Abstract
What Is Known and Objective. The primary cause of trabeculectomy failure in glaucoma surgery is the imperfect formation of the filter bubble, which blocks the filtration effect. This systematic review and meta-analysis aimed to compare the effects and safety of mitomycin C (MMC) or no antimetabolite in trabeculectomies cases that require needling revision. Methods. We searched PubMed, Cochrane, and EMBASE to identify randomized trials published between the time the databases were built and May 31, 2022. To compare the effectiveness and safety of mitomycin with or without mitomycin in trabeculectomy, intraocular pressure (IOP), the surgical failure rate, and functional follicle formation were used as efficacy indicators, and the occurrence of postoperative complications was used as a safety indicator. Meta-analyses were performed for comparisons. Results and Discussion. After trabeculectomy, MMC was significantly better than a placebo at lowering postoperative IOP (MD = −11.31 mmHg, 95% CI −19.73 to −2.88 mmHg). MMC outperformed the control group in terms of filtering blebs formation (relative risk (RR) = 1.18, 95% CI: 1.09 to 1.27). The surgical failure rate was significantly lower with MMC compared to placebo (RR = 0.35, 95% CI: 0.22 to 0.58). No significant difference was observed between MMC and placebo in terms of hypotony, anterior chamber bleeding, filter bubble leakage, and endophthalmitis, apart from the shallow anterior chamber (RR: 1.51, 95% CI: 1.02 to 2.25). What Is New and Conclusion. The use of MMC in glaucoma trabeculectomy can increase the success rate of the procedure and provide significant patient benefits. However, it is important to be extremely careful and aware of complications such as shallow anterior chambers.
1. What Is Known and Objective
Glaucoma is a group of clinical symptoms or eye diseases that threaten and damage the optic nerve and its visual pathway, eventually resulting in visual impairment primarily caused by pathological intraocular pressure (IOP) elevation. Glaucoma treatment typically includes topical or systemic application of IOP-lowering drugs, laser therapy, and surgery. Trabeculectomy is still the primary method for treating glaucoma, with a success rate of only 70%–90% [1]. According to previous studies, the main reason for trabeculectomy failure in glaucoma is the excessive proliferation of subconjunctival fibroblasts, which results in the formation of scars under the filtering bleb and blocks the filtering effect [2–4].
Mitomycin is a cell cycle-specific drug that is most effective against tumor cells in the G1 phase, particularly in the late G1 and early S phases. It acts as a bifunctional or trifunctional alkylating agent after being activated by enzymes in the tissues. It can cross-link with DNA, inhibit DNA synthesis, and inhibit ribonucleic acid (RNA) and protein synthesis. It is also thought to possess antiscarring properties. As a result, mitomycin has been used in glaucoma trabeculectomy surgery to prevent scarring, and when satisfactory follicles are not obtained after trabeculectomy, it is used again. However, several clinical studies and systematic reviews have found that the benefits of mitomycin during and after filtration surgery are debatable and unclear [5–8]. As a result, this study aimed to search for clinical evidence of the use of mitomycin in glaucoma trabeculectomy, evaluate its efficacy and safety, and provide a reference for the off-label use of MMC in glaucoma surgery.
2. Methods
We searched PubMed, EMBASE, the Cochrane Library, ClinicalTrial.gov, CNKI, and Wanfang databases for information on the efficacy and safety of mitomycin for glaucoma trabeculectomy during and after surgery until May 2022. MeSH subject headings were combined with free words to form the search method: (trabeculectomy (glaucoma) and (mitomycin)). The search strategy is detailed in the supplementary file. We established the inclusion and exclusion criteria using the PICOs principle.
Inclusion criteria were as follows:(1)Study population: patients with glaucoma who underwent trabeculectomy.(2)Intraoperative application of mitomycin.(3)Control measures: intraoperative placebo or no mitomycin.(4)Outcome indicators: effectiveness: visual acuity, surgical success rate, IOP, and functional filtering blebs. Safety: postoperative complications.(5)Type of study: randomized controlled trials. The languages were limited to English and Chinese.
Exclusion criteria were as follows:(1)Conference abstracts, reviews, letters, translations, dissertations, and so on.(2)Studies without relevant outcome indicators.(3)If the same research team published research results at different stages of a study, only the final results of the research were included in this paper.(4)Chinese core journals with a sample size of <30 cases.
