To report the risk of endophthalmitis and other long-term complications in patients randomized to trabeculectomy in the Collaborative Initial Glaucoma Treatment Study.
A longitudinal cohort study using data collected from a multicenter, randomized clinical trial.
Long-term postoperative complications in the 300 patients randomized to trabeculectomy in the Collaborative Initial Glaucoma Treatment Study were tabulated. Kaplan-Meier analyses were used to estimate the time-related probabilities of blebitis, hypotony, and endophthalmitis.
Two hundred eighty-five patients were included in the final trabeculectomy cohort after accounting for declining treatment assignment and other early events. Patients were followed up for an average of 7.2 years. One hundred sixty-three patients (57%) received 5-fluorouracil during surgery. Of the 247 patients with at least 5 years of follow-up, 50 required further treatment for glaucoma. Cataract extraction was performed in 57 patients (20%). Forty patients (14%) required bleb revision at least once. Bleb-related complications included bleb leak (n = 15), blebitis (n = 8), and hypotony (n = 4). Three patients were noted to have endophthalmitis, although the diagnosis in 2 patients was presumptive. The occurrences of blebitis, hypotony, or endophthalmitis were not significantly associated with 5-fluorouracil use. The Kaplan-Meier calculated risks of blebitis and hypotony at 5 years were both 1.5%, whereas the risk of endophthalmitis was 1.1%.
The potential efficacy of trabeculectomy must be weighed against the long-term risk of complications, especially endophthalmitis, when selecting treatments for patients with open-angle glaucoma. We report a low 5-year risk of endophthalmitis (1.1%) and other bleb-related complications in the trabeculectomy cohort of the Collaborative Initial Glaucoma Treatment Study.
Trabeculectomy is the most common penetrating surgical intervention for the treatment of open-angle glaucoma. Although this filtering surgical procedure has been used widely over the past several decades, the concern for complications of filtering surgery, especially endophthalmitis, has given rise to several nonfiltering surgical procedures that putatively carry a lower risk of endophthalmitis. Discussions around such procedures as viscocanalostomy, deep sclerectomy, and canaloplasty have emphasized the risks of endophthalmitis from standard filtering procedures as compared with nonpenetrating surgery. Similarly, procedures such as mechanical goniotomy, tube shunts, and intraocular shunting devices have been promoted as having lower risks for endophthalmitis because they do not produce a filtering bleb. In addition to the risk of endophthalmitis, there is a paucity of data on longer-term complications of trabeculectomy.
An earlier communication reported on the intraoperative and early postoperative complications of initial treatment with trabeculectomy in the Collaborative Initial Glaucoma Treatment Study (CIGTS), a multicenter, randomized, clinical trial that was unique in its comparison of trabeculectomy versus topical medications as initial treatment for patients with newly diagnosed open-angle glaucoma. Up to 1 month of postoperative follow-up revealed only transient, self-limited complications of trabeculectomy, none of which were expected to result in subsequent loss of visual acuity (VA). With subsequent follow-up of the study patients for an average of 7.2 years and up to 11 years, we now report on the longer-term surgical complications, especially those such as endophthalmitis that have major implications for visual loss.
Although the lack of serious short-term complications of trabeculectomy in the CIGTS is encouraging, the risk-to-benefit assessment of a consideration for trabeculectomy surgery must include consideration of longer-term risks. Reported longer-term complications have included visually significant cataract with increased rates of cataract extraction after trabeculectomy, as well as bleb-related complications, such as hypotony, bleb leak, blebitis, and endophthalmitis. More recent studies have shed greater light on long-term complications. For example, a retrospective study with at least 4 years of follow-up of 797 eyes of 634 patients who underwent trabeculectomy by 2 surgeons confirmed the finding of worsening lens opacity in most of their cohort. These same authors also report bleb leaks and infection in 4.9% (39 eyes) and 3.4% (27 eyes) of the 797 eyes, respectively, occurring later than 6 weeks after surgery, with a slightly higher rate and later onset of infection for limbus-based compared with fornix-based conjunctival flaps. A smaller percentage of eyes (n = 5; 0.6%) were described as exhibiting endophthalmitis. In 105 patients who underwent trabeculectomy with 5 years of follow-up in the Tube Versus Trabeculectomy study, 4.8% (n = 5) were reported to have endophthalmitis or blebitis, with 1.9% (n = 2) of patients exhibiting endophthalmitis. In a study comparing complication rates of trabeculectomy between patients with primary open-angle glaucoma and angle-closure glaucoma, 6 patients (2.9%) exhibited bleb leaks and 2 (1.0%) experienced endophthalmitis of 208 patients with primary open-angle glaucoma. Finally, a prospective population-based study in the United Kingdom estimated the incidence per year of blebitis with bleb leak and endophthalmitis after trabeculectomy at 0.11% and 0.17%, respectively.
Although previous studies have improved our understanding of long-term complications of trabeculectomy, they include patients who have taken topical medications or who have undergone previous surgery. Further, most studies are retrospective. The CIGTS provides a unique opportunity to study the complications of trabeculectomy in previously untreated eyes, because the participants underwent thorough evaluations at regular follow-up intervals and data were collected within the context of a carefully monitored clinical trial. We took advantage of this opportunity to examine the rates of longer-term complications in the trabeculectomy arm of the CIGTS study.
