Glaucoma Surgery

1. the mechanical theory,
2. the cellular (biologic) theory, and
3. the cell division theory.

The American Optometric Association's guideline on care of the patient with OAG (AOA, 2002; reviewed 2007) listed argon laser trabeculoplasty as an alternative to drug therapy for the management of patients with POAG.  The Singapore Ministry of Health's guideline on glaucoma stated that laser trabeculoplasty may be used as an adjunct to medical therapy.  Furthermore, the American Academy of Ophthalmology (AAO)'s guideline on POAG (2005) stated that laser trabeculoplasty is an appropriate initial therapeutic alternative (e.g., patients with memory problems or are intolerant to the medication).

Trabeculectomy is a surgical procedure used in the treatment of glaucoma to relieve intraocular pressure by removing part of the eye's trabecular meshwork and adjacent structures; the most common glaucoma surgery performed, it allows drainage of aqueous humor from within the eye to underneath the conjunctiva where it is absorbed.

The term aqueous drainage device refers to a broad class of tools used to facilitate aqueous flow out of the anterior chamber to control IOP. They may also be referred to as glaucoma drainage devices, tubes or shunts and may be valved or nonvalved. Such drainage devices may be placed in individuals with advanced disease in whom medical and laser therapies are inadequate and who have an underlying diagnosis that increases the risk of failure of conventional surgery. Examples of U.S. Food and Drug Administration (FDA) approved standard aqueous drainage devices include Ahmed glaucoma valve, Baerveldt seton, Schocket shunt, Krupin-Denver valve implant, Molteno implant, and the Glaucoma pressure regulator. These aqueous drainage/shunt devices are implanted to reduce IOP in the anterior chamber of the eye. The basic design of these devices is similar -- a silicone tube shunts aqueous humor from the anterior chamber to a fibrous capsule surrounding a synthetic plate or band positioned at the equatorial region of the globe. The capsule serves as a reservoir for aqueous drainage.  Many studies have demonstrated that these devices are comparable and are effective in treating patients with POAG.

Guidelines from the AAO (2003) stated that “[t]he use of drainage devices (such as those described by Molteno, Ahmed, Krupin, Baerveldt, and others) is generally reserved for patients who have failed filtering surgery with antimetabolites or for patients whose conjunctiva is so scarred from previous surgery that filtering surgery with antimetabolites is at high risk for failure.”

In a report on aqueous shunts in glaucoma by the AAO, Minckler et al (2008) provided an evidence-based summary of commercially available aqueous shunts currently used in substantial numbers (Ahmed [New World Medical, Inc., Rancho Cucamonga, CA], Baerveldt [Advanced Medical Optics, Inc., Santa Ana, CA], Krupin [Eagle Vision, Inc, Memphis, TN], Molteno [Molteno Ophthalmic Ltd., Dunedin, New Zealand]) to control IOP in various glaucomas.  A total of 17 previously published randomized trials, 1 prospective non-randomized comparative trial, 1 retrospective case-control study, 2 comprehensive literature reviews, and published English language, non-comparative case series and case reports were reviewed and graded for methodologic quality.  Aqueous shunts are used primarily after failure of medical, laser, and conventional filtering surgery to treat glaucoma and have been successful in controlling IOP in a variety of glaucomas.  The principal long-term complication of anterior chamber tubes is corneal endothelial failure.  The most shunt-specific delayed complication is erosion of the tube through overlying conjunctiva.  There is a low incidence of this occurring with all shunts currently available, and it occurs most frequently within a few millimeters of the corneo-scleral junction after anterior chamber insertion.  Erosion of the equatorial plate through the conjunctival surface occurs less frequently.  Clinical failure of the various devices over time occurs at a rate of approximately 10 % per year, which is approximately the same as the failure rate for trabeculectomy.  The authors concluded that based on level I evidence, aqueous shunts seem to have benefits (IOP control, duration of benefit) comparable with those of trabeculectomy in the management of complex glaucomas (phakic or pseudophakic eyes after prior failed trabeculectomies).  Level I evidence indicates that there are no advantages to the adjunctive use of anti-fibrotic agents or systemic corticosteroids with currently available shunts.  Too few high-quality direct comparisons of various available shunts have been published to assess the relative efficacy or complication rates of specific devices beyond the implication that larger-surface-area explants provide more enduring and better IOP control.  Long-term follow-up and comparative studies are encouraged.

