Oral Ibuprofen is Associated With Reduced Likelihood of Early Bleb Failure After Trabeculectomy in High-Risk Glaucoma Patients : Journal of Glaucoma

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Novel Glaucoma Insights: Original Studies

Oral Ibuprofen is Associated With Reduced Likelihood of Early Bleb Failure After Trabeculectomy in High-Risk Glaucoma Patients

Sim, Jackie Jia Lin*; Man, Ryan Eyn Kidd PhD†,‡,§; Foo, Reuben Chao Ming MMed; Huang, Olivia S. FRCOphth†,§; Betzler, Bjorn Kaijun*; Husain, Rahat FRCOphth†,§; Ho, Ching Lin FRCS(Ed)†,§; Boey, Pui Yi FRCS(Ed)†,§; Perera, Shamira A. FRCOphth†,‡,§; Low, Jin Rong FRCOphth†,‡; Aung, Tin PhD*,†,‡,§; Lamoureux, Ecosse L. PhD†,‡,§,∥¶,¶; Wong, Tina T. PhD*,†,‡,§

Author Information
Journal of Glaucoma 32(4):p 237-244, April 2023. | DOI: 10.1097/IJG.0000000000002188


Trabeculectomy surgery, the most commonly performed incisional surgical procedure for glaucoma,1 is often regarded as the “gold standard” surgical treatment for this disease.2 It aims to reduce intraocular pressure (IOP), which remains the major modifiable risk factor,3 by creating a fistula between the anterior chamber and subconjunctival space through a sclerostomy.4 A major determinant of long-term surgical success lies in the wound healing response, as excessive inflammation can lead to scarring and eventual bleb failure.5 As such, intraoperative antimetabolites such as mitomycin C (MMC) are used to inhibit fibroblasts, in conjunction with postoperative topical corticosteroids to reduce the production of inflammatory mediators, thereby increasing surgical success rates.6,7

Despite these prophylactic interventions, Asian, Afro-Caribbean and Hispanic eyes have been observed to be at significantly higher risk of an aggressive wound-healing response.8,9 Adjunctive treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) is increasingly being viewed as an attractive option in such cases as it offers an alternative pathway to dampen the inflammatory response by inhibiting cyclooxygenase enzymes, with minimal side effects.10

However, there remains sparse and conflicting literature relating to the effectiveness of postoperative administration of NSAIDs in further reducing the risk of bleb failure after trabeculectomy. Early Molteno implant trials were one of the first studies to demonstrate the efficacy of a 6-week adjunctive dose of postoperative oral diclofenac in controlling IOP, a finding that was later replicated in a randomized controlled trial (RCT) by Petrov and colleagues, who administered a 2-week regime of topical nepafenac as an adjunct to topical dexamethasone pretrabeculectomy.11,12 In contrast, an RCT by Cantor et al13 observed no significant difference in postoperative outcomes despite the administration of adjunctive topical flurbiprofen posttrabeculectomy. To address this knowledge gap, we evaluated the independent associations of the early adjunctive use of oral ibuprofen in posttrabeculectomy patients with IOP reduction and bleb failure over 1 year in a retrospective clinical cohort. We hypothesized that the use of early adjunctive oral ibuprofen is associated with a reduced likelihood of bleb failure in eyes at high risk of failure, compared with eyes not administered ibuprofen.


