Aqueous Shunts and Devices for Glaucoma - CAM 90321

Description
Glaucoma surgery is intended to reduce intraocular pressure (IOP) when the target IOP cannot be reached using medications. Due to complications with established surgical approaches (eg, trabeculectomy), a variety of shunts are being evaluated as alternative surgical treatments for patients with inadequately controlled glaucoma. Microstents are also being evaluatedin patients with mild-to-moderate open-angle glaucoma (OAG) currently treated with ocular hypotensive medication.

For individuals who have refractory OAG who receive ab externo aqueous shunts, the evidence includes randomized controlled trials (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 U.S. Food and Drug Administration (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 withcataract 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. 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.

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 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 (eg, 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 evidence review 9.03.26). 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 evidence review 9.03.26).

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 (eg, <15 mm Hg) and are not indicated for patients for whom very low IOP is desired (eg, 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 is 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 microstentsis 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 first microstent, 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 regulatory status of additional glaucoma devices is shown in Table 1.

In August 2018, Alcon announced an immediate voluntary recall of the CyPass microstent, which had been approved by the FDA in 2016 for use in conjunction with cataract surgery in adults with mild-to-moderate open-angle glaucoma. The recall was based on 5 year postsurgery data from the COMPASS-XT long-term safety study. Results showed a statistically significant increase in endothelial cell loss among patients receiving the CyPass microstent compared with patients receiving cataract surgery alone. 

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  
Beacon Aqueous Microshunt MicroOptx Micro-Shunt, ab externo Not approved; in clinical trial  
PRESERFLO® MicroShunt Santan Micro-Shunt, ab externo Not approved; in clinical trial  

FDA: U.S. Food and Drug Administration; PMA: premarket approval.
FDA product codes: OGO, KYF.

Related Policies
90306 Ophthalmologic Techniques for Evaluating Glaucoma
90326 Viscocanalostomy and Canaloplasty

Policy:

Insertion of ab externo aqueous shunts approved by the U.S. Food and Drug Administration may be considered medically necessary as a method to reduce intraocular pressure in patients with glaucoma where medical therapy has failed to adequately control intraocular pressure.

Use of an ab externo aqueous shunt for all other conditions, including in patients with glaucoma when intraocular pressure is adequately controlled by medications, is investigational and/or unproven and therefore NOT MEDICALLY NECESSARY.

Insertion of ab interno aqueous stents approved by the Food and Drug Administration as a method to reduce intraocular pressure in patients with glaucoma where medical therapy has failed to adequately control intraocular pressure is considered medically necessary.

Implantation of 1 or 2 Food and Drug Administration-approved ab interno stents in conjunction with cataract surgery may be considered medically necessary in patients with mild-to-moderate open-angle glaucoma treated with ocular hypotensive medication.

Use of ab interno stents for all other conditions is investigational and/or unproven and therefore NOT MEDICALLY NECESSARY.

Use of a microstent for all other conditions is  investigational and/or unproven and is therefore considered NOT MEDICALLY NECESSARY.    

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

CODING
There is a category I CPT code for insertion of aqueous shunt using an external approach:

66183 Insertion of anterior segment aqueous drainage device, without extraocular reservoir, external approach.

There are CPT category III codes for these procedures using an internal approach:

0191T Insertion of anterior segment aqueous drainage device, without extraocular reservoir; internal approach, into the trabecular meshwork; initial insertion
0376T each additional device insertion (List separately in addition to code for primary procedure)
0253T Insertion of anterior segment aqueous drainage device, without extraocular reservoir; internal approach, into the suprachoroidal space
0449T Insertion of aqueous drainage device, without extraocular reservoir, internal approach, into the subconjunctival space; initial device
0450T each additional device (List separately in addition to code for primary procedure).

Effective July 1, 2017, there is a CPT category III code for insertion of the CyPass device:

0474T Insertion of anterior segment aqueous drainage device, with creation of intraocular reservoir, internal approach, into the supraciliary space.

