Micro-Invasive Glaucoma Surgery (MIGS)

Title XVIII of the Social Security Act, §1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.

Title XVIII of the Social Security Act, §1862(a)(1)(D) indicates no payment may be made in the case of clinical care where items and services provided are in research and experimentation.

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 14, §10 Coverage of Medical Devices

CMS Internet-Only Manual, Pub. 100-08, Medicare Program Integrity Manual, Chapter 13, §13.5.3 Evidentiary Content and §13.5.4 Reasonable and Necessary Provisions in LCDs

Indications of Coverage

The following are considered reasonable and necessary and covered:

1. 1 trabecular aqueous stent device per eye which is approved for the treatment of adults with mild or moderate open-angle glaucoma (OAG) and a cataract when the individual is currently being treated with an ocular hypotensive medication and the procedure is being performed in conjunction with cataract surgery.
2. 1 subconjunctival space stent or trabecular aqueous stent device is approved for use as a standalone procedure device per eye for the management of refractory glaucoma, defined as prior failure of a filtering/cilioablative procedure OR uncontrolled intraocular pressure (IOP) defined a progressive damage or mean diurnal medicated IOP ≥20 mmHg on maximally tolerated medical therapy (MTMT) (i.e., ≥4 classes of topical IOP-lowering medications, or fewer in the case of tolerability or efficacy issues).
3. Phacoemulsification/intraocular lens placement can be performed with a single MIGS procedure.

Limitations

1. Minimally invasive glaucoma surgery (MIGS) is not considered a first line treatment for mild-moderate glaucoma.
2. A combination of a surgical MIGS procedure and an aqueous shunt cannot be performed at the same time of service in the same eye.
3. Phacoemulsification/intraocular lens placement performed with a combination of a MIGS procedure, (e.g., cataract + stent + canaloplasty or goniotomy) at the same time of service in the same eye is non-covered.

A Contractor Advisory Committee Meeting on Micro-Invasive Glaucoma Surgery was held on 1/5/2023 hosted by Palmetto GBA, CGS, NGS, Noridian, and WPS. Transcripts are available at: Jurisdiction J Part A - Multi-Jurisdictional Micro-Invasive Glaucoma Surgery Contractor Advisory Committee Meeting: January 5, 2023 (palmettogba.com). The input from subject matter experts (SMEs) will be referenced throughout this LCD.

Provider Qualifications

The Medicare Program Integrity Manual states services will be considered medically reasonable and necessary only if performed by appropriately trained providers. XEN^®45 insertion must be performed by an ophthalmologist with experience with trabeculectomy and bleb management.

Patient safety and quality of care mandate that healthcare professionals who perform MIGS are appropriately trained and/or credentialed by a formal residency/fellowship program and/or are certified by either an accredited and nationally recognized organization or by a post-graduate training course accredited by an established national accrediting body or accredited professional training program whose core curriculum includes the performance and management of the procedures addressed in this LCD. Credentialing or privileges are required for procedures performed in inpatient and outpatient settings.¹

Definitions

Canaloplasty- Cannulation of Schlemm’s canal with a catheter or stent with either an internal or external approach for at least 3 clock hours with an injection of viscoelastic while removing the stent to dilate the canal or via 3 or more punctures of the trabecular meshwork (TM) spanning at least 3 clock hours (90 degrees) to dilate Schlemm’s canal.²

Goniotomy- Incision and/or excision with blade or surgical instrument for at least 3 clock hours of TM to create an opening into Schlemm’s canal from the anterior chamber, via the internal approach through anterior chamber.³

High quality literature- Further research is very unlikely to change our confidence in the estimate of effect.⁴

Maximum tolerated medical therapy (MTMT)- Is attained as soon as the patient is successfully using the greatest number of topical glaucoma medication classes he or she can tolerate and that add additional IOP reduction.⁵

Minimally Invasive glaucoma surgery (MIGS)- A group of surgical procedures that are performed using an ab interno approach and designed to reduce trauma to ocular tissues.⁶

Moderate quality literature- Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.⁴

Primary open-angle glaucoma (POAG)- Potentially blinding condition caused by chronic, progressive optic neuropathy in adults in which there is acquired atrophy of the optic nerve with loss of retinal ganglion cells and their axons.⁶

Refractory Glaucoma- When the intraocular pressure remains above target values selected to slow or halt the disease, despite the use of multiple classes of medications, or fewer medications when tolerability or effectiveness limits the use of other drug classes or failed surgical therapy.⁵

POAG affects approximately 53 million people in the world with a prevalence of 3% in the population aged 40-80 years.⁶ POAG is a chronic, progressive optic neuropathy in adults in which there is a characteristic acquired atrophy of the optic nerve and loss of retinal ganglion cells and their axons. In the primary (conventional) outflow pathway from the eye, aqueous humor passes through the TM, enters a space lined with endothelial cells (Schlemm’s canal), drains into collector channels, and then into the aqueous veins. Increases in resistance in the TM or the inner wall of the Schlemm’s canal can disrupt the balance of aqueous humor inflow and outflow, resulting in an increased IOP and glaucoma risk. The etiology is not fully understood but there is an association with increased IOP, due to a buildup of aqueous fluid within the eye which can lead to visual field loss and optic nerve damage, usually without any associated pain or discomfort. The increased IOP is secondary to an imbalance between aqueous fluid secretion and fluid outflow despite an open angle. Nearly 40% of those with otherwise characteristic POAG may not have elevated IOP measurement.⁶ Established risk factors for POAG include older age, African American or Latino/Hispanic ethnicity, family history of glaucoma, type 2 diabetes and underlying eye conditions that predispose to glaucoma.⁶

The Ocular Hypertension Study was a randomized controlled trial (RCT) with 1636 participants from 22 clinical centers with no evidence of glaucoma between the ages of 40 to 80 years old and IOP between 24 and 32 mmHg in 1 eye and between 21 to 32 mmHg in the other eye. Subjects were randomized to either observation or treatment with commercially available topical ocular hypotensive medications. A comprehensive eye evaluation was conducted every 6 months for 72 months. Mean ±SD reduction in IOP in the medication group was 22.5%±9.9%. The IOP declined by 4.0±11.6% in the observation group. At 60 months, the cumulative probability of developing POAG was 4.4% in the medication group and 9.5% in the observation group (hazard ratio, 0.40; 95% confidence interval, 0.27-0.59; P<0.0001).⁷ As the only known modifiable risk factor treatment of elevated IOP to reduce risk of progression to glaucoma is considered standard of care with the goal of reduction or slowing the progression of vision loss. Elevated IOP has since been the main standard to which glaucoma treatment measures. The long-standing risk of glaucoma is progressive vision loss is the most significant outcome but challenging to use as primary outcome in studies. The SMEs emphasized the benefits of early reduction in IOP through medication or MIGS procedures to reduce or delay vision loss associated with glaucoma. They explained that reduction in IOP is currently the only intervention and is therefore, the only marker in studies to date. While the outcome of progression of glaucoma is the final endpoint given the benefits of lowering IOP as reported in this study, they do not feel a control group without intervention is appropriate.

