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The PRESERFLO MicroShunt is an 8.5-mm-long (70-µm lumen) controlled ab externo filtration surgery device made from poly[styrene-block-isobutylene-block-styrene] (SIBS). Three prospective, open-label clinical trials (ClinicalTrials.gov Identifiers: NCT00772330; NCT01563237; NCT02177123) evaluated the 2-year effectiveness and safety of MicroShunt implantation plus mitomycin C (MMC). This pooled analysis compared outcomes in patients receiving 0.2 or 0.4 mg/ml MMC during MicroShunt implantation.
Methods
Patients aged 18–85 years with primary open-angle glaucoma (intraocular pressure [IOP] 18–35 mmHg) uncontrolled on maximal tolerated medical therapy and/or where glaucoma progression warranted surgery who underwent MicroShunt implantation with/without cataract surgery, and with adjunctive use of 0.2 or 0.4 mg/ml MMC. Two-year outcomes included changes in IOP and glaucoma medications, complete success rates (IOP ≥ 6 to < 14 mmHg or ≥ 20% reduction, without medications), and rates of procedure/device-related adverse events (AEs) and serious AEs (SAEs).
Results
Of the 125 included patients, 58 received 0.2 mg/ml MMC and 67 received 0.4 mg/ml MMC). Mean percent reduction in IOP was significantly greater in patients receiving 0.4 than 0.2 mg/ml MMC (− 40.9% vs. − 34.5%, P < 0.05). Mean glaucoma medication use was reduced to a lower level between baseline and year 2 in the 0.4 than in the 0.2 mg/ml MMC group. At year 2, the percentage of medication-free patients (85.2% vs. 58.0%, P < 0.01) and the complete success rates (71.6% vs. 48.3%, P < 0.01) were significantly higher in the 0.4 than in the 0.2 mg/ml MMC group. Rates of procedure/device-related AEs and SAEs did not differ significantly in the two groups (P > 0.05).
Conclusions
IOP and glaucoma medication use at year 2 were lower, and complete success rate was higher, in patients administered 0.4 mg/ml than 0.2 mg/ml MMC. Although there is no consensus on the optimal concentration of MMC, these findings may guide surgeons until further evidence from controlled trials becomes available.
Prior Presentation: (i) Batlle JF, Beckers HJM, Riss I, et al. A 2-year pooled analysis of the MicroShunt in patients with primary open-angle glaucoma. Presented at the 36th Asia–Pacific Academy of Ophthalmology (APAO) virtual congress (202,171). (ii) Batlle JF, HJM Beckers HJM, Riss I. A 2-year pooled analysis of the MicroShunt in patients with primary open-angle glaucoma. Poster presented at the Canadian Ophthalmological Society (COS) Virtual Annual Meeting; 2021. Riss I, Batlle JF, García-Feijoó J, et al. Effect of lens status at baseline on surgical outcomes following MicroShunt implantation in patients with primary open-angle glaucoma: a 2-year pooled analysis. Poster presented at the 14th European Glaucoma Society (EGS) virtual congress; 2020 (P299). (iii) Aptel F, García-Feijoó J, Beckers HJM, et al. Outcomes of bleb needling in patients with primary open-angle glaucoma implanted with the MicroShunt. Poster presented at the 14th European Glaucoma Society (EGS) virtual congress; 2020 (P307). (iv) Beckers HJM, Battle JF, García-Feijoó J, et al. Two-year pooled safety outcomes from three studies following MicroShunt implantation in patients with primary open-angle glaucoma (POAG). Poster presented at the 10th International Congress on Glaucoma Surgery (ICGS); London, UK, 2020 (P052). (v) Batlle JF, Beckers HJM, Riss I. Pooled 1-year outcomes in patients with low intraocular pressure following MicroShunt implantation. Poster presented at the American Academy of Ophthalmology (AAO) congress; San Francisco, CA, USA, 2019 (PO218). (vi) Aptel F, Batlle JF, Beckers HJM, et al. Effect of baseline IOP on MicroShunt outcomes in POAG: a 2-year pooled analysis. Poster presented at the American Academy of Ophthalmology (AAO) congress; San Francisco, CA, USA, 2019 (PO171). (vii) Sadruddin O, Beckers HJM, Riss I, et al. Unique properties and 2-year pooled outcomes of the PRESERFLO® MicroShunt in patients with primary open-angle glaucoma. Poster presented at the Advances in Glaucoma Research and Clinical Science (AGRCS) congress; Amsterdam, The Netherlands, 2019 (21–43630). (viii) Aptel F, Batlle JF, Beckers HJM, et al. One-year results from a pooled analysis of three studies assessing the MicroShunt in patients with primary open-angle glaucoma with low or high preoperative intraocular pressure. Oral presentation at the 37th Congress of the European Society of Cataract & Refractive Surgeons (ESCRS); Paris, France, 2019. (ix) Batlle JF, Beckers HJM, Riss I. A 2-year pooled analysis of the MicroShunt in patients with primary open-angle glaucoma. Oral presentation at the American Society of Cataract and Refractive Surgery (ASCRS) congress; San Diego, CA, USA, 2019. (x) García-Feijoó J, Batlle JF, Riss I, et al. A 2-year pooled analysis of the MicroShunt in patients with primary open-angle glaucoma (POAG): 0.2 vs. 0.4 mg/ml Mitomycin C (MMC) outcomes. Poster presented at the World Glaucoma Congress (WGC); Melbourne, Australia, 2019 (P-FS-133). (xi) García-Feijoó J, Aptel F, Batlle JF, et al. The MicroShunt glaucoma drainage system in patients with primary open-angle glaucoma: 2-year pooled analysis. Poster presented at the American Academy of Ophthalmology (AAO) congress; Chicago, IL, USA, 2018 (PO388). (xii) Beckers HJM, Kujovic-Aleksov S, Webers CAB, et al. One-year results of a three-site study of the InnFocus MicroShunt. Poster presented at the Netherlands Ophthalmology Society (NOG) congress; Maastricht, Netherlands, 2017.