A review by the AAO (Minckler et al, 2008) concluded that Level I evidence indicates that there are no advantages to the adjunctive use of antifibrotic agents with currently available shunts. The AAO assessment stated that two of three randomized controlled trials concluded that antifibrotic agents have no beneficial long-term outcome effect when used with aqueous shunts (citing Cantor, et al., 1998, Costa, et al., 2004). The AAO assessment stated that, among published randomized controlled trials, only the study of Duan, et al. (2003) concluded that adjunctive mitomycin C was helpful to promote bleb formation and duration. The AAO assessment noted that, as pointed out in the Cochrane Review on aqueous shunts (citing Minckler, et al., 2006), this study had several methodologic flaws. The AAO assessment (Minckler, et al., 2008) concluded: "Thus, there is sufficient level I evidence that demonstrates no benefit in using antifibrotic agents as adjuncts to aqueous shunt procedures." This conclusion was reaffirmed in an AAO Preferred Practice Pattern on primary open-angle glaucoma (AAO, 2010).

The ExPress glaucoma filtration device, a stainless steel nonvalved shunt, is inserted through a conjunctival flap to drain aqueous from the anterior chamber without removal of any scleral or iris tissue. Optinol (Kansas City, KS) introduced the Ex-PRESS mini glaucoma shunt in an attempt to simplify the glaucoma drainage device implantation.  This device is a single-piece, stainless steel, translimbal implant that is placed using an inserter.  Although its ease of implantation is greatly desired, its long-term efficacy and risk of complications have yet to be determined.  The Ex-PRESS mini glaucoma shunt is a 400-micron diameter tube made from implantable stainless steel that is less than 3 mm long, and is loaded on a specially designed disposable inserter.  The device reduces IOP by diverting excess aqueous humor from the anterior chamber to a subconjunctival bleb.  The Ex-PRESS shunt has an advantage over conventional filtering surgery in that it is minimally invasive.  Originally, the Ex-PRESS was designed for a direct limbus insertion through the irido-corneal angle under a conjunctival flap to drain aqueous from the anterior chamber to the subconjunctival space.  However, because of long-term complications, including conjunctival erosions, hypotony, tube dislocation, conjunctival scarring or fibrosis within the tube, the device was re-designed.  The new device is inserted via an external approach in the superficial scleral flap through the trabeculum into the anterior chamber.

In a multi-center study evaluating the safety and effectiveness of the Ex-PRESS R-50 mini glaucoma shunt, researchers found the device effective in reducing IOP.  The success rate of the Ex-PRESS in lowering IOP to less than 21 mm Hg was 69 % after 1 year without medications.  This represented a 30 to 40 % IOP reduction.  The overall average number of glaucoma medications dropped significantly from 1.65 to 0.38 at 1 year (Optonol, Inc., 2002).

In a retrospective comparative series of 100 eyes, Maris et al (2007) compared the Ex-PRESS mini implant (Model R 50) placed under a partial-thickness scleral flap with standard trabeculectomy.  Success was defined as IOP greater than or equal to 5 mm Hg and less than or equal to 21 mm Hg, with or without glaucoma medications, without further glaucoma surgery or removal of implant.  Early post-operative hypotony was defined as IOP less than 5 mm Hg during the first post-operative week.  The average follow-up was 10.8 months (range of 3.5 to 18) for the Ex-PRESS group and 11.2 months (range of 3 to 15) for the trabeculectomy group.  Although the mean IOP was significantly higher in the early post-operative period in the Ex-PRESS group compared with the trabeculectomy group, the reduction of IOP was similar in both groups after 3 months.  The number of post-operative glaucoma medications in both groups was not significantly different.  Kaplan-Meier survival curve analysis showed no significant difference in the success between the 2 groups (p =   0.594).  Early post-operative hypotony and choroidal effusion were significantly more frequent after trabeculectomy compared with the Ex-PRESS implant under scleral flap (p <  0.001).  The authors concluded that the Ex-PRESS implant under a scleral flap had similar IOP lowering efficacy with a lower rate of early hypotony compared with trabeculectomy.

