Ab interno trabecular bypass surgery with iStent for open‐angle glaucoma

Jimmy T Le; Amanda K Bicket; Lin Wang; Tianjing Li

doi:10.1002/14651858.CD012743.pub2

. 2019 Mar 28;2019(3):CD012743. doi: 10.1002/14651858.CD012743.pub2

Ab interno trabecular bypass surgery with iStent for open‐angle glaucoma

Jimmy T Le ^1,^✉, Amanda K Bicket ², Lin Wang ¹, Tianjing Li ¹

Editor: Cochrane Eyes and Vision Group

PMCID: PMC6437719 PMID: 30919929

Abstract

Background

Glaucoma is a leading cause of irreversible blindness worldwide. In early stages, glaucoma results in progressive loss of peripheral (side) vision; in later stages, it results in loss of central vision leading to blindness. Elevated intraocular pressure (IOP) is the only known modifiable risk factor for glaucoma. Minimally invasive glaucoma surgical (MIGS) techniques, such as ab interno trabecular bypass surgery with iStent (Glaukos Corporation, Laguna Hills, CA, USA), have been introduced as a new treatment modality for glaucoma. However, the effectiveness of MIGS on keeping people 'drop‐free' (i.e. not having to use eye drops to control IOP) and other outcomes is uncertain.

Objectives

To assess the effectiveness and safety of ab interno trabecular bypass surgery with iStent (or iStent inject) for open‐angle glaucoma in comparison to conventional medical, laser, or surgical treatment.

Search methods

Cochrane Eyes and Vision's Information Specialist searched the following databases on 17 August 2018: the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register; 2018, Issue 7), MEDLINE Ovid, Embase Ovid, the ISRCTN registry, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We applied no date or language restrictions. We searched the reference lists of reports from included studies.

Selection criteria

We included randomized controlled trials (RCTs) that had compared iStent or iStent inject to medical therapy, laser treatment, conventional glaucoma surgery (trabeculectomy), or other MIGS procedures. We included RCTs that had compared iStent or iStent inject in combination with phacoemulsification to phacoemulsification alone.

Data collection and analysis

We used standard methodological procedures expected by Cochrane. Two review authors independently screened search results, assessed risk of bias, and extracted data from reports of included RCTs using an electronic data collection form.

Main results

We included seven RCTs (765 eyes of 764 participants; range per study 33 to 239 participants) that evaluated iStent in people with open‐angle glaucoma. We also identified 13 studies that are ongoing or awaiting publications of results. Most participants in the included studies were women (417/764 (55%) participants) and older age (age range: 49 to 89 years). We assessed most trials at unclear or high risk of bias: four trials did not clearly report the method of generating the random sequence or concealing allocation; five were unmasked, open‐label studies, which we assessed at high risk of bias for performance and detection bias. All seven trials were funded by the Glaukos Corporation. We graded the certainty of evidence as very low.

Four RCTs compared iStent in combination with phacoemulsification to phacoemulsification alone. The summary estimate which we derived from two of the four RCTs suggested that participants in the iStent in combination with phacoemulsification group were 1.38 times more likely to be drop‐free between six and 18 months than those in the phacoemulsification alone group (risk ratio (RR) 1.38, 95% confidence interval (CI) 1.18 to 1.63, I² = 67%). Data from two RCTs also suggested that iStent in combination with phacoemulsification compared to phacoemulsification alone may have offered a small reduction in number of IOP‐lowering drops (mean difference (MD) –0.42 drops, 95% CI –0.60 to –0.23). It is uncertain whether there was any difference in terms of mean reduction in IOP from baseline (no meta‐analysis).

Two RCTs compared treatment with iStent to medical therapy; one of the two trials used the iStent inject. We determined the two trials to be clinically and methodologically heterogeneous and did not conduct a meta‐analysis; however, the investigators of both trials reported that over 90% of participants in the treatment groups were drop‐free compared to no participants in the medical therapy groups at six to 18 months.

One RCT compared treatment with one versus two versus three iStents. There was no difference in terms of participants who were drop‐free at 36 months or less; however, at longer follow‐up (i.e. at 42 months) participants in the one iStent treatment were less likely to be drop‐free than those in the two iStent (RR 0.51, 95% CI 0.34 to 0.75) or three iStent (RR 0.49, 95% CI 0.34 to 0.73) treatment groups. The study did not report the mean change in number of IOP‐lowering drops.

The type and timing of complications reported varied by RCTs. Similar proportions of participants who underwent treatment with iStent in combination with phacoemulsification and who underwent phacoemulsification alone needed secondary glaucoma surgery. None of RCTs reported findings related to quality of life.

Authors' conclusions

There is very low‐quality evidence that treatment with iStent may result in higher proportions of participants who are drop‐free or achieving better IOP control, in the short, medium, or long‐term. Results from the 13 studies with results not yet available may clarify the benefits of treatment of people with iStent. Additionally, future MIGS studies should consider measuring quality of life and outcomes that reflect people's ability to perform vision‐dependent activities.

Plain language summary

iStent for open‐angle glaucoma

What was the aim of this review?  The aim of this Cochrane Review was to find out whether the implantation of one or more iStent or iStent inject devices ('iStents'), compared with conventional medical, laser, or surgical treatments, can keep people who have primary open‐angle glaucoma from needing to use glaucoma drops (i.e. keep them 'drop‐free'). The glaucoma drops are used to control the fluid pressure within their eyes (called the intraocular pressure (IOP)). We also looked at average change from baseline in number of glaucoma drops needed to control IOP, average change from baseline (i.e. before treatment) in IOP, and health‐related quality of life as defined by study investigators. We examined all outcomes at short‐term (less than six months), medium‐term (six to ≤ 18 months), long‐term (> 18 months and ≤ 36 months) and greater than 36‐month time points. We collected and analyzed all relevant randomized controlled trials (RCTs; clinical studies where people are randomly put into one of two or more treatment groups) to answer this question and found seven RCTs evaluating iStents.

Key messages  There was very low‐quality evidence that treatment with iStents may have resulted in higher proportions of people who were drop‐free at medium‐term time points or who had better control of their IOP. None of the seven RCTs examined how the iStent affected quality of life and reporting on complications was highly variable. At present, clinical practice decisions should be based on provider judgment and patient preferences, given inconsistency in results and risk of bias in relevant studies published to date.

What did we study in this review?  Glaucoma is a group of eye diseases that cause irreversible damage to the optic nerve in the eye. If untreated, glaucoma can lead to blindness. Elevated IOP is the only known modifiable risk factor for open‐angle glaucoma, which is the most common form of glaucoma. Conventional first‐choice treatments for open‐angle glaucoma include medical (e.g. glaucoma drops) or laser interventions. Surgery, which has a higher risk profile, is offered when glaucoma progresses despite treatment with medication or laser.

Minimally invasive glaucoma surgical procedures involve implantation of devices such as the iStent. They have been proposed as a safer alternative to standard glaucoma surgeries in people with mild‐to‐moderate forms of open‐angle glaucoma. The iStent creates a 'bypass' between the front chambers of the eye and its natural drainage pathway. This bypass increases the flow of fluids out of the eye, which may decrease IOP and the need to use glaucoma drops to control IOP.

What were the main results of this review?  We identified four RCTs that randomized participants to treatment with iStents in combination with cataract surgery (called phacoemulsification) or with phacoemulsification alone. Additionally, we identified two RCTs that randomized participants to treatment with iStents or to medical interventions. We also identified one RCT that randomized participants to treatment with one iStent, with two iStents, or with three iStents. The manufacturer of the iStent provided funding and sponsorship for all the RCTs in this review.

Based on low‐quality evidence, we found that participants who received iStent in combination with cataract surgery were more likely to be drop‐free and may have experienced a modest reduction in number of glaucoma drops used per day to control IOP in the medium term, compared with participants who underwent cataract surgery alone; however, there was no difference in average change from baseline in IOP between the two groups.

Due to substantial heterogeneity, we did not conduct an analysis of the two studies comparing treatment with iStent to medical therapy. Investigators of those two studies reported that no participants in the medical therapy group were drop‐free at 12 months, compared to over 90% in the iStent treatment groups. Data suggested that treatment of people with two or with three iStents may have been more effective than treatment with one iStent in terms of IOP control.