Key Summary Points
Why carry out this study?
Three similarly designed studies analyzed the 2-year effects on intraocular pressure and glaucoma medication use of MicroShunt implantation with application of 0.4 mg/ml or 0.2 mg/ml mitomycin C.
Pooled analysis of these results may provide insight into the efficacy and safety of MicroShunt implantation with mitomycin C application.
What was learned from this study?
Intraocular pressure and medication use were significantly lower at 2 years following MicroShunt implantation with 0.4 mg/ml than 0.2 mg/ml mitomycin C.
No patient showed evidence of blebitis, endophthalmitis, implant extrusion, or long-term sight-threatening adverse events.
Outcomes were not evaluated according to the duration of mitomycin C application.
Introduction
Glaucoma is a leading cause of blindness worldwide [1‐3]. Intraocular pressure (IOP) is an important modifiable risk factor for glaucoma and is targeted for reduction to prevent disease progression [3‐5]. Glaucoma treatment initially consists of topical and/or oral medications; however, adherence remains a concern, with 30–70% of patients not adhering to treatment [4, 5]. Laser therapy is another possible treatment option [4‐6], but it is not always sufficient at all stages of open-angle glaucoma [7].
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When medical treatment or laser surgery inadequately controls IOP and glaucoma progression, incisional surgery, such as trabeculectomy, may be considered [4, 5]. Traditional trabeculectomy, however, has been associated with significant risks of vision-threatening hypotony, bleb-related complications, and endophthalmitis, with many patients resuming medical treatment within 5 years [8]. Minimally invasive bleb-forming surgery (MIBS), using two subconjunctival-based bleb-forming devices, the PRESERFLO MicroShunt and XEN, has been found to reduce IOP and glaucoma medication use in patients with primary open-angle glaucoma (POAG), while also demonstrating low complication rates [9, 10]. These devices are implanted either ab interno or ab externo; however, greater outflow resistance and variability in bleb formation have been observed following the ab interno approach [11].
The MicroShunt is a controlled ab externo glaucoma filtration surgery device, measuring 8.5 mm in length and with a 70-µm lumen [12]. This device is made from poly[styrene-block-isobutylene-block-styrene] or ‘SIBS’, a highly biocompatible and bioinert material [13, 14]. It is designed to drain aqueous humor from the anterior chamber to a bleb in the sub-Tenon’s space [12, 14].
The effectiveness and safety of MicroShunt implantation with mitomycin C (MMC) was evaluated across three prospective, single-arm, open-label studies [15‐17]. Based on the findings from a study conducted in 23 patients in the Dominican Republic, the MicroShunt was approved in 2012 by the Conformité Européenne (CE) for the reduction of IOP in the eyes of patients with POAG for whom IOP remains uncontrolled on maximal tolerated medical therapy and/or where glaucoma progression warrants surgery [12, 14, 18]. This device also gained regulatory approval in Canada, Australia and New Zealand, Japan, and other countries in Latin America and Asia [19]. Two sponsored studies were initiated to determine the effectiveness and safety of the MicroShunt in a larger patient population. One study was conducted at a single site in France, whereas the second study was a post-market, multicenter study conducted in France, Spain, Switzerland, and the Netherlands [15, 17]. The methodology and results for each study have been previously reported (Supplementary Table 1) [12, 20‐22]. The concentrations of MMC varied slightly among studies. Although patients in one study received 0.4 mg/ml MMC during the surgical procedure [12], MMC concentration in a second study differed among study sites, with 0.2 mg/ml MMC applied at three sites (two sites for 2 min and one site for 3 min), 0.4 mg/ml MMC applied at two sites (one site each for 2 and 3 min), and 0.28 mg/ml MMC applied at one site for 2 min [21]. Patients in a third study were administered 0.2 or 0.4 mg/ml MMC at the discretion of the investigator on a case-by-case basis. IOP-lowering and associated outcomes varied among studies, indicating the need to further evaluate the impact of MMC concentration on MicroShunt outcomes.