2.1. Screening of the Literature, Data Extraction, and Quality Assessment
Two reviewers (Z.S. and S.X.) independently browsed the titles and abstracts to screen the literature against the inclusion and exclusion criteria and viewed the full text when necessary. Two reviewers independently extracted data from the literature that met the inclusion criteria using a unified data extraction form. Disagreements were resolved through negotiations or by referring to a third party (G.L.) for adjudication. The first author, publication date, study type, inclusion criteria, number of cases, sex, intervention and control measures, number of interventions, follow-up time, and clinical outcomes were extracted. Two reviewers independently assessed the methodological quality of the included studies (Z.S. and S.X.). The methodological quality of the included randomized controlled trials (RCTs) and non-RCTs was assessed using the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 quality assessment criteria. The case reports/series were assessed using the JBI checklist assessment criteria for study quality.
2.2. Statistical Analysis
The methodological quality of the included studies was independently assessed by two reviewers (Z.S. and S.X.). The methodological quality of the RCT/CCT studies was assessed with the Cochrane risk of bias tool (Cochrane RoB).
The meta-analysis was performed using RevMan 5.1 software. For dichotomous variables, the efficacy statistic for RCTs was expressed as the relative risk (RR), and for non-RCTs, the OR and 95% confidence intervals (CIs) were calculated. For continuous variables, the MD and its 95% CI were mainly used. When I2 ≥ 50%, , a random-effects model was used for the meta-analysis; when I2 < 50%, , a fixed-effects model was used for the meta-analysis. Qualitative analysis was used to describe the research results if the included research data could not be quantitatively synthesized. Differences were considered statistically significant at .
3. Results and Discussion
3.1. Literature Search Results
The initial screening identified 149 studies in the literature. Fifteen RCTs were eventually included after thorough screening in accordance with the inclusion and exclusion criteria (Figure 1). A total of 1211 patients were included. Various forms of glaucoma and glaucoma with cataracts were researched in the included studies. Trabeculectomy was the only procedure performed. Males made up 31.9% to 87.5% of the patients in each study, which ranged in size from 14 to 66. The follow-up period ranged from three to 12 months. A comparison of mitomycin and no mitomycin during trabeculectomy was performed (Table 1).
3.2. Quality Evaluation
The quality of the included studies was evaluated, and the overall quality of the results was not high. Most studies were of moderate to high risk, or the risk was unknown (Figures 2 and 3).
3.3. Evaluation of the Efficacy and Safety of Mitomycin during Trabeculectomy in Patients with Glaucoma
3.3.1. Intraocular Pressure (IOP) [9–19]
This systematic review used a random-effects model to analyze IOP control three, six, and twelve months after trabeculectomy (Figure 4). MMC was significantly better than the placebo after trabeculectomy for reducing postoperative IOP (MD = −11.31 mmHg, 95% CI −19.73 to −2.88 mmHg). However, in the subgroup analysis, there was only a trend for MMC to benefit at three, six, and twelve months but no statistical significance.
3.3.2. Functional Filter Bubbles [15–22]
According to the Moorfields classification of follicles, there are four types of follicles after trabeculectomy: type I follicles with thin, ischemic, gray-white walls, and limited subconjunctival tissue formation with cystic cavities; type II follicles with slightly thick, grayish-white, widespread, and diffuse walls, and subconjunctival sparse tissue formation; type III follicles with thick walls, significant congestion, coarse neovascularization, subconjunctival dense tissue formation, and a flattened shape; and type IV follicles, which are confined, dome-shaped, elevated, and form a large subconjunctival cavity that is filled with fluid. Type I and type II follicles are functional follicles; type III follicles are flat/flat follicles; and type IV follicles are encapsulated vesicles, all of which are nonfunctional follicles.
Types I and II are functional follicles, whereas types III and IV are nonfunctional follicles. Using a random-effects model, functional filtering vesicles in the MMC group were superior to those in the control group (RR: 1.18; 95% CI: 1.09 to 1.27) (Figure 5).
3.3.3. Surgical Failure Rate [14–22]
In our study, the included studies characterized trabeculectomy success and failure as success, partial success, and failure, and the assessment criteria were not fully uniform. Our study specified the failure rate as an evaluation index for analysis, and surgical failure was defined as failure to achieve the normal IOP after trabeculectomy. From the point of view of surgical failure, the surgical failure rate was significantly lower with MMC compared with placebo (RR = 0.35, 95% CI: 0.22 to 0.58) (Figure 6).
