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Journal of Current Glaucoma Practice logoLink to Journal of Current Glaucoma Practice
. 2018 Aug 1;12(2):67–84. doi: 10.5005/jp-journals-10008-1248

Efficacy and Adverse Event Profile of the iStent and iStent Inject Trabecular Micro-bypass for Open-angle Glaucoma: A Meta-analysis

Marko Popovic 1, Xavier Campos-Moller 2, Hady Saheb 3, Iqbal Ike K Ahmed 4,✉
PMCID: PMC6236117  PMID: 30473602

ABSTRACT

Aim

This meta-analysis explores the efficacy and adverse event profile of the iStent, an ab interno implant for the treatment of open-angle glaucoma.

Methods

A systematic literature search of Ovid MEDLINE and EMBASE was used to identify peer-reviewed original studies that provided efficacy data on the first or second generation iStent for at least five eyes. Intraocular pressure (IOP) was the primary efficacy endpoint, while the number of medication classes was the secondary outcome. Weighted mean differences were reported for continuous endpoints, while a relative risk was computed for dichotomous variables.

Review Results

The search revealed 545 results, of which 1767 eyes from 28 studies were included. The cohort age was 71.4 ± 5.4 years, and 44.9% of patients were male. There was a significantly greater IOP reduction after the use of two first-generation stents compared to one, irrespective of phacoemulsification status (p < 0.001). Additionally, there was a significantly greater IOP reduction following iStent alone relative to phaco-iStent for the first-generation iStent (p < 0.001) and the iStent inject (p < 0.001). For the first generation stent, combined phaco-iStent provided a greater level of IOP reduction (p < 0.001) and reduction in the number of medication classes relative to phacoemulsification alone (p < 0.001). In total, 22.5% of eyes that received iStent implantation sustained some type of adverse event. The most common adverse events were intraocular pressure elevation, stent blockage or obstruction, stent malposition and hyphema.

Conclusion and Clinical Significance

Statistically significant differences in efficacy outcomes exist between different numbers of stents and the presence or absence of concurrent phacoemulsification.

How to cite this article: Popovic M, Campos-Moller X, Saheb H, Ahmed IIK. Efficacy and Adverse Event Profile of the iStent and iStent Inject Trabecular Micro-bypass for Open-angle Glaucoma: A Meta-analysis. J Curr Glaucoma Pract 2018;12(2):67-84.

Keywords: Clinical efficacy, Glaucoma, Meta-analysis, Surgical instruments,

BACKGROUND

Given the irreversible retinal ganglion cell damage resulting from open-angle glaucoma (OAG), current treatment modalities are focused on preserving the structural integrity of the optic nerve and visual function.1-3 Prospective evaluations in glaucoma have demonstrated that the reduction of IOP leads to significant sparing of vision: namely, every 1 mm Hg reduction of IOP is correlated with an approximate 10% decrease in the risk of glaucomatous progression.4

In OAG, IOP elevation is often a result of reduced aqueous humor flow through the trabecular meshwork5 In early stages, ocular hypotensive medications and laser trabeculoplasty have been shown to attenuate glaucoma progression; however there are well known issues with compliance, tolerability, persistence, and difficulty of proper instillation.3,5 In the situations in which these treatments are insufficient in reducing IOP to target pressures according to disease severity, ab externo filtering procedures are utilized to provide a more significant IOP reduction. Unfortunately, these techniques are higher risk options that may result in a bleb-related complication, hemorrhage, hyphema, hypotony, infection, inflammation, loss of vision or reoperation.6,7

Recently, there has been increasing interest in the ability of microinvasive glaucoma surgery (MIGS) devices to provide a significant level of IOP reduction with less severe postoperative adverse events.8 One such device, the iStent ® (Glaukos Corporation, San Clemente, California), is the first ab interno glaucoma implant that has been approved for the management of mild-to-moderate OAG.9 The iStent works by allowing aqueous humor to drain directly from the anterior chamber into Schlemm’s canal, thus bypassing a portion of the trabecular meshwork and reducing IOP.10 Currently, the iStent has only received food and drug administration approval for use combined with cataract surgery.

Multiple randomized controlled trials and case series have investigated the efficacy and adverse event profile of the iStent device.2,11-37 Some have directly compared the combination of iStent implantation and phacoemulsification to phacoemulsification alone.3,16,17,19-22,30 Others have been single-armed case series or have compared the iStent to ocular hypotensive medications.11-15,18,23-29 More recent research has focused on a second-generation trabecular micro-bypass device termed the iStent inject,11,14,20,24,29,34,36 which consists of two heparin coated titanium stents that are both inserted ab interno through the trabecular mesh-work into Schlemm’s canal.29 Differences in outcomes between single versus multiple iStents have also been investigated.11,13,14,17,20,21,23-25,29,31 In general, most studies have focused on patients with early stages of primary OAG 11,14-16,21,22,27-29,32

There has been a rapid expansion of iStent research in recent years.3,11-37 Given these new data, it is uncertain whether there are any differences in efficacy between single versus multiple stents or between phaco-iStent compared to either iStent alone or phacoemulsification alone. Additionally, the most frequently reported adverse events in the literature following iStent therapy should be identified. As such, the following meta-analysis aims to investigate the efficacy and adverse event profile of iStent implantation for the management of OAG.

METHODS

Literature Search and Data Collection

A systematic literature search was performed on Ovid MEDLINE (2006-Week 1 2018) and Ovid EMBASE (20062018 Week 3). The search strategy that was used can be found in Table 1A and B. Further, Google, Google Scholar and the reference lists of past reviews were manually searched to elicit further relevant literature. Any original prospective or retrospective clinical study that provided relevant efficacy data (i.e., IOP and number of medication classes) on the implantation of the iStent for at least five eyes was included. Only peer-reviewed journal articles were included. Non-english studies, letters to the editor, correspondences, editorials, reviews, opinions, case reports, articles reporting on other surgical procedures and studies that contained repeat data or less than 4 week follow-up were excluded. Studies were screened first by consulting titles and abstracts and afterwards by examining full-text versions. To assist with the screening process, a quality assessment of articles was performed. The Cochrane criteria were used in the assessment of randomized controlled trials, while the National Institute for Health and Care Excellence tool was used to evaluate case series.38,39 In both cases, studies were excluded if there was a high risk of bias in at least half of the assessment categories.

Table 1A: Search strategy for Ovid MEDLINE

#      Searches      Results     
1      iStent.m_titl.      29     
2      iStent.mp.      62     
3      Trabecular micro-bypass.mp.      25     
4      Glaukos.mp.      30     
5      Microinvasive glaucoma surgery.mp.      12     
6      Minimally invasive glaucoma surgery.mp.      38     
7      Minimally Invasive Surgical Procedures/      24740     
8      Ophthalmologic Surgical Procedures/      12012     
9      7 and 8      86     
10      Stents/      65102     
11      Glaucoma/      37134     
12      10 and 11      43     
13      1 or 2 or 3 or 4 or 5 or 6 or 9 or 12      222     
14      Limit 13 to yr = “2006-Current”      205     
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Table 1B: Search strategy for Ovid EMBASE

#      Searches      Results     
1      iStent.m_titl.      47     
2      iStent.mp.      158     
3      Trabecular micro-bypass.mp.      52     
4      Glaukos.mp.      125     
5      Microinvasive glaucoma surgery.mp.      27     
6      Minimally invasive glaucoma surgery.mp.      73     
7      Minimally invasive surgery/      33752     
8      Eye surgery/      66     
9      1 and 8      66     
10      Stent/      81559     
11      Glaucoma/      51832     
12      10 and 11      87     
13      1 or 2 or 3 or 4 or 5 or 6 or 9 or 12      358     
14      Limit 13 to yr = “2006-Current”      340     
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Variables that were included for the baseline demographic evaluation were country of origin, study design, distribution of right and left eyes, age, gender, ethnicity, cup-to-disc ratio, visual field, mean deviation and time of follow-up. The primary efficacy endpoint, IOP, was collected as a continuous variable (i.e., IOP postoperatively and reduction pre- to post-operatively). The postoperative number of hypotensive medication classes and pre- to post-operative reduction in the number of medication classes was the secondary endpoint. For the efficacy analysis, data on the number of iStents and phacoemulsification status (i.e., whether concomitant phacoemulsification was performed) were extracted. For adverse event analysis, the number of events and the four most prevalent events for each study arm were recorded. Postoperative outcomes were collected at last follow-up.