None of the seven studies included in this review provided information on quality of life, and differences in complications or side effects between treatment groups were uncertain, given few reported events and varied effectiveness.

How up to date is the review?  We searched for studies published up to 17 August 2018.

Summary of findings

Background

Description of the condition

Glaucoma is a group of diseases characterized by clinical and histopathological manifestations of optic nerve damage that leads to irreversible vision loss (Allingham 2010). Glaucoma is the second leading cause of blindness, affecting approximately 60 million people worldwide (Quigley 2006). One systematic review estimated that the global prevalence of glaucoma in people between 40 and 80 years of age may increase to 76 million by 2020 and to 111.8 million by 2040 (Tham 2014). Open‐angle glaucoma (OAG) is the most common type of glaucoma and accounts for approximately 74% of all cases (Quigley 2006). Women comprise 55% of OAG cases, and OAG disproportionately affects people of African ancestry and older adults (NEI 2015).

OAG is a progressive disease. In early mild‐to‐moderate stages, there are no symptoms (AAO 2015). Due to the 'silent' nature of OAG, people do not usually have any visual problems; there are optic nerve abnormalities consistent with glaucoma, but little to no aberrations in visual fields. In severe stages of glaucoma, people may notice vision loss or blind spots due to significant amounts of irreversible optic nerve damage (AAO 2015). Main signs of glaucoma include atrophied optic nerve and presence of an open angle, both of which can only be seen using specialized instruments.

Many people with OAG also experience elevated intraocular pressure (IOP); however, IOP is not a direct measure of structural or functional glaucomatous optic neuropathy and not all people with glaucoma present with elevated IOP (AAO 2015; Le 2016; Medeiros 2015). Nevertheless, because IOP is the only known modifiable risk factor, treatment for OAG has focused predominantly on lowering IOP (Li 2016; Quigley 2007).

Description of the intervention

Lowering IOP is achieved through medical, laser, and surgical interventions, typically implemented in a step‐wise manner (AAO 2015; Le 2018a; NICE 2009). Since the early 2000s, a series of new treatment modalities, which the US Food and Drug Administration (FDA) refers to as "minimally invasive glaucoma surgical" (MIGS) devices, has emerged. MIGS are ab interno procedures that require minimal to no conjunctival manipulation or scleral dissection, which are readily combined with another intraocular procedure such as cataract extraction by phacoemulsification (cataract surgery). MIGS typically lower IOP to a more modest degree than traditional filtering surgeries (e.g. trabeculectomy or tube shunt implantation); however, MIGS may pose fewer risks than those more invasive surgeries (Caprioli 2015; Francis 2011; Spaeth 2015). While MIGS generally are not used as first‐line therapy for glaucoma at this time, they may reduce the need for medication.

Examples of MIGS interventions include the iStent and iStent Inject, trabectome ab interno trabeculectomy, endoscopic cyclophotocoagulation (ECP), gonioscopy‐assisted transluminal trabeculotomy (GATT), the Hydrus Microstent intracanalicular scaffold, the XEN Gel Stent, and the Innfocus Microshunt. Of these, the first four are currently FDA approved for use in the US; the others are being evaluated in clinical trials.

This Cochrane Review examined the iStent and iStent inject (Glaukos Corporation, Laguna Hills, CA, USA), the former of which was the first MIGS device to have received FDA approval, for people with mild‐to‐moderate OAG.

The iStent is a heparin‐coated non‐ferromagnetic titanium 'L‐shaped' device, 1 mm in length with a head 0.3 mm in height facing the anterior chamber (Glaukos 2016). This MIGS device is preloaded into a single‐use injector and then inserted ab interno through the trabecular meshwork under direct gonioscopic view (Manasses 2016). The iStent creates a permanent opening that directly connects the anterior chamber to Schlemm's canal.
The iStent inject is a second‐generation 'mushroom‐shaped' MIGS device, 360 μm in length with a conical head with maximum width of 230 μm. Like the iStent, the iStent inject is made of heparin‐coated titanium but the conical head contains four evenly spaced outlets that allow fluid to pass from the anterior chamber into Schlemm's canal (Bahler 2012). The injector is preloaded with two iStent inject MIGS devices and is designed to deliver both stents, ab interno, into Schlemm's canal while entering the eye only once (Bahler 2012; Klamann 2015).

How the intervention might work

IOP increases when there is an imbalance between production and outflow of aqueous humor (a clear fluid that provides avascular ocular structures with nutrition). Aqueous humor drains through a complex network of cells and tissue (trabecular meshwork, Schlemm's canal, and collector channels) in an area known as the drainage angle (AAO 2015).

Given that the trabecular meshwork is the primary site of aqueous outflow and that resistance to aqueous humor outflow in this region largely determines IOP (Manasses 2016), bypassing the trabecular meshwork is a viable method to decrease IOP. Ab interno implantation of MIGS devices such as the iStent and iStent inject may increase outflow facility by providing direct access to Schlemm's canal and downstream collector channels via a permanent opening through trabecular meshwork (Francis 2011).

Why it is important to do this review

Most treatments for OAG rely primarily on lowering IOP (AAO 2015; AGIS 2000; EGS 2014), but they all have limitations. Many people with mild‐to‐moderate OAG elect to start with medical treatment (e.g. topical eye drops) as first‐line therapy (AAO 2015; Li 2016; NICE 2009); commercially available eye drops have short durations of effect and adherence is poor (Friedman 2009; Okeke 2009). Conventional surgical procedures to bypass the trabecular meshwork and drainage angle, such as trabeculectomy and tube shunts or valves, are associated with variable frequencies of success and complications (Gedde 2012a; Gedde 2012b; Spaeth 2015). Trabeculectomies fail after about five years in approximately 50% of cases (Gedde 2012a; Gedde 2012b; Kirwan 2013; Lichter 2001). Laser trabeculoplasty (LTP) represents an intermediate intervention between drops and surgery, or can be used as an alternative first line to drops, but its efficacy has been noted to decrease over time and most people ultimately require repeat LTP or surgery (Leahy 2015; Patel 2015; Rolim de Moura 2007; Woo 2015).

MIGS procedures are becoming increasingly common, with their proponents claiming better safety profiles than other glaucoma surgical techniques (Brandao 2013; Larsen 2017). In this review, we specifically examined the evidence for the effectiveness and safety of one type of MIGS device – the iStent and iStent inject – in people with mild‐to‐moderate OAG of any type. This review was undertaken as part of the Cochrane Eyes and Vision MIGS Consortium. The Consortium also reviewed other types of MIGS techniques and devices including the Trabectome (NeoMedix, Tustin, CA, USA), Hydrus Microstent (Ivantis, Irvine, CA, USA) (Otarola 2017), ECP (Endo Optiks, Waltham, MA, USA) (Tóth 2019), and XEN Glaucoma Implant (AqueSys Implant, Aliso Viejo, CA, USA) (King 2018).

Objectives

Methods

Criteria for considering studies for this review

Types of studies

We included only randomized controlled trials (RCTs), prepared in any language, irrespective of their publication status.

Types of participants

We included studies of people with mild‐to‐moderate OAG of any type, including primary and secondary OAG. Primary OAG refers to glaucoma that develops due to an unknown cause; secondary OAG develops from a known cause, such as trauma to the eye or ocular inflammatory diseases. In the absence of a universally accepted definition for glaucoma, we permitted studies to use their own criteria to define OAG; however, we excluded studies of participants with angle‐closure glaucoma (where increased IOP occurs because abnormal iris anatomy obstructs aqueous flow to the drainage angle). In addition, we allowed studies that included participants with ocular hypertension (OHT), normal tension glaucoma, or possible OAG (i.e. suspected).

Types of interventions

We included studies that compared iStent or iStent inject (Glaukos Corporation, Laguna Hills, CA, USA) to any of the following:

laser treatment (selective LTP or argon LTP);
other MIGS procedures/techniques;
conventional glaucoma surgery (trabeculectomy);
medical therapy; or
in combination with phacoemulsification compared with phacoemulsification alone. iStent devices are approved in people undergoing phacoemulsification.

Additionally, we conducted stratified analyses based on iStent procedures (e.g. iStent versus iStent inject).

Types of outcome measures

We did not use reporting of particular outcomes as a criterion for including a trial into our systematic review. We, as with other review teams in the Consortium, adapted primary and secondary outcomes from a Cochrane systematic review prepared by Hu and colleagues (Hu 2016).

