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Efficacy of Cataract Surgery With Trabecular Microbypass Stent Implantation in Combined-Mechanism Angle Closure Glaucoma Patients
Accepted Manuscript Efficacy of cataract surgery with trabecular micro-bypass stent implantation in combined-mechanism angle closure glaucoma patients Sunee Chansangpetch, Kevin Lau, Claudio I. Perez, Ngoc Nguyen, Travis C. Porco, Shan C. Lin PII:
S0002-9394(18)30443-4
DOI:
10.1016/j.ajo.2018.08.003
Reference:
AJOPHT 10621
To appear in:
American Journal of Ophthalmology
Received Date: 10 June 2018 Revised Date:
27 July 2018
Accepted Date: 1 August 2018
Please cite this article as: Chansangpetch S, Lau K, Perez CI, Nguyen N, Porco TC, Lin SC, Efficacy of cataract surgery with trabecular micro-bypass stent implantation in combined-mechanism angle closure glaucoma patients, American Journal of Ophthalmology (2018), doi: 10.1016/j.ajo.2018.08.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Abstract Purpose: To evaluate the effectiveness of trabecular microbypass stent (iStent) implantation in combined mechanism glaucoma (CMG). Design: Retrospective cohort study
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Methods: We reviewed the medical charts of patients with the following scenarios: (1) primary open angle glaucoma (POAG) undergoing phacoemulsification (PE), (2) POAG undergoing PE with iStent (POAG-PE/iStent), (3) CMG undergoing PE (CMG-PE), and (4) CMG undergoing PE with iStent (CMG-PE/iStent). CMG was defined as narrow angle glaucoma patients whose angle had opened after iridotomy. Linear mixed effect models were performed to determine the effect of iStent on postoperative 1-year success rate (IOP≤18 without medication), intraocular pressure (IOP), and number of medications.
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Results: Data from 301 eyes were available. The number of eyes (subjects) was 61(45) in POAG-PE, 60(50) in POAG-PE/iStent, 93(76) in CMG-PE, and 87(70) in CMG-PE/iStent group. Success criteria was achieved in 13.1% for POAG-PE, 33.3% for POAG-PE/iStent (POAG-PE vs POAG-PE/iStent B 3.01; p<0.001), 37.6% for CMG-PE, and 43.7% for CMGPE/iStent (CMG-PE vs CMG-PE/iStent B 2.25; p<0.001). There was no difference in the IOP between POAG-PE and POAG-PE/iStent, and between CMG-PE and CMG-PE/iStent. The iStent significantly reduced number of medications in POAG (B -0.70; p<0.001) and CMG group (B -0.52; p<0.001). Comparing the effect of iStent on POAG and CMG, the analysis showed similar iStent efficacy in terms of the success rate, IOP, and number of medications (p>0.05).
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Conclusions: Combined PE/iStent significantly increased success rate and reduced number of medications in CMG patients compared to PE alone. The effect of iStent were comparable between POAG and CMG groups.
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Efficacy of cataract surgery with trabecular micro-bypass stent implantation in combined-mechanism angle closure glaucoma patients
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Sunee Chansangpetch1,2; Kevin Lau1; Claudio I Perez1,3; Ngoc Nguyen4; Travis C Porco1; Shan C Lin1,5 Department of Ophthalmology, University of California, San Francisco, CA, USA
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Department of Ophthalmology, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross, Bangkok, Thailand Fundación Oftalmológica Los Andes, Universidad de los Andes, Santiago, Chile
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Ngoc Nguyen Eye Clinic, San Jose, USA
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Glaucoma Center of San Francisco, San Francisco, CA, USA
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Correspondence and reprint requests to: Shan Lin, MD
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Glaucoma Center of San Francisco, San Francisco, CA 55 Stevenson Street, San Francisco, CA 94105
Tel: +1-415-981-2020, Fax: +1-415-981-2019, E-mail: [email protected] Manuscript word count: 3,143 Abstract word count: 250
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Financial support: None
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This article was presented as an oral presentation at the World Ophthalmology Congress 2018, Barcelona, Spain, June 2018.
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Conflict of Interest: No conflicting relationship exists for any author
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Introduction
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Glaucoma is a leading cause of irreversible blindness worldwide.1 Lowering intraocular pressure (IOP) is currently a mainstay of treatment to prevent further progression. Conventional glaucoma therapy includes medications, laser, filtering surgeries, and tube shunt surgeries. Micro-invasive glaucoma surgeries (MIGS) are a relatively new class of surgeries that have been introduced during the past decade. They have the benefit of being less invasive with better safety profiles compared to conventional surgeries.2 Trabecular microbypass stent, or iStent (Glaukos Corporation, Laguna Hills, CA), is a type of MIGS device that lowers the IOP by allowing the aqueous fluid to drain from the anterior chamber directly into Schlemm’s canal. Previous publications have shown the efficacy of combined iStent with cataract surgery in primary open angle glaucoma (POAG) and pseudoexfoliation glaucoma.3-8
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Two major types of primary glaucoma in adults are open angle and angle closure glaucoma. As aforementioned, the pathogenesis of POAG involves trabecular outflow resistance; whereas, in primary angle closure glaucoma (PACG), the narrowing and closure of the anterior chamber angle is thought to be a main mechanism for IOP elevation. However, in narrow angle cases where IOP still remains elevated despite opening of the angle by iridotomy, these eyes are thought to possess both ‘pre-trabecular’ and ‘trabecular’ factors for the IOP level. The term ‘mixed-mechanism glaucoma’ or ‘combined-mechanism glaucoma’ (CMG) refers to this kind of situation where both components are presented.9
Methods
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Management of CMG should include modalities to address both underlying etiologies. For the angle closure component, cataract surgery is an alternative option apart from the standard care of medications and iridotomy. Evidence showed the significant IOP reduction after lens removal in angle closure disease.10,11 Regarding the open angle component, the iStent can potentially help bypass the pathologic trabecular meshwork (TM), which may result in better glaucoma control. However, whether combined cataract surgery with iStent implantation in CMG will provide additional benefit to simple cataract surgery in terms of IOP control and medication reduction is still unknown. The objective of this study is to evaluate the effectiveness of the iStent implantation in CMG eyes which had prior laser peripheral iridotomy (LPI) and compare to its effect in POAG eyes.
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A retrospective comparative study of consecutive patients was undertaken at the ophthalmology clinic of a single glaucoma specialist (N.N.). The study was conducted in accordance to the Tenets of the Declaration of Helsinki with the approval from the institutional review board of the University of California, San Francisco. Medical charts of patients who received cataract surgery alone or cataract surgery with iStent implantation by a single surgeon (N.N.) during 2012-2017 were reviewed. The subjects who met the following criteria were included for the complete review: (1) age greater than 40 years, (2) underwent successful phacoemulsification with intraocular lens (IOL) implantation (with or without iStent implantation), (3) completed 1 year follow up after cataract surgery, and (4) diagnosis of primary glaucoma based on the International Society of Geographical and Epidemiological Ophthalmology (ISGEO) guidelines.12 The subjects were classified into open angle and closed angle group. Open angle was defined in eyes that had Shaffer angle grading of at least 2 for more than 180 degrees. For the closed angle group, we recruited only angle closure glaucoma cases that had combined
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mechanism. CMG was defined in eyes that had been documented to have occludable angle, which was defined as Shaffer angle grading 1 or less for 180 degrees or more, and the angle subsequently deepened and met the open angle definition after laser iridotomy but the IOP remained elevated and/or required glaucoma medications. Each group was further divided into 2 subgroups - simple phacoemulsification (PE) and phacoemulsification with iStent (PE/iStent) implantation - resulting in 4 subgroups in total: (1) POAG-PE, (2) POAG-PE/iStent, (3) CMG-PE, and (4) CMG-PE/iStent. The presence of peripheral anterior synechiae (PAS) was not an exclusion for CMG; however, the CMG eyes that had significant PAS at the nasal angle were excluded from the study.