Statistical Analysis

Weighted mean differences (WMD) and corresponding 95% confidence intervals (95% CI) were reported in the analysis of primary and secondary endpoints. Throughout the analysis, the number of eyes (i.e., sample size) was used as a weighted variable. Alongside a random effects model, the inverse variance method was used in the meta-analysis. The weighted mean was defined as

graphic file with name jocgp-12-067-i001.jpg

while the weighted standard deviation was computed using the formula

graphic file with name jocgp-12-067-i002.jpg

Due to the differential reporting of included studies, each unique endpoint contains data from a different collection of studies. A consequence of this is that the WMDs of IOP and medication class reduction will likely not equal the difference between the preoperative and postoperative values for IOP and medication class count.

In the test for overall effect, a p-value of less than 0.05 was considered statistically significant. The main analysis was performed based on whether patients had 1, 2 or 3 iStents implanted and whether they did or did not receive combined phacoemulsification and iStent. All statistical analyses were performed using Review Manager (RevMan 5.3; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and Microsoft ® Excel (Microsoft Corporation, Redmond, Washington).

REVIEW RESULTS

Study Inclusions and Baseline Demographics

The systematic search revealed 545 results. Upon title and abstract screening, the number of potential articles was reduced to 135. Afterwards, full-text screening resulted in 28 studies that met al.l inclusion criteria (Fig. 1).3,11-37 Baseline characteristics and the results of quality assessment for included studies are reported on Table 2A. Within the cohort of 1773 eyes for which there was relevant demographic information, the mean age was 71.4 ± 5.4 years (n = 1606; cohort range: 54.4-78.8 years), and 747 out of 1662 eyes were male (44.9%). Most eyes came from Caucasian patients (870 out of 1089 eyes, 79.9%). Generally, studies were moderate to high quality (Tables 2B and C). No study met the a priori condition for exclusion based on the quality assessment.

Fig. 1:

Fig. 1:

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Modified preferred reporting Items for systematic reviews and meta-analysis (PRISMA) flow diagram

Table 2A: Baseline demographics of included trials

Study    Country    Single center or multicenter    Study design    2016 journal 2-year cites per document    Number of eyes    Age    Number of males    Number of Caucasians    Mean cup-to-disk ratio    Mean visual field (MD, dB)   
Samuelson et al., 2011    United States    Multicenter    Prospective randomized controlled trial    Ophthalmology; 7.40    117    74 ±8    46    83    n/a    –3.75 ± 3.03   
Fea etal., 2014    Europe    Multicenter    Prospective randomized controlled trial    Clinical ophthalmology; 1.86    94    64.5 ± 10.3    37    94    n/a    n/a   
Buchacra et al., 2011    Spain    Single center    Prospective case series    Clinical ophthalmology; 1.86    10    54.4 ±7.9    9    n/a    n/a    n/a   
Ahmed etal., 2014    Armenia    Single center    Prospective case series    Journal of Cataract and Refractive Surgery; 2.69    39    62.8 ± 12.6    21    39    0.7 ±0.1    –6.47 ± 7.2   
Voskanyan et al., 2014    Europe    Multicenter    Prospective case series    Advances in therapy; 2.98    99    66.4 ± 10.9    43    95    0.7 ±0.2    n/a   
Vandewalle et al., 2009    Belgium    Single center    Prospective case series    Bulletin de la Societe Beige d’Ophtalm ologie; 0.158 (2015)    10    69    n/a    n/a    n/a    –13.7   
Fea, 2010    Italy    Single center    Prospective randomized controlled trial    Journal of Cataract and Refractive Surgery; 2.69    12    64.5 ±3.4    4    n/a    n/a    n/a   
Belovay etal., 2012    Canada    Single center    Prospective case series    Journal of Cataract and Refractive Surgery; 2.69    26    78.8 ± 7    7    18    0.76 ±0.16    –12.6 ±7.1   
2nd study arm    Canada    Single center    Prospective case series    Journal of Cataract and Refractive Surgery; 2.69    23    75 ± 7.3    9    11    0.71 ±0.17    .-10.2 ±8.1   
Patel etal., 2013    United Kingdom    Single center    Prospective case series    Clinical and Experimental Ophthalmology; 2.93    44    76.8    n/a    n/a    n/a    n/a   
Arriola- Villalobos et al., 2012)    Spain    Single center    Prospective case series    British Journal of Ophthalmology; 3.52    19    74.63 ± 8.44    9    19    n/a    n/a   
Arriola-Villalobos et al., 2013    Spain    Single center    Prospective case series    British Journal of Ophthalmology; 3.52    20    75.1 ± 8.6    9    20    n/a    n/a   
Fernandez-Barrientos et al., 2010    Spain    Single center    Prospective randomized controlled trial    Investigative Ophthalmology and Visual Science; 3.15    17    75.2 ±7.2    6    n/a    n/a    n/a   
Spiegel etal., 2009    Europe    Multicenter    Prospective case series    European Journal of Ophthalmology; 1.15    47    76.2 ±6.7    18    46    n/a    n/a   
Wang etal., 2015    Canada    Single center    Retrospective case series    Journal of Ophthalmology; 1.79    96    70.6 ±2.8    53    86    n/a    –7.3 ±2.1   
Klamann etal., 2015    Germany    Single center    Retrospective case series    Graefe’s Archive for Clinical and Experimental Ophthalmology; 2.42    35    61.3 ±3.5    15    n/a    n/a    n/a   
Khan etal., 2015    Canada and United States    Multicenter    Retrospective case series    Journal of Cataract and Refractive Surgery; 2.69    49    77.5 ±11.9    20    34    n/a    –11.5 ±8.0   
Seibold etal., 2016    United States    Single center    Retrospective case series    Journal of Cataract and Refractive Surgery; 2.69    64    73.9 ±8.8    23    34    n/a    n/a   
Gallardo etal., 2016    United States    Single center    Retrospective case series    Clinical Ophthalmology; 1.86    100    74.6 ±8.9    37    14    0.7 ±0.2    n/a   
Ferguson et al., 2016    United States    Single center    Retrospective case series    Clinical Ophthalmology; 1.86    350    74.1 ± 9.0    133    n/a    n/a    n/a   
Lindstrom et al., 2016    Armenia    Single center    Prospective case series    Advances in Therapy; 2.98    57    65.3 ±9.0    30    57    0.7 ±0.1    –4.9 ±5.3   
El Wardani etal., 2015    Switzerland    n/a    Retrospective case series    Klinische Monatsblatter fur Augenheilkunde; 0.52    31    n/a    n/a    n/a    n/a    n/a   
2nd Study Arm    Switzerland    n/a    Retrospective case series    Klinische Monatsblatter fur Augenheilkunde; 0.52    22    n/a    n/a    n/a    n/a    n/a   
Katzetal., 2015    Armenia    Single center    Prospective randomized controlled trial    Clinical Ophthalmology; 1.86    38    68.1 ± 9.1    27    38    0.68 ±0.11    –4.72 ± 4.42   
2nd Study Arm    Armenia    Single center    Prospective randomized controlled trial    Clinical Ophthalmology; 1.86    41    67.8 ±9.3    19    41    0.71 ±0.14    –5.20 ± 5.65   
3rd Study Arm    Armenia    Single center    Prospective randomized controlled trial    Clinical Ophthalmology; 1.86    40    60.9 ±8.1    19    40    0.70 ±0.12    –4.81 ± 4.22   
Shiba etal., 2017    Japan    Single center    Prospective case series    Journal of Ophthalmology; 1.79    10    64.6 ± 10.7    7    0    n/a    –15.4 ±8.1   
Zheng etal., 2017    USA    Single center    Retrospective case series    International Journal of Ophthalmology; 1.30    34    74    9 of 30    21 of 30    n/a    n/a   
Berdahl etal., 2017    Armenia    Single center    Prospective case series    Clinical & Experimental Ophthalmology; 2.93    53    64.7 ±9.6    27    53    0.7 ±0.1    n/a   
Ferguson et al., 2017    USA    Single center    Retrospective case series    Journal of Cataract and Refractive Surgery; 2.69    115    77.42 ±8.51    86    n/a    0.68 ±0.11    n/a   
Gonnermann et al., 2017    Germany    Single center    Retrospective case series    Graefe’s Archivefor Clinical and Experimental Ophthalmology; 2.42    27    73.8 ±7.8    13    27    n/a    n/a   
Kurji etal., 2017    Canada    Single center    Retrospective case series    Canadian Journal of Ophthalmology; 1.57    34    75.02 ± 10.34    11    n/a    n/a    n/a   
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*MD = Mean deviation; dB = Decibels; n/a = Not available.

