Populations	Interventions	Comparators	Outcomes
Individuals: ● With refractory open-angle glaucoma	Interventions of interest are: ● Ab externo aqueous shunts	Comparators of interest are: ● Ocular medication ● Trabeculectomy	Relevant outcomes include: ● Change in disease status ● Functional outcomes ● Medication use ● Treatment-related morbidity
Individuals: ● With refractory open-angle glaucoma	Interventions of interest are: ● Ab interno aqueous stents	Comparators of interest are: ● Ocular medication ● Trabeculectomy	Relevant outcomes include: ● Change in disease status ● Functional outcomes ● Medication use ● Treatment-related morbidity
Individuals: ● With mild-to-moderate open-angle glaucoma who are undergoing cataract surgery	Interventions of interest are: ● Aqueous microstents	Comparators of interest are: ● Cataract surgery alone	Relevant outcomes include: ● Change in disease status ● Functional outcomes ● Medication use ● Treatment-related morbidity
Individuals: ● With indications for glaucoma treatment other than cataract surgery or refractory open-angle glaucoma	Interventions of interest are: ● Aqueous shunts or microstents	Comparators of interest are: ● Standard of care	Relevant outcomes include: ● Change in disease status ● Functional outcomes ● Medication use ● Treatment-related morbidity

Background

Glaucoma

Glaucoma is characterized by elevated intraocular pressure (IOP), which results in visual field loss and irreversible blindness if left untreated. In the primary (conventional) outflow pathway from the eye, aqueous humor passes through the trabecular meshwork, enters a space lined with endothelial cells (Schlemm canal), drains into collector channels, and then into the aqueous veins. Increases in resistance in the trabecular meshwork and/or the inner wall of the Schlemm canal can disrupt the balance of aqueous humor inflow and outflow, resulting in an increase in IOP and glaucoma risk.

Treatment

Ocular Medication

First-line treatment typically involves pharmacologic therapy. Topical medications either increase the aqueous outflow (prostaglandins, alpha-adrenergic agonists, cholinergic agonists, Rho kinase inhibitors) or decrease aqueous production (alpha-adrenergic agonists, beta-blockers, carbonic anhydrase inhibitors). Pharmacologic therapy may involve multiple medications, have potential side effects, and may be inconvenient for older adults or incapacitated patients.

Surgery
Surgical intervention may be indicated in patients with glaucoma when the target IOP cannot be reached pharmacologically. Surgical procedures for glaucoma aim to reduce IOP from impaired aqueous humor drainage in the trabecular meshwork and/or Schlemm canal. Trabeculectomy (guarded filtration surgery) is the most established surgical procedure for glaucoma, which involves dissecting the conjunctiva, creating a scleral flap and scleral ostomy then suturing down the flap and closing the conjunctiva, allowing aqueous humor to directly enter the subconjunctival space. This procedure creates a subconjunctival reservoir, which can effectively reduce IOP, but commonly results in filtering “blebs” on the eye, and is associated with numerous complications (e.g., hemorrhage, scarring, hypotony, infection, leaks, bleb-related endophthalmitis) and long-term failure. Other surgical procedures (not addressed herein) include trabecular laser ablation, deep sclerectomy (which removes the outer wall of the Schlemm canal and excises deep sclera and peripheral cornea), and viscocanalostomy (which unroofs and dilates the Schlemm canal without penetrating the trabecular meshwork or anterior chamber) (see separate policy on 'Viscocanalostomy and Canaloplasty' - Policy #070 in the Medicine Section).. Canaloplasty involves dilation and tension of the Schlemm canal with a suture loop between the inner wall of the canal and the trabecular meshwork. This ab externo procedure uses the iTrack illuminated microcatheter (iScience Interventional) to access and dilate the entire length of the Schlemm canal and to pass the suture loop through the canal (see separate policy on 'Viscocanalostomy and Canaloplasty' - Policy #070 in the Medicine Section)..

Insertion of shunts from outside the eye (ab externo) is another surgical option to lower IOP. Examples of ab externo devices cleared by the U.S. Food and Drug Administration (FDA) include the Ahmed, Baerveldt, Molteno, and EX-PRESS mini-shunt, which shunt aqueous humor between the anterior chamber and the suprachoroidal space. These devices differ by explant surface areas, shape, plate thickness, presence or absence of a valve, and details of surgical installation. Generally, the risk of hypotony (low pressure) is reduced with aqueous shunts compared with trabeculectomy, but IOP outcomes are worse than after standard guarded filtration surgery. Complications of anterior chamber shunts include corneal endothelial failure and erosion of the overlying conjunctiva. The risk of postoperative infection is lower with shunts than with trabeculectomy, and failure rates are similar (»10% of devices fail annually). The primary indication for aqueous shunts is for failed medical or surgical therapy, although some ophthalmologists have advocated their use as a primary surgical intervention, particularly for selected conditions such as congenital glaucoma, trauma, chemical burn, or pemphigoid.
Minimally Invasive Glaucoma Surgeries

MIGS are alternative, less invasive techniques that are being developed and evaluated. MIGS, which use microscopic-sized equipment and smaller incisions, involves less surgical manipulation of the sclera and the conjunctiva compared with other surgical techniques. There are several categories of MIGS: miniaturized trabeculectomy, trabecular bypass, milder laser photocoagulation, and totally internal or suprachoroidal stents (ab interno). This policy evaluates the placement of ab interno stents.

Examples of ab interno devices either approved or given marketing clearance by the FDA include the iStent, which is a 1-mm long stent inserted into the end of the Schlemm canal through the cornea and anterior chamber; the CyPass suprachoroidal stent; and XEN gelatin stent.

Because aqueous humor outflow is pressure-dependent, the pressure in the reservoir and venous system is critical for reaching the target IOP. Therefore, some devices may be unable to reduce IOP below the pressure of the distal outflow system used (e.g., <15 mm Hg) and are not indicated for patients for whom very low IOP is desired (e.g., those with advanced glaucoma). It has been proposed that stents such as the iStent, CyPass, and Hydrus Microstent may be useful in patients with early-stage glaucoma to reduce the burden of medications and problems with compliance. One area of investigation are patients with glaucoma who require cataract surgery. An advantage of ab interno stents is that they may be inserted into the same incision and at the same time as cataract surgery. Also, most devices do not preclude subsequent trabeculectomy if needed. It may also be possible to insert more than one stent to achieve desired IOP. Therefore, health outcomes of interest are the IOP achieved, reduction in medication use, ability to convert to trabeculectomy, complications, and device durability.

Regulatory Status

The regulatory status of the various ab externo and ab interno aqueous shunts and microstents is summarized in Table 1. The first-generation Ahmed™ (New World Medical), Baerveldt® (Advanced Medical Optics), Krupin (Eagle Vision), and Molteno® (Molteno Ophthalmic) ab externo aqueous shunts were cleared for marketing by the FDA through the 510(k) process between 1989 and 1993; modified Ahmed and Molteno devices were cleared in 2006. They are indicated for use “in patients with intractable glaucoma to reduce IOP where medical and conventional surgical treatments have failed.” The AquaFlow™ Collagen Glaucoma Drainage Device (STAAR Surgical) was approved by the FDA through the premarket approval process for the maintenance of the subscleral space following nonpenetrating deep sclerectomy. In 2003, the ab externo EX-PRESS® Mini Glaucoma Shunt was cleared for marketing by the FDA through the 510(k) process. In 2016, the XEN® Glaucoma Treatment System (Allergan), which consists of the XEN45 Gel Stent preloaded into the XEN Injector, was cleared for marketing by the FDA through the 510(k) process as an ab interno aqueous stent for management of refractory glaucoma. The approval was for patients with refractory glaucoma who failed previous surgical treatment or for patients with primary open-angle glaucoma unresponsive to maximum tolerated medical therapy. The FDA determined that this device was substantially equivalent to existing devices, specifically the Ahmed™ Glaucoma Valve and the EX-PRESS® Glaucoma Filtration Device.

In 2018, the iStent® Trabecular Micro-Bypass Stent preloaded into the iStent inject device (Glaukos) was approved by the FDA through the 515(d) process for use in conjunction with cataract surgery for the reduction of IOP in adults with mild-to-moderate open-angle glaucoma currently treated with ocular hypotensive medication.

The labeling describes the following precautions^1,:

1. “The safety and effectiveness of the iStent® Trabecular Micro-Bypass Stent has not been established as an alternative to the primary treatment of glaucoma with medications. The effectiveness of this device has been demonstrated only in patients with mild-to-moderate open-angle glaucoma who are undergoing concurrent cataract surgery for visually significant cataract.

2. The safety and effectiveness of the iStent® Trabecular Micro-Bypass Stent has not been established in patients with the following circumstances or conditions, which were not studied in the pivotal trial:

• In children
• In eyes with significant prior trauma
• In eyes with abnormal anterior segment
• In eyes with chronic inflammation
• In glaucoma associated with vascular disorders
• In pseudophakic patients with glaucoma
• In uveitic glaucoma
• In eyes with prior incisional glaucoma surgery or cilioablative procedures
• In eyes with prior laser trabeculoplasty with selective LT within 90 days prior to screening or prior to argon laser trabeculectomy at any time
• In patients with medicated IOP greater than 24 mmHg
• In patients with unmedicated IOP less than 21 mmHg nor greater than 36 mmHg after ‘washout’ of medications
• For implantation of more or less than two stents
• After complications during cataract surgery, including but not limited to, severe corneal burn, vitreous removal/vitrectomy required, corneal injuries, or complications requiring the placement of an anterior chamber IOL [intraocular lens]
• When implantation has been without concomitant cataract surgery with IOL implantation for visually significant cataract
• In patients with pseudoexfoliative glaucoma or pigmentary glaucoma, or in patients with other secondary open-angle glaucoma."