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Exclusion criteria included: (1) any ocular or systemic condition that could affect vision and/or visual field interpretation; (2) any ocular or systemic condition that could affect IOP or preclude accurate tonometry (e.g., corneal pathology, previous refractive surgery, concurrent use of systemic steroid); (3) previous intraocular surgery including filtering surgery, glaucoma drainage device implantation, and retina surgery; (4) history of ocular trauma; and (5) complicated cataract surgery such as posterior capsule rupture, vitreous loss, intraoperative zonular instability, and dropped nucleus. Prior laser trabeculoplasty, intraoperative hyphema and intraoperative floppy iris syndrome were not considered as exclusions. Surgical technique
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The patients received standard phacoemulsification with temporal clear cornea incision. An acrylic foldable IOL was successfully implanted in all cases. For the iStent group, the stent was implanted after IOL implantation. The anterior chamber was filled with viscoelastic. After tilting the microscope and repositioning the patient’s head, the Hill surgical gonioprism (Ocular Instrument Inc., Bellevue, WA) was placed over the cornea to visualize the nasal angle. Once the TM was identified, the iStent applicator was inserted through the main corneal incision aiming towards the nasal quadrant. The iStent was implanted by sliding the leading edge through the TM into Schlemm’s canal. The tip of the applicator was used to tap on the iStent to make sure it was secure in the canal. The viscoelastic was then removed. The wound was closed by irrigating the wound with BSS.
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The patient was prescribed a fluorometholone drop 4 times a day for 5 weeks, a 0.3% nepafenac drop once a day for 5 weeks, and a fluoroquinolone antibiotic drop 4 times a day for 1 week. All antiglaucoma medications were kept the same as pre-operation until the IOP was reassessed at post-operative day 1, on which the glaucoma medications were adjusted. Further changes to the medications were based on the IOP at each follow up visit at the discretion of the surgeon (N.N.). Data collection and outcomes Pre-operative clinical information including best-corrected visual acuity (BCVA), IOP measured by Goldmann applanation tonometry, number of glaucoma medications, vertical cupto-disc (C/D) ratio, and visual field mean deviation obtained from automated perimetry (24–2 on Humphrey Field Analyzer-2; Carl Zeiss Meditec, Dublin, CA) were reviewed and recorded. The applanation IOP and number of medications were recorded at week 1, month 1, 3, 6, 9, and 1 year. The outcome measures were (1) the success rate which was defined as a proportion of subjects that had IOP≤18 mmHg without glaucoma medications, (2) the absolute post-operative IOP, and (3) the number of glaucoma medications at one year after surgery. The need for postoperative procedures such as glaucoma surgery and laser was collected and these subjects were excluded from the primary outcome comparison.
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Statistical analysis
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Assessment of normality was conducted using the Shapiro-Wilk statistic test. Depending on the distribution and type of variables, descriptive statistics were calculated as means and standard deviations, medians and interquartile range, or proportions. An independent t-test, Pearson Chi-square test, and Mann-Whitney U test were performed to compare the baseline characteristics of each studied group. Linear mixed effect regression was utilized to account for two eyes from the same subject as follows. For each group (open angle and closed angle), a multiple regression model was built to evaluate the effect of iStent in each measure outcome. Then, a second model containing the interaction between ‘iStent’ and ‘open/closed’ variables was performed to compare the effect of iStent between open angle and closed angle groups. Follow-up time was modeled using up to a third order polynomial. Pre-operative IOP was included as a covariate in all models. For the number of medications outcome, pre-operative number of medications was also used for the adjustment in the analysis models. A limit of statistical significance was set at p<0.05. All analyses were performed using R version 3.3 for Macintosh (R Foundation for Statistical Computing, Vienna, Austria). Results
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The study was comprised of 301 eyes from 241 subjects. The number of eyes (subjects) in each subgroup was 61 (45) in the POAG-PE group, 60 (50) in the POAG-PE/iStent group, 93 (76) in the CMG-PE group, and 87 (70) in the CMG-PE/iStent group. Only a single iStent was placed in all iStent cases. The PE/iStent subgroup had more pre-operative number of medications than the PE subgroup for both POAG (p=0.02) and CMG (p<0.001) groups. The baseline characteristics of subjects in each subgroup are summarized in Table 1.
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At 1-year post-operation, the success rates for the POAG group were 13.1% for POAGPE and 33.3% for POAG-PE/iStent, and the success rates for the CMG group were 37.6% for CMG-PE and 43.7% for CMG-PE/iStent. Figure 1 shows the success rate of each group over time. After adjustment for confounding variables, the linear mixed effect regression showed significantly higher success rate in POAG-PE/iStent than POAG-PE (B 3.01 p<0.001) in the POAG group and higher success rate in CMG-PE/iStent than CMG-PE (B 2.25 p<0.001) in the CMG group. The interaction model revealed no significant difference of the iStent effect on the success rate between the POAG and CMG groups (p=0.23).
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There was no difference in the absolute IOP at 1-year post-operation between POAGPE vs POAG-PE/iStent (13.58 vs 14.38 mmHg, p=0.28) and CMG-PE vs CME-PE/iStent (13.90 vs 14.58 mmHg, p=0.17). Data on IOP at each follow-up time point are shown in Table 2. Multiple regression models revealed no significant effect of the iStent on IOP in both the POAG group (p=0.07) and the CMG group (p=0.43). We could not demonstrate the difference of the iStent impact on absolute IOP between the POAG and CMG groups from the interaction model (p=0.46). For the number of medications, the PE/iStent subgroups had significantly higher baseline number of medications in both the POAG and CMG groups. Among POAG eyes, mean reduction in medications at 1 year was 1.32 ± 1.15 in the iStent group which was significantly higher than 0.40 ± 1.05 in the PE group (p<0.001). For the CMG group, mean reduction was 1.54 ± 0.96 in the iStent group, significantly greater than the 0.73 ± 0.79 reduction in the PE group (p<0.001). The number of medications and percentage of mediation-free eyes at each
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follow-up visit are shown in Figures 2 and 3, respectively. The mixed effect regression model with adjustment for baseline number of medications also showed significant reduction in medications for both POAG (B -0.70 p<0.001) and CMG (B -0.52 p<0.001). The interaction model revealed similar effects of the iStent on lowering medications between POAG and CMG group (p=0.09). Table 3 shows the effect of iStent for each outcome and the comparison of the effect between the POAG and CMG groups.
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Regarding visual outcome and safety, all groups had significant improvement of BCVA (all p<0.001). We found incidents of decreased BCVA at 1 year compared to pre-operation in 3 (6.7%), 0 (0%), 5 (6.7%), and 5 (7.1%) cases in POAG-PE, POAG-PE/iStent, CMG-PE, and CMG-PE/iStent, respectively (p=0.27, Fisher’s exact test). There was an intraoperative stent malposition in one case of CMG-PE/iStent. The first stent was removed, and the second attempt was successfully made. Another case in the CMG-PE/iStent group had intraoperative hyphema. The hyphema resolved subsequently within a few weeks without the need for an additional procedure. Both cases were included in the analysis. One case in the POAG-PE/iStent group required laser cyclophotocoagulation at approximately one year after surgery. This case was excluded from the final analysis. Discussion
Our retrospective study suggests that there may be a possible added benefit of iStent implantation, in conjunction with cataract surgery, in terms of the success rate and number of glaucoma medications at 1 year after surgery, in both POAG and CMG groups. The additional effect of combined PE/iStent to PE alone was not different between the POAG and CMG groups.