Table 2B: Quality assessment of included randomized controlled trials (Cochrane criteria)

Study      Year      Random sequence generation (Selection bias)      Allocation concealment (Selection bias)      Blinding of participants and personnel (Performance bias)      Blinding of outcome assessment (Detection bias)      Incomplete outcome data (Attrition bias)      Selective reporting (Reporting bias)      Other bias     
Samuelson et al.      2011      Low      Unclear      High      Low      High      Low      Low     
Fea et al.      2014      Unclear      Unclear      High      High      Low      Low      Low     
Fea      2010      Low      Unclear      Low      Low      Low      Low      Low     
Fernandez-Barrientos et al.      2010      Low      Unclear      Unclear      Low      Low      Low      Low     
Katz et al.      2015      Unclear      Unclear      High      High      Low      Low      Low     
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Table 2C: Quality assessment of included case series (National Institute for Health and Care Excellence Criteria)

Study    Year    Multicen-tered    Study objective described    Inclusion and exclusion criteria reported    Outcomes definition reported    Prospective    Consecutive recruitment    Description of study findings    Stratification of out-omes   
Buchacra et al.    2011    No    Yes    Yes    No    Yes    Unclear    Yes    No   
Ahmed et al.    2014    No    Yes    No    Yes    Yes    Unclear    Yes    No   
Voskanyan et al.    2014    Yes    Yes    Yes    Yes    Yes    Unclear    Yes    No   
Vandewalle et al.    2009    No    Yes    Yes    Yes    Yes    Unclear    Yes    No   
Belovay et al.    2012    No    Yes    Yes    No    Yes    Unclear    Yes    No   
Patel et al.    2013    No    Yes    Yes    No    Yes    Unclear    Yes    No   
Arriola- Villalobos et al.    2012    No    Yes    Yes    No    Yes    Unclear    Yes    No   
Arriola- Villalobos et al.    2013    No    Yes    Yes    No    Yes    Yes    Yes    No   
Spigel et al.    2009    Yes    Yes    Yes    No    Yes    Unclear    Yes    No   
Wang et al.    2015    No    Yes    No    Yes    No    Yes    Yes    Yes   
Klamann et al.    2015    No    Yes    Yes    Yes    No    Yes    Yes    No   
Khan et al.    2015    Yes    Yes    Yes    No    No    Unclear    Yes    Yes   
Seibold et al.    2016    No    Yes    Yes    Yes    No    Unclear    Yes    No   
Gallardo et al.    2016    No    Yes    Yes    Yes    No    Yes    Yes    Yes   
Ferguson et al.    2016    No    Yes    Yes    Yes    No    Yes    Yes    Yes   
Lindstrom et al.    2016    No    Yes    Yes    Yes    Yes    Unclear    Yes    No   
El Wardani et al.    2015    No    Yes    Yes    Yes    No    Yes    Yes    Yes   
Shiba et al.    2017    No    Yes    Yes    Yes    Yes    Yes    Yes    No   
Zheng et al.    2017    No    Yes    Yes    No    No    Unclear    Yes    No   
Berdahl et al.    2017    No    Yes    Yes    Yes    Yes    Unclear    Yes    No   
Ferguson et al.    2017    No    No    Yes    Yes    Yes    Yes    Yes    Yes   
Gonnermann et al.    2017    No    Yes    Yes    Yes    No    Unclear    Yes    No   
Kurji et al.    2017    No    Yes    Yes    Yes    No    Yes    Yes    Yes   
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Of the 1767 eyes included in the efficacy and adverse event analysis, a total of 1217 (68.9%) underwent combined iStent implantation and phacoemulsification, while 497 eyes (28.1%) underwent iStent implantation alone (Table 3). More than half of included eyes had one iStent implanted (999, 56.5%), while 685 eyes had two (38.8%) and 63 eyes received three (3.6%). Overall, the vast majority of eyes (1398, 79.1%) received a first generation iStent, while only 369 eyes (20.9%) received an iStent inject. The distribution of relevant clinical features between groups is presented in Table 4.

Table 3: Efficacy endpoints and stratification characteristics of included trials