The CIGTS was approved by the University of Michigan Institutional Review Board as well as by the institutional review board at each of the 14 clinical centers. The detailed methodology of the CIGTS has been described previously. Briefly, the CIGTS involved 36 surgeons at 14 clinical centers and was approved by the institutional review boards at each site; written informed consent was obtained from all participants. The study enrolled 607 patients with newly diagnosed open-angle glaucoma and randomized them to initial treatment with either a trabeculectomy or medical therapy. The first eye to be treated with either intervention was designated as the study eye, although if both eyes qualified for the study, the study eye was chosen by the treating ophthalmologist before randomization. Surgery for the contralateral eye was permitted 4 weeks after surgery in the study eye.
Although surgeons in the CIGTS were free to perform a trabeculectomy using their own technique, all surgeons viewed a videotape illustrating the specifics of the procedure (eg, mandating use of an iridectomy). Intraoperative or postoperative use of 5-fluorouracil (5-FU), or both, was permitted in the initial trabeculectomy procedure, whereas use of mitomycin C (MMC) was not permitted. The operative characteristics of the trabeculectomy arm as well as perioperative and 1-month postoperative complications have been reported previously.
Protocol-dictated follow-up visits were conducted at 3 and 6 months after the treatment began and at 6-month intervals thereafter. Data on complications occurring beyond 1-month after surgery were collected from standardized forms that were completed at these follow-up visits. The forms listed a finite number of specific complications and provided the opportunity to record unlisted complications. After tabulation of the frequencies of complications using descriptive statistics, we assessed the time to occurrence after surgery using Kaplan-Meier survival curves. All statistical analyses were conducted using SAS software version 9.2 (SAS Institute, Cary, North Carolina, USA).
Three hundred of the 607 CIGTS patients were randomized to intervention with trabeculectomy. After randomization, 10 patients changed their minds and chose not to undergo initial trabeculectomy. Eight of these patients underwent ALT as the first intervention, whereas 2 patients opted for medications. Four patients had no follow-up either because of death or drop-out before or shortly after treatment, whereas 1 patient had only 9 months of follow-up after a several-year delay in undergoing trabeculectomy, during which other treatment might have been administered. The remaining 285 patients (mean follow-up, 7.2 years; standard deviation, 2.2 years; range, 0.7 to 10.8 years; median, 7.7 years) who underwent trabeculectomy were assessed for long-term complications, which are summarized in Table 1 . Of note, in 247 patients with at least 5 years of follow-up, 50 patients (20.4%) required further treatment for glaucoma (such as argon laser trabeculoplasty, medications, or both) secondary to treatment failure. The most common reason for further treatment was a failure to reach the CIGTS target intraocular pressure (IOP) with trabeculectomy alone.
|CIGTS Trabeculectomy||No. of Patients (%) a|
|Originally randomized to trabeculectomy||300|
|Final trabeculectomy cohort||285 (95)|
|Trabeculectomy only cohort at 5 years (after excluding patients requiring further treatment, including argon laser trabeculoplasty, medications, or repeat trabeculectomy)||197 (79.8)|
|Mitomycin C||4 (1.4)|
|Cataract extraction||57 (20)|
|Bleb revision||40 (14.0)|
|Anterior chamber reformation||7 (2.5)|
|Bleb-related complications||27 (9.5)|
|Bleb Leak||15 (5.3)|
|Endophthalmitis||3 (1.1) b|
|Corneal dellen||4 (1.4)|
|Choroidal detachment||1 (0.4)|
|PVD with vitreomacular traction||1 (0.4)|
|Aqueous misdirection||1 (0.4)|
|Ptosis surgery||1 (0.4)|
|Ophthalmologic emergency room visits||24 (8.4)|
a Percentages are based on the total number of patients in the final trabeculectomy cohort (n = 285), except for the final trabeculectomy cohort, where the denominator was set as the total number of patients initially randomized to trabeculectomy (n = 300). Percentage for the trabeculectomy only cohort at 5 years is based on 247 patients remaining at 5 years.
Of 285 subjects, 163 (57%) received 5-FU and 4 (1%) received MMC (a protocol violation), and the remainder (117; 41%) underwent trabeculectomy without use of an antimetabolite. One patient had missing data for antimetabolite use.
Rates of cataract surgery in patients with trabeculectomy in the CIGTS have been described previously. Briefly, patients in the entire CIGTS cohort (n = 607) who underwent cataract extraction (n = 99) were more likely to have undergone initial treatment with trabeculectomy than with medication ( P = .01). Further, cataract extraction was noted to occur earlier and more frequently in patients randomized to trabeculectomy when compared with the medically managed group. The probability of cataract extraction at 5 years was significantly higher in the surgical group (19% vs 6.5%), but the intergroup differences diminished beyond 5 years. In 285 initial trabeculectomy patients, cataract extraction was performed in 57 patients (20%).