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Several published reports have shown the advantage of iStent in IOP control in POAG subjects.3-7 A study using a fluorophotometric method demonstrated that iStent enhanced conventional outflow facility by bypassing the pathologic TM, and thus, allowed the aqueous to drain into Schlemm’s canal.13 In agreement with previous literature, our findings in the POAG group showed that iStent had better success rate and significantly reduced number of medications.4,5,14 At 1 year after cataract surgery, both iStent and PE groups showed significant reduction of glaucoma medication use (reduction by 1.32 ± 1.13 and 0.40 ± 1.04, respectively) with more benefit in the iStent group (B -0.70 p<0.001). In our study, the final number of medications and percentage reduction of mean medications were comparable to a randomized controlled trial previously reported by Samuelson et al.5 The iStent treatment group also achieved greater success rate at every time-point through 12 months’ follow up. The success rate at 1 year in our study was 33.3% in the PE/iStent and 13.1% in the PE alone group, both of which were lower than what has previously been reported by studies from Samuelson et al. and Craven et al.5,14 The difference could be attributed to more stringent success criteria (IOP≤18 mmHg without medication) used in our study. As opposed to our criteria, both aforementioned studies defined the success as the proportion of subjects with IOP≤21 mmHg without medication. Moreover, our study is retrospective in nature. The difference in duration of follow up and study design may also limit direct comparison among studies. The benefit of cataract surgery in closed angle glaucoma is evident.10,15-18 Data showed that simple cataract surgery can reduce IOP by 6.4 mmHg in angle closure glaucoma concurrent with cataract11 and by 12.9 mmHg in eyes with clear lens.10 The mechanism is speculated to be related to the widening of the angle from changes in anterior segment anatomy and ciliary body position.19-21 CMG is an entity of angle closure glaucoma which is thought to have components from both POAG-related (trabecular) and PACG-related (pre-trabecular) mechanisms.9,22 Most commonly, CMG was diagnosed in the scenarios that angle-closure
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glaucoma is treated successfully with iridotomy, eliminating most if not all appositional closure, and IOP still remains elevated.9 The residual high IOP reflects the outflow resistance which is either from a preexisting TM dysfunction or acquired pathologic damage from prior angle apposition as documented by previous histopathological studies.23,24 It has been questioned whether iStent, which can address the trabecular resistance issue, can add further benefit to simple cataract surgery in angle closure with combined mechanism.
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Although the success rate of CMG-PE, which was as high as 37.6%, was better than what was achieved in both arms of the POAG group, the iStent further raised the success rate up to 43.7% in CMG eyes. The average number of medications was lower in the iStent group at every time point. The overall reduction was also significantly higher with iStent treatment. At 1 year, the iStent subgroup had a decreased medication burden by 1 drop in CMG patients which was comparable to the reduction achieved in POAG eyes in this study and a study from Fea et al.4 Moreover, in order to assess whether the beneficial effect in CMG is equivalent to the benefit obtained from the stent in POAG eyes, we compared the effect of iStent in CMG to the effect of iStent in the POAG group. Our analysis, which accounted for the baseline clinical differences and time factor, found no difference in the magnitude of the stent effect between POAG and CMG in all measured outcomes. Our results suggested that enhancing trabecular outflow can also provide therapeutic benefit to combined-mechanism angle closure subjects. The benefit was comparable to that observed with POAG diagnosis. However, it should be noted that the regression model comparison of iStent effect on POAG and CMG groups yielded marginal p value (p=0.09). There is still a possibility that the difference of iStent effect between 2 glaucoma groups can be demonstrated with greater statistical power in a larger data set.
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Of note, the IOP outcome did not show a significant difference between adjunctive iStent and simple PE in both POAG and CMG groups. The effect of PE either with or without iStent on IOP was likely to be confounded by medication adjustment during the follow-up course. The decrease in number of medications may reflect more of the IOP control in this retrospective assessment. In addition, our data showed that the success rate was greatest in the early postoperative period and gradually declined in all groups. The number of medications also slowly increased over time in a corresponding pattern. We observed that the downtrend reached its plateau around post-operative month 9. Whether the benefit of the iStent is sustained in the longer term for POAG and CMG will need to be explored by future longitudinal studies.
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It is also interesting to note that our study used the same success definition for both POAG and CMG eyes. In addition, the treatment in both groups was dictated by the same therapeutic decision to achieve the IOP ranges which were generally based on each patient’s glaucoma staging. However, since POAG and angle closure glaucoma are in different entities, the course of these diseases may differ. Currently, little is known about the exact target IOP for angle closure glaucoma eyes, which may tolerate higher IOP than POAG eyes. The comparison of iStent effect on POAG and CMG under different target IOP or definition of success still needs to be validated. Within the past few years, there has been emerging evidence supporting the role of cataract surgery as a treatment modality in angle closure disease.10,15-18,25 However, cataract surgery alone may be inadequate for some cases, especially those with moderate glaucoma or intolerance to hypotensive medication(s). The need for lower post-operative IOP or cessation of some of the eyedrops could be an issue in these cases. Apart from advancing to trabeculectomy, iStent implantation at the time of cataract surgery could be another alternative for selected angle closure patients for its lesser invasiveness and higher safety margin. Nevertheless, future prospective randomized studies to verify the role of this combined procedure in angle closure eyes are warranted.
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To best of our knowledge, this is the first study to evaluate the performance of iStent in angle closure patients. However, our study has some limitations. First, the retrospective design precluded the assessment of the washout IOP. Thus, the adjustment of the medications throughout the follow-up period was based solely on medicated IOP. Second, given that all IOPs recorded were medicated IOPs, we could not evaluate the true IOP reduction in this study. Third, the present data were derived mostly from cases of mild to moderate glaucoma. The results may not be able to be generalized to other glaucoma severities. Lastly, we included only angle closure cases that had been documented to have angle opening after LPI. The results of our study may not be applicable to all PACG cases.
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In conclusion, combined cataract surgery with iStent implantation significantly increased the success rate and reduced the number of medications in angle closure patients who showed deepening of the angle after LPI. The effects of iStent on the success rate and number of medications were comparable between the POAG and CMG groups. Acknowledgement
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Funding: This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Financial disclosures: SL is a consultant for Allergan, Aleyegn Technologies, Iridex Corporation, Tomey Corporation, and Aerie Pharmaceuticals. The other authors have no financial disclosure. Reference
Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90(3):262-267.
2.
Chen DZ, Sng CCA. Safety and Efficacy of Microinvasive Glaucoma Surgery. J Ophthalmol. 2017;2017:3182935.
3.
Ferguson TJ, Swan R, Ibach M, Schweitzer J, Sudhagoni R, Berdahl JP. Trabecular microbypass stent implantation with cataract extraction in pseudoexfoliation glaucoma. J Cataract Refract Surg. 2017;43(5):622-626.
4.
Fea AM. Phacoemulsification versus phacoemulsification with micro-bypass stent implantation in primary open-angle glaucoma: randomized double-masked clinical trial. J Cataract Refract Surg. 2010;36(3):407-412.
6.
EP
AC C
5.
TE D
1.
Samuelson TW, Katz LJ, Wells JM, Duh YJ, Giamporcaro JE, Group USiS. Randomized evaluation of the trabecular micro-bypass stent with phacoemulsification in patients with glaucoma and cataract. Ophthalmology. 2011;118(3):459-467.
Patel I, de Klerk TA, Au L. Manchester iStent study: early results from a prospective UK case series. Clin Exp Ophthalmol. 2013;41(7):648-652.
7.
Tan SZ, Au L. Manchester iStent study: 3-year results and cost analysis. Eye (Lond). 2016;30(10):1365-1370.
8.
Belovay GW, Naqi A, Chan BJ, Rateb M, Ahmed, II. Using multiple trabecular microbypass stents in cataract patients to treat open-angle glaucoma. J Cataract Refract Surg. 2012;38(11):1911-1917.
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Samples JR, Schacknow PN. Clinical Glaucoma Care: The Essentials. Springer New York; 2013:306.
10.
Azuara-Blanco A, Burr J, Ramsay C, et al. Effectiveness of early lens extraction for the treatment of primary angle-closure glaucoma (EAGLE): a randomised controlled trial. Lancet. 2016;388(10052):1389-1397.
11.
Masis M, Mineault PJ, Phan E, Lin SC. The role of phacoemulsification in glaucoma therapy: A systematic review and meta-analysis. Surv Ophthalmol. 2017.
12.
Foster PJ, Buhrmann R, Quigley HA, Johnson GJ. The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol. 2002;86(2):238-242.
13.
