Anti-vascular endothelial growth factor for control of wound healing in glaucoma surgery

Review question
Anti-vascular endothelial growth factor (VEGF) agents versus control or mitomycin C (MMC) for the outcome of trabeculectomy.

Background
Glaucoma filtration surgery, an eye operation in which a drainage fistula is created in the wall of the eye to reduce intraocular pressure (IOP), is usually reserved for glaucoma patients whose IOP cannot be sufficiently managed by medical and/or laser intervention. Scarring during wound healing can lead to failure of the operation, therefore, drugs are used to modify wound healing. Anti-VEGF agents have been proposed to decrease scar formation. This review asks whether there is evidence that the use of anti-VEGF drugs reduces the risk of failure of glaucoma surgery. We searched the medical literature for studies that evaluated the benefit and harms of anti-VEGF subconjunctival injection during trabeculectomy for control of wound healing, compared to control or MMC.

Date of searches
The evidence is up to date to November 2015.

Key results
Five studies (conducted in India, Turkey, USA and two in Iran) with a total of 175 participants were included in this review. The effect of anti-VEGF agents on IOP control is uncertain.

We found one small study, comparing anti-VEGF with control, which did not provide data on the primary outcome: the proportion of complete successful trabeculectomies at 12 months after surgery.

Four trials compared anti-VEGF to MMC, and two trials reported one or more outcomes of IOP control (complete success, qualified success, or mean IOP) at 12 months. There was low quality evidence compatible with decreased chance of complete success for anti-VEGF agents, suggesting that for patients using MMC with an 81.0% rate of complete success, the complete success rate using anti-VEGF agents would be between 37.2% and 87.4%. There was moderate quality evidence suggesting that for patients using MMC with a 95.2% qualified success rate, the qualified success rate using anti-VEGF agents would be between 82.9% and 100.0%, with no difference between anti-VEGF and MMC. Additionally, there was low quality evidence compatible with higher mean IOP for anti-VEGF agents between 0.15 mm Hg and 3.57 mm Hg, compared to MMC, and the effect was still uncertain.

The conclusion of this review is that there is still uncertainty of the effect on IOP control of the subconjunctival use of anti-VEGF in patients undergoing trabeculectomy, compared to the use of MMC.

Quality of evidence
There is currently evidence of low quality which is insufficient to refute or support anti-VEGF subconjunctival injection in glaucoma surgery. Several trials are ongoing and will be included in updates of the review.

Authors' conclusions: 

The evidence is currently of low quality which is insufficient to refute or support anti-VEGF subconjunctival injection for control of wound healing in glaucoma surgery. The effect on IOP control of anti-VEGF agents in glaucoma patients undergoing trabeculectomy is still uncertain, compared to MMC.

Further RCTs of anti-VEGF subconjunctival injection in glaucoma surgery are required, particularly compared to sham treatment with at least 12 months follow-up.

Read the full abstract...
Background: 

Trabeculectomy is performed as a treatment for glaucoma to lower intraocular pressure (IOP). The surgical procedure involves creating a channel through the wall of the eye. However scarring during wound healing can block this channel which will lead to the operation failing. Anti-vascular endothelial growth factor (VEGF) agents have been proposed to slow down healing response and scar formation.

Objectives: 

To assess the effectiveness of anti-VEGF therapies administered by subconjunctival injection for the outcome of trabeculectomy at 12 months follow-up and to examine the balance of benefit and harms when compared to any other anti-scarring agents or no additional anti-scarring agents.

Search strategy: 

We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2015, Issue 10), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 12 November 2015.

Selection criteria: 

We included randomised controlled trials (RCTs) of anti-VEGF therapies administered by subconjunctival injection compared to any other anti-scarring agents or no additional anti-scarring agents (no treatment or placebo) in trabeculectomy surgery.

Data collection and analysis: 

We used standard methodological procedures expected by Cochrane. Our primary outcome was successful trabeculectomy at 12 months after surgery which was defined as achieving a target IOP (usually no more than 21 mm Hg) without any additional intervention. Other outcomes included: qualified success (achieving target IOP with or without additional intervention), mean IOP and adverse events.

Main results: 

We included five RCTs (175 participants, 177 eyes) that met the inclusion criteria in this review.

One trial conducted in Iran (37 participants, 37 eyes) compared anti-VEGF (bevacizumab 0.2 mg) versus control (sham injection) in people with refractory glaucoma. We judged this study to be at low risk of bias.The primary outcome of this review was not reported; mean IOP at three months was 15.1 mm Hg (standard deviation 1.0) in both anti-VEGF and control groups.

Four trials compared anti-VEGF to mitomycin C (MMC) (138 particpants, 140 eyes). These studies were conducted in India, Iran, Turkey and the USA. The anti-VEGF agent used in these four trials was bevacizumab 2.5 mg (two trials), bevacizumab 1.25 mg three times and ranibizumab 0.5 mg. Two trials were at high risk of bias in two domains and one trial was at high risk of bias in four domains.

Only one of these trials reported the primary outcome of this review (42 participants, 42 eyes). Low quality evidence from this trial showed that people receiving bevacizumab 2.5 mg during primary trabeculectomy were less likely to achieve complete success at 12 months compared to people receiving MMC but the confidence interval (CI) was wide and compatible with increased chance of complete success for anti-VEGF (risk ratio (RR) 0.71, 95% CI 0.46 to 1.08), Assuming that approximately 81% of people receiving MMC achieve complete success, the anticipated success using anti-VEGF agents would be between 37.2% and 87.4%. The same trial suggested no evidence for any difference in qualified success between bevacizumab and MMC (RR 1.00, 95% CI 0.87 to 1.14, moderate quality evidence). Two trials of primary trabeculectomy provided data on mean IOP at 12 months; one trial of bevacizumab 2.5 mg and one trial of ranibizumab 0.5 mg. Mean IOP was 1.86 mm Hg higher (95% CI 0.15 to 3.57) in the anti-VEGF groups compared to the MMC groups (66 people, low quality evidence). Data were reported on wound leak, hypotony, shallow anterior chamber and endophthalmitis, but these events occurred rarely and currently there are not enough data available to detect any differences, if any, between the two treatments.

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