A prospective, multicenter interventional cohort from the pre randomization phase of a randomized clinical trial at multiple ophthalmology clinics included 603 eyes with OAG using up to 3 glaucoma meds. IOP pressure was measured using routine medications and subsequently eligible participants underwent washout of all IOP-lowering drops and measurement was taken 2-4 weeks later off medications. The authors reported the following “The mean (SD) ON IOPs for participants using 0 (n=102), 1 (n=272), 2 (n=147), or 3 (n=82) medications were 24.2 (3.2), 17.5 (3.2), 17.2 (3.1), and 17.2 (3.1) mmHg, respectively. Patients not using medication had a mean (SD) IOP decrease of 0.2 (2.8) mmHg at the OFF visit. Patients using 1, 2, and 3 medications had mean (SD) IOP increases of 5.4 (3.0), 6.9 (3.3), and 9.0 (3.8) mmHg, respectively, at the OFF visit. The percentages of patients with less than a 25% increase in IOP were 38%, 21%, and 13% for those using 1, 2, and 3 medications, respectively.” This study demonstrated discontinuation of medication resulted in a clinically significant increase in IOP, especially the first medication period of proportion of patients only saw small change in IOP after the washout suggesting they were not using the medication properly or they were not working for that patient.⁸ This is a significant factor in study design for studies looking at IOP reduction as the primary endpoint since a lack of a washout can limit the detection of the complete surgical effect in terms of IOP reduction. Additionally, a higher baseline IOP can lead to overestimation of the real IOP reduction.

The goal of treatment in primary open angle glaucoma (POAG) is to reduce the IOP to slow the progression of optic nerve damage and associated vision and visual field loss. The IOP can be reduced by medical treatment or surgery, alone or in combination. IOP >21 mmHg has been shown to increase rates of visual field loss. However, because of the differences in susceptibility to pressure-related disc damage among POAG patients, pressure-lowering treatments are aimed at achieving a lower “target” pressure individualized to each patient’s baseline IOP in which glaucomatous damage occurred. American Academy of Ophthalmology (AAO) Guidelines state that although medical management is the most common initial intervention to lower IOP in patients with glaucoma, there are many options to consider, including a variety of surgical interventions. Further, the effectiveness, potential side effects, tolerance of medications, and desired target IOP must all be balanced for each individual patient when choosing a regimen best suited for that patient, whether medical or surgical.⁹

When the MTMT fails to control progression of glaucomatous optic neuropathy, surgical care is considered the next treatment option. Traditional filtration surgery includes trabeculectomy (including ExPress^® shunt) and aqueous drainage implants (Ahmed, Baerveldt, Molteno). Trabeculectomy uses the patient’s own sclera to create a fistula to the subconjunctival space over the sclera superiorly. Aqueous drainage implants use silicone/plastic tubing and large plates to shunt aqueous to the subconjunctival space in the equatorial region of the eyeball. Complications from surgery can include cataract formation, scarring, and potentially vision-threatening complications such as over-filtration, hypotony, and infection.¹⁰ The 5-year cataract rate was greater in those treated with surgery (19%) than medication 6.5%.¹¹ AAO guidelines state that laser trabeculoplasty may be used for initial and adjuvant treatment of glaucoma, which is supported by evidence from >25 RCTs that demonstrate safety and successful decrease in IOP lasting for up to 3 years.⁹ UpToDate states for most patients pharmacological or laser therapy is first-line treatment for OAG, to avoid increased risk of complications from surgical therapy.⁹ Novel or emerging surgical techniques for the treatment of OAG show some promise as an alternative treatment to reduce IOP for OAG; however, it is not yet possible to conclude whether these novel procedures are superior, equal to or inferior to surgery such as trabeculectomy, or to one another.¹²

The AAO Preferred Practice Guidelines states “a reasonable initial treatment goal in a POAG patient is to reduce IOP 20% to 30% below baseline and to adjust up or down as indicated by disease course and severity”.⁶

IOP and Cataract Surgery

The effect of cataract surgery on IOP in patients with OAG has been a subject of debate. Studies have found that there is a small decrease in IOP after phacoemulsification for cataract removal in patients without glaucoma, glaucoma suspects and glaucoma patients. This modest effect seems to decrease after 2 years, but is sustained until 5 years after the cataract surgery. A significant IOP reduction has been found in patients with pseudoexfoliation glaucoma (PEXG). The AAO conducted a meta-analysis¹³ that concluded a 13% average decrease in IOP after phacoemulsification while other studies report ranges from -7% to -22% reductions and the range of medication usage after cataract surgery for glaucoma was widely variable.¹⁴ Overall, there seems to be a modest reduction in IOP after cataract surgery by phacoemulsification; however, the results are unpredictable and not always sustainable. Patients with higher baseline IOP’s seem to have the greatest effect. However, cataract removal does not seem to be a sufficient treatment for POAG patients who have a surgical indication for IOP reduction. This has led to the frequent practice of performance of MIGS at the time of cataract removal.

The AAO published a systematic review (SR) in 2015 on the effect of phacoemulsification (cataract removal) on IOP in glaucoma patients. Thirty-two studies met inclusion criteria assigned level of evidence based on grading adopted by AAO. The studies indicated improvement in IOP for all 3 types of glaucoma reviewed: open-angle glaucoma (POAG; including normal-tension glaucoma), PEXG, or primary angle-closure glaucoma (PACG). For POAG, 9 studies (total, 461 patients; follow-up, 17 months) showed that phacoemulsification reduced IOP by 13% and glaucoma medications by 12%. For PEXG, 5 studies (total, 132 patients; follow-up, 34 months) showed phacoemulsification reduced IOP by 20% and glaucoma medications by 35%. For chronic PACG, 12 studies (total, 495 patients; follow-up, 16 months) showed phacoemulsification reduced IOP by 30% and glaucoma medications by 58%. Patients with acute PACG (4 studies; total, 119 patients; follow-up, 24 months) had a 71% reduction from presenting IOP and rarely required long-term glaucoma medications when phacoemulsification was performed soon after medical reduction of IOP. Trabeculectomy was uncommon after cataract removal in this study population.¹³

A 2017 SR and meta-analysis was conducted to evaluate 32 studies for the effect of phacoemulsification on IOP and topical medication use for glaucoma patients. A 12%, 14%, 15%, and 9% reduction in IOP from baseline occurred 6, 12, 24, and 36 months after phacoemulsification and medication use was slightly decreased at all endpoints. The benefits of cataract removal on decreasing IOP lasted at least 36 months but gradually lost effect after the first 24 months.¹⁵ This study is limited by high heterogeneity, few high quality RCT available, small sample sizes and risk of bias.

A 2019 retrospective analysis of 70 eyes with POAG controlled medically who underwent cataract surgery by phacoemulsification were included. One year after phacoemulsification, IOP decreased by a mean 1.15±3 mmHg (6.8±18.1%) (p=0.01) and the number of glaucoma medications remained unchanged with a difference of − 0.1±0.43 (p=0.09). Higher preoperative IOP was associated with a greater IOP decrease after 1 year of follow-up (p<0.001). A spike in IOP was common in the first week following the surgery. The study found that the drop in IOP from cataract surgery alone was modest and did not significantly impact the amount of glaucoma medication used.¹⁴ This study was limited by the retrospective design, small sample size, lack of randomization and control groups.

The HORIZON Study¹⁶ and an analysis from the Fight Glaucoma Blindness (FGB) international registry¹⁷ which followed patients who had cataract surgery with either an iStent inject^® or Hydrus^® microstent for 24 months demonstrated sustained IOP reduction with good safety profile. Five-year data from this study (n=369) reported the Hydrus^® microstent group had IOP of 18 mmHg or less without medications than the cataract surgery group (49.5% vs. 33.8%; P=0.003), as well as a greater likelihood of IOP reduction of 20% or more without medications.¹⁸ The SMEs stated that the placement of a stent at the time of cataract surgery and patients at risk for glaucoma due to elevated IOP has become standard of care due to the potential reduction in vision loss and blindness secondary to glaucoma.