The category III CPT codes specify insertion of an aqueous drainage device without drainage to an extraocular reservoir and are therefore differentiated from the existing codes for trabeculectomy or placement of shunts that drain to an extraocular reservoir (below). Procedures using the Trabectome device are considered similar to trabecular laser ablation and are not within the scope of this policy.

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all devices, drugs, or biologics approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.

Rationale
This evidence review was created in July 2008 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through July 27, 2020.

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 function¾including 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, 2 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 evidence review 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 PICO was used to select literature to inform this review.

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

Interventions
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
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: 

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

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

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

  • Studies with duplicative or overlapping populations were excluded.

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

Ab Externo Aqueous Shunts
Review of Evidence
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.1 Trabeculectomy was found to lower mean IOP by 3.8 mm Hg more than the Ahmed shunt at 1 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 1 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).2 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.

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.2-4 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.5 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 2 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.6 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 (eg, 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 (Table 2).7 Five year follow-up was reported by de Jong et al (2011).8 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 5 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) (Table 2).9 Comparator groups were similar at baseline. Throughout a 2 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 1 month after EX-PRESS implantation (median, 0.7 months) and at 3 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),10 presenting 1-year results, and by Gonzalez-Rodriguez et al (2016), presenting 3-year results (Table 2).11 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 (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)7;de Jong et al. (2011)8 Netherlands 1 2003-2004 Patients with primary OAG not controlled by IOP medication EX-PRESS

(n=39)
Trabeculectomy

(n=39)
Netland et al. (2014)9 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)10; Gonzalez-Rodriguez et al. (2016)11 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)7; de Jong et al. (2011)8          
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)9          
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)10; Gonzalez-Rodriguez e al (2016)11      



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.

Comparative Effectiveness Analyses
Five-year results of 2 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 and Baerveldt Glaucoma Implant in 276 adults with previous incisional eye surgery or refractory glaucoma.12,13 The ABC was funded by National Eye Institute, Research to Prevent Blindness, and New World Medical. 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 that was funded by the Glaucoma Research Society of Canada.14

Christakis et al. (2017) analyzed 5-year pooled data from the ABC and AVB trials comparing the relative efficacy of the 2 implants.15 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 Ahmed group (0.4%; p=.002).

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 1 to 5 years. Results from ab externo aqueous shunts are similar to trabeculectomy. Adverse event rates were higher among patients undergoing trabeculectomy.

The comparative effectiveness of 2 ab externo devices (the Ahmed and Baerveldt shunts) has been evaluated in 2 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.

Ab Interno 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.

Review of Evidence
Xen Glaucoma Treatment System
Observational Studies
Comparative Studies
Schlenker et al. (2017) published a multicenter, retrospective comparative 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).16 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 2 consecutive IOP readings of less than 6 mm Hg, including vision loss. Success was measured by the withdrawal of glaucoma-related medications at 1 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 (Table 4).17 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).

Hengerer et al. (2017) retrospectively analyzed 146 patients (242 eyes) receiving the XEN implant for treatment-refractory to antiglaucoma medication or glaucoma surgery (Table 4).18 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.

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)16 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 to30 mo(last visit in chart)
Mansouri et al. (2018)17 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
Hengerer et al. (2017)18 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

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)16 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)17 XEN alone 20 (IQR: 17 to 23) 40.0% reduction 2.5 (IQR: 1 to 4) NR
Hengerer et al. (2017)18 XEN alone 31.5 (8.4) 14.3 (4.2) 3.1 (1.0) 0.3 (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 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 2 stents, have FDA approval for use in conjunction with cataract surgery. An additional stent, the CyPass, had 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.

Review of Evidence
iStent
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).19 The authors identified 7 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, 2 RCTs compared treatment with iStent or iStent inject to medical therapy, and 1 RCT compared 1, 2, or 3 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 4 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)19 - 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)19      
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).20,21 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 2 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 (eg, 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 1 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).21 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).22 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 2 main limitations are that there was no masking to treatment and durability of these microstents after 2 years was not reported. Continued patency of the stents and need for additional treatments has been evaluated through 4 years in studies from the Microinvasive Glaucoma Surgery (MIGS) study group and are described below..