Fernandez-Barrientos Y, Garcia-Feijoo J, Martinez-de-la-Casa JM, Pablo LE, Fernandez-Perez C, Garcia Sanchez J. Fluorophotometric study of the effect of the glaukos trabecular microbypass stent on aqueous humor dynamics. Invest Ophthalmol Vis Sci. 2010;51(7):3327-3332.
14.
Craven ER, Katz LJ, Wells JM, Giamporcaro JE, iStent Study G. Cataract surgery with trabecular micro-bypass stent implantation in patients with mild-to-moderate open-angle glaucoma and cataract: two-year follow-up. J Cataract Refract Surg. 2012;38(8):13391345.
15.
Barbosa DT, Levison AL, Lin SC. Clear lens extraction in angle-closure glaucoma patients. Int J Ophthalmol. 2013;6(3):406-408.
16.
Nonaka A, Kondo T, Kikuchi M, et al. Cataract surgery for residual angle closure after peripheral laser iridotomy. Ophthalmology. 2005;112(6):974-979.
17.
Tham CC, Kwong YY, Leung DY, et al. Phacoemulsification versus combined phacotrabeculectomy in medically controlled chronic angle closure glaucoma with cataract. Ophthalmology. 2008;115(12):2167-2173 e2162.
18.
Tham CC, Kwong YY, Leung DY, et al. Phacoemulsification versus combined phacotrabeculectomy in medically uncontrolled chronic angle closure glaucoma with cataracts. Ophthalmology. 2009;116(4):725-731, 731 e721-723.
19.
Nonaka A, Kondo T, Kikuchi M, et al. Angle widening and alteration of ciliary process configuration after cataract surgery for primary angle closure. Ophthalmology. 2006;113(3):437-441.
20.
Nolan WP, See JL, Aung T, et al. Changes in angle configuration after phacoemulsification measured by anterior segment optical coherence tomography. J Glaucoma. 2008;17(6):455-459.
22. 23.
24.
SC
M AN U
TE D
EP
AC C
21.
RI PT
9.
Lee W, Bae HW, Kim CY, Seong GJ. The change of anterior segment parameters after cataract surgery in normal-tension glaucoma. Int J Ophthalmol. 2017;10(8):1239-1245.
Hyams SW, Keroub C, Pokotilo E. Mixed glaucoma. Br J Ophthalmol. 1977;61(2):105106. Hamanaka T, Kasahara K, Takemura T. Histopathology of the trabecular meshwork and Schlemm's canal in primary angle-closure glaucoma. Invest Ophthalmol Vis Sci. 2011;52(12):8849-8861.
Sihota R, Lakshmaiah NC, Walia KB, Sharma S, Pailoor J, Agarwal HC. The trabecular meshwork in acute and chronic angle closure glaucoma. Indian J Ophthalmol. 2001;49(4):255-259.
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SC
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Brown RH, Zhong L, Lynch MG. Lens-based glaucoma surgery: using cataract surgery to reduce intraocular pressure. J Cataract Refract Surg. 2014;40(8):1255-1262.
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Figure captions
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Figure 1 Success rate for each study group at 1, 3, 6, 9, and 12 months: POAG-PE = primary open angle glaucoma (POAG) with phacoemulsification (PE) only; POAG-PE/iStent = POAG with PE and iStent; CMG-PE = combined mechanism glaucoma (CMG) with PE only; CMG-PE/iStent = CMG with PE and iStent. Success rate was defined as a proportion of subjects that had IOP≤18 mmHg without glaucoma medications.
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Figure 2 Mean of number of glaucoma medications for each study group at pre-operative and post-operative week 1, and months 1, 3, 6, 9, and 12: POAG-PE = primary open angle glaucoma (POAG) with phacoemulsification (PE) only; POAG-PE/iStent = POAG with PE and iStent; CMG-PE = combined mechanism glaucoma (CMG) with PE only; CMG-PE/iStent = CMG with PE and iStent.
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Figure 3 Percentage of medication-free eyes for each study group at 1, 3, 6, 9, and 12 months: POAG-PE = primary open angle glaucoma (POAG) with phacoemulsification (PE) only; POAG-PE/iStent = POAG with PE and iStent; CMG-PE = combined mechanism glaucoma (CMG) with PE only; CMG-PE/iStent = CMG with PE and iStent
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Table 1 Demographic and baseline clinical characteristics Open angle group POAG-PE/iStent
p-value
CMG-PE
CMG-PE/iStent
p-value
61 (45)
60 (50)
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93 (76)
87 (70)
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72.76 (9.88)
72.90 (6.41)
0.97
75.55 (7.51)
77.13 (4.89)
0.27
Gender b
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Age a (years)
POAG-PE
0.12 32 (71.11)
27 (54.00)
Female
13 (28.89)
23 (46.00)
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Male
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No. of eyes (subjects)
Closed angle group
Laterality b
0.39
34 (44.74)
24 (40.98)
42 (55.26)
36 (59.02)
0.32
0.68
25 (40.98)
30 (50.00)
42 (45.16)
42 (48.28)
Left
36 (59.02)
30 (50.00)
51 (54.84)
45 (51.72)
0.8 (0.6 to 0.9)
0.8 (0.6 to 0.9)
0.81
0.6 (0.4 to 0.8)
0.7 (0.4 to 0.9)
0.19
-4.83 (-6.80 to -2.53)
0.63
-4.05 (-6.07 to -2.29)
-4.89 (-9.05 to -3.59)
0.01
14.59 (2.86)
0.36
14.34 (2.96)
14.69 (3.39)
0.47
2 (1 to 2)
0.02
1 (1 to 2)
2 (1 to 3)
<0.001
0.22 (0.15)
0.82
0.23 (0.12)
0.19 (0.14)
0.02
Intraocular pressure (mmHg) a Number of medications c Best-corrected visual acuity (decimal) a
-4.59 (-7.43 to -2.9) 15.13 (3.53) 1 (1 to 2)
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Visual field mean deviation c (dB)
0.22 (0.14)
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Cup-to-disc ratio c
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Right
a
Data was shown in mean (standard deviation) and p-value was obtained by t-test
b
Data was shown in n (%) and p-value was obtained by Chi-square test
c
Data was shown in median (interquartile range) and p-value was obtained by Mann-Whitney U test
POAG = primary open angle glaucoma; CMG = combined mechanism glaucoma
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Open angle group
Closed angle group
POAG-PE/iStent
p-value
CMG-PE
CMG-PE/iStent
p-value
15.13 (3.53)
14.59 (2.86)
0.36
14.34 (2.96)
14.69 (3.39)
0.47
Week 1
16.42 (4.46)
14.48 (4.31)
0.02
15.18 (3.65)
15.02 (4.27)
0.78
Month 1
15.14 (3.31)
13.93 (2.43)
0.03
14.97 (4.06)
14.35 (3.83)
0.30
Month 3
14.80 (3.56)
13.68 (3.01)
0.09
14.41 (4.31)
13.94 (3.84)
0.47
Month 6
14.38 (3.74)
13.88 (4.26)
0.55
14.00 (2.87)
14.42 (3.66)
0.43
Month 9
14.05 (3.31)
14.15 (3.38)
0.90
14.36 (2.59)
14.67 (3.18)
0.54
Month 12
13.58 (3.36)
14.38 (3.04)
0.28
13.90 (3.10)
14.58 (2.46)
0.17
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Post-operative
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POAG-PE Pre-operative
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Table 2 Intraocular pressure at each follow-up time point
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Data was shown in mean (standard deviation) mmHg and p-value was obtained by t-test
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POAG-PE = primary open angle glaucoma (POAG) with phacoemulsification (PE) only; POAG-PE/iStent = POAG with PE and iStent; CMG-PE = combined mechanism glaucoma (CMG) with PE only; CMG-PE/iStent = CMG with PE and iStent.
