Micro-Invasive Glaucoma Surgery (MIGS)

Language quoted from Centers for Medicare and Medicaid Services (CMS), National Coverage Determinations (NCDs) and coverage provisions in interpretive manuals is italicized throughout the policy. NCDs and coverage provisions in interpretive manuals are not subject to the LCD Review Process (42 CFR 405.860[b] and 42 CFR 426 [Subpart D]). In addition, an administrative law judge may not review an NCD. See Section 1869(f)(1)(A)(i) of the Social Security Act.

Unless otherwise specified, italicized text represents quotation from one or more of the following CMS sources:

Title XVIII of the Social Security Act (SSA):

Section 1862(a)(1)(A) excludes expenses incurred for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.

Section 1862(a)(1)(D) refers to limitations on items or devices that are investigational or experimental.

Section 1833(e) prohibits Medicare payment for any claim which lacks the necessary information to process the claim.

CMS Publications:

CMS Publication 100-02, Medicare Benefit Policy Manual, Chapter 14,

10 Coverage of Medical Devices

CMS Publication 100-04, Medicare Claims Processing Manual, Chapter 23,

30 Services paid under the Medicare Physicians Fee Schedule

CMS Publication 100-08, Medicare Program Integrity Manual, Chapter 13,

5.1 Reasonable and necessary provisions in LCDs

7.1 Evidence supporting LCDs.

This LCD addresses a group of new surgical procedures for glaucoma referred to as micro-invasive glaucoma surgery (MIGS).

To be considered reasonable and necessary current and future MIGS procedures/device must meet the following requirements:

1. FDA approved.
2. Demonstrated effectiveness of ≥20% or more reduction of intraocular pressure (IOP) on the same or reduced medication for duration of 24 months or longer demonstrated by moderate-high quality literature.

The literature defines the patient population who may best benefit from the procedure.

3. Literature supports the new technology is at least equivalent to current treatment options.
4. Literature supports low risk of serious adverse events.
5. Literature supports that the surgery/procedure does not interfere with ability to perform definitive surgical management in future if indicated.
6. New devices that offer the same or similar function must demonstrate they are equivalent (or superior) to existing devices with published peer-reviewed literature.

Based on this criterion the following MIGs procedures are considered reasonable and medically necessary under the following conditions:

1. WPS considers 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 supraconjunctival space stent or trabecular stent approved for use as standalone procedure device aqueous per eye for the management of refractory glaucoma, defined as prior failure of a filtering/cilioablative procedure AND/OR uncontrolled intraocular pressure (IOP) defined a progressive damage OR mean diurnal medicated IOP ≥20 mmHg on maximally tolerated medical therapy (i.e., ≥4 classes of topical IOP-lowering medications, or fewer in the case of tolerability or efficacy issues). XEN45 insertion must be performed by an ophthalmologist with experience with trabeculectomy and bleb management.
3. Goniotomy* or ab interno trabecular bypass surgery (*consistent with definition of goniotomy) when the following criteria has been met:
   1. The patient does not have advanced glaucoma who need eye pressures lower than mid-teens AND
   2. The patient is currently being treated with an ocular hypotensive medication procedure and is at high risk for vision loss due to uncontrolled IOP and being performed in conjunction with cataract surgery OR
   3. For standalone procedure the patient is on maximally tolerated ocular hypotensive medication and is at high risk for vision loss due to uncontrolled IOP
   4. The patient is a suboptimal candidate for definitive surgery such as trabeculectomy or aqueous tube shunt.
4. Cyclophotocoagulation will be considered medically reasonable and necessary for patients with refractory glaucoma when:
   1. Have failed trabeculectomy or tube shunt procedures OR
   2. Minimal useful vision and elevated intraocular pressure OR
   3. Have no visual potential and need pain relief

Limitations of Coverage

1. The following are considered investigational in patients over the age of 18 for glaucoma management:
   1. Excimer laser trabeculostomy (i.e., ExTra ELT)
   2. Viscocanaloplasty
   3. Canaloplasty in combination with trabeculotomy ab interno (e.g.,OMNI® Surgical) System)
   4. Gonioscopy-assisted transluminal trabeculotomy (GATT)
   5. Ab Interno Canaloplasty
   6. Transcliary Fistulization
2. MIGs is not considered a first line treatment for mild-moderate glaucoma.
3. A combination of surgical MIGs procedure and aqueous shunts cannot be performed at the same time of service in the same patient.
4. Phacoemulsification can be performed in conjunction with a single MIGS procedure (stent or surgical but not both at same time of service)

A Contractor Advisory Committee Meeting on Micro-Invasive Glaucoma Surgery was held on 1/5/2023 hosted by Palmetto, 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 will be referenced through this policy.

Provider Qualifications

The Medicare Program Integrity Manual states services will be considered medically reasonable and necessary only if performed by appropriately trained providers.

Patient safety and quality of care mandate that healthcare professionals who perform minimally invasive glaucoma surgeries 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 policy. 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 three clock hours with an injection of viscoelastic while removing the stent to dilate the canal or via three or more punctures of the trabecular meshwork spanning at least three clock hours (90 degrees) to dilate Schlemm’s canal.

Goniotomy- The procedure performed is consistent with definition of goniotomy as incision and/or excision with blade or surgical instrument for at least 3 clock hours to create an opening into Schlemm canal from the anterior chamber, via the internal approach through anterior chamber.²

High quality literature- Further research is very unlikely to change our confidence in the estimate of effect.³

Maximum tolerated medical therapy- is attained as soon as the patient is using successfully the greatest number of topical glaucoma medication classes he or she can tolerate and that add additional IOP reduction.⁴

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.³

Refractory Glaucoma- glaucoma that is difficult to treat and poorly controlled on maximally tolerated medical therapy or failed surgical therapy regardless of stage of disease.⁴

Literature submitted during the open comment period was reviewed. This included 260 articles, some of these were already included in the LCD while others represented new literature to review. Case report, case series and retrospective reports with small numbers (<30), review papers, editorials and unpublished reports were not included in the analysis.

Primary open-angle glaucoma (POAG) affects approximately 53 million people in the world with a prevalence of 3% in the population aged 40-80 years.⁵ 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 trabecular meshwork (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 trabecular meshwork or the inner wall of the Schlemm’s canal can disrupt the balance of aqueous humor inflow and outflow, resulting in an increased intraocular pressure (IOP) and glaucoma risk. The etiology is not fully understood but there is an association with an 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.⁵

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 one 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).⁶ As the only known modifiable risk factor treatment of elevated IOP to reduce risk of progression to glaucoma is considered standard of care with 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 progressive vision loss is the most significant outcome but challenging to use as primary outcome in studies. The subject matter experts (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.

The goal of treatment in primary open glaucoma (POAG or OAG) 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.⁷

When the maximum tolerated medical therapy 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.⁸ The 5 year cataract rate was greater in those treated with surgery (19%) than medication 6.5%.⁹ AAO guidelines state that laser trabeculectomy 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.⁷ UpToDate states for most patients pharmacological or laser therapy is first-line treatment for OAG, to avoid increased risk of complications from surgical therapy.⁸ 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.¹⁰

Canaloplasty, in some cases, is a non-penetrating surgery performed with a microcatheter in which the Schlemm’s canal is expanded circumferentially by injecting a small amount of high weight molecular viscoelastic agent through the catheter, sometimes followed by placement of a permanent suture under tension in the Schlemm’s canal to create an intrascleral reservoir.^11,12 A systematic review and meta-analysis compared canaloplasty with trabeculectomy and concluded at 12 months that trabeculectomy was more successful in reduction of IOP at the cost of higher complication rate and more demanding postoperative care than canaloplasty.¹³

Goniotomy is surgery in which an incision or excision of trabecular meshwork with a blade or other surgical instrument for at least 3 clock hours to create an opening into the Schlemm's canal from the anterior chamber, via an internal approach through the anterior chamber.¹⁴ Goniotomy was first described by Barkan as the incision of 1/4 to 1/3 of the nasal trabecular meshwork (TM) via a temporal peripheral corneal incision under intraoperative gonioscopy in a series of 11 adult eyes in 1936.¹⁵ Trabecular meshwork tissue is not removed in this technique. Traditional goniotomy is the procedure of choice for congenital glaucoma and needs simple and inexpensive equipment.¹⁶ Until recently, goniotomy was viewed as a surgical approach reserved for the treatment of trabeculodysgenesis associated with congenital glaucoma, as minimally invasive glaucoma surgical options have burgeoned, goniotomy for adult eyes with glaucoma has resurfaced. There is limited moderate to high quality literature on the role of goniotomy in adult glaucoma and in the absence of trabecular dysgenesis with most literature being case reports, series and retrospective reports.¹⁷ Early studies in adults had mixed long-term results with these procedures, possibly due to incomplete removal of the trabecular meshwork or inflammation from damage to surrounding structures. Newer techniques strive to allow precise removal of trabecular meshwork without damage to the outer wall of Schlemm canal. Suture goniotomy techniques such as GATT also preserve the outer wall of the canal and collector channels. These procedures create a permanent opening between the anterior chamber and Schlemm canal which provides durable, safe, and effective IOP control. While this is promising literature is limited and lacks prospective studies and long-term outcome data.

IOP and Cataract Surgery

The effect of cataract surgery on IOP in patients with open-angle glaucoma 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 two years but is sustained until five years after the cataract surgery. A significant IOP reduction has been found in patients with pseudoexfoliation glaucoma (PXG). The American Academy of Ophthalmology (AAO) conducted a meta-analysis18 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.¹⁹ Overall, there seems to be a modest reduction in IOP after cataract surgery by phacoemulsification, however the results are somewhat 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 minimally invasive glaucoma surgeries (MIGS) at the time of cataract removal.

The American Academy of Ophthalmology (AAO) published a systematic review in 2015 on the effect of phacoemulsification (cataract removal) on intraocular pressure 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 three types of glaucoma reviewed: open-angle glaucoma (POAG; including normal-tension glaucoma), pseudoexfoliation glaucoma (PXG), 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 PXG, 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.¹⁸

A 2017 systematic review 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.²⁰ 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.¹⁹ This study was limited by the retrospective design, small sample size lack of randomization and control groups.

The Horizon Study²¹ and an analysis from the Fight Glaucoma Blindness (FGB) international registry²² which followed patients who had cataract surgery with either an eye stent 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 18mmHG of less without medications than the cataract surgery group (49.5% vs. 33.8%; P ¼ 0.003), as well as a greater likelihood of IOP reduction of 20% or more without medications.²³ The SMEs stated that the placement of a stent at the time of cataract surgery and patients at risk for glaucoma due to elevated intraocular pressure has become standard of care due to the potential reduction in vision loss and blindness secondary to glaucoma.