Table 1. Regulatory Status of Aqueous Shunts and Stents

Device	Manufacturer	Type	FDA Status	Date
AquaFlow™	STAAR Surgical	Drainage device	PMA	2001
Ahmed™	New World Medical	Aqueous glaucoma shunt, ab externo	510(k)	<1993
Baerveldt®	Advanced Medical Optics	Aqueous glaucoma shunt, ab externo	510(k)	<1993
Krupin	Eagle Vision	Aqueous glaucoma shunt, ab externo	510(k)	<1993
Molteno®	Molteno Ophthalmic	Aqueous glaucoma shunt, ab externo	510(k)	<1993
EX-PRESS®	Alcon	Mini-glaucoma shunt, ab externo	510(k)	2003
XEN® Gel Stent; XEN injector	AqueSys/Allergan	Aqueous glaucoma stent, ab interno	510(k)	2016
iStent®; iStent inject®	Glaukos	Microstent, ab interno	515(d) in conjunction with cataract surgery	2018
iStent supra®	Glaukos	Suprachoroidal stent	Not approved; in clinical trial
CyPass®	Alcon	Suprachoroidal stent, ab interno	Company voluntarily recalled	2018
Hydrus™	Ivantis	Microstent, ab interno	PMA approval	2018
SOLX® Gold	SOLX	Micro-Shunt, ab externo	Not approved; in clinical trial

FDA: Food and Drug Administration; PMA: premarket approval.

FDA product codes: OGO, KYF.

Related Policies

• Ophthalmologic Techniques that Evaluate the Posterior Segment for Glaucoma (Policy #005 in the Medicine Section)
• Viscocanalostomy and Canaloplasty (Policy #070 in the Medicine Section)

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

Policy Guidelines: (Information to guide medical necessity determination based on the criteria contained within the policy statements above.)

Shunts and stents are only able to reduce intraocular pressure (IOP) to the mid-teens and may be inadequate when very low IOP is needed to reduce glaucoma damage.


[RATIONALE: This policy was created in July 2008 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through July 23, 2019.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function - including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Aqueous Shunts and Stents for Glaucoma

Clinical Context and Therapy Purpose

The purpose of aqueous shunts and stents in patients who have glaucoma is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does the use of aqueous shunts and stents improve the net health outcomes of patients with glaucoma compared to standard of care (including medical therapy or trabeculectomy)?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant populations of interest are:

• Patients with refractory open-angle glaucoma (OAG)
• Patients with mild-to-moderate primary open-angle glaucoma (POAG) who are undergoing cataract surgery
• Patients with indications for glaucoma treatment other than cataract surgery or refractory OAG

The therapies being considered are:

• For patients with refractory OAG
  • Ab externo aqueous shunts
  • Ab interno aqueous stents
• For patients with mild-to-moderate OAG undergoing cataract surgery: ab interno aqueous stents
• For patients with indications for glaucoma treatment other than cataract surgery or refractory OAG: ab externo aqueous shunts or ab interno aqueous stents

Comparators include medical therapies and trabeculectomy.

Outcomes

The general outcomes of interest are a change in intraocular pressure (IOP) and change in medication use. Changes in IOP and medication use are measured for at least 12 months. Safety measures involve longer follow-up, for several years.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

c. To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

d. Studies with duplicative or overlapping populations were excluded.

This section reviews the evidence for ab externo aqueous shunts with the U.S. Food and Drug Administration (FDA) approval. Evidence on nonapproved devices and indications are discussed in the Appendix.

Systematic Reviews

A Cochrane review by Minckler et al (2006) included 15 randomized or pseudo-RCTs (total n=1153 participants) evaluating the Ahmed, Baerveldt, Molteno, and Schocket shunts.^3, Trabeculectomy was found to lower mean IOP by 3.8 mm Hg more than the Ahmed shunt at one year. This systematic review did not compare complications, because reviewers considered them to be too variably reported to permit comparative tabulation. There was no evidence of the superiority of one shunt over another.

A technology assessment on commercially available aqueous shunts, including the Ahmed, Baerveldt, Krupin, and Molteno devices, from the American Academy of Ophthalmology was published by Minckler et al (2008).^4, It indicated that IOP would generally settle at higher levels (»18 mm Hg) with aqueous shunts than with standard trabeculectomy (14-16 mm Hg) or trabeculectomy with antifibrotic agents 5-fluorouracil or mitomycin C (8-10 mm Hg). In 1 study, mean IOPs with the Baerveldt shunt and adjunct medications were equivalent to trabeculectomy with mitomycin C (13 mm Hg). Five-year success rates for the 2 procedures were similar (50%). The assessment concluded that, based on level 1 evidence, aqueous shunts were comparable to trabeculectomy for IOP control and duration of benefit. The risk of postoperative infection was lower with aqueous shunts than with trabeculectomy. Complications of aqueous shunts included: immediate hypotony after surgery, excessive capsule fibrosis and clinical failure, erosion of the tube or plate edge, strabismus, and, very rarely, infection. The most problematic long-term consequence of anterior chamber tube placement was accelerated damage to the corneal endothelium.

A comparative effectiveness review on glaucoma treatments, prepared for the Agency for Healthcare Research and Quality by Boland et al (2012), found that available data on the role of aqueous drainage devices in OAG (primary studies, systematic review) were inadequate to permit conclusions on the comparative effectiveness of these treatments vs laser and other surgical treatments.^5,

Baerveldt Glaucoma Shunt

Randomized Controlled Trials

Results from the open-label, multicenter, randomized Tube vs Trabeculectomy study were reviewed in the 2008 American Academy of Ophthalmology technology assessment and by Gedde et al (2012) who reported on the 5-year follow-up.^4,5,6,That study included 212 eyes of 212 patients (age range, 18-85 years) from 17 study centers, who had trabeculectomy and/or cataract extraction with intraocular lens implantation and uncontrolled glaucoma with IOP of 18 mm Hg or greater and 40 mm Hg or lower on maximally tolerated medical therapy, randomized to tube (Baerveldt shunt) or trabeculectomy. Excluding patients who had died, the study had an 82% follow-up rate at 5 years, with a similar proportion of patients in the tube and trabeculectomy groups. At 5 years, neither IOP (14.3 mm Hg in the shunt group vs 13.6 mm Hg in the trabeculectomy group) nor the number of glaucoma medications (1.4 in the shunt group vs 1.2 in the trabeculectomy group) differed significantly based on intention-to-treat analysis. The cumulative probability of failure over the 5 years was lower in the shunt group (29.8%) than in the trabeculectomy group (46.9%), and the rates of reoperation were lower (9% vs 29%, respectively). The rates of loss of 2 or more lines of visual acuity were similar (46% in the shunt group vs 43% in the trabeculectomy group).

Kotecha et al (2017) assessed the vision-related quality of life outcomes in the Tube vs Trabeculectomy study.^7,Quality of life was measured using the National Eye Institute Visual Functioning Questionnaire-25, administered at baseline and annual follow-ups over 5 years. A comparison of composite quality of life scores and change in scores over time among the two groups revealed no significant differences at any of the follow-up measurements.

EX-PRESS Mini Shunt

Systematic Reviews

A Cochrane review by Wang et al (2015) evaluated the efficacy of adjunctive procedures for trabeculectomy.^8, Three RCTs were included which compared trabeculectomy alone with trabeculectomy plus EX-PRESS Mini Shunt. These trials were rated as having a high or unclear risk of bias using the Cochrane criteria. None of the RCTs reported a significant improvement for the EX-PRESS group. However, in the pooled analysis, IOP was lower in the combination group than in the trabeculectomy alone group (weighted mean difference, -1.58; 95% confidence interval [CI], -2.74 to -0.42). The pooled analysis also showed that subsequent cataract surgery was less frequent in the combination group than in trabeculectomy alone (relative risk, 0.34; 95% CI, 0.14 to 0.74). The combination group had a lower rate of some complications (e.g., hyphema, needling).

Randomized Controlled Trials

De Jong et al (2009) reported on a randomized study that compared the EX-PRESS Mini Shunt with standard trabeculectomy in 78 patients (80 eyes) diagnosed with OAG uncontrolled using maximally tolerated medical therapy (see Table 2).^9, Five-year follow-up was reported by de Jong et al (2011).^10, The 2 groups were similar after randomization, except mean age (62 years for the EX-PRESS group vs 69 years for the trabeculectomy group). At 12-month follow-up, mean IOP and antiglaucoma medications use decreased in both groups (see Table 2). Twelve-month Kaplan-Meier success rates (defined as an IOP >4 mm Hg with medication and ≤18 mm Hg without medication) were 82% for the EX-PRESS shunt and 48% for trabeculectomy. At five years, success rates did not differ significantly between groups. In the EX-PRESS group, IOP remained stable from year 1 (12.0 mm Hg) to year 5 (11.5 mm Hg), while, in the trabeculectomy group, IOP decreased from year 3 (13.5 mm Hg) to year 5 (11.3 mm Hg) (see Table 3). More complications occurred after trabeculectomy than after EX-PRESS implantation.

A U.S. multicenter randomized trial by Netland et al (2014), compared trabeculectomy with EX-PRESS implantation in 120 patients (120 eyes) (see Table 2).^11, Comparator groups were similar at baseline. Throughout a two-year postsurgical follow-up, average IOP and number of medications were similar between groups (see Table 3). Surgical success was 90% and 87% at 1 year and 83% and 79% at 3 years in the EX-PRESS and trabeculectomy groups, respectively. Visual acuity returned to near baseline levels at one month after EX-PRESS implantation (median, 0.7 months) and at three months after trabeculectomy (median, 2.2 months; p=0.041). Postoperative complications were higher after trabeculectomy (41%) than after EX-PRESS implantation (18.6%).