Minimally Invasive Stent Procedures

The Food and Drug Administration (FDA) approved/cleared micro-invasive surgical stents available at the time of this LCD revision includes the iStent^® Trabecular Micro-Bypass Stent (Month, 2011), the CyPass^® Micro-Stent System (July, 2016), the XEN^® Glaucoma Treatment System (November, 2016), the Hydrus^® Microstent (August, 2018), the iStent^® inject (June, 2018), iStent inject^® W (July, 2020), iStent Infinite^® (August, 2022). The iStent^® is a small (1 mm x 0.5 mm) L-shaped titanium device that is inserted into Schlemm’s canal to augment the natural outflow system. The iStent^® inject system comprises 2 heparin-coated titanium stents (each having 0.23 mm diameter x 0.36 mm height, 0.08 mm central lumen diameter, and (4) 0.05 mm side outlets to allow for multidirectional outflow), both inserted into Schlemm’s canal using a pre-loaded auto-injection trocar. Hydrus^® is an 8 mm nitinol, crescent-shaped microstent with alternating spines for support and windows to provide outflow, also placed into Schlemm’s canal. The iStent inject^® W Trabecular Micro-Bypass System Model G2-W stents include a wider proximal end in the anterior chamber of 360 µm, rather than 230 µm for Model G2-M-IS. The iStent Infinite^® is a sterile, single-use injector system preloaded with 3 micro-scale wide-flange stents (each having 0.36 mm diameter x 0.36 mm height, 0.08 mm central inlet and outlet lumen diameter, and (4) 0.05 mm side outlets to allow for multidirectional outflow), inserted into Schlemm’s canal. CyPass^® is a 6.35 mm long fenestrated microstent made of biocompatible polyimide inserted into the supraciliary space, thus using an alternative outflow system. The XEN^®45 is a 6 mm long porcine-derived gelatin stent inserted into the subconjunctival space, bypassing the natural outflow system.

iStent^®, iStent^® inject, iStent inject^® W. Hydrus^® and CyPass^® were FDA approved (CyPass^® was voluntarily recalled for safety concerns September 2018) for use in combination with cataract surgery to reduce IOP in adults with mild or moderate OAG and a cataract that are currently being treated with medication to reduce IOP. The iStent Infinite^® is indicated for use in adult patients with POAG in whom previous medical and surgical treatment has failed. XEN^®45 was granted FDA clearance for the management of refractory glaucoma, including cases where previous surgical treatment has failed, cases of POAG, and pseudoexfoliative or pigmentary glaucoma with open angles that are unresponsive to MTMT.

Schlemm’s Canal Scaffold (Hydrus^®, Ivantis, Irvine, CA, USA)

The HORIZON study was a prospective multicenter, single-masked, RCT that enrolled 369 eyes with mild-moderate open angle glaucoma (OAG) and IOP between 22-34 mmHg after medication wash-out. Using 2:1 randomization 369 eyes were treated with Hydrus^® microstent and cataract surgery and 187 received cataract surgery alone. In 78% the IOP was ≤21 mmHg without medication for the treatment group and 48% for the control group (p<0.001). They reported a medication reduction at baseline 1.7±0.9 to 0.7±0.9 (p<0.001).¹⁶

A 2020 Cochrane review on ab interno trabecular bypass surgery with Hydrus^® microstent for OAG reported on 3 studies (all sponsored by manufacturer Ivantis Inc. who makes the Hydrus^® stent) with 808 patients from the USA and other countries with mild-moderate OAG who had Hydrus^® stent placement at the time of cataract surgery reduced unmedicated IOP (after washout) by 2 mmHg more compared to cataract surgery alone (mean difference (MD) -2.00, 95% CI -2.69 to -1.31; 2 studies, 619 participants; I²=0%; moderate-certainty evidence). Their review concludes with moderate-certainty evidence that the Hydrus^® microstent with cataract surgery compared to cataract surgery alone can decrease IOP lowering medication.¹⁹ Ahmed et al. reported on 152 eyes with OAG were randomized to MIGS with Hydrus^® microstent or 2 iStents^® and followed for 12 months. At 12 months, the Hydrus^® had a greater rate of complete surgical success (p<0.001) and reduced medication use (difference -0.6 medications, P=0.004). More Hydrus^® subjects were medication free at 12 months (difference 22.6% P=0.0057) leading to study conclusion that Hydrus^® related to higher surgical success rates than iStent^®.²⁰

Trabecular Microbypass Stent (iStent^®, Glaukos, Laguna Hills, CA, USA)

A prospective, randomized, open label, controlled, multi-centered study reported outcomes from 240 eyes with mild to moderate OAG with IOP ≤ 24 mmHg despite medical management. The treatment group (n=111) had iStent^® placement at the time of cataract surgery and the control group (n=122) had cataract surgery alone (p<0.001). They reported 72% of the iStent^® group and 50% of the control group had IOP ≤21 mmHg without medication in 1 year (p=0.003).²²

Another RCT enrolled subjects with mild-moderate OAG and unmedicated IOP between 22-36 mmHg received cataract surgery with iStent^® (treatment) or cataract surgery alone (control). At 2 years, and the authors reported that 61% in the treatment group (n=116) and 50% in the control group (n=123) achieved IOP reduction ≤21 mmHg without medication (p=0.036) and 53% of the treatment group and 44% of the control group had >20% reduction in IOP (p=0.09).²³

A prospective randomized study reported on 119 subjects over a 42-month with POAG, IOP 18-30 mmHg in subjects with uncontrolled, mild/moderate glaucoma using 1-3 glaucoma medications or range of IOP from 22-38 mmHg without medication were randomized to 1 (n=38), 2 (n=41), or 3 (n=40) iStent^® trabecular micro-bypass stents in a standalone procedure. Preoperative mean medicated IOP was 19.8±1.3 mmHg on 1.71 medications in 1-stent eyes, 20.1±1.6 mmHg on 1.76 medications in 2-stent eyes, and 20.4±1.8 mmHg on 1.53 medications in 3-stent eyes. At 42-months medicated IOP was 15.0±2.8, 15.7±1.0 and 14.8±1.3 mmHg in the 3 groups and IOP reduction ≥20% without medication was achieved in 89%, 90%, and 92% of 1-, 2-, and 3-stent eyes, respectively, at Month 12; and in 61%, 91%, and 91% of eyes, respectively, at Month 42. The authors conclude that multiple iStent^® device(s) produced safe, clinically meaningful IOP and medication reductions through 42 months postoperatively and there was greater and more sustained reduction with multiple stents.²⁴ Limitations include lack of blinding, missing data points (baseline and post-operative IOP measurements), lack of standardized cataract grading system or threshold for completion of cataract surgery, potential confounding, and risk of bias.

A prospective, RCT evaluated the safety and efficacy of 2 trabecular micro bypass stents (iStents^®) vs prostaglandin as initial standalone treatment for newly diagnosed, treatment naive POAG for 5 years. Study subjects (n=101) were randomized to either 2 eye stents or once daily topical travoprost (1:1) ratio. Five-year mean diurnal IOP (MDIOP) was 16.5±1.2 mmHg in stent eyes (35.3% reduced vs 25.5±2.5 mmHg preoperatively; P<0.0001) and 16.3±1.9 mmHg in travoprost eyes (35.1% reduced vs 25.1±4.6 mmHg preoperatively; P<0.0001). The authors concluded that the stents were comparably favorable to the topical prostaglandin.²⁵ Limitations include lack of standardized cataract grading, potential risk of bias, and generalizability.