Despite the differences in MMC concentrations used in these studies, similarities in other parameters, including patient cohorts, surgical procedures, and study duration, suggested the need for a post hoc retrospective analysis of pooled data from these three studies. The authors of these three studies therefore retrospectively analyzed the effects of MMC concentration (0.2 vs. 0.4 mg/ml) on 2-year effectiveness and safety outcomes in patients with POAG who underwent MicroShunt implantation.
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Methods
Study Design
This post hoc pooled analysis evaluated the effectiveness and safety of the MicroShunt in patients with POAG who participated in three prospective, open-label studies (two single arm and one multicenter) over 2 years (ClinicalTrials.gov Identifiers [Study Identifiers]: NCT00772330 [INN003]; NCT01563237 [INN004]; NCT02177123 [INN007]). The data collected were from three sites in France and one site each in the Netherlands, Spain, Switzerland, and the Dominican Republic [15‐17]. Outcomes were evaluated retrospectively according to the MMC concentration (0.2 vs. 0.4 mg/ml) used during the surgical procedure. Outcomes, however, were not evaluated according to duration of MMC application (2 vs. 3 min). Patients in these three studies were enrolled between October 2007 and November 2017 [15‐17]. Patients were assessed at baseline, and followed up on day 1, day 7, week 3 (INN003 and INN004 only), week 4 (INN007 only), week 6 (INN003 and INN004 only), month 3, month 6, month 9, year 1, and year 2.
The individual studies were conducted in line with the principles of the Declaration of Helsinki and the following medical device standards: CFR 21 (INN003 only), MEDDEV 2.12-1 and MEDDEV 2.12/2 revision 2 (INN007 only), MEDDEV 2.7/1 and the European Directive 93/42/EEC (INN004 and INN007 only), and EN ISO 14155 (INN003, INN004, and INN007). Each study site obtained institutional review board approval. Informed consent was gained from all patients prior to enrollment in the individual studies.
Patients
Patients (aged 18–85 years) with POAG (IOP 18–35 mmHg) uncontrolled on maximal tolerated medical therapy and/or where glaucoma progression warranted surgery were enrolled across the individual studies and included in this dataset. Patients were excluded from the individual studies if they met any of the following criteria: absence of light perception, history of incisional ophthalmic surgery (excluding uncomplicated cataract and corneal refractive surgery), and/or need or potential need for glaucoma surgery plus an ocular procedure other than cataract surgery during the study period. The key inclusion and exclusion criteria for each study have been previously published [15‐17, 20‐22].
Procedure and Assessments
The surgical procedure used in each study is described in the individual publications [20‐22]. In brief, the MicroShunt was implanted ab externo via a 90–120° fornix-based incision that was approximately 8 mm deep in accordance with the Peng-Khaw technique for bleb-forming surgery [23]. MMC, at a concentration of 0.2 or 0.4 mg/ml, was applied to the scleral surface for 2–3 min using three round LASIK shield sponges, after which the scleral surface was rinsed with a balanced salt solution prior to device insertion. The choice of MMC concentration and duration of application was at the discretion of each investigator. The scleral incision site for the formation of the scleral tunnel was approximately 3 mm posterior to the limbus, as instructed by the manufacturer.
Study Measures
Goldmann applanation tonometry was used to derive the IOP at each study visit, except when irregular corneal astigmatism, scarring, or edema precluded an accurate reading, with Tono-Pen (Mentor/Medtronic) or non-contact tonometry used as an alternative measure in these patients. Safety of the MicroShunt was assessed at each study visit using slit-lamp examination. Monoyer visual acuity (VA) was measured using a standard VA chart; the data were converted to Snellen’s VA, if required, for the purpose of this analysis.
Endpoints
The primary effectiveness endpoints in the INN003, INN004, and INN007 studies were the IOP reduction compared to baseline, and complete/qualified success, at year 1 [12, 15, 21]. Secondary endpoints included the change in glaucoma medication use at years 1, 2, and 3 (INN003 only). The rates of procedure- and device-related adverse events (AEs) were also reported throughout each study.
This pooled analysis retrospectively evaluated the IOP reduction from baseline, as well as success rates, at year 2. Success was defined as the absence of pressure or surgical failure with (qualified) or without (complete) glaucoma medication. Pressure failure was defined as an IOP outside the target range (≥ 6 mmHg and < 14 mmHg) or a less than 20% reduction below baseline on two consecutive scheduled follow-up visits after 3 months, and a less than 20% reduction below baseline at the last visit at which success was reported. Surgical failure was defined as a need for reoperation, except for bleb needling, in the operating room. Overall success was defined as success with or without glaucoma medication use. Complete success was defined as success without glaucoma medication use. Both success rates are reported herein. Change in the number of glaucoma medications per patient from baseline to year 2 was also evaluated in the 0.2 and 0.4 mg/ml MMC groups. Safety outcomes included rates of procedure/device-related AEs and serious AEs (SAEs), as determined by the investigator; change in VA from baseline to year 2 (also an efficacy outcome); and rates of bleb needling, reoperation, and bleb revision.
Statistical Methods
Following database lock, statistical analyses were performed with SAS System Version 9.1 or higher (Buckinghamshire, UK). The present study included the patients from previous studies with an IOP ≥ 18 and ≤ 35 mmHg, no protocol deviations, and at least one IOP score collected at month 6 or later. Because the first 43 patients in the INN004 trial were treated prior to the adoption of a standard treatment involving MMC application throughout the flap, these patients were excluded from the present analysis to maintain consistency in the surgical procedure used in the three studies.
