Intraoperative Mitomycin C Versus Intraoperative5-Fluorouracil for Trabeculectomy:

A Systematic Review and Meta-Analysis

Zhong-Jie Lin,1,* You Li, M.D.,1,2,* Jin-Wei Cheng, M.D.,1 and Xiao-He Lu, M.D.2

Abstract

Purpose: The aim of this study was to assess the intraoperative application of mitomycin C (MMC) compared to5-fluorouracil (5-FU) on the outcome of trabeculectomy and to examine the balance of risk and benefit.Methods: Pertinent studies were selected through systematic searches of major literature databases, includingthe Cochrane Library, PubMed, Embase, and Chinese Biomedicine Database. Internet searches of search engines,the professional associations’ websites, and the manufacturers’ databases were also performed. Clinical con-trolled trials comparing 5-FU with MMC in trabeculectomy were selected. The primary efficacy measure was theweighted mean difference (WMD) in percentage intraocular pressure reduction (IOPR%) at follow-up end point.The secondary efficacy measure was the relative risk (RR) for ‘‘qualified’’ (with or without medical therapy)success of trabeculectomy at follow-up end point. The third efficacy measure was RR for ‘‘complete’’ (withoutmedical therapy) success of trabeculectomy at follow-up end point. The fourth efficacy measure was RR foradverse events, including wound leak, hypotony, endophalmitis, and shallow anterior chamber (AC). Thepooled effects were calculated using the random effects model by RevMan version 5.0 software.Results: Eight studies enrolling a total of 536 patients were included in the meta-analysis. MMC was associatedwith significantly more IOPR% compared with 5-FU, with a WMD of 7.09 [95% confidence interval (CI) 1.47–12.70] at follow-up end point (P = 0.01). MMC was comparable with 5-FU in qualified success rate, with a RR of1.09 (0.99–1.20) at follow-up end point (P = 0.09). MMC was comparable with 5-FU in complete success rate, witha RR of 1.17 (0.79– 1.75) at follow-up end point (P = 0.43). Rates of adverse events did not differ significantlybetween 5-FU and MMC, with an RR of 0.71 (0.22–2.28) for bleb leakage, 1.40 (0.72–2.72) for hypotony, 1.63(0.27–9.75) for endophthalmitis, and 0.95 (0.41–2.21) for shallow AC.Conclusions: Intraoperative MMC is more effective in lowering IOP in trabeculectomy compared with in-traoperative 5-FU, but is comparable with intraoperative 5-FU in both qualified and complete success rate.Intraoperative use of both agents may contribute equally to adverse events.

Introduction

In trabeculectomy, the problem to be resolved is thehealing response, which leads to failure of some operated

eyes after a period of time. To resolve this problem and fa-cilitate intraocular pressure (IOP)-lowering efficacy, variousantifibrosis agents have been used in trabeculectomy. Mito-mycin C (MMC) and 5-fluorouracil (5-FU) were first used tomodify the wound healing response in the early 1980s.1

MMC is a drug used during the initial stages of glaucoma

surgery to prevent the conjunctiva healing onto the sclera.The alkylating properties of MMC inhibit DNA replication,which led to its use first as an anticancer drug.2 5-FU is aDNA topoisomerase I inhibitor and works through irre-versible inhibition of thymidylate synthase.3

MMC has been reported in randomized controlled trials4–12

(RCTs) to reduce mean IOP at 12 months. Postoperative 5-FUimplications have been assessed with RCTs.13–16 A system-atic review has proved that MMC reduces mean IOP at 12months17 and RCTs for 5-FU have proved IOP reduction

1Department of Ophthalmology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.2Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.*These authors contributed equally to this work.

JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICSVolume 28, Number 2, 2012ª Mary Ann Liebert, Inc.DOI: 10.1089/jop.2011.0117

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at 1 year compared to placebo.18 Khaw suggested that asingle intraoperative application of 5-FU might be sufficientto control postoperative proliferation of scar tissue at thedrainage site.19 Clinicians now appear to prefer the in-traoperative application of agents for the modification ofwound healing, and routine postoperative injections of 5-FUare rarely used. Therefore, we focused on intraoperative ra-ther than perioperative use of 5-FU in this review.