We evaluated each outcome at a time point in the six to 18 months (medium‐term) time window, in addition to less than six months (short‐term), over 18 but less than or equal to 36 months (long‐term), and over 36 months time windows. We recognized that our primary outcome may not be relevant in RCTs that randomized participants to medical therapy in lieu of an iStent procedure.

Primary outcomes

Proportion of participants who were drop‐free (i.e. not using eye drops) at a time point in each of the time windows.

Secondary outcomes

Mean change in number of IOP‐lowering drops taken per day from baseline to a time point in each of the time windows.
Mean change in IOP, measured using Goldmann applanation tonometry, from baseline to a time point in each of the time windows.
Any health‐related quality of life measures, measured as mean change from baseline or proportion meeting a threshold at a time point in each of the time windows, as defined by the investigators of the included trials.

Adverse outcomes

Proportions of participants experiencing intra‐ and postoperative complications at a time point in each of the time windows, including but not restricted to the following:
1. loss of visual acuity of more than 2 Snellen lines, or more than 0.3 logMAR, according to the method of recording visual acuity; or loss of light perception;
2. bleeding, as recorded by the investigators;
3. endophthalmitis, as recorded by the investigators;
4. IOP spikes, defined as postoperative rise in IOP, measured using Goldmann applanation tonometry, of more than 10 mmHg compared to the previous assessment, including during the first postoperative month;
5. secondary glaucoma surgery, including laser, as recorded by the investigators of the included trials.

Search methods for identification of studies

Electronic searches

The Cochrane Eyes and Vision Information Specialist searched the following electronic databases for RCTs and controlled clinical trials. We used no restrictions on language or year of publication.

Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 7; which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (searched 17 August 2018; Appendix 1).
MEDLINE Ovid (1946 to 17 August 2018; Appendix 2).
Embase Ovid (1980 to 17 August 2018; Appendix 3).
ISRCTN registry (www.isrctn.com/editAdvancedSearch; searched 17 August 2018; Appendix 4).
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 17 August 2018; Appendix 5).
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp; searched 17 August 2018; Appendix 6).
US FDA website (www.fda.gov; searched 17 August 2018; Appendix 7).

Searching other resources

We searched the reference lists of included studies for possible studies and the website of the manufacturer for information regarding forthcoming trials (Glaukos 2016).

Data collection and analysis

Selection of studies

Two review authors (JL and TL) worked independently to screen titles and abstracts of all records identified by the search using web‐based review management software (Covidence 2015). We removed duplicates from the search results. The review authors classified each record as either relevant (a 'Yes' vote) or not relevant (a 'No' vote) for full‐text review. The two review authors independently assessed the full‐text copies of all titles and abstracts that they identified as relevant to determine if the reports met the inclusion criteria (an 'Include' vote) or not (an 'Exclude' vote). We did not need to contact the trial authors of any record to clarify details necessary to make a complete assessment of the eligibility. We documented reasons for exclusion for each study assessed as not eligible after review of the full‐text articles. We resolved all discrepancies between review authors by discussion at each stage of the screening process. We then linked multiple reports originating from the same trial.

Data extraction and management

Two review authors (JL and LW) independently extracted data using a web‐based electronic data collection form in SRDR (srdr.ahrq.gov/). We extracted the information as described in Appendix 8, including: study setting, countries where recruitment took place, sample size, study duration and follow‐up time, study design, analysis choice, sources of funding, and potential conflicts of interests; characteristics of the participants (e.g. inclusion/exclusion criteria), underlying disease conditions, and medical history (including IOP at baseline, number of glaucoma medications at baseline, visual acuity, and other vision‐related characteristics); interventions (e.g. iStent or iStent inject) and comparators (e.g. type of laser, drugs, surgery, duration, and timing); outcomes (e.g. domain, specific measurement, specific metric, method of aggregation, and time frame); and quantitative results.

The review authors compared the extracted data and resolved discrepancies by discussion. One review author (JL) completed data entry into Review Manager 5 (Review Manager 2014), and a second review author (LW) verified the data entered.

Assessment of risk of bias in included studies

Two review authors (JL and LW) independently assessed the risk of bias in included studies, following guidance described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). Specific items for consideration included random sequence generation and allocation concealment (selection bias), masking of study personnel (performance bias), masking of outcome assessors (detection bias) for number of IOP‐lowering drops used and for IOP measurement, missing data and intention‐to‐treat analysis (attrition bias), and selective outcome reporting (reporting bias).

We assigned each item as having low risk, high risk, or, if the information provided was insufficient to make an assessment, unclear risk. We documented reasons for those assessments and resolved discrepancies through discussion. We presented the overall assessments as the 'Risk of bias' summary figure (Higgins 2017).

Measures of treatment effect

We used mean difference (MD) as the measure of effect for all continuous outcomes, with 95% confidence intervals (CI). We used risk ratio (RR) with 95% CIs as the measure of effect for all binary and categorical outcomes.

Unit of analysis issues

We assessed whether the included trials included one or both eyes from each participant and whether the trial investigators randomized (and analyzed) at the participant‐level or at the eye‐level. When both eyes were randomized to different treatments, we planned to extract the results that had accounted for the correlation.

Dealing with missing data

Where data on included studies were unclear or missing, we planned to write to the authors and analyze the data using the best information available if we received no response within two weeks. We planned to consider multiple imputation or other imputation approaches for handling missing data if needed. If the quality of the available data prevented any meaningful analysis, we planned to omit the study from quantitative analyses and note this decision in the discussion.

Assessment of heterogeneity

We assessed clinical and methodological heterogeneity by examining participant characteristics, MIGS techniques and devices, and outcomes, taking into consideration potential risk of bias. We assessed forest plots and examined the I² statistic and its CI for statistical heterogeneity. Similar to other protocols on MIGS procedures, we considered an I² statistic greater than 50% as indicative of substantial heterogeneity, suggesting that a meta‐analysis may not be appropriate. However, if all estimates were in the same direction, we pursued a meta‐analysis despite substantial statistical heterogeneity, and we interpreted the findings taking into consideration the heterogeneity.

Assessment of reporting biases

We planned to assess small‐study effects using funnel plots if there were more than 10 trials for each meta‐analysis. We assessed selective reporting as part of the 'Risk of bias' assessment, for example, examining differences between trial registration, protocol, and publication.

Data synthesis

We followed Chapter 9 of theCochrane Handbook for Systematic Reviews of Interventions for data synthesis and analysis (Deeks 2017). We first provided a descriptive, qualitative synthesis of studies and their results. We used fixed‐effect models for all meta‐analyses.

Subgroup analysis and investigation of heterogeneity

We planned to conduct a subgroup analysis by type of iStent (iStent or iStent inject).

Sensitivity analysis

We planned to conduct additional sensitivity analyses to determine the impact of any post hoc decisions made during the review process.

'Summary of findings' tables

We prepared 'Summary of findings' tables using the GRADE approach to assess the certainty of the evidence (GRADEpro GDT 2015). We planned to include following outcomes in the summary.

Proportion of participants who were drop‐free (not using eye drops) at six to 18 months.
Mean change in number of IOP‐lowering drops taken per day from baseline to six to 18 months
Mean change in IOP, measured using Goldmann applanation tonometry, from baseline to six to 18 months.
Health‐related quality of life at six to 18 months.
Intraoperative complications at six to 18 months.
Postoperative complications up to six to 18 months.
Secondary glaucoma surgery, including laser, as recorded by the investigators of the included trials between baseline and six to 18 months.

We summarized findings from two comparison groups: in combination with phacoemulsification compared with phacoemulsification alone and iStent compared to medical therapy. We downgraded the level of certainty of the evidence if the contributing studies were at high or unclear risk of bias for masking of outcome assessors (one level), provided inconsistent estimates (one level) or imprecise estimates (one level) due to small sample size or wide CIs, or may have been subject to publication bias (one level). Guyatt 2011 noted that inclination to downgrade for publication bias should increase when evidence comes from small studies which are "industry sponsored or likely to be industry sponsored (or if the investigators share another conflict of interest)." We also presented results of one trial which compared one iStent with two iStents with three iStents, but did not assess the certainty of the evidence or present a 'Summary of findings' table for this single trial.