Table 8. Summary of Pivotal RCT Characteristics 

Study Countries Sites Dates Participants Interventions
          Active Comparator
Samuelson et al. (2011)20; Craven et al (2012)21 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)22 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)20; Craven et al. (2012)21                
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)22iStent 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. Study Relevance Limitations 

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Samuelson et al. (2011)20         Patency after 2 years is unknown
Samuelson et al. (2019)22         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 gaps 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.

Table 11. Study Design and Conduct Limitations 

Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
Samuelson et al. (2011)20   2, 3. No blinding of assessors        
Samuelson et al. (2019)22   2, 3. No blinding of assessors        

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

One non-randomized comparative study was reported by Hooshmand et al (2019) on outcomes with the use of the iStent inject, which simultaneously injects 2 stents through a single ab interno opening, compared to the first generation single iStent (see Table 12).23 The iStent inject was developed to provide easier ab interno insertion and comes preloaded with 2 stents that are smaller than the first-generation iStent. There was no significant difference between the earlier model and the second generation device on outcomes at 12 months (see Table 13) but Kaplan-Meier analysis found an earlier time to add topical medications in the iStent inject patients. Limitations of the study include the length of follow-up, which was limited by the time that the iStent inject had been available, and the non-randomized design (see Tables 14 and 15). In addition, the study compared 2 cohorts from different time periods, those who had been treated with the first generation device and those who had been treated with the second-generation device. Efficacy of the iStent inject at longer follow-up is unknown.

Table 12. Summary of Comparative Study Characteristics 

Study; Trial Countries Sites Dates Participants Interventions
          Active Comparator
Hooshmand et al. (2019)23 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)23 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.

Table 14. Study Relevance Limitations 

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Hooshmand et al. (2019)23         1. Follow-up was limited by the time that the iStent inject was available.

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

Table 15. Study Design and Conduct Limitations 

Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
Hooshmand et al. (2019)23 1. Study was not randomized 1, 2, 3. No blinding of assessors     1. Post-hoc power calculations  

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

Hydrus Microstent
Systematic Reviews
A Cochrane review by Otarola et al. (2020) included 3 studies with 808 participants.24 Two studies (described below) were conducted in patients with cataracts and OAG (n=653), and compared the Hydrus microsent combined with cataract surgery to cataract surgery alone.25,26 They found moderate-certainty evidence that adding the Hydrus microstent to cataract surgery in patients with mild or moderate OAG increased the proportion of participants who were medication-free at 12 month (risk ratio 1.59, 95% confidence interval 1.39 to 1.83) and 24 month follow-up (risk ratio 1.63, 95% confidence interval 1.40 to 1.888), and reduced unmedicated IOP by 2 mm Hg, the number of medications by -0.41, and the need for secondary glaucoma surgery.

The third study compared the Hydrus microstent with the iStent in patients without cataract surgery.27 This study is described in the next section on microstents as a stand-alone procedure.

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).25 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 (HORIZON) comparing implantation of a single Hydrus Microstent following cataract surgery vs cataract surgery alone (Table 16).26 Patients were masked 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)25 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)26 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)25            
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)26            
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.28 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 6 months to 0.5, which was maintained through 2 years of follow-up (0.7).

Xen Glaucoma Treatment System
Observational Studies
Mansouri et al. (2018)17 and Hengerer et al. (2017)18, 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.

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

Study Country Participants Treatment Delivery FU
Mansouri et al. (2018)17 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)18 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

 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)17 XEN + cataract 18 (IQR: 14 to 23) 22.9% reduction 2 (IQR: 1 to 3) NR
Hengerer et al. (2017)18 XEN + cataract 35.7 (12) 13.9 (2.5) 3.3 (1.0) 0.4 (0.7)

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 1 or 2 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 2 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
iStent
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.19 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 (Tables 21 and 22). Limitations of these studies are described in Tables 23 and 24.