One additional small RCT was published by Wagschal et al (2015),^12, presenting 1-year results, and by Gonzalez-Rodriguez et al (2016), presenting 3-year results (see Table 2).^13,The trial corroborated the results of the earlier RCTs, reporting no differences between trabeculectomy and EX-PRESS shunt groups on outcomes for mean IOP, success rates, number of medications used, or complication rates (see Table 3).

Table 2. Summary of Key RCT Characteristics for EX-PRESS

Study	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
de Jong et al (2009)9,; de Jong et al (2011)10,	Netherlands	1	2003 - 2004	Patients with primary OAG not controlled by IOP medication	EX-PRESS (n=39)	Trabeculectomy (n=39)
Netland et al (2014)11,	U.S., Canada	7	NR	Patients with OAG treated with IOP medications who were candidates for glaucoma surgery	EX-PRESS (n=59)	Trabeculectomy (n=61)
Wagschal et al (2015)12,; Gonzalez-Rodriguez et al (2016)13,	Canada	1	2011 - 2012	Patients with OAG not controlled by IOP medication	EX-PRESS (n=33)	Trabeculectomy (n=31)

IOP: intraocular pressure; NR: not reported; OAG: open-angle glaucoma; RCT: randomized controlled trial.

Table 3. Summary of Key RCT Results for EX-PRESS

Study	Mean IOP (SD), mm Hg		p	Mean Medication Use (SD)
	EX-PRESS	Trabeculectomy		EX-PRESS	Trabeculectomy
de Jong et al (2009)9,; de Jong et al (2011)10,
Baseline	23.6 (7.0)	20.7 (7.0)	0.09	NR	NR
Year 1	12.2 (3.8)	13.9 (3.8)	0.05	0.31	0.74
Year 2	12.0 (3.3)	13.8 (3.2)	0.01	0.49	1.05
Year 3	12.1 (3.4)	13.5 (3.4)	0.08	0.62	1.28
Year 4	11.4 (2.5)	11.6 (2.5)	0.69	0.69	1.33
Year 5	11.4 (2.2)	11.2 (2.2)	0.71	0.85	1.10
Netland et al (2014)11,
Baseline	25.1 (6.0)	26.4 (6.9)	0.27	3.1 (1.1)	3.1 (1.2)
Month 6	13.8 (4.7)	11.9 (4.6)	0.03	NR	NR
Year 2	14.7 (4.6)	14.6 (7.1)	0.93	0.9 (1.3)	0.7 (1.2)
Wagschal et al (2015)12,; Gonzalez-Rodriguez et al (2016)13,
Baseline	22.6 (10.2)	21.9 (6.8)	0.75	3.5 (0.9)	3.4 (1.3)
Year 1	11.2 (4.3)	10.7 (3.5)	0.85	0.4 (1.0)	0.6 (1.0)
Year 2	12.5 (5.1)	10.3 (3.7)	0.07	0.6 (1.3)	1.3 (1.5)
Year 3	13.3 (4.5)	11.1 (4.4)	0.10	1.4 (1.7)	1.2 (1.3)

IOP: intra-ocular pressure; NR: not reported; SD: standard deviation; RCT: randomized controlled trial.

Observational Studies

Dib Bustros et al (2017) published a retrospective chart review that offered 1-year results from 56 African American patients who underwent EX-PRESS (n=28) implantation or trabeculectomy (n=28).^14, Outcomes included IOP and glaucoma medication used presurgery, postsurgery, and at 12-months of follow-up. In both groups, IOP and glaucoma-related medication use dropped significantly. Postoperative and follow-up interventions included 5-fluorouracil injections and laser suture lysis. Patients who underwent trabeculectomy needed a significantly greater number of laser suture lysis and 5-fluorouracil interventions in the 3 months after surgery (trabeculectomy: 3.89; EX-PRESS: 2.36, p=0.007). The results showed that EX-PRESS was noninferior to trabeculectomy in reducing IOP and reducing the need for glaucoma-related medications.

Omatsu et al (2018) compared changes in corneal endothelial cells among patients undergoing trabeculectomy (n=60) and patients receiving EX-PRESS shunts (n=50).^15, Both groups experienced significant decreases in IOP compared with baseline. After two years of follow-up, patients undergoing trabeculectomy experienced significant decreases in corneal endothelial cells compared with the baseline, while the EX-PRESS group did not.

Comparative Effectiveness Analyses

Five-year results of two RCTs comparing the Ahmed and Baerveldt shunts have been published.

The Ahmed Baerveldt Comparison (ABC) study was a multicenter international RCT evaluating the comparative safety and efficacy of the Ahmed Glaucoma Valve FP7 and Baerveldt Glaucoma Implant BG 101-350 (1:1 ratio) in 276 adults with previous incisional eye surgery or refractory glaucoma.^16,17, The ABC was funded by National Eye Institute, Research to Prevent Blindness, and New World Medical. Mean IOP was 14.7 mm Hg in the Ahmed group and 12.7 mm Hg in the Baerveldt group at 5 years (p=0.01). The number of glaucoma medications in use at five years, the cumulative probability of failure at five years, and visual acuity at five years did not differ statistically between the two groups. The number of patients with inadequately controlled IOP or reoperation for glaucoma was 46 (80%) with the Ahmed shunt and 25 (53%) with the Baerveldt shunt (p=0.003). The 5-year cumulative reoperation rate for glaucoma was 21% in the Ahmed group and 9% in the Baerveldt group (p=0.01).^16, Late complications were defined as those developing after three months. Such complications occurred in 56 (47%) patients in the Ahmed group and 67 (56%) patients in the Baerveldt group during 5 years of follow-up (p=08). The cumulative incidences of serious complications at 5 years were 16% and 25% in the Ahmed and Baerveldt groups, respectively (p=0.03).^17,

The Ahmed Versus Baerveldt (AVB) study, reported by Christakis et al (2016), was an international, multicenter RCT enrolling 238 patients with uncontrolled glaucoma despite maximally tolerated medical therapy.^18,The AVB is funded by the Glaucoma Research Society of Canada. Patients were randomized in a 1:1 ratio to the Ahmed FP7 implant and the Baerveldt 350 implant. Failure of the shunt implant was the primary outcome, defined as any one of the following: IOP of less than 5 mm Hg or greater than 18 mm Hg or a reduction of less than 20% from baseline for 2 consecutive visits after 3 months; de novo glaucoma surgery required; removal of the implant; severe vision loss related to the surgery; or progression to no light perception for any reason. The cumulative failure rate was 53% in the Ahmed group and 40% in the Baerveldt group at 5 years (p=0.04). In the Ahmed and Baerveldt shunts, the mean percent reduction in IOP was 47% and 57% (p=0.001) and mean percent reduction in medication use was 44% and 61% (p=0.03), all respectively. Hypotony was reported in 5 (4%) patients in the Baerveldt group but not in the Ahmed group (p=0.02).

Christakis et al (2017) analyzed 5-year pooled data from the ABC and AVB trials comparing the relative efficacy of the 2 implants.^19, Patients were randomized to an Ahmed implant (n=267) or a Baerveldt implant (n=247). IOP, glaucoma medication use and visual acuity were compared. At year 5, mean IOP was 15.8 mm Hg in the Ahmed group and 13.2 mm Hg in the Baerveldt group (p=.007). The cumulative failure rate in the Ahmed group was 49%; in the Baerveldt group, it was 37%. Mean glaucoma medication use was significantly lower in patients receiving the Baerveldt implant than in patients receiving the Ahmed implant (p=0.007). Visual acuity was similar between both groups. While efficacy measures were significantly better in the Baerveldt group, these patients experienced more hypotony (4.5%) than patients in the Ahmet group (0.4%; p=.002).

A small RCT by Bo et al (2018) randomizing 68 patients compared the EX-PRESS shunt (n=33) and the Ahmed shunt (n=35).^20, Follow-up at nine months showed no difference in best-corrected visual acuity or in postoperative complications. Control of IOP was superior in EX-PRESS compared with the Ahmed shunt.

Section Summary: Ab Externo Aqueous Shunts

Evidence for the use of ab externo aqueous shunts for the treatment of OAG uncontrolled by medications consists of RCTs comparing shunts with trabeculectomy. Outcomes of interest are IOP and antiglaucoma medication use. Follow-up among the trials ranged from one to five years. Results showed that ab externo aqueous shunts are noninferior to trabeculectomy. Adverse event rates were higher among patients undergoing trabeculectomy.

The comparative effectiveness of two ab externo devices (the Ahmed and Baerveldt shunts) has been evaluated in two trials, the AVB, and the ABC trials. These trials reported similar results, with both devices lowering IOP significantly. Compared with patients receiving the Ahmed shunt, patients receiving the Baerveldt shunt experienced lower IOP and needed fewer medications. However, patients receiving the Baerveldt shunt experienced higher rates of hypotony-related complications.

AbInterno Aqueous Stents

This section reviews the evidence for ab interno stents with the FDA approval or marketing clearance. At this time, the XEN gel stent and injector is the only stent system FDA-approved as a stand-alone procedure for the treatment of refractory OAG.