Study   Numbei of Eyes   IOP ’ reduction   IOP Preoperative   IOP Postopera-tively   Reduction in medications   Number of Medica-tions Preopera-tively   Number of Medications Postopera-tively   Follow-up (months)   Number of iStents   Combined Phacoe– mulsification   iStent Generation   Type of Glaucoma  
Samuelson et al., 2011   117   8.4± 3.6   25.2 ±3.5   n/a   1.4±0.8   1.5 ±0.7   0.2±0.6   12   1   Yes   First   Any  
Fea et al., 2014   94   12.2± 2.5   25.2 ±1.4   13.0±2.3   n/a   1.0±0   n/a   12   2   No   Second   Primary  
Buchacra et al., 2011   8   6.6±5.4   26.5± 7.9   17.0±2.5   1.1±0.6   2.9±0.7   2   12   1   No   First   Secondary  
Ahmed et al., 2014   39   13.5   25.3 ±1.8   11.8±2.1   1.0±0   2.0±0   1.0±0   18   2   No   First   Any  
Voskanyan et al., 2014   88   10.4±3.2   26.3± 3.5   15.7±3.7   n/a   2.21±0.44   n/a   12   2   No   Second   Pseudoexfol iative  
Vandewalle et al., 2009   9   4.2   20   15.8   1   2.7   1.7   12   1   Mixed   First   Primary  
Fea, 2010   12   3.2±3   17.9± 2.6   14.8±1.2   1.6   2±0.9   0.4±0.7   15   1   Yes   First   Primary  
Belovay et al., 2012   28   3.5   17.3±4   13.8±4   1.8   2.8±0.8   1.0±1.1   12   2   Yes   First   Primary, mixed  
2nd study arm   25   3.9   18.6±4   14.8±3   2.2   2.6±1.2   0.4±0.5   12   3   Yes   First   Primary, mixed  
Patel et al., 2013   44   5   21.5 ±5   16.5±3   1.7   2.3±0.9   0.6±1.0   6   1   Mixed   First   Any  
Arriola Villalobos et al., 2012   19   3.16±3.9   19.42±1.89   16.26±4.23   0.47±0.96   1.32±0.48   0.84±0.89   Mean: 53.68±9.26   1   Yes   First   Any  
Arriola-Villalobos et al., 2013   20   9.42±3   26±3.11   16.75±2.24   1±0.79   1.3±0.66   0.3±0.57   12   1 or 2   Yes   Second   Any open angle  
Fernandez-Barrientos et al., 2010   17   6.6±3.0   24.2±1.8   17.6±2.8   1.1   1.1±0.5   0   12   2   Yes   First   Primary  
Spiegel et al., 2009   42   4.4±4.54   21.7±3.98   17.4±2.99   1.2±0.7   1.6±0.8   0.4±0.62   12   1   Yes   First   Primary  
Wang et al., 2015   96   2.50±5.80   n/a   n/a   1.38±1.43   2.14±0.16   0.76   3   2   Yes   First   Any  
Klamann et al., 2015   32   7.67   22.39±1.81   14.72±0.80   1.3   2.26±0.1   0.96±0.11   6   2   No   Second   Primary, pseudoexfol iative, pigmentary  
Khan et al., 2015   49   n/a   19.6±5.2   14.3±3.1   n/a   2.86±0.91   1.22±1.28   12   2   Yes   First   Primary, pseudoexfol iative, pigmentary  
Seibold et al., 2016   64   1.5   14.7±3.2   13.2±2.8   0.4   1.8±1.1   1.4±1.5   12   1   Yes   First   Any  
Gallardo et al., 2016   134   3.6   16.5±3.7   12.9±2.1   1.4   2.3±1.1   0.9±1.2   12   1   Yes   First   Primary  
Ferguson et al., 2016   350   4.0   19.1±6.3   15.2±3.5   0.6   1.2±1.0   0.6±1.0   24   1   Yes   First   Primary  
Lindstrom et al., 2016   57   10.0   24.4±1.3   14.4±2.1   1.0   1.0±0   0.02   18   2   No   Second   Primary  
El Wardani et al., 2015   31   1.6   16.7   15.1   1.7   2.5   0.8   6   1   Yes   First   N/a  
2nd Study Arm   22   3.2   17   13.8   1.1   2.1   1   6   2   Yes   First   N/a  
Katz et al., 2015   37   10.6   25.0±1.1   14.4 ±1.2   1.6   1.71± 0.61   0.11   12   1   No   First   Primary, pseudoexfol iative, pigmentary  
2nd study arm   41   12.2   25.0±1.7   12.8 ±1.4   1.66   1.76±0.54   0.10   12   2   No   First   Primary, pseudoexfol iative, pigmentary  
3rd study arm   38   12.9   25.1±1.9   12.2 ±1.5   1.43   1.51± 0.69   0.08   12   3   No   First   Primary, pseudoexfol iative, pigmentary  
Shiba et al., 2017   10   5.1   22.0±3.0   16.9 ±3.6   0   3± 0   3±0   6   2   No   First   Primary  
Zheng et al., 2017   17   3   19.7±4.1   16.7 ±2.1   1.4   2.2± 1.2   0.8±1.3   6   1   Yes   First   Any  
Berdahl et al., 2017   53   6.8   19.7±1.5   12.9 ±2.1   1±0   2± 0   1±0   18   2   No   Second   Any  
Ferguson et al., 2017   115   5.49   20.00 ±6.95   14.51 ±2.79   0.7   1.41± 1.04   0.71   24   1   Yes   First   Pseudoexfol iative  
Gonnerman n et al., 2017   25   7.8   21.3±4.1   0. 13.5 ±5   0.72   2.0± 0.9   1.28±1.17   12   2   Yes   Second   Primary, pseudoexfol iative  
Kurji et al., 2017   34   3.87   17.47 ±4.87   13.6 ±3.4   0.32±0.59   2.15± 1.21   1.83±1.2   6   2   yes   First   Primary, pseudoexfol iative  
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* IOP = intraocular pressure.

Table 4: Distribution of clinical features for first generation studies by type of analysis

Type of analysis    Baseline feature    Comparator 1    Comparator 2    Proportion of baseline feature in comparator 1 (%)    Proportion of baseline feature in comparator 2   
Number of iStents-reduction in IOP    Phacoemulsification status    One iStent    Two iStents    iStent alone: 45/999 (4.5%)    iStent alone: 90/287 (31.4%)   
Number of iStents-preoperative IOP    Phacoemulsification status    One iStent    Two iStents    iStent alone: 45/999 (4.5%)    iStent alone: 90/240 (37.5%)   
Number of iStents-postoperative IOP    Phacoemulsification status    One iStent    Two iStents    iStent alone: 45/882 (5.1%)    iStent alone: 90/240 (37.5%)   
Number of iStents-reduction in medications    Phacoemulsification status    One iStent    Two iStents    iStent alone: 45/999 (4.5%)    iStent alone: 90/287 (31.4%)   
Number of iStents-preoperative medications    Phacoemulsification status    One iStent    Two iStents    iStent alone: 45/999 (4.5%)    iStent alone: 90/336 (26.8%)   
Number of iStents- postoperative medications    Phacoemulsification status    One iStent    Two iStents    iStent alone: 45/999 (4.5%)    iStent alone: 90/336 (26.8%)   
Number of iStents-reduction in IOP    Phacoemulsification status    One iStent    Three iStents    iStent alone: 45/999 (4.5%)    iStent alone: 38/63 (60.3%)   
Number of iStents-preoperative IOP    Phacoemulsification status    One iStent    Three iStents    iStent alone: 45/999 (4.5%)    iStent alone: 38/63 (60.3%)   
Number of iStents-postoperative IOP    Phacoemulsification status    One iStent    Three iStents    iStent alone: 45/882 (5.1%)    iStent alone: 38/63 (60.3%)   
Number of iStents-reduction in medications    Phacoemulsification status    One iStent    Three iStents    iStent alone: 45/999 (4.5%)    iStent alone: 38/63 (60.3%)   
Number of iStents-preoperative medications    Phacoemulsification status    One iStent    Three iStents    iStent alone: 45/999 (4.5%)    iStent alone: 38/63 (60.3%)   
Number of iStents - postoperative medications    Phacoemulsification status    One iStent    Three iStents    iStent alone: 45/999 (4.5%)    iStent alone: 38/63 (60.3%)   
Number of iStents -reduction in IOP    Phacoemulsification status    Two iStents    Three iStents    iStent alone: 90/287 (31.4%)    iStent alone: 38/63 (60.3%)   
Number of iStents -preoperative IOP    Phacoemulsification status    Two iStents    Three iStents    iStent alone: 90/240 (37.5%)    iStent alone: 38/63 (60.3%)   
Number of iStents -postoperative IOP    Phacoemulsification status    Two iStents    Three iStents    iStent alone: 90/240 (37.5%)    iStent alone: 38/63 (60.3%)   
Number of iStents -reduction in medications    Phacoemulsification status    Two iStents    Three iStents    iStent alone: 90/287 (31.4%)    iStent alone: 38/63 (60.3%)   
Number of iStents -preoperative medications    Phacoemulsification status    Two iStents    Three iStents    iStent alone: 90/336 (26.8%)    iStent alone: 38/63 (60.3%)   
Number of iStents - postoperative medications    Phacoemulsification status    Two iStents    Three iStents    iStent alone: 90/336 (26.8%)    iStent alone: 38/63 (60.3%)   
Phacoemulsification status - IOP reduction    Number of iStents    iStent alone    Phaco-iStent    One iStent: 45/173 (26.0%)    One iStent: 901/1123 (80.2%)   
Phacoemulsification status - preoperative IOP    Number of iStents    iStent alone    Phaco-iStent    One iStent: 45/173 (26.0%)    One iStent: 901/1076 (83.7%)   
Phacoemulsification status - postoperative IOP    Number of iStents    iStent alone    Phaco-iStent    One iStent: 45/173 (26.0%)    One iStent: 784/959 (81.8%)   
Phacoemulsification status - reduction in medications    Number of iStents    iStent alone    Phaco-iStent    One iStent: 45/173 (26.0%)    One iStent: 901/1123 (80.2%)   
Phacoemulsification status -preoperative medications    Number of iStents    iStent alone    Phaco-iStent    One iStent: 45/173 (26.0%)    One iStent: 901/1172 (76.9%)   
Phacoemulsification status -postoperative medications    Number of iStents    iStent alone    Phaco-iStent    One iStent: 45/173 (26.0%)    One iStent: 901/1172 (76.9%)   
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IOP = intraocular pressure.