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Quantitative endpoints were reported as mean ± standard deviation (SD) or as median (interquartile range [IQR]). The number of glaucoma medications at each visit was calculated based on medication start/end dates, visit date, and study exit date. Procedure/device-related AEs, SAEs, needlings, reoperations, and bleb revisions were reported by the investigators from baseline to the year 2 visit or day 730 if the year 2 visit was missing. Data collected after reoperation were excluded from this analysis. Owing to the differences in the number of visits among studies, week 3 and week 6 data are presented for INN003 and INN004: and week 4 data are presented for INN007.
Qualitative endpoints were reported as a number and/or percentage. Descriptive summaries were based on observed cases; any missing IOP scores were imputed using the last observed IOP score to calculate success rates at year 2. Missing AE start dates were imputed as the MicroShunt surgery date to derive the resolution time, if required. Summary statistics for the time to resolution were missing if any AE mapped to the corresponding preferred term had a missing end date (i.e., was ongoing at study exit).
Post hoc continuous variables were compared by two-sample t tests, and categorical variables were compared by the chi-squared or Fisher’s exact test, as appropriate. Comparisons were not adjusted for potential confounding factors, such as baseline IOP/glaucoma medications, MMC doses, sites, or multiplicity.
Results
Study Patients
A total of 147 patients underwent MicroShunt surgery across the three studies between October 2007 and November 2017; the present analysis included 125 patients (Fig. 1); the remaining 22 patients were excluded from the pooled analysis because they did not undergo what has become the standard procedure (e.g., they did not receive 0.2 or 0.4 mg/ml MMC). Of the 125 included patients, 58 received 0.2 mg/ml MMC and 67 received 0.4 mg/ml MMC during the surgical procedure. Six patients in each group discontinued the individual studies owing to an AE, medical reason, loss of follow-up, or withdrawal of consent. One patient in the 0.4 mg/ml MMC group died during study participation for reasons unrelated to the surgical procedure or device. Mean Snellen VA score at baseline was 20/26 (mean ± SD, logarithm of the minimum angle of resolution [LogMAR] 0.1 ± 0.2; n = 58) in the 0.2 mg/ml MMC group and 20/30 (mean ± SD LogMAR 0.4 ± 0.8; n = 67) in the 0.4 mg/ml MMC group (P = 0.02; Table 1). Other baseline demographic and clinical characteristics were similar in the two groups.
Baseline demographic and clinical characteristics of patients included in this study (per-protocol population)
0.2 mg/ml MMC
(n = 58)
0.4 mg/ml MMC
(n = 67)
Mean ± SD age, years
65.3 ± 12.5
62.9 ± 13.5
Male, n (%)
28 (48.3)
36 (53.7)
Lens status, n (%)
Phakic
39 (67.2)
50 (74.6)
Pseudophakic
19 (32.8)
17 (25.4)
MicroShunt implantation plus cataract surgery
11 (19.0)
11 (16.4)
Mean medicated IOP, mmHg ± SD
22.7 ± 4.4
22.2 ± 4.0
IOP 18 and 21 mmHg, n (%)
29 (50.0)
35 (52.2)
IOP > 21 mmHg, n (%)
29 (50.0)
32 (47.8)
IOP, mmHg, median (IQR)
21.5 (6.5)
21.0 (5.5)
Mean ± SD number of glaucoma medications
2.4 ± 1.3
2.1 ± 1.2
Number of glaucoma medications, median (IQR)
2.5 (2.0)
2.0 (2.0)
Snellen’s mean ± SD VA (LogMAR)
20/26 (0.1 ± 0.2)
20/30 (0.4 ± 0.8)
IOP intraocular pressure, IQR interquartile range, LogMAR logarithm of the minimum angle of resolution, MMC mitomycin C, SD standard deviation, VA visual acuity
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IOP Outcomes
Mean ± SD IOP in the 0.4 mg/ml MMC group was reduced between baseline (22.2 ± 4.0 mmHg [n = 67]) and year 2 (13.0 ± 3.4 mmHg [n = 53]) with an absolute decrease of 9.6 ± 5.2 mmHg (40.9%). Mean ± SD IOP in the 0.2 mg/ml MMC group was reduced between baseline (22.7 ± 4.4 mmHg [n = 58]) and year 2 (14.8 ± 4.5 mmHg [n = 50]) with an absolute decrease of 8.2 ± 5.5 mmHg [34.5%]). Significant between-group differences in IOP were observed at week 3, week 6, and from month 6 onward (all P < 0.05; Fig. 2A and B).
Fig. 2
Determination of intraocular pressure over time in patients administered 0.2 and 0.4 mg/ml MMC. A Mean IOP from baseline to year 2. B Mean and median IOP over 2 years of follow-up (per-protocol population). IOP intraocular pressure, MMC mitomycin C
Overall, greater reductions in IOP were observed in patients who received MicroShunt implantation with cataract surgery than standalone implantation (Supplementary Table 2). Furthermore, IOP outcomes were more improved at year 2 in the 0.4 than in the 0.2 mg/ml MMC group, irrespective of combination with cataract surgery.