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Table 3 Multivariable linear mixed effect regression of the iStent effect on success rate, absolute intraocular pressure, and number of medications at 1-year post-operation iStent effect on POAG
iStent effect on CMG
Comparison of iStent effect on POAG and CMG groups
Beta coeff.
p-value
Beta coeff.
p-value
Beta coeff.
p-value
Success rate
3.01
<0.001
2.25
<0.001
-0.91
0.23
Absolute IOP
-0.30
0.43
-0.69
0.07
0.41
0.46
Number of medications
-0.70
<0.001
-0.52
<0.001
0.24
0.09
Negative beta coefficient indicates lower value in iStent subgroups
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POAG = primary open angle glaucoma; CMG = combined mechanism glaucoma
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Positive beta coefficient indicates higher value in iStent subgroups
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S0002-9394(18)30443-4
DOI:
10.1016/j.ajo.2018.08.003
Reference:
AJOPHT 10621
To appear in:
American Journal of Ophthalmology
Received Date: 10 June 2018 Revised Date:
27 July 2018
Accepted Date: 1 August 2018
Please cite this article as: Chansangpetch S, Lau K, Perez CI, Nguyen N, Porco TC, Lin SC, Efficacy of cataract surgery with trabecular micro-bypass stent implantation in combined-mechanism angle closure glaucoma patients, American Journal of Ophthalmology (2018), doi: 10.1016/j.ajo.2018.08.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Abstract Purpose: To evaluate the effectiveness of trabecular microbypass stent (iStent) implantation in combined mechanism glaucoma (CMG). Design: Retrospective cohort study
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Methods: We reviewed the medical charts of patients with the following scenarios: (1) primary open angle glaucoma (POAG) undergoing phacoemulsification (PE), (2) POAG undergoing PE with iStent (POAG-PE/iStent), (3) CMG undergoing PE (CMG-PE), and (4) CMG undergoing PE with iStent (CMG-PE/iStent). CMG was defined as narrow angle glaucoma patients whose angle had opened after iridotomy. Linear mixed effect models were performed to determine the effect of iStent on postoperative 1-year success rate (IOP≤18 without medication), intraocular pressure (IOP), and number of medications.
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Results: Data from 301 eyes were available. The number of eyes (subjects) was 61(45) in POAG-PE, 60(50) in POAG-PE/iStent, 93(76) in CMG-PE, and 87(70) in CMG-PE/iStent group. Success criteria was achieved in 13.1% for POAG-PE, 33.3% for POAG-PE/iStent (POAG-PE vs POAG-PE/iStent B 3.01; p<0.001), 37.6% for CMG-PE, and 43.7% for CMGPE/iStent (CMG-PE vs CMG-PE/iStent B 2.25; p<0.001). There was no difference in the IOP between POAG-PE and POAG-PE/iStent, and between CMG-PE and CMG-PE/iStent. The iStent significantly reduced number of medications in POAG (B -0.70; p<0.001) and CMG group (B -0.52; p<0.001). Comparing the effect of iStent on POAG and CMG, the analysis showed similar iStent efficacy in terms of the success rate, IOP, and number of medications (p>0.05).
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Conclusions: Combined PE/iStent significantly increased success rate and reduced number of medications in CMG patients compared to PE alone. The effect of iStent were comparable between POAG and CMG groups.
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Efficacy of cataract surgery with trabecular micro-bypass stent implantation in combined-mechanism angle closure glaucoma patients
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Sunee Chansangpetch1,2; Kevin Lau1; Claudio I Perez1,3; Ngoc Nguyen4; Travis C Porco1; Shan C Lin1,5 Department of Ophthalmology, University of California, San Francisco, CA, USA
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Department of Ophthalmology, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross, Bangkok, Thailand Fundación Oftalmológica Los Andes, Universidad de los Andes, Santiago, Chile
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Ngoc Nguyen Eye Clinic, San Jose, USA
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Glaucoma Center of San Francisco, San Francisco, CA, USA
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Correspondence and reprint requests to: Shan Lin, MD
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Glaucoma Center of San Francisco, San Francisco, CA 55 Stevenson Street, San Francisco, CA 94105
Tel: +1-415-981-2020, Fax: +1-415-981-2019, E-mail: [email protected] Manuscript word count: 3,143 Abstract word count: 250
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Financial support: None
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This article was presented as an oral presentation at the World Ophthalmology Congress 2018, Barcelona, Spain, June 2018.
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Conflict of Interest: No conflicting relationship exists for any author
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Introduction
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Glaucoma is a leading cause of irreversible blindness worldwide.1 Lowering intraocular pressure (IOP) is currently a mainstay of treatment to prevent further progression. Conventional glaucoma therapy includes medications, laser, filtering surgeries, and tube shunt surgeries. Micro-invasive glaucoma surgeries (MIGS) are a relatively new class of surgeries that have been introduced during the past decade. They have the benefit of being less invasive with better safety profiles compared to conventional surgeries.2 Trabecular microbypass stent, or iStent (Glaukos Corporation, Laguna Hills, CA), is a type of MIGS device that lowers the IOP by allowing the aqueous fluid to drain from the anterior chamber directly into Schlemm’s canal. Previous publications have shown the efficacy of combined iStent with cataract surgery in primary open angle glaucoma (POAG) and pseudoexfoliation glaucoma.3-8
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Two major types of primary glaucoma in adults are open angle and angle closure glaucoma. As aforementioned, the pathogenesis of POAG involves trabecular outflow resistance; whereas, in primary angle closure glaucoma (PACG), the narrowing and closure of the anterior chamber angle is thought to be a main mechanism for IOP elevation. However, in narrow angle cases where IOP still remains elevated despite opening of the angle by iridotomy, these eyes are thought to possess both ‘pre-trabecular’ and ‘trabecular’ factors for the IOP level. The term ‘mixed-mechanism glaucoma’ or ‘combined-mechanism glaucoma’ (CMG) refers to this kind of situation where both components are presented.9
Methods
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Management of CMG should include modalities to address both underlying etiologies. For the angle closure component, cataract surgery is an alternative option apart from the standard care of medications and iridotomy. Evidence showed the significant IOP reduction after lens removal in angle closure disease.10,11 Regarding the open angle component, the iStent can potentially help bypass the pathologic trabecular meshwork (TM), which may result in better glaucoma control. However, whether combined cataract surgery with iStent implantation in CMG will provide additional benefit to simple cataract surgery in terms of IOP control and medication reduction is still unknown. The objective of this study is to evaluate the effectiveness of the iStent implantation in CMG eyes which had prior laser peripheral iridotomy (LPI) and compare to its effect in POAG eyes.
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A retrospective comparative study of consecutive patients was undertaken at the ophthalmology clinic of a single glaucoma specialist (N.N.). The study was conducted in accordance to the Tenets of the Declaration of Helsinki with the approval from the institutional review board of the University of California, San Francisco. Medical charts of patients who received cataract surgery alone or cataract surgery with iStent implantation by a single surgeon (N.N.) during 2012-2017 were reviewed. The subjects who met the following criteria were included for the complete review: (1) age greater than 40 years, (2) underwent successful phacoemulsification with intraocular lens (IOL) implantation (with or without iStent implantation), (3) completed 1 year follow up after cataract surgery, and (4) diagnosis of primary glaucoma based on the International Society of Geographical and Epidemiological Ophthalmology (ISGEO) guidelines.12 The subjects were classified into open angle and closed angle group. Open angle was defined in eyes that had Shaffer angle grading of at least 2 for more than 180 degrees. For the closed angle group, we recruited only angle closure glaucoma cases that had combined
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mechanism. CMG was defined in eyes that had been documented to have occludable angle, which was defined as Shaffer angle grading 1 or less for 180 degrees or more, and the angle subsequently deepened and met the open angle definition after laser iridotomy but the IOP remained elevated and/or required glaucoma medications. Each group was further divided into 2 subgroups - simple phacoemulsification (PE) and phacoemulsification with iStent (PE/iStent) implantation - resulting in 4 subgroups in total: (1) POAG-PE, (2) POAG-PE/iStent, (3) CMG-PE, and (4) CMG-PE/iStent. The presence of peripheral anterior synechiae (PAS) was not an exclusion for CMG; however, the CMG eyes that had significant PAS at the nasal angle were excluded from the study.