In terms of study design, the majority (19/28; 67.9%) of studies were case series, while another 17.9% (5/28) were randomized controlled trials. A total of 60.7% of studies were prospective (17/28), while the rest (11/28, 39.3%) were retrospective. Most studies (22/27; 81.5%) extracted data from a single center while a smaller number were multicentered (5/27; 18.5%).

Number of iStents-First Generation

Not accounting for phacoemulsification status, meta-analysis was only possible to evaluate the effect of the number of stents on IOP and medication class reduction for first generation iStents (Table 5A-C, Figs 2A and B). When examining IOP reduction, there was a significantly greater decrease after two stents compared to one [WMD = -1.36 mm Hg, 95% CI = (-1.92 mm Hg, -0.80 mm Hg), p < 0.001]. This may have been influenced by the fact that two-stent patients had a significantly greater preopera-tive IOP than one-stent patients [WMD = -1.35 mm Hg, 95% CI = (-1.85 mm Hg, -0.85 mm Hg), p < 0.001]. At the same time, implantation of two stents led to a lesser postoperative IOP when compared to one [WMD = 1.02 mm Hg, 95% CI = (0.80 mm Hg, 1.24 mm Hg), p < 0.001]. There was a greater IOP reduction [WMD= -4.66 mm Hg, 95% CI = (-6.20 mm Hg, -3.12 mm Hg), p < 0.001], higher preoperative IOP [WMD = -2.80 mm Hg, 95% CI = (-3.93 mm Hg, -1.67 mm Hg), p < 0.001] and lower postoperative IOP [WMD = 1.57 mm Hg, 95% CI = (1.12 mm Hg, 2.02 mm Hg), p < 0.001] following three stents relative to one. There was a greater IOP reduction [WMD = -3.30 mm Hg, 95% CI = (-4.93 mm Hg, -1.67 mm Hg), p < 0.001], higher preoperative IOP [WMD = -1.45 mm Hg, 95% CI = (-2.65 mm Hg, -0.25 mm Hg), p = 0.02] and a lower postoperative IOP [WMD = 0.55 mm Hg, 95% CI =(0.06 mm Hg, 1.04 mm Hg), p = 0.03] after three stents relative to two.

Table 5A: Efficacy outcomes of one versus two first generation iStent implantation

   One iStent    Two iStents    Meta-analysis   
Outcome    Mean    Standard deviation    Number of eyes    Mean    Standard deviation    Number of eyes    Weighted mean difference    95% CI - lower bound    95% CI – upper bound    p-value   
IOP reduction    4.67    2.18    999    6.03    4.66    355    –1.36    –1.86    –0.86    p <0.001   
Preoperati ve IOP    19.72    3.06    999    21.07    3.66    240    –1.35    –1.85    –0.85    p <0.0   
Postopera tive IOP    14.80    1.25    882    13.78    1.62    240    1.02    0.80    1.24    p <0.001   
Reduction in medications    0.97    0.46    999    1.20    0.51    287    –0.23    –0.30    –0.16    p <0.001   
Preoperati ve medicatio ns    1.62    0.48    999    2.21    0.48    336    –0.59    –0.65    –0.53    p <0.0 01   
Postopera tive medications    0.67    0.34    999    0.95    0.64    336    –0.28    –0.35    –0.21    p <0.001   
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*IOP = Intraocular pressure. CI = Confidence interval

Table 5C: Efficacy outcomes of two versus three first generation iStent implantation

   Two iStents    Three iStents    Meta-Analysis   
Outcome    Mean    Standard deviation    Number of eyes    Mean    Standard deviation    Number of eyes    Weighted mean difference    95%CI –Lower bound    95%CI –Upper bound    p-value   
IOP reduction    6.03    4.66    287    9.33    6.23    63    –3.30    –4.93    –1.67    p <0.001   
Preoperative IOP    21.07    3.66    240    22.52    4.50    63    –1.45    –2.65    –0.25    p = 0.02   
Postoperative IOP    13.78    1.62    240    13.23    1.80    63    0.55    0.06    1.04    p = 0.03   
Reduction in medications    1.20    0.51    287    1.74    0.53    63    –0.54    –0.68    –0.40    p <0.001   
Preoperative medications    2.21    0.48    336    1.94    0.75    63    0.27    0.08    0.46    p = 0.006   
Postoperative medications    0.95    0.64    336    0.21    0.22    63    0.74    0.65    0.83    p <0.001   
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*IOP = Intraocular pressure. CI = Confidence interval. n/a = Not available. Note: Red text denotes endpoints that substantially differed from those of the original analysis.

Fig. 2A:

Fig. 2A:

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Number of first generation iStents-IOP

Fig. 2B:

Fig. 2B:

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Number of First Generation iStents-number of medication classes

Table 5B: Efficacy outcomes of one versus three first generation iStent implantation

   One iStent    Three iStents    Meta-Analysis   
Outcome    Mean    Standard deviation    Number of eyes    Mean    Standard deviation    Number of eyes    Weighted mean difference    95%CI –Lower bound    95%CI –Upper bound    p-value   
IOP reduction Preoperative    4.67    2.18    999    9.33    6.23    63    –4.66    –6.20    –3.12    p <0.001   
IOP Postoperative    19.72    3.06    867    22.52    4.50    63    –2.80    –3.93    –1.67    p <0.001   
IOP Reduction in    14.80    1.25    882    13.23    1.80    63    1.57    1.12    2.02    p <0.001   
medications Preoperative    0.97    0.46    999    1.74    0.53    63    –0.77    –0.90    –0.64    p <0.001   
medications    1.62    0.48    999    1.94    0.75    63    –0.32    –0.51    –0.13    p <0.001   
Postoperative medications    0.67    0.34    999    0.21    0.22    63    0.46    0.40    0.52    p <0.001   
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*IOP = Intraocular pressure. CI = Confidence interval. n/a = Not available. Note: red text denotes endpoints that substantially differed from those of the original analysis.