Xen Glaucoma Treatment System

Observational Studies

Comparative Studies

Schlenker et al (2017) published a multicenter, retrospective interventional cohort study that compared the risk, safety, and efficacy for stand-alone ab interno microstent implantation with mitomycin C (MMC) and trabeculectomy plus MMC (Table 4).^21, Implantations of the ab interno XEN 45 gelatin microstent is a less invasive surgery than trabeculectomy. Outcomes included: IOP differences, medication reductions, interventions, complications, and the need for additional surgery. The primary outcome was the hazard ratio of failure. Failure was defined as two consecutive IOP readings of less than 6 mm Hg, including vision loss. Success was measured by the withdrawal of glaucoma-related medications at one month postsurgery. The adjusted hazard ratio of failure of the microstent relative to trabeculectomy was 1.2 for complete success (95% CI, 0.7 to 2.0). Both surgeries had a 75% survival of approximately 10 months for complete success. During the last reported follow-up (varying times), antiglaucoma medications were being used by 25% of patients who received the microstent implantation and 33% of trabeculectomy patients. Patients in both groups reported similar numbers of postoperative interventions, such as laser suture lysis and needling. The need for reoperation was higher among those who had undergone microstent implantation-but this difference was not statistically significant. The authors concluded that the ab interno gelatin microstent with MMC was noninferior to trabeculectomy plus MMC. Changes in IOP and medication use appear in Table 5.

Noncomparative Studies

Mansouri et al (2018) reported on results from a study of 149 eyes (113 patients); 109 eyes received the XEN implant plus cataract surgery and 40 eyes received the implant alone (see Table 4).^22, There was a range of glaucoma severity represented in the study sample, with most patients in the mild-to-moderate stages. Of the 149 eyes, data for 87 (58%) eyes was available at 12 months. The high loss to follow-up was mainly due to high travel times for patients referred to the study treatment center from various provinces and countries, and to lack of interest among physicians to treat referred patients. At 12 months, mean IOP and mean medication use, both decreased (see Table 5). The proportion achieving 20% or more reduction in IOP was higher among patients receiving XEN alone than those undergoing cataract surgery and XEN implantation. Adverse events included bleb revision (n=5), choroidal detachment (n=2), and second glaucoma surgery (n=9).

Groveret al (2017) published results from the single-arm, open-label clinical study evaluating the effectiveness and safety of the XEN Glaucoma Treatment System in 65 patients with refractory glaucoma (see Table 4).^23, Effectiveness data were collected for 12 months and safety data for 18 months. Forty-six (75%) patients of 61 with available data had a 12-month mean diurnal IOP reduction of 20% or more without increasing IOP-lowering medications. The mean IOP reduction at 12 months was -9.1 mm Hg (95% CI, -10.7 to -7.5 mm Hg) on a mean of 1.7 medications (see Table 5). Efficacy was consistent across age groups, baseline IOP, baseline medication use, sex, and ethnicity. The most common adverse events were glaucoma surgery, hypotony, IOP increase of 10 mm Hg or more, and needling procedures. The FDA cited results from this study to conclude that the XEN System was as safe and effective as predicate devices.

Hengerer et al (2017) retrospectively analyzed 146 patients (242 eyes) receiving the XEN implant for treatment-refractory to antiglaucoma medication or glaucoma surgery (see Table 4).^24, In the subset of eyes with 12-month data (n=148), IOP reduction of 20% or more was achieved by 73.0% of patients. Mean antiglaucoma medications decreased (see Table 5). The decreases in IOP and medication use were statistically significant, in patients receiving the XEN implant alone and in patients receiving the XEN implant while undergoing cataract surgery.

Additional smaller case series assessing the use of the XEN implant are described in Tables 4 and 5. These case series, by Galal et al (2017),^25, Ozal et al (2017),^26, and Tan et al (2018),^27, reported significant reductions in IOP and medication use. Low rates of the following complications were reported: hypotony (which resolved), need for bleb intervention, iris tissue obstruction, implant extrusion, and choroidal detachment.

Table 4. Summary Characteristics for Observational Studies Using the XEN Implant as a Stand-Alone Procedure for Refractory Open-Angle Glaucoma

Study	Country	Participants	Treatment Delivery	FU
Schlenker et al (2017)21,	Austria, Belgium, Canada, Germany	Patients with OAG, pseudoexfoliation, pigment dispersion, normal-tension, angle-recession, combined mechanism, history of angle-closure, or juvenile glaucoma and no prior incisional surgery	XEN alone (n=185) Trabeculectomy (n=169)	Up to 30 mo (last visit in chart)
Mansouri et al (2018)22,	Switzerland	Patients with OAG and uncontrolled IOP, progressive glaucoma, and/or refractory to IOP medications	XEN alone (n=40) XEN plus cataract surgery (n=109)	12 mo
Grover et al (2017)23,	U.S.	Patients with OAG and uncontrolled IOP, refractory to IOP medications	XEN alone, (n=65)	12 mo
Hengerer et al (2017)24,	Germany	Patients with OAG and uncontrolled IOP, optic disc damage, and refractory to IOP medications or prior surgery	XEN alone (n=203) XEN plus cataract surgery (n=39)	12 mo
Galal et al (2017)25,	Germany	Patients with OAG	XEN alone (n=3) XEN plus cataract surgery (n=10) Both groups also received subconjunctival mitomycin-C	12 mo
Ozal et al (2017)26,	Turkey	Patients with OAG and uncontrolled IOP, progressive glaucoma, and/or refractory to IOP medications or prior surgery	XEN alone (n=9) XEN plus cataract surgery (n=6)	12 mo
Tan et al (2018)27,	U.K.	Patients with OAG and taking at least 1 IOP-lowering medication	XEN alone (n=39)	12 mo

FU: follow-up; IOP: intraocular pressure; OAG: open-angle glaucoma.

Table 5. Summary of Results for the XEN Implant as Stand-Alone Procedure for Refractory Open-Angle Glaucoma

Study	Population	Median IOP (SD), mm Hg		Medication, Median (SD)
		Baseline	1 Yeara	Baseline	1 Yeara
Schlenker et al (2017)21,	XEN alone	24.0 (IQR: 19 to 32)	13.0 (IQR: 10 to 15)	3.0 (IQR: 3 to 4)	0.0 (IQR: 0 to 1)
	Trabeculectomy	24.0 (IQR: 19 to 30))	13.0 (IQR: 10 to 16)	3.0 (IQR: 3 to 4)	0.0 (IQR: 0 to 0)
Mansouri et al (2018)22,	XEN alone	20 (IQR: 17 to 23)	40.0% reduction	2.5 (IQR: 1 to 4)	NR
Grover et al (2017)23,,	XEN alone	25.1 (3.7)	15.9 (5.2)	3.5	1.7
Hengerer et al (2017)24,	XEN alone	31.5 (8.4)	14.3 (4.2)	3.1 (1.0)	0.3 (0.7)
Galal et al (2017)25,	All patients	16 (4)	12 (3)	1.9 (1)	0.3 (0.5)
Ozal et al (2017)26,	All patients	36.1	16.7	3.6 (0.5)	0.3 (0.9)
Tan et al (2018)27,	XEN alone	24.9 (7.8)	14.5 (3.4)	3	0.7

^a Follow-up for Schlenker (2017) was not 1 year, but last visit in retrospective chart review

IOP: intraocular pressure; IQR: interquartile range; NR: not reported; SD: standard deviation.

Section Summary: Ab Interno Aqueous Stents

Currently, the XEN gel stent is the only stent approved by the FDA for the treatment of refractory OAG as a stand-alone procedure. Clearance for the stent was based on a review in which the FDA concluded that while there were technical differences between the stent and predicate devices (shunts), the differences did not affect safety and effectiveness in lowering IOP and medication use. Evidence for the use of the XEN implant consists of a nonrandomized comparative study which retrospectively reviewed charts of patients either receiving the XEN implant or undergoing a trabeculectomy. Additional evidence consists of several single-arm studies. The comparative study included patients with different types of glaucoma (57% with POAG) and reported that patients receiving the XEN implant experienced reductions in IOP and medication use similar to patients undergoing a trabeculectomy. However, there was no discussion on how patients were chosen to receive the different treatments and no subgroup analysis by glaucoma type was provided. The single-arm studies, with 12 months of follow-up, consistently showed that patients receiving the XEN implant experienced reductions in IOP and medication use, with reductions in IOP ranging from 4 mm Hg to over 15 mm Hg.

Aqueous Microstents in Conjunction with Cataract Surgery

The iStent and iStent inject, which is preloaded with two stents, have the FDA approval for use in conjunction with cataract surgery. An additional stent, the CyPass, had the FDA approval but was voluntarily recalled by the manufacturer in 2018, as follow-up data has shown significant endothelial cell loss among patients receiving the CyPass in conjunction with cataract surgery compared with patients receiving cataract surgery alone. Studies comparing implantation of stents during cataract surgery with cataract surgery alone are discussed below.

Stent

Systematic Reviews

A 2019 Cochrane review on the iStent in patients with open-angle glaucoma was published by Le at al (2019, see Table 6). ^28, The authors identified seven RCTs, all of which were considered to be at high or unclear risk of bias. Four of the trials compared iStent in combination with cataract surgery to cataract surgery alone, two RCTs compared treatment with iStent or iStent inject to medical therapy, and one RCT compared one, two, or three iStents. Results of the meta-analyses on use of the iStent in combination with cataract surgery are shown in Table 7. Implantation of 1 or 2 iStents resulted in a higher proportion of patients who were drop free (relative risk: 1.38) and reduced the mean number of drops when compared to phacoemulsification alone (-0.42 drops). The review concluded that based on the four trials, there was very low-quality evidence that iStent may result in a higher proportion of patients who are drop free or achieve better IOP control.