Success Rates
Overall success rates (IOP target range: ≥ 6 and < 14 mmHg) were greater in the 0.4 than in the 0.2 mg/ml MMC group at years 1 (74.6% [50/67] vs. 70.7% [41/58]) and 2 (77.6% [52/67] vs. 74.1% [43/58]), although these differences were not statistically significant (P > 0.05). The probability of success over time is summarized in Fig. 3. In total, a greater percentage of patients in the 0.2 than in the 0.4 mg/ml MMC group were regarded as experiencing pressure failures at years 1 (29.3% [17/58] vs. 20.9% [14/67]) and 2 (24.1% [14/58] vs. 17.9% [12/67]).
Fig. 3
Kaplan–Meier analysis of the overall probabilities of success, defined as an IOP ≥ 6 and < 14 mmHg, in patients treated with 0.2 and 0.4 mg/ml MMC from baseline to year 2 in the per-protocol population. IOP intraocular pressure, MMC mitomycin C
Complete success rates (without medication) were higher in the 0.4 than in the 0.2 mg/ml MMC group at year 1 (65.7% [44/67] vs. 50.0% [29/58], P = 0.08) and year 2 (71.6% [48/67] vs. 48.3% [28/58]; P < 0.01). Greater overall and complete success rates were reported at years 1 and 2 in patients who underwent MicroShunt implantation with than without cataract surgery in both the 0.4 and 0.2 mg/ml MMC groups (Supplementary Table 3).
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Glaucoma Medication Outcomes
Mean ± SD number of glaucoma medications per patient showed a greater reduction from baseline to year 2 in the 0.4 mg/ml MMC (from 2.1 ± 1.2 [n = 67] to 0.2 ± 0.6 [n = 54]) than in the 0.2 mg/ml MMC (from 2.4 ± 1.3 [n = 58]) to 0.8 ± 1.1 [n = 50]) group Fig. 4A). Beginning at 6 months, the number of glaucoma medications used per patient was significantly lower in the 0.4 than in the 0.2 mg/ml MMC group (P ≤ 0.02). The percentage of medication-free patients at year 2 was higher in the 0.4 than in the 0.2 mg/ml MMC group (85.2% [46/54] vs. 58.0% [29/50]; Fig. 4B). Greater reductions in medication use were observed in the 0.2 mg/ml MMC group for patients who received combined cataract surgery than in those who underwent standalone implantation, but no differences were observed in the 0.4 mg/ml MMC group (Supplementary Table 4). Eleven patients in each of the MMC groups underwent both MicroShunt implantation and cataract surgery.
Fig. 4
A Mean and median numbers of glaucoma medications per patient over 2 years of follow-up. B Percentage of patients who were medication-free over 2 years of follow-up (per-protocol population)
The most frequently observed AE was increased IOP, as determined by each investigator, in the 0.2 mg/ml (31.0% [8/58]) and 0.4 mg/ml (17.9% [12/67]) MMC groups. A greater incidence of hyphema was reported in the 0.2 mg/ml than in the 0.4 mg/ml MMC group (P < 0.04), but there were no other significant between-group differences observed in AEs (P > 0.05). All 75 AEs in the 0.2 mg/ml MMC group resolved within a mean ± SD 55.3 ± 100.2 days and all 93 AEs in the 0.4 mg/ml MMC group resolved within a mean ± SD 50.1 ± 88.3 days. No cases of blebitis, endophthalmitis, implant extrusion, or long-term sight-threatening AEs were reported in either group. Implant migration was observed in one eye in the 0.4 mg/ml MMC group following a needling procedure. AEs reported in ≥ 5% of patients up to year 2 are shown in Table 2.