For the number of hypotensive medication classes, there was a greater reduction in medication classes following two iStents relative to one [WMD = -0.23, 95% CI = (-0.30, -0.16), p < 0.001]. There was a significantly greater number of medication classes in two stent patients compared to one both preoperatively [WMD = -0.59, 95% CI = (-0.65, -0.53), p < 0.001] and postoperatively [WMD = -0.28, 95% CI = (-0.35, -0.21), p < 0.001]. Comparing between one and three stents, there was a significantly higher number of medication classes [WMD = -0.32, 95%CI = (-0.51, -0.13), p < 0.001] in the three stent cohort preoperatively, as well as a greater reduction in medication class number [WMD = -0.77, 95% CI = (-0.90, -0.64), p < 0.001). Postoperatively, the three stent group had a significantly lower medication class count [WMD = 0.46, 95% CI = (0.40, 0.52), p < 0.001]. There was a greater reduction in medication classes [WMD = -0.54, 95% CI = (-0.68, -0.40), p < 0.001], lower preoperative [WMD = 0.27, 95% CI = (0.08, 0.46), p = 0.006] and lower postoperative medication class count [WMD = 0.74, 95% CI = (0.65, 0.83), p < 0.001] following three stents relative to two.

Phacoemulsification Status-First Generation

Next, studies were categorized by whether phacoemulsification was performed, irrespective of the number of first-generation iStents (Table 6A, Figs 3A and B). Data revealed that the iStent alone group produced a significantly more pronounced reduction in IOP than the phaco-iStent cohort [WMD = -7.44 mm Hg, 95% CI = (-7.82 mm Hg, -7.06 mm Hg), p < 0.001]. The iStent alone group also had a significantly greater preoperative IOP than the phaco-iStent cohort [WMD = -5.72 mm Hg, 95% CI = (-5.93 mm Hg, -5.51 mm Hg), p < 0.001]. Nonetheless, the iStent alone cohort had a lower postoperative IOP relative to the phaco-iStent cohort [WMD = 1.42 mm Hg, 95% CI = (1.15 mm Hg, 1.69 mm Hg), p < 0.001].

Table 6A: First Generation iStent - Efficacy Outcomes of Phaco-iStent versus iStent Implantation Alone

   Phaco-istent    Istent implantation alone    Meta-analysis   
Outcome    Mean    Standard deviation    Number of eyes    Mean    Standard deviation    Number of eyes    Weighted mean difference    95% CI –Lower bound    95% CI –Upper bound    P-value   
IOP reduction Preoperative    4.20    1.82    1123    11.64    2.47    173    –7.44    –7.82    –7.06    p <0.001   
IOP Postoperative    19.27    2.78    1076    24.99    0.88    173    –5.72    –5.93    –5.51    p <0.001   
IOP Reduction in    14.64    1.21    959    13.22    1.72    173    1.42    1.15    1.69    p <0.001   
medications    0.99    0.49    1123    1.33    0.46    173    –0.34    –0.41    –0.27    p <0.001   
Preoperative medications    1.62    0.60    1172    1.87    0.44    173    –0.25    –0.32    –0.18    p <0.001   
Postoperative medications    0.73    0.36    1172    0.55    0.87    173    0.18    0.05    0.31    p = 0.007   
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*IOP = Intraocular pressure. CI = Confidence interval. Note: Red text denotes endpoints that substantially differed from those of the original analysis.

Fig. 3A:

Fig. 3A:

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First generation phaco-iStent versus iStent alone-IOP

Fig. 3B:

Fig. 3B:

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First generation phaco-iStent versus iStent alone-number of medication classes

Preoperatively, patients receiving combined phaco-iStent were taking significantly fewer medication classes relative to the iStent alone group [WMD = -0.25 mm Hg, 95% CI = (-0.32 mm Hg, -0.18 mm Hg), p < 0.001]. There was a significantly greater reduction in medication class number following iStent alone [WMD=-0.34mmHg, 95% CI = (-0.41 mm Hg, -0.27 mm Hg), p < 0.001] along with a significantly lower postoperative medication class number in the iStent alone arm relative to phaco-iStent [WMD = 0.18 mm Hg, 95% CI = (0.05 mm Hg, 0.31 mm Hg), p = 0.007].

The combination of phacoemulsification and a first generation iStent was also compared to phacoemulsification alone (Table 6B, Figs 4A and B). This comparison only included studies that contained both a phaco-iStent arm and a phacoemulsification alone arm. For this analysis, there was a significantly greater IOP reduction [WMD = 1.68 mm Hg, 95% CI = (1.11 mm Hg, 2.25 mm Hg), p < 0.001] and a higher preoperative IOP [WMD = 2.15 mm Hg, 95% CI = (1.35 mm Hg, 2.95 mm Hg), p < 0.001] following phaco-iStent relative to phacoemulsification alone. However, there was no significant difference between comparators for postoperative IOP (p = 0.07). Phaco-iStent resulted in a significantly more pronounced reduction in medication class number [WMD = 0.80 mm Hg, 95% CI = (0.75 mm Hg, 0.85 mm Hg), p < 0.001] and lower postoperative number of medication classes [WMD = -0.69 mm Hg, 95% CI = (-0.78 mm Hg, -0.60 mm Hg), p < 0.001] relative to phacoemulsification alone. Preoperatively, there was no significant difference between comparators (p = 0.78).

Table 6B: First Generation iStent-Efficacy Outcomes of Phaco-iStent versus Phacoemulsification Alone

   Phaco-istent    Phacoemulsification alone    Meta-analysis   
Outcome    Mean    Standard deviation    Number eyes    of Mean    Standard deviation    Number of eyes    Weighted mean difference    95%Ci –Lower bound    95%Ci –Upper bound    P-value   
IOP reduction    6.30    3.10    199    4.62    3.47    319    1.68    1.11    2.25    p <0.001   
Preoperative IOP    22.44    4.24    199    20.29    4.93    319    2.15    1.35    2.95    p <0.001   
Postoperative IOP    15.23    1.53    82    14.84    1.80    196    0.39    –0.03    0.81    p = 0.07   
Reduction in medications    1.40    0.21    199    0.60    0.36    319    0.80    0.75    0.85    p <0.001   
Preoperative medications    1.72    0.47    199    1.71    0.25    319    0.01    –0.06    0.08    p = 0.78   
Postoperative medications    0.38    0.36    199    1.07    0.63    319    –0.69    –0.78    –0.60    p <0.001   
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*IOP = Itraocular pressure. CI = Confidence interval. Note: Red text denotes endpoints that substantially differed from those of the original analysis.

Fig. 4A:

Fig. 4A:

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First generation phaco-iStent versus phacoemulsification alone-IOP

Fig. 4B:

Fig. 4B:

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First generation phaco-iStent versus phacoemulsification alone-number of medication classes

Phacoemulsification Status-Second Generation

For the second generation iStent inject, studies reporting on iStent alone had a significantly greater IOP reduction [WMD = -1.47 mm Hg, 95% CI = (-1.88 mm Hg, -1.06 mm Hg), p < 0.001] and a greater preoperative IOP [WMD = -0.79 mm Hg, 95% CI = (-1.54 mm Hg, -0.04 mm Hg), p = 0.04] compared to studies reporting on phaco-iStent (Table 7, Fig. 5A). Postoperatively, the phaco-iStent cohort had a significantly higher IOP relative to iStent alone [WMD = 0.81 mm Hg, 95% CI = (0.13 mm Hg, 1.49 mm Hg), p < 0.001]. There was a significantly greater reduction in medication classes [WMD=-0.22, 95% CI = (-0.28, -0.16), p < 0.001], higher number of pre-operative medication classes [WMD = 0.20, 95% CI = (0.04, 0.36), p = 0.01] and a lower number of postoperative medication classes [WMD = 0.24, 95% CI = (0.02, 0.46), p = 0.03] following iStent alone relative to phaco-iStent (Fig. 5B).