A retrospective cohort of 82 mild-moderate glaucomatous eyes were followed for 24 months after iStent^® or iStent^® inject and reported decrease in IOP from 9.8% reduction for iStent^®, (16.4 mmHg to 14.8 mmHg) and 26.0% reduction, (17.7 mmHg to 13.1 mmHg) for iStent^® inject with medication use decrease without complications.²⁶

A retrospective analysis of 315 eyes with mild to moderate glaucoma were divided into 2 groups with baseline IOP 18.2 (0.3) mmHg in the Phaco-Kahook Dual Blade (KDB) group (n=134) and 16.7 (0.3) mmHg in the Phaco-iStent^® group (n=96) (p=0.001). The authors report reduction in IOP and medication use for both groups and report a statistically significant greater reduction in the Phaco-KDB group out to 12 months [- 5.0 (0.3) mmHg vs - 2.3 (0.4) mmHg, p\0.001]. At Month 12 IOP reductions ≥20% were achieved by 64.2% and 41.6% (p<0.001) in the Phaco-KDB and Phaco-iStent^® groups, respectively.²⁷

A 2021 Cochrane SR and network meta-analysis explores the outcomes from 6 to 60 months of MIGS. The report concluded that in comparison with cataract surgery alone, the addition of trabecular bypass surgery (Hydrus^® or iStent^®) safely improved glaucoma control without use of medication and the Hydrus^® also conferred approximately 2.0 mmHg IOP lowering (95% CI, −2.7 to −1.3 mmHg; estimate based on 2 trials). Available data was insufficient to compare other MIGS techniques.²⁸ AAO rated this as moderate quality, strong recommendation.⁶ Very low-certainty evidence suggested that adding iStent^® to cataract extraction lowered IOP an additional 5.0 mmHg (95% CI, −7.5 to −2.5 mmHg; estimate based on 3 trials) at short-term follow-up, but this outcome was not statistically significant at medium-term follow-up and was rated as insufficient quality evidence by AAO with recommendation to leave to the discretion of the treating ophthalmologist.⁶

A retrospective study reports 10-year outcomes on 63 eyes in which iStent^® trabecular microbypass stent with cataract surgery was performed for POAG, PEXG or ocular hypertension. Mean IOP was reduced by 12.9-19.0% (p<0.005) from a baseline mean IOP of 18.6 ±4.4 mmHg and medication burden reduced by 37.8-51.4% (p<0.006) from baseline of 1.83±1.03 mean medications. At 10 years postoperatively, 77.8% of eyes had IOP ≤ 18 mmHg and 47.6% had IOP ≤ 15 mmHg (vs. 50.8% and 25.4% preoperatively, respectively; p = 0.016) and one-third were medication-free. Over the 10 years, 9 eyes required secondary glaucoma surgeries. Four had additional eye stent implementation and no filtering surgery such as trabeculectomy or tube shunt were completed. There was no sight threatening or device related adverse events (AEs) reported. This report is the longest-term data to date for any glaucoma procedure.²⁹

Studies that compare iStent^® to excisional angle procedures

A study compares iStent^® to trabeculectomy. A retrospective review compared 70 patients who had multiple (2–3) trabecular micro-bypass stents (iStent^® inject ± iStent^®) (multi-stent group) to 40 who had trabeculectomy + Mitomycin C (Trab group) for moderate to severe OAG and followed for at least 3 months. They reported treatment success as ≥20% IOP reduction was 62.9% vs 30.0% in multi-Stent vs Trab eyes, respectively (p=0.001) with 3-stents achieving best results.³⁰ Lack of a control group, risk of selection bias and small sample size limit these findings.

A RCT was conducted to compare the reduction in IOP in eyes undergoing excision goniotomy with KDB to iStent^® microbypass implant system at the time of phacoemulsification with eyes with mild to moderate OAG.³¹ Baseline IOP were between 14-28 mmHg. The patients were randomized using sequential envelope system to undergo KDB-Phaco or iStent^®-Phaco and if both eyes were enrolled, they had the alternative treatment of second eye. The mean percentage IOP reductions from 1 month on ranged from 14.6% to 17.2% in the KDB-Phaco group and from 5.7% to 14.1% in the iStent^®-Phaco group; differences were not significant at any time point after 1 day. Both groups achieved target IOP of 18 mmHg or less at all postoperative time points, including, among 155 eyes seen at 12 months, 61 (77.2%) of 79 eyes in the KDB-Phaco group and 53 (67.9%) of 78 eyes in the iStent^®-Phaco group (p=0.19). At 12 months, the proportion of eyes achieving this primary outcome of 20% or greater reduction in IOP or 1 or more medication reduction was (74/79 [93.7%] in the KDB-Phaco group vs 65/78 [83.3%] in the iStent^® group (p=0.04) which did not reach a statistically significant difference. The authors conclude both procedures are effective for lowering IOP and medications. A second similar report compared patients undergoing phacoemulsification for OAG with 48 receiving iStent^® and 29 undergoing KDB procedure and followed for 12 months. Authors report the overall percentage of IOP reduction was 14.3% in the iStent^® group and 12.6% in the KDB group at 12 months of follow-up.³¹ Limitations to both studies include small sample size and short-term follow up.

A retrospective study compared patients who underwent goniotomy with KDB (n=32) to iStent^® inject implant (n=30), with or without cataract surgery. They report a reduction in IOP in both groups at 24 months except iStent^® inject alone (n=14).³³

A study compares iStent^® to Trabectome^®. A retrospective comparison study reported on 78 eyes matched by pairs with baseline IOP of 18.3±5.1 mmHg compared trabecular bypass stenting (IS2, iStent^® inject) to ab interno trabeculectomy (Trabectome^®). They report reduction in IOP to 13-14 mmHg range in both groups, but the stent group had a rise after 6 months to baseline or higher, so Trabectome^® had sustained results.³⁴ These results would need to be confirmed in a controlled study to confirm the findings.

A small retrospective study of 27 eyes with previous aqueous stents (iStent^®/iStent^® inject) evaluated results after canaloplasty and trabeculotomy using the OMNI^® surgical system and reported improved IOP control,³⁵ but the sample size was too small for significant as well as lack of controls and short-term follow-up.

Glaukos iAccess^® Trabecular Trephine is another device for cutting of the TM. A retrospective case series compared outcomes with phaco/iStent^® alone (n=63) vs phaco/iStent^®/iAccess^® (n=93) and found that adding TM trephination with the iAccess^® device resulted in significantly greater postoperative IOP reduction (p=0.043); medication reductions were similar.³⁶ A control group would be necessary to understand if this finding is reproducible, short-term data (3 months) and retrospective design limit the findings.

The KDB Goniotomy Study Group conducted a retrospective analysis of patients who had cataract surgery plus KDB excisional goniotomy (n=237) or cataract surgery plus iStent^® trabecular micro-bypass (n=198) in eyes with mild to moderate OAG and visually significant cataract whose IOP was controlled with 1 or more topical IOP-lowering medications. The primary end point was reduction of IOP ≥20% from baseline or reduction of IOP-lowering medications from baseline. Mean IOP in the phaco-goniotomy with KDB group decreased from 17.9±4.4 mmHg at baseline to 13.6±2.7 mmHg at Month 6 (P<0.001), with mean medication use decreasing from 1.7±0.9 to 0.6±1.0 (P<0.001). In the phaco-iStent^® group, mean IOP decreased from 16.7±4.4 mmHg to 13.9±2.7 mmHg (P<0.001), with mean IOP-lowering medication use decreasing from 1.9±0.9 to 1.0±1.0 (P<0.001). Mean IOP reduction from baseline was significantly greater in the phaco-goniotomy with KDB group at Month 6 (phaco-goniotomy with KDB −4.2 mmHg [23.7%] vs phaco-iStent^® −2.7 mmHg [16.4%]; P<0.001) as well as a reduction in IOP-lowering medication. The most common AE was an IOP spike occurring in 12.6% of phaco-iStent^® eyes and 6.3% of phaco-goniotomy with KDB eyes (P=0.024). The authors concluded that goniotomy with the KDB combined with cataract surgery significantly lowers both IOP and the need for IOP-lowering medications compared with cataract extraction with iStent^® implantation in glaucomatous eyes through 6 months of postoperative follow-up.³⁷ Limitations include retrospective design with lack of randomization or controls, baseline IOPs were different between the 2 groups, high-risk of bias, single measure of IOP, and the population with mild-moderate glaucoma with mean of 17.5 mmHg at baseline.