Table 2
Procedure- or device-related AEs occurring in ≥ 5% of patients during 2 years of follow-up (per-protocol population)
0.2 mg/ml MMC (n = 58)
0.4 mg/ml MMC (n = 67)
Non-serious AEs (procedure- or device-related), n (%)
Any non-SAE
34 (58.6)
46 (68.7)
Increased IOP reported at the discretion of each investigatora
18 (31.0)
12 (17.9)
Numerical hypotony (IOP < 6 mmHg at any time)
7 (12.1)
10 (14.9)
Hyphemab
9 (15.5)
3 (4.5)
Keratitis and/or corneal ulcerc
8 (13.8)
9 (13.4)
Bleb-related complication
1 (1.7)
4 (6.0)
Corneal edema
0
4 (6.0)
Tube touching iris
0
4 (6.0)
Flat anterior chamber
0
4 (6.0)
AEs observed in ≥ 5% of patients in either group within 2 years of follow-up or within 730 days if 2-year data were missing
The summary is based on observed cases. AEs collected after the reoperation date were excluded from the summary
aOne patient in the 0.4 mg/ml MMC group experienced an IOP increase ≥ 10 mmHg over baseline. Following increased IOP, the following actions were taken in the 0.2 and 0.4 mg/ml MMC groups: postsurgical injection of 5-FU in the bleb area (2 and 0 patients, respectively), medication (12 and 2 patients, respectively), medication/needling (1 patient each), medication/surgical procedure (0 and 1 patient, respectively), needling (3 and 2 patients, respectively), no intervention (4 and 1 patient, respectively), surgical procedure (0 and 6 patients, respectively), and surgical procedure/needling (1 and 0 patient, respectively)
bP < 0.04
cCorneal ulcer was defined as an epithelial erosion
SAEs included unplanned glaucoma-related surgical reintervention (0.2 mg/ml MMC, n = 1 [1.7%]; 0.4 mg/ml MMC, n = 1 [1.5%]), increased IOP reported at the discretion of each investigator (0.2 mg/ml MMC, n = 1 [1.7%]; 0.4 mg/ml MMC, n = 1 [1.5%]); keratitis (0.2 mg/ml MMC, n = 1 [1.7%]), posterior capsular opacification (0.4 mg/ml MMC, n = 2 [3.0%]), and one event (1.5%) each of conjunctival dehiscence, corneal ulcer, leakage of wound site based on Seidel test, posterior synechiae, and pupillary capture in the 0.4 mg/ml MMC group. Of the two patients who experienced an SAE of increased IOP, the patient in the 0.2 mg/ml MMC group was treated with trabeculectomy, whereas the patient in the 0.4 mg/ml MMC) was treated with medication plus a glaucoma surgical procedure. Three SAEs in the 0.2 mg/ml MMC group resolved within a mean ± SD 8.0 ± 8.5 days, and all nine SAEs in the 0.4 mg/ml MMC group resolved within a mean ± SD 10.3 ± 15.9 days; one event requiring unplanned surgical reintervention in the 0.2 mg/ml MMC group did not resolve during the study period.
Safety outcomes in patients who underwent MicroShunt surgery with or without cataract surgery are summarized in Supplementary Table 5.
Overall, more patients in the 0.2 (n = 8) than in the 0.4 mg/ml (n = 4) MMC group required ≥ 1 bleb needling procedure. The incidence of reoperations was higher in the 0.4 (8/67 [11.9%]) than in the 0.2 mg/ml (4/58 [6.9%]) MMC group. In the 0.2 mg/ml MMC group, two patients underwent a bleb revision and placement of a new glaucoma drainage implant and two patients required trabeculectomy. In the 0.4 mg/ml MMC group, one patient required flap resuture after trabeculectomy, and one required a surgical procedure in the sclera of the eye owing to increased IOP and placement of a second MicroShunt at the opposite angle of the anterior chamber. Five patients in the 0.4 mg/ml MMC group required bleb revision on or before year 2.
Mean Snellen VA score at year 2 did not differ significantly in the 0.2 mg/ml and 0.4 MMC groups (20/25 [LogMAR, 0.2 ± 0.4; n = 48] vs. 20/28 [LogMAR, 0.4 ± 0.8; n = 53]; P = 0.07). Snellen VA scores returned to baseline values at week 6 and month 3 following surgery in the 0.2 and 0.4 mg/ml MMC groups, respectively (Supplementary Fig. 1).
Discussion
This post hoc analysis in three studies of patients undergoing MicroShunt implantation found that the higher MMC concentration (0.4 mg/ml) was associated with significant improvements in IOP and medication outcomes compared with the lower MMC concentration (0.2 mg/ml). Although the overall success rates at year 2 did not differ significantly in these groups, the complete success was significantly higher in the 0.4 than in the 0.2 mg/ml MMC group, indicating that patients in the former group were more likely to achieve an IOP < 14 mmHg without the use of glaucoma medications. Overall, these findings suggested that an MMC concentration of 0.4 mg/ml may better control postsurgical IOP than 0.2 mg/ml MMC.
Overall, there were no significant between-group differences in the incidence of procedure- or device-related AEs or SAEs over 2 years of follow-up, except that the incidence of hyphema at 2 years was significantly higher in the 0.2 than in the 0.4 mg/ml MMC group (9 [15.5%] vs. 3 [4.5%], [P < 0.04]). Low rates of numerical hypotony were reported in both the 0.2 (12.1%) and 0.4 mg/ml (14.9%) MMC groups. Twelve patients required bleb needling, and approximately one-tenth of the overall population required reoperations, with the incidence of bleb revision being higher in patients administered 0.4 (8 [11.9%]) than 0.2 (4 [6.9%]) mg/ml MMC. The posterior capsular opacification observed in two patients in the 0.4 mg/ml MMC group may have been due to cataract surgery [24, 25]. Snellen’s VA returned to baseline values at week 6 in the 0.2 mg/ml MMC group and month 3 in the 0.4 mg/ml MMC group and was maintained thereafter. VA was similar between baseline and year 2 in both groups. Better IOP outcomes and higher success rates at years 1 and 2 were observed in patients in both MMC groups who underwent combined than standalone surgery.