Chen and colleagues (2014) evaluated the safety and effectiveness of Ex-PRESS implantation (Ex-PRESS) compared to trabeculectomy in the treatment of patients with OAG.  A comprehensive literature search using the Cochrane Methodology Register to identify randomized controlled clinical trials (RCCTs) comparing Ex-PRESS to trabeculectomy in patients with OAG.  Efficacy estimates were measured by weighted mean difference (WMD) for the percentage IOP reduction (IOPR%) from baseline to end-point, and odds ratios (OR) for the complete success rate and post-operative interventions.  Safety estimates were measured by OR for post-operative complications.  Statistical analysis was performed using the RevMan 5.1 software.  A total of 4 RCCTs were selected for this meta-analysis, including 215 eyes of 200 patients (110 eyes in the Ex-PRESS group, 105 eyes in the trabeculectomy group).  There was no significant difference between Ex-PRESS and trabeculectomy in the IOPR%.  The pooled OR comparing Ex-PRESS to trabeculectomy for the complete success rate at 1 year after surgery were in favor of Ex-PRESS.  The Ex-PRESS procedure was found to be associated with lower number of post-operative interventions and with a significantly lower frequency of hyphema than trabeculectomy, whereas other complications did not differ statistically.  The authors concluded that in OAG, Ex-PRESS and trabeculectomy provided similar IOP control, but Ex-PRESS was more likely to achieve complete success, with fewer post-operative interventions.  Complication rates were similar for the 2 types of surgery, except for a lower frequency of hyphema in the Ex-PRESS group.

Transciliary fistulization (transciliary filtration, Singh filtration) uses a thermo-cauterization device called the Fugo Blade to create a filter track from the sclera through the ciliary body to allow aqueous fluid to drain from the posterior chamber of the eye. This differs from conventional filtering surgeries in which aqueous fluid is filtered from the anterior chamber. Transciliary filtration (TCF) (Singh filtration, Fugo Blade transciliary filtration) was developed by Daljit Singh, M.D., Amistar, India for advanced glaucoma cases in which conventional surgery has failed or is most likely to fail.  Transciliary filtration creates an opening in the region of the pars plana of the ciliary body, the least vascularized part of the uveal tract and very close to the site of aqueous formation.  An opening in this region provides almost direct passage outwards without risking uveal tissue prolapse.  Currently, the literature is limited to case series reports by the same author on the technical feasibility of the procedure (Singh et al, 1979, 1981, 2002).  Singh and Singh (2002) described the procedure using a new thermo-cauterization device called the Fugo Blade^™ (plasma blade) (Medisurg Ltd., Norristown, PA).  The Fugo Blade, which is also used in anterior capsulotomies, received 510(k) marketing clearance from the FDA for sclerostomy in the treatment of POAG where maximum tolerated medical therapy and trabeculoplasty have failed.  However, the manufacturer was not required to submit to the FDA the evidence of efficacy that is necessary to support a premarket approval application (PMA).  The Fugo Blade utilizes plasma energy surrounding a thin, blunt ablation filament about as thick as a human hair to dissolve tissue bonds.  The blade generates a cloud of plasma, which produces a microablation path comparable to the effect of a miniature excimer laser.  The proposed benefit of the Fugo Blade is that there is very little bleeding, and compared with traditional trabeculectomy, Fugo Blade TCF is quicker to perform and eliminates the risk of anterior chamber collapse, since aqueous fluid drains from behind rather than from in front of the iris.  However, at the present time, there is insufficient evidence in the peer-reviewed medical literature on the TCF procedure.  Randomized controlled studies are needed to determine whether TCF is an effective procedure for glaucoma compared to other traditional forms of filtering techniques, and which glaucoma patients, if any, would benefit.