Study Design and Population

Our study was a retrospective, clinical review of patients with glaucoma receiving care at the Singapore National Eye Centre. In brief, we reviewed the medical, pharmaceutical, and intraoperative records of all patients who underwent trabeculectomy or phacotrabeculectomy at Singapore National Eye Centre from April 2020 to April 2021, with a follow-up duration of at least 1 year. A standard Cairn’s type trabeculectomy with sclerostomy creation and scleral flap closure was performed for all patients, either independently by a glaucoma specialist or by a glaucoma fellow under the supervision of a glaucoma specialist. We included patients who were diagnosed with primary open angle glaucoma, primary angle closure glaucoma, and normal tension glaucoma. MMC was routinely used intraoperatively for all surgeries, either through injection of 0.2 mL of 0.2 mg/mL MMC or application of 0.4 mg/mL for 1–3 minutes using a sponge. All patients have prescribed a combination of topical corticosteroids and antibiotics postoperatively as per standard in the institution. During each subsequent clinic visit, the blebs were assessed and IOP was measured by the attending glaucoma specialist for any signs of imminent bleb failure. Clinical signs of early bleb failure included at least one of the following features: increased conjunctival vascularization, low-lying flat blebs, encapsulation of the blebs, presence of tenon cysts, or raised IOP.14 Those at-risk subjects would be started on oral ibuprofen for a minimum of 1 week at a dose of 400 mg Three times a day with concomitant prescription of gastric protective medications such as omeprazole or famotidine, barring any contraindications such as drug allergies or severe renal impairment. Patients diagnosed with secondary glaucoma, or who were administered ibuprofen >3 months posttrabeculectomy for any reason, were excluded from the analyses. The latter was done as the postsurgical inflammatory response should have largely abated after 3 months, and anti-inflammatory drugs are not usually indicated to manage fibrosis after this point. A waiver of informed consent was obtained from the SingHealth Centralized Institutional Review Board (CIRB Reference #2022/2550) due to the retrospective nature of this study, and all data were anonymized before analyses were carried out.

Data Collection

We collected sociodemographic data from the patient’s electronic medical records, including age, sex, and ethnicity. Preoperative details and medical histories such as type of glaucoma, preoperative visual acuity and IOP, type, number and duration of baseline topical glaucoma medications, use of systemic glaucoma medications, pre-existing ocular surface conditions (scarring and ocular surface disease), and history of any previous ocular surgeries or lasers were included. Postoperative data included the use of ibuprofen, duration between surgery and starting ibuprofen, total duration of ibuprofen use, postoperative IOP at week 1, week 2–3, month 1, month 2, month 3, month 6, and year 1, presence and a number of bleb needlings, the type of adjunctive antifibrotic injected [5-fluorouracil (5-FU), MMC, or dexamethasone], duration between surgery and bleb needlings, restarting of topical glaucoma medications, and any laser procedures (ie, trans-scleral cyclophotocoagulation) or repeat surgeries performed. We also tabulated the number of bleb failures, defined as 2 consecutive IOP measurements over 3 stated thresholds (>15 mm Hg, >18 mm Hg, and >21 mm Hg), and/or having had surgery trans-scleral cyclophotocoagulation to resolve uncontrolled IOP after trabeculectomy, based on previously published trial reporting guidelines.

Statistical Analyses

All analyses were performed using STATA 16.1 (StataCorp LP, College Station). Differences in baseline patient characteristics and postoperative variables between individuals who were prescribed oral ibuprofen after trabeculectomy (“ibuprofen group”) versus those who were not (“non-ibuprofen group”) were tested using the independent t test for continuous variables, and the χ2 test and Fisher exact tests for categorical variables. Generalized linear models were then constructed to determine the association between ibuprofen use with change in IOP from baseline across the 7 time points. We also utilized generalized linear models, assuming a log-link function for binary data, to elicit the associations between ibuprofen use and bleb failure at the 3 IOP thresholds. In both cases, we adjusted for baseline and postoperative variables that are known confounders or were significantly different between the ibuprofen and non-ibuprofen groups. This included age, sex, ethnicity, total duration of baseline topical glaucoma medications and oral acetazolamide use, type and a number of antifibrotic agents used for bleb needling and subconjunctival injections, need for postoperative glaucoma medications, and postoperative laser procedures. Because of the small number of individuals prescribed ibuprofen in this study, the backward stepwise selection was utilized for both models, with the threshold for variable removal set at 0.1. Robust standard errors were used to account for any potential clustering effects resulting from high between-eye correlations. Based on previous work and guidelines,15,16 we also tested for potential interactions (ie, effect-modification) between patient sociodemographic variables (age, sex, and ethnicity) and the outcomes. No significant interactions were found; hence no stratified analyses were conducted. A 2-sided P value of <0.05 was considered to be statistically significant.