At year 2, the rate of IOP reduction from baseline in the 0.4 mg/ml MMC group was higher (40.9%) than that observed in the INN007 (37.6%) study [21], but lower than that in the INN003 study (50%), in which all patients were administered 0.4 mg/ml MMC [20]. The most common procedure- or device-related AE in the pooled analysis was investigator-reported increased IOP, in line with reports from the individual INN004 and INN007 studies in patients receiving 0.4 mg/ml MMC [14, 21]. The most common AEs reported in the INN003 3-year study were tube in contact with the iris, transient hypotony (< 5 mmHg) after day 1, and shallow or flat anterior chamber [12]. The difference in findings between this retrospective analysis that pooled data from seven study sites and the INN003 study may have been due to variations in patient management among surgeons, as well as the fewer number of patients in the INN003 study (n = 23) than in this dataset (n = 125) [12].
Other studies have examined the effect of increasing MMC concentration on surgical outcomes. A complete success rate (IOP ≥ 6 and ≤ 14 mmHg with no clinical hypotony on two consecutive visits and a ≥ 20% IOP reduction with no medications) of 75.6% was observed 1 year after MicroShunt implantation with 0.2 or 0.4–0.5 mg/ml MMC [26], a result comparable to the findings of this analysis. Moreover, a multivariate analysis found that receiving 0.2 mg/ml MMC resulted in a higher risk of surgical failure than most of the other variables evaluated [26]. Two randomized, masked, prospective studies comparing the effects of 0.4 and 0.2 mg/ml MMC on trabeculectomy outcomes found that MMC concentration did not significantly affect IOP [27, 28].
A low rate of postoperative complications was also observed following MicroShunt implantation with 0.2 or 0.4–0.5 mg/ml MMC in a real-world setting [26]. Choroidal detachment was the most frequently reported complication during the early (< 3 months, 6.7%) and late (≥ 3 months, 2.5%) postoperative periods [26]; this complication, however, was not among the most commonly reported AEs in the present study. The incidence of AEs in patients who underwent trabeculectomy was found to be higher in those treated with 0.4 than 0.2 mg/ml MMC [26]. A similar trend was observed in the current analysis, although the between-group difference was not statistically significant, a finding consistent with reports in patients who had undergone trabeculectomy [28]. Although the risk of cataract progression in patients who underwent trabeculectomy has been reported significantly higher with MMC than with placebo [29], cataract was not among the most commonly reported AEs in the present analysis. Endophthalmitis, which has also been associated with trabeculectomy [30], was not observed in any patient included in the present analysis. The incidence of bleb revisions/reoperations following MicroShunt implantation with 0.2 or 0.4–0.5 mg/ml MMC was also low in a real-world setting (1.2% [2/164]) [26]. The needling rate following MicroShunt implantation in this pooled analysis was 9.6%, similar to the 8.5% rate in the real-world setting [26].
This ad hoc analysis suggested that the higher 0.4 mg/ml MMC dose resulted in significantly lower IOP and lower medication use over 2 years than the lower 0.2 mg/ml MMC dose. Interestingly, a prospective, randomized, Premarket Approval (PMA) study of the MicroShunt versus trabeculectomy (ClinicalTrials.gov Identifier [Santen Identifier]: NCT01881425 [INN005]) across 29 sites in the USA and Europe, where the MMC dose was restricted to 0.2 mg/ml, found that IOP at year 1 in the MicroShunt group (n = 395) was 14.3 ± 4.3 mmHg, with the number of glaucoma medications per patient averaging 0.6 ± 1.1, compared with 3.1 ± 1.0 at screening [31]. At 2 years, mean IOP in the MicroShunt group was 13.9 ± 3.9 mmHg, whereas the number of glaucoma medications per patient averaged 0.9 ± 1.3 [32]. These results were similar to those reported in the present study for the 0.2 mg/ml MMC group.
This post hoc pooled analysis had several limitations. The three clinical studies were not powered to compare the effectiveness and safety of the 0.2 and 0.4 mg/ml MMC concentrations evaluated in this analysis. The pooled analysis also did not compare bleb morphology and other effects specific to the MicroShunt in patients receiving 0.2 and 0.4 mg/ml MMC.
In addition, this analysis had a retrospective design. Patients enrolled in the individual studies were not randomized to receive 0.2 or 0.4 mg/ml MMC; rather, the MMC concentration was at the discretion of each investigator, with each investigator using a selected MMC dose for all patients. Site and/or investigator differences may have also been confounding factors in studies at multiple sites with multiple investigators. This subjectivity may also have introduced confounding factors associated with the rationale for the choice of MMC concentration in each patient. Using 0.4 mg/ml MMC, rather than 0.2 mg/ml MMC, may have been more frequent in patients with more severe ocular inflammation, a longer history of glaucoma medication use, and/or because of standard practice in a particular group. Differences in ocular inflammation between the 0.2 and 0.4 mg/ml MMC groups may have led to an underestimation of the between-group differences. The severity of ocular inflammation, however, was not assessed in all studies.