An AAO's technology assessment on "Novel glaucoma procedures" (Francis et al, 2011) noted that the disadvantages of FUGO Blade TCF are that it is an external filtration procedure with bleb formation, risk of over-filtration, and hypotony.

Trabectome is the name of the device and procedure during which a strip of tissue along the edge of the iris is removed in an attempt to reestablish normal pressure and drainage in affected eyes.

In a retrospective, cohort study, Jea and colleagues (2012) compared the effect of ab interno trabeculectomy with trabeculectomy.  A total of 115 patients who underwent ab interno trabeculectomy (study group) were compared with 102 patients who underwent trabeculectomy with intra-operative mitomycin as an initial surgical procedure (trabeculectomy group).  Inclusion criteria were open-angle glaucoma, aged greater than or equal to 40 years, and uncontrolled on maximally tolerated medical therapy.  Exclusion criterion was concurrent surgery.  Clinical variables were collected from patient medical records.  Main outcome measures included IOP and Cox proportional hazard ratio (HR) and Kaplan-Meier survival analyses with failure defined as IOP greater than 21 mmHg or less than 20 % reduction below baseline on 2 consecutive follow-up visits after 1 month; IOP less than or equal to 5 mmHg on 2 consecutive follow-up visits after 1 month; additional glaucoma surgery; or loss of light perception vision.  Secondary outcome measures included number of glaucoma medications and occurrence of complications.  Mean follow-up was 27.3 and 25.5 months for the study and trabeculectomy groups, respectively.  Intra-ocular pressure decreased from 28.1 +/- 8.6 mmHg at baseline to 15.9 +/- 4.5 mmHg (43.5 % reduction) at month 24 in the study group, and from 26.3 +/- 10.9 mmHg at baseline to 10.2 +/- 4.1 mmHg (61.3 % reduction) at month 24 in the trabeculectomy group.  The success rates at 2 years were 22.4 % and 76.1 % in the study and trabeculectomy groups, respectively (p < 0.001).  Younger age (p = 0.037; adjusted HR, 0.98 per year; 95 % CI: 0.97 to 0.99) and lower baseline IOP (p = 0.016; adjusted HR, 0.96 per 1 mmHg; 95 % CI: 0.92 to 0.99) were significant risk factors for failure in the multi-variate analysis of the study group.  With the exception of hyphema, the occurrence of post-operative complications was more frequent in the trabeculectomy group (p < 0.001).  More additional glaucoma procedures were performed after ab interno trabeculectomy (43.5 %) than after trabeculectomy (10.8 %, p < 0.001).  The authors concluded that ab interno trabeculectomy has a lower success rate than trabeculectomy.

Furthermore, a Cochrane review on “Medical versus surgical interventions for open angle glaucoma” (Burr et al, 2012), and a U.S. Preventive Services Task Force's review on "Comparative effectiveness of treatments for open-angle glaucoma" (Boland et al, 2013), as well as an UpToDate review on “Open-angle glaucoma: Treatment” (Jacobs, 2013) mentioned trabeculectomy, but not ab interno trabeculectomy.

