The authors have declared that no competing interests exist.
Conceived and designed the experiments: WW WH XZ. Performed the experiments: MH WW XZ. Analyzed the data: MH WW WH. Contributed reagents/materials/analysis tools: MH WW WH. Wrote the paper: MH WW WH.
To evaluate the application of the Ologen implant compared to mitomycin C (MMC) on the outcome of trabeculectomy and to examine the balance of risks and benefits.
A systematic literature search (Pubmed, Embase, the Cochrane Library, and the Chinese Biomedicine Database) was performed. Randomized controlled trials comparing the Ologen implant with MMC in trabeculectomy were selected. The efficacy measures were the weighted mean differences (WMDs) for the intraocular pressure reduction (IOPR), the reduction in glaucoma medications, and the relative risks (RRs) for success rates. The tolerability measures were RRs for adverse events. The pooled effects were calculated using the random-effects model.
Seven randomized controlled trials including 227 eyes were included in this meta-analysis. The WMDs of the IOPR comparing the Ologen group with the MMC group were −2.98 (95% Cl: −5.07 to −0.89) at one month, −1.41 (−3.72 to 0.91) at three months, −1.69 (−3.68 to 0.30) at six months, −1.94 (−3.88 to 0.01) at 12 months, and 0.65 (−2.17 to 0.47) at 24 months. There was no statistically significance except at one and 12 months after surgery. No significant difference in the reduction in glaucoma medications or complete and qualified success rates were found. The rates of adverse events also did not differ significantly between Ologen and MMC.
The Ologen implant is comparable with MMC for trabeculectomy in IOP-lowering efficacy, reduction in the number of glaucoma medications, success rates, and tolerability. However, the results should be interpreted cautiously since relevant evidence is still limited, although it is accumulating. Further large-scale, well-designed randomized controlled trials are urgently needed.
Since it was introduced in 1968 by Cairns, trabeculectomy remains the most common surgical procedure for the treatment of glaucoma
MMC was originally used as a systemic chemotherapeutic agent; it has been widely used in ophthalmic practice both intraoperatively and postoperatively for enhancing the success rate of glaucoma filtration surgery. Recent systematic reviews have demonstrated significant enhancement of success rates and postoperative IOP through the intraoperative use of MMC during glaucoma filtering surgery
The Ologen implant was developed aiming at replacing MMC for trabeculectomy. It is a disc-shaped porcine-derived biodegradable collagen matrix that has been developed to prevent excessive scarring after trabeculectomy
These conflicting results have made it difficult to draw conclusions that could be applied in clinical practice. Therefore, the aim of this study was to undertake a systematic review and meta-analysis to evaluate the application of the Ologen implant compared to mitomycin C (MMC) on the outcome of trabeculectomy and to examine the balance of risks and benefits.
This systematic review and meta-analysis were performed according to a predetermined protocol described in the next paragraph, and the standard systematic review guidelines, as outlined by the Cochrane Reviewers’ Handbook and the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement (
Reports of clinical trials comparing trabeculectomy with Ologen and with MMC were identified through a systematic search consisting of (i) an electronic search of Pubmed, Embase, the Cochrane Library, and the Chinese Biomedicine Database; (ii) manual searches of the reference lists of original reports and review articles retrieved through the electronic searches; and (iii) extensive Internet searches, including manufacturers’ databases, websites of professional associations, and the Google Scholar search engine. Searches were conducted using the keywords “trabeculectomy,” “sclerectomy,” “Ologen implant,” “OculusGen,” “iGen,” “collagen matrix implant,” “MMC,” and “mitomycin C.” No language or date restrictions were applied. The computerized searches covered the period from 1966 to July 2013. The retrieved studies were imported into Refworks (version 1.0; Refworks, Bethesda, MD), where duplicate articles were manually deleted. The titles and abstracts of the remaining studies were independently scanned by two reviewers (W.W. and M.H.). The full texts of the potentially relevant reports were then read to determine whether they met the inclusion criteria.
Published and unpublished trials fulfilling the following selection criteria were included in the present meta-analysis: (1) study design–randomized controlled clinical trials (RCTs); (2) population–adult patients (>18 years) with uncontrolled glaucoma undergoing trabeculectomy; (3) intervention–Ologen was compared with intraoperative MMC of any concentration and dose; (4) outcome variables–at least one of the following outcome variables: IOPR, reduction in glaucoma medications, complete and qualified success rates, or incidence of adverse events; and (5) and a follow-up time of at least six months. The following were excluded: (1) studies that involved other types of glaucoma surgery, such as non-penetrating glaucoma surgery and (2) studies that included pediatric cases or patients with repeated glaucoma surgery. Where multiple publications based on the same group of patients were identified, the report with the largest number of patients was used.