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)19      
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 to 2 ocular hypotensive agents.29 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 results of an RCT comparing 2 stand-alone iStent inject 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.30 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 with visiting surgeons from the U.S. 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 2 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.

Four year follow-up of iStent inject is reported in 2 phase 4 publications from the MIGS study group.31,32 Berdahl et al. (2020) reported on 53 patients who were on 2 preoperative medications who received 2 iStent inject implants and started on travoprost on postoperative Day 1. At 48 month follow-up, 85% of eyes had reduced IOP (> 20%) with a single medication as compared to the baseline IOP on 2 medications. Mean IOP on 1 medication was 11.9 to 13.0 mm Hg, compared to 19.7 on 2 medications preoperatively. Lindstrom et al (2020) reported on 57 patients who were on 1 preoperative medication before implantation of 2 iStent inject devices. Month 48 IOP without medication was reduced (> 20%) in 95% of eyes with iStent inject. There were no adverse events that were considered to be related to the devices.

Hydrus versus iStent
Hydrus microstent was compared with the iStent in a double-blind multicenter RCT by Ahmed et al. (COMPARE, 2020).27 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 2 groups.

Table 21. Summary of RCT Characteristics 

Study; Trial Countries Sites Dates Participants Interventions
          Active Comparator
Fea et al. (2014)29 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)30 Armenia with U.S. surgeons 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)27 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) 29 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)30 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. (2020)27   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. Study Relevance Limitations 

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Fea et al. (2014)29         1. Follow-up was limited to 12 months. Monitoring for occlusion of the stents at longer follow-up is needed
Vold et al. (2016)30   4. Not the currently marketed device      
Ahmed et al. (2019)27     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 gaps 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.

Table 24. Study Design and Conduct Limitations 

Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
Fea et al. (2014) 29 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)30 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. (2020)27   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

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

Greater Than Two Stents
An RCT comparing the efficacy of 1 iStent with multiple iStent devices was published by Katz et al. (2015).33 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 pseudorandom 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% of the 1-stent group, by 90.2% of the 2-stent group, and by 92.1% of the 3-stent group. The secondary endpoint (percentage of patients achieving an IOP £15 mm Hg off medication) was reached by 64.9% of the 1-stent group, by 85.4% of the 2-stent group, and by 92.1% of the 3-stent group. Forty-two-month follow-up results for 109 patients were published by Katz et al. (2018).34 Post-washout IOP was 17.4±0.9, 15.8±1.1 and 14.2±1.5 mmHg, for 1, 2, or 3 stents, respectively. 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 3 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 2 iStents. Outcomes from the Hydrus microstent were significantly better than 2 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 randomized controlled trials (RCTs), retrospective studies, and systematic reviews. Relevant outcomes are a change in disease status, functional outcomes, medication use, and treatment-related morbidity. RCTs assessing U.S. Food and Drug Administration (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 5 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. 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. Relevant outcomes are a change in disease status, functional outcomes, medication use, and treatment-related morbidity. Implantation of 1 or 2 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 2 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 3 heterogeneous RCTs. 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. 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 2 iStents. Outcomes from the Hydrus microstent were significantly better than 2 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.

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.2 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.35 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.36 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"37. 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 review are listed in Table 25. 

Table 25. Summary of Key Trials

NCT No. Trial Name Planned Enrollment Completion Date
Ongoing      
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
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
NCT04440527 Intraocular Pressure After Preserflo/Innfocus Microshunt vs Trabeculectomy: a Prospective, Randomised Control-trial (PAINT-Study) 70 Jul 2024
Unpublished      
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)
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

NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.