In a retrospective, non-comparative cases-series study, Grover et al (2014) introduced a minimally invasive, ab interno approach to a circumferential 360-degree trabeculotomy and reported the preliminary results.  A total of 85 eyes of 85 consecutive patients with uncontrolled OAG and underwent gonioscopy-assisted transluminal trabeculotomy (GATT) for whom there was at least 6 months of follow-up data were included in this analysis.  These investigators performed retrospective chart review of patients who underwent GATT by 4 of the authors between October 2011 and October 2012.  The surgery was performed in adults with various OAG.  Main outcome measures included (IOP, glaucoma medications, visual acuity, and intra-operative as well as post-operative complications.  Eighty-five patients with an age range of 24 to 88 years underwent GATT with at least 6 months of follow-up.  In 57 patients with POAG, the IOP decreased by 7.7 mm Hg (standard deviation [SD], 6.2 mm Hg; 30.0 % [SD, 22.7 %]) with an average decrease in glaucoma medications of 0.9 (SD, 1.3) at 6 months.  In this group, the IOP decreased by 11.1 mm Hg (SD, 6.1 mm Hg; 39.8 % [SD, 16.0 %]) with 1.1 fewer glaucoma medications at 12 months.  In the secondary glaucoma group of 28 patients, IOP decreased by 17.2 mm Hg (SD, 10.8 mm Hg; 52.7 % [SD, 15.8 %]) with an average of 2.2 fewer glaucoma medications at 6 months.  In this group, the IOP decreased by 19.9 mm Hg (SD, 10.2 mm Hg; 56.8 % [SD, 17.4 %]) with an average of 1.9 fewer medications (SD, 2.1) at 12 months.  Treatment was considered to have failed in 9 % (8/85) of patients because of the need for further glaucoma surgery.  The cumulative proportion of failure at 1 year ranged from 0.1 to 0.32, depending on the group.  Lens status or concurrent cataract surgery did not have a statistically significant effect on IOP in eyes that underwent GATT at either 6 or 12 months (p > 0.35).  The most common complication was transient hyphema, seen in 30 % of patients at the 1-week visit.  The authors concluded that the preliminary results and safety profile for GATT, a minimally invasive circumferential trabeculotomy, are promising and at least equivalent to previously published results for ab externo trabeculotomy.

Bussel et al (2015) evaluated outcomes of ab interno trabeculectomy (AIT) with the trabectome following failed trabeculectomy. The indication for AIT was IOP above target on maximally tolerated therapy, and for phaco-AIT a visually significant cataract and need to lower IOP or glaucoma medications.  Outcomes included IOP, medications, complications, secondary procedures and success, defined as IOP of less than 21 mm Hg and a greater than 20 % reduction from baseline without further surgery.  Exclusion criteria were trabeculectomy less than 3 months prior to AIT or follow-up under 1 year.  A total of 73 eyes of 73 patients with 1 year follow-up were identified.  At 1 year, mean IOP in AIT significantly decreased by 28 % from 23.7 ± 5.5 mm Hg, and medications from 2.8 ± 1.2 to 2 ± 1.3 (n = 58).  In phaco-AIT, the mean IOP decreased 19 % from 20 ± 5.9 mm Hg and medications from 2.5 ± 1.5 to 1.6 ± 1.4 (n = 15).  Transient hypotony occurred in 7 %, and further surgery was necessary in 18 %.  For AIT and phaco-AIT, the 1-year cumulative probability of success was 81 % and 87 %, respectively.  The authors concluded that both AIT and phaco-AIT showed a reduction in IOP and medication use after 1 year, suggesting that AIT with or without cataract surgery is a safe and effective option following failed trabeculectomy.

Kaplowitz et al (2016) analyzed all of the PubMed publications on AIT with the Trabectome to determine the reduction in IOP and medications following the procedure. For IOP outcomes, PubMed was searched for “trabectome”, “ab interno trabeculotomy” and “ab interno trabeculectomy” and all available papers retrieved.  The meta-analysis used a random-effects model to achieve conservative estimates and assess statistical heterogeneity.  To investigate complications, these researchers included all abstracts from the American Glaucoma Society, AAO, American Society of Cataract and Refractive Surgery and the Association for Research in Vision and Ophthalmology.  The overall arithmetic mean baseline IOP for stand-alone Trabectome was 26.71 ± 1.34 mm Hg and decreased by 10.5 ± 1.9 mm Hg (39 % decrease) on 0.99 ± 0.54 fewer medications.  Defining success as IOP less than or equal to 21 with a 20 % decrease while avoiding re-operation, the overall average success rate after 2 years was 46 ± 34 %.  For combined phacoemulsification-Trabectome, the baseline IOP of 21 ± 1.31 mm Hg decreased by 6.24 ± 1.98 mm Hg (27 % decrease) on 0.76 ± 0.35 fewer medications.  The success rate using the same definition at 2 years was 85 ± 7%.  The weighted mean IOP difference from baseline to study end-point was 9.77 mm Hg (95 % CI: 8.90 to 10.64) stand-alone and 6.04 mm Hg (95 % CI: 4.95 to 7.13) for combined cases.  Despite heterogeneity, meta-analysis showed significant and consistent decrease in IOP and medications from baseline to end-point in AIT and phaco-AIT.  The rate of visually threatening complications was less than 1 %.  On average, trabectome lowered the IOP by approximately 31 % to a final IOP near 15 mm Hg while decreasing the number of medications by less than 1, with a low rate of serious complications.  After 2 years, the overall average success rate is 66 %.