Bleb Status and Bleb-Related Complications
All 285 patients were recorded as having an observable bleb at some point during follow-up, but the number of visits with an observable bleb varied depending on length of follow-up. Bleb status and encapsulation status at 3, 5, and 7 years of follow-up are shown in Table 2 . Most patients with available data at each time point exhibited an observable bleb (≥89.8%) and did not exhibit encapsulation (≥93.3%). Bleb revision was undertaken in 40 patients (14%), with 6 patients requiring revision twice. The estimated average time from randomization to the first bleb revision was 2.0 years (standard deviation, 2.1 years; range, 0.2 to 7.5 years; median, 1.0 years). The CIGTS reporting form did not specify what type of bleb revision was used.
|Bleb Status||No. of Patients (%) a|
|At 3 years of follow-up|
|Patients with bleb data at 36-month visit||243|
|Observable bleb at 36-month visit||227 (93.4)|
|At 5 years of follow-up|
|Patients with bleb data at 60-month visit||222|
|Observable bleb at 60-month visit||202 (91.0)|
|At 7 years of follow-up|
|Patients with bleb data at 84-month visit||157|
|Observable bleb at 84-month visit||141 (89.8)|
|At 3 years of follow-up||240|
|No encapsulation||224 (93.3)|
|Untreated encapsulation||10 (4.2)|
|Encapsulation, treated with medications||0 (0.0)|
|Encapsulation, treated with surgery||5 (2.1)|
|Encapsulation, treated with surgery and medications||1 (0.4)|
|At 5 years of follow-up||218|
|No encapsulation||208 (95.4)|
|Untreated encapsulation||6 (2.8)|
|Encapsulation, treated with medications||1 (0.5)|
|Encapsulation, treated with surgery||3 (1.4)|
|At 7 years of follow-up||152|
|No encapsulation||145 (95.4)|
|Untreated encapsulation||4 (2.6)|
|Encapsulation, treated with medications||1 (0.7)|
|Encapsulation, treated with surgery||2 (1.3)|
Interval hypotony was noted in 4 patients (1 of whom demonstrated hypotony maculopathy), bleb leak was noted in 15 patients, and blebitis was noted in 8 patients. Patients who had interval hypotony exhibited a normal IOP at the protocol visit wherein this was noted, ranging from 15 to 20 mm Hg. The occurrence of blebitis or hypotony was not statistically significantly associated with 5-FU use ( P = 1.00 for both, Fisher exact test). The Kaplan-Meier calculated risks of blebitis ( Figure 1 , Top) and hypotony ( Figure 1 , Middle) at 5 years were both 1.5%.
One patient was noted to have a definitive diagnosis of endophthalmitis. An additional 2 patients were noted to have interval blebitis requiring hospitalization. We are including these 2 patients as having had presumptive endophthalmitis. The Kaplan-Meier calculated risk of endophthalmitis at 5 years was 1.1% ( Figure 1 , Bottom). 5-FU was used during surgery in all 3 of these patients, although there was no statistically significant association with 5-FU use and endophthalmitis ( P = .26, Fisher exact test). It should be noted that these 3 patients did not necessarily exhibit signs of active infection during the protocol visits at which endophthalmitis or blebitis were noted, indicating that the episodes occurred during the interval between follow-up protocol visits. This assumption also is supported by the lack of documented anterior chamber flare or cells at these visits on follow-up forms. Two of these patients, however, did exhibit anterior chamber flare at a subsequent follow-up visit, although none had anterior chamber cells documented at any follow-up visit.
The patient with a definitive diagnosis of endophthalmitis exhibited a significant drop in VA in the protocol visit at which this diagnosis was identified. The VA in the affected study eye dropped to 20/150 from an average of 20/63 in the 7 visits before the diagnosis, but recovered to 20/63 at the next visit and exhibited an average VA of 20/63 in 8 visits after the episode. One of the patients with blebitis requiring hospitalization did not exhibit any changes in VA around the time of presumptive endophthalmitis, whose condition remained stable with an average VA of 20/25 during a 9-year follow-up. The other patient exhibited a drop in VA from 20/25 to 20/50, but recovered to a VA of 20/25, although follow-up was limited to 24 months. No information was available regarding the severity of the definitive or presumptive endophthalmitis diagnoses or the treatment regimens used.
In the 10 patients with endophthalmitis or blebitis (2 patients had endophthalmitis only, 7 patients had blebitis only, and 1 patient had both endophthalmitis and blebitis), there was no statistically significant association between time to endophthalmitis or blebitis and intraoperative 5-FU use ( P = .32, log-rank test from a Kaplan-Meier survival analysis).
Anterior chamber reformation was performed in 7 patients. Four patients exhibited corneal dellen and 3 were noted to have iritis. One patient each exhibited hyphema, aqueous misdirection, keratoconjunctivitis, scleritis or episcleritis, choroidal detachment, posterior vitreous detachment with vitreomacular traction, and ptosis surgery. Twenty-four patients underwent at least 1 emergency room visit for an ophthalmologic reason, although the specific reasons for these visits were not indicated on the follow-up forms.