Micro-invasive or Minimally Invasive Glaucoma Surgeries (MIGS)

The term micro-invasive or minimally invasive glaucoma surgery (MIGS) refers to a group of newer surgical procedures that are performed by using an ab interno (from inside the eye) approach via gonioscopic guidance and involve minimal trauma to ocular tissues. Ab-interno disruption and ablation of the TM increases outflow at the level of the juxtacanalicular TM and the inner wall of Schlemm’s canal (SC).²⁴ In contrast to external filtration surgeries such as trabeculectomy and aqueous tube shunt, these procedures are categorized as internal filtration surgeries. Compared with traditional filtration surgery, MIGS holds the promise of faster recovery time and fewer severe complications.

It is this potential to improved safety profile that opened the indications for MIGS to include patients with early- stage glaucoma to reduce the burden of medications and problems with compliance (due to eye drop application difficulty, cost, cosmetic effects, and frequency). Another area of investigation is patients with glaucoma who require cataract surgery. An advantage of ab interno shunts is that they may be inserted into the same incision and at the same time as cataract surgery. In addition, most devices do not preclude subsequent trabeculectomy if needed. Therefore, health outcomes of interest are the IOP achieved, reduction in medication use, ability to convert to trabeculectomy, complications, and device durability. MIGS fall into two main categories: bleb-forming MIGS which are placed through an ab externo (outside the eye) or ab interno (inside the eye approach and non-bleb forming which are ab-interno.⁴

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. CPC and iStent placement were the most common concurrent procedures (55.4%). The authors report a significant increase in MIGs use over the study. Despite limited evidence of their long-term safety or efficacy and call for trials comparing safety and outcomes of novel MIGs versus traditional surgical treatments for glaucoma.²⁵

Minimally Invasive Stent Procedures

Aqueous shunts emerged and there was hope these could replace trabeculectomy to bypass these complications. However approximately 10% of devices fail annually and shunts still have other complications, including corneal endothelial failure and erosion of the overlying conjunctiva.²⁴ A 2017 Cochrane meta-analysis included 3 randomized control trials (n=380) and reported that IOP was not different in patients who underwent aqueous shunt compared with trabeculectomy (mean difference 2.55 mmHg, 95% CI -0.78 to 5.87).¹² The authors conclude that methodology and data quality among existing randomized controlled trials of aqueous shunts was heterogeneous across studies, and there are no well-justified or widely accepted generalizations about the superiority of one surgical procedure or device over another. In addition to the paucity of high-quality literature there is a lack of long -term outcome data regarding these procedures.

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 four 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 XEN45 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 primary open-angle glaucoma (POAG) in whom previous medical and surgical treatment has failed. XEN45 was granted FDA clearance for the management of refractory glaucoma, including cases where previous surgical treatment has failed, cases of primary open angle glaucoma, and pseudoexfoliative or pigmentary glaucoma with open angles that are unresponsive to maximum tolerated medical therapy. The published pivotal trial data for each, constituting the main evidentiary support, is summarized in the attached table.^21,26-29 MIGS Pivotal Trials

A 2021 Cochrane Systematic Review and Network Meta-analysis explores the outcomes from 6 to 60 months of minimally invasive glaucoma surgery. 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 minimally invasive glaucoma surgery techniques.³⁰ AAO rated this as moderate quality, strong recommendation.⁵ 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.⁵

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

A 2020 Cochrane review on ab interno trabecular bypass surgery with Hydrus microstent for OAG reported on 3 studies (all sponsored by manufacturer Iventis Inc. who makes the Hydrus stent) with 808 patients from 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.³¹ Ahmed et al reported on 152 eyes with OAG were randomized to MIGS with Hydros 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.³²

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

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 two-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.³³ 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, randomized, controlled trial evaluated the safety and efficacy of two trabecular micro bypass stents (iStents) versus prostaglandin as initial standalone treatment for newly diagnosed, treatment naive primary open angle glaucoma for five years. Study subjects (n=101) were randomized to either two eye stent or once daily topical travoprost (1:1) ratio. Five-year mean diurnal IOP 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.³⁴ 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, (16.4mmHg to 14.8mmHg) and 26.0% reduction, (17.7mmHg to 13.1mmHg) for iStent inject with medication use decrease without complications.³⁵

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

The XEN Gel Stent was designed to function similar to trabeculectomy to enable drainage from the anterior chamber to the suprascleral space. Is a 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.^36,37

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.³⁸ Limitations include retrospective study design with small sample size and lack of controls.

A systematic review 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 one 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 14-15mmHg 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 various studies, differing methodologies and populations as well as the inclusion of non-randomized data places these findings at risk of confounding and limit’s 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 in conjunction with cataract surgery or stand alone. In comparing POAG to pseudoexfoliation glaucoma, data was limited but found encouraging outcomes in the setting of you 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.³⁹

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. Complication rate was 13% with no serious complications.⁴⁰ 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.⁴¹ 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-KBD and 23 KDB alone by a single surgeon and followed for 18 months. They conclude that KBD is effective whether combined with cataract surgery or standalone surgery with reduction of IOP into mid-teens.⁴²

Studies that compared stents to each other or to trabeculectomy

Several reports compare the gel stent to trabeculectomy. A retrospective clinical cohort study compared 68 patients with glaucoma with uncontrolled IOP on maximally tolerated medical therapy who underwent trabeculectomy (n=34) to XEN gel implant (n=34) for 36 months. The report 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.

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=.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 mm Hg 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 14mmHg range.¹⁵⁷ Strength of the study is the randomized design and limitations include small sample size, short term follow-up and potential risk of bias.

A study compares iStents 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 open-angle glaucoma (OAG) and followed for at least 3 months. They reported treatment success as ≥20% intraocular pressure (IOP) reduction was 62.9% vs 30.0% in Multi-Stent vs Trab eyes, respectively (p = 0.001) with 3-stents achieving best results. ⁴³ Lack of a control group, risk of selection bias and small sample size limit these findings of these reports.

Goniotomy

Goniotomy (ab interno trabeculectomy) is defined as a procedure in which the trabecular meshwork is opened for at least 3 contiguous clock hours or when multiple incisions are performed opening the trabecular meshwork over an area of at least 90 degrees at the level of the juxtacanalicular TM and the inner wall of Schlemm’s canal (SC).^14,24 There has been a shift in practice to the use of tube-shunt procedures and a decrease in the use of trabeculectomy over the past decade.^44,45 There has been the emergence of multiple new devices and procedures for the excision or cleavage, dilation, or stenting of various extents of the trabecular meshwork and the inner wall of Schlemm’s canal under gonioscopic guidance. The IOP-lowering effect of the trabecular MIGS is limited by resistance in the distal outflow pathways and the episcleral venous pressure with a mean in mid-teens.⁵ The subject matter experts state that clinical experience and glaucoma fellowship guide their decision in terms of patient selection but acknowledge a lack of standards in terms of patient selection for procedures beyond stents. It was stated that laser trabeculoplasty is the least invasive and often first line option for open angle glaucoma with progressive invasiveness with devices such as Trabectome, Excimer laser and KDB as methods of goniotomies.⁵

Trabectome Device (MicroSurgical Technologies)

The Trabectome™ (NeoMedix, Tustin, CA, USA) is a device consisting of a handpiece, footplates, and electrocautery electrodes. The footplate enters Schlemm’s canal and energy is applied from the electrode disrupting the TM exposing the canal to the anterior chamber.⁴⁶ The use of the instrument was initially reported in a prospective trial of 101 patients with open angle glaucoma with a mean preoperative IOP of 27.6 ± 7.2 mmHg. They were followed for 30 months where the mean IOP was 16.3 ± 3.3 mmHg (n=11). The mean percentage drop over the course of follow-up was 40% and the decrease was statistically significantly less at all postoperative measurements from the preoperative level. They reported overall success defined as IOP ≤ 21 mmHg with or without medications and no subsequent surgery was 84%. One hundred percent of patients experienced interoperative reflux bleeding, but complications were minimal and not vision threatening. The authors concluded that Trabectome offers a minimally invasive and effective approach to glaucoma treatment which spares conjunctiva and does not preclude subsequent standard filtering procedures.⁴⁷ Limitations include a lack of a control group, randomization, and risk of bias.

A 2021 Cochrane Review of RCTs to evaluate safety and efficacy of ab interno trabecular bypass surgery with Trabectome for open angle glaucoma at 2 year follow-ups identified 10/19 subjects in the intervention group concluding low certainty evidence. The authors conclude there is no high-quality evidence for the outcome of ab interno trabecular bypass surgery with Trabectome for open angle glaucoma calling for the need for properly designed RCTs.⁴⁸

A prospective interventional case series of 304 consecutive eyes with glaucoma undergoing cataract surgery received trabeculectomy with Trabectome. The mean IOP was 20.0 mmHg 6.3 (SD) preoperatively, 14.8 ± 3.5 mmHg at 6 months, and 15.5 ±2.9 mmHg in 1 year. Use of glaucoma medication was reduced at 1 year. Nine patients underwent subsequent glaucoma procedures. 78.4% of the patients had blood reflux which resolved within a few days. The authors support the use of trabeculectomy by the internal approach using the Trabectome at the time of cataract surgery for lowering IOP.⁴⁹ Limitations to the study include the lack of control group or randomization, high-risk of bias and lack of long-term follow-up.

A retrospective interventional single surgeon, single center case series reported on 246 patients undergoing ab interno trabeculectomy with Trabectome was reported. Eighty-eight cases were ab interno trabeculectomy alone and 158 were in combination with cataract surgery. The mean preoperative IOP was 21.6 ± 8.6 mmHg and at 24 months post operatively the mean IOP was reduced by 29% to 15.3 ± 4.6 mmHg (p=0.001) with a reduction in the number of glaucoma medications needed. The authors divided the patients into Criteria A requiring a postoperative of IOP ≤ 21 mmHg or ≥ 20% reduction from preoperative IOP and Criteria B requiring IOP of ≤ 18 mmHg and ≥ 20% reduction in IOP. Success rate was 62% (95% CI, 56%–68%) using Criteria A and 22% (95% CI, 16%–29%) using Criteria B. Using a more stringent criteria for success the overall success rate of ab interno trabeculectomy can drop within 24 months after surgery to levels that may be clinically unacceptable. The authors conclude that the surgery was most appropriate for patients requiring a target IOP of 21 mmHg or above.⁵⁰ The study is limited by the retrospective design with lack of control group or randomization and strengthened by large sample size, longer term follow-up than other studies and while it was funded by outside sources, they did not have a role in the design or conduct of the research or reporting of results.

Another retrospective review reported on 101 patients with OAG who underwent goniotomy with Trabectome and followed for mean of 30 months (n=11). The authors report 40% drop in IOP from baseline. Failure rate was 16 percent with nine patients undergoing trabeculectomy and two having sustained elevated IOP despite resuming medications.⁴⁷ The study is limited by retrospective design and few patients included in the 30 month follow up. Benefits to this approach are that it is conjunctiva sparing therefore does not preclude future bleb-associated surgeries and the reported studies show low complication rates. However, complications can occur with symptomatic delayed onset hyphema between 2 to 31 months after the procedure in the absence of further surgeries of trauma reported. Additionally transient increase in IOP has been reported and vision threatening IOP increase requiring urgent surgery was also reported.⁵⁰

Trabectome-mediated ab-interno trabeculectomy states an average the IOP was reduced by 36% to a final mean IOP of 16 mmHg in a meta-analysis.⁵¹ The meta-analysis included 14 papers, but was fraught with significant heterogeneity, combining prospective, cohort, and retrospective studies and case series, lack of clear definition for glaucoma, variable outcome and duration of follow-up questioning the reliability of this conclusion.