Table 6. Meta-analysis Characteristics

Study	Dates	Trials	Participants	N (Range)	Design	Duration
Le et al (2019)28,	- Aug 2018	7	Eyes with open-angle glaucoma	765 (33 to 239)	RCT	42 months

Table 7. Meta-analysis Results

Study	Drop Free Compared to Phacoemulsification Alone	Change in Drops Compared to Phacoemulsification Alone	Change in IOP Compared to Phacoemulsification Alone
Le et al (2019)28,
N	239 (2 RCTs)	282 (2 RCTs)	284 (3 RCTs)
Pooled effect (95% CI)	RR: 1.38 (1.18 to 1.63)	-0.42 (-0.60 to -0.23)	-1.24 mmHg
I2 (p)	67% (p)	0%

CI: confidence interval; IOP: intraocular pressure; RCT: randomized controlled trial; RR: relative risk

iStent and iStent inject Pivotal Trials

Included in the Cochrane review were results from the iStent U.S. investigational device exemption, open-label, 29-site, multicenter RCT. Results were reported to the FDA in 2010, with 1-year results published by Samuelson et al (2011) and 2-year results published by Craven et al (2012) (see Table 8).^29,30, Trial objectives were to evaluate the incremental effect on IOP of iStent implantation compared to cataract surgery alone and to determine the potential benefit of combining two therapeutic treatments into a single surgical event. A total of 240 patients (mean age, 73 years) with cataracts and mild-to-moderate OAG (IOP ≤24 mm Hg controlled on 1-3 medications) underwent a medication washout period. Patients were randomized to cataract surgery plus iStent implantation or cataract surgery only. Follow-up visits were performed at 1, 3, 6, and 12 months. Results were assessed by intention-to-treat analysis with the last observation carried forward and per-protocol analysis. The proportion of eyes meeting both the primary (unmedicated IOP ≤21 mm Hg) and secondary outcomes (IOP reduction ≥20% without medication) was higher in the treatment group than in the control group through 1-year follow-up (72% of treatment eyes vs 50% of control eyes achieved the primary efficacy endpoint, p<0.001). The proportion of patients achieving the secondary efficacy endpoint was 66% in the treatment group and 48% in the control group (p=0.003). Ocular hypotensive medications were initiated later in the postoperative period and used in a lower proportion of patients in the treatment group throughout 1-year follow-up (e.g., 15% vs 35% at 12 months). Mean reduction in IOP was similar in both groups, though the control group used slightly more medication (mean, 0.4 medications) than the treatment group (0.2 medications) at one year (see Table 9). At 2-year follow-up, 199 (83%) patients remained in the study. The primary endpoint (unmedicated IOP ≤21 mm Hg) was reached by 61% of patients in the treatment group and 50% of controls (p=0.036).^30, Secondary outcomes¾IOP reduction of 20% or more without medication (53% vs 44%) and the mean number of medications used (0.3 vs 0.5)¾no longer differed significantly between groups at 2 years. As noted by the FDA, this study was conducted in a restricted population with an unmedicated IOP of 22 mm Hg or higher and a medicated IOP of 36 mm Hg or lower.

The pivotal trial on the iStent inject was reported by Samuelson et al (2019).^31, A total of 505 patients undergoing cataract surgery were randomized after lens implantation to insertion of 2 smaller iStents or control. Results were assessed by intention-to-treat analysis and per-protocol analysis, with patients requiring additional surgical procedures considered to be failures. The addition of medications was based on a standardized protocol. At the 2-year follow-up, a greater percentage of patients had achieved at least a 20% reduction in IOP (75.8% vs 61.9%, p=0.005), had a greater reduction in IOP (7.0 vs 5.4, p<0.001), and required fewer topical medications (0.4 vs 0.8, p<0.001).

Limitations of these studies are described in Tables 10 and 11. The two main limitations are that there was no blinding to treatment and durability of these microstents have not been determined after two years. Continued patency of the stents and need for additional treatments is unknown.

Table 8. Summary of Pivotal RCT Characteristics

Study	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Samuelson et al (2011)29,; Craven et al (2012)30,	U.S.	29	2005-2007	Patients with mild-to-moderate POAG, unmedicated IOP ≥22 and ≤36 mm Hg	iStent plus cataract surgery (n=116)	Cataract surgery alone (n=123)
Samuelson et al (2019)31,	U.S.		2011-	Patients with mild-to-moderate POAG, unmedicated IOP ≥21 and ≤36 mm Hg	iStent inject (2 stents) plus cataract surgery (n=387)	Cataract surgery alone (n=118)

IOP: intraocular pressure; POAG: primary open-angle glaucoma; RCT: randomized controlled trial.

Table 9. Summary of Pivotal RCT Results

Study	> 20% Reduction in Unmedicated IOP at 24 mo n (%)	Mean Reduction in IOP at 24 mo mm Hg (SD)	Mean IOP (SD), mm Hg		p	Mean Medication Use (SD)		p
			iStent	Cataract Alone			iStent	Cataract Alone
Samuelson et al (2011)29,;  Craven et al (2012)30,
Baseline			18.6 (3.4)	17.9 (3.0)	NR	1.6 (0.8)	1.5 (0.6)
Year 1			17.0 (2.8)	17.0 (3.1)	NR	0.2 (0.6)	0.4 (0.7)	0.016
Year 2			17.1 (2.9)	17.8 (3.3)	NR	0.3 (0.6)	0.5 (0.7)
Samuelson et al (2019)31, iStent inject	288/380 (75.8%)	7.0 (4.0)	17.1 (3.6)			0.4 (0.8)
Cataract Alone	73/118 (61.9%)	5.4 (3.7)	17.8 (3.5)			0.8 (1.0)
p-Value	0.005	<0.001				<0.001

IOP: intraocular pressure; NR: not reported; SD: standard deviation.

Table 10. Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Samuelson et al (2011)29,					Patency after 2 years is unknown
Samuelson et al (2019)31,					Patency after 2 years is unknown

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.

^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.

^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.

^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.

^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Samuelson et al (2011)29,		2, 3. No blinding of assessors
Samuelson et al (2019)31,		2, 3. No blinding of assessors

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.

^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.

^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.

^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).

^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.

^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Table 12. Summary of Comparative Study Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Hooshmand et al (2019)32,	AU	2		Patients with POAG undergoing cataract surgery	iStent at the time of cataract surgery (n=145)	iStent inject at the time of cataract surgery (n=100)

POAG: primary open-angle glaucoma

Table 13. Summary of Comparative Study Results

Study	IOP < 18 mm Hg without medication at 12 months n (%)	IOP < 18 mm Hg with medication at 12 months n (%)	> 20% reduction in IOP at 12 months n (%)
Hooshmand et al (2019)32,	N=219	N=219	N=219
iStent	79 (56.0)	89 (63.1)	49 (34.8)
iStent inject	40 (51.3)	45 (57.7)	23 (29.5)
p-Value	0.50	0.43	0.43

CI: confidence interval; IOP: intraocular pressure.

¹ Include number analyzed, effect in each group, and measure of effect (absolute or relative) with CI,

² Describe the range of sample sizes, effects, and other notable features in text.

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Hooshmand et al (2019)32,					1. Follow-up was limited by the time that the iStent inject was available.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.

^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.

^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.

^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.

^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Hooshmand et al (2019)32,	1. Study was not randomized	1, 2, 3. No blinding of assessors			1. Post-hoc power calculations

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.

^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.

^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.

^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).

^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.

^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Randomized Controlled Trials

Pfeiffer et al (2015) reported on a single-masked, randomized trial with 100 patients (100 eyes) that compared the effectiveness of the Hydrus Microstent plus cataract surgery with cataract surgery alone (Table 16).^33,At the 24-month follow-up, the proportion of patients with a 20% reduction in IOP was significantly higher with the Hydrus Microstent (80% vs 46%, p<0.001) and the mean IOP after medication washout was lower (16.9 mm Hg vs 19.2 mm Hg, p=0.009) compared with cataract surgery alone, respectively. The microstent group used significantly fewer medications (0.5 vs 1.0, p=0.019) and had a higher proportion of patients taking no hypotensive medications at the time of cataract surgery (73% vs 38%, p=0.001). Comparisons of mean washed out IOP and the mean number of medications used are presented in Table 17.

Samuelson et al (2019) reported on a multicenter RCT comparing implantation of a single Hydrus Microstent following cataract surgery vs cataract surgery alone (Table 16).^34, Patients were blinded to treatment assignment for the course of the study. The primary endpoint was percent demonstrating a 20% reduction in unmedicated IOP. Significantly more patients receiving the microstent following cataract surgery experienced a 20% reduction in unmedicated IOP compared with patients undergoing cataract surgery alone (77% vs 58%; p<0.001). Additional results (mean washed out IOP and the mean number of medications used) are presented in Table 17.

Table 16. Summary of Key RCT Characteristics for the Hydrus Microstent

Study	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Pfeiffer (2015)33,	Germany, Italy, Spain, the Netherlands	7	2011 to 2012	Patients with concurrent open-angle glaucoma and cataract	Cataract surgery plus Hydrus Microstent implantation (n=50)	Cataract surgery alone (n=50)
Samuelson (2019)34,	Germany, Italy, Mexico, Philippines, Poland, Spain, United Kingdom, United States	26	2012 to 2015	Patients with age-related cataract and mild to moderate primary open-angle glaucoma	Cataract surgery plus Hydrus Microstent implantation (n=369)	Cataract surgery alone (n=187)

RCT: randomized controlled trial.

Table 17. Summary of Key RCT Results for the Hydrus Microstent

Study	Mean washed out IOP			Mean medication use
	Hydrus Microstent	Cataract alone	p	Hydrus Microstent	Cataract alone	p
Pfeiffer (2015)33,
Baseline	26.3 +/- 4.4	26.6 +/- 4.2	0.7	2.0 +/- 1.0	2.0 +/ - 1.1	0.8
Year 2	16.9 +/- 3.3	19.2 +/- 4.7	0.009	0.5 +/- 1.0	1.0 +/- 1.0	0.02
Samuelson (2019)34,
Baseline mean	25.5 +/- 3.0	25.4 +/- 2.9	NS	1.7 +/- 0.9	1.7 +/- 0.9	NS
Year 2	17.4 +/- 3.7	19.2 +/- 3.8	NR	0.3 +/- 0.8	0.7 +/- 0.9	<0.001

IOP: intraocular pressure; NR: not reported; NS: not significant; RCT: randomized controlled trial.