Sample Size Calculations

Assuming a margin of equivalence of 2 mm Hg between the ibuprofen and the non-ibuprofen groups and based on the current proportion of ibuprofen cases within the study database (~30%), we estimate that we would need 370 total individuals, comprising 111 persons on ibuprofen and 259 not prescribed this oral NSAID, to achieve results at 80% power and the 5% significance level.


A total of 344 eyes of 324 patients with glaucoma who underwent phacotrabeculectomy or trabeculectomy with at least 1 year of follow-up were identified. After excluding 34 patients who were diagnosed with secondary glaucoma, and 16 patients who were administered ibuprofen more than 3 months after trabeculectomy was performed, a total of 288 eyes from 273 eligible patients were eventually included in our final analysis (Table 1).

TABLE 1 - Comparison of Baseline Participant Characteristics Between Eyes Treated With and Without Ibuprofen
Mean (SD)
Parameter All patients, 288 eyes 273 patients; n (%) Without ibuprofen, 211 eyes 200 patients; n (%) With ibuprofen, 77 eyes 73 patients; n (%) P *
Patient demographics
Age (y) 68.56 (10.47) 70.29 (9.50) 63.82 (11.56) <0.001
 Male 184 (67.40) 131 (65.50) 53 (72.60) 0.268
 Female 89 (32.60) 69 (34.50) 20 (27.40)
 Chinese 229 (83.88) 166 (83.00) 63 (86.30) 0.427
 Malay 13 (4.76) 8 (4.00) 5 (6.85)
 Indian 24 (8.79) 20 (10.00) 4 (5.48)
 Others 7 (2.56) 6 (3.00) 1 (1.37)
Type of glaucoma
 POAG 159 (55.21) 120 (56.87) 39 (50.65) 0.322
 PACG 81 (28.12) 60 (28.44) 21 (27.27)
 NTG 48 (16.67) 31 (14.69) 17 (22.08)
 Preopertaive VA 0.42 (0.34) 0.40 (0.31) 0.46 (0.41) 0.253
 Preopertaive IOP 18.44 (6.52) 17.90 (5.78) 19.92 (8.08) 0.045
Type of surgery
Trabeculectomy only 76 (26.39) 61 (28.77) 17 (21.79) 0.242
 Phacotrabeculectomy 212 (73.61) 151 (71.23) 61 (78.21)
Alpha antagonist
 No 81 (28.12) 61 (28.77) 20 (25.64) 0.616
 Yes 207 (71.88) 151 (71.23) 58 (74.36)
Beta blocker
 No 35 (12.15) 26 (12.26) 9 (11.54) 0.869
 Yes 253 (87.85) 186 (87.74) 69 (88.46)
 No 85 (29.51) 59 (27.83) 26 (33.33) 0.379
 Yes 203 (70.49) 153 (72.17) 52 (66.67)
 No 7 (2.43) 3 (1.42) 4 (5.13) 0.088
 Yes 281 (97.57) 209 (98.58) 74 (94.87)
No. eye drops utilized by each patient 3.28 (0.89) 3.29 (0.86) 3.23 (0.97) 0.645
Duration (mo) of use of each type of topical glaucoma eyedrop
 Alpha antagonist 25.34 (30.42) 25.91 (32.08) 23.84 (25.77) 0.649
 Beta blocker 62.18 (58.75) 68.12 (60.15) 46.01 (51.80) 0.005
 Carbonic Anhydrase Inhibitor 38.23 (41.08) 40.88 (41.98) 30.33 (37.54) 0.101
 Prostaglandin analogs 66.21 (54.89) 71.89 (56.79) 50.02 (45.64) 0.002
Total duration (mo) of use of any topical glaucoma eyedrop 68.28 (58.05) 74.54 (59.30) 52.62 (51.48) 0.003
 No 254 (88.19) 189 (89.15) 65 (83.33) 0.185
 Yes 34 (11.81) 23 (10.85) 13 (16.67)
Pre-existing conjunctival scarring
 No 287 (99.65) 211 (99.53) 78 (100.00) NA
 Yes 1 (0.35) 1 (0.47) 0 (0.00)
Pre-existing ocular surface disease
 No 278 (96.53) 205 (96.70) 75 (96.15) 0.829
 Yes 10 (3.47) 7 (3.30) 3 (3.85)
Previous eye operations on the operated eye
 No 233 (80.90) 169 (79.72) 64 (82.05) 0.657
 Yes 55 (19.10) 43 (20.28) 14 (17.95)
Previous eye lasers on the operated eye
 No 193 (67.01) 138 (65.09) 57 (73.08) 0.219
 Yes 95 (32.99) 74 (34.91) 21 (26.92)
*Eye-level characteristics: generalized linear models adjusted for possible clustering effect by eye.
Includes selective laser trabeculoplasty, pan retinal photocoagulation, laser peripheral iridotomy, laser-assisted in situ keratomileusis, photodynamic therapy, and micropulse laser trans-scleral cyclophotocoagulation.
Patient-level characteristics (age, sex, ethnicity, and diagnosis): t test or χ2 test at patient-level.
NA indicates not possible to estimate differences due to null (“0”) value in comparison group.
IOP indicates intraocular pressure; NTG, normal tension glaucoma; PACG, primary angle closure glaucoma; PGA, Prostaglandin analogue; POAG, primary open angle glaucoma; VA, visual acuity.