A single centered prospective observational study included 557 eyes and reported on intraoperative and postoperative complications of Tracectome. The authors report a decline from preoperative IOP baseline for OAG of 24 ± 5.5mmHg 218 ± 6.1 mmHg with a mean follow-up of 204 ± 238 days with a reduction in medication use. For pseudoexfoliation glaucoma decline from a baseline IOP of 25 ± 5.9 mmHg to 18 ± 8.2 mmHg with a mean follow-up of 200 ± 278 days was reported. No severe interoperative or postoperative complications were observed with reflux bleeding in 92% that resolved spontaneously.⁵²

A retrospective report on a Japanese eyes with or without previous surgery or laser treatment who underwent Trabectone for glaucoma reported a decrease in IOP at six months. 16.3% of cases received surgical reintervention and one case received cataract extraction during follow up.⁵³

One subject matter expert stated there were at least 9 studies in support of Trabectome. These were retrospective and prospective but resulted in a decrease in IOP, and while there are no randomized controlled trials, they felt that there are data to support the procedure.

The Goniotome + I/A (Irrigation and Aspiration), while like the Trabectome, does not require a high frequency generator or peristaltic pump end utilizes V shaped, serrated sharp blades made with femtosecond laser to induce a dual cut along the anterior and posterior TM and is available with active aspiration and irrigation. Results are like the Trabectome.²⁴

Needle Goniotomy

Needle goniotomy performed with a disposable needle as done in the pediatric population has been described in adults such as in a retrospective report of 76 eyes with moderate OAG undergoing cataract surgery alone compared to cataract surgery with needle goniotomy. The reported the reduction in IOP and medication use from baseline in the combined goniotomy group was significantly greater at 12 months compared to the Phaco group (−3.1 ± 2.9 mmHg vs −1.3 ± 2.4 mmHg and −1.2 ± 0.9 vs −0.7 ± 0.9, respectively, both P < 0.05).⁵⁴ This report is limited by lack of control, short term follow-up and small sample size.

A prospective interventional case series reported on 32 eyes of 30 consecutive patients with early to moderate glaucoma and IOP ≥21 mmHg without medication or < 21 mmHg with medication with cataracts. Goniotomies were performed with a 25-gauge needle which was bent from its hub for better handling and connected to irrigation and advanced for at least 45 degrees in the superior and inferior direction to incise the pigmented part of the trabecular meshwork and expose the Schlemm’s canal into the anterior chamber for 90 degrees. Patients were followed at one day, one week, one month, three months and six months after surgery and two IOP measurements were taken at each visit. Mean ± SD IOP at baseline was 21.8 ± 4.6 mmHg. Mean ± SD IOP at one-day (13.8 ± 4.4 mmHg), one-week (13.4 ± 4.3 mmHg), one-month (16.9 ± 6), three-month (16.3 ± 4.5 mmHg) and six-month (14.8 ± 3.9 mmHg) visits was significantly lower than baseline (P < 0.001). There was a 25.2% and 32.1% IOP reduction at three months and six months after surgery, respectively. There was a reduction in antiglaucoma medications from baseline. There were no serious complications and minor complications were transient.¹⁶ The authors report no conflicts of interest. Limitations of this study include a lack of control group, short term follow-up, and small sample size.

Kahook Dual Blade Goniotomy (New World Medical)

The Kahook Dual Blade (KDB, New World Medical, Rancho Cucamonga, CA) is a device designed for more complete removal of the TM through a minimally invasive approach. The tip of the blade is inserted through the TM, the ramp of the device gently stretches the TM and guides it towards the dual blades, which create parallel incisions, allowing excision of a strip of the TM. The developers report that this achieves near complete removal of the TM with less damage to the surrounding structures and that minimizing residual TM leaflets may reduce fibrosis and enhance outcomes.⁵⁵ Although TM tissue is removed, superior and inferior leaflets remain, which often cause scarring.³⁷

A single-center, longitudinal, randomized controlled trial followed 42 eyes randomly allocated to Phaco-KBD (n=21) or Phaco alone (n=21). They found IOP decreased from 17.9 ± 3.5 to 16.0 ± 2.2mmHG and from 17.3 ± 2.5 to 15 ± 3.2mmHG at the last visit in the treatment and control groups (p = 0.47) at 12 months. There was a reduction in glaucoma medication. They conclude that in patients with well controlled, mild to moderate glaucoma adding ab interno trabeculectomy with KDB with phacoemulsification might not be more effective than phacoemulsification alone to reach mid-teens IOP values. They conclude that while the procedure is overall safe patients with lower endothelial cell counts could develop corneal decompensation.⁵⁷ While most of the studies on KDB blade are sponsored by the manufacturer this study was done independently without conflicts of interest. It is the only randomized study comparing these procedures. Limitations include small sample size and short-term follow-up.

An early report on 71 eyes with mild-severe glaucoma who had phacoemulsification plus goniotomy with single use dual blade were followed for 6 months. They report baseline IOP decreased from 17.4 mm Hg G 5.2 (SD) to 12.8 G 2.6 mm Hg 6 months postoperatively and decrease in medication usage by 1.6 ± 1.3 to 0.9 ± 1.0, respectively (p<0.001 and p=.005, respectively).⁵⁸ Another retrospective report followed 52 eyes for 6 months with similar findings. Limitations include study design, short term follow-up and lack of control.

A prospective study followed 48 of patients from a single surgeon undergoing combined Phaco-KBD, with simultaneous goniosynechialysis for glaucoma. For acute closure glaucoma the baseline IOP was reduced from 20.8 mmHG to 12.1-14.2 mmHG over a 2 year follow-up representing 6.1-8.77mmHG reduction (23.4-39%), p≤0.0353).⁵⁹ Limitations of the study include retrospective studies design, the addition of goniosynechialysis, single surgeon and small sample size.

A prospective, interventional case series included 52 eyes undergoing phacoemulsification combined with goniotomy using KBD for OAG and followed for 12 months. The authors report mean IOP was reduced from 16.8 ± 0.6 mmHg at baseline to 12.4 ± 0.3 mmHg at month 12 (P<0.001), a 26.2% reduction.⁶⁰ Another case series with 69 eyes report similar modest reductions at 12 months after KDB with cataract surgery.⁶¹ Another reported on 75 eyes with glaucoma treated with KBD blade and followed for 6 months found similar results.⁶² Limitations to these reports include lack of controls, small sample size and lack of long-term data.

A retrospective review of 55 eyes of 38 patients with glaucoma who underwent ab interno goniotomy at the time of cataract surgery to remove the 3 to 5 clock hour trabecular meshwork reports a decrease in IOP from baseline. For high tension glaucoma (n=44) IOP decrease was 19.4±3.3 to 15.1±3.3 mmHg; p<0.001 and for normal tension glaucoma (n=11) IOP reduction of 14.0±2.3 to 11.5±2.3 mmHG; p=0.004. The change was maintained for 6 months. Limitations of this study include a small sample size for normal tension glaucoma and short term follow up as well as retrospective study design.⁶³

Additional retrospective report on 42 eyes that were followed for 24 months after phacoemulsification with KDB- assisted goniosynechialysis and excisional goniotomy with glaucoma and cataract. Authors reported a reduction in IOP from baseline mean of 25.5 (0.7) mmHG to 13.5 (0.4) mmHg, p<0.001 and decrease in medication usage.⁶⁴ Another retrospective report included 63 eyes showed a 19.5% reduction in IOP 17.4mmHg at baseline to 14.0 mmHG at 6 months (p=0.0012) after KDB goniotomy with or without cataract surgery.⁶⁵ These are limited by retrospective study design without controls, and small sample size and uncertain effect goniosynechialysis.

Another retrospective report on 111 eyes with glaucoma who underwent KDB goniotomies with cataract surgery (n=100) and stand-alone (n=11). The report IOP reduction up to 12 months. They found eyes with pre-operative IOP>21 mmHG were more likely to undergo reoperation.⁶⁶ A retrospective report included 385 glaucomatous ryes eye with phacoemulsification alone (n=309) or Phaco-KDB (n-76) and reported on refractory surprise with refractive surprise greater than ±0.5 D occurred in 26.3% of eyes in the Phaco-KDB group and 36.2% in the phacoemulsification group (p = 0.11). The conclude no difference in refractory outcomes between the 2 groups.⁶⁷ Limitations of the studies includes retrospective design, risk of bias including selection bias, variability in mean baseline IOP and uncertain impact on the overall IOP reduction results between the two techniques, results need to be confirmed in controlled setting.

A retrospective review on 53 eyes treated with KBD blade and followed for 6 months report reduction from 7-10.3 mmHg (29.8-43.8%; p<00001) without significant adverse events.⁶⁸ A retrospective study reported on 32 eyes that had KDB goniotomy alone and 165 eyes with KDB goniotomy combined with cataract surgery. Surgical success was defined as a reduction in IOP of at least 20% from baseline at 12 months and/or reduction of at least 1 glaucoma medication. They reported that 71.8% in the cataract plus KBD group (n=124) and 68.8% for the KBD alone group reached this measure. Long-term visual acuity was unchanged from baseline in the KCD-alone group and improved in the group that also had cataract removal. The most common complications were transient hyphema (17.3% at day 1) and IOP spike >10 mmHg from baseline at 1 week (10.2%). The authors conclude that goniotomy with the KBD knife is a safe and effective procedure at reducing IOP and medication burden as a standalone procedure or in combination with cataract removal.⁵⁵ Limitations of the study include the retrospective design with lack of randomization or control, small sample size especially in the non-cataract removal group, lack of long-term follow-up, risk of bias, and mild to moderate baseline IOPs.

