Cumulative effect of risk factors on short-term surgical success of mitomycin augmented trabeculectomy.HC Agarwal, TK Sharma, R Sihota, V Gulati
RP Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi - 110 029, India., India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 12215687
Source of Support: None, Conflict of Interest: None
CONTEXT: Risk factors for failure of trabeculectomy may have a cumulative effect on the outcome. AIMS: To study the effect of preoperative ocular risk factors on the surgical outcome of trabeculectomy augmented with 2 commonly used doses of Mitomycin C. SETTINGS AND DESIGN: In a prospective cohort study, cases were recruited over an 18 month period. 92 eyes of 83 patients with one to three known risk factors for failure of trabeculectomy underwent Mitomycin-C (MMC) augmented trabeculectomy. METHODS AND MATERIAL: Trabeculectomy was done with a randomly chosen MMC dose of 0.2 mg/ml or 0.4 mg/ml. All cases were followed up for a period of at least 3 months. Surgical success was defined as the lowering of intraocular pressure (IOP) below 21 mmHg during the follow up period. STATISTICAL ANALYSIS USED: Chi square test, paired t test, odds ratio, effect size. RESULTS: Eyes with two or three risk factors (out of aphakic glaucoma, failed trabeculectomy, neovascular glaucoma, post uveitic glaucoma, traumatic glaucoma, adherent leucoma, juvenile glaucoma, prolonged medical therapy, steroid induced glaucoma, post penetrating keratoplasty glaucoma and developmental glaucoma) had a significantly poorer surgical success rate (88% and 78%) than eyes with one risk factor (100%). 0.4 mg/ml MMC used sub-sclerally had a statistically similar effect on lowering the IOP as 0.2 mg/ml in all groups. The rate of complications was significantly higher in the 0.4 mg/ml subgroup. CONCLUSIONS: The presence of more than one preoperative ocular risk factor, affects the surgical success of MMC augmented trabeculectomy in high-risk cases. Because of the significantly higher rate of complications with the higher dose of MMC, this should be used sparingly, only in cases with more than two risk factors.
Keywords: Adult, Chemotherapy, Adjuvant, Cohort Studies, Comparative Study, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Follow-Up Studies, Glaucoma, drug therapy,surgery,Human, Intraocular Pressure, Male, Middle Age, Mitomycin, administration &dosage,Odds Ratio, Postoperative Complications, Preoperative Care, Probability, Prospective Studies, Risk Factors, Trabeculectomy, methods,Treatment Outcome,
The success of trabeculectomy in uncomplicated primary glaucoma cases vary from 75% to 100%.,,, However, in cases with a complicating factor like neovascular glaucoma, aphakic and pseudophakic glaucoma, traumatic glaucoma, post-uveitic glaucoma, glaucoma associated with mesodermal dysgenesis of the anterior chamber, juvenile glaucoma and failed trabeculectomy, the success rate of trabeculectomy may be as low as 29-50%.,,,,,,, These conditions are called ‘high risk factors’ for failure of glaucoma filtering surgery. More than one risk factor in a glaucomatous eye could further reduce the chances of surgical success. Efforts have been made to improve the success rate of trabeculectomy in these cases, with the intra-operative use of anti-fibroblastic drugs like Mitomycin-C (MMC).,,,,
It would be useful to know if the presence of multiple risk factors in a case has a cumulative negative effect on the outcome of filtering surgery. We studied the short-term success of Mitomycin augmented trabeculectomy in a cohort of cases with ‘high risk factors’ for failure of glaucoma filtering surgery. Our study compares the surgical outcome of two commonly used intraoperative doses of MMC, 0.2mg/ml and 0.4mg/ml, with regards to the number of preoperative ‘high risk factors’ present in an eye.
Consecutive patients having one to three ‘high risk factors’, in eyes with uncontrolled IOP on maximum tolerated topical therapy, were enrolled after informed consent for the study over a 18 month period. Clearance was obtained from institutional review board.
Through a clinical history and ocular examination, the risk factor(s) for the failure of glaucoma filtering surgery were identified. Prolonged medical therapy, which was also included as one of the risk factors, was defined as continuous medical therapy for more than 12 months. Based on the number of risk factors present, the eyes were subcategorised into groups with one, two and three risk factors respectively.