3.4. Complications
There was no significant difference between MMC and placebo in terms of low IOP [9–12, 14, 17, 20–23], anterior chamber bleeding [9–14, 16, 17, 19, 21, 22], filtering bleb leakage [10–14, 16, 19, 22], hypohypertensive macular degeneration [19, 20], and endophthalmitis [24]. However, the occurrence of shallow anterior chamber [9–16, 19–23] was significantly higher with MMC than the placebo (RR: 1.51, 95% CI: 1.02 to 2.25) (Figure 7).
3.5. Further Discussion
Although the use of antimetabolites, including MMC, for glaucoma filtration surgery, has become clinically routine, they are still used off-label. As for the use of MMC in trabeculectomy, since the systematic review by Wilkins et al. [7], no new review has evaluated the evidence for the off-label use of MMC. Therefore, this study was based on the Wilkins systematic review and the latest research [7]. The evaluation indicators were enriched, and the benefits and risks of MMC in trabeculectomy were thoroughly assessed.
This study found that the control of IOP is consistent with most studies [2, 6–8], and there is no doubt that the addition of MMC will further increase the reduction of IOP. In this study, IOP control at three months was considered the most favorable. However, the included studies had high heterogeneity (I2 = 100%), with the data at six and 12 months only showing a trend of possible reduction. It is suggested that the use of MMC may be beneficial for IOP control in the short term, but over time, the benefit is less clear. Another indicator, the surgical success rate, was limited by the literature and only evaluated the success rate at 12 months. The MMC groups tended to show better results than the control group; however, Zhao’s study [18] showed that the longer the follow-up time, the lower the success rate. This was also confirmed by a Taiwanese study [24] and the study by Jabeen et al. [25]. The formation of functional filtering blebs is an important indicator of the success of trabeculectomy [26, 27], but it is more of an assessment of the short-term effects. This study found that after the application of MMC, the formation of functional filtering vesicles was significantly better than that of the control group (RR: 1.18, 95% CI: 1.09 to 1.27), and the included studies had low heterogeneity (I2 = 0%), suggesting that in this indicator, the results of the studies are very consistent.
There are many complications after trabeculectomy, but in the previous meta-analysis, the safety evaluation indicators mainly focused on wound leak, hypotony, late endophthalmitis, and expulsive hemorrhage. In addition to these indicators, this study included more safety metrics. The incidences of hypotony, hyphema, bleb leakage, hypotony macular degeneration, and endophthalmitis in the MMC group were not significantly different from those in the placebo group. However, MMC was associated with a significantly higher occurrence of shallow anterior chambers than the placebo (OR: 1.51, 95% CI: 1.02 to 2.25). This finding is not consistent between studies. The study by Wilkins et al. [7] showed that while there is a tendency for the occurrence of shallow anterior chambers in the MMC group to be higher than that in the control group (OR: 1.38, 95% CI: 0.73 to 2.63), this difference was not statistically significant. On the one hand, this may be because more studies were included in our meta-analysis, the sample size was enlarged, and the results may be closer to the real situation. However, many Chinese studies were included. This suggests that the occurrence of shallow anterior chambers may be more likely in the Chinese population. Although we did not conduct a further subgroup analysis, it also suggests that more attention should be paid to the prevention of shallow anterior chambers in patients undergoing trabeculectomy with mitomycin.
This systematic review of the application of MMC in trabeculectomy will provide new evidence for the off-label application of mitomycin in patients undergoing glaucoma surgery; however, there are also certain limitations. The risk of bias was predominantly unclear in the included studies. To some extent, this may reduce the credibility of the evidence. The quality evaluation of the research was not high; only Andreanos et al., [9] Costa et al., [11], and Martini et al. [12] were rated as medium quality, while the others were rated as low quality. However, the included studies were all RCTs, and the results were very similar to those reported previously, which further supports that the use of MMC in trabeculectomy is more beneficial to the prognosis of patients with glaucoma. Nevertheless, clinicians should remain highly vigilant about the occurrence of shallow anterior chambers.
3.6. What Is New and Conclusion
The application of MMC in glaucomatous trabeculectomy can reduce postoperative IOP and the risk of trabeculectomy failure and promote the formation of functional filtering vesicles, with obvious benefits for patients. However, the occurrence of shallow anterior chambers should be carefully monitored.
Data Availability
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study. All data used for the meta-analysis are provided in tables and figures based on publicly available data.
Conflicts of Interest
The authors declare that they have no conflicts of interest.