A Japanese retrospective review of 84 eyes who had KDB and 44 eyes with iStent^® placed at time of phacoemulsification reported surgical success defined as ≥20% reduction from pre-operative IOP. The authors reported 60.2% in KDB group and 46.4% in iStent^® group achieved this level (p=0.019).³⁷ Another retrospective report included 58 eyes with iStent^®-Phaco and 44 KDB-Phaco and reported lower rates of IOP lowering for KDB group (43.2% vs 17.2%, p=0.004).³⁹ Another reported on 45 eyes that underwent Phaco with KDB or microhook ab interno trabeculectomy and compared to 21 eyes that underwent cataract surgery alone. They reported more higher-order aberrations in the Phaco/microhook group.⁴⁰ These findings would need to be confirmed in a controlled study with a larger sample size.

XEN^®45 Gel Stent Implant (Aquesys, Aliso Viejo, CA, USA/Allergan, Irvine, CA, USA)

The XEN^® Gel Stent was designed to function like trabeculectomy to enable drainage from the anterior chamber to the suprascleral space. It is subject to the same complications as trabeculectomy with risk of blood formation and need for postoperative procedures to reestablish flow. Up to 62% of patients have been reported to require needle and procedures to reestablish aqueous outflow.^41,42

A prospective multi-centered, single-arm, open label study followed 65 eyes with OAG and IOP between 20-35 mmHg or failed prior filtering/cilioablative procedure who received the XEN^®45 Gel Stent. They reported 75.4% achieved IOP ≤21 mmHg without medication for 1 year. Mean IOP change from baseline was L9.1 mmHg (95% confidence interval [CI]: L10.7, L7.5) (n=52; observed data) at 12 months; however, this does not include 13 of the original patients due to missing data or need for secondary surgical intervention. They report mean medication reduction of 3.5 (baseline) to 1.7 (post-treatment).⁴³

A prospective, interventional study enrolled 110 eyes of patients with POAG or PEXG with uncontrolled IOP despite medical management. Subjects underwent cataract removal with placement of XEN^® stent or XEN^® stent placement alone. Reduction in IOP from baseline of 19.8±5.8 mmHg (POAG group) and 19.8±8.3 mmHg (PEXG) group to 14.5±3.6 mmHg and 14.2±3.68 mmHg, respectively at 2 years post-surgery. Needling was required in 42.8% (POAG) and 43.2% (PEXG) by 24 months.⁴⁴

A retrospective, single center study of 68 eyes in which XEN^® gel stent was placed for OAG alone or in combination with phacoemulsification were followed for 12 months. The authors report a reduction in IOP from 22.3 (21.0-23.5) mmHg at baseline to 15.3 (14.3–16.3) mmHg, p<0.0001. At month 12, 53 (72.6%) eyes were classified as success defined as a reduction in antiglaucoma medications.⁴⁵ Limitations include retrospective study design with small sample size and lack of controls.

A retrospective cohort study of 92 eyes that were implanted with gelatin stents (XEN^®45 Gel Stent) with or without cataract surgery were followed for 12 months. The investigators reported 48% achieved ≥ 20% reduction in IOP or decrease in medication. The complication rate was 13% with no serious complications.⁴⁶ This study is limited perspective design, small sample size, and single surgeon.

A retrospective review of 212 eyes that were implanted with gelatin stents (XEN^®45 Gel Stent) with or without cataract surgery were followed for 36 months. Mean IOP and medication decreased from 20.7 mmHg and 2.5 at baseline (n=163 primary/first implanted eyes) to 13.9 mmHg with or without cataract surgery.⁴⁷ This study represented multiple sites; however, was limited by retrospective study design and lack of control group. Another retrospective study compared 93 eyes which underwent Phaco-KDB and 23 KDB alone by a single surgeon and followed for 18 months. They conclude that KDB is effective whether combined with cataract surgery or standalone surgery with reduction of IOP into mid-teens.⁴⁸

A SR on the XEN^® Gel Stent concludes XEN^® Gel Stent can reduce post-op IOP from mean baseline of 15.3-36.1 mmHg to a mean of 14 mmHg and reduce glaucoma medications to 1 or less based on 59 studies (41 retrospective and 18 prospective) with 6 studies extending to 36 months. The weighted mean pre-operative IOP was 22.0 mmHg and attrition analysis reported a post-operative mean IOP of around 14-15 mmHg regardless of pre-operative IOP so those with higher baseline IOP had greater effect from the stent. The authors acknowledge the wide variety and inclusion and exclusion criteria of the numerous studies, differing methodologies, and populations as well as the inclusion of non-randomized data places these findings at risk of confounding and limits the ability to draw definitive conclusions. They were unable to sufficiently review data on baseline factors to determine if this influenced outcome due to limitations in data reporting across studies. They did not report a difference in outcomes if the surgery was performed with cataract surgery or standalone stents. In comparing POAG to PEXG, data was limited but found encouraging outcomes in the setting of uveitic glaucoma. The authors reviewed the rate of needling after gel stent surgery which ranged from 2.5 to 67% and it is unclear how often this should be repeated and the impact it has. The report was funded by Allergen.⁴⁹

Studies that compared Gel Stents to surgical MIGS

A retrospective clinical cohort study compared 68 patients with glaucoma with uncontrolled IOP on MTMT who underwent trabeculectomy (n=34) to XEN^® gel implant (n=34) for 36 months. The report said the trabeculectomy group has greater reduction in IOP while the XEN^® gel implant group had less complications. They conclude if target IOP is low teens trabeculectomy has better likelihood of success.⁵⁰

A retrospective, cohort study compared 142 patients with POAG or PEXG with uncontrolled IOP who underwent XEN^®45 with Mitomycin C (n=58 eyes of 51 patients) to trabeculectomy with Mitomycin C (n=84 eyes of 73 patients). The study showed, compared to XEN^®, the trabeculectomy resulted in lower IOP (mean reduction of 50%, 95% CI 41-60%, p<0.001; vs 35%, 95% CI 23-48, p<0.001) in the XEN^® group. A decreased need for IOP-lowering medications was different at Month 12, but not Month 24 or 36. Complete surgical success (56.8% (trabeculectomy) vs 27.3% (XEN^®) with an adjusted odds ratio of 4.36; 1.25-15.18, p=0.021) defined as IOP <18 mmHg and >20% IOP reduction without IOP lowering medications, at 36 months.⁵¹

A prospective, randomized, multi-centered, non-inferiority study randomized patients with OAG and IOP ranges from 15-44 mmHg on IOP lowering drops at 2:1 ratio to gel stent implant (n=77) or trabeculectomy (n=38). At 12 months the gel stent was statistically non inferior to trabeculectomy with 62.1% (stent) and 68.2% (trabeculectomy) achieving the primary endpoint of ≥20% IOP reduction from baseline (p=0.487) with a statistically significant reduction in medication use (p<0.001). Trabeculectomy had a great IOP reduction with change of 2.8 mmHg (p=0.24) and gel stent resulted in fewer post-operative interventions and faster recovery. The most common AEs were reduced visual acuity at any time (gel stent, 38.9%; trabeculectomy, 54.5%) and hypotony (IOP<6 mmHg at any time) (gel stent, 23.2%; trabeculectomy, 50.0 %). Of the study population 33/144 had IOP <18 mmHg while the result had baseline IOP ≥18 mmHg and in the 33 who had gel stents that had reduction in IOP to mid-14 mmHg range.⁵² Strength of the study is the randomized design and limitations include small sample size, short-term follow-up and potential risk of bias.