The mean age of all patients was 68.56 ± 10.47 years, with those on ibuprofen (N = 77 eyes of 73 patients) being significantly younger (63.82 ± 11.56 y) than those not prescribed ibuprofen (N = 211 eyes of 200 patients; 70.29 ± 9.50 y; P < 0.001). Compared with those not on ibuprofen, those on ibuprofen had a significantly higher preoperative IOP (19.92 vs 17.90 mm Hg, P = 0.045) and a significantly shorter duration of use of topical glaucoma eyedrops (52.62 vs 74.54 mo, P = 0.003), especially for beta-blockers and prostaglandin analogs (Table 1). No other significant differences were noted in terms of preoperative characteristics.

Those on oral ibuprofen were started on average at 2.2 ± 2.3 weeks after trabeculectomy for an average total duration of 4.08 ± 2.28 weeks (Table 2). Supplemental Table (Supplemental Digital Content 1, https://links.lww.com/IJG/A727) further shows the breakdown of patients stratified by the number of postoperative days before ibuprofen administration. A greater proportion of patients prescribed ibuprofen underwent early (<3 mo) bleb needling postoperatively compared with those not prescribed ibuprofen (32.47% vs 12.80%, P < 0.001; Table 2); however, the average number of bleb needlings per person did not differ between the 2 groups at any timepoint [all P <0.05 for early, intermediate (3–6 mo) and late (>6 mo); Table 2]. Similarly, individuals in the ibuprofen group were more likely to have undergone ≥1 subconjunctival injection with 5-FU and dexamethasone (9.09% vs 1.42% for 5-FU; 7.79% vs 3.79% for dexamethasone, P=0.007; Table 2), compared with those not on ibuprofen, although the mean number of injections (1.28 ± 0.61 vs 1.50±0.85, P = 0.452) per person again did not differ between the 2 groups. There was also no significant increase in low IOP events requiring remedial surgery, for example, ocular hypotony, between the 2 groups (1.28% vs 2.83%, P=0.446; Table 2).