Table 7: Second generation iStent - efficacy outcomes of phaco-iStent versus iStent implantation alone

   Phaco-iStent    iStent i mplantation Alone    Meta-analysis   
Outcome    Mean    Standard deviation    Number of eyes    Mean    Standard deviation    Number of eyes    Weighted mean difference    95% CI –Lower bound    95% CI– Upper bound    p-value   
IOP reduction    8.52    1.14    45    9.99    2.14    324    –1.47    –1.88    –1.06    p <0.001   
Preoperative IOP    23.39    2.39    45    24.18    2.53    324    –0.79    –1.54    –0.04    p = 0.04   
Postoperative IOP    14.94    2.28    45    14.13    1.29    324    0.81    0.13    1.49    p = 0.02   
Reduction in medications    0.84    0.20    45    1.06    0.16    142    –0.22    –0.28    –0.16    p <0.001   
Preoperative medications    1.69    0.49    45    1.49    0.64    324    0.20    0.04    0.36    p = 0.01   
Postoperative medications    0.84    0.69    45    0.60    0.58    142    0.24    0.02    0.46    p = 0.03   
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*IOP = Intraocular pressure. CI = Confidence interval.

Fig. 5A:

Fig. 5A:

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Second generation phaco-iStent versus iStent alone-IOP

Fig. 5B:

Fig. 5B:

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Second generation phaco-iStent versus iStent alone-number of medication classes

Adverse Event Analysis

Overall, a total of 261 out of 1159 eyes (22.5%) that received iStent implantation sustained some type of adverse event (Table 8). In order from most to least common, the following adverse events were reported: IOP elevation or spike (reported in 12 of 27 papers; 44.4%), stent blockage or obstruction (8/27; 29.6%), stent malposition (7/27; 25.9%), hyphema (6/27; 22.2%), progression of cataract (3/27; 11.1%), blood reflux (3/27; 11.1%), corneal event (3/27; 11.1%), early postoperative event (2/27; 7.4%), stent not visible (2/27; 7.4%), formation of peripheral anterior synechiae (2/27; 7.4%), need for additional surgery (2/27, 7.4%), hypotony (1/27; 3.7%), posterior capsular opacification (1/27; 3.7%), replacement applicator (1/27; 3.7%), patients soreness/discomfort (1/27; 3.7%), transient visual acuity loss (1/27; 3.7%), intraoperative hemorrhage (1/27; 3.7%) and subconjunctival hemorrhage (1/27, 3.7%). Most studies reported either stable or improved visual acuity at last follow-up.

Table 8: Safety endpoints of included trials

Study    Number ofeyes    Complications    Adverse event 1    Adverse event 2    Adverse event 3    Adverse event 4    Visual acuity change   
Samuelson et al., 2011    111    37    Anticipated early postoperative event    Stent obstruction    Posterior capsular opacification    Stent malposition    97% BCVA improvement   
Fea et al., 2014    94    3    IOP elevation    Soreness/ discomfort    Stent not visible    n/a    Five people experienced decrease   
Buchacra et al., 2011    8    17    Hyphema    IOP elevation    Corneal edema    n/a    No significant change   
Ahmed et al., 2014    39    7    Hypotony    Progression of cataract    Transient visual acuity loss    n/a    CDVA maintained in most eyes   
Voskanyan et al., 2014    88    18    IOP elevation    Stent obstruction    Progression of cataract    Stent not visible    Slight improvement   
Vandewalle et al., 2009    9    10    IOP elevation    Stent malposition    Corneal Erosion    Blood reflux    Stable/improved   
Fea, 2010    12    n/a    n/a    n/a    n/a    n/a    n/a   
Belovay et al., 2012    28    n/a    Stent blockage    Hyphema    Stent malposition    IOP elevation    Stable/improved   
2nd study arm    25    n/a    Stent blockage    Hyphema    Stent Malposition    IOP elevation    Stable/improved   
Patel et al., 2013    44    1    Hyphema    n/a    n/a    n/a    Mean improved   
Arriola-villalobos et al., 2012    19    12    Stent malposition    Stent blockage    Replacement applicator    IOP elevation    Significantly improved   
Arriola-villalobos et al., 2013    20    10    Stent malposition    Stent blockage    Iop elevation    n/a    Significantly improved   
Fernandez-barrientos et al., 2010    17    n/a    Stent malposition    n/a    n/a    n/a    n/a   
Spiegel et al., 2009    42    22    Stent blockage    Stent malposition    Iop elevation    Cataract surgery Complication    Significantly improved   
Wang et al., 2015    96    0    n/a    n/a    n/a    n/a    n/a   
Klamann et al., 2015    32    32    Blood reflux    n/a    n/a    n/a    No decrease   
Khan et al., 2015    49    26    Peripheral anterior synechiae formation    IOP spike    Early postoperative interventions    Hyphema    n/a   
Seibold et al., 2016    64    n/a    n/a    n/a    n/a    n/a    Significant improvement   
Gallardo et al., 2016    134    0    n/a    n/a    n/a    n/a    83% of eyes achieved a BCVA of 20/40 or better after surgery relative to 20% preoperatively   
Ferguson et al., 2016    350    n/a    IOP spike    n/a    n/a    n/a    n/a   
Lindstrom et al.    57    1    Progression of cataract    n/a    n/a    n/a    Stable   
El wardani et al.    31    n/a    n/a    n/a    n/a    n/a    n/a   
2nd study arm    22    n/a    n/a    n/a    n/a    n/a    n/a   
Katz et al.    37    0    n/a    n/a    n/a    n/a    76% of eyes achieved a BCVA of 20/40 or better after surgery relative to 68%   
2nd study arm    41    0    n/a    n/a    n/a    n/a    Preoperatively 66% of eyes achieved a BCVA of 20/40 or better after surgery relative to 61%   
3rd study arm    38    0    n/a    n/a    n/a    n/a    Preoperatively 80% of eyes achieved a BCVA of 20/40 or better after surgery relative to 73% preoperatively   
Shiba et al., 2017    12    Hyphema    Peripheral anterior synechiae    Occlusion by iris    Iop spike    n/a    n/a   
Berdahl et al, 2017    n/a    n/a    n/a    n/a    n/a    n/a    Stable   
Ferguson et al., 2017    8    Iop spike    Need for additional surgery    n/a    n/a    n/a    n/a   
Gonnermann et al 2017    29    Reflux bleeding    Trabulectomy    n/a    n/a    n/a    n/a   
Kurji et al., 2017    3    Blocked istent    n/a    n/a    n/a    n/a    Approximate 2 line gain on snellen chart   
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* BCVA = Best corrected visual acuity; CDVA = Corrected distance visual acuity; IOP = Intraocular pressure.

DISCUSSION

The efficacy and adverse event profile of the iStent device have been explored in a variety of different settings. To evaluate the efficacy and adverse events following iStent implantation based on the consolidation of all peer-reviewed research on the iStent, the present meta-analysis was undertaken.