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Exclusion criteria included: (1) any ocular or systemic condition that could affect vision and/or visual field interpretation; (2) any ocular or systemic condition that could affect IOP or preclude accurate tonometry (e.g., corneal pathology, previous refractive surgery, concurrent use of systemic steroid); (3) previous intraocular surgery including filtering surgery, glaucoma drainage device implantation, and retina surgery; (4) history of ocular trauma; and (5) complicated cataract surgery such as posterior capsule rupture, vitreous loss, intraoperative zonular instability, and dropped nucleus. Prior laser trabeculoplasty, intraoperative hyphema and intraoperative floppy iris syndrome were not considered as exclusions. Surgical technique
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The patients received standard phacoemulsification with temporal clear cornea incision. An acrylic foldable IOL was successfully implanted in all cases. For the iStent group, the stent was implanted after IOL implantation. The anterior chamber was filled with viscoelastic. After tilting the microscope and repositioning the patient’s head, the Hill surgical gonioprism (Ocular Instrument Inc., Bellevue, WA) was placed over the cornea to visualize the nasal angle. Once the TM was identified, the iStent applicator was inserted through the main corneal incision aiming towards the nasal quadrant. The iStent was implanted by sliding the leading edge through the TM into Schlemm’s canal. The tip of the applicator was used to tap on the iStent to make sure it was secure in the canal. The viscoelastic was then removed. The wound was closed by irrigating the wound with BSS.
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The patient was prescribed a fluorometholone drop 4 times a day for 5 weeks, a 0.3% nepafenac drop once a day for 5 weeks, and a fluoroquinolone antibiotic drop 4 times a day for 1 week. All antiglaucoma medications were kept the same as pre-operation until the IOP was reassessed at post-operative day 1, on which the glaucoma medications were adjusted. Further changes to the medications were based on the IOP at each follow up visit at the discretion of the surgeon (N.N.). Data collection and outcomes Pre-operative clinical information including best-corrected visual acuity (BCVA), IOP measured by Goldmann applanation tonometry, number of glaucoma medications, vertical cupto-disc (C/D) ratio, and visual field mean deviation obtained from automated perimetry (24–2 on Humphrey Field Analyzer-2; Carl Zeiss Meditec, Dublin, CA) were reviewed and recorded. The applanation IOP and number of medications were recorded at week 1, month 1, 3, 6, 9, and 1 year. The outcome measures were (1) the success rate which was defined as a proportion of subjects that had IOP≤18 mmHg without glaucoma medications, (2) the absolute post-operative IOP, and (3) the number of glaucoma medications at one year after surgery. The need for postoperative procedures such as glaucoma surgery and laser was collected and these subjects were excluded from the primary outcome comparison.
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Statistical analysis
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Assessment of normality was conducted using the Shapiro-Wilk statistic test. Depending on the distribution and type of variables, descriptive statistics were calculated as means and standard deviations, medians and interquartile range, or proportions. An independent t-test, Pearson Chi-square test, and Mann-Whitney U test were performed to compare the baseline characteristics of each studied group. Linear mixed effect regression was utilized to account for two eyes from the same subject as follows. For each group (open angle and closed angle), a multiple regression model was built to evaluate the effect of iStent in each measure outcome. Then, a second model containing the interaction between ‘iStent’ and ‘open/closed’ variables was performed to compare the effect of iStent between open angle and closed angle groups. Follow-up time was modeled using up to a third order polynomial. Pre-operative IOP was included as a covariate in all models. For the number of medications outcome, pre-operative number of medications was also used for the adjustment in the analysis models. A limit of statistical significance was set at p<0.05. All analyses were performed using R version 3.3 for Macintosh (R Foundation for Statistical Computing, Vienna, Austria). Results
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The study was comprised of 301 eyes from 241 subjects. The number of eyes (subjects) in each subgroup was 61 (45) in the POAG-PE group, 60 (50) in the POAG-PE/iStent group, 93 (76) in the CMG-PE group, and 87 (70) in the CMG-PE/iStent group. Only a single iStent was placed in all iStent cases. The PE/iStent subgroup had more pre-operative number of medications than the PE subgroup for both POAG (p=0.02) and CMG (p<0.001) groups. The baseline characteristics of subjects in each subgroup are summarized in Table 1.
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At 1-year post-operation, the success rates for the POAG group were 13.1% for POAGPE and 33.3% for POAG-PE/iStent, and the success rates for the CMG group were 37.6% for CMG-PE and 43.7% for CMG-PE/iStent. Figure 1 shows the success rate of each group over time. After adjustment for confounding variables, the linear mixed effect regression showed significantly higher success rate in POAG-PE/iStent than POAG-PE (B 3.01 p<0.001) in the POAG group and higher success rate in CMG-PE/iStent than CMG-PE (B 2.25 p<0.001) in the CMG group. The interaction model revealed no significant difference of the iStent effect on the success rate between the POAG and CMG groups (p=0.23).
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There was no difference in the absolute IOP at 1-year post-operation between POAGPE vs POAG-PE/iStent (13.58 vs 14.38 mmHg, p=0.28) and CMG-PE vs CME-PE/iStent (13.90 vs 14.58 mmHg, p=0.17). Data on IOP at each follow-up time point are shown in Table 2. Multiple regression models revealed no significant effect of the iStent on IOP in both the POAG group (p=0.07) and the CMG group (p=0.43). We could not demonstrate the difference of the iStent impact on absolute IOP between the POAG and CMG groups from the interaction model (p=0.46). For the number of medications, the PE/iStent subgroups had significantly higher baseline number of medications in both the POAG and CMG groups. Among POAG eyes, mean reduction in medications at 1 year was 1.32 ± 1.15 in the iStent group which was significantly higher than 0.40 ± 1.05 in the PE group (p<0.001). For the CMG group, mean reduction was 1.54 ± 0.96 in the iStent group, significantly greater than the 0.73 ± 0.79 reduction in the PE group (p<0.001). The number of medications and percentage of mediation-free eyes at each
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follow-up visit are shown in Figures 2 and 3, respectively. The mixed effect regression model with adjustment for baseline number of medications also showed significant reduction in medications for both POAG (B -0.70 p<0.001) and CMG (B -0.52 p<0.001). The interaction model revealed similar effects of the iStent on lowering medications between POAG and CMG group (p=0.09). Table 3 shows the effect of iStent for each outcome and the comparison of the effect between the POAG and CMG groups.
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Regarding visual outcome and safety, all groups had significant improvement of BCVA (all p<0.001). We found incidents of decreased BCVA at 1 year compared to pre-operation in 3 (6.7%), 0 (0%), 5 (6.7%), and 5 (7.1%) cases in POAG-PE, POAG-PE/iStent, CMG-PE, and CMG-PE/iStent, respectively (p=0.27, Fisher’s exact test). There was an intraoperative stent malposition in one case of CMG-PE/iStent. The first stent was removed, and the second attempt was successfully made. Another case in the CMG-PE/iStent group had intraoperative hyphema. The hyphema resolved subsequently within a few weeks without the need for an additional procedure. Both cases were included in the analysis. One case in the POAG-PE/iStent group required laser cyclophotocoagulation at approximately one year after surgery. This case was excluded from the final analysis. Discussion
Our retrospective study suggests that there may be a possible added benefit of iStent implantation, in conjunction with cataract surgery, in terms of the success rate and number of glaucoma medications at 1 year after surgery, in both POAG and CMG groups. The additional effect of combined PE/iStent to PE alone was not different between the POAG and CMG groups.