Results

Description of studies

Results of the search

The electronic search yielded 362 records (Figure 1). After removal of 90 duplicates, we screened the remaining 272 records and excluded a further 237 records based on information in the title and abstract. We obtained full‐text reports of 35 records for further investigation. We included 19 reports of seven studies (see Characteristics of included studies table) and excluded three reports of three studies (see Characteristics of excluded studies table). We identified 13 ongoing studies that potentially met the inclusion criteria, these studies will be assessed when data become available (see Characteristics of ongoing studies table for further details).

Included studies

Type of studies

We included seven RCTs (Fea 2010; Fea 2014; Fernandez‐Barrientos 2010; Katz 2015; NCT00721968; Samuelson 2011; Vold 2016). Most RCTs were multi‐center trials in which participants were recruited from Armenia (two RCTs); Italy (one RCT); Spain (one RCT); the US (two RCTs); or the previous four countries in addition to Germany and the UK (one RCT) (see Characteristics of included studies table). Six trials began enrollment of participants prior to 2010, and the maximal planned length of follow‐up ranged from one to five years (Fea 2010; Fea 2014; Fernandez‐Barrientos 2010; Katz 2015; NCT00721968; Samuelson 2011). All seven RCTs reported having received support – including financial, non‐study financial, or non‐financial support (e.g. study devices, editorial assistance, or payment of article processing charges) – from the Glaukos Corporation (Laguna Hills, CA, USA), manufacturer of the iStent and iStent inject.

Type of participants

The seven RCTs enrolled 764 participants (765 eyes; range per study: 33 to 239 participants). Most participants were white, female sex (417/764 (55%)), and older age (range: 49 to 89 years). The diagnosis of participants varied between studies: some included people with OHT, pseudoexfoliative glaucoma (PXG), or pigmentary glaucoma (PG) in addition to OAG. Most excluded participants with prior incisional glaucoma surgery, and four trials included only participants with OAG in need of cataract surgery (Fea 2010; Fernandez‐Barrientos 2010; NCT00721968; Samuelson 2011). Four trials reported that participants were washed out of current glaucoma medication (Fea 2014; Fernandez‐Barrientos 2010; Katz 2015; Samuelson 2011); one trial recruited only treatment‐naïve participants (Vold 2016). Table 3 provides a synopsis of the trial‐level eligibility criteria.

1. Eligibility criteria of included studies.

Study	Diagnosis	Intraocular pressure	Number of glaucoma medication currently taking	Visual acuity (Snellen; BCVA)	Prior incisional glaucoma surgery	Prior laser surgery	Washout period
Comparison 1: iStent in combination with phacoemulsification vs phacoemulsification alone
Fea 2010	OAG in need of cataract surgery	> 18 mmHg (medicated)	≥ 1	20/80 or worse	Excluded	NR	NR
Fernandez‐Barrientos 2010	OHT or OAG in need of cataract surgery	> 17 mmHg and < 31 mmHg (medicated); > 21 mmHg and < 36 mmHg (unmedicated)	≤ 2	20/40 or worse	Excluded	Excluded	Yes
NCT00721968	OAG in need of cataract surgery	NR	NR	NR	NR	NR	NR
Samuelson 2011	OAG, PEXG, or PG, in need of cataract surgery	≤ 24 mmHg (medicated); ≥ 22 mmHg and ≤ 36 mmHg (unmedicated)	≥ 1 and ≤ 3	20/40 or worse	Excluded (except for iridectomy)	Excluded	Yes
Comparison 2: iStent or iStent inject vs medical therapy
Fea 2014	OAG, PEXG, or PG	≥ 22 mmHg and < 38 mmHg (unmedicated)	1	20/200 or better	Excluded	Included^a	Yes
Vold 2016	OHT, OAG, or PEXG	≥ 21 mmHg and ≤ 40 mmHg (unmedicated)	0	NR	Excluded	Excluded	NA
*Additional comparison: 1 iStent vs 2 iStents vs 3 iStents*
Katz 2015	OAG, PEXG, or PG; and phakic	≥ 18 mmHg and ≤ 30 mmHg (medicated); > 22 mmHg and < 38 mmHg (unmedicated)	2	20/200 or better	Excluded	Included^a	Yes

Comparison 1: iStent in combination with phacoemulsification vs phacoemulsification alone
Fea 2010	—	—
Adverse events	"No postoperative stent‐related adverse events were observed in these eyes [N = 24] through 48 months. IOP was well controlled in both groups throughout the entire follow‐up period; no secondary surgical intervention was required to control IOP."
Fernandez‐Barrientos 2010	2 iStents in combination with phacoemulsification at 1 year	Phacoemulsification alone at 1 year
Stent malposition	Authors noted that "six of the 34 (18%) implanted stents appeared to be malpositioned"	NA
Need for selective trabeculoplasty	0	1/16
NCT00721968	iStent in combination with phacoemulsification at 1 year	Phacoemulsification alone at 1 year
Posterior capsule opacification	4/27	1/17
IOP increase ≥ 10 mmHg vs baseline IOP at any visit	3/27	9/17
Conjunctivitis	3/27	2/17
Corneal abrasion	2/27	1/17
Iritis	2/27	0
Punctate corneal staining	1/27	1/17
Superficial punctate keratitis	1/27	1/17
Blurry vision	1/27	1/17
BCVA loss ≥ 1 line after 3 months postoperative	0	2/17
Eye pain	0	2/17
Retinal detachment	0	1/17
Samuelson 2011	iStent in combination with phacoemulsification at 2 years	Phacoemulsification alone at 2 years
Anticipated early postoperative event (as defined by investigators)	20/116	22/117
Posterior capsule opacification	7/116	12/117
Elevated IOP	5/116	8/117
Stent obstruction	5/116	NA
Blurry vision or visual disturbance	4/116	8/117
Stent malposition	3/116	NA
Iritis	1/116	6/117
Conjunctival irritation due to hypotensive medication	1/116	3/117
Disk hemorrhage	1/116	3/117
Comparison 2: iStent (or iStent inject) vs medical therapy
Fea 2014	iStent inject at 1 year (94 eyes of 94 participants)	Medical therapy at 1 year (98 eyes of 98 participants)
IOP decompensation	1/94	0
Soreness/discomfort	1/94	0
Eye burning	0	1/98
Medical allergy	0	1/98
Secondary glaucoma surgery	1/94	NA
Vold 2016	"Safety was favorable in both groups [Two iStents, N = 54; Medical therapy, N = 47; at 36 months). Two complications were reported during stent insertion in the surgery group, both of which were attributed to subject movement during surgery: one of these subjects had hyphema which resolved by day 1 and one subject had a small iridodialysis which resulted in no postoperative ocular sequelae...In the remaining non‐operated subjects, three‐year BCVA was 20/40 or better in 6 eyes (2 in stent group and 4 in med group), 20/100 in 1 eye (stent group), and 20/200 in 6 eyes (3 per group). No other post‐treatment adverse events were reported in either group."
Additional comparison: 1 iStent vs 2 iStents vs 3 iStents
Katz 2015	"No complications occurred intraoperatively or perioperatively, including no hypotony, choroidal effusion, hyphema, nor iridodialysis [One iStent, N=38; two iStents, N= 41; three iStents, N=40]. During 42 months of postoperative follow‐up, no device‐related or sight‐threatening adverse events occurred; furthermore, no eyes required additional glaucoma surgery. In this cohort of almost entirely phakic subjects (117 of 119) with mean baseline age between 62 and 69 years, the most common (and expected) adverse event over 3.5 years of follow‐up was progression of preexisting cataract. By Month 42 postoperatively, a total of eight one‐stent eyes, five two‐stent eyes, and seven three‐stent eyes had BCVA loss 1 line due to cataract progression. Of these cases, five one‐stent eyes, two two‐stent eyes, and three three‐stent eyes underwent cataract surgery by Month 42, and their IOP and medication data thereafter were excluded from efficacy analyses; two additional eyes (three‐stent group) had cataract surgery shortly after the Month 42 visit."