In a review on the use of novel devices for control of IOP, Minckler and Hill (2009) noted that Trabectome, Glaukos iStent, iScience (canaloplasty), and SOLX (suprachoroidal shunt) are newly developed surgical technologies for the treatment of OAG.  These new approaches to angle surgery have been demonstrated in preliminary case series to safely lower IOP in the mid-teens with far fewer complications than expected with trabeculectomy and without anti-fibrotics.  Trabectome and iStent are relatively non-invasive, aim to improve access of aqueous to collector channels and do not preclude subsequent standard surgery.  SOLX potentially offers an adjustable aqueous outflow from the anterior chamber into the suprachoroidal space.

An AAO's technology assessment on "Novel glaucoma procedures" (Francis et al, 2011) noted that the SOLX gold shunt is limited to investigational use in the U.S.  The disadvantages of the SOLX gold shunt are the presence of a permanent implant in the anterior chamber and suprachoroidal space with the risk of erosion or exposure, and that the mechanism of action is not well-delineated.  The assessment also stated that randomized controlled trials (RCTs) are needed to ascertain the effectiveness of procedures (including FUGO Blade goniotomy, iStent, and the SOLX gold shunt) compared with trabeculectomy, with one another, and with phacoemulsification alone (in the case of  combined procedures).

In a Cochrane review, Kirwan and colleagues (2009) evaluated the effectiveness of beta radiation during glaucoma surgery (trabeculectomy).  These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (which includes the Cochrane Eyes and Vision Group Trials Register) (Issue 4 2008), MEDLINE (January 1966 to October 2008) and EMBASE (January 1980 to October 2008).  The databases were last searched on 24 October 2008.  They included randomized controlled trials comparing trabeculectomy with beta radiation to trabeculectomy without beta radiation.  Data on surgical failure (IOP greater than 21 mm Hg), IOP, and adverse effects of glaucoma surgery were collected.  Data were pooled using a fixed-effect model.  These researchers found 4 trials that randomized 551 people to trabeculectomy with beta irradiation versus trabeculectomy alone -- 2 studies were in Caucasian people (n = 126), 1 study in black African people (n = 320), and 1 study in Chinese people (n = 105).  People who had trabeculectomy with beta irradiation had a lower risk of surgical failure compared to people who had trabeculectomy alone (pooled risk ratio (RR) 0.23 (95 % confidence interval [CI]: 0.14 to 0.40).  Beta irradiation was associated with an increased risk of cataract (RR 2.89, 95 % CI: 1.39 to 6.0).  The authors concluded that trabeculectomy with beta irradiation has a lower risk of surgical failure compared to trabeculectomy alone.  They stated that a trial of beta irradiation versus anti-metabolite is needed.

Iridotomy, iridectomy or iridoplasty may be necessary for angle-closure glaucoma. Current guidelines (AAO, 2010) describe the indication for laser peripheral iridoplasty in the treatment of acute angle closure crisis (AACC) when laser iridotomy is not possible or if the AACC cannot be medically broken. Iridectomy involves surgical removal of part of the iris of the eye. Iridoplasty is a procedure using laser energy to shrink the peripheral iris; also called gonioplasty. Iridotomy is a surgical procedure in which a laser is used to cut into the iris. 