TABLE 2 - Comparison of Participant Postintervention Characteristics
Mean (SD)
Parameter Without ibuprofen, 211 eyes of 200 patients; n (%) With ibuprofen, 77 eyes of 73 patients; n (%) P *
Total duration (wk) of postoperative ibuprofen given 4.08 (2.28)
No. postoperative months before starting ibuprofen (d) 0.56 (0.58)
Postoperative IOP
 POW1 14.50 (7.10) 14.06 (8.45) 0.687
 POW2–3 15.23 (7.11) 15.72 (6.57) 0.601
 POM1 14.20 (6.49) 14.10 (6.16) 0.901
 POM2 12.37 (6.17) 12.89 (6.03) 0.528
 POM3 11.55 (4.37) 12.40 (5.27) 0.236
 POM6 11.54 (3.92) 11.61 (3.78) 0.898
 POY1 12.27 (3.57) 12.19 (3.53) 0.879
Change in postoperative IOP from preoperative IOP
 POW1 −3.46 (8.51) −5.65 (10.57) 0.108
 POW2–3 −2.46 (8.37) −4.23 (8.86) 0.139
 POM1 −3.75 (8.05) −5.85 (8.30) 0.058
 POM2 −5.64 (8.65) −7.16 (9.63) 0.231
 POM3 −6.45 (6.89) −7.60 (9.16) 0.337
 POM6 −6.39 (7.20) −8.41 (8.37) 0.065
 POY1 −6.03 (6.59) −7.70 (8.29) 0.130
Bleb failure (>21 mm Hg on 2 consecutive visits)
 No 166 (78.67) 62 (80.52) 0.733
 Yes 45 (21.33) 15 (19.48)
Bleb failure (>18 mm Hg on 2 consecutive visits)
 No 142 (67.30) 57 (74.03) 0.274
 Yes 69 (32.70) 20 (25.97)
Bleb failure (>15 mm Hg on 2 consecutive visits)
 No 94 (44.55) 38 (49.35) 0.469
 Yes 117 (55.45) 39 (50.65)
 POD1 VA 0.67 (0.67) 0.58 (0.47) 0.170
Change in POD1 VA compared with preoperative VA 0.27 (0.64) 0.11 (0.38) 0.011
Intraoperative complications
 No 210 (99.06) 78 (100.00) NA
 Yes 2 (0.94) 0
Bleb needling
 Total 43 (20.75) 28 (37.18) <0.001
 Fluorouracil 12 (5.69) 0
 MMC 22 (10.43) 21 (27.27)
 Dexamethasone 9 (4.27) 7 (9.09)
No. bleb needlings (per person) 1.40 (0.65) 1.72 (0.84) 0.077
Early bleb needling (0–<3 mo)
 Total 28 (12.80) 25 (32.47) <0.001
 Fluorouracil 7 (3.32) 0
 MMC 16 (7.58) 19 (24.68)
 Dexamethasone 4 (1.90) 6 (7.79)
No. bleb needlings (per person) 1.21 (0.49) 1.45 (0.73) 0.189
Intermediate bleb needling (3–6 mo), yes
 Total 13 (6.16) 7 (9.09) 0.221
 Fluorouracil 2 (0.95) 0
 MMC 6 (2.84) 6 (7.79)
 Dexamethasone 5 (2.37) 1 (1.30)
No. bleb needlings (per person) 1.00 (0.00) 1.14 (0.37) 0.292
Late bleb needling (>6 mo)
 Total 14 (6.64) 1 (2.60) 0.308
 Fluorouracil 5 (2.37) 0
 MMC 8 (3.79) 1 (1.30)
 Dexamethasone 1 (0.47) 1 (1.30)
No. bleb needlings (per person) 1.07 (0.26) 1.00 (0.00) 0.315
Subconjunctival injection of antifibrotics
 Total 14 (6.64) 14 (18.18) 0.007
 Fluorouracil 3 (1.42) 7 (9.09)
 MMC 3 (1.42) 1 (1.30)
 Dexamethasone 8 (3.79) 6 (7.79)
No. subconjunctival injections of antifibrotics (per person) 1.5 (0.85) 1.28 (0.61) 0.452
Use of glaucoma medications postoperative
 No 157 (74.41) 55 (71.43) 0.612
 Yes 54 (25.59) 22 (28.57)
Uncontrolled IOP requiring repeat laser
 No 210 (99.53) 77 (100.00) 0.545
 Yes 1 (0.47) 0
Uncontrolled IOP requiring repeat surgery§
 No 210 (99.53) 77 (100.00) NA
 Yes 1 (0.47) 0
Low IOP requiring surgery
 No 206 (97.17) 77 (98.72) 0.446
 Yes 6 (2.83) 1 (1.28)
Any intervention done postoperative to lower IOP
 No 127 (60.19) 36 (46.75) 0.042
 Yes 84 (39.81) 41 (53.25)
Bold values indicate P <0.05.
*Eye-level characteristics: generalized linear models adjusted for possible clustering effect by eye.
Excluding postoperative day 1 visit, also includes need for additional surgery and/or laser (trans-scleral cyclophotocoagulation) for uncontrolled intraocular pressure.
Trans-scleral cyclophotocoagulation.
§Repeat trabeculectomy.
Includes glaucoma medication, repeat laser or repeat surgery.
NA indicates not possible to estimate differences due to null (“0”) value in comparison group.
IOP indicates intraocular pressure; MMC, mitomycin C; POD1, Post-operative day 1; POM1, Post-operative month 1; POW1, Post-operative week 1; POY1, Post-operative year 1; VA, visual acuity.