The results of two reviews comparing MMC and 5-FU toplacebo have suggested a similar effect for the two agents ininhibiting scarring after trabeculectomy.17,18 Some cliniciansconsider MMC more powerful and some prefer 5-FU. Aprevious review suggested that MMC results in a greaterdecrease in IOP than 5-FU.20 However, a recent meta-analysisfound no statistically significant difference between the in-traoperative application of these two antifibrosis agents.21

Clinically, these two agents seem to have different results.Therefore, to evaluate the efficacy and safety of these twoantifibrosis agents, we undertook a systematic review andmeta-analysis focusing on intraoperative MMC and in-traoperative 5-FU use in all relevant controlled clinical trials.

Materials and Methods

This meta-analysis was performed according to a pre-determined protocol described in the following paragraph,and standard systematic review techniques, as outlined bythe Cochrane Reviewers’ Handbook, were followed at allstages of the process.22

Outcome measures

The primary outcome was the percentage reduction frompreoperative to postoperative in IOP (IOPR%). When authorsreported mean and standard deviation (SD) of IOP and IOPR,we used them directly. When not available, we computed themaccording to the methods described in the Cochrane Handbookfor Systematic Reviews of Interventions: IOPR = IOPbaseline -IOPend point and SDIOPR = (SD2

baseline + SD2end point –SDbaseline ·

FIG. 1. The selection flowchart of clinical trials included inthe present meta-analysis.

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MMC VERSUS 5-FU FOR TRABECULECTOMY 167

SDend point)1/2. IOPR% = IOPR/IOPbaseline and SDIOPR% =

SDIOPR/IOPbaseline.When the difference in means (MD) and its t-value [t-

value also can be obtained from a computer by entering =tinv (P value, Ntreat + Ncontrol - 2) into any cell in a MicrosoftExcel spreadsheet] were reported, SD = MD - t - 1 ·(N - 1

treat + N - 1control)

- 1/2.For efficacy, the proportion of qualified success and

complete success was also used. Qualified success was de-fined as target end point IOP with or without medications.Compete success was defined as target end point IOPwithout medications. The fourth outcomes were adverseevent rates in either group, including wound leaks, hypot-ony, late endophthalmitis, and shallow anterior chamber.

Search strategy

Clinical trials comparing intraoperative MMC use with in-traoperative 5-FU use were identified through a systematicsearch of the Cochrane Library, PubMed, and EMbase. A broadsearch strategy combined terms related to MMC (includingMeSH search using mitomycins and keyword search usingwords mmc, mutamycin, m?tom?cin, mitoc?n and amet?cin?),terms related to 5-FU (including MeSH search using fluoro-uracil and keyword search using words fluorouracil, flur-acilium, fluracil, fluoruracil and flu), and terms related tosurgery (including MeSH search using exp Filtering-Surgeryand Glaucoma-Surgery, and keyword search using wordstrabeculectom, sclerostom, filter near surg, filtrat near surg andglaucoma near surg), with a filter to restrict results to clinicaltrial, meta-analysis and randomized controlled trial. The orig-inal search was performed in January, 2011. Regular alertsevery 3 months were established on PubMed and Embasedatabases to capture new studies until June, 2011, and updatedsearches on the Cochrane databases regularly.

The internet was searched using the Google and Yahoo!search engines and using the terms 5-fluorouracil and mi-tomycin C. A manual search was performed by checking thereference lists of original reports and review articles, re-trieved through the electronic searches, to identify studiesnot yet included in the computerized databases.

Trials selection

Published and unpublished trials fulfilling the followingselection criteria were included in the present meta-analysis:(1) Study design—controlled clinical studies, including co-hort studies or randomized trials; (2) population—patientswith glaucoma, including primary and secondary, who were

undergone trabeculectomy or phacotrabeculectomy; (3)intervention—intraoperative MMC was administered at anyconcentration and dose, and was compared with in-traoperative 5-FU of any concentration and dose; (4) outcomevariables—at least one of the following outcome variables,IOPR%, complete success rate, and qualified success rates.Studies involving other types of glaucoma surgery, such asnonpenetrating glaucoma surgery, were excluded. Other ex-clusion criteria included repeated glaucoma surgery.

