Abstract: We identified 11 trials that enrolled 687 eyes of 679 participants. The studies were conducted in the United States, Europe, Asia and Africa. Five studies enrolled participants at low risk of trabeculectomy failure, five studies enrolled participants at high risk of failure, and one study enrolled people with both high and low risk of failure. None of the included trials enrolled participants with combined trabeculectomy/cataract surgery. We considered one study to be at low risk of bias in all domains, six studies to be at high risk of bias in one or more domains, and the remaining four studies to be at an unclear risk of bias in all domains. The risk of failure of trabeculectomy at one year after surgery was less in those participants who received MMC compared to those who received 5-FU, however the confidence intervals were wide and are compatible with no effect (risk ratio (RR) 0.54, 95% confidence interval (CI) 0.30 to 1.00; studies = 11; I2 = 40%). There was no evidence for any difference between groups at high and low risk of failure (test for subgroup differences P = 0.69). On average, people treated with MMC had lower intraocular pressure at one year (mean difference (MD) -3.05 mmHg, 95% CI -4.60 to -1.50), but the studies were inconsistent (I2 = 52%). The size of the effect was greater in the high-risk group (MD -4.18 mmHg, 95% CI -6.73 to -1.64) compared to the low-risk group (MD -1.72 mmHg, 95% CI -3.28 to -0.16), but again the test for interaction was not statistically significant (P = 0.11). Similar proportions of eyes treated with MMC lost 2 or more lines of visual acuity one year after surgery compared to 5-FU, but the confidence intervals were wide (RR 1.05, 95% CI 0.54 to 2.06). Adverse events occurred relatively rarely, and estimates of effect were generally imprecise. There was some evidence for less epitheliopathy in the MMC group (RR 0.23, 95% CI 0.11 to 0.47) and less hyphaema in the MMC group (RR 0.62, 95% CI 0.42 to 0.91). None of the studies reported quality of life. Overall, we graded the quality of the evidence as low largely because of risk of bias in the included studies and imprecision in the estimate of effect. We found low-quality evidence that MMC may be more effective in achieving long-term lower intraocular pressure than 5-FU. Further comparative research on MMC and 5-FU is needed to enhance reliability and validity of the results shown in this review. Furthermore, the development of new agents that control postoperative scar tissue formation without side effects would be valuable and is justified by the results of this review.

Plain-language summary: We included 11 randomised controlled trials conducted in the United States, Europe, Asia and Africa in this review. In total, 687 eyes of 679 participants underwent routine trabeculectomy for glaucoma control. Some participants were at a higher risk of failure than others, for example if they had had previous glaucoma surgery, were of African origin, or if they had secondary glaucoma. Five studies enrolled participants at low risk of trabeculectomy failure, five studies enrolled participants at high risk of failure, and one study enrolled people with both high and low risk of failure. None of the included trials enrolled participants with combined trabeculectomy/cataract surgery. Our review showed that the risk of failure of trabeculectomy at one year after surgery was slightly less in those participants treated with MMC compared to 5-FU. All of the included randomised controlled trials contributed to this result, with a mixed study population of high- and low-risk participants and varied methodology of antimetabolite application. We did not detect any significant differences between the subgroups of participants at low and high risk of failure, but the power of this analysis was low. We identified no difference between the visual outcomes of the group that received MMC and the group that received 5-FU at one year postoperatively nor in the number of drops used postoperatively. However, we found evidence to suggest that MMC was more effective at lowering intraocular pressure than 5-FU in both high- and low-risk participants, achieving a lower mean intraocular pressure postoperatively than in those who were treated with 5-FU at one year. This effect seemed to be greater in the high-risk populations. Evaluating the overall complications across all studies revealed a slight favour toward using MMC, particularly with the incidence of epitheliopathy and hyphaema. There was a trend towards bleb leaks, wound leaks, late hypotony and cataract formation in the MMC-treated group. None of the studies reported quality of life. We graded the quality of the evidence as low, mostly due to the risk of bias in the included studies. One bias we commonly encountered came from the different techniques of antimetabolite administration, making it difficult to conceal which medicine was being used. Furthermore, most studies only had a few complications to report, which meant that there were low numbers overall to include in the analysis of complications.