravitreally at three time points: 9 days prior to surgery, 1 month post-surgery and 2 months post-surgery. Control patients underwent the same procedure without ranibizumab.

Main Outcome Measure:  Success at 6 months postoperatively was defined as intraocular pressure <18 mmHg with no adjunctive medications or intraocular pressure <15 mmHg with one adjunctive medication.

Results:  The study and control arms included six and five subjects, respectively, with four in each arm undergoing combined cataract surgery. In the ranibizumab arm, the preoperative and postoperative intraocular pressure/medication usage was 21.0 ± 6.7 mmHg on 3.2 ± 1.5 medications and 14.7 ± 1.9 mmHg on 0.5 ± 0.8 medications, respectively. In the control arm, preoperative and postoperative intraocular pressure/medication usage was 18.8 ± 3.8 mmHg on 2.8 ± 1.3 medications and 16.2 ± 3.6 mmHg with 1.8 ± 1.6 medications, respectively. Success was achieved in 83% of subjects in the ranibizumab group compared with 40% in the control group (two-tailed Fisher's exact test, P = 0.24).

Conclusion:  The findings from this small pilot comparative study suggest that intravitreal ranibizumab use may be a safe and potentially effective adjunctive treatment modality in improving success after Ahmed tube placement.


Introduction

  1. Top of page
  2. A
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The most common cause of glaucoma filtration surgery failure is conjunctival and scleral wound healing, manifest following drainage device implantation as cicatrization into the lumen and/or scarring over the explant portion of the device. Although a variety of signalling molecules are involved in wound healing, vascular endothelial growth factor (VEGF) plays a particularly important role by increasing permeability of local vasculature, facilitating exudation of fibrinogen, promoting proliferation of resident fibroblasts from Tenon's capsule into manipulated tissue and providing a vascular scaffold of new vessels.1–4

Because of its important role in the initiation of scar tissue formation following glaucoma surgery, VEGF has been targeted for the purpose of inhibiting wound healing in an effort to improve surgical success. In animal models of trabeculectomy, adjunctive bevacizumab, a monoclonal antibody to VEGF-A, was associated with inhibition of Tenon's fibroblast proliferation, decreased collagen deposition and decreased fibroblast differentiation into myofibroblasts, leading to more favourable bleb morphology and longer bleb survival.5–8

Given these encouraging animal model results, we designed a pilot clinical trial using ranibizumab, a Fab fragment of a recombinant humanized immunoglobulin G1κ isotype murine monoclonal antibody to VEGF-A. The purpose of our small randomized, controlled trial was to determine whether or not intravitreal ranibizumab therapy before and after Ahmed tube insertion for open-angle glaucoma (OAG) could be a safe method to prevent scar tissue formation and achieve better intraocular pressure (IOP) control.

Methods

  1. Top of page
  2. A
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This randomized, non-sham controlled, open-labelled, safety study received Institutional Review Board approval from the University of California, San Francisco (UCSF) and was funded by a grant from Genentech, Inc. Informed consent was obtained for all enrolled subjects using a form approved by the UCSF Institutional Review Board.

All patients meeting the following enrolment criteria were recruited from the UCSF Glaucoma Service: (i) age ≥21 years; (ii) a diagnosis of OAG including primary OAG, pseudoexfoliative or pigmentary glaucoma; and (iii) necessity of receiving drainage device implantation for purposes of IOP control. The study exclusion criteria included: (i) neovascularization of the iris or angle; (ii) pregnancy or current oral contraceptive intake; (iii) corneal scarring precluding adequate visualization of anterior segment structures; (iv) previous intravitreal injection of ranibizumab or bevacizumab in either eye; (v) usage of clopidogrel bisulfate or coumadin; (vi) uncontrolled hypertension; and (vii) renal or liver disease.

All enrolled patients were randomized 1:1 to the study or control groups. For patients in the study group, ranibizumab (0.5 mg in 0.05 mL) was administered intravitreally at three time points: 9 days before surgery, 1 month post-surgery and 2 months post-surgery. All ranibizumab (Genentech Inc., South San Francisco, CA, USA) injections were delivered in the inferotemporal quadrant, 3.5–4.0 mm from the limbus. Sham injections were not performed in the control group, and thus, the study subjects were not masked with regard to treatment.