In multivariable analyses, all patients experienced significant reductions in IOP across all postoperative time points charted. However, the ibuprofen group consistently registered a greater IOP reduction from baseline compared with those not on ibuprofen, reaching significance at postoperative week 1 (mean difference: −2.89 mm Hg, 95% CI: −5.22 to −0.56, P = 0.015) and month 1 (−2.29 mm Hg, 95% CI: −4.53 to −0.05, P = 0.045) timepoints as compared with those not on ibuprofen (Table 3 and depicted graphically in Fig. 1). We further observed that ibuprofen use was significantly associated with lower odds of bleb failure when failure threshold was defined as 2 consecutive IOP readings >18 mm Hg (OR: 0.39, 95% CI: 0.20–0.79, P = 0.009) and >15 mm Hg (odds ratio: 0.52, 95% CI: 0.29–0.94, P = 0.032), but not at the >21 mm Hg threshold (odds ratio: 0.53, 95% CI: 0.25–1.10, P = 0.088), although a nonsignificant reduction in the likelihood of failure was observed (Table 4).

TABLE 3 - Association Between Postsurgical Change in Intraocular Pressure and Postoperative Adjuvant Treatment With Ibuprofen
Mean (SE)
IOP change from baseline (mm Hg) No ibuprofen* Percentage reduction from baseline Ibuprofen Percentage reduction from baseline§ Between group difference (95% CI) P
1 wk −3.46 (0.62) 19.33 −5.65 (1.23) 28.36 −2.89 (−5.22, −0.56) 0.015
2–3 wk −2.46 (0.65) 13.74 −4.23 (1.02) 21.23 −1.13 (−3.52, 1.26) 0.355
1 mo −3.75 (0.58) 20.95 −5.85 (0.94) 29.37 −2.29 (−4.53, −0.05) 0.045
2 mo −5.64 (0.65) 31.51 −7.16 (1.09) 35.94 −0.97 (−3.55, 1.60) 0.459
3 mo −6.45 (0.49) 36.03 −7.60 (1.10) 38.15 −1.29 (−3.54, 0.96) 0.261
6 mo −6.39 (0.51) 35.70 −8.41 (0.98) 42.22 −1.98 (−4.14, 0.17) 0.072
1 y −6.03 (0.50) 33.69 −7.70 (0.98) 38.65 −1.20 (−3.33, 0.92) 0.266
Bold values indicates P <0.05.
*Adjusted for age, sex, race, total duration of medication use at baseline, type and number of early bleb needling (<3 mo) with antifibrotic agent used, type of subconjunctival antifibrotic injection agent used, postoperative glaucoma medication prescribed (yes/no), postoperative laser done (yes/no), using stepwise selection.
Predicted means from generalized linear mixed models adjusted for potential clustering effect by study eye.
Calculated from mean preoperative IOP of 17.95 mm Hg.
§Calculated from mean preoperative IOP of 20.00 mm Hg.
All changes from baseline were statistically significant using paired t tests.
Tests for interaction were done for sex and race.
IOP indicates intraocular pressure.