Data were extracted from each RCT by two independent reviewers (W.W. and M.H.). Any discrepancies between the two independent data extractions were resolved by discussion to reach a consensus among all authors. For the eligible studies, the following data were extracted: (1) general characteristics (title, first author, journal title, and year of publication); (2) methodology (type of study, country of origin, sequence generation, allocation concealment, masking or blinding, incomplete outcome data, selective reporting, and other sources of bias); (3) subjects (recruitment site, enrollment periods, inclusion criteria, exclusion criteria, and general patient characteristics); (4) interventions (concentration of MMC and exposure time); (5) outcomes (measurement, follow-up time and loss of follow-up); (6) analysis (statistical methods); and (7) results (quantitative results and qualitative results). If the appropriate data were not obtainable, we requested the data from the study's investigators.
The methodological quality of each study was assessed using the risk-of-bias tool outlined in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0)
The primary outcome was the IOP (IOPR) reduction from preoperative to postoperative. When authors reported the mean and SD of IOP and IOPR, we used them directly. When not available, we computed them according to the methods described in the Cochrane Handbook for Systematic Reviews of Interventions: IOPR = IOPbaseline-IOPendpoint and SDIOPR = (SD2baseline+SD2endpoint–SDbaseline×SDendpoint)1/2
Not all of the trials reported on all the outcomes of interest. For each comparison and outcome, we undertook separate meta-analyses. Outcome measures were assessed on an intent-to-treat basis. Considering the different clinical characteristics among study groups and the variation of sample sizes, we assumed that heterogeneity was present even when no statistical significance was identified, and we decided to combine data by using a random-effects model to achieve more conservative estimates
Statistical heterogeneity was analyzed using a chi-square test. The
Dichotomous data were presented as the relative ratio (RR) with a 95% confidence interval (CI). Weighted mean differences (WMD) with a 95% CI were calculated for continuous variables. Both RRs and WMDs were considered statistically significant at the P<0.05 level. One-way sensitivity analyses were performed by iteratively removing one study at a time to assess the stability of the meta-analysis results. Only outcomes of interest that were reported in >5 studies were included in the sensitivity analysis. Potential publication bias was estimated by both visually evaluating a funnel plot and the Egger test
The selection of studies is summarized in
The RCTs were published between 2010 and 2013 and involved a total of 227 eyes (134 in the Ologen group and 143 in the MMC group). The characteristics of the eligible studies are summarized in
Trial (year) | Center | Location | Goup | NO. ofeyes | Endpointlength(m) | Age(year) | Sex(M/F) | Type of glaucoma | MMC | ||||
POAG | PACG | PXFG | Others | Con(mg/ml) | Time(min) | ||||||||
Senthil (2013) | single | India | Ologen | 19 | 24 | 48±10 | 9/10 | 8 | 11 | 0 | 0 | ||
MMC | 20 | 24 | 45±12 | 11/9 | 12 | 8 | 0 | 0 | 0.4 | 2 | |||
Marey (2013) | single | Egypt | Ologen | 30 | 12 | 50.2±10.2 | 18/12 | 18 | 4 | 2 | 6 | ||
MMC | 30 | 12 | 49.07±5.8 | 17/13 | 13 | 5 | 4 | 8 | 0.2 | 2 | |||
Mitra (2012) | single | UK | Ologen | 28 | 6 | 61.22±12.24 | 16/12 | 19 | 0 | 6 | 3 | ||
MMC | 36 | 6 | 62.43±14.43 | 22/14 | 21 | 0 | 12 | 3 | na | na | |||
Maheshwari (2012) | single | India | Ologen | 20 | 12 | na | na | 20 | 0 | 0 | 0 | ||
MMC | 20 | 12 | 20 | 0 | 0 | 0 | na | na | |||||
Cillino (2011) | single | Italy | Ologen | 20 | 24 | 65.8±6.4 | 12/8 | 13 | 0 | 7 | 0 | ||
MMC | 20 | 24 | 63.2±7.2 | 11/9 | 12 | 0 | 8 | 0 | 0.2 | 2 | |||
Nilforushan (2011) | single | Iran | Ologen | 7 | 13 | 59±12.6 | 4/3 | 7 | 0 | 0 | 0 | ||
MMC | 7 | 14 | 59±12.6 | 4/3 | 7 | 0 | 0 | 0 | 0.2 | 3 | |||
Rosentreter (2010) | single | Germany | Ologen | 10 | 12 | 62.8±9.5 | 8/12 | na | na | 0 | na | ||
MMC | 10 | 12 | na | na | 0 | na | 0.2 | 3 |
M/F indicates male/female; MMC, mitomycin C; POAG, primary open-angle glaucoma; PACG, primary angle-closure glaucoma; PXFG, pseudoexfoliation glaucoma; con, concentration; min, minutes.