Observational Study

Fea et al (2017) conducted a retrospective review of 92 patients undergoing cataract surgery plus Hydrus Microstent implantation.^35, Two-year follow-up showed improvements in IOP and medication use. Mean IOP at baseline was 19.4 mm Hg, decreasing significantly by 6 months to 15.6 mm Hg, which was maintained at 2 years of follow-up (15.7 mm Hg). The mean number of medications was 2.1 at baseline, decreasing significantly by six months to 0.5, which was maintained through two years of follow-up (0.7).

Xen Glaucoma Treatment System

Observational Studies

Mansouri et al (2018)^22,, Hengerer et al (2017)^24,, Galal et al (2017)^25,, and Ozal et al (2017)^26, are described above in the section on aqueous stents used as a stand-alone treatment for refractory OAG. These studies also included patients who received the XEN implant in conjunction with cataract surgery and study characteristics and results for this subgroup appear in Tables 18 and 19.

Additional single-arm studies (Perez-Torregrosa et al [2016]^36, and De Gregorio et al [2017]^37,) evaluating the use of the XEN implant in conjunction with cataract surgery are also described in Tables 18 and 19 below.

Table 18. Summary of Key Study Characteristics for the XEN Implant with Cataract Surgery

Study	Country	Participants	Treatment Delivery	FU
Mansouri et al (2018)22,	Switzerland	Patients with POAG and uncontrolled IOP, progressive glaucoma, and/or refractory to IOP medications	XEN alone (n=40) XEN plus cataract surgery (n=109)	12 mo
Hengerer et al (2017)24,	Germany	Patients with POAG and uncontrolled IOP, optic disc damage, and refractory to IOP medications or prior surgery	XEN alone (n=203) XEN plus cataract surgery (n=39)	12 mo
Perez-Torregrosa et al (2016)36,	Spain	Patients with POAG and cataract and taking at least 2 IOP-lowering medications	XEN plus cataract (n=30)	12 mo
De Gregorio et al (2017)27,	Italy	Patients with POAG under maximally tolerated medical therapy and with cataract	XEN plus cataract (n=41)	12 mo
Galal et al (2017)25,	Germany	Patients with POAG	XEN alone (n=3) XEN plus cataract surgery (n=10) Both groups also received subconjunctival mitomycin-C	12 mo
Ozal et al (2017)26,	Turkey	Patients with POAG and uncontrolled IOP, progressive glaucoma, and/or refractory to IOP medications or prior surgery	XEN alone (n=9) XEN plus cataract surgery (n=6)	12 mo

FU: follow-up; IOP: intraocular pressure; POAG: primary open-angle glaucoma.

Table 19. Summary of Key Study Results for the XEN Implant with Cataract Surgery

Study	Population	IOP (SD), mm Hg		Medication, Median (SD)
		Baseline	1 Year	Baseline	1 Year
Mansouri et al (2018)22,	XEN + cataract	18 (IQR: 14 to 23)	22.9% reduction	2 (IQR: 1 to 3)	NR
Hengerer et al (2017)24,	XEN + cataract	35.7 (12)	13.9 (2.5)	3.3 (1.0)	0.4 (0.7)
Perez-Torregrosa et al (2016)36,	XEN + cataract	21.2 (3.4)	8.1 (3.0)	3.1	0.2 (0.7)
De Gregorio et al (2017)37,	XEN + cataract	22.5 (3.7)	13.1 (2.4)	2.6 (0.9)	0.4 (0.8)
Galal et al (2017)25,	All patients	16 (4)	12 (3)	1.9 (1)	0.3 (0.5)
Ozal et al (2017)26,	All patients	36.1	16.7	3.6 (0.5)	0.3 (0.9)

IOP: intraocular pressure; IQR: interquartile range; NR: not reported; SD: standard deviation.

CyPass

The FDA evaluated the clinical performance of the CyPass Micro-Stent system based on the pivotal Clinical Study to Assess the Safety and Effectiveness of the Transcend CyPass Glaucoma Implant in Patients With Open-Angle Glaucoma Undergoing Cataract Surgery (COMPASS) trial (NCT01085357). COMPASS was a multicenter RCT comparing the safety and efficacy of CyPass Micro-Stent plus cataract surgery with cataract surgery alone for treating mild-to-moderate primary OAG in patients undergoing cataract surgery. Evidence from the RCT supported the use of the CyPass stent in conjunction with cataract surgery; however, in August 2018, the manufacturer voluntarily withdrew the device from the market because a long-term study showed that patients receiving CyPass in conjunction with cataract surgery experienced statistically significant endothelial cell loss compared with patients who underwent cataract surgery alone.

Section Summary: Ab Interno Aqueous Microstents

Implantation of one or two microstents has received the FDA approval for use in conjunction with cataract surgery for reduction of IOP in adults with mild-to-moderate OAG currently treated with ocular hypotensive medication. RCTs and meta-analyses of RCTs have compared cataract surgery alone to microstent implantation in conjunction with cataract surgery when IOP is at least partially controlled with medication. When compared to cataract surgery alone, the studies showed modest but statistically significant decreases in IOP and medication use through the first two years when stents were implanted in conjunction with cataract surgery. A decrease in topical medication application is considered to be an important outcome for patients and reduces the problem of non-compliance that can affect visual outcomes.

Microstent Implantation as a Stand-Alone Procedure

The iStent was approved by the FDA to be used in conjunction with cataract surgery to reduce IOP in patients with mild-to-moderate open-angle glaucoma. The studies described below evaluated the use of the iStent or iStent inject as a stand-alone procedure.

The Cochrane review by Le et al (2019) on the iStent in patients with open-angle glaucoma identified 2 RCTs that compared treatment with iStent or iStent inject to medical therapy and 1 RCT that compared 1, 2, or 3 iStents.^28, Results of the meta-analyses are shown in Table 20. Meta-analysis was not performed due to heterogeneity. However, in both trials, iStent implantation resulted in a higher proportion of patients who were drop free and reduced the mean number of drops when compared to medical therapy. One RCT indicated that compared to implantation of 1 stent, implantation of 2 or 3 stents resulted in a similar proportion of patients who were drop free at 36 months or less, but a higher proportion of patients who were drop free after 36 months. The 2 studies included in the 2019 Cochrane review are described in greater detail below (see Tables 22 and 23).. Limitations of these studies are described in Tables 24 and 25.

Table 20. Meta-analysis Results

Study	Drop Free Compared to Medical Therapy	Drop Free with 2 Stents Compared to 1 Stent at 42 months	Drop Free with 3 Stents Compared to 1 Stent at 42 months
Le et al (2019)28,
N	2 RCTs	1 RCT	1 RCT
Pooled effect (95% CI)	90% of patients in the iStent groups were drop free	RR:0.51 (0.34 to 0.75)	RR:0.49 (0.34 to 0.73)

CI: confidence interval; RCT: randomized controlled trial; RR: relative risk.

A 2014 industry-sponsored, multicenter, unblinded, randomized trial compared implantation of 2 iStent inject devices with 2 ocular hypotensive agents.^38, The 192 patients enrolled in this unmasked trial had an IOP not controlled by 1 hypotensive medication. At 12-month follow-up, the 2 groups were comparable for IOP reduction of at least 20%, IOP of 18 mm Hg or less, and mean decrease in IOP. A greater proportion of patients in the iStent inject group achieved an IOP reduction of at least 50% (53.2% vs 35.7%, respectively). One patient in the iStent inject group experienced elevated IOP (48 mm Hg) and 4 required ocular hypotensive medication. Longer-term studies are in progress.

Vold et al (2016) reported on results of an RCT comparing 2 stand-alone iStent implants to topical travoprost (1:1 ratio) in 101 phakic eyes with an IOP between 21 and 40 mm Hg and newly diagnosed POAG, pseudoexfoliative glaucoma, or ocular hypertension that had not been treated previously.^39,The patients were not undergoing cataract surgery. The trial was unmasked, and methods for allocation concealment and calculation of power were not described. One hundred patients (54 iStent; 47 travoprost) completed 24 months of follow-up and 73 completed 36 months of follow-up. The trial was performed at a single-center in Armenia. Statistical analyses were not provided. Baseline mean IOP was 25 mm Hg in both groups. Mean IOP at 3 years was 15 mm Hg in both groups. Medication (or second medication) was added to 6 eyes in the iStent group and 11 eyes in the travoprost group. Progression of cataract was reported in 11 eyes in the iStent group and 8 eyes in the travoprost group, with cataract surgery being performed in 5 eyes in the iStent group and 1 eye in the travoprost group. The results would suggest that two iStents might reduce the number of medications required to maintain target IOP compared with travoprost but also hasten time to cataract surgery. However, the study methods were poorly reported, and statistical analyses were not reported.

iStent was compared with the Hydrus microstent in a double-blind multicenter RCT by Ahmed et al (COMPARE, 2019).^40, Eyes (n=152) with mild-to-moderate glaucoma and an IOP of 23 to 39 after washout of medication were randomized to either 1 Hydrus stent or 2 iStents as a stand-alone treatment. Both stents have FDA approval in the U.S. when used in conjunction with cataract surgery but not as a stand-alone procedure. Follow-up was performed through 12 months post-operatively with medications added at the investigator's discretion. The Hydrus outperformed 2 iStents in nearly every measure (see Table 22). Eyes implanted with the Hydrus microstent were able to maintain IOP < 18 mm Hg on fewer medications and a greater percentage of patients were medication-free compared to the iStent group (46.6% vs 24.0%, p<0.001). The decision to increase medications was up to the investigator and not pre-specified, but posthoc analysis indicated that the IOP at which medications were increased was similar in the two groups.