After completion of the searches, two review authors(Z.J.L., Y.L.) working independently assessed the titles andabstracts of all obtained reports for a rough judgment of anarticle’s eligibility. The full-text copies of possibly and defi-nitely relevant trials were obtained and assessed by the twoauthors independently according to the definitions in thecriteria, which were checked by J.W.C. Only trials meetingthese criteria were assessed for methodological quality. Forthe publications reporting on the same study population, thearticle reporting the results of the last end point was in-cluded, and data that could not be obtained from this pub-lication were obtained from others.

The observers were blinded to the names of the authorsand their institutions, the names of the journals, sources offunding, and acknowledgments, as well as the financer of thestudy.

Data extraction

Data extraction was performed by two reviewers (Z.J.L.,Y.L.) independently. Any disagreement was resolved by dis-cussion. For each study and each type of treatment, the fol-lowing data were extracted: The authors of the study, the yearof publication, information on study design, location of trial,length of study, number of subjects, patient age, sex, and IOPmeasurements. Numeric discrepancies between the two in-dependent data extractions were resolved after discussion.

Qualitative assessment

The qualities of clinical trials included were assessed bytwo independent observers (Z.J.L. and Y.L.) using a previ-ously reported quality assessment system that was for bothrandomized and nonrandomized studies.23 The systemcontained 27 items distributed between five subscales aboutreporting (10 items), external validity (3 items), bias (7 items),confounding (6 items), and power (1 item). Any discrepancyin the qualitative assessment between the two observers wasdiscussed and a consensus was reached. The total score ofeach trial was expressed as a percentage of the maximum

Table 2. Quality Scoring Components for 8 Cinical Trials Included

Quality score component Score

First Author (year)Ref. I II III IV V Over all Percentage (%)

Palanca-Capistrano (2009)24 11 2 7 4 4 28 87.50Kim (2008)25 11 2 4 1 3 21 65.63Singh (2000)26 11 2 7 5 4 29 90.63Smith (1997)27 11 2 4 1 3 21 65.63Budenz (1999)28 10 2 4 1 2 19 59.38Vijaya (2000)29 11 2 4 1 1 19 59.38SeiY (1994)30 7 0 4 0 2 13 40.63Singh (1997)31 11 2 6 3 4 26 81.25

168 LIN ET AL.

achievable score. Good quality refers to a quality score notlower than 50%.

Statistical analysis

Not all of the trials reported on all the outcomes of inter-est. For each comparison and outcome, we undertook sepa-rate meta-analyses. Outcome measure was assessed on anintent-to-treat (ITT) basis. Considering the different clinicalcharacteristics among study groups and the variation ofsample sizes, we assumed that heterogeneity was present,even when no statistical significance was identified, and wedecided to combine data by using a random-effects model toachieve more conservative estimates.

For dichotomous outcomes, relative risk (RR) was esti-mated. Weighted mean difference (WMD) was calculated forcontinuous outcomes. Analyses were carried out in RevManversion 5.0 software (Cochrane Collaboration, Oxford, UnitedKingdom). The results were reported with 95% confidenceintervals (CIs). A P value < 0.05 was considered statisticallysignificant on the test for overall effect. To detect publicationbiases, asymmetry in funnel plots was visually examined.

Sensitivity analysis

Sensitivity analysis was undertaken to evaluate the effect ofmethodological characteristics of controlled clinical trials interm of trial design, which was differentiated as retrospective,prospective nonrandomized, and randomized. Another sensi-tivity analysis was undertaken to evaluate the effect of baselineof controlled clinical trials in term of operation, which wasdifferentiated as phocotrabeculectomy and trabeculectomy.