Postoperative intraocular pressure reduction of non-ibuprofen group versus ibuprofen group. Adjusted for age, sex, race, total duration of medication use at baseline, bleb needling done (yes/no), subconjunctival antifibrotic injection done (yes/no), postoperative glaucoma medication prescribed (yes/no), postoperative laser done (yes/no), using stepwise selection.
TABLE 4 - Multivariable Adjusted* Association Between Ibuprofen and Bleb Failure
OR (95% CI)
IOP >21 mm Hg P IOP >18 mm Hg P IOP >15 mm Hg P
No ibuprofen Reference Reference Reference
Ibuprofen 0.53 (0.25, 1.10) 0.088 0.39 (0.20, 0.79) 0.009 0.52 (0.29, 0.94) 0.032
Bold values indicates P <0.05.
*Adjusted for age, sex, race, total duration of preoperative medication use, type of early bleb needling with antifibrotic agent used (<3 mo), type of subconjunctival antifibrotic injection agent used, postoperative glaucoma medication prescribed (yes/no), using stepwise selection.
Defined as any 2 consecutive readings above the stated IOP thresholds and/or need for corrective surgery/laser (ie, trans-scleral cyclophotocoagulation) for uncontrolled IOP.
Tests for interaction was done for sex and race.
IOP indicates intraocular pressure; OR, odds ratio.


Our study found that the use of adjunctive oral ibuprofen in patients at high risk of early bleb failure posttrabeculectomy resulted in greater levels of IOP reduction and a reduced likelihood of experiencing bleb failure up to a year posttrabeculectomy, compared with patients who were not prescribed ibuprofen. In addition, we did not observe any significant increase in severe adverse events related to low IOP between the 2 groups. Despite the lack of statistical power, our results suggest that starting adjunctive oral ibuprofen early may be a potential low-risk management strategy to decrease the likelihood of bleb failure in high-risk individuals.

Our findings are consistent with early trials of Molteno and Dempster11 implants, which showed that the addition of an oral NSAID (diclofenac) on top of oral prednisone, prescribed for a duration of about 6 weeks to all patients regardless of the risk of bleb failure, produced a synergistic anti-inflammatory effect that greatly reduced bleb inflammation and provided better postoperative IOP control than using oral steroids alone. Similarly, an RCT by Petrov et al12 showed that patients who have prescribed a combination of topical nepafenac and dexamethasone for 2 weeks before trabeculectomy had a less frequent need for postoperative needling, remedial hypotensive therapy, and a greater likelihood of complete trabeculectomy success in the first postoperative year, compared with patients on topical dexamethasone only. In contrast, Cantor et al13 did not find any additional benefit to using topical flurbiprofen on top of topical prednisolone after trabeculectomy in terms of postoperative IOP and visual acuity. We suspect that the differences in outcomes may be because of the differences in type, dosage, and method and timing of administration of the NSAIDs used. Moreover, Cantor’s study was limited by a high attrition rate (~28.6%) over its follow-up period. Larger-scale RCTs evaluating the efficacy of adjunctive oral NSAID administration in improving posttrabeculectomy outcomes are therefore warranted to confirm the validity of our findings.