Table 21. Summary of RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Fea et al (2014) 38,	EU, Armenia	8		Patients with OAG not controlled on one medication, Post-washout IOP >22 and <38 mmHg	iStent inject (n=94)	Two medications (n=98)
Vold et al (2016)39,	Armenia	1		Patients with Patients with OAG (n=101) or PEX (n=1) who were naive to therapy with IOP > 21 and < 40 mmHg	Two iStents (n=54)	One medication (n=47)
Ahmed et al (2019)40,	U.S., E.U., Canada, Asia	12	2013-2015	152 patients with mild-to-moderate glaucoma (OAG, PEX, or PG and IOP 23 to 39 mmHg after washout	Hydrus (n=75)	Two iStents (n=77)

IOP: intraocular pressure; PEX: pseudoexfoliative glaucoma; PG: pigmentary glaucoma; OAG: open-angle glaucoma; RCT: randomized controlled trial.

Table 22. Summary of RCT Results

Study	>20% reduction in IOP n (%)	IOP < 18 mmHg	Mean IOP mmHg (SD)	Mean reduction in IOP from baseline mmHg (SD)	Mean number of medications at 12 months	Percent Medication Free at 12 months n (%)
Fea et al (2014) 38,	at 12 months	at 12 months n (%)	at 12 months
iStent inject	89/94 (94.7)	87/94 (92.6)	13.0 (2.3)	8.1 (2.6)
Medical therapy	88/98 (91.8)	88/98 (89.8)	13.2 (2.0)	7.3 (2.2)
p-Value	0.02	NR	NR	0.43
Vold et al (2016)39,	IOP < 18 mmHg n (%) at 24 months	at 36 months	at 36 months
iStent	90%	91%	14.6 mmHg
Medical therapy	87%	79%	15.3 mmHg
p-Value
Ahmed et al (2019)40,		without medication
Hydrus	39.7%	30.1%	17.3 (3.7).	-8.2 (3.7)	1.0	34 (46.6)
2 iStents	13.3%	9.3%	19.2 (2.4)	-5.1 (2.9)	1.7	18 (24.0)
p-Value	<0.001	<0.001	0.037	0.003	<0.001	0.006

IOP: intraocular pressure; NR: not reported; RCT: randomized controlled trial; SD: standard deviation.

Table 23. Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Fea et al (2014) 38,					1. Follow-up was limited to 12 months. Monitoring for occlusion of the stents at longer follow-up is needed
Vold et al (2016)39,		4. Not the currently marketed device
Ahmed et al (2019)40,			4. Not the currently marketed device		1. Follow-up was through 12 months, longer follow-up is continuing.

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.

^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.

^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.

^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.

^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Fea et al (2014) 38,	3. Randomization procedure was not described	1, 2, 3. Study could not be blinded		1. Unequal loss to follow-up in the 2 groups, and the subjects lost to follow-up were treated as failures	1. Power calculations not reported
Vold et al (2016)39,	3. Randomization procedure was not described	1, 2, 3. Study could not be blinded		1. There was 27% loss to follow-up at 36 months	1. Power calculations not reported	4. Statistical analysis not reported
Ahmed et al (2019)40,		2, 3. Investigators were not bllinded and there was no independent adjudication or preset criteria for increase in medication				2. Did not use repeated measures for multiple assessments

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.

^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.

^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.

^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).

^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.

^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Series have also been reported that evaluated the use of two iStent inject devices for treatment of patients with uncontrolled open-angle glaucoma in stand-alone procedures. Berdahl et al (2017) treated 53 patients and reported that 91% of patients achieved an IOP reduction of at least 20% at the 12-month follow-up.^42, Chang et al (2017) treated 39 patients and reported that 97% of patients achieved an IOP reduction of at least 20% after 3 years of follow-up. No device-related adverse events were reported in either study.^43,

Greater Than Two Stents

An RCT comparing the efficacy of 1 iStent with multiple iStent devices was published by Katz et al (2015).^44, This trial, from a single-institution in Armenia, randomized 119 patients with mild-to-moderate OAG and an IOP between 22 and 38 mm Hg (off medications) to 1 stent (n=38), 2 stents (n=41), or 3 stents (n=40). Randomization was performed using a pseudo-random number generator. The primary endpoint was the percentage of patients with a reduction of 20% or more in IOP off medications at 12 months. This endpoint was reached by 89.2% (95% CI, 74.6% to 97.0%) of the 1-stent group, by 90.2% (95% CI, 76.9% to 97.3%) of the 2-stent group, and by 92.1% (95% CI, 78.6% to 98.3%) of the 3-stent group. The secondary endpoint (percentage of patients achieving an IOP £15 mm Hg off medication) was reached by 64.9% (95% CI, 47.5% to 79.8%) of the 1-stent group, by 85.4% (95% CI, 70.8% to 94.4%) of the 2-stent group, and by 92.1% (95% CI, 78.6% to 98.3) of the 3-stent group. Forty-two-month follow-up results for 109 patients were published by Katz et al (2018).^45, Mean medicated IOPs for the 1-stent, 2-stent, and 3-stent groups were 15.0 ± 2.8 mm Hg, 15.7 ± 1.0 mm Hg, and 14.8 ± 1.3 mm Hg, respectively. Post-washout IOP (Months 36–37) was 17.4±0.9, 15.8±1.1 and 14.2±1.5 mmHg, respectively. IOP reduction >20% without medication was achieved in 89%, 90%, and 92% of one-, two-,and three-stent eyes, respectively, at month 12; and in 61%, 91%, and 91% of eyes, respectively, at month 42. The need for additional medication increased in single-stent eyes from 4 eyes at 12 months to 18 eyes at 42 months, suggesting a reduction in patency of the microstents over time. The need for additional medication did not increase from months 12 and 42 in multi-stent eyes. No between-group statistical comparisons were reported.

Section Summary: Microstent Implantation as a Stand-Alone Procedure

The evidence on microstents as a stand-alone procedure in patients with mild-to-moderate glaucoma that is controlled on medical therapy includes RCTs and a systematic review of three heterogeneous RCTs. Two RCTs indicate that implantation of a microstent can reduce IOP at a level similar to ocular medications at 12-month follow-up. Reduction in medications is an important outcome for patients with glaucoma, both for the patients themselves and because lack of compliance can lead to adverse health outcomes. Whether microstents remain patent after 12 months is uncertain, and whether additional stents can subsequently be safely implanted is unknown. Some evidence on longer-term outcomes is provided by an RCT that compared implantation of a single iStent with multiple iStents. At longer-term (42-month) follow-up, the need for additional medication increased in eyes implanted with a single iStent but not with multiple iStents. The durability of multiple iStents is unknown. A fourth RCT compared implantation of the Hydrus microstent to two iStents. Outcomes from the Hydrus microstent were significantly better than two iStents, both statistically and clinically, for all outcome measures. The primary limitation of this study is that the duration of follow-up in the present publication is limited to 12 months. Longer-term follow-up from this study is continuing and will answer important questions on the durability of the procedure. Corroboration in an independent study and comparison with a medical therapy control group would also increase confidence in the results.

Summary of Evidence

For individuals who have refractory OAG who receive ab externo aqueous shunts, the evidence includes RCTs, retrospective studies, and systematic reviews. The relevant outcomes are a change in disease status, functional outcomes, medication use, and treatment-related morbidity. RCTs assessing the FDA-approved shunts have shown that the use of large externally placed shunts reduces IOP to slightly less than standard filtering surgery (trabeculectomy). Reported shunt success rates show that these devices are noninferior to trabeculectomy in the long-term. The FDA-approved shunts have different adverse event profiles and avoid some of the most problematic complications of trabeculectomy. Two trials have compared the Ahmed and Baerveldt shunts. Both found that eyes treated with the Baerveldt shunt had slightly lower average IOP at five years than eyes treated with the Ahmed but the Baerveldt also had a higher rate of serious hypotony-related complications. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have refractory OAG who receive ab interno aqueous stents, the evidence includes a nonrandomized retrospective comparative study and several single-arm studies. The relevant outcomes are a change in disease status, functional outcomes, medication use, and treatment-related morbidity. The comparative study reported that patients receiving the stent experienced similar reductions in IOP and medication use as patients undergoing trabeculectomy. The single-arm studies, with 12-month follow-up results, consistently showed that patients receiving the stents experienced reductions in IOP and medication use. Reductions in IOP ranged from 4 mm Hg to over 15 mm Hg. In addition, the FDA has given clearance to a gel stent based on equivalent IOP and medication use reductions as seen with ab externo shunts. Clearance for the stent was based on a review in which the FDA concluded that while there were technical differences between the stent and predicate devices (shunts), the differences did not affect safety and effectiveness in lowering IOP and medication use. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have mild-to-moderate OAG who are undergoing cataract surgery who receive aqueous microstents, the evidence includes RCTs and meta-analyses of RCTs. The relevant outcomes are a change in disease status, functional outcomes, medication use, and treatment-related morbidity. Implantation of one or two microstents has received the FDA approval for use in conjunction with cataract surgery for reduction of IOP in adults with mild-to-moderate OAG currently treated with ocular hypotensive medication. When compared to cataract surgery alone, the studies showed modest but statistically significant decreases in IOP and medication use through the first two years when stents were implanted in conjunction with cataract surgery. A decrease in topical medication application is considered to be an important outcome for patients and reduces the problem of non-compliance that can affect visual outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals with mild-to-moderate OAG who are not undergoing cataract surgery who receive aqueous microstents as a stand-alone procedure, the evidence includes RCTs and a systematic review of three heterogeneous RCTs. The relevant outcomes are a change in disease status, functional outcomes, medication use, and treatment-related morbidity. Several RCTs have evaluated the use of multiple microstents but comparators differed. Two RCTs indicate that implantation of a microstent can reduce IOP at a level similar to ocular medications at 12-month follow-up. Reduction in medications is an important outcome for patients with glaucoma, both for the patients themselves and because lack of compliance can lead to adverse health outcomes. Whether microstents remain patent after 12 months is uncertain, and whether additional stents can subsequently be safely implanted is unknown. Some evidence on longer-term outcomes is provided by an RCT that compared implantation of a single iStent to implantation of multiple iStents. At longer-term (42-month) follow-up, the need for additional medication increased in eyes implanted with a single microstent but not with multiple microstents. The durability of multiple iStents is unknown. A fourth RCT compared implantation of the Hydrus microstent to two iStents. Outcomes from the Hydrus microstent were significantly better than two iStents, both statistically and clinically, for all outcome measures. The primary limitation of this study is that the duration of follow-up in the present publication is limited to 12 months. Longer-term follow-up from this study is continuing and will answer important questions on the durability of the procedure. Corroboration in an independent study and comparison with a medical therapy control group would also increase confidence in the results. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 1 physician specialty society and 2 academic medical centers while this policy was under review in 2013. Input supported the use of aqueous shunts in patients with glaucoma uncontrolled by medication. Input supported the use of a single microstent in patients with mild-to-moderate glaucoma undergoing cataract surgery to reduce the adverse events of medications and to avoid noncompliance.