All eyes underwent a standard trabeculectomy augmented with intraoperative Mitomycin C. The dose of Mitomycin C used, was based on a random selection between 0.2 mg/ml and 0.4 mg/ml. In all cases, a limbus based conjunctival flap was raised and a half thickness 4mm by 4mm rectangular, lamellar scleral flap was prepared. Mitomycin-C (0.2 mg/ml or 0.4 mg/ml) soaked in a cellulose sponge of 4x4 mm size was applied below the partial thickness scleral flap for 3 minutes. The tissues were gently rinsed with 10 ml of Ringer’s lactate solution and the filtering surgery was completed in the usual manner. The superficial scleral flap was approximated with three interrupted 10-0 nylon sutures and the conjunctival flap, with a continuous 8-0 Vicryl sutures.
Post-operatively the patients were prescribed antibiotic-steroid drops four times a day for 6 weeks. All patients were followed up for a minimum of 3 months, with masked observation of the intraocular pressure, bleb status and visual fields. Any postoperative complications were managed accordingly. No additional IOP lowering drugs were required in any of the patients during the study period. Surgical success was defined as, an IOP below 21 mmHg at the end of the study period.
92 eyes of 83 patients were enrolled in the study. For the 9 patients, who had both eyes included, the two eyes fell into different risk categories and were analysed and treated independently, maintaining the statistical requirement of independence of observations. The demographic and clinical data of the study population are summarised in [Table - 1]. Forty-five eyes underwent Mitomycin augmented trabeculectomy with a dose of 0.2mg/ml (Group A) and 47 eyes underwent the procedure with 0.4 mg/ml Mitomycin (Group B). The number of eyes with one (grade I), two (grade II) and three (grade III) ‘high risk factors’ was 36, 33 and 23 respectively. The break up of risk factors in the two groups is summarised in [Table - 2].
The preoperative IOP was 27.0 mmHg (SD=6.4 mmHg) group A and 29.5 mmHg (SD=4.8 mmHg) in group B on maximum tolerated anti-glaucoma medication. Despite a random distribution to the two Mitomycin dose categories, we found the baseline IOP to be higher in group B, considered as a whole (p= 0.04). However, in none of the subcategories based on the number of risk factors, was this difference found to be significant (p=0.19, 0.07 and 0.82 for grade I, II and III respectively). Since the comparison between the two doses of Mitomycin was restricted within these individual subcategories, the subjects within the subgroup can be considered adequately matched for baseline IOP. Moreover, we used effect size to measure IOP reduction, thereby correcting for any less than statistically significant differences in the baseline IOP in any of the subgroups of our sample population.
After MMC augmented trabeculectomy the pressure reduction attained with 0.4-mg/ml MMC, was greater as measured by the effect size, in all subgroups at all follow-up periods [Table - 3]. However, the difference in effect size between 0.2mg/ml and 0.4 mg/ml doses of Mitomycin had a considerable overlap in the 95% confidence interval, thereby not allowing the difference to be significant from a statistical standpoint.
The success rate of trabeculectomy augmented with 0.2 mg/ml and 0.4mg/ml Mitomycin C was identical in grade I eyes (100%) and similar in grade II eyes (approximately 88%) [Table - 4]. In grade III eyes, the success rate was higher with 0.4-mg/ml dose of Mitomycin C (85%), as compared to the 0.2-mg/ml dose (70%), but the difference was not statistically significant (p=0.41). On the whole, the surgical success rate was significantly worse in eyes with two (p=0.03) or three risk factors (p=0.01), as compared to eyes with only one risk factor. In the individual treatment groups, a statistically significant difference in surgical success rate was seen only between Grade I and Grade III eyes in the 0.2-mg/ml subgroup. No statistically significant difference was seen in the 0.4-mg/ml MMC subgroups with 1-3 risk factors.
The effect of individual risk factors on surgical success was analysed as odds ratio [Table - 2]. The odds ratio was highest for neovascular glaucoma (4.73), adherent leucoma (3.67) and previous failed trabeculectomy (3.35). The surgical success rate was not significantly different, with respect to the individual risk factors, between the 0.2 mg/ml and 0.4 mg/ml dose of Mitomycin C. However, eyes with an adherent leucoma did significantly better with the 0.4 mg/ml dose (100% vs. 33%; p=0.01).