All surgeries were performed by the same investigator (SCL) who was masked to the treatment at the time of surgery. After making a fornix-based superotemporal conjunctival/Tenon's flap between two adjacent recti muscles, the body of the Ahmed valve implant (New World Medical, Inc., Rancho Cucamonga, CA, USA) was inserted into the conjunctival/Tenon's pocket and sutured to the sclera with non-absorbable 9-0 nylon sutures approximately 7–8 mm posterior to the limbus. A partial-thickness limbal-based scleral flap was made, and the tube cut with beveled tip was inserted into the anterior chamber through a 23-gauge needle puncture made under the flap. The flap was sutured with 10-0 nylon, and the conjunctival incisions were sutured with 8-0 Vicryl (Ethicon, Inc., Somerville, NJ, USA).

Patients in both study arms were examined at postoperative days 1 and 7, and postoperative months 1 through 6. At each visit, patients were assessed for best-corrected Snellen visual acuity, IOP (Goldmann applanation tonometry), number of glaucoma medications (topical and oral), blood pressure, significant adverse effects and tube placement. Outcome parameters were assessed by investigators masked to the treatment groups. Patients in the study group were also examined 5–10 days after injections to assess for complications.

The criteria for success at 6 months postoperatively was IOP <18 mmHg without the necessity for adjunctive medications or IOP <15 mmHg with ≤1 adjunctive medication. The need for additional glaucoma procedures was deemed to be a treatment failure. Statistical analysis was performed with Stata/IC 12 software (StataCorp LP, College Station, TX, USA) using a two-tailed Fisher's exact test, with a P-value <0.05 considered statistically significant.

Results

  1. Top of page
  2. A
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The six subjects in the study group and five in the control arm were followed for a mean of 186 days (Table 1). There were no significant ocular or systemic adverse effects found in any subject in either group.

Table 1. Results from the control and ranibizumab arms of the trial
 IDRace/Sexcombined phacof/u (days)IOP preop (mmHg)IOP last f/u (mmHg)IOP change (mmHg)# Meds preop# Meds last f/uDecrease in # meds
  1. Patients who did or did not undergo combined phacoemulsification cataract surgery with the Ahmed tube insertion are identified as ‘Y’ or ‘N’. IOP, intraocular pressure.

Control1White/FY17516124312
2White/FY18117161110
3Black/MY22325223431
4Asian/MY7520164202
5White/FN19716151440
   Average170.218.816.22.62.81.81.0
Ranibizumab6Asian/FY17613130202
7White/FY21718135110
8Asian/MY23320146404
9Black/FY20323176404
10White/FN212331716525
11White/MN17819145303
   Average203.221.014.76.33.20.52.7

In the control arm, the mean preoperative IOP was 18.8 ± 3.8 mmHg on 2.8 ± 1.3 medications. Treatment resulted in an average IOP reduction to 16.2 ± 3.6 mmHg (a 2.6 ± 1.5 mmHg decrease, P = 0.30) with 1.8 ± 1.6 medications (a 1.0 ± 1.0 medication decrease, P = 0.32), at the 6-month postoperative time point. In the study arm, the average preoperative IOP of 21.0 ± 6.7 mmHg on 3.2 ± 1.5 medications was reduced to 14.7 ± 1.9 mmHg (a 6.3 ± 5.2 mmHg decrease, P = 0.06) on 0.5 ± 0.8 medications (a 2.7 ± 1.5 medication decrease, P = 0.01).

Success was achieved in five of the six ranibizumab eyes compared with two of five control eyes (P = 0.39). Compared with the control group, the ranibizumab group was noted to have a greater reduction in IOP by 3.7 mmHg (P = 0.15) and in medications by 1.7 (P = 0.06). Among the subjects who had undergone combined cataract and Ahmed valve implantation surgery, the study eyes were found to have a reduced IOP (4.3 vs. 3.0 mmHg, P = 0.54) and reduced number of medications (4.0 vs. 1.3, P = 0.16) relative to the control group, but these differences were not statistically significant.