iStent in combination with phacoemulsification compared to phacoemulsification alone for open‐angle glaucoma
Patient or population: open‐angle glaucoma  Setting: –  Intervention: iStent in combination with phacoemulsification  Comparison: phacoemulsification alone
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Outcomes	Risk with phacoemulsification alone	Risk with iStent in combination with phacoemulsification	Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Proportion of participants who were drop‐free Follow‐up: range 6 to ≤ 18 months	583 per 1000	804 per 1000  (688 to 950)	RR 1.38  (1.18 to 1.63)	239  (2 RCTs)	⊕⊝⊝⊝  Very low^a,b,c	Estimate based on data from 2 trials.
Mean change in number of IOP‐lowering drops from baseline Follow‐up: range 6 to ≤ 18 months	The mean change in number of IOP‐lowering drops from baseline ranged from –1.0 to 0.9 drops	MD 0.42 drops fewer  (0.6 fewer to 0.23 fewer)	—	282  (2 RCTs)	⊕⊝⊝⊝  Very low^a,b,c	In addition, Fernandez‐Barrientos 2010 reported the change in number of IOP‐lowering drops was 0 (SD 0) in the iStent in combination of phacoemulsification treatment group and 0.7 (SD 1) in the phacoemulsification alone group.
Mean change in IOP from baseline Follow‐up: range 6 to ≤ 18 months	The mean change in IOP from baseline ranged from –8.5 to –1.6 mmHg	MD 1.24 mmHg lower  (3.07 lower to 0.58 higher)	—	284  (3 RCTs)	⊕⊝⊝⊝  Very low^a,b,c,d	—
Health‐related quality of life	—		—	—	—	Not reported in any of the 4 studies.
Intraoperative complications	—		—	—	—	Samuelson 2011 reported that "[i]n an eye with intraoperative stent malposition, a second stent was implanted during the same surgery."
Postoperative complications	Based on available data, participants who were randomized to treatment with phacoemulsification in combination with iStent were less likely to experience elevated IOP (or IOP spikes) and loss of vision than those randomized to phacoemulsification alone.		—	334 (4 RCTs)	—	We did not conduct a meta‐analysis of complications.
Secondary glaucoma surgery Follow‐up: range 6 to ≤ 18 months	1 participant randomized to treatment with phacoemulsification in combination with iStent and 1 participant randomized to phacoemulsification alone underwent selective laser trabeculoplasty at 12 months.		—	290 (3 RCTs)	—	We did not conduct a meta‐analysis of complications.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; IOP: intraocular pressure; MD: mean difference; RCT: randomized controlled trial; RR: risk ratio; SD: standard deviation.
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

IStent (or iStent inject) compared to medical therapy for open‐angle glaucoma
Patient or population: open‐angle glaucoma  Setting: –  Intervention: iStent (or iStent inject)  Comparison: medical therapy
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Outcomes	Risk with medical therapy	Risk with iStent (or iStent inject)	Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Proportion of participants who were drop‐free Follow‐up: range 6 to ≤ 18 months	At 12 months, 0/138 participants randomized to medical therapy were drop‐free at 12 months, while 141/148 (95%) participants randomized to treatment with iStent were drop‐free at 12 months. We did not derive an RR because no events occurred in the control groups of either trial.		—	286  (2 RCTs)	⊕⊝⊝⊝  Very low^a,b,c	In addition, Vold 2016 noted that 48/54 (88%) participants in the iStent treatment group were drop‐free at 36 months.
Mean change in number of IOP‐lowering drops from baseline	—	—	—	—	—	Not reported in either study.
Mean change in IOP from baseline Follow‐up: range 6 to ≤ 18 months	The mean change in IOP from baseline was –11.6 mmHg	MD 0.6 mmHg lower  (1.28 lower to 0.08 higher)	—	184  (1 RCT)	⊕⊝⊝⊝  Very low^a,b,c	Vold 2016 did not report mean change in IOP but did provide mean IOP (without SD) at 6 months (14.2 mmHg), 18 months (13.5 mmHg), and 36 months (14.6 mmHg) in the iStent treatment groups; and at 6 months (13.8 mmHg), 18 months (14.6 mmHg), and 36 months (15.3 mmHg) in the medical therapy group.
Health‐related quality of life	—		—	—	—	Not reported in either study.
Intraoperative complications	1 participant in the iStent treatment group experienced hyphema which resolved by day 1		—	101 (1 RCT)	—	We did not conduct a meta‐analysis of complications.
Postoperative complications	Vold 2016 noted that best‐corrected visual acuity was stable between both groups and did not report on any other postoperative complications. Fea 2014 reported that 1 participant in the iStent inject group experienced IOP decompensation with an elevated IOP of 48 mmHg.		—	286  (2 RCTs)	—	We did not conduct a meta‐analysis of complications.
Secondary glaucoma surgery	Fea 2014 reported that 1 participant needed laser treatment to remove an apparent obstruction		—	286  (2 RCTs)	—	We did not conduct a meta‐analysis of complications.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; IOP: intraocular pressure; MD: mean difference; RCT: randomized controlled trial; RR: risk ratio; SD: standard deviation.
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Study	Pharmaceutical industry involvement	Other financial support
Comparison 1: iStent in combination with phacoemulsification vs phacoemulsification alone
Fea 2010	Glaukos Corporation provided funding/support (including study devices)	Ricerca Finalizaata della Regione Pimonte 2007
Fernandez‐Barrientos 2010	Glaukos Corporation provided funding/support	—
NCT00721968	Glaukos Corporation provided funding/support	—
Samuelson 2011	Glaukos Corporation provided funding/support (Investigators were consultants to Glaukos for the conduct of this study)	—
Comparison 2: iStents vs medical therapy
Fea 2014	Glaukos Corporation provided funding/support (including study devices, editorial assistance, payment of article processing charges, financial support, and non‐study financial support)	—
Vold 2016	Glaukos Corporation provided funding/support (including non‐financial, financial, and non‐study financial support to some/all authors)	—
Additional comparison: iStent vs 2 iStents vs 3 iStents
Katz 2015	Glaukos Corporation provided funding/support (including study devices and non‐financial, financial, and non‐study financial support to some/all authors)	—

Mandatory items		Optional items
Methods
Study design	Parallel group RCTi.e. people randomized to treatment Within‐person RCTi.e. eyes randomized to treatment Cluster RCTi.e. communities randomized to treatment Cross‐over RCT Other, specify	Number of study arms Method of randomization Exclusions after randomization Losses to follow‐up Number randomized/analyzed Method of masking How were missing data handled? e.g. available case analysis, imputation methods Reported power calculation (Y/N), if yes, sample size and power Unusual study design/issues
Eyes Unit of randomization/unit of analysis	One eye included in study, specify how eye selected Two eyes included in study, both eyes received same treatment, briefly specify how analyzed (best/worst/average/both and adjusted for within person correlation/both and not adjusted for within person correlation) and specify if mixture of one eye and two eyes Two eyes included in study, eyes received different treatments,specify if correct pair‐matched analysis done
Participants
Country	—	Setting Ethnic group Method of recruitment Participation rate Equivalence of baseline characteristics (Y/N) Diagnostic criteria
Total number of participants	This information should be collected for total study population recruited into the study. If these data are reported for the people who were followed up only, please indicate.
Number (%) of men and women
Average age and age range
Inclusion criteria	—
Exclusion criteria	—
Interventions
Intervention (n= ) Comparator (n= ) *See MECIR 65 and 70*	Number of people randomized to this group Intervention name Comparator name Specify whether phacoemulsification, or other intervention, performed at same time as intervention	iStent or iStent inject surgical parameters, e.g. degrees of meshwork ablated, electrosurgical power Comparator parameters, e.g. dosage of drugs
Outcomes
Primary and secondary outcomes as defined in study reports *See MECIR R70*	Proportion of participants who were drop‐free at 2 years' follow‐up Mean change in number of IOP‐lowering drops taken per day from baseline to 2 years' follow‐up Mean change in IOP from baseline to 2 years' follow‐up Health‐related quality of life measures at 2 years' follow‐up Intraoperative complications Adverse events reported (Y/N)	Planned/actual length of follow‐up
Notes
Date conducted	Specify dates of recruitment of participants mm/yr to mm/yr	Full study name: (if applicable) Date of publication Reported subgroup analyses (Y/N) Were trial investigators contacted?
Sources of funding	—
Declaration of interest *See MECIR 69*	—