Overall, the rate of complications was significantly higher in the 0.4 mg/ml (38%) subgroup as compared to the 0.2 mg/ml (22%) subgroup (p=0.04). The most significant contributor to this difference was chronic ocular hypotony (IOP =8 mmHg four weeks after surgery), which was present in 3 out of 45 eyes (6.67%) in Group A and 9 out of 47 eyes (19.1%) in group B. Also, hypotony associated with maculopathy (3 eyes), and one case of endophthalmitis, due to infection through a polycystic thin bleb, was seen only in the 0.4 mg/ml subgroup.
Visual acuity at the end of follow up improved or remained stable in 82.2% eyes in group A and 78.7% of eyes in group B. The visual deterioration occurred due to progression of cataract in eight eyes in group-A (17.8%) and seven eyes (14.9%) in group-B. The drop in vision in the remaining 4 eyes in Group B was due to maculopathy and endophthalmitis mentioned above.
The use of Mitomycin-C during glaucoma filtering surgery has improved the outlook for cases known to have a high risk of surgical failure. Several doses and application time regimens have been evaluated for Mitomycin C. Higher doses and duration of Mitomycin C increase the surgical success rate, but also unfortunately, the complications. There is therefore a need to know, the optimum dose of Mitomycin C. Our study evaluated two commonly used dosage regimes of Mitomycin C in eyes stratified with respect to the number of ocular risk factors for surgical failure.
The overall surgical success rate in our study was 88.9% with 0.2 mg/ml and 91.5% with 0.4 mg/ml Mitomycin C. This is comparable to previous reports by Palmer et al, Ramakrishan et al (93.4% success rate with 0.4 mg/ml) MMC-trabeculectomy in primary glaucomas. However, the follow up period was shorter for our study than the two studies quoted. This is a shortcoming of the present study.
Our study showed that surgical success rates decrease with the increase in number of ocular risk factors present. Both the doses showed a similar success rate in eyes with 1-2 risk factors. To the best of our knowledge, the outcome of glaucoma surgery in relation to the number of risk factors present has not been previously reported. It is possible that the lower surgical success rate in the eyes with a higher number of risk factors could be due to a higher baseline pressure in these eyes. Due to this difference in baseline pressure, we cannot address the question, whether a greater number of risk factors leads to a more severe baseline disease, or presents an independent additive obstacle to the therapeutic surgical intervention. Also, a higher baseline pressure in itself has been considered as an independent risk factor by some authors.,,,
The success rate of trabeculectomy in eyes with individual risk factors in our study was comparable with other studies reported in the literature. Some of the previously reported success rates of Mitomycin augmented trabeculectomy in high risk cases are as follows: traumatic angle recession 85%, failed glaucoma filtering surgery 88.2%, childhood glaucomas 82%, iridocorneal endothelial syndrome 80%, developmental glaucoma 75%, juvenile glaucoma,, 84% to 91%. The odds ratio was the highest for neovascular glaucoma in our study. One previous study has also shown neovascular glaucoma to carry the worst prognosis, among the high-risk cases, for surgical success (80% failure rate without intraoperative antimetabolite use).
We did not find a statistically significant difference between the 0.2 mg/ml and 0.4-mg/ml dose of Mitomycin C in any of the individual subgroups of risk stratification. However the numerical effect size was consistently higher with the 0.4 mg/ml dose. This consistent edge of the 0.4-mg/ml dose over 0.2 mg/ml can be taken to be clinically significant. The difference was most marked in the subgroup with 3 risk factors. Hence, the higher dose of Mitomycin C is likely to add the most to the surgical success rate in this particular group. But in our study, the rate of complications was significantly higher in the subgroup with a higher dose of Mitomycin C. The optimum concentration of Mitomycin C appears to be 0.2mg/ml. The difference was in most part due to the difference in the rate of ocular hypotony in the two groups, as the rates of other complications were similar in the two groups. In our study, nine eyes (19.1%) developed chronic ocular hypotony with 0.4 mg/ml Mitomycin C three eyes (6.3%) had a hypotensive maculopathy. The rate of this complication in our study is similar to the ones previously reported by other authors. Chen et al reported 17% incidence of prolonged hypotony and Kitazava et al reported 18% incidence of hypotony maculopathy following MMC augmented trabeculectomy. To summarise, our study suggests that, a greater number of preoperative ocular risk factors in a given eye, have an additive adverse effect on the outcome of glaucoma filtration surgery. It is suggested that in view of the significantly higher complication rate of 0.4 mg/ml MMC, its use if at all, should be restricted to cases with more than two risk factors for the failure of glaucoma filtration surgery.
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5]