A retrospective analysis with data collected from 8 US centers including 42 eyes of which 36 had mild to severe open angle glaucoma and the remaining having other forms of glaucoma with baseline IOP of 21.6 mmHg were included. Patients underwent excisional goniotomy with KDB as a standalone procedure. At 3, 6, and 12 months postoperatively, mean IOP reductions from baseline were 4.6 mmHg (22.3%), 5.6 mmHg (27.7%), and 3.9 mmHg (19.3%) (p≤0.001 at each time point). 14.3% (6/42) required additional glaucoma surgery during the 12 month follow-up.⁶⁹ Limitations include retrospective design with lack of randomization and control, small sample size, lack of long-term follow-up, inclusion of eyes without glaucoma and risk of bias. Another retrospective report of 57 eyes who had KDB goniotomy at time of phacoemulsification reported a modest decrease in IOP at 6 months with IOP was reduced from 15.5 ± 4.2 mmHG to 12.2 ± 2.4mmHG at 6 months (p<0.001).⁷⁰

A retrospective review of 42 eyes from 36 patients with severe glaucoma (severe-stage glaucoma, defined by ICD-10 as optic nerve abnormalities consistent with glaucoma, and glaucomatous visual field abnormalities had cataract removal with KDB goniotomy were reported. Preoperative baseline mean IOP was 17.1±4.8 mmHg (mean ± SD) and mean IOP reduction was 2.1±4.67 mmHg (p=0.022). At 6 months, 64.3% (27/42) of eyes had achieved IOP ≤ 15 mmHg without additional glaucoma procedures, 45.2% (19/42) and 45.2% (19/42) were on fewer medications and 31% (13/42) on no medications. Visually significant complications were experienced by 7.1% (3/42) of eyes, and 7.1% (3/42) required additional IOP-lowering procedures within 6 months of surgery.⁷¹ Limitations of the study include retrospective design with lack of control group, small sample size, short term follow up, and risk of bias.

A retrospective case series reported on 90 eyes with medically uncontrolled glaucoma underwent KBD alone (n=39) or KDB goniotomy a combination with phacoemulsification (n=51).⁷² Surgical success was defined as a reduction in IOP of ≥ 20% or reduction in one or more medications. The authors report a reduction from baseline IOP of 24.8±8.3 to 15.0 ± 5.3mmHG in KBD-alone (p<0.001) and from 22.3 ± 5.8 to 13.9 ± 3.0mmHG in KCD-paco group (p<0.001) at 24 months. Limitations include small sample size, retrospective design, baseline differences between the two groups, and need for a control group for reproducible conclusions.

A retrospective comparative study sought to understand outcome of goniotomy in adults reported on 76 patients with moderately controlled IOP ≤ 21 mmHg using medication who underwent conventional goniotomy using keratome blade and viscoelastic material during cataract surgery and were compared to those undergoing cataract surgery alone. Baseline IOP was 18.2 ± 2.4 mmHg in the goniotomy + cataract group and 17.4 ± 1.9 mmHg in the cataract only group. The reduction in IOP from baseline in the combined goniotomy group was significantly greater at 12 months compared to the cataract alone group (−3.1 ± 2.9 mmHg vs −1.3 ± 2.4 mmHg p < 0.05). The success rate was 76.7% in the combined goniotomy group and 50.0% in the cataract only group at 12 months (p = 0.021). Medication use was reduced and there were no significant complications observed in either group.⁵⁴ The authors report no disclosures and limitations include retrospective design with lack of control group, small sample size and short-term follow-up.

A retrospective case series compared 22 eyes that underwent microhook ab interno trabeculectomy and 81 eyes that underwent KBD-Phaco. The authors reported comparable reduction in IOP in both groups.⁷³ Limitations include sample size and lack of controls so results would need to be confirmed in controlled study and risk of bias.

A retrospective study reported on KDB (n=90) and Trabectome (n=125) at the time of cataract surgery and followed for 12 months. The authors report a decrease in IOP of -1.9 ± 4.9mmHG (11.2%, p=0.002) in KDB group and -3.5 ± 5.5mHg (19.1%, p< 0.001) in the Trabectome group without a significant difference between the groups. Hyphema was the most common complication with an incidence of 3% in the KDB group and 14% in the Trabectome group. They conclude that it is safe at the time of cataract surgery and decreases IOP for up to 12 months.⁷⁴ This study is limited by retrospective design, lack of control group, short term follow up and inclusion of multiple types of glaucoma.

A Japanese retrospective study reported on 59 eyes after ab interno trabeculectomy with phacoemulsification with Micro-hook or the KDB Blade and followed for 6 months. The studies report that the two techniques were similar in terms of decrease in IOP and medication use post procedure.⁷⁵ Another investigation by same author reported similar outcomes between spatula- shaped and dual-blade micro hooks with 12 month follow up.⁷⁶

A retrospective report on 44 eyes from Latino patients with OAG who underwent KBD goniotomy for OAG reported reduced IOPs. IOP reductions of ≥20% were achieved by 48.4–56.2% of eyes in the full cohort, by 20.0–33.3% in the low IOP group, and by 66.7–100% in the high IOP group with 24-month follow-up.⁷⁷

A retrospective comparison of 160 eyes on 12-month outcomes of KDB goniotomy performed by attending verses resident surgeons conclude outcomes were similar and resident cases to about 10 minutes longer.⁷⁸ A retrospective comparison of 132 eyes who underwent combined KBD and pharcoemulsification with a minimum of 6 month follow-up reported ≥20 mmHg lowering of IOP in 63.6% at 6 months and 46.1% at 12 months.⁷⁹

A retrospective investigation included 43 eyes which underwent selective laser trabeculoplasty previously and subsequently underwent combined Phaco-KBD goniotomy for mild to severe OAG. They report that the selective laser trabeculoplasty was successful in 46.5% and 63.6% had successful Phaco/KBD at 12 month follow-up.⁸⁰

A retrospective case series reported on 73 eyes that underwent ab interno trabeculectomy using TrabEx+ (MicroSurgical Technology, Redmond, WA) is a serrated trapezoidal dual-bladed single-use device, designed to perform irrigating goniectomy through a corneal microincision, aiming to remove 3 to 6 clock hours of TM. 63% of these patients were treated at the time of cataract surgery and they reported a mean IOP decrease from 33.3 ± 7.3 to 20.9 ± 10.4mmHg followed up to 24 months (p,0.001). There were no serious adverse but 70% did experience hyphema in which 18% required reoperation because of treatment failure. The authors concluded as effective for lowering IOP however long term safety and efficacy will require further prospective studies.⁸¹

Some reports investigated prognostic indicators with KDB goniotomy. A retrospective series on 205 eyes undergoing KDB goniotomy reported on successful reduction of IOP ≤ 20 mmHg. The authors report that pressures were rarely reduced below 15 mmHg and found age and combined procedure with phacoemulsification associated with a good prognosis while previous selective laser trabeculoplasty, post operative adhesion formation and failure of previous cataract surgeries were all poor prognostic indicators.⁸² A retrospective report on 202 eyes were evaluated for factors associated with hyphema development after KBD goniotomy with phacoemulsification. They found hyphema occurred in 8.4% and were increased in males, narrow iridocorneal angles and low IOP on post-op day one. They did not find that anticoagulation or antiplatelet therapy was an increased risk, but calls for further investigation.⁸³ These results were also found in another retrospective review of 72 eyes after Phaco/KDB which also adds patients with combined circumferential goniosynchialysis procedure may benefit more in IOP control.⁸⁴ A retrospective study was conducted on 76 eyes with exfoliation glaucoma (EFG) and 56 with OAG seeking risk factors for IOP elevation at six months after KDB* ab interno trabeculectomy. Intraocular pressure was reduced by 32.1% in EFG group, and 17.7% in OAG at six months. Post-operative IOP ≥20 mmHG was observed in 56.6% of EFG and 51.8% of POG with spikes occurring in about 15% of both groups. Logistic regression analysis factors that were associated with these outcomes include multiple preoperative medications and higher IOP (≥20 mmHG) on post-op day one and require careful follow-up.⁸⁵

A small prospective study included 37 eyes compared phacoemulsification with the KCD blade which is tri-modal therapy (n=21) to those with bi-modal therapy (n=16). They reported greater reduction in IOP with the tri-modal approach. A controlled study would be necessary to confirm these findings with larger sample size.⁸⁶

Ab interno canaloplasty (Viscocanalostomy and Phacoviscocanalostomy)

Ab interno canaloplasty uses an internal approach where a microcatheter is introduced into the canal through a small opening in the trabecular meshwork and advanced around its entire circumference. As the catheter tip is withdrawn, viscoelastic fluid is injected to dilate the canal. The viscoelastic fluid disperses down the collector channels of the eye within 2 to 3 days aimed at permanently dilating the canal to allow increased drainage of aqueous humor from the eye and thereby lower IOP. Some devices allow canaloplasty to be done simultaneously with trabeculotomy.⁸⁷

Viscocanalostomy and Phacoviscocanalostomy involves creating a scleral reservoir and the injection of viscoelastic fluid into the ostia of the canal via an ab externo approach. Unlike trabeculectomy this avoid full thickness penetration into the anterior chamber of the eye. When performed at the time of cataract surgery, it is called phacoviscocanalostomy. Ab interno canaloplasty, also called viscocanaloplasty, differs from viscocanalostomy by injection of viscous medication to create the opening in Schlemm’s canal. The procedure is performed through a single corneal incision and involves a 360-degree viscodilation of the canal using a device (such as the iTrack microcatheter (Ellex) or the VISCO360® handpiece (Sight Sciences) and an ophthalmic visco-elastic device inserter. If performed with cataract surgery the same corneal incision can be used or performed as a standalone procedure. As of April 30, 2019, the VISCO360 is no longer available for commercial distribution (Access Gudid, 2020). Studies consist of retrospective reviews.⁸⁸

Ab interno canaloplasty, differs from viscocanalostomy, by which is a limited injection of viscous medication to create an opening in Schlemm’s canal. The procedure ab interno canaloplasty is performed through a single corneal incision and involves a 360-degree viscodilation of the canal using a device (such as the iTrack microcatheter (Ellex) or, the VISCO360R handpiece or the OMNI device (Sight Sciences) and an ophthalmic visco-elastic device inserter. If performed with cataract surgery, the same corneal incision can be used or performed as a standalone procedure. As of April 30, 2019, the VISCO360 is no longer available for commercial distribution (Access Gudid, 2020). Studies consist of retrospective reviews.