A retrospective, single-centered, case series compared Xen^® Gel Microstent implantation and KDB goniotomy in 75 eyes. At 24 months, the mean IOP of the XEN^® implant was 14.7±.2 mmHg (32.7% reduction from baseline, p=0.018) and KDB was 16.7±3.2 mmHg (40.4% reduction from baseline, p=0.049). The authors conclude both devices can reduce IOP for moderate to severe glaucoma and stated a higher need for postoperative interventions in the microstent group.⁵³ Limitations of the study include retrospect design, potential risk for bias, small sample size and lack of a control group.

A retrospective cohort study of consecutive patients with OAG received a XEN^® gel stent implant with Mitomycin C (n=82) or trabeculectomy with Mitomycin C (n=89) and followed for 1 year. The complete success proportion was 65.5% (95%-CI: 55.6–75.9%) in the trabeculectomy group, and 58.5% (95%-CI: 47.6–69.4%) in the XEN^® group and not statistically different in the analysis model. The secondary outcome measures showed a better reduction in IOP with trabeculectomy compared to XEN^®.⁵⁴ The authors recognize the limitation of the retrospective design and called for randomized controlled studies to further investigate. Another retrospective study of similar design included 57 patients followed for 24 months reported success was 71.4% vs. 73.3% (p=0.850) and complete success was 62.9% vs. 62.2% (p=0.954) for XEN^® and trabeculectomy, respectively.⁵⁵

CyPass^® MicroStent (Alcon, Fort Worth, TX)

The COMPASS study evaluated 505 subjects who had a supraciliary microstenting (CyPass^® MicroStent) for mild to moderate OAG (baseline around 24 mmHg in both groups) in patients undergoing cataract surgery. The treatment arm included 374 subjects who received a stent at the time of cataract surgery while 131 controls had cataract surgery alone. At 2 years, the authors reported that 77% in the treatment group (n=374) and 60% in the control group (n=131) achieved IOP reduction ≤21 mmHg without medication (p=0.001). The report mean 24-month medication use was 67% lower in the treatment group (p<0.001) with 59% of controls and 85% of the treatment group medication free.⁵⁶

Comparative Studies

A 2020 SR/MA included 77 articles including 28 comparative studies and 12 RCTs on the available MIGS procedures. The authors report weighted mean IOP reductions from all analyzed studies were: 15.3% (iStent^®), 29.1% (iStent^® inject), 36.2% (ab interno canaloplasty), 34.4% (Hydrus^®), 36.5% (gonioscopically assisted transluminal trabeculotomy), 24.0% (Trabectome^®), 25.1% (KDB), 30.2% (CyPass^®), 38.8% (XEN^®), and 50.0% (Preserflo™).⁵⁸ This review provides an excellent historic review of the MIGS procedures and goals of optimal surgical outcomes. They acknowledge that MIGS procedures bring favorable safety profiles and quick postoperative recoveries with a decrease in IOP reduction that is more modest than traditional filtrating surgery. While they have provided clinicians with a wider range of options, there is a lack of evidence-based criteria for procedure selection and expected outcomes. The authors acknowledge the current evidence is limited to heterogeneous nonrandomized studies and uncontrolled retrospective comparisons with few quality RCT and lack of comparative studies calling for the needs for carefully designed RCTs.

A 2017 SR and meta-analysis also aimed to compare studies related to the various MIGS procedures. Limiting their review to studies with at least 1 year follow-up in patients affected by POAG, PEXG or pigmentary glaucoma. Twenty-one case series and 9 RCTs met this inclusion from 3,069 studies. Studies were assessed for risk of bias using the Cochrane Risk of Bias and the ROBINS-I tools. In the RCTs risk of bias include lack of blinding, allocation concealment and attrition bias and in the non-RCT patients’ selection, masking of participants and co-intervention management was cited as risk. Evidence to compare MIGS surgery with medical therapy or other MIGS procedures was lacking. The authors conclude “Although MIGS seem efficient in the reduction of the IOP and glaucoma medication and show good safety profile, this evidence is mainly derived from non-comparative studies and further, good quality RCTs are warranted.”⁵⁹

Stent placement without cataract surgery

Sarkisian et al. conducted a prospective, multi-center, single-arm trial evaluating 72 patients with open angle and inadequate response to MTMT (n=11) or more conventional incisional or cilioablative procedures (n=61) with baseline IOP of 23.4±2.8 mmHg (range permitted was 20-35 mmHg). The iStent Infinite^® Trabecular Micro-Bypass System was placed as standalone surgery. They reported preoperative MDIOP on medication of 23.4±2.8 mmHg and mean reduction (SE) in MDIOP at Month 12 of 5.9(0.6) mmHg [5.5(0.7) mmHg Failed-Surgery subgroup, 8.1(0.9) mmHg MTMT subgroup]. A total of 76.1% of all enrolled patients met the responder endpoint (73.4% Failed-Surgery, 90.9% MTMT), with mean reduction (SE) in MDIOP at Month 12 of 5.9(0.6) mmHg. No intraoperative AEs were reported. Postoperatively, no unanticipated adverse device effects and no serious ocular AEs were reported. Device-related AEs that were considered nonserious (n=13 events in 9 eyes).⁶⁰ Limitations include single imputation method for missing data points (authors note a trial completion rate of 98.6% at 12 months), lost to follow up, 2 major protocol deviations were noted (glaucoma secondary to elevated episcleral venous pressure in 1 patient, and impaired visualization due to arcus senilis, corneal striae, and external marker location-dye during surgery in another patient), short follow up of 12 months, lack of medication washout protocol potentially causing undo risk and risk of bias.

A SR and meta-analysis included 13 studies, 4 RCTs and 9 nonrandomized or single-arm studies with accumulative data for 778 eyes, addressing standalone trabecular micro bypass glaucoma surgery with iStent^® aqueous stent devices in patients with OAG. The authors reported a weighted mean IOP reduction of 31.1% at 6 and 12 months with similar ranged reduction in the studies that reported up to 60-months. They also reported a reduction in medication burden by approximately 1 medication up to a 60-month endpoint.⁶¹ Limitations of this analysis include combining RCTs and perspective case series into the same analysis. Additionally, there were a wide variety of comparators (when comparators were present), variability in the baseline patient characteristics, medication use, type of device used, the number of stents, duration of follow-up, lack of control and randomization in the case series, significant risk of bias creating broad heterogeneity and making the conclusion from this analysis of uncertain reliability. The most valuable input from the analysis was lack of harm noted from the standalone insertion of the device.

In direct comparison of Hydrus^® and iStent^® without cataract extraction, moderate-certainty evidence showed Hydrus^® lowered IOP by 3.1 mmHg (95% CI, 2.0 to 4.2 mmHg; estimate based on 1 trial) more than iStent^® alone.²⁸

Combined MIGS Procedures

A retrospective paper of 271 patients who underwent a combination of MIGs procedures were evaluated. They report further reduction of IOP in patients who had Kahook pEcK, which they describe as a combination procedure including phacoemulsification with endoscopic cyclophotocoagulation (ECP) and KDB. They call for further research.⁶² This study is limited by retrospective design, lack of controls, lack of standardized patient selection, short-term follow-up and low baseline IOPs.