Patients who have prescribed a course of ibuprofen in our study were deemed to have a higher risk of bleb failure and a greater proinflammatory and scarring profile. Despite the higher risk of bleb failure in the ibuprofen group, which would typically require multiple bleb needling interventions to rescue, the total number of bleb needlings that the 2 groups underwent remained similar over the 1-year follow-up duration, even during the early postoperative period (<3 mo), suggesting that the adjunctive treatment with ibuprofen may play a role in reducing the need for multiple instances of needling in eyes at high risk of early subconjunctival scarring. Moreover, the lack of serious adverse events related to low IOP, such as ocular hypotony consequent to bleb leaks, supports the relatively low risk of ibuprofen administration. Of note, the significantly greater IOP reductions observed in the ibuprofen group at week 1 may be misleading as only ~30% of the ibuprofen group had been prescribed the medication at this time; the greater decrease observed may simply reflect these patients’ higher preoperative IOP levels and, therefore, represent a regression to the mean. In contrast, the reduced risk of bleb failure by absolute IOP criteria suggests that the effect may be real. These results warrant more in-depth RCT studies to validate the efficacy of early adjunctive oral ibuprofen to rescue failing blebs.

The observed synergistic effect of ibuprofen in combination with topical steroids observed in our study may be explained by the different mechanisms of action that steroids and NSAIDs use to block the synthesis of inflammatory mediators.17 Steroids inhibit the action of phospholipase-A2 and the subsequent release of arachidonic acid, preventing its metabolism, whereas ibuprofen inhibits the conversion of available arachidonic acid to leukotrienes and prostaglandins as explained.18 Moreover, although oral NSAIDs are almost always prescribed with gastro-protection (eg, omeprazole), there is no evidence that their anti-inflammatory effects are modulated by this class of gastro-protective drugs.19 All things considered, the synergistic effect of oral NSAIDs with routinely prescribed posttrabeculectomy topical steroid regimes, together with their relatively benign side-effect profile, further supports their use as adjunctive treatment to safely manage posttrabeculectomy outcomes in routine clinical care.

Strengths of our study include it being an audit of trabeculectomies performed in a real-world clinical setting, with a comprehensive list of patient sociodemographic and clinical characteristics, enabling detailed multivariable statistical models to be constructed. Therefore, not only does our study sample resemble that of real-world clinical populations, but it also reflects the decision-making process that clinicians go through on a day-to-day basis, ensuring the generalizability of results. However, our study also had some limitations. Firstly, our study did not reach sufficient statistical power as the number of recruited patients in our study fell short of the optimal number derived from sample size calculations, which prevented us from conducting further stratified analyses, for example, by the type of glaucoma. Secondly, our study design did not allow us to establish a definitive cause-and-effect relationship between the use of oral ibuprofen and the reduced likelihood of bleb failure, nor could we eliminate the effects of selection bias.20 Thirdly, even though multivariable analyses were conducted in an attempt to adjust for the effects of potential confounders, for example, the number and type of antifibrotic agents used in needling and subconjunctival injections, not all information were readily available, for example, visual fields data, hence resulting in residual confounding that may be unaccounted for. Fourthly, the retrospective nature of this analysis did not permit us to include any photos or utilize a formal bleb grading system, that would have allowed us to assess the effects of oral ibuprofen on bleb morphology. Finally, we were unable to ascertain if patients self-administered ibuprofen or other NSAIDs postoperatively for other conditions given that ibuprofen is readily available as an over-the-counter medication, or whether patients prematurely discontinued the ibuprofen themselves without informing the clinician due to the side effects, which could potentially result in spurious associations. Our findings should hence be interpreted with caution.


Early adjunctive oral ibuprofen use in patients at risk of posttrabeculectomy bleb failure is associated with greater postoperative IOP reduction and a lower likelihood of bleb failure, as compared with patients not prescribed ibuprofen. We suggest that starting oral NSAIDs early is a potentially low-risk intervention for clinicians, for managing blebs at high risk of scarring and subsequent failure. Future studies using an RCT design are warranted to explore and confirm our findings.


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glaucoma; trabeculectomy; NSAIDs; ibuprofen; inflammation; restrospective study

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