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of participants who were drop‐free	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1 At 6 to ≤ 18 months	2	239	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [1.18, 1.63]
2 Mean change in number of intraocular pressure (IOP)‐lowering drops taken per day from baseline	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.1 At ≤ 6 months	1	33	Mean Difference (IV, Fixed, 95% CI)	‐0.4 [‐0.82, 0.02]
2.2 At 6 to ≤ 18 months	3	315	Mean Difference (IV, Fixed, 95% CI)	‐0.42 [‐0.60, ‐0.23]
3 Mean change in IOP	3		Mean Difference (IV, Random, 95% CI)	Totals not selected
3.1 At ≤ 6 months	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 At 6 to ≤ 18 months (unmedicated IOP)	3		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of participants who were drop‐free	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1 At 6 to ≤18 months	2	286	Risk Ratio (M‐H, Random, 95% CI)	125.43 [17.80, 883.89]
1.2 At 18 to ≤ 36 months	1	101	Risk Ratio (M‐H, Random, 95% CI)	84.65 [5.36, 1336.23]
2 Mean change in intraocular pressure	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.1 At ≤ 6 months	1	184	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.72, 0.92]
2.2 At 6 to ≤ 18 months	1	184	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐1.28, 0.08]

Methods	Study design: parallel‐group RCT Unit of randomization: participant (1 eye per participant) Number randomized: 36 participants; 12 eyes of 12 participants in the 1 iStent in combination with phacoemulsification group and 24 eyes of 24 participants in phacoemulsification alone group Unit of analysis: participant (1 eye per participant) Number analyzed: 33 total; 12 eyes of 12 participants in the 1 iStent in combination with phacoemulsification group and 21 eyes of 21 participants in phacoemulsification alone group Exclusions and losses to follow‐up: 3 participants in the phacoemulsification alone group (1 capsule rupture, 1 did not present at 6 months' follow‐up, 1 died from complications from ankle surgery) Handling of missing data: analysis excluded participants lost to follow‐up
Participants	Country: Torino, Italy (single site) Age (mean ± SD): 64.5 ± 3.4 years (range: 60–70 years) in the 1 iStent in combination with phacoemulsification group; 64.9 ± 3.1 years (range: 59–71 years) in the phacoemulsification alone group Gender: 4 men and 8 women in the 1 iStent in combination with phacoemulsification group; 9 men and 15 women in the phacoemulsification alone group Medicated IOP (mean ± SD): 17.9 ± 2.6 mmHg in the 1 iStent in combination with phacoemulsification group; 17.3 ± 3.0 mmHg in the phacoemulsification alone group Inclusion criteria: previous diagnosis of POAG, scheduled for cataract surgery IOP > 18 mmHg at 3 separate visits on ≥ 1 ocular hypotensive medications, or on ≥ 2 medications with uncontrolled IOP on 3 separate visits preoperative corrected distance visual acuity ≤ 0.6 (20/80) likely to follow surgeon instructions able to give informed consent Exclusion criteria: glaucoma diagnosis other than POAG (i.e. Scheie grade < 2) presence of peripheral anterior synechiae cloudy cornea likely to inhibit gonioscopic view of the angle previous ocular surgery (including glaucoma‐filtering surgery) history of trauma or ocular surface disease history of preproliferative or proliferative diabetic retinopathy age‐related macular degeneration with macular scar or large macular atrophy that would inhibit potential visual acuity Diagnoses in participants: POAG and cataract
Interventions	Intervention 1: 1 iStent in combination with phacoemulsification Intervention 2: phacoemulsification alone Length of follow‐up: 4 years
Outcomes	Primary outcome: mean IOP at 1, 2, 3, 6, 9, 12, 15, and 48 months Secondary outcomes: number and type of glaucoma medication; proportion of participants who "do not require ocular hypotensive medication"; mean change in IOP from baseline; mean IOP "after washout of ocular hypotensive agents"; and need for secondary intervention to control IOP at 1, 2, 3, 6, 9, 12, 15, and 48 months
Notes	Type of study: published Enrollment start year: 2006 Funding source: study devices provided by Glaukos Corporation, Laguna Hills, CA, USA; supported by Ricerca Finalizzata Della Regione Piemonte 2007 Disclosures of interest: "The author has no financial or proprietary interest in any material or method mentioned." Publication language: English Trial registration: NCT0084718
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Investigators used a computer random number generator. Quote: "Patient randomization was generated with a 2:1 ratio using Stata data analysis and statistical software."
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not reported.
Blinding of outcome assessment (detection bias)   Number of IOP‐lowering drops	Unclear risk	Unclear who assessed number of IOP‐lowering drops.
Blinding of outcome assessment (detection bias)   IOP measurement	Low risk	Investigators noted that "[p]atients were masked to their assignment, as were staff members who measured IOP throughout the study."
Incomplete outcome data (attrition bias)   All outcomes	High risk	3/36 participants (all randomized to the phacoemulsification alone group) were excluded from the final analysis.
Selective reporting (reporting bias)	Low risk	Outcomes described in the results matched those specified in methods and in the ClinicalTrials.gov record.

Study	Reason for exclusion
Bacharach 2014	Not a randomized controlled trial
NCT03274323	Study was withdrawn before enrolling participants
Vlasov 2017	Not a randomized controlled trial

Trial name or title	Evaluación aleatorizada prospectiva en abierto del iStent® (GTS400) frente a dos agentes hipotensores oculares en pacientes con glaucoma primario de ángulo abierto – second line study [Open prospective randomized evaluation of iStent® (GTS400) versus two ocular hypotensive agents in patients with primary open‐angle glaucoma]
Methods	Study design: parallel‐group RCT Unit of randomization: not reported Number randomized: not reported Unit of analysis: not reported Number analyzed: not reported Exclusions and losses to follow‐up: not reported Handling of missing data: not reported
Participants	Country: Spain Age: not reported Gender: not reported Inclusion criteria: Diagnosis by researchers of primary open angle glaucoma (including pseudoexfoliation or pigmentary glaucoma) Male or female, at least 18 years of age and able to give written informed consent Diurnal untreated mean IOP (at the initial visit after having rested from all medication taken) of at least 22 mmHg, but less than 38 mmHg The scleral spur of the patient must be clearly visible with the gonioscope Able to attend follow‐up visits No prior incisional surgery or laser interventions to treat glaucoma; previous surgery for cataracts is acceptable Minimum BCVA of 20/200 or better Exclusion criteria: not reported (in Spanish) Diagnoses in participants: OAG
Interventions	Intervention 1: iStent Intervention 2: latanoprost; timolol Length of follow‐up: not reported
Outcomes	Primary outcomes: Mean IOP at each visit for the study; mean reduction in IOP; percentage of patients achieving an objective IOP> 18 mmHG; responses to the patient's questionnaire Secondary outcomes: not reported Safety outcomes: not reported
Starting date	11 March 2010
Contact information	No contact details
Notes	Type of study: awaiting classification Funding source: Glaukos Corporation, Laguna Hills, CA, USA provided funding/support Disclosures of interest: not reported Publication language: not reported Trial registration: EudraCT Number 2009‐018066‐36

Trial name or title	A study of the Glaukos trabecular micro‐bypass stent in open angle glaucoma subjects 1 stent versus 2
Methods	Study design: parallel‐group RCT Unit of randomization: not reported Number randomized: not reported Unit of analysis: not reported Number analyzed: not reported Exclusions and losses to follow‐up: not reported Handling of missing data: not reported
Participants	Country: Austria, Germany, Spain, Turkey Age: not reported Gender: not reported Inclusion criteria: diagnosed with OAG taking ≥ 1 glaucoma medication signed informed consent Exclusion criteria: angle closure glaucoma secondary glaucomas except pseudoexfoliative and pigmentary; no neovascular, uveitic, or angle recession glaucoma prior glaucoma procedures (e.g. trabeculectomy, viscocanalostomy, ALT, SLT, shunt implant, collagen implant, cyclodestructive procedures, etc.) fellow eye already enrolled Diagnoses in participants: OAG
Interventions	Intervention 1: implantation of 1 Glaukos iStent Intervention 2: implantation of 2 Glaukos iStents Length of follow‐up: 2 years
Outcomes	Primary outcomes: efficacy at 2 years Secondary outcomes: IOP measurement from preoperative baseline; incidence of adverse events during the surgical procedure and postoperative period Safety outcomes: (see secondary outcomes)
Starting date	August 2004
Contact information	No contact details
Notes	Type of study: awaiting classification – described as unknown on ClinicalTrials.gov Funding source: Glaukos Corporation, Laguna Hills, CA, USA provided funding/support Disclosures of interest: not reported Publication language: not reported Trial registration: NCT00326079