A retrospective investigations 131 eyes who underwent Phaco/Hydrus^® or Phaco/KDB and followed for 36 months. They report both groups experienced significant reduction in IOP and medication burden for 12 months with similar outcomes.⁶³

Intelligent Research in Sight (IRIS^®) Registry Analysis from 2013-2018 conducted a retrospective analysis to understand the trends and patterns on the use of MIGs procedures stating concern with the relative expense and unknown long-term safety and efficacy. Using data from the IRIS^® Registry the annual number of MIGS and standard surgical technique procedures were evaluated, and secondary analysis explored concurrent and subsequent surgeries. They report on 232,537 unique procedures and found a substantial increase in MIGS procedures (7,586 in 2013 to 39,677) with a small decrease in standard glaucoma procedures (16,215 to 13,701). The proportion of eye stent procedures tripled from 14% to 40% and accounted for 43.7% of glaucoma surgeries in the US by 2018. 10.3% of eyes underwent multiple procedures (21,025) with 36.3% of those on the same day (7,638) and 63.7% (13,387) on subsequent days. Cyclophotocoagulation (CPC) and iStent^® placement were the most common concurrent procedures (55.4%). The authors report a significant increase in MIGS use over the 6-year study period. Despite limited evidence of their long-term safety or efficacy and call for trials comparing safety and outcomes of novel MIGs vs traditional surgical treatments for glaucoma.⁶⁴

A retrospective study compared the outcomes of phacoemulsification combined with Hydrus^® microstent implantation alone (n=42) or in combination with canaloplasty using the OMNI^® Surgical System (n=32) for mild to moderate POAG. The authors report a reduction in mean IOP at 6 months from 14.1±3.5 mmHG (13% reduction) after microstent alone and 13.6±3.1 mmHG (17% reduction) after the canaloplasty-microstent procedure. Both groups experienced a reduction in medication use with a greater reduction or likelihood to discontinue medication in the canaloplasty-microstent group. No secondary surgical interventions occurred in either group. Limitations include the retrospective design and small sample size. It is not sufficiently designed to determine if the improvement is due to the combined procedure or other factors. The sample size is not sufficient to determine statistical significance. There is not a sufficient number of patients or duration of follow-up to ensure safety of this combined procedure over time.⁶⁵

A retrospective report on TM-bypass receiving cataract extraction with iStent^® (n=100) or cataract extraction with TM-bypass and ab interno canaloplasty with VISCO360 (n=86) for POAG. Primary endpoints measured were reduction in IOP ≥20% at 6 months and IOP <18 mmHg on same or fewer medications, mean medication reduction and proportion medication independent. The authors report primary endpoint was met for 46% who received cataract extraction with TM-bypass and canaloplasty as compared to 35% for cataract extraction and TM-bypass at 6 months. Limitations include retrospective design, risk of selection bias, incomplete data and variability in assessment methodology.⁶⁶ Due to the lack of a control groups, the modest difference between the groups cannot be definitively attributed to the intervention. Safety of this approach is not established due to short-term follow-up and lack of long-term outcome data.

Combined trabecular meshwork bypass and goniotomy

A retrospective consecutive case series including 63 patients with OAG undergoing phacoemulsification iStent^® inject implementation alone (Group A) and 93 patients in combination with iAccess^® goniotomy (Group B) were compared. The authors reported a greater reduction in mean IOP in the group who received cataract + iStent + goniotomy most notably at 3 months. The percent of eyes with IOP ≤ 12 mmHg remained at 32.4% in Group A (p = 1.0) and rose from 21.7% to 60.9% in group B (p = 0.0177). Eyes with IOP ≤ 15 mmHg rose from 52.9% to 76.5% in group A (p = 0.0963) and from 43.5% to 91.3% in group B (p = 0.0034). While there are 2 groups being compared, they are not randomized; therefore, selection bias is a risk which is particularly concerning given the notable differences in the mean baseline IOP between the groups (14.9 ± 3.2 mmHg vs 16.0 ± 4.2 mmHg). Incomplete data including patient follow-up, treatment and adherence, lack of medication washout and other factors contribute to the challenges in reliability of these results. Short-term follow-up (3 months) is not sufficient and long-term data outcomes are necessary to determine safety and effectiveness of the combined procedures.³⁶

Health Care Disparities

Glaucoma is most prevalent in the elderly population with approximately 130,000 cases of blindness due to glaucoma in the US. African Americans and Latinos are disproportionately affected. There is also a higher rate of blindness in the African American population of 19% compared to 3% for Caucasians. The risk in Latinos was nearly 5% and increases with age. Studies have not been conclusive as to why this disproportionate representation is present and while some studies have suggested higher IOP in the African American populations others have not found this. Outreach and education for appropriate screening and treatment for the African American and Latinos has been proposed as a potential solution to help reduce the disease burden in these populations.⁶⁷ The IRIS^® Registry found notable demographic differences in surgical procedures performed with Caucasian patients disproportionately more likely to undergo an aqueous stent procedure as compared to younger and African American patients who were more likely to undergo glaucoma drainage device placement, goniotomy and trabeculectomy.⁶⁴ Additional investigation to better understand the etiology is necessary.

Despite this known prevalence, these populations have been underrepresented in current research. A SR and meta-analysis reviewed 105 clinical trials on glaucoma and found 70.7% of participants were Caucasian, 16.8% African American, 3.4% Latino and 9.1% of other races including Asian, native Hawaiian or Pacific Islander. The author concludes that despite a higher prevalence of the disease in the African American population they had a lower participation in clinical trials.⁶⁸

Societal Guidance

The American Academy of Ophthalmology (AAO)

AAO Technology Assessment on Aqueous Shunts in Glaucoma concludes, based on Level I evidence, aqueous shunts seem to have benefits, such as IOP control and duration of benefit, and are comparable to trabeculectomy in the management of complex glaucoma. Too few high-quality direct comparisons of the various available shunts have been published to assess relative efficacy or complications of specific devices and additional comparative studies are encouraged.⁶⁹

The AAO Technology Assessment of Novel Glaucoma Procedures reviewed 23 relevant publications on novel or emerging surgical techniques for the treatment of OAG. They conclude that these devices show some promise as an alternative treatment to reduce IOP for OAG; however, it is not yet possible to conclude whether these novel procedures are superior, equal to or inferior to surgery such as trabeculectomy or to one another. Additional research is needed.¹²

The 2023 AAO Summary Benchmarks for PPP Guidelines whose recommendations are defined by Grading of Recommendation Assessment, Development and Evaluation (GRADE) concludes⁹:

• Target IOP is an estimate and must be individualized and/or adjusted during the disease course.
• The initial target pressure is set at least 25% lower than pretreatment IOP.
• IOP can be lowered by medical treatment, laser therapy or incisional surgery (alone or in combination).
• Medical therapy presently is the most common initial intervention to lower IOP.
• If progression occurs at the target pressure, undetected IOP fluctuations and adherence to the therapeutic regimen and recommendations for therapeutic alternatives should be discussed before adjusting target IOP downwards.