Discussion

  1. Top of page
  2. A
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

In this small, randomized pilot study, we found that adjunctive intravitreal ranibizumab was safe and potentially effective in improving success with Ahmed tube implantation. The ranibizumab protocol lead to success in 83% of eyes compared with 40% of controls, with no significant ocular or systemic adverse events in either treatment group. To the best of our knowledge, ours is the first prospective comparative study demonstrating the safety of intravitreal ranibizumab as an adjunct with glaucoma drainage device implantation surgery.

Kahook et al. were the first to successfully demonstrate the use of anti-VEGF antibodies as modulators of fibrosis following glaucoma surgery.9 Their findings as well as those of several subsequent groups focused on trabeculectomy rather than drainage device implantation surgery.10–13 In an uncontrolled case series, Grewal et al. performed trabeculectomy with a single adjunctive injection of subconjunctival bevacizumab, reducing IOP from 24.4 mmHg preoperatively to 11.6 mmHg without the need for supplemental medications at 6 months.10 Kahook, in another study, demonstrated that when administered during trabeculectomy with mitomycin C, intravitreal ranibizumab increased peripheral bleb areas and decreased peripheral bleb vasculature.12 Finally, Rojo-Arnao et al. presented a randomized controlled trial involving subconjunctival bevacizumab with Ahmed valve implantation and found that although IOP was not significantly reduced 3 months postoperatively, there was an increase in bleb area and a shorter postoperative ocular hypertensive phase.14

In our study, intravitreal delivery was chosen over subconjunctival injection for two reasons. First, the safety profile of the subconjunctival delivery method of ranibizumab has not been well defined. It should be noted, however, that subconjunctival administration of most drugs is considered safer than intravitreal delivery. Second, because adjunctive intravitreal anti-VEGF therapy reduces bleb collagen deposition up to 30 days after filtration surgery, a reliably therapeutic rate of ranibizumab action was needed.3,15 With 3 days to reach peak aqueous humour concentration and a half-life of 2.8 days, intravitreal ranibizumab would provide a theoretical depot of the drug, releasing a sufficiently steady concentration to the sub-Tenon's space.16 Although subconjunctival injections provide the most direct route for ranibizumab into the sub-Tenon's space, the concentrations may be at risk of faster clearance via conjunctival and lymphatic flow. As demonstrated in a rabbit model studying subconjunctival bevacizuamb, most of the ocular concentration of drug was derived from the systemic recirculation and not from the primary subconjunctival site of delivery.17 Ranibizumab was chosen over bevacizumab because the former is approved for intraocular use by the Food and Drug Administration, with a well-studied ocular safety profile. In addition, as a smaller molecule, ranibizumab was expected to achieve higher concentrations in the anterior chamber and, accordingly, to the sclerectomy and subconjunctival space.17,18,19,20

As this was primarily a pilot study focusing on treatment safety, the results relating to IOP control have to be interpreted with caution. The small sample size decreased the likelihood of statistically confirming possible clinically meaningful differences between treatment and control groups. In addition, a majority of subjects in each arm underwent combined cataract surgery with Ahmed valve implantation, and thus, the IOP reduction attributable to cataract surgery may have confounded the reduction attributable to ranibizumab use. Although our participants did not experience any serious side-effects related to intravitreal ranibizumab injection, we should emphasize that further studies are needed to provide larger sample size and longer follow-up. Despite the obvious limitations of our pilot study, the demonstration of the short-term safety and potential efficacy of intravitreal ranibizumab as an adjunct to Ahmed drainage device surgery opens the door for further investigation of this approach with the purpose of improving surgical success. Further studies will be necessary to demonstrate the efficacy of anti-VEGF therapy in improving surgical success and in delineating the optimal therapeutic method, dosage and frequency of such therapy.

Acknowledgements

  1. Top of page
  2. A
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study was funded by a research grant from Genentech, Inc. to SCL.

References

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  2. A
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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