Trial name or title	GTS400 stent implantation in conjunction with cataract surgery in subjects with open‐angle glaucoma
Methods	Study design: parallel‐group RCT Unit of randomization: not reported Number randomized: not reported Unit of analysis: not reported Number analyzed: not reported Exclusions and losses to follow‐up: not reported Handling of missing data: not reported
Participants	Country: US Age: not reported Gender: not reported Inclusion criteria: diagnosed with OAG in the study eye using 1–3 glaucoma medications able and willing to attend follow‐up visits for 2 years postoperation able and willing to sign informed consent Exclusion criteria: PEXG and PG prior glaucoma surgery of any type Diagnoses in participants: OAG
Interventions	Intervention 1: cataract surgery with subsequent implantation of GTS400 stents Intervention 2: cataract surgery Length of follow‐up: 1 year
Outcomes	Primary outcomes: proportion of participants with 12‐month diurnal IOP ≤ 21 mmHg without use of ocular hypotensive medications for ≥ 4 weeks prior to 12‐month visit Secondary outcomes: not reported Safety outcomes: not reported
Starting date	20 January 2010
Contact information	No contact details
Notes	Type of study: awaiting classification – described as "completed" on ClinicalTrials.gov Funding source: Glaukos Corporation, Laguna Hills, CA, USA provided funding/support Disclosures of interest: not reported Publication language: not reported Trial registration: NCT01052558

Trial name or title	Purpose of this study is to evaluate the safety and efficacy of one, two, or three iStents for the reduction of intraocular pressure in open‐angle glaucoma subjects
Methods	Study design: parallel‐group RCT Unit of randomization: not reported Number randomized: not reported Unit of analysis: not reported Number analyzed: not reported Exclusions and losses to follow‐up: not reported Handling of missing data: not reported
Participants	Country: Armenia Age: not reported Gender: not reported Inclusion criteria: diagnosed with POAG using 2 topical hypotensive medications Exclusion criteria: traumatic, uveitic, neovascular, or angle closure glaucoma fellow eye already enrolled Diagnoses in participants: POAG
Interventions	Intervention 1: implantation of 1 iStent through a small temporal clear corneal incision Intervention 2: implantation of 2 iStents through a small temporal clear corneal incision Intervention 3: implantation of 3 iStents through a small temporal clear corneal incision Length of follow‐up: 1 year
Outcomes	Primary outcomes: mean diurnal IOP reduction ≥ 20% at month 12 vs baseline at 1 year Secondary outcomes: mean diurnal IOP < 18 mmHg at 1 year Safety outcomes: not reported
Starting date	3 December 2010
Contact information	No contact details
Notes	Type of study: awaiting classification POAG described as "active, not recruiting" on ClinicalTrials.gov Funding source: Glaukos Corporation, Laguna Hills, CA, USA provided funding/support Disclosures of interest: not reported Publication language: not reported Trial registration: NCT01252849

Trial name or title	Subjects with open‐angle glaucoma, pseudoexfoliative glaucoma, or ocular hypertension naïve to medical and surgical therapy, treated with two trabecular micro‐bypass stents (iStent inject) or travoprost
Methods	Study design: parallel‐group RCT Unit of randomization: not reported Number randomized: not reported Unit of analysis: not reported Number analyzed: not reported Exclusions and losses to follow‐up: not reported Handling of missing data: not reported
Participants	Country: Armenia Age: not reported Gender: not reported Inclusion criteria: phakic study eye IOP ≥ 21 mmHg and ≤ 40 mmHg at the screening visit (people with OHT require a second screening IOP measurement Exclusion criteria: aphakic or pseudophakic eyes (AC‐IOLs or PC‐IOLs) previous usage of topical prostaglandin analogues or prior medical therapy for glaucoma Diagnoses in participants: OAG
Interventions	Intervention 1: implantation of 2 iStent inject devices Intervention 2: travoprost drops Length of follow‐up: 5 years
Outcomes	Primary outcomes: change from screening in mean diurnal IOP (mmHg) at 1 year Secondary outcomes: change in mean diurnal IOP vs screening at 2 years; change in screening in time‐wise IOPs at "Various Month 12‐60"; proportion of responders at "Various 12‐60 months." "A responder is defined as a subject with a certain target IOP value or a certain reduction of IOP as compared to screening." Safety outcomes: not reported
Starting date	30 September 2011
Contact information	No contact details
Notes	Type of study: awaiting classification PC‐IOL described as "Active, not recruiting" on ClinicalTrials.gov Funding source: Glaukos Corporation, Laguna Hills, CA, USA provided funding/support Disclosures of interest: not reported Publication language: not reported Trial registration: NCT01444040

Trial name or title	Open‐angle glaucoma subjects on one ocular hypotensive medication randomized to treatment with two trabecular micro‐bypass stents or selective laser trabeculoplasty
Methods	Study design: parallel‐group RCT Unit of randomization: not reported Number randomized: not reported Unit of analysis: not reported Number analyzed: not reported Exclusions and losses to follow‐up: not reported Handling of missing data: not reported
Participants	Country: Armenia Age: not reported Gender: not reported Inclusion criteria: phakic study eye requiring cataract removal and PC‐IOL implantation POAG (including PG or PEXG) Exclusion criteria: aphakic or pseudophakic with PC‐IOL or AC‐IOL (study eye) prior stent implantations (study eye) Diagnoses in participants: OAG
Interventions	Intervention 1: implantation of 2 iStent devices Intervention 2: SLT laser treatment Length of follow‐up: not reported
Outcomes	Primary outcomes: change from baseline in mean diurnal IOP (mmHg) at 1 year Secondary outcomes: not reported Safety outcomes: not reported
Starting date	30 September 2011
Contact information	No contact details
Notes	Type of study: awaiting classification, PC‐IOL described as "active, not recruiting" on ClinicalTrials.gov Funding source: Glaukos Corporation, Laguna Hills, CA, USA provided funding/support Disclosures of interest: not reported Publication language: not reported Trial registration: NCT01444105

Trial name or title	Open‐angle glaucoma subjects on one topical hypotensive medication randomized to treatment with one or two trabecular micro‐bypass stents in conjunction with cataract surgery
Methods	Study design: parallel‐group RCT Unit of randomization: not reported Number randomized: not reported Unit of analysis: not reported Number analyzed: not reported Exclusions and losses to follow‐up: not reported Handling of missing data: not reported
Participants	Country: Armenia Age: not reported Gender: not reported Inclusion criteria: phakic study eye requiring cataract removal and PC‐IOL implantation POAG (including PG or PEXG) Exclusion criteria: aphakic or pseudophakic with PC‐IOLs or AC‐IOLs (study eye) prior stent implantations (study eye) Diagnoses in participants: OAG
Interventions	Intervention 1: implantation of 1 iStent in conjunction with cataract surgery Intervention 2: implantation of 2 iStent in conjunction with cataract surgery Length of follow‐up: 1 year
Outcomes	Primary outcomes: mean diurnal IOP reduction of ≥ 20% vs baseline mean diurnal IOP at 1 year Secondary outcomes: not reported Safety outcomes: not reported
Starting date	20 October 2011
Contact information	No contact details
Notes	Type of study: awaiting classification, described as "active, not recruiting" on ClinicalTrials.gov Funding source: Glaukos Corporation, Laguna Hills, CA, USA provided funding/support Disclosures of interest: not reported Publication language: not reported Trial registration: NCT01455467

Trial name or title	Multicenter study using Glaukos® trabecular micro‐bypass stent model GTS400 using the G2‐M‐IS injector system in conjunction with cataract surgery
Methods	Study design: parallel‐group RCT Unit of randomization: not reported Number randomized: not reported Unit of analysis: not reported Number analyzed: not reported Exclusions and losses to follow‐up: not reported Handling of missing data: not reported
Participants	Country: US Age: not reported Gender: not reported Inclusion criteria: mild‐to‐moderate OAG characteristics consistent with mild/moderate glaucoma use of 1–3 medications at time of screening exam Exclusion criteria: PG or PEXG prior incisional glaucoma surgery Diagnoses in participants: POAG
Interventions	Intervention 1: implantation of 2 GTS400 stents using G2‐M‐IS iStent inject Intervention 2: cataract surgery alone Length of follow‐up: 2 years
Outcomes	Primary outcomes: ≥ 20% reduction in IOP at 2 years Secondary outcomes: diurnal IOP reduction from baseline at 2 years Safety outcomes: not reported
Starting date	28 October 2011
Contact information	No contact details
Notes	Type of study: awaiting classification, described as "active, not recruiting" on ClinicalTrials.gov Funding source: Glaukos Corporation, Laguna Hills, CA, USA provided funding/support Disclosures of interest: not reported Publication language: not reported Trial registration: NCT01461291