A retrospective study of 206 eyes from 130 patients reported on the outcome of canaloplasty on IOP and medication use in patients with OAG for 36 months. Canaloplasty was performed using the VISCO360 or OMNI surgical system as a stand-alone procedure in 22 eyes and concomitantly with cataract extraction (CE) in 185 eyes with chronic OAG insufficiently controlled or intolerant to IOP-lowering medications. The number of hypotensive medications and IOP were recorded at baseline, day 1, week 1, month 1, month 3, and every 3 months thereafter, with the last follow-up visit at 36 ± 6 months postoperatively. Patients were stratified by baseline IOP (Group 1, IOP >18 mm Hg; Group 2, IOP ≤18 mm Hg). Treatment success in Group 1 was defined as a reduction in IOP and the use of IOP-lowering medications; Group 2 success was defined as maintenance of a lower IOP and a reduction in medication use. The preoperative mean IOP of both groups was 21.1 ± 8.8 mm Hg, with a mean of 2.0 ± 0.9 hypotensive medications. The primary success end point was met by 73% of patients, with a mean IOP reduction in Group 1 (131 eyes; 21.8 to 15.6 mm Hg, P < .0001) and a maintenance of IOP control in Group 2 (76 eyes; 15.4 to 13.9 mm Hg, P = .24). Medications decreased from 2.2 ± 0.9 to 0.9 ± 1.1 in Group 1 (P = .024) and from 1.8 ± 0.8 to 0.7 ± 1.0 in Group 2 (P = .003). While this study offers further evidence of the durable and clinically meaningful reductions in IOP and use of IOP-lowering medications attainable with canaloplasty it is limited by retrospective design, lack of control group to compare outcomes reliable over time, and potential risk of bias.⁸⁸

A Cochrane review included five studies with 311 eyes. The studies reviewed were randomized and quasi-randomized and compared trabeculectomy (160 eyes) to viscocanalostomy (50 eyes) for OAG and concluded based on limited evidence that trabeculectomy is better in terms of achieving total success (pressure controlled without eyedrops) than non-penetrating filtering procedures, although the outcome of partial success (pressure controlled with additional eyedrops) was more imprecise and the included studies were not designed to compare if one surgical technique was superior to another.⁸⁹ A meta-analysis reviewed 10 RCT with 458 eyes and concluded trabeculectomy requires significantly less postoperative antiglaucoma medications as compared to viscocanalostomy. Trabeculectomy was associated with a significantly lower mean intraocular pressure at 6, 12 and 24 months when compared to viscocanalostomy (six months MD 2.25 mmHg, 95% CI 1.38 to 3.12; eight studies, 12 months MD 3.64 mmHg, 95% CI 2.74 to 4.54; six studies and 24 months MD 3.42 mmHg, 95% CI 1.80 to 5.03; three studies) and was consistently superior to viscocanalostomy in all subgroup analyses. The risk of complications including hypotony, hyphema, shallow anterior chamber and cataract formations were lower in the viscocanalostomy group so overall lower risk profile, however the viscocanalostomy group had a significantly higher risk of perforation of Descemet membrane.⁹⁰ This meta-analysis was limited by methodological concerns within some of the studies, significant heterogenicity and short-term follow-up. Additional case series and retrospective reviews address phacoviscocanalostomy but the paper concludes a lack of evidence to support the procedure.

A non-randomized, retrospective, single centered paired eye study assessed the 12-month outcome of 12 patients (mean age 73.8 ±12.6 years) with POAG who underwent ab interno canaloplasty in one eye and ab externo canaloplasty in the other eye as either a standalone procedure or combined with cataract excision. In the ab externo canaloplasty group, the mean preoperative IOP was 18.1±3.9 mmHg on 2.4±0.5 medications, which reduced to 13.5±2.2 mmHg (p<0.05) on 0.9±0.9 medications (p<0.001). In the ab interno group, the mean preoperative IOP was 18.5±3.4 mmHg on 2.4±0.5 medications and postoperative IOP was 13.8±2.2 mmHg (p<0.05) on 0.8±0.8 medications (p<0.05). The authors conclude comparable results from the two procedures.⁹¹ This study is limited by the small sample size, risk of bias, lack of control group and randomization.

A retrospective cohort study Included 36 eyes who underwent ab interno canaloplasty alone or in combination with cataract surgery and followed for 12 months. They report IOP decreased from 19.8 ± 4.1 to 13.8 ± 3 mmHg at 12 months follow-up (n = 21, p < 0.001) without major complications.⁹² The study was limited by retrospective design, small sample size, llack of control or randomization.

A retrospective cohort of 25 eyes was followed after ab interno canaloplasty with or without cataract surgery and reported a reduction from baseline mean IOP of 20.24 mmHg ± 5.92 (n = 25) was reduced to 10.64 mmHg ± 2.77 (n = 25, p < 0.001), 12.55 mmHg ± 3.33 (n = 22, p < 0.001) and 13.67 mmHg ± 2.15 (n = 21, p < 0.001) at 1 day, 1 year and 2 year follow-up visit, respectively. The authors conclude this is a safe and effective option with long-term reduction in IOP; however, the study was limited by retrospective design, small sample size, lack of controls and risk of bias.⁹³

A retrospective study included 54 eyes that underwent ab interno canaloplasty with cataract surgery and reported a mean IOP decreased from 23.6 ± 7.4 mmHg preoperatively to 14.2 ± 2.9 mmHg (-39.8%; p<0.001) after 12 months. The authors reported a reduction in the need for antiglaucoma medication and concluded that at 12 months complete success (IOP reduction ≥ 20%) in 46% of eyes and qualified success in 65% of eyes. They reported the most common post operative adverse event was IOP spikes in 22.2%. Nineteen eyes (35.2%) were considered surgical failures due to uncontrolled IOP and 36.8% required filtering surgery (n=7).⁹⁴ Limitations of this study include the retrospective design, risk of bias, Caucasian only population, lack of controls, variability in patient selection and follow-up.

The AAO Preferred Practice Guidelines states ab interno canaloplasty reduces the IOP for up to 12-months, but success in reduction of postoperative glaucoma medication use is not clear. AAO does state that it appears to be equivalent to ab externo canaloplasty; however, this is based on a single low-quality evidence study.⁵

A single center retrospective case series of 44 eyes reported on 36 months efficacy of ab interno canaloplasty performed with the iTrack microcatheter (Nova Eye Medical) as standalone procedure (n=23) or combined with cataract surgery (n=21) for POAG. Both groups reported a decrease in IOP at 12 months (p<0.001) which remained stable up to 36 months. IOPs decreased from 20.5±5.1 mmHg preoperatively to 13.3±2.1, 13.1±2.4, and 13.3±2.1 mmHg at 12, 24, and 36 months, respectively; the numbers of medications were reduced. Visual acuity was improved at 24 months, and in 29 eyes that had canaloplasty plus phacoemulsification, there was a statistically significant improvement in the proportion of people with 20/40 vision from 34.5% before surgery to 80.8% at 24 months after surgery (p=0.0042).^87,95,96

Gonioscopy-Assisted Transluminal Trabeculectomy (GATT)

Gonioscopy-assisted transluminal trabeculectomy (GATT) involves a circumferential 360-degree trabeculectomy without conjunctival or scleral incisions. It is performed by making a microincision in the cornea and uses a retractable illuminated microcatheter as an alternative means of performing 180- to 360- degree ab interno trabeculectomy unroofing the entire TM.⁵ This can employ either a microcatheter, suture or TRAB 360 handpiece (Sight Science).

A retrospective case series introduced the procedure and reported on 85 consecutive patients with OAG who underwent GATT with at least 6 months follow-up data available. The authors reported 57 patients with primary OAG had a mean decrease in IOP by 7.7 mmHg and with secondary OAG a decrease of 17.2 mmHg. 9% of patients required further glaucoma surgery with a cumulative failure rate of one year ranging from 0.1 to 0.32.⁹⁷ Limitations include retrospective design, lack of control and randomization. Another retrospective report included 32 patients who underwent GATT at the time of cataract surgery and reported a decrease in IOP from average preoperative IOP was 34.2 ± 10.6 mmHg to 11.2 ± 2.4 mmHg at 6 months.⁹⁸

A prospective, single armed trial including twenty eyes of 20 subjects with mild to severe POAG underwent incisional goniotomy and canal of Schlemm’s viscodilation using the STREAMLINE Surgical System (New World Medical, Rancho Cucamonga, CA) following cataract extraction after a washout of all glaucoma medication. The authors reported at six months greater than 20% reduction in IOP from baseline in 89.5% of eyes from a mean IOP of 23.5±2.5 mmHg preoperatively (unmedicated IOP) to 14.7±2.4 mmHg at the 6-month follow-up visit (p<0.001) with a 57.9% decrease in IOP lowering medication.⁹⁹ Application of this technology outside of a setting of cataract was not explored in this study. Limitations include lack of control group, lack of long-term data, lack of randomization, risk of surgical learning curve impacting complications or outcomes and risk of selection bias.

A retrospective review of 33 eyes with steroid induced or uveitic glaucoma that underwent GATT (n=33) or excisional goniotomy (n=24), either with or without cataract surgery and followed for 24 months. Surgical success was defined as at least 20% IOP reduction or a specific IOP reduction based on preset criterion and failure was the need for additional glaucoma surgery or loss of light perception vision. At 24 months GATT eyes had mean IOP 12.9 ± 3.5 mmHG and goniotomy eyes had mean IOP 14.3 ± 4.1 mmHg. Surgical failure rate was 8% for GATT and 14% for goniotomy. In which 10% of GATT eyes required surgical evacuation of hyphema. The authors concluded both techniques were favorable in terms of efficacy and safety with sustained results at 24 months.¹⁰⁰

A retrospective chart review of 85 patients who underwent GATT with at least six months follow up were evaluated and the authors reported a decrease from baseline IOP 7.7mmHg for OAG. 9% required further surgery. 30% experienced postoperative hyphema.⁹⁷

A retrospective study examined 12-month results in a total of 73 eyes (GATT=38; PHACO-GATT=35). At 12 months, the mean IOP was reduced from 24.9±8.5 to 12.1±2.1 mm Hg (p<0.001). Surgery was performed with viscoelastic fluid and needle tip and circumferential trabeculotomy performed with 360-degree suture. The mean number of glaucoma medications was reduced from 3.5±0.7 to 1.2±1.2 (p<0.001). The success rate was 87% at 12 months. The most common postoperative complication was transient hyphema (39%; median duration, 5 d). No sight-threatening adverse event was documented. The authors conclude that GATT was effective and safe at lowering IOP with or without cataract extraction in OAG.¹⁰¹ The report is limited by retrospective design, short term follow-up and lack of controls.

OMNI® Surgical System (OSS Sight Science, Menlo Park, CA, USA)

The OMNI Surgical system introduced in 2018 performs canaloplasty and trabeculectomy to address outflow resistance at multiple points in the pathway including TM.¹⁰² The OMNI device is used to viscodilate SC and cut trabecular meshwork tissue with the long flexible microcatheter allowing the procedures to be performed sequentially in the same surgical session using a single corneal incision, a single device, operated by a single operator (i.e. the surgeon) using either hand in either eye in conjunction with cataract extraction or as a standalone intervention in phakic or pseudophakic eyes.¹⁰²

A retrospective, observational, multi centered, evaluation of OMNI (ROMEO) reported on 81 patients who underwent sequential canaloplasty in combination with trabeculectomy ab interno with the OMNI system (Sight Science) in conjunction with cataract surgery in mild-moderate OAG were followed for 12 months. The authors reported a reduction in IOP in those with IOP > 18 mmHg at baseline of 21.9 to 15.1 mmHg, (p < .0001) and remained controlled in those with IOP at 18 mmHg (14.1 to 13.4 mmHg, p = .3177).¹⁰³ Longer term follow-up of this cohort reports sustained benefits at two-years. 8.3% (n=6) required additional surgeries after 12 months.^103-105 A retrospective study called ROMEO2 included 136 eyes with mild-to moderate OAG treated with canaloplasty combined with trabeculectomy using the OMNI surgical system with or without combined cataract surgery were followed for 12 months. Primary endpoint included ≥20% reduction in IOP on the same or fewer medications and was achieved in 71%. Mean IOP was reduced (22.3–15.9 mmHg, p < 0.0001) and adverse events were mild.¹⁰⁶ Strength of the study include a defined primary endpoint, multiple surgical sites and surgeons, while limitations to both ROMEO trials include retrospective study design without controls, short term follow up and risk of bias.