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Coding Section

Codes Number Decription
CPT 66183 Insertion of anterior segment aqueous drainage device, without extraocular reservoir, external approach
  66989 (effective 01/01/2022)  With insertion of intraocular (eg, trabecular meshwork, supraciliary, suprachoroidal) anterior segment aqueous drainage device, without extrocular reservoir, internal approach, one or more 
  66991 (effective 01/01/2022)  with insertion of intraocular (eg, trabecular meshwork, supraciliary, suprachoroidal) anterior segment aqueous drainage device without extraocular reservoir, internal approach, one or more 
  0191T (delete code effective 01/01/2022) Insertion of anterior segment aqueous drainage device, without extraocular reservoir; internal approach, into the trabecular meshwork
  0376T (delete code effective 01/01/2022) each additional device insertion (List separately in addition to code for primary procedure)
  0253T Insertion of anterior segment aqueous drainage device, without extraocular reservoir; internal approach, into the subarachnoid space
  0449T (effective 1/1/2017) Insertion of aqueous drainage device, without extraocular reservoir, internal approach, into the subconjunctival space; initial device 
  0450T (effective 1/1/2017) each additional device (List separately in addition to code for primary procedure) 
  0474T  Insertion of anterior segment aqueous drainage device, with creation of intraocular reservoir, internal approach, into the supraciliary space
  0671T (effective 01/01/2022) Insertion of anterior segment aqueous drainage device into the trabecular meshwork, without external reservoir, and without concomitant cateract removal, one or more 
ICD-9-CM Diagnosis 365.00-365.89 Glaucoma code range
  366.00-366.9 Cataract code range
HCPCS C1783 Ocular implant, aqueous drainage assist device
ICD-10-CM (effective 10/1/15) H25.011-H26.9 Cataract code range
  H40.1-H42  Glaucoma code range 
ICD-10-PSC (effective 10/01/15)    ICD-10PSC codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure.
Type of service     
Place of service    

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

Appendix
AQUEOUS SHUNTS AND STENTS NOT APPROVED BY FDA
iStent supra
Myers et al (2018) presented 4-year outcomes of a single-arm study implanting 2 iStent trabecular micro-bypass stents and 1 iStent supra suprachoroidal stent in 80 patients with refractory glaucoma.25 At 4-years follow-up, patients experienced a 37% or more mean reduction in IOP. All patients received travoprost following the procedure, with 6 patients requiring additional medication when IOP exceeded 21 mm Hg. No intraoperative adverse events were reported. 

SOLX Gold Shunt
Tanito et al (2017) published results from a 2-center single-arm study in which 24 patients with refractory open-angle glaucoma received the SOLX GoldShunt.28 Outcomes evaluated at baseline through 1 year of follow-up included medication use, IOP, and surgical complications. IOP was significantly reduced at every follow-up visit, with an average 23% reduction from baseline at 1-year follow-up (p<0.001). Patients also experienced a 40% reduction in medication use at 1-year follow-up from baseline (p<0.001). Inflammation-related complications were reported.31

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

11/23/2021 

Updating policy with 2022 coding. Adding codes 66989, 66991 and 0671T. DELETE CODES 0191T and 0376T effective on 01/01/2022.  No other change made. 

10/01/2021 

Annual review, no change to policy intent. Updating regulatory status, rationale, references and appendix. 

11/06/2020 

Interim review to include coverage for ab interno shunts. No other changes made. 

10/01/2020 

Annual review, no change to policy intent. Updating description, rationale and references. 

10/01/2019 

Annual review, updating description, background, regulatory status, guidelines, rationale and references. Statements regarding procedures that were previously listed as investigational have been expanded to read" investigational and/or unproven and therefore considered not medically necessary". 

10/18/2018 

Annual review, rewriting policy statement, previously, ab externo and ab interno devices were combined in one policy statement, they are now each addressed in individual policy statements. Also updating background, regulatory status, guidelines, rationale and references. Adding appendix A which discusses aqueous shunts and stents not approved by the FDA. 

10/02/2017 

Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references. 

11/30/2016 

Updated the coding section with 2017 codes. 

10/06/2016

Annual review, no change to policy intent. Updating background, description, rationale, references, regulatory status, guidelines, coding. 

10/13/2015

Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references. 

10/02/2014

Annual review. No change to policy intent. Updated rationale, references,& background. Added coding and policy guidelines.

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