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Several published reports have shown the advantage of iStent in IOP control in POAG subjects.3-7 A study using a fluorophotometric method demonstrated that iStent enhanced conventional outflow facility by bypassing the pathologic TM, and thus, allowed the aqueous to drain into Schlemm’s canal.13 In agreement with previous literature, our findings in the POAG group showed that iStent had better success rate and significantly reduced number of medications.4,5,14 At 1 year after cataract surgery, both iStent and PE groups showed significant reduction of glaucoma medication use (reduction by 1.32 ± 1.13 and 0.40 ± 1.04, respectively) with more benefit in the iStent group (B -0.70 p<0.001). In our study, the final number of medications and percentage reduction of mean medications were comparable to a randomized controlled trial previously reported by Samuelson et al.5 The iStent treatment group also achieved greater success rate at every time-point through 12 months’ follow up. The success rate at 1 year in our study was 33.3% in the PE/iStent and 13.1% in the PE alone group, both of which were lower than what has previously been reported by studies from Samuelson et al. and Craven et al.5,14 The difference could be attributed to more stringent success criteria (IOP≤18 mmHg without medication) used in our study. As opposed to our criteria, both aforementioned studies defined the success as the proportion of subjects with IOP≤21 mmHg without medication. Moreover, our study is retrospective in nature. The difference in duration of follow up and study design may also limit direct comparison among studies. The benefit of cataract surgery in closed angle glaucoma is evident.10,15-18 Data showed that simple cataract surgery can reduce IOP by 6.4 mmHg in angle closure glaucoma concurrent with cataract11 and by 12.9 mmHg in eyes with clear lens.10 The mechanism is speculated to be related to the widening of the angle from changes in anterior segment anatomy and ciliary body position.19-21 CMG is an entity of angle closure glaucoma which is thought to have components from both POAG-related (trabecular) and PACG-related (pre-trabecular) mechanisms.9,22 Most commonly, CMG was diagnosed in the scenarios that angle-closure
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glaucoma is treated successfully with iridotomy, eliminating most if not all appositional closure, and IOP still remains elevated.9 The residual high IOP reflects the outflow resistance which is either from a preexisting TM dysfunction or acquired pathologic damage from prior angle apposition as documented by previous histopathological studies.23,24 It has been questioned whether iStent, which can address the trabecular resistance issue, can add further benefit to simple cataract surgery in angle closure with combined mechanism.
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Although the success rate of CMG-PE, which was as high as 37.6%, was better than what was achieved in both arms of the POAG group, the iStent further raised the success rate up to 43.7% in CMG eyes. The average number of medications was lower in the iStent group at every time point. The overall reduction was also significantly higher with iStent treatment. At 1 year, the iStent subgroup had a decreased medication burden by 1 drop in CMG patients which was comparable to the reduction achieved in POAG eyes in this study and a study from Fea et al.4 Moreover, in order to assess whether the beneficial effect in CMG is equivalent to the benefit obtained from the stent in POAG eyes, we compared the effect of iStent in CMG to the effect of iStent in the POAG group. Our analysis, which accounted for the baseline clinical differences and time factor, found no difference in the magnitude of the stent effect between POAG and CMG in all measured outcomes. Our results suggested that enhancing trabecular outflow can also provide therapeutic benefit to combined-mechanism angle closure subjects. The benefit was comparable to that observed with POAG diagnosis. However, it should be noted that the regression model comparison of iStent effect on POAG and CMG groups yielded marginal p value (p=0.09). There is still a possibility that the difference of iStent effect between 2 glaucoma groups can be demonstrated with greater statistical power in a larger data set.
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Of note, the IOP outcome did not show a significant difference between adjunctive iStent and simple PE in both POAG and CMG groups. The effect of PE either with or without iStent on IOP was likely to be confounded by medication adjustment during the follow-up course. The decrease in number of medications may reflect more of the IOP control in this retrospective assessment. In addition, our data showed that the success rate was greatest in the early postoperative period and gradually declined in all groups. The number of medications also slowly increased over time in a corresponding pattern. We observed that the downtrend reached its plateau around post-operative month 9. Whether the benefit of the iStent is sustained in the longer term for POAG and CMG will need to be explored by future longitudinal studies.
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It is also interesting to note that our study used the same success definition for both POAG and CMG eyes. In addition, the treatment in both groups was dictated by the same therapeutic decision to achieve the IOP ranges which were generally based on each patient’s glaucoma staging. However, since POAG and angle closure glaucoma are in different entities, the course of these diseases may differ. Currently, little is known about the exact target IOP for angle closure glaucoma eyes, which may tolerate higher IOP than POAG eyes. The comparison of iStent effect on POAG and CMG under different target IOP or definition of success still needs to be validated. Within the past few years, there has been emerging evidence supporting the role of cataract surgery as a treatment modality in angle closure disease.10,15-18,25 However, cataract surgery alone may be inadequate for some cases, especially those with moderate glaucoma or intolerance to hypotensive medication(s). The need for lower post-operative IOP or cessation of some of the eyedrops could be an issue in these cases. Apart from advancing to trabeculectomy, iStent implantation at the time of cataract surgery could be another alternative for selected angle closure patients for its lesser invasiveness and higher safety margin. Nevertheless, future prospective randomized studies to verify the role of this combined procedure in angle closure eyes are warranted.
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To best of our knowledge, this is the first study to evaluate the performance of iStent in angle closure patients. However, our study has some limitations. First, the retrospective design precluded the assessment of the washout IOP. Thus, the adjustment of the medications throughout the follow-up period was based solely on medicated IOP. Second, given that all IOPs recorded were medicated IOPs, we could not evaluate the true IOP reduction in this study. Third, the present data were derived mostly from cases of mild to moderate glaucoma. The results may not be able to be generalized to other glaucoma severities. Lastly, we included only angle closure cases that had been documented to have angle opening after LPI. The results of our study may not be applicable to all PACG cases.
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In conclusion, combined cataract surgery with iStent implantation significantly increased the success rate and reduced the number of medications in angle closure patients who showed deepening of the angle after LPI. The effects of iStent on the success rate and number of medications were comparable between the POAG and CMG groups. Acknowledgement
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Funding: This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Financial disclosures: SL is a consultant for Allergan, Aleyegn Technologies, Iridex Corporation, Tomey Corporation, and Aerie Pharmaceuticals. The other authors have no financial disclosure. Reference
Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90(3):262-267.
2.
Chen DZ, Sng CCA. Safety and Efficacy of Microinvasive Glaucoma Surgery. J Ophthalmol. 2017;2017:3182935.
3.
Ferguson TJ, Swan R, Ibach M, Schweitzer J, Sudhagoni R, Berdahl JP. Trabecular microbypass stent implantation with cataract extraction in pseudoexfoliation glaucoma. J Cataract Refract Surg. 2017;43(5):622-626.
4.
Fea AM. Phacoemulsification versus phacoemulsification with micro-bypass stent implantation in primary open-angle glaucoma: randomized double-masked clinical trial. J Cataract Refract Surg. 2010;36(3):407-412.
6.
EP
AC C
5.
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1.
Samuelson TW, Katz LJ, Wells JM, Duh YJ, Giamporcaro JE, Group USiS. Randomized evaluation of the trabecular micro-bypass stent with phacoemulsification in patients with glaucoma and cataract. Ophthalmology. 2011;118(3):459-467.
Patel I, de Klerk TA, Au L. Manchester iStent study: early results from a prospective UK case series. Clin Exp Ophthalmol. 2013;41(7):648-652.
7.
Tan SZ, Au L. Manchester iStent study: 3-year results and cost analysis. Eye (Lond). 2016;30(10):1365-1370.
8.
Belovay GW, Naqi A, Chan BJ, Rateb M, Ahmed, II. Using multiple trabecular microbypass stents in cataract patients to treat open-angle glaucoma. J Cataract Refract Surg. 2012;38(11):1911-1917.
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Samples JR, Schacknow PN. Clinical Glaucoma Care: The Essentials. Springer New York; 2013:306.
10.
Azuara-Blanco A, Burr J, Ramsay C, et al. Effectiveness of early lens extraction for the treatment of primary angle-closure glaucoma (EAGLE): a randomised controlled trial. Lancet. 2016;388(10052):1389-1397.
11.
Masis M, Mineault PJ, Phan E, Lin SC. The role of phacoemulsification in glaucoma therapy: A systematic review and meta-analysis. Surv Ophthalmol. 2017.
12.