A prospective, multicentered study (GEMINI) reported 6-month outcomes for 137 patients who underwent 360° canaloplasty and 180° trabeculectomy using the OMNI® Surgical System concomitantly with phacoemulsification in patients with mild to moderate open-angle glaucoma (OAG). Medication washout was performed and IOP after washout was 23.8 ± 3.1 mmHg at baseline. At month 6, 78% (104/134) were medication free with IOP of 14.2 mmHg with a mean reduction of 9.0 mmHg (38%). 100% (104/104) had a ≥ 20% reduction in IOP and 86% (89/104) had IOP ≥6 and ≤18 mmHg.¹⁰⁷ Twelve month outcomes were reported on 120/149 original subjects reporting 84.2% of eyes achieved IOP reductions >20% from baseline, 80% of eyes were medication-free, and 76% of eyes achieved IOP between 6–18 mmHg inclusive. Adverse events were uncommon. Most were mild and self-limited including transient hyphema (9 of 149; 6%) and transient IOP elevations (3 of 149; 2.0%). No eyes required secondary surgical interventions or experienced loss of visual acuity that was attributable to the device or procedure.¹⁰⁸ A strength of this study is the medication wash-out and limitations are lack of randomization and controls, short-term data and risk of bias. Longer term data will be obtained as the study is planned to continue for 24 months.

A retrospective observational study included 88 eyes from 73 patients with mild to moderate OAG with (n=30) or without (n=50) cataract surgery who underwent 360 ab-interno Schlemm’s canal viscodilation performed with the OMNI system. The authors reported a reduction in IOP from 23.0 to 15.6 mmHg, (p < 0.001) in those OMNI alone, and from 21.5 to 14.1, p < 0.001, in those with OMNI + cataract surgery. Complications included hyphema, mild hypotony, IOP spikes up to one-month post-surgery but without major complications and 15% required subsequent surgical procedures.¹⁰⁹

A small retrospective study included 38 eyes which underwent trabeculectomy/viscodilation using OMNI and reported 100% of eyes achieved IOP reduction >20% from baseline at 24 months.¹¹⁰ Additional studies include case series.

Excimer laser trabeculetomy (ELT)

Excimer laser trabeculectomy is a MIGS procedure that uses non thermal excimer laser to create multiple microscopic channels in the TM and wall of Schlemm’s canal. This is proposed to prevent scarring to allow fluid flow through the TM to reduce IOP. The device has been used in Europe and has received Category III CPT codes in the US, however it is not currently FDA approved in the United States.³⁷

Transciliary Fistulization

Transciliary fistulization, also called Singh filtration, is a minimally invasive glaucoma procedure in which a specialized laser device (e.g., Fugo Blade) is used to create a small opening in the sclera under the conjunctival flap to drain the aqueous from the eyes posterior chamber and reduce IOP. The Fugo Blade (MediSURG Ltd., Norristown, PAreceived 510(k) clearance for marketing from the U.S. Food and Drug Administration (FDA) for sclerostomy for the treatment of primary open-angle glaucoma where maximum tolerated medical therapy and trabeculoplasty have failed.¹¹²

This approach was introduced in 2002 in a case series of 147 patients followed for 6 months after transcilary fistulization with modified Fugo Blade (Plasma Blade) reporting successful decrease in IOP.¹¹³ Another case series reported on 60 eyes but lacked long-term follow-up due to high lost to follow-up (>50%).¹¹⁴ There are no US clinical trials, RCT or SR that address this technology. The Category III code, fistulation of sclera for glaucoma, through ciliary body, is no longer active.

Cyclophotocoagulation (CPC)

Cyclophotocoagulation decreases the production of aqueous humor rather than enabling outflow.³⁷ The AAO technical assessment on cyclophotocoagulation (CPC) states that this technique is predominantly used in the United states for refractory glaucoma such as neovascular glaucoma, traumatic glaucoma, glaucoma and affixing eyes, advanced developmental glaucoma, inflammatory glaucoma chemical, associated with corneal transplantation, silicon oil induced glaucoma and glaucoma in eyes with conjunctival scarring from previous surgery which represents some of the most difficult to treat with conventional glaucoma filtration. They describe 4 types of CPC transpupillary CPC, transvitreal endophotocoagulation, transscleral CPC (TSCPC), and Endoscopic CPC.¹¹⁵ Risk include exposure to risks of inflammation and chronic ocular hypotony or phthisis with irreversible visual loss.¹¹⁶

A report by the AAO on Cyclophotocoagulation for glaucoma reviewed 19 articles and strength of evidence rating was applied to each article. They conclude the current literature is challenged by lack of definition of success which makes comparison difficult. The recommend “Cyclophotocoagulation is indicated for patients with refractory glaucoma who have failed trabeculectomy or tube shunt procedures, patients with minimal useful vision and elevated intraocular pressure, and patients who have no visual potential and need pain relief (based on Level III evidence). It may be useful for patients whose general medical condition precludes invasive surgery or who refuse more aggressive surgery (i.e., filter or tube). It is also useful in emergent situations, such as the acute onset of neovascular glaucoma. There is insufficient evidence to definitively compare the relative efficacy of the cyclophotocoagulation procedures for glaucoma.”¹¹⁵

A systematic review and meta-analysis evaluated micropulse transscleral laser (mTLT) treatment in glaucoma patients. There were six eligible studies including 2 RCTs with a total of 386 participants. The authors reported a significant decrease in IOP after mTLT at 1 and 3 months with decrease in medication use and less complications than continuous wave transscleral CPC.¹¹⁷ These results are limited by including various types of glaucoma, different baseline characteristics, short term follow up and lack of randomization in most studies calling for further evaluation with properly conducted RCTs.

A RCT on patients with primary angle-closure (PAC) or primary angle-closure glaucoma (PACG) after laser peripheral iridotomy (LPI) included 25 eyes in the Phaco-ECPL group and 20 eyes in phacotrabeculectomy with variable follow-up times ranging from 8-25months. Mean preoperative and postoperative IOP and number of medications did not differ between the groups. However, the rate of complications (P =0.011) and interventions (P = 0.047) was greater in the phacotrabeculectomy group.¹¹⁸ Small sample size and variable follow-up are limitations.

A prospective case series describes outcomes for 71 eyes that were treated with MicroPulse® TSCPC (MP-TSCPC) for glaucoma and followed for 24 months. The authors report median reduction in IOP of 52% at 12 months. Reoperation time was a mean of 22.8 months with most receiving repeat TSCPC. The authors conclude the technology is a temporary treatment option for high IOP on maximally tolerated medical therapy when incision surgery was not ideal.¹¹⁹ Limitations include short term follow-up, small sample size and study design.

A pilot study randomized 27 patients to phacoemulsification alone (n=21) and phacoemulsifcation plus endoscopic cyclophtocoagulation (ECP). ECP was described as a cyclodestructive procedure in which the ciliary body processes are ablated with laser photocoagulation. The report the Phaco-ECP group had a lower mean post-op IOP up to 24 months post-surgery, but was not statistically significant.¹²⁰ The samples size was too small for definitive conclusions and the authors call for a larger scale study.

TSCPC consists of using a laser to deliver thermal energy to the pigmented tissue of the ciliary body to induce coagulation necrosis.¹²¹ This gained in popularity in the 1930s but is limited due to complications, but modifications of the technique have reduced these complications. A Cochrane review on cyclodestructive procedures for glaucoma limited to RCT found one RCT that compared CPC to other procedures. This trial included 92 eyes that underwent diode TSCPC and concluded there was not sufficient evidence to evaluate effectiveness.¹²² Another concern with the procedure is the risk of scarring and the potential impact that could have on future filtrating surgeries if necessary.

A prospective series followed 68 eyes for up to 10 year after contact transscleral neodymium:yttrium–aluminum–garnet (Nd:YAG) laser cyclophotocoagulation for advanced uncontrolled glaucoma. The mean preoperative IOP of 36.3_10.1 mmHg decreased to 22.6_11.3 mmHg at 1 year of follow-up (P<0.001). The mean postoperative IOP at 5 years was 21.8 ± 13.3 mmHg (P<0.001) and was 18.9 ± 12.2 mmHg at 10 years of follow-up (P<0.001) with the failure rate by 10 years of follow-up at 51.5% (35/68 eyes).¹²³

A randomized, comparative, exploratory study of patients with refractory end stage glaucoma were randomized to micropulse and continuous wave diode transscleral CPC. A successful primary outcome was achieved in 75% of patients who underwent m MP-TSCPC and 29% of patients who received continuous wave cyclophotocoagulation after 12 months (P < 0.01) and outcome was 52% and 30% (P = 0.13), respectively at 18 months.¹²⁴

A retrospective chart review of 116 eyes with refractory glaucoma that underwent MP-TSCPC were followed for six months. They reported a decrease in IOP from baseline with 74.3% success at six months with eyes that had undergone prior traditional glaucoma surgery having the highest probability of success at 67.6% compared to eyes that had not at 41.4%; p = 0.014.¹²⁵

A retrospective study included 51 eyes comparing the post-surgical outcomes of trabeculectomy and transscleral CPC followed for 2-3 years post-surgery. The authors report both groups experienced IOP decrease (trabeculectomy: 24.9 ± 6.4 to 14.9 ± 3.1 mmHg, p = 0.001/CPC: 23.0 ± 6.5 to 16.0 ± 4.1 mmHg, p = 0.001) although more pronounced and less depending on IOP-lowering medication in eyes after trabeculectomy. They also reported visual fields remain stable in the trabeculectomy group but deteriorated in the CPC group concluding favorability of trabeculectomy over CPC.¹²⁶

A retrospective report includes 143 glaucomatous eyes that underwent micropulse transscleral CPC and followed for 12 months. They reported a mean IOP decline of 7.3mmHG with 78% of patients achieving IOP less than 20% at 12 months.¹²⁷

In a retrospective report evaluated double session MP-TSCPC In patients with previous glaucoma surgery and patients without prior surgery and reported on intraocular pressures for 10-12 months. They report the reduction in IOP was higher in those who had no previous glaucoma surgery as compared to those who had With 92.9% of the no prior surgery and 87.1% of the prior surgery cases achieving reduced IOP.¹²⁸ These findings will need to be confirmed in a controlled study.

A retrospective case series of 95 eyes with refractory glaucoma and report candidates for traditional filtering surgery were treated with MC-TSCPC. The authors reported success with one treatment of 76.8% and all patients with reduction in IOP with multiple treatments for unspecified duration of follow up.³⁷

A retrospective report of patients undergoing MC-TSCPC was performed on eyes with baseline best corrected visual acuity of ≥ 20/60 and followed for approximately 10 months. They report a decrease in IOP and glaucoma medication from baseline with statistical significance and 85.4% having a reduction ≥20%. The authors consider this as a possible treatment option for incisional glaucoma surgery.¹²⁹ Limitations of the study include the retrospective nature, variable follow up and small sample size.