The agreement between the two reviewers’ quality assessment of the trials was scored by the κ coefficient (a measure of agreement), which was 0.85, with 92.1% observed agreement. The risk of bias in the RCTs is shown in
Trial (year) | Sequence Generation | Allocation Concealment | Blinding | Adequate asseement of each outcome | Selective reporting avoided | No Other Bias | ||
Patient | Personnel | Assessor | ||||||
Senthil (2013) | yes | no | no | no | no | yes | yes | yes |
Marey (2013) | unclear | no | no | no | no | yes | yes | yes |
Mitra (2012) | unclear | unclear | unclear | unclear | unclear | yes | yes | yes |
Maheshwari (2012) | unclear | unclear | unclear | unclear | unclear | yes | yes | yes |
Cillino (2011) | yes | yes | no | yes | yes | yes | yes | yes |
Nilforushan (2011) | yes | no | no | no | no | yes | yes | yes |
Rosentreter (2010) | yes | yes | no | no | no | yes | yes | yes |
Seven studies reported the IOPR at various time points, five of them at one month, six at three months, six at six months, six at 12 months, and two at 24 months. The IOP reduction was numerically smaller for the Ologen group at all intervals with the exception of 24 months. When comparing the Ologen group with the MMC group, the WMDs of the IOPR were −2.98 (95% Cl: −5.07 to −0.89) at one month, −1.41 (−3.72 to 0.91) at three months, −1.69 (−3.68 to 0.30) at six months, −1.94 (−3.88 to 0.01) at 12 months, and 0.65 (−2.17 to 0.47) at 24 months. There was no significant heterogeneity in these analyses, and the differences in IOPR were all not statistically significant, with the exception of one month and 12 months (
Time | NO. of studies | WMD (95% CI) | Test for Heterogeneity | Test for Overall Effect | |||||
Estimate | ll | ul | ?2 | I2 | P | Z | P | ||
Reduction In Intraocular Pressure | |||||||||
1m | 5 | −2.98 | −5.07 | −0.89 | 5.65 | 29.2% | 0.227 | 2.79 | 0.005 |
3m | 6 | −1.41 | −3.72 | 0.91 | 10.94 | 54.3% | 0.053 | 1.19 | 0.233 |
6m | 6 | −1.69 | −3.68 | 0.30 | 8.69 | 42.5% | 0.122 | 1.67 | 0.096 |
12m | 6 | −1.94 | −3.88 | −0.01 | 8.10 | 38.2% | 0.151 | 1.97 | 0.049 |
24m | 2 | 0.65 | −2.17 | 3.47 | 0.36 | 0.00% | 0.547 | 0.45 | 0.652 |
Reduction in Glaucoma Medication | |||||||||
6m | 3 | −0.31 | −0.58 | −0.045 | 0.08 | 0.00% | 0.961 | 2.28 | 0.022 |
12m | 2 | −0.59 | −1.36 | 0.19 | 0.00 | 0.00% | 0.980 | 1.49 | 0.136 |
24m | 2 | 0.01 | −0.13 | 0.15 | 0.13 | 0.00% | 0.723 | 0.10 | 0.923 |
Weighted mean differences were computed by using a random effects model. 95% CI indicates 95% confidence interval; MMC, mitomycin C.
There was no significant difference in glaucoma medication reduction between the two groups except at one month (
Six studies reported the proportions of patients achieving the target endpoint IOP without anti-glaucoma medication at various time points, three of them at six months, five at 12 months, and two at 24 months. Ologen was associated with similar complete success rates compared with MMC at all time points (Table. 4), with the pooled RR being 1.19 (0.56 to 2.55) at six months, 0.74 (0.53 to 1.02) at 12 months, and 1.09 (0.77 to 1.56) at 24 months.