The present study also did not compare routes of MMC application. Studies in patients who underwent trabeculectomy have compared outcomes in patients administered MMC by subconjunctival injection and sponge application. For example, a prospective, randomized trial compared 3-year outcomes in 137 patients who underwent trabeculectomy and were administered 0.2 mg/ml MMC by subconjunctival injection (n = 66) and sponge application (n = 71), finding that the two methods yielded comparable surgical outcomes and complications [33]. A second study compared 6-month outcomes in 124 patients who underwent twin-site phaco-trabeculectomy and were administered 0.04% MMC and 2% lignocaine for 4 min by sponge application (n = 62) or by subconjunctival injection (n = 62) [34]. Mean IOP at 6 months was significantly lower in the injection (14.8 ± 3.7 mmHg) than in the sponge (17.1 ± 6.4 mmHg) group (p = 0.02). Although complications and 6-month post-operative visual outcomes were comparable in the two groups, significantly higher percentages in the sponge arm required removal of the releasable suture (p = 0.0001) and additional anti-glaucoma medications (p = 0.04). Other recent studies have reported similar outcomes in patients who underwent trabeculectomy and phaco-trabeculectomy with the two methods of MMC application [35‐38].
Patients who underwent combined cataract surgery with 0.2 mg/ml MMC showed greater reductions in medication use than those who underwent standalone implantation with 0.2 mg/ml MMC. In contrast, the opposite was observed in the 0.4 mg/ml MMC group, although few patients underwent the combined procedure. The results of this analysis may have been affected by inclusion of the single-center INN-003 study, in which patients received 0.4 mg/ml MMC. In addition, Kaplan–Meier analysis of the probability of success over time did not include data collection between years 1 and 2. This analysis also presents outcomes from multiple surgeons and study sites. These investigators had different levels of experience with the MicroShunt and may have employed slightly different surgical techniques. There is also no consensus worldwide regarding the application of MMC [39]. Differences in surgical technique may have influenced the outcomes presented in each study, as well as the outcomes reported by each site in the INN007 study. Differences in postoperative management of patients in each study may have affected the number and type of reoperations completed across the three studies.
Conclusions
In conclusion, this retrospective post hoc analysis of three prospective, single-arm, open-label studies (two single-center and one multicenter study) showed that IOP and medication use were significantly lower in patients who received 0.4 mg/ml than 0.2 mg/ml MMC, beginning at 6 months. The greater effectiveness of the higher MMC concentration did not compromise the safety profile reported. The incidence of hyphema was higher in the 0.2 than in the 0.4 mg/ml MMC group, but there were no other significant between-group differences in AEs. In addition, none of these patients experienced blebitis, endophthalmitis, implant extrusion, or long-term sight-threatening AEs. Although there is no consensus on the optimal concentration of MMC, these findings may guide surgeons until further evidence from randomized controlled trials becomes available.
Medical Writing, Editorial, and Other Assistance
Medical writing support was provided by Jade Murdoch, MChD, Helios Medical Communications, Alderley Park, Cheshire, UK, which was funded by Santen Inc., Emeryville, CA, USA. The authors would like to thank Hui Shao, of Santen, for statistical support and data analysis.
Declarations
Conflict of Interest
Julian Garcia-Feijoo: Consultant—Alcon, AbbVie, Glaukos, iSTAR, Santen; Thea; Sight Science; Alimera; Elios Vision; Financial support—Alcon, AbbVie, iSTAR, Novartis, Théa, Glaukos, Pfizer, Santen, Elios, ZEISS; Heidelberg; AJL; J&J; B&L; Thea; Sight Science; Rayner; Cutting Edge; Physiol; Biotech and Pfizer. Juan F. Batlle: Consultant—Santen Inc., Aquea Health, W.L. Gore & Associates, Inc.; Paid speaker—Johnson & Johnson Vision; Research support—CORD LLC, InnFocus Inc. (a Santen Pharmaceutical Co Ltd Company), Johnson & Johnson Vision, LensGen Inc., New World Medical Inc., Omega Ophthalmics, Inc., TECLens LLC; Investment interest: Aquea Health, CORD LLC, LensGen Inc. Florent Aptel: Consultant—Allergan, Glaukos, Novartis, Santen, Théa. Yves Lachkar: Consultant for Allergan, Novartis, Santen, Théa. Isabelle Riss: Consultant—Santen; Research support—Santen. Omar Sadruddin: is an employee of Glaukos. Tuan Nguyen: is an employee of Edwards Lifesciences. Henny J.M. Beckers: Consultant—InnFocus Inc. (a Santen Pharmaceutical Co. Ltd. company), Santen, Glaukos, AbbVie, Novartis, Théa, Elios, Nova Eye Medical; Research support—InnFocus Inc. (a Santen Pharmaceutical Co. Ltd. company); Investment interest: Peyeoneer Medtech B.V.
Ethical Approval
The individual studies were conducted in line with the principles of the Declaration of Helsinki and the following medical device standards: CFR 21 (INN003 only), MEDDEV 2.12-1 and MEDDEV 2.12/2 revision 2 (INN007 only), MEDDEV 2.7/1 and the European Directive 93/42/EEC (INN004 and INN007 only), and EN ISO 14155 (INN003, INN004, and INN007). Each study site obtained institutional review board approval. Informed consent was gained from all patients prior to enrollment in the individual studies.
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