Foster PJ, Buhrmann R, Quigley HA, Johnson GJ. The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol. 2002;86(2):238-242.
13.
Fernandez-Barrientos Y, Garcia-Feijoo J, Martinez-de-la-Casa JM, Pablo LE, Fernandez-Perez C, Garcia Sanchez J. Fluorophotometric study of the effect of the glaukos trabecular microbypass stent on aqueous humor dynamics. Invest Ophthalmol Vis Sci. 2010;51(7):3327-3332.
14.
Craven ER, Katz LJ, Wells JM, Giamporcaro JE, iStent Study G. Cataract surgery with trabecular micro-bypass stent implantation in patients with mild-to-moderate open-angle glaucoma and cataract: two-year follow-up. J Cataract Refract Surg. 2012;38(8):13391345.
15.
Barbosa DT, Levison AL, Lin SC. Clear lens extraction in angle-closure glaucoma patients. Int J Ophthalmol. 2013;6(3):406-408.
16.
Nonaka A, Kondo T, Kikuchi M, et al. Cataract surgery for residual angle closure after peripheral laser iridotomy. Ophthalmology. 2005;112(6):974-979.
17.
Tham CC, Kwong YY, Leung DY, et al. Phacoemulsification versus combined phacotrabeculectomy in medically controlled chronic angle closure glaucoma with cataract. Ophthalmology. 2008;115(12):2167-2173 e2162.
18.
Tham CC, Kwong YY, Leung DY, et al. Phacoemulsification versus combined phacotrabeculectomy in medically uncontrolled chronic angle closure glaucoma with cataracts. Ophthalmology. 2009;116(4):725-731, 731 e721-723.
19.
Nonaka A, Kondo T, Kikuchi M, et al. Angle widening and alteration of ciliary process configuration after cataract surgery for primary angle closure. Ophthalmology. 2006;113(3):437-441.
20.
Nolan WP, See JL, Aung T, et al. Changes in angle configuration after phacoemulsification measured by anterior segment optical coherence tomography. J Glaucoma. 2008;17(6):455-459.
22. 23.
24.
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9.
Lee W, Bae HW, Kim CY, Seong GJ. The change of anterior segment parameters after cataract surgery in normal-tension glaucoma. Int J Ophthalmol. 2017;10(8):1239-1245.
Hyams SW, Keroub C, Pokotilo E. Mixed glaucoma. Br J Ophthalmol. 1977;61(2):105106. Hamanaka T, Kasahara K, Takemura T. Histopathology of the trabecular meshwork and Schlemm's canal in primary angle-closure glaucoma. Invest Ophthalmol Vis Sci. 2011;52(12):8849-8861.
Sihota R, Lakshmaiah NC, Walia KB, Sharma S, Pailoor J, Agarwal HC. The trabecular meshwork in acute and chronic angle closure glaucoma. Indian J Ophthalmol. 2001;49(4):255-259.
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Brown RH, Zhong L, Lynch MG. Lens-based glaucoma surgery: using cataract surgery to reduce intraocular pressure. J Cataract Refract Surg. 2014;40(8):1255-1262.
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Figure captions
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Figure 1 Success rate for each study group at 1, 3, 6, 9, and 12 months: POAG-PE = primary open angle glaucoma (POAG) with phacoemulsification (PE) only; POAG-PE/iStent = POAG with PE and iStent; CMG-PE = combined mechanism glaucoma (CMG) with PE only; CMG-PE/iStent = CMG with PE and iStent. Success rate was defined as a proportion of subjects that had IOP≤18 mmHg without glaucoma medications.
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Figure 2 Mean of number of glaucoma medications for each study group at pre-operative and post-operative week 1, and months 1, 3, 6, 9, and 12: POAG-PE = primary open angle glaucoma (POAG) with phacoemulsification (PE) only; POAG-PE/iStent = POAG with PE and iStent; CMG-PE = combined mechanism glaucoma (CMG) with PE only; CMG-PE/iStent = CMG with PE and iStent.
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Figure 3 Percentage of medication-free eyes for each study group at 1, 3, 6, 9, and 12 months: POAG-PE = primary open angle glaucoma (POAG) with phacoemulsification (PE) only; POAG-PE/iStent = POAG with PE and iStent; CMG-PE = combined mechanism glaucoma (CMG) with PE only; CMG-PE/iStent = CMG with PE and iStent
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Table 1 Demographic and baseline clinical characteristics Open angle group POAG-PE/iStent
p-value
CMG-PE
CMG-PE/iStent
p-value
61 (45)
60 (50)
-
93 (76)
87 (70)
-
72.76 (9.88)
72.90 (6.41)
0.97
75.55 (7.51)
77.13 (4.89)
0.27
Gender b
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Age a (years)
POAG-PE
0.12 32 (71.11)
27 (54.00)
Female
13 (28.89)
23 (46.00)
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No. of eyes (subjects)
Closed angle group
Laterality b
0.39
34 (44.74)
24 (40.98)
42 (55.26)
36 (59.02)
0.32
0.68
25 (40.98)
30 (50.00)
42 (45.16)
42 (48.28)
Left
36 (59.02)
30 (50.00)
51 (54.84)
45 (51.72)
0.8 (0.6 to 0.9)
0.8 (0.6 to 0.9)
0.81
0.6 (0.4 to 0.8)
0.7 (0.4 to 0.9)
0.19
-4.83 (-6.80 to -2.53)
0.63
-4.05 (-6.07 to -2.29)
-4.89 (-9.05 to -3.59)
0.01
14.59 (2.86)
0.36
14.34 (2.96)
14.69 (3.39)
0.47
2 (1 to 2)
0.02
1 (1 to 2)
2 (1 to 3)
<0.001
0.22 (0.15)
0.82
0.23 (0.12)
0.19 (0.14)
0.02
Intraocular pressure (mmHg) a Number of medications c Best-corrected visual acuity (decimal) a
-4.59 (-7.43 to -2.9) 15.13 (3.53) 1 (1 to 2)
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a
Data was shown in mean (standard deviation) and p-value was obtained by t-test
b
Data was shown in n (%) and p-value was obtained by Chi-square test
c
Data was shown in median (interquartile range) and p-value was obtained by Mann-Whitney U test
POAG = primary open angle glaucoma; CMG = combined mechanism glaucoma
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Open angle group
Closed angle group
POAG-PE/iStent
p-value
CMG-PE
CMG-PE/iStent
p-value
15.13 (3.53)
14.59 (2.86)
0.36
14.34 (2.96)
14.69 (3.39)
0.47
Week 1
16.42 (4.46)
14.48 (4.31)
0.02
15.18 (3.65)
15.02 (4.27)
0.78
Month 1
15.14 (3.31)
13.93 (2.43)
0.03
14.97 (4.06)
14.35 (3.83)
0.30
Month 3
14.80 (3.56)
13.68 (3.01)
0.09
14.41 (4.31)
13.94 (3.84)
0.47
Month 6
14.38 (3.74)
13.88 (4.26)
0.55
14.00 (2.87)
14.42 (3.66)
0.43
Month 9
14.05 (3.31)
14.15 (3.38)
0.90
14.36 (2.59)
14.67 (3.18)
0.54
Month 12
13.58 (3.36)
14.38 (3.04)
0.28
13.90 (3.10)
14.58 (2.46)
0.17
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Table 2 Intraocular pressure at each follow-up time point
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Table 3 Multivariable linear mixed effect regression of the iStent effect on success rate, absolute intraocular pressure, and number of medications at 1-year post-operation iStent effect on POAG
iStent effect on CMG
Comparison of iStent effect on POAG and CMG groups
Beta coeff.
p-value
Beta coeff.
p-value
Beta coeff.
p-value
Success rate
3.01
<0.001
2.25
<0.001
-0.91
0.23
Absolute IOP
-0.30
0.43
-0.69
0.07
0.41
0.46
Number of medications
-0.70
<0.001
-0.52
<0.001
0.24
0.09
Negative beta coefficient indicates lower value in iStent subgroups
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Positive beta coefficient indicates higher value in iStent subgroups
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