Comparative Studies

A 2020 systematic review and meta-analysis included 77 articles including 28 comparative studies and 12 RCTs on the available MIGS procedures. The authors report weighted mean intraocular pressure 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 trabeculectomy), 24.0% (trabectome), 25.1% (Kahook dual blade), 30.2% (Cypass), 38.8% (XEN), and 50.0% (Preserflo).¹²¹ 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 primary open angle glaucoma, pseudoexfoliative glaucoma or pigmentary glaucoma. 21 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.”¹³⁰

KBD to Trabeculectomy¹³¹

A retrospective report compared 76 eyes that underwent external Phaco-trabeculectomy and 40 eyes that underwent Phaco-KDB and followed for two years. They report a 28.4 and a 27.8% reduction in IOP respectively with no significant difference between the groups.¹³² Limitations include study design and small sample size.

Stents to KBD goniotomy

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 ±3.2 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.¹³¹ Limitations of the study include retrospect design, potential risk for bias, small sample size and lack of a control group.

A retrospective analysis of 315 eyes with mild to moderate glaucoma were divided into two groups with baseline IOP 18.2 (0.3) mmHG in the Phaco-KBD 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-KBD 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.¹³³

The KDB Goniotomy Study Group conducted a retrospective analysis of patients who had cataract surgery plus Kahook Dual Blade excisional goniotomy (n=237) or cataract surgery plus iStent trabecular micro-bypass (n=198) in eyes with mild to moderate open-angle glaucoma and visually significant cataract whose IOP was controlled with 1 or more topical IOP-lowering medications. Baseline characteristics were mostly similar except baseline mean IOP (standard error) was higher in the KDB+cataract group. Exclusions included ocular co-morbidities that reduced potential post-operative best-corrected distance visual acuity, if cataract surgery was complicated by vitreous loss, vitrectomy, or lens implantation in the sulcus or the anterior chamber; or if the eye had undergone any prior incisional glaucoma surgery. The primary end point was reduction of IOP ≥ 20% from baseline or reduction of IOP-lowering medications from baseline. A single measure of IOP was obtained at day 1, week 1, month 1, month 3 and month 6. Mean IOP in the phaco-goniotomy with KDB group decreased from17.9±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 (phacogoniotomy with KDB −4.2 mmHg [23.7%] vs phaco-iStent −2.7 mmHg [16.4%]; P<0.001). IOP-lowering medication reduction was greater in the phaco-goniotomy with KDB group compared to the phaco-iStent group (1.1 vs 0.9 medications, respectively; P=0.001). The most common adverse event 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.⁵⁶ 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 RCT was conducted to compare the reduction in IOP in eyes undergoing excision goniotomy with KCD blade to iStent microbypass implant system at the time of phacoemulsification with eyes with mild to moderate OAG.¹³⁴ 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 mm Hg 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 = .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 verses 65/78 [83.3%] in the iStent group (p=0.04) which did not reach 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.¹³⁵ 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. The report a reduction in IOP in both groups at 24 months except iStent inject-alone (n=14).¹³⁶

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 KBD group and 46.4% in IStent group achieved this level (p=0.019).¹³⁷ 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).¹³⁸ 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.¹³⁹ These findings would need to be confirmed in a controlled study with larger sample size.

Stents to Trabectome

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 (T,Trebectome). The report both reduced IOP to 13-14 mmHg range, but the stent group had a rise after 6 months to baseline or higher, so Trabectome had sustained results.¹⁴⁰ These results would need to be confirmed in controlled study to confirm findings.

A small retrospective study of 27 eyes with previous aqueous stents (iStent/iStent inject) evaluated results after OMNI and reported improved IOP control¹⁴¹, but the sample size was too small for significant as well as lack of controls and short term follow-up.

Canaloplasty to Trabeculectomy

A meta-analysis was conducted that compared the efficacy and safety of canaloplasty and trabeculectomy for glaucoma with follow up to 12 months after operation. The authors reported no difference in IOP at six months with a higher IOP at 12 months in the canaloplasty group as compared to trabeculectomy (WMD = 1.90, 95%CI: 0.12-3.69), P < 0.05). The authors conclude at 12 months trabeculectomy was more successful in reduction of IOP at the cost of higher complication rate and more demanding postoperative care than canaloplasty.¹³ This meta-analysis is limited by the included studies being prospective and retrospective cohort studies.

The analysis included 28 studies with 2 RCTs, 11 prospective reviews and 18 retrospective reviews for 1498 subjects. The authors found that the reduction in IOP was significantly higher after trabeculectomy with an average difference of 3.61 (95% CI 1.69 to 5.53) compared to a reduction of 2.11 (95% CI 1.80 to 2.42) in one year. Canaloplasty was associated with a lower incidence of complications than trabeculetomy. The authors concluded that canaloplasty was “able to achieve similar postoperative success rates and reduce the number of glaucoma medications”.¹² Limitations included the inclusion of retrospective studies without control groups resulting in high heterogeneity and risk of publication bias. There was no conflict of interest reported. Another meta-analysis included eight retrospective or prospective cohort studies. This report drew similar conclusions with a greater reduction in IOP from trabeculectomy as compared to canaloplasty with reduction in complications in the canaloplasty group at 12 months. This report was limited by few randomized controlled trials and high heterogeneity especially at 12 months.¹³

A prospective RCT of eyes clinical trial included 62 patients with 32 receiving trabeculectomy and 30 canaloplasty with iTrack followed prospectively for two years. Primary endpoint was defined as IOP of ≤ 18mmHg (definition 1) or IOP ≤ 20mmHg and ≥ 20% IOP reduction (definition 2) without vision loss or further glaucoma surgery. Surgical treatment significantly reduced IOP in both groups (p < 0.001). “Complete success was achieved in 74.2% and 39.1% (definition 1, p = 0.01), and 67.7% and 39.1% (definition 2, p = 0.04) after 2 years in the trabeculectomy and canaloplasty group, respectively. Mean absolute IOP reduction was 10.8 ± 6.9 mmHg in the trabeculectomy and 9.3 ± 5.7 mmHg in the canaloplasty group after 2 years (p = 0.47). Mean IOP was 11.5 ± 3.4 mmHg in the trabeculectomy and 14.4 ± 4.2 mmHg in the canaloplasty group after 2 years. Following trabeculectomy, complications were more frequent including hypotony (37.5%), choroidal detachment (12.5%) and elevated IOP (25.0%).” The authors conclude trabeculectomy had a stronger reduction in IOP and less need for medication and that canaloplasty could play a role for patients whom only a moderate IOP reduction is necessary due to its reduced complications and quicker recovery.¹⁴² The strength of this study is well defined and points, randomization, two year follow up in comparison to the current gold standard treatment. Limitations include small sample size, inconsistent postoperative follow up and lack of medication wash-out.

Canaloplasty to non-penetrating deep sclerectomy

A small trial randomized 29 subjects to phaco-canalopasty (PC) and 30 subjects to phaco non-penetrating deep sclerectomy (PDS) with 12 month follow up. Success was defined as a reduction in IOP ≤ 18mmHg and was achieved in both groups with mean IOP decreased in the PC group from 19.0 ±6.9 mmHg to 12.6 ±2.7 mmHg, and in the PDS group, from 19.1 ±5.8 mmHg to 14.3 ±3.5 mmHg (P < 0.05). Authors conclude both procedures similar in effectiveness and safety however the results are limited by small sample size.¹⁴³

iAccess to aqueous stent

Glaukos iAccess Trabecular Trephine is another device for cutting of the TM, A retrospective case series compared outcomes with phaco/iStent alone (n=63) versus phaco/iStent/iAccess (n=93) and found that adding trabecular meshwork trephination with the iAccess device resulted in significantly greater postoperative IOP reduction (p =0.043); medication reductions were similar.¹⁴⁴ A control group would be necessary to understand if this finding is reproducible, short-term data (3 months) and retrospective design limit the findings.

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 maximally tolerated medical therapy (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 mean medicated MDIOP 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 [5.5(0.7) mmHg Failed-Surgery subgroup, 8.1(0.9) mmHg MTMT subgroup]. 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).¹⁴⁵ 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 systematic review and meta-analysis included 13 studies, 4 randomized control trials 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 one medication up to a 60 month endpoint.¹⁴⁶ Limitations of this analysis include combining randomized control trials 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.³⁰

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 PEcK which they describe as a combination procedure including phacoemulsification with ECP and KDB. They call for further research.¹⁴⁷ 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.¹⁴⁸

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 one 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.¹⁴⁹ 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.¹⁵⁰

Other Pertinent Studies

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 three 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.¹⁵¹ 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.

Societal Guidance

The 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.¹⁵²

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.¹⁰

The 2022 AAO Summary Benchmarks for Preferred Practice Pattern Guidelines whose recommendations are defined by Grading of Recommendation Assessment, Development and Evaluation (GRADE) concludes⁷:

• Target IOP is an estimate and must be individualized and/or adjusted during the course of disease.
• 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

American Academy of Ophthalmology’s Glaucoma Preferred Practice Pattern 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.⁵

American Glaucoma Society (AGS)⁴

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 high 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 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. The state evidence is adequate in quality and quantity. The also recommend it only be performed by clinicians with specific training in the procedure.¹⁵³ 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.⁸⁷

Health Care Disparities

Glaucoma is most prevelent in the elderly population with approximately 130,000 cases of blindess due to glaucome in the United States. African Americans and Latinos are disproportionally affected. There is also a higher rate of blindess 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 populatons 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.¹⁵⁴ The IRIS Registry found notable demographic differences in surgical procedures performed with white patients disproportionately more likely to undergo an aqueous stent procedure as compared to younger and black patients who were more likely to undergo glaucoma drainage device placement, goniotomy and trabeculectomy.²⁵ Additional investigation to better understand the etiology is necessary.

Despite this known prevlence these populatons have been underrepresented in current research. A systematic review and meta analysis reviewed 105 clinical trials on glaucoma and found 70.7% of participants were white, 16.8% black, 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.¹⁵⁵

According to the 2020 AAO POAG Preferred Practice Pattern (PPP), the “potential benefits of a combined procedure (cataract extraction with IOL implantation and trabeculectomy) are protection against the IOP rise that may complicate cataract surgery alone, the possibility of achieving long-term glaucoma control with a single operation, and elimination of the risk of bleb failure with subsequent cataract surgery when glaucoma surgery is performed first. A 2015 Cochrane Systematic Review identified low quality evidence for better IOP control with combined surgery over cataract surgery alone, and more high-quality studies are required with outcomes that are relevant to patients. Therefore, the selection of a combined surgery or cataract surgery alone can be left to the discretion of the treating ophthalmologist in consultation with the individual patient. (I-, Insufficient Quality, Strong Recommendation)”⁵ The AAO POAG PPP also suggests other types of glaucoma surgery can also be combined with cataract surgery, such as implantation of aqueous shunts, nonpenetrating glaucoma surgery, minimally invasive glaucoma surgery (MIGS), and endoscopic cyclophotocoagulation.⁵ 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 American Academy of Ophthalmology’s Glaucoma Preferred Practice Pattern states that while several other incisional glaucoma surgeries exist as alternatives to trabeculectomy or aqueous shunt implantation, the precise role of these procedures is in surgical management of glaucoma continues to evolve. Multiple studies including RCTs and systematic review 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.