However, there is insufficient evidence for the use of laser peripheral iridoplasty in the nonacute setting. In a Cochrane review, Ng and colleagues (2012) evaluated the effectiveness of laser peripheral iridoplasty in the treatment of narrow angles (i.e., primary angle-closure suspect), primary angle-closure (PAC) or primary angle-closure glaucoma (PACG) in non-acute situations when compared with any other intervention.  In this review, angle-closure will refer to patients with narrow angles (PACs), PAC and PACG.  These investigators searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2011, Issue 12), MEDLINE (January 1950 to January 2012), EMBASE (January 1980 to January 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to January 2012), the metaRegister of Controlled Trials (mRCT), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP). There were no date or language restrictions in the electronic searches for trials.  The electronic databases were last searched on January 5,  2012.  These researchers included only RCTs in this review.  Patients with narrow angles, PAC or PACG were eligible.  They excluded studies that included only patients with acute presentations, using laser peripheral iridoplasty to break acute crisis.  No analysis was carried out as only 1 trial (n = 158) was included in the review.  The trial reported laser peripheral iridoplasty as an adjunct to laser peripheral iridotomy compared to iridotomy alone.  The study reported no superiority in using iridoplasty as an adjunct to iridotomy for IOP, number of medications or need for surgery.  The authors concluded that there is currently no strong evidence for laser peripheral iridoplasty's use in treating angle-closure.

On behalf of the AAO, Francis and cooleagues (2011) reviewed the published literature and summarized clinically relevant information about novel, or emerging, surgical techniques for the treatment of open-angle glaucoma and described the devices and procedures in proper context of the appropriate patient population, theoretic effects, advantages, and disadvantages.  Devices and procedures that have FDA clearance or are currently in phase III clinical trials in the United States were included: the Fugo blade (Medisurg Ltd., Norristown, PA), Ex-PRESS mini glaucoma shunt (Alcon, Inc., Hunenberg, Switzerland), SOLX Gold Shunt (SOLX Ltd., Boston, MA), excimer laser trabeculotomy (AIDA, Glautec AG, Nurnberg, Germany), canaloplasty (iScience Interventional Corp., Menlo Park, CA), trabeculotomy by internal approach (Trabectome, NeoMedix, Inc., Tustin, CA), and trabecular micro-bypass stent (iStent, Glaukos Corporation, Laguna Hills, CA).  Literature searches of the PubMed and the Cochrane Library databases were conducted up to October 2009 with no date or language restrictions.  These searches retrieved 192 citations, of which 23 were deemed topically relevant and rated for quality of evidence by the panel methodologist.  All studies but 1, which was rated as level II evidence, were rated as level III evidence.  All of the devices studied showed a statistically significant reduction in IOP and, in some cases, glaucoma medication use.  The success and failure definitions varied among studies, as did the calculated rates.  Various types and rates of complications were reported depending on the surgical technique.  On the basis of the review of the literature and mechanism of action, the authors also summarized theoretic advantages and disadvantages of each surgery.  The authors concluded that the novel glaucoma surgeries studied all show some promise as alternative treatments to lower IOP in the treatment of open-angle glaucoma.  It is not possible to conclude whether these novel procedures are superior, equal to, or inferior to surgery such as trabeculectomy or to one another.  The studies provide the basis for future comparative or randomized trials of existing glaucoma surgical techniques and other novel procedures.

The iStent (trabecular bypass device or microbypass implant) is a small heparin-coated, titanium implant, placed into Schlemm’s canal, intended to restore more normal fluid drainage and reduce IOP in individuals who are also undergoing cataract surgery. Schlemm’s Canal is a circular channel in the eye that collects aqueous humor from the anterior chamber and delivers it into the bloodstream. CyPass Micro-Stent is a small drainage device inserted under goinioscopic view through a clear corneal incision using a retractable guidewire. Once in place, it is designed to directly connect the anterior chamber to the suprachoroidal space (between the sclera and choroid) to increase uveoscleral outflow, thereby purportedly decreasing IOP. The iStent G3 Supra