Six studies reported the proportions of patients achieving the target endpoint IOP with or without medications, no significant differences between groups were also found at three time points (
NO. of studies | Success Rate, n/N (%) | RR (95% CI) | Test for Heterogeneity | Test for Overall Effect | |||||||
Ologen | MMC | Estimate | ll | ul | ?2 | I2 | P | Z | P | ||
Completed success rate | |||||||||||
6m | 3 | 42/54 | 41/63 | 1.19 | 0.56 | 2.55 | 11.72 | 82.90% | 0.003 | 0.45 | 0.652 |
12m | 5 | 56/87 | 74/87 | 0.74 | 0.53 | 1.02 | 9.81 | 59.20% | 0.044 | 1.84 | 0.066 |
24m | 2 | 21/39 | 19/40 | 1.09 | 0.77 | 1.56 | 0.09 | 0.00% | 0.765 | 0.49 | 0.623 |
Qualified success rate | |||||||||||
6m | 3 | 47/54 | 57/63 | 0.98 | 0.87 | 1.10 | 1.52 | 0.00% | 0.468 | 0.37 | 0.709 |
12m | 3 | 31/46 | 39/47 | 0.80 | 0.57 | 1.11 | 3.60 | 44.40% | 0.166 | 1.35 | 0.178 |
24m | 2 | 24/39 | 23/40 | 1.06 | 0.84 | 1.33 | 0.00 | 0.00% | 0.991 | 0.49 | 0.625 |
RR indicates relative risk, which were computed by using a random effects model. 95% CI indicates 95% confidence interval; n, number of patients achieving target endpoint intraocular pressure; N, number of patients; Ologen, trabeculectomy with Ologen implant; MMC, trabeculectomy with intraoperative mitomycin C.
No significant differences in comparing the Ologen group and the MMC group were found in the incidence of bleb leak, hyphema, a shallow anterior chamber, hypotony, choroidal effusion, encapsulated bleb, blebitis, hypotony maculopathy, and implant exposure, with the pooled RRs being 1.08 (0.41 to 2.82), 1.78 (0.54 to 5.91), 0.85 (0.33 to 2.16), 1.02 (0.55 to 1.91), 0.74 (0.28 to 1.93), 1.68 (0.30 to 9.43), 1.13 (0.10 to 12.34), 0.50 (0.18 to 1.40), and 3.83 (0.16 to 90.53), respectively (
Adverse event | NO. of studies | Crude Rate, n/N (%) | RR (95% CI) | Test for Heterogeneity | Test for Overall Effect | ||||||
Ologen | MMC | Estimate | ll | ul | ?2 | I2 | P | Z | P | ||
Bleb leak | 5 | 7/107 | 7/116 | 1.08 | 0.41 | 2.82 | 3.17 | 0.00% | 0.530 | 0.15 | 0.881 |
Hyphema | 4 | 13/79 | 6/80 | 1.78 | 0.54 | 5.91 | 3.86 | 22.20% | 0.277 | 0.95 | 0.344 |
Shallow anterior chamber | 4 | 7/87 | 9/98 | 0.85 | 0.33 | 2.16 | 1.24 | 0.00% | 0.743 | 0.34 | 0.732 |
Hypotony | 3 | 10/57 | 10/66 | 1.02 | 0.55 | 1.91 | 0.03 | 0.00% | 0.984 | 0.07 | 0.944 |
Choroidal effusion | 3 | 6/49 | 9/50 | 0.74 | 0.28 | 1.93 | 1.74 | 0.00% | 0.419 | 0.62 | 0.535 |
Encapsulated Bleb | 2 | 3/38 | 2/46 | 1.68 | 0.30 | 9.43 | 0.06 | 0.00% | 0.806 | 0.58 | 0.559 |
Blebitis | 2 | 1/58 | 1/66 | 1.13 | 0.10 | 12.34 | 1.14 | 12.60% | 0.285 | 0.10 | 0.921 |
Hypotony maculopathy | 1 | 4/20 | 8/20 | 0.50 | 0.18 | 1.40 | – | – | – | 1.32 | 0.186 |
Implant Exposure | 1 | 1/28 | 0/36 | 3.83 | 0.16 | 90.53 | – | – | – | 0.83 | 0.406 |
RR indicates relative risk, which were computed by using a random effects model. 95% CI indicates 95% confidence interval; n, number of patients achieving target endpoint intraocular pressure; N, number of patients; Ologen, trabeculectomy with Ologen implant; MMC, trabeculectomy with intraoperative mitomycin C.