In a recent meta-analysis by Malvankar-Mehta et al., the efficacy of the iStent without adjunctive phacoemulsification was analyzed in 248 patients from five studies.40 Meta-analysis revealed a significant reduction in IOP after implantation of one [standardized mean difference (SMD) = -1.68, 95% CI = (-2.7, -0.61)], two [SMD = -1.88, 95% CI = (-2.2, -1.56)] and three iStents [SMD = -2, 95%CI = (-2.62, -1.38)]. Glaucoma medication class number was reduced by a mean of 1.2 bottles after one iStent implant, 1.45 bottles after two iStents and one bottle after three iStents.

Another meta-analysis by the same team aimed to investigate the reduction of IOP after phaco-iStent compared to phacoemulsification alone.41 A total of 396 patients from 10 studies received phaco-iStent and 1768 patients from 26 studies received phacoemulsification alone. Phaco-iStent produced a significantly greater reduction in IOP relative to cataract extraction alone [SMD = -0.46, 95%CI = (-0.87, -0.06)]. Relative to phacoemulsification alone, phaco-iStent demonstrated a statistically significantly greater reduction in glaucoma medication class number [SMD = -0.65, 95% CI = (-1.18, -0.12)]. Relative to the two studies by Malvankar-Mehta and colleagues, 20 of our 28 included peer reviewed articles have not been reported in previous meta-analyses.40,41

The greater IOP reduction with multiple iStents compared to one has been documented in previous laboratory studies and was also confirmed by the findings of the present meta-analysis.42 For instance, both postoperative IOP and IOP reduction were significantly improved in the two-stent comparator relative to one. We hypothesize that a selection bias may have influenced these findings, as the higher initial IOP or more severe disease seen in the two-stent comparator may have contributed to the greater IOP reduction following stent implantation. For patients with high preoperative IOP (average of 22.5 mm Hg), three stents provided a more pronounced level of

IOP reduction (9.3 mm Hg) relative to one or two stents. However, interpretations of the three-stent data should be made with caution, as data from only 63 eyes existed for this comparison.

Regardless of the number of implanted iStents, the cohort that underwent first-generation iStent implantation alone saw a more pronounced IOP reduction and lower postoperative IOP than the phaco-iStent group. However, this comparison considers two different patient populations, namely (1) patients receiving iStent alone, who normally do not have cataracts and are receiving the device specifically for IOP reduction, and (2) patients undergoing combined phacoemulsification and iStent, who are receiving the treatment for both their cataracts and an elevated IOP. As such, the finding of a higher preoperative IOP in the iStent alone group may have influenced the difference in IOP reduction between comparators. Even though some included studies contained both patients who received phaco-iStent and iStent alone, subgroup analysis analyzing the differences in outcomes between these two groups was never performed in individual studies.15,18 As such, the conclusions derived from comparing phaco-iStent versus iStent alone have not been previously established.

Analysis of phaco-iStent compared to phacoemul-sification alone revealed that there was a greater IOP reduction following phaco-iStent relative to phaco-emulsification alone. This aligns with the findings of Malvankar-Mehta et al., who also showed that there was a significantly greater IOP reduction following phaco-iStent relative to phacoemulsification alone [SMD = -0.46, 95% CI = (0.87, -0.06)].41 Despite the similarity, it is important to note that uncontrolled, one-armed studies examining the efficacy of phacoemulsification alone were included in the previous analysis but were excluded in the present article.41 Instead, we limited our analysis of phaco-iStent versus phacoemulsification only to the studies that had a phaco-iStent arm and a phacoemulsification only comparator, thus resulting in a more controlled analysis. Beyond analysis of IOP, both meta-analyses concluded that phaco-iStent was statistically superior relative to phacoemulsification alone in the reduction of medication class number pre- to post-operatively.

The adverse event analysis revealed that fewer than 25% of eyes carried some type of adverse event postoperatively, most of which were not serious nor visually threatening. This compares favorably with the postoperative adverse event rates of both trabeculec-tomy and the Baerveldt glaucoma implant.43 However, due to differential reporting of adverse events between individual studies, caution should be used when interpreting these findings. In our cohort, IOP elevation, stent blockage or obstruction, stent malposition and hyphema were the most common adverse events following iStent implantation.

Beyond the efficacy and adverse event profile, the cost-effectiveness of the iStent relative to topical glaucoma medications has been studied by Iordanous and colleagues.44 Following implantation of two iStents, the authors analyzed cost differences at 6 years postop-eratively. At 6 years, the iStent was $20.77 more expensive relative to monodrug therapy but was cheaper by $1272.55 compared to bidrug treatment and $2124.71 versus tridrug therapy. The authors concluded that the iStent may offer a modest cost saving when compared to glaucoma medications.

Given that past meta-analyses included lower numbers of eyes receiving iStent implantation (first article: 5 studies, n = 248; second article: 10 studies, n = 396), the present work (28 studies, n = 1767) represents the largest quantitative synthesis of efficacy and adverse event data for the iStent device.40,41 The large statistical power provided by such a high sample size allowed us to conduct certain analyses that were novel to the published literature; for example, an analysis comparing phaco-iStent to iStent alone. We only included published articles, thus ensuring that the rigors of peer-review were met for each included study.

Limitations of the analysis include the fact that there was no restriction of studies based on design. As such, baseline values for included endpoints were significantly different between comparator arms. As shown in Table 4, the relevant clinical features were often not balanced between groups. As noted by Kaplowitz et al., variation in study design and implementation such as length of follow-up, etiology of disease and baseline clinical indicators may account for the high degree of heterogeneity upon meta-analysis.45 Further, since some articles did not include sociodemographic and clinical characteristics of their study cohorts (e.g. surgeon experience), it is uncertain whether there was a balance of these factors between comparator arms. For instance, there

is variable reporting of surgeon experience in the literature: two articles19,20 noted that the study surgeon was in an early stage in the learning curve, one noted that the data incorporate the surgeon learning curve,3 and another hypothesized how the learning curve influenced the greater number of adverse events in an initial set of patients.22 Two studies reported that their surgeons were experienced,24,30 while another found no significant difference in outcomes between initial and late procedures.28 Another limitation was that the lack of available studies prevented us from performing a robust meta-analysis for some endpoints, such as IOP reduction following three stents, where there was only 63 included patients. Limited reporting of adverse event severity across studies prevented us from analyzing severity in the adverse event analysis. Studies were variable in how they handled medication washout before stent implantation, which made it impossible to analyze the effect of preoperative medications on baseline IOP. Given that data was extracted from study cohorts, conclusions should be limited to the level of the cohort.

CONCLUSION AND CLINICAL SIGNIFICANCE

The following meta-analysis has shown that there may be differences in treatment response for the iStent due to varying parameters, including the number of iStents and phaco-iStent compared to either iStent alone or phaco-emulsification alone. In our analysis, two stents delivered a greater response in terms of IOP reduction relative to one and iStent alone had a significantly greater IOP reduction compared to phaco-iStent. Combined phaco-iStent was statistically superior relative to phacoemulsification alone in the reduction of IOP and medication classes pre-to post-operatively. Future research should determine whether similar conclusions are reached following meta-analysis in a more controlled environment.

ETHICAL APPROVAL

This article does not contain any studies with human participants or animals performed by any of the authors. As such, there was no informed consent process needed for this study.

AUTHORSHIP CONTRIBUTIONS

  • Conception and design of study: M.P., X.C.M., I.I.K.A.

  • Acquisition of data: M.P., X.C.M.

  • Analysis and interpretation of data: M.P., X.C.M., H.S., I.I.K.A.

  • Drafting and revising article: M.P., X.C.M., H.S., I.I.K.A.

  • Final approval of the version to be submitted: M.P., X.C.M., H.S., I.I.K.A.

Footnotes

Source of support: Nil

Conflict of interest: Consultant to Glaukos and Allergan.

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