This contractor considers one trabecular aqueous stent (iStent, iStent inject, istent inject W, or Hydrus as of 08/2023) device per eye medically reasonable and necessary for the treatment of adults with mild or moderate open-angle glaucoma 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 procedures offer a reduction in 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, all other indications are considered not reasonable and necessary at this time. One study³³ supports the role of additional stent’s providing further reduction in intraocular pressure; however, this is limited data; and 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 Subconjunctival space stent, the only available at the time of this policy is the XEN45 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.²⁹ Equivalency was further established by a relatively large retrospective cohort study comparing XEN45 with trabeculectomy, finding “no detectable difference in risk of failure and safety profiles.”¹⁵⁶ In addition, the American Glaucoma Society (AGS), the New York State Ophthalmological Society (NYSOS), and numerous glaucoma experts wrote CGS to support XEN45 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 randomized controlled trial has demonstrated non inferiority to trabeculectomy and included intraocular pressure range as low as 15 mmHg with similar reduction in IOP to mid 14mmHg therefore the policy has been modified to allow for progressive damage with pressures under 20mmHg.¹⁵⁷ This contractor considers one XEN45 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 and/or uncontrolled IOP (progressive damage or mean diurnal medicated IOP ≥20 mmHg) on maximally tolerated medical therapy (i.e., ≥ 4 classes of topical IOP-lowering medications, or fewer in the case of tolerability or efficacy issues).¹⁵⁷ XEN45 insertion must be performed by an ophthalmologist with experience with trabeculectomy and bleb management.

The iStent Infinite® device received 510(k) clearance with an indication for use to reduce the intraocular pressure of the eye for adult patients with primary open-angle glaucoma 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 randomized controlled trial¹⁵⁶ this contractor will consider 1 device per eye reasonable and medically necessary for refractory glaucoma as defined above.

The SMEs are enthusiastic about new innovations providing additional treatment options for patients. They acknowledge evidence is lagging and welcome further studies but feel that there are barriers to RCTs and comparative studies. They acknowledge the potential impact bias may have within the papers but feel that they can be adequately assessed.

While multiple approaches for minimally invasive glaucoma surgery have emerged, there is a lack of high-quality data to understand the role of these procedures in adult glaucoma management and how this compares to standard of care medical and surgical treatment options. The IRIS Registry report summarizes this as the rate of MIGS procedures, as well as combinations of procedures at the same time, has increase significantly despite unknown safety and effectiveness.²⁵

During the Open Comment period 260 articles were submitted. To provide stakeholders a transparent understanding of the quality of literature required for review was added to the LCD. Additional literature was added to the evidence analysis and a criterion to be considered for coverage was added to coverage requirements to understand minimum quality of literature to be considered medically and reasonably necessary. Moderate and high quality were added to definitions section as defined by GRADE or similar strength of evidence criteria.

While goniotomy is well studied as first line management for pediatric glaucoma, with emerging data in adults, however long-term follow-up is lacking. The primary end points of most studies are lowering of IOP. There are not studies to determine the degree of IOP lowering required to have meaningful impact on vision and it is not determined if these technologies effectively delay or reduce vision loss in the long-term.

Goniotomy has emerged as an alternative to trabeculectomy in effort to reduce IOP in OAG patients while reducing risk of complications related to trabeculectomy. The policy has expanded to a limited coverage of goniotomy based on additional literature submitted that reached this criterion. Two RCTs have been conducted. The first compared KBD goniotomy to iStent shunt and follows for 12 months concluding similar results in IOP reductions and similar safety profiles.¹³⁴ The second includes 42 eyes and compared KBD goniotomy to phacoemulsification alone and concludes there was not significant difference in outcomes for mild to moderate glaucoma and adding ab interno trabeculectomy with KDB with phacoemulsification might not be more effective than phacoemulsification alone to reach mid-teens IOP values. Prospective studies on the KDB-blade goniotomy are moderate quality, however the small sample size and lack of controls call for more rigorous investigation.⁵⁷ Two prospective studies confirmed reduction in IOP after KBD goniotomy to 12-24 months. While long term data is lacking but prospective and retrospective reports to 24 months provides reassurance results are sustainable in the short term and no emerging complications have been reported. A 2021 Cochrane Review of randomized controlled trials to evaluate safety and efficacy of ab interno trabecular bypass surgery with Trabectome for open angle glaucoma conclude there is no high-quality evidence for the outcome of ab interno trabecular bypass surgery with Trabectome for open angle glaucoma calling for the need for properly designed randomized controlled trials.⁴⁸ On the contrary a meta-analysis on the Trabectome including 5091 patients conclude that trabeculectomy ab interno (goniotomy) is a mature surgical technique with an extensive body of experience since 2004. Goniotomies can be expected to lower the IOP by approximately 36% to a final average IOP around 16 mm Hg while decreasing the number of medications by less than one. After 2 years, the overall average success rate is 66%. The rate of visually threatening complications is <1%. This report was limited by significant heterogeneity, low-quality evidence, lack of clear definition for glaucoma, variable outcome and duration of follow-up to support the procedure.⁵¹

There is still not an understanding of optimal population for use, role in combination with other procedures and long-term outcomes. There is not data to support role as primary treatment in lieu of medical management. Despite these limitations we have expanded coverage to ensure access to care as this procedure has demonstrated short term benefit and safety and plays a role for patients who have not responded to medical management but are not good candidates or to decrease risk associated with more invasive surgical management.

Additional submitted evidence and societal input has clarified the role of CPC for challenging patients and limited coverage criteria has been added to the LCDs.

The remaining MIGS surgeries are supported by low-quality evidence and lack 24-month data in moderate to high quality literature to assume minimum level of evidence has been demonstrated.

There is emerging evidence of a role canaloplasty and the management of mild to moderate primary open angle glaucoma. The challenges are defining which surgical techniques can reach the goal, whether it should be combined with cataract surgery and the baseline IOP needed for improvements in vision over the long term. In several small before and after studies visual acuity was measured and found to improve after canaloplasty performed at the time of phacoemulsification but not canaloplasty alone.⁹⁶ Canaloplasty in combination with trabeculectomy ab interno (e.g., OMNI® Surgical System) is supported by 27 studies since 2017 however most are low quality, retrospective design. A prospective study which includes medication wash out has promising 12 month results but is limited by short-term follow-up and a further consideration can be made as evidence matures.¹⁰⁸ It is unclear if the clinical benefit being found to this point is from the trabeculectomy or the combination of procedures performed with this device. Meta-analysis has been conducted it is limited by low-quality evidence and concludes lack of evidence to support the procedure.⁹⁰

Viscocanalostomy is also not supported by moderate-high quality literature to understand role in glaucoma management.⁸⁹

Gonioscopy-assisted transluminal trabeculectomy (GATT) and ab Interno canaloplasty are supported by low quality evidence consisting of case series and retrospective reviews making up the body of literature. There are no comparison studies, understanding of the role in conjunction with cataract surgery or the application of shunts or long-term outcomes reported. Case series and retrospective reviews address phacoviscocanalostomy, however meta-analysis shows inferiority to trabeculectomy and uncertain long-term outcomes.

There are no studies that evaluate performance of multiple procedures on the same eye at the same time except in combination with phacoemulsification. There are few studies to evaluate combination of MIGs surgical procedures and stents at the same time of service. Safety and effectiveness of this approach has not been proven.

• Many of the study population have baseline IOP in the high teens (below the threshold of elevated IOP as define by IOP >21 mm Hg) 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 intraocular pressure 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.

  Patient selection has not been standardized within the studies so appropriate patient selection has not been clearly established. The long-term impact of these procedures and if they affect the outcomes of more definitive glaucoma management procedures in the future has not been established.

• Due to short-term follow-ups the impact these procedures can have on future procedures (such as scar tissue formation/loss of anatomical landmarks) eligibility/effectiveness of future interventions is not established. Studies do not report long-term outcome data and potential future harms are not yet established.⁴

In summary there are many shortcomings within the body of literature to support MIGS including:

• Largely retrospective study designs with resultant low-quality evidence.
• Lack of defined primary endpoints.
• Unclear impact of the reduction of IOP into the mid-teens on the progression of glaucoma over time.
• Paucity in the degree of IOP reduction necessary to reduce disease progression for mild to moderate glaucoma especially in those with baseline IOP <21 mmHg.
• Lack of measured visual fields and impact on sight over time.
• Few studies measure the need for additional surgical interventions in the future.
• Few studies compare surgical procedures to each other.
• Lack of medication washout in most studies which can impact results.
• Mixed inclusion populations, and it is not clear which procedures provide optimal benefit for different types of glaucoma and baseline level of disease.
• Many studies have potential risk of bias.
• Few studies have been conducted in a diverse population or populations that represent the burden of disease in the population.
• While the preliminary data on these procedures appear to be safe long term safety data has not yet been developed nor the impact of multiple procedures in the same eye over time.

For a service to be considered “reasonable and necessary” under §1862(a) (1) (A) of the Act it must be furnished in accordance with acceptable standard medical practice for the diagnosis or treatment of the condition.¹ To meet this requirement, an intervention must be established and supported by medical literature and cannot be considered experimental or investigational. In this case, there is insufficient evidence to support clear standards for patient selection, established benefit of these procedures over standard of care and how they improve health outcomes for beneficiaries, therefore do not meet these criteria. Without sufficient evidence to support these procedures they are considered investigational.

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 new develops in this field.

Documentation Requirements:

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.

1. Title XVIII of the Social Security Act: Sec. 1861.(s)(2) Part E—Miscellaneous Provisions: De?nitions of Services e. https://www.ssa.gov/OP_Home/ssact/title18/1861.htm#ft495. Published 2021. Accessed4/7/23.
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14. AAO Fact Sheets for Stent Coding and for Goniotomy https://www.aao.org/Assets/c1c5ad6a-f611-4c41-988c-991514f68602/637896975656770000/goniotomy-fs-pdf?inline=1. Published 2022. Accessed 3/23/23.
15. Barkan O. Goniotomy for the relief of congenital glaucoma. The British journal of ophthalmology. 1948;32(9):701.
16. Eslami Y, Mohammadi M, Safizadeh M, Tabatabaei SM. Six-month outcomes of combined conventional needle goniotomy and phacoemulsification in eyes with early to moderate primary open-angle and pseudoexfoliation glaucoma and ocular hypertension. Indian Journal of Ophthalmology. 2022;70(6):2030.
17. Ray VP. Commentary: Needle goniotomy in adults: Is it a viable minimally-invasive glaucoma surgery option? Indian Journal of Ophthalmology. 2022;70(6):2036.
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