Practice Guidelines and Position Statements

American Academy of Ophthalmology

The AAO (2008) published a technology assessment on commercially available aqueous shunts, including the Ahmed, Baerveldt, Krupin, and Molteno devices.^4, The assessment indicated that, in general, IOP would settle at higher levels (»18 mm Hg) with shunts than after standard trabeculectomy (14-16 mm Hg). Five-year success rates of 50% were found for the 2 procedures, indicating that aqueous shunts are comparable with trabeculectomy for IOP control and duration of benefit (based on level I evidence; well-designed randomized controlled trials). The assessment also indicated that although aqueous shunts have generally been reserved for intractable glaucoma when prior medical or surgical therapy has failed, indications for shunts have broadened (based on level III evidence; case series, case reports, and poor-quality case-control or cohort studies). The AAO concluded that, based on level I evidence, aqueous shunts offer a valuable alternative to standard filtering surgery and cyclodestructive therapy for many patients with refractory glaucoma.

The AAO’s (2015) preferred practice patterns on primary open-angle glaucoma indicated that the Academy considered laser trabeculoplasty as initial therapy in select patients or an alternative for patients who cannot or will not use medications reliably due to cost, memory problems, difficulty with installation, or intolerance to the medication.^46,The AAO stated that aqueous shunts have traditionally been used to manage refractory glaucoma when trabeculectomy has failed to control IOP or is unlikely to succeed, but these devices are being increasingly used in other indications for the surgical management of glaucoma. The AAO also stated that micro-invasive glaucoma surgeries that are frequently combined with phacoemulsification have limited long-term data but seem to result in modest IOP reduction with postoperative pressures in the mid to upper teens. Although they are less effective in lowering IOP than trabeculectomy and aqueous shunt surgery, micro-invasive glaucoma surgeries may have a more favorable safety profile in the short term.

National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence (2017) updated guidance on trabecular stent bypass microsurgery for open-angle glaucoma.^47, The guidance stated that “Current evidence on trabecular stent bypass microsurgery for open-angle glaucoma raises no major safety concerns. Evidence of efficacy is adequate in quality and quantity.

The National Institute for Health and Care Excellence(2018) published guidance entitled "Microinvasive subconjunctival insertion of a trans-scleral gelatin stent for primary open-angle glaucoma"^48,. The guidance states that evidence is limited in quantity and quality and therefore, the procedure should only be used with special arrangements and that patients should be informed of the uncertainty of the procedure.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this policy are listed in Table 25.

Table 25. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01461291a	A Prospective, Randomized, Single-Masked, Controlled, Parallel Groups, Multicenter Clinical Investigation of the Glaukos® Trabecular Micro-Bypass Stent Model GTS400 Using the G2-M-IS Injector System in Conjunction With Cataract Surgery	1200	Dec 2019
NCT01461278a	A Prospective, Randomized, Single-Masked, Controlled, Parallel Groups, Multicenter Clinical Investigation of the Glaukos® Suprachoroidal Stent Model G3 In Conjunction With Cataract Surgery	1200	Dec 2020
NCT01539239a	The Safety and Effectiveness of the Hydrus Aqueous Implant for Lowering Intraocular Pressure in Glaucoma Patients Undergoing Cataract Surgery, A Prospective, Multicenter, Randomized, Controlled Clinical Trial	1143	Jun 2020
NCT01841450a	A Prospective, Randomized, Controlled, Parallel Groups, Multicenter Post-Approval Study Of The Glaukos® iStent® Trabecular Micro-Bypass Stent System In Conjunction With Cataract Surgery	360	Jul 2021
Unpublished
NCT01282346a	Clinical Evaluation of the SOLX Gold Shunt for the Reduction of Intraocular Pressure (IOP) in Refractory Glaucoma	60	Dec 2015 (completed)
NCT02023242a	A Prospective, Multicenter, Randomized Comparison of the Hydrus to the iStent® for Lowering Intraocular Pressure in Primary Open Angle Glaucoma	152	Jan 2018 (completed)
NCT01444040a	A Prospective, Randomized Evaluation of 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 Ophthalmic Solution 0.004%	200	Jun 2018 (unknown)

NCT: national clinical trial.

^a Denotes industry-sponsored or cosponsored trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Aqueous Shunts and Stents for Glaucoma
Aqueous Shunts for Glaucoma
Shunts for Glaucoma
AquaFlow
iTrack
Trabectome™
Ahmed™
Baerveldt®
Krupin
Molteno®
EX-PRESS®
iStent®
iStent inject®
iStent supra®
EyePass
Solx Gold
CyPass®
Hydrus™
AquaFlow™
XEN Gel Stent

References:
1. Glaukos Corporation (GC). Glaukos Corporation iStent inject Trabecular Micro-Bypass System. 2018; https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170043c.pdf. Accessed January 24, 2019.

2. Food and Drug Administration (FDA). Alcon Announces Voluntary Global Market Withdrawal of CyPass Micro-Stent for Surgical Glaucoma. 2018; https://www.fda.gov/Safety/Recalls/ucm619109.htm. Accessed January 24, 2019.

3. Minckler DS, Vedula SS, Li TJ, et al. Aqueous shunts for glaucoma. Cochrane Database Syst Rev. Apr 19 2006(2):CD004918. PMID 16625616.

4. Minckler DS, Francis BA, Hodapp EA, et al. Aqueous shunts in glaucoma: a report by the American Academy of Ophthalmology. Ophthalmology. Jun 2008;115(6):1089-1098. PMID 18519069.

5. Boland MV, Ervin AM, Friedman D, et al. Treatment for Glaucoma: Comparative Effectiveness. Comparative Effectiveness Review No. 60 (AHRQ Publication No. 12-EHC038-EF). Rockville, MD: Agency for Healthcare Research and Quality; 2012.

6. Gedde SJ, Schiffman JC, Feuer WJ, et al. Treatment outcomes in the Tube Versus Trabeculectomy (TVT) study after five years of follow-up. Am J Ophthalmol. May 2012;153(5):789-803 e782. PMID 22245458.

7. Kotecha A, Feuer WJ, Barton K, et al. Quality of Life in the Tube Versus Trabeculectomy Study. Am J Ophthalmol. Apr 2017;176:228-235. PMID 28161049.

8. Wang X, Khan R, Coleman A. Device-modified trabeculectomy for glaucoma. Cochrane Database Syst Rev. Dec 1 2015;12(12):CD010472. PMID 26625212.

9. de Jong LA. The Ex-PRESS glaucoma shunt versus trabeculectomy in open-angle glaucoma: a prospective randomized study. Adv Ther. Mar 2009;26(3):336-345. PMID 19337705.

10. de Jong L, Lafuma A, Aguade AS, et al. Five-year extension of a clinical trial comparing the EX-PRESS glaucoma filtration device and trabeculectomy in primary open-angle glaucoma. Clin Ophthalmol. May 2011;5:527-533. PMID 21607021.

11. Netland PA, Sarkisian SR, Jr., Moster MR, et al. Randomized, prospective, comparative trial of EX-PRESS glaucoma filtration device versus trabeculectomy (XVT study). Am J Ophthalmol. Feb 2014;157(2):433-440 e433. PMID 24210765.

12. Wagschal LD, Trope GE, Jinapriya D, et al. Prospective randomized study comparing Ex-PRESS to trabeculectomy: 1-year results. J Glaucoma. Oct-Nov 2015;24(8):624-629. PMID 24247999.

13. Gonzalez-Rodriguez JM, Trope GE, Drori-Wagschal L, et al. Comparison of trabeculectomy versus Ex-PRESS: 3-year follow-up. Br J Ophthalmol. Sep 2016;100(9):1269-1273. PMID 26674779.

14. Dib Bustros Y, Fechtner R, A SK. Outcomes of Ex-PRESS and trabeculectomy in a glaucoma population of African origin: one year results. J Curr Glaucoma Pract. May-Aug 2017;11(2):42-47. PMID 28924337.

15. Omatsu S, Hirooka K, Nitta E, Ukegawa K. Changes in corneal endothelial cells after trabeculectomy and EX-PRESS shunt: 2-year follow-up. BMC Ophthalmol. Sep 10 2018;18(1):243. PMID 30200927.

16. Budenz DL, Barton K, Gedde SJ, et al. Five-year treatment outcomes in the Ahmed Baerveldt comparison study. Ophthalmology. Feb 2015;122(2):308-316. PMID 25439606.

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Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

66183
0191T
0253T
0376T
0449T
0450T
0474T

L8612