AAO’S Glaucoma PPP states that while several other glaucoma surgeries exist as alternatives to trabeculectomy or aqueous shunt implantation, the precise role of these procedures continues to evolve. The authors stated that “modest IOP reduction has been reported following MIGS, and postoperative pressures are typically in the middle to upper teens. Although less effective in lowering IOP than trabeculectomy and aqueous shunt surgery, MIGS appears to have a more favorable safety profile in the short term.” They acknowledge lack of evidence for several of the MIGS techniques.⁶

American Glaucoma Society (AGS)⁵

An AGS position paper states that many patients struggle with eye drops and adherence can be problematic. Traditional glaucoma surgeries are typically reserved for patients with progressive disease who are at higher risk for severe vision loss and have a higher complication rate. MIGS procedures are emerging procedures that enhance physiological outflow pathways of the eye to reduce IOP with less complications. They state they are well suited for patients with ocular hypertension who are at elevated risk for experiencing vision loss due to uncontrolled IOP or with early-stage glaucoma who cannot tolerate or afford medication. Additionally, patients with moderate to severe stage glaucoma whose ocular or medical comorbidities make them suboptimal candidates for traditional glaucoma surgery may benefit. They explained that MIGS procedures require a high level of skill because they are working in sensitive and small spaces in the eye and require appropriate training. They also state that preoperative counseling should include the lack of long-term outcomes for many MIGS procedures and unanticipated risks associated with these surgeries. The paper also provides suggestions for clinical trial design for future MIGS trials and FDA approval pathways.

National Institute for Health and Care Excellence (NICE)

An interventional procedure guidance published by NICE concluded current evidence demonstrates that trabecular stent bypass microsurgery for OAG is safe and effective. They state evidence is adequate in quality and quantity. They also recommend it only be performed by clinicians with specific training in the procedure.⁷⁰ They state canaloplasty for OAG shows no major safety concerns but evidence for efficacy is limited in quality and quantity especially long-term outcomes and should be used only in the setting of research.⁷¹

This A/B MAC considers 1 trabecular aqueous stent (iStent^®, iStent^® inject, iStent inject^® W, or Hydrus^® as of 8/2023) device per eye medically reasonable and necessary for the treatment of adults with mild or moderate OAG and a cataract when the individual is currently being treated with an ocular hypotensive medication and the procedure is being performed in conjunction with cataract surgery. In that setting these reduce IOP, decreased dependence on glaucoma medications, and an excellent safety profile. However, their role within the glaucoma treatment algorithm continues to be clarified and differs from the role of more invasive, external filtration glaucoma surgeries such as trabeculectomy or external aqueous drainage implants. Therefore, other indications are considered not reasonable and necessary currently. One study²⁴ supports the role of additional stents providing further reduction in IOP; however, this is limited data; therefore, the number of stents allowed will be consistent with the stents contained within the device. Multiple stents (so-called “dosing”), regardless of method is not supported by sufficient evidence.

The iStent Infinite^® device received 510(k) clearance with an indication for use to reduce the IOP of the eye for adult patients with POAG and is considered reasonable and necessary to be performed in conjunction with cataract surgery or as a standalone procedure in whom previous medical and surgical treatment has failed. Given the challenges of treating this patient population and the positive outcome seen in the RCT⁷², this A/B MAC will consider 1 device per eye reasonable and medically necessary for refractory glaucoma as defined above.

The subconjunctival space stent, the only available at the time of this LCD is the XEN^®45 device, received 510K clearance based on having a similar mechanism (subconjunctival pathway) as “gold standard” filtration procedure (trabeculectomy and tube shunts), demonstrating “substantial equivalence” in the pivotal prospective study of patients with refractory glaucoma.⁴³ Equivalency was further established by a relatively large retrospective cohort study comparing XEN^®45 with trabeculectomy, finding “no detectable difference in risk of failure and safety profiles.”⁷² The AGS, the New York State Ophthalmological Society (NYSOS), and numerous glaucoma experts wrote the MACs to support XEN^®45 as a minimally invasive method that, “would improve the access of older patients with refractory glaucoma to surgical care with reduction in post-operative discomfort, shorter post-operative disability, equivalent efficacy and safety.” A RCT has demonstrated non-inferiority to trabeculectomy and included IOP range as low as 15 mmHg with similar reduction in IOP to mid-14 mmHg; therefore, the LCD has been modified to allow for progressive damage with pressures under 20 mmHg.⁵² This A/B MAC considers 1 XEN^®45 device per eye medically reasonable and necessary for the management of refractory glaucoma, defined (based on the pivotal trial criteria) as prior failure of filtering/cilioablative procedure or uncontrolled IOP (progressive damage or mean diurnal medicated IOP≥20 mmHg) on MTMT (i.e., ≥4 classes of topical IOP-lowering medications, or fewer in the case of tolerability or efficacy issues.⁵² XEN^®45 insertion must be performed by an ophthalmologist with experience with trabeculectomy and bleb management.

The IRIS^® Registry reported a substantial increase in multiple procedures being performed in the same eye at the same time.⁶⁴ There is a paucity of literature that evaluates the performance of multiple procedures on the same eye on the same day except in combination with phacoemulsification. There are few studies to evaluate the combination of MIGS surgical procedures and stents at the same time of service. Safety and the effectiveness of this approach has not been proven. Therefore, combining multiple procedures on the same eye in the same day is non-covered.

The AAO POAG PPP also suggests glaucoma surgery can also be combined with cataract surgery, such as implantation of aqueous shunts, nonpenetrating glaucoma surgery, MIGS, and endoscopic cyclophotocoagulation.⁶ Per the SMEs, it has become standard to offer IOP reduction at the time of cataract surgery for those with elevated IOP as the benefits outweigh the risk and it is consistent with AAO recommendations. The AAO’s Glaucoma PPP states that while several other incisional glaucoma surgeries exist as alternatives to trabeculectomy or aqueous shunt implantation, the precise role of these procedures in surgical management of glaucoma continues to evolve. Multiple studies including RCTs and SR with meta-analysis have shown the minimally invasive surgical approach with aqueous stents placement has been shown to accomplish reduction in IOP and potentially reduce the risk of vision loss secondary to glaucoma.

Many of the study population have baseline IOP in the high teens (below the threshold of elevated IOP as define by IOP>21 mmHg) and while it is established that patients with POAG can have disease with IOP’s within the normal range and the potential benefit for early intervention the threshold for intervention is not fully established. There is concern that the majority of MIGS procedures are not as effective in lowering eye pressure as traditional trabeculectomy and studies thus far show that the IOP after MIGS procedure typically remains in the low-mid teen range; therefore, may not be appropriate for those with advanced glaucoma or those who need lower eye pressures. Many of the MIGS surgical procedures seem to be aimed at reducing the need for eye drops, which may provide benefit for those who struggle with medication adherence, but the effectiveness as compared to medical management is not established. There is no data to support the role of primary treatment in lieu of medical management. Therefore, these procedures are non-covered as first line options and reserved for those with refractory glaucoma.

MIGS is an emerging area of glaucoma management which may potentially reduce the burden from glaucoma. Future investigations are encouraged to explore long term impact on vision, utilize standard and reproducible selection criteria and measurements of outcomes, include diverse populations, compare outcomes to gold standards and objectively measure long-term impact of the treatments on long-term eye health. We will continue to follow-up on new developments in this field.

The patient's medical record must contain documentation that fully supports the medical necessity for services included within this LCD. (See "Indications and Limitations of Coverage.") This documentation includes but is not limited to, relevant medical history, physical examination, and results of pertinent diagnostic tests or procedures. The medical record and/or test results documenting medical necessity should be maintained and made available on request.

iStent^®, iStent^® inject, and Hydrus^® must be performed in conjunction with cataract surgery on the same date of service and documented in the medical record.

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• MIGS