Results

The selection flow of controlled clinical trials is shown inFig. 1. We reviewed the full text of 12 articles from 118studies identified from our initial literature search and handsearch. A total of 9 studies met criteria for inclusion, andthere was one duplicate publication. Therefore, 8 clinicaltrials involving 536 patients were included in the final meta-analysis.24–31

Trials characteristics, populations, and quality

The trials were conducted in various countries, includingWest Africa, United States, India, and Korea. The charac-

teristics of the eligible studies are summarized in Table 1. Atotal of 589 eyes of 536 patients were enrolled. The durationof follow-up ranged from 6 months to 84 months. Mean ageranged from 47 to 75 years. Among the 262 patients whosesex were available,24,25,27,29 135 were male and 127 were fe-male. Trabeculectomy with intraoperative MMC or 5-FU wasundergone in 7 trials, and phacotrabeculectomy was under-gone in 1 trial. Three trials had a prospective, parallel, ran-domized design; 2 had a prospective, nonrandomizeddesign; and 3 had a retrospective, nonrandomized design.The quality assessment is summarized in Table 2. Funnelplots on qualified success rate was asymmetric while funnelplots on IOPR was symmetric (Fig. 2), suggesting probablepublication bias.

Percentage of IOPR

The percentage of IOPR comparing MMC with 5-FU wasreported. Five studies reported data related to IOPR% atvarious time. We chose the IOPR at follow-up end point (for 1trial we chose the figure of the 12-month to reduce bias, theothers of follow-up end point). MMC was found more effec-tive than 5-FU in lowering IOP. The differences in IOPR%comparing MMC with 5-FU were statistically significant, withWMD 7.09 (95% CI, 1.47–12.70). For the subgroup includingRCTs, the differences in IOPR% were also statistically signif-icant (WMD 3.70, 1.23–6.17). For the subgroup including pro-nonrandomized clinical trials, the differences in IOPR% werealso statistically significant (WMD 9.61, 2.94–16.28). For thesubgroup including retrospective clinical trials, the differencesin IOPR% were not statistically significant (WMD 7.53,- 1.39–16.46). For the phacotrabeculectomy subgroup, thedifferences in IOPR% were not statistically significant (WMD2.00, - 1.41–5.41). When excluding the study that phaco-trabeculectomy was undergone, the differences in IOPR%were statistically significant (WMD 8.46, 1.99–14.93) (Table 3).

Qualified success rate

Eight studies reported the proportions of patients achiev-ing target end point IOP with or without medications atfollow-up end point; the difference in qualified success ratebetween the MMC group and 5-FU group was not statisti-cally significant (pooled RR 1.09, 0.99–1.20). For the subgroupincluding RCTs, the difference in qualified success rate be-tween the MMC group and 5-FU group was not statistically

FIG. 2. Funnel plot of stud-ies comparing intraoperativemitomycin C (MMC) andintraoperative 5-fluorouracil(5-FU) on qualified successrate (left) and percentage in-traocular pressure reduction(IOPR%, right). RR, relativerate; MD, mean difference(both calculated in a random-effects model); SE, standarderror.

MMC VERSUS 5-FU FOR TRABECULECTOMY 169

significant (RR 1.07, 0.94–1.21). For the subgroup includingretrospective clinical trials, the difference in qualified successrate between the MMC group and 5-FU group was not sta-tistically significant (RR 1.22, 0.68–2.19). For the subgroupincluding pro-nonrandomized clinical trials, the difference inqualified success rate between the MMC group and 5-FUgroup was not statistically significant (RR 1.06, 0.86–1.30). For

the phacotrabeculectomy subgroup, the difference in quali-fied success rate between the MMC group and 5-FU groupwas not statistically significant (RR 2.00, - 1.41–5.41). Whenexcluding the study in which phacotrabeculectomy occurred,the difference in qualified success rate between the MMCgroup and 5-FU group was not statistically significant, either(pooled RR 1.10, 1.00–1.22) (Table 4).

Table 3. IOPR% Comparing the MMC Group with the 5-FU Group

MMC 5-FU

Mean (SD) Mean (SD) WMD(random) Weight

WMD(random)

Trial No. (%) No. (%) 95% CI (%) 95% CI (%)

AllPalanca-Capistrano et al.24 58 55.96(5.92) 57 52.26(7.50) 22.10 3.70 (1.23 to 6.17)Kim et al.25 30 49.20(14.48) 38 34.11(14.48) 17.10 6.09 ( - 0.84 to 13.02)Smith et al.27 36 63.79(6.59) 37 61.79(8.20) 21.30 2.00 ( - 1.41 to 5.41)Budenz et al.28 29 27.57(4.52) 28 13.43(4.81) 22.10 14.14 (11.72 to 16.56)Vijaya et al.29 16 64.65(11.25) 16 55.04(7.65) 17.40 9.61 (2.94 to 16.28)Subtotal 169 176 100.00Heterogeneity: Tau2 = 35.59,

chi2 = 48.40, df = 4P < 0.00001, I2 = 92%Test for overall effect:

Z = 2.47, P = 0.017.09 (1.47 to 12.70)

RandomizedPalanca-Capistrano et al.24 58 55.96(5.92) 57 52.26(7.50) 100.00 3.70 (1.23 to 6.17)Heterogeneity: not applicableTest for overall effect:

Z = 2.38, P = 0.02Pro-nonrandomized

Vijaya et al.29 16 64.65(11.25) 16 55.04(7.65) 100.00 9.61 (2.94 to 16.28)Heterogeneity: not applicableTest for overall effect:

Z = 2.83, P = 0.005Retrospective

Kim et al.25 30 40.20(14.48) 38 34.11(14.48) 29.90 6.09 ( - 0.84 to 13.02)Smith et al.27 36 63.79(6.59) 37 61.79(8.20) 34.60 2.00 ( - 1.41 to 5.41)Budenz et al.28 29 27.57(4.52) 28 13.43(4.81) 35.50 14.14 (11.72 to 16.56)Subtotal 95 103 100.00Heterogeneity: Tau2 = 56.90,

chi2 = 33.52, df = 2P < 0.00001, I2 = 94%Test for overall effect:

Z = 1.65, P = 0.107.53 ( - 1.39 to 16.46)

Phaco-exludedPalanca-Capistrano et al.24 58 55.96(5.92) 57 52.26(7.50) 27.90 3.70 (1.23 to 6.17)Kim et al.25 30 40.20(14.48) 38 34.11(14.48) 21.80 6.09 ( - 0.84 to 13.02)Vijaya et al.29 16 64.65(11.25) 16 55.04(7.65) 22.20 9.61 (2.94 to 16.28)Budenz et al.28 29 27.57(4.52) 28 13.43(4.81) 28.00 14.14 (11.72 to 16.56)Subtotal 133 139 100.00Heterogeneity: Tau2 = 37.43,

chi2 = 35.61, df = 3,P < 0.00001, I2 = 92%Test for overall effect:

Z = 2.56, P = 0.018.46 (1.99 to 14.93)

PhacoSmith et al.27 36 63.79(6.59) 37 61.79(8.20) 100.00 2.00 ( - 1.41 to 5.41)Heterogenity: Not applicableTest for overall effect:

Z = 1.15, P = 0.25

MMC, mitomycin C; 5-FU, 5-fluorouracil; SD, standard deviation; WMD, weighted mean difference (random-effect model); CI, confidenceinterval. WMDs more than zero denoted an advantage for mitomycin C, and those less than zero denoted an advantage for 5-fluorouracil;95%CIs of WMDs not including 0 denoted a statistically significant advantage.

170 LIN ET AL.

Complete success rate

Three studies reported the proportions of patientsachieving target end point IOP without medications at fol-low-up end point, the difference in complete success ratebetween the MMC group and 5-FU group was not statisti-cally significant (pooled RR 1.17, 0.79–1.75). For the sub-group including retrospective clinical trials, the difference incomplete success rate between MMC group and 5-FU groupwas not statistically significant, either (RR 1.46, 0.50–4.25).For the subgroup including pro-nonrandomized clinical tri-als, the difference in complete success rate between the MMCgroup and 5-FU group was not statistically significant, either(RR 1.00, 0.89–1.12) (Table 5).

Side effects

No significant differences comparing between MMC and5-FU were found in the incidence of bleb leakage, hypotony,endophthalmitis, and shallow anterior chamber, with thepooled RRs being 0.71 (0.22–2.28), 1.40 (0.72–2.72), 1.63(0.27–9.75), and 0.95 (0.41–2.21), respectively (Table 6).

Sensitivity analysis

Trials designed as retrospective, prospective non-randomized, and randomized were stratified, and the differ-ences of qualified success rate and IOPR% were compared,respectively. For the subgroup including retrospective clinicaltrials, the differences in IOPR% were not statistically signifi-cant (WMD 7.53, - 1.39–16.46). Results of the rest were sta-tistically significant. Trials that included trabeculectomy andphocotrabeculectomy were stratified and the differences ofqualified success rate and IOPR% were compared, respec-tively. For the phacotrabeculectomy subgroup, the differ-ences in IOPR% were not statistically significant (WMD 2.00,- 1.41–5.41). Results of the rest were statistically significant.

Discussion

The present systematic review suggested that in-traoperative MMC is more statistically effective in IOP low-ering in trabeculectomy compared with intraoperative 5-FU,but comparable with intraoperative 5-FU in both qualifiedand complete success rate. Both agents contribute equally toadverse events.

Abdu et al. analyzed data from 9 clinical trials and re-ported that intraoperative MMC is comparable with perio-perative 5-FU in mean IOP and success rate.21 In contrast tothat analysis, we focused on intraoperative MMC and in-traoperative 5-FU instead of perioperative 5-FU and reviewed8 controlled clinical studies in trabeculectomy, comparingintraoperative MMC with intraoperative 5-FU, and foundthat intraoperative MMC application was associated withgreater IOP-lowering efficacy, with statistically significantdifferences in IOP reduction compared with intraoperative 5-FU at follow-up end point. However, both groups achievedcomparable qualified success rate at follow-up end point.

The first strength of the present analysis is that we focusedon direct comparison between intraoperative MMC and in-traoperative 5-FU rather than indirect comparison betweenperioperative MMC and perioperative 5-FU. Furthermore, inthe quality assessment of trials, we used a system for bothrandomized and nonrandomized trials that was definitelybetter than the Jadad scoring system only for randomizedtrials. Five (62.5%) of all including studies were non-randomized design, which may fail to detect actual results.32

The third strength is that we undertook subgroup meta-an-alyses by only including randomized clinical trials andsubgroup meta-analyses by excluding trials in which pha-cotrabeculectomy occurred. Two independent co-authorsjudged the eligibility of articles and extracted data from theeligible articles, with discrepancies resolved after discussionby all of the authors. Only the series of the same patient

Table 4. Qualified Success Rate Comparing MMC Group with 5-FU Group

MMC 5-FU

No.of trials

No.of eyes

Qualifiedsuccess rate

No.of eyes

Qualifiedsuccess rate

RR95% CI

Test forheterogeneity

Test foroverall effect

All 8 296 0.91 293 0.82 1.09 (0.99, 1.20) Q = 26.71, P = 0.0004 Z = 1.67, P = 0.09Randomized 3 156 0.92 148 0.86 1.07 (0.94, 1.21) Q = 4.72, P = 0.09 Z = 1.07, P = 0.29Retrospective 3 95 0.88 103 0.74 1.22 (0.68, 2.19) Q = 38.55, P < 0.00001 Z = 0.65, P = 0.51Prospective 2 45 0.93 42 0.86 1.06 (0.86, 1.30) Q = 2.48, P = 0.12 Z = 0.54, P = 0.59Phaco-ex 7 260 0.90 256 0.79 1.10 (1.00, 1.22) Q = 14.30, P = 0.03 Z = 1.91, P = 0.06Phaco 1 36 1.00 37 1.00 2.00 (-1.41, 5.41) Not applicable Z = 1.15, P = 0.25

MMC, mitomycin C; 5-FU, 5-fluorouracil; RR, relative risk (calculated using a random-effect model); CI, confidence interval; Phaco,phacotrabeculectomy.

Table 5. Complete Success Rate Comparing the MMC Group with 5-FU Group

MMC 5-FU

No. oftrials

No. ofeyes

Completesuccess rate

No.of eyes

Completesuccess rate

RR95% CI

Test forheterogeneity

Test foroverall effect

All 3 82 0.76 91 0.62 1.17 (0.79, 1.75) Q = 15.69, P = 0.0004 Z = 0.79, P = 0.43Retro 2 66 0.70 75 0.53 1.46 (0.50, 4.25) Q = 9.76, P < 0.002 Z = 0.70, P = 0.49Pro 1 16 1.00 16 1.00 1.00 (0.89, 1.12) Not applicable Z = 0.00, P = 1.00

MMC, mitomycin C; 5-FU, 5-fluorouracil; RR, relative risk (calculated using a random-effect model); Retro, retrospective; Pro, prospective.

MMC VERSUS 5-FU FOR TRABECULECTOMY 171

group at the last end point were included in the presentanalysis. Asymmetry was showed by funnel plots, indicatingless possibility of publication biases.

One major limitation of this analysis was that patientswere not stratified into high, medium, and low risk of tra-beculectomy failure subgroups, which may possibly producemore interesting results.33 A second limitation is that ouranalyses of IOPR, success rate, and adverse events werebased on data pooled from trials of different durations. Itwas due to lack of data reported in all phases of follow-up. Itwas a compromise proposal to choose the data of follow-upend point. Another limitation is that only published studieswere included. To avoid publication bias, we conducted notonly an electronic search but also a manual search to identifyall potentially relevant articles, including published andnonpublished ones. Unfortunately, it is possible that we mayhave failed to include some papers, especially those pub-lished in other languages. The other limitations are the fac-tors such as small sample size, inadequate allocationconcealment, or inadequate or no double blinding, whichmay greatly affect the interpretation of the results. The in-clusion in meta-analysis of studies with very small samplesizes may have a paradoxical effect of decreasing the powerof random-effects tests.34 Therefore, in future, rigorous ran-domized controlled trials with long enough follow-up andbig enough sample size are strongly recommended to furtherevaluate the real IOP-lowering effect of intraoperative MMC,compared with intraoperative 5-FU in trabeculectomy.

In conclusion, the results of this meta-analysis of 8 ran-domized controlled trials suggested that intraoperativeMMC is more effective in IOP lowering in trabeculectomycompared with intraoperative 5-FU but comparable withintraoperative 5-FU in both qualified and complete successrate. Intraoperative use of both agents may contributeequally to adverse events.

Acknowledgment

This paper was supported by Shanghai Municipal NaturalScience Foundation, and National Natural Science Founda-tion of China.

Author Disclosure Statement

The authors have no competing financial interests.

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Table 6. Side Effect Comparing MMC Group with 5-FU Group

MMC 5-FU

No.of trials

No.of eyes Rate

No.of eyes Rate

RR95% CI

Test forheterogeneity

Test foroverall effect

Bleb-leak 4 177 0.0904 176 0.1023 0.71 (0.22, 2.28) Q = 5.59, P = 0.13 Z = 0.58, P = 0.57Hypotony 5 214 0.0935 202 0.0644 1.40 (0.72, 2.72) Q = 1.71, P = 0.79 Z = 0.98, P = 0.33Endophthalmitis 2 88 0.0341 95 0.0211 1.63 (0.27, 9.75) Q = 0.06, P < 0.81 Z = 0.53, P = 0.59Shallow AC 5 180 0.0556 182 0.0604 0.95 (0.41, 2.21) Q = 1.95, P = 0.75 Z = 0.12, P = 0.90

MMC, mitomycin C; 5-FU, 5-fluorouracil; RR, relative risk (calculated using a random-effect model); CI, confidence interval; AC, anteriorchamber.

172 LIN ET AL.

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Received: July 7, 2011

Accepted: September 9, 2011

Address correspondence to:Jin-Wei Cheng, M.D.

Department of Ophthalmology, Shanghai Changzheng Hospital415 Fengyang Road

Shanghai 200003China

E-mail: jinnwave@gmail.com

and

Xiao-He Lu, M.D.Department of Ophthalmology

Zhujiang HospitalSouthern Medical University

Guangzhou 515282China

E-mail: lu.xiaohe@yahoo.cn

MMC VERSUS 5-FU FOR TRABECULECTOMY 173