Trial name or title	Comparing effectiveness of the Hydrus Microstent (TM) to two iStents to lower IOP in phakic eyes (COMPARE)
Methods	Study design: parallel‐group RCT Unit of randomization: not reported Number randomized: not reported Unit of analysis: not reported Number analyzed: not reported Exclusions and losses to follow‐up: not reported Handling of missing data: not reported
Participants	Country: US Age: not reported Gender: not reported Inclusion criteria: diagnosis of POAG, PXG, or PG phakic lens with BCVA 20/30 or worse Exclusion criteria: forms of primary or secondary glaucoma not listed above prior glaucoma surgery in the study eye Diagnoses in participants: OAG
Interventions	Intervention 1: Hydrus Microstent Intervention 2: iStent trabecular micro bypass Length of follow‐up: 2 years
Outcomes	Primary outcomes: difference in proportion of participants unmedicated at 12 months following surgery Secondary outcomes: mean medication use at 12 and 24 months post procedure Safety outcomes: not reported
Starting date	30 December 2013
Contact information	Principal Investigator: Julian Garcia Feijoo, Professor of Medicine, Madrid, Spain
Notes	Type of study: awaiting classification, described as "completed" on ClinicalTrials.gov Funding source: Ivantis, Inc Disclosures of interest: not reported Publication language: not reported Trial registration: NCT02023242

Trial name or title	Comparing Hydrus Microstent(TM) to the iStent for lowering IOP in glaucoma patients undergoing cataract surgery
Methods	Study design: parallel‐group RCT Unit of randomization: not reported Number randomized: not reported Unit of analysis: not reported Number analyzed: not reported Exclusions and losses to follow‐up: not reported Handling of missing data: not reported
Participants	Country: US Age: not reported Gender: not reported Inclusion criteria: diagnosis of POAG, PXG, or PDG operable age‐related cataract with BCVA 20/40 or worse, eligible for phacoemulsification Exclusion criteria: forms of primary or secondary glaucoma not listed above prior glaucoma surgery in the study eye Diagnoses in participants: POAG, PXG, PDG
Interventions	Intervention 1: Hydrus Microstent Intervention 2: iStent trabecular micro bypass Length of follow‐up: 2 years
Outcomes	Primary outcomes: IOP at 2 years Secondary outcomes: proportion of participants requiring supplemental medication and loss of BCVA at 2 years Safety outcomes: not reported
Starting date	31 December 2013
Contact information	Principal Investigator: Iqbal K Ahmed, MD, Mississauga, ON, Canada
Notes	Type of study: awaiting classification, described as "active, not recruiting" on ClinicalTrials.gov Funding source: Ivantis, Inc Disclosures of interest: not reported Publication language: not reported Trial registration: NCT02024464

Trial name or title	Multicenter investigation of trabecular micro‐bypass stents vs. laser trabeculoplasty
Methods	Study design: parallel‐group RCT Unit of randomization: not reported Number randomized: not reported Unit of analysis: not reported Number analyzed: not reported Exclusions and losses to follow‐up: not reported Handling of missing data: not reported
Participants	Country: US Age: not reported Gender: not reported Inclusion criteria: OAG Exclusion criteria: active corneal inflammation or edema choroidal detachment, effusion, choroiditis Diagnoses in participants: POAG
Interventions	Intervention 1: 2 trabecular meshwork micro‐bypass stents into the study eye Intervention 2: laser trabeculoplasty Length of follow‐up: 2 years
Outcomes	Primary outcomes: IOP reduction up to 2 years Secondary outcomes: % IOP reduction up to 2 years Safety outcomes: not reported
Starting date	30 December 2014
Contact information	Jeff Wells jwells@glaukos.com
Notes	Type of study: awaiting classification, described as "recruiting" on ClinicalTrials.gov Funding source: Glaukos Corporation, Laguna Hills, CA, USA provided funding/support Disclosures of interest: not available Publication language: not available Trial registration: NCT02327312

PERMALINK

Ab interno trabecular bypass surgery with iStent for open‐angle glaucoma

Jimmy T Le

Amanda K Bicket

Lin Wang

Tianjing Li

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Adverse outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' tables

Results

Description of studies

Results of the search

1.

Included studies

Type of studies

Type of participants

1. Eligibility criteria of included studies.

Type of interventions

Type of outcomes

2. Postoperative complications reported by included studies.

Excluded studies

Ongoing studies

Risk of bias in included studies

2.

Allocation

Random sequence generation

Allocation concealment

Blinding

Incomplete outcome data

Selective reporting

Effects of interventions

Summary of findings for the main comparison. IStent in combination with phacoemulsification compared to phacoemulsification alone for open‐angle glaucoma.

Summary of findings 2. IStent (or iStent inject) compared to medical therapy for open‐angle glaucoma.

Comparison 1: iStent in combination with phacoemulsification versus phacoemulsification alone

Proportion of participants who were drop‐free

3.

Mean change in number of intraocular pressure‐lowering drops

4.

Mean change in intraocular pressure

5.

Health‐related quality of life

Intra‐ and postoperative complications from baseline

Trial name or title	A comparison of cataract surgery alone and cataract surgery with iStent
Methods	Study design: parallel‐group RCT Unit of randomization: unclear Number randomized: not reported Unit of analysis: not reported Number analyzed: not reported Exclusions and losses to follow‐up: not reported Handling of missing data: not reported
Participants	Country: Australia Age: not reported Gender: not reported Inclusion criteria: age > 18 years diagnosis of mild‐to‐moderate OAG presence of cataract requiring surgery good understanding of both verbal and written English able to provide informed consent Exclusion criteria: recent intraocular surgery within last 3 months other ocular pathology affecting visionInability to complete the elements of the study, e.g. coma, hemodynamic instability, ventilator dependence, that could be of concern in the investigator's judgment non‐elective hospitalization within the past 60 days that could be of concern in the investigator's judgment medical illness that in the judgment of the investigator would jeopardize the safe completion of the study. Examples include cancer, chronic inflammatory disease, chronic liver insufficiency, epilepsy, thrombocytosis Diagnoses in participants: OAG
Interventions	Intervention 1: iStent inject Intervention 2: phacoemulsification Length of follow‐up: 2 years
Outcomes	Primary outcomes: IOP reduction up to 2 years Secondary outcomes: number of glaucoma medications; participant treatment satisfaction up to 2 years Safety outcomes: not reported
Starting date	10 April 2017
Contact information	Jennifer C Fan Gaskin, FRANZCO drjfan@gmail.com
Notes	Type of study: awaiting classification, described as "recruiting" on ClinicalTrials.gov Funding source: Glaukos Corporation, Laguna Hills, CA, USA provided funding/support Disclosures of interest: not reported Publication language: not reported Trial registration: NCT03106181

Trial name or title	A randomized study of efficacy of trabecular micro bypass stent with cataract surgery for open angle glaucoma
Methods	Study design: parallel‐group RCT Unit of randomization: not reported Number randomized: not reported Unit of analysis: not reported Number analyzed: not reported Exclusions and losses to follow‐up: not reported Handling of missing data: not reported
Participants	Country: Japan Age: not reported Gender: not reported Inclusion criteria: not reported Exclusion criteria: not reported Diagnoses in participants: OAG
Interventions	Intervention 1: iStent during cataract surgeries Intervention 2: no iStent during cataract surgeries Length of follow‐up: 1 year
Outcomes	Primary outcomes: IOP post cataract operation at 1, 2, 3, 6, and 12 months Secondary outcomes: not reported Safety outcomes: not reported
Starting date	12 June 2017
Contact information	Yoshiaki Kiuchi Ykiuchi@hiroshma‐u.ac.jp
Notes	Type of study: awaiting classification Funding source: Glaukos Corporation, Laguna Hills, CA, USA provided funding/support Disclosures of interest: not reported Publication language: not reported Trial registration: UMIN000027734