To evaluate the robustness of the results, each study in the meta-analysis was excluded in turn to reflect the influence of individual studies on the pooled estimates of IOPR at three months, six months, and 12 months. The results indicated that the random-effect estimates before or after the deletion of any single study were generally similar, suggesting high stability in the meta-analysis results (data not shown). A funnel plot analysis indicated that the outcomes of IOPR at three months, six months, and 12 months were distributed symmetrically, showing no evidence of publication bias. Egger’s tests confirmed these results (
Glaucoma is the leading cause of irreversible blindness worldwide and represents a significant public health concern
To the best of our knowledge, this is the first meta-analysis to explore the role of Ologen in trabeculectomy. The pooled results from the meta-analysis of seven RCTs using a random-effects model suggest similar postoperative behavior between the Ologen group and the MMC group, with stable IOP reduction and anti-glaucoma medications, indicating that the efficacy of the Ologen implant is analogous to that of MMC. The similarity between Ologen and MMC is further confirmed by their success rates at various times. In addition, the two agents contribute equally to adverse events. Sensitivity analysis suggested that the results were robust.
Ologen is composed of more than 90% lyophilized porcine collagen and <10% lyophilized glycos-aminoglycan with a pore size of 10–300 mm
Ologen was numerically associated with somewhat lower IOP compared with MMC in the present study, but no significant differences were arrived. This may be related to differences inherent in each procedure. Ologen only functions as a wound modulator and does not have any antifibrotic properties to counter the scarring response. However,in previous human studies, Ologen implants used along with deep sclerectomy enhanced the success rates when compared to deep sclerectomy
Theoretically, the Ologen implant may protect against known MMC-associated complications. However, there was no significant difference in post-operative complications in the two groups, and no serious post-operative complications were noticed. In addition, there is a theoretical risk of increased inflammation in eyes with Ologen implants, as the implants are non-human (porcine) in origin
The first strength of the present analysis is that we undertook meta-analyses by including only randomized clinical trials and excluding trials in which phacotrabeculectomy occurred. Furthermore, to avoid publication bias, we conducted not only an electronic search but also a manual search of the references of all the retrieved trials to identify all the potentially relevant articles, including published ones and non-published ones. The third strength is that only studies with a minimum follow-up period of six months were selected. Two independent co-authors judged the eligibility of articles and extracted data from the eligible articles, with discrepancies resolved after discussion by all of the authors. Only the series of the same patient group at the last endpoint were included in the present analysis.
This meta-analysis has several potential limitations that should be taken into account. One major limitation of this analysis was that patients were not stratified into high, medium, and low risk of trabeculectomy failure subgroups, which may produce more interesting results. Furthermore, although no significant heterogeneity was found, the studies were carried out with small or very small sample sizes, inadequate allocation concealment, or inadequate or no double blinding. These factors can greatly affect the interpretation of the results. The other limitations are the non-standardized assessment criteria of success. Success was defined as target endpoint IOP, and there were several different criteria for normal IOP, such as IOP≤18 mm Hg, ≤20 mm Hg, ≤21 mm Hg, and so on. Although such assessments of success are widely used as outcome measures in clinical trials, further research is still needed to determine fully their validity, reliability, and sensitivity to choose the best one. Finally, all participants in the studies were Caucasian, these results may not be generalized to other races such as Asians.
Nonetheless, the present study provides additional interesting clues that may be useful for future research on this important topic. First, future studies need to focus on other important clinical endpoints (e.g. visual acuity, visual field, and inflammation reactions) and biochemical indicators to understand the benefits, mechanisms, and role of Ologen in trabeculectomy better. In addition, only two RCTs with a modest sample size provided data on IOPR at 24 months; therefore, rigorous randomized controlled trials with long enough follow-up and large enough sample sizes are strongly recommended to evaluate further the real IOP-lowering effect of Ologen compared with MMC in trabeculectomy. Finally, further studies are needed to standardize a protocol (i.e. type of glaucoma, dosage and duration of MMC, and postoperative management) since variability exists in the literature.
In summary, our systematic review indicates that trabeculectomy with Ologen is a safe and effective procedure in patients with glaucoma, but it does not seem to offer any significant advantages compared with trabeculectomy plus MMC. However, relevant evidence is still limited but is accumulating. Thus, studies with larger numbers of patients and longer follow-ups are urgently required to confirm these findings and to examine the safety and long-term outcomes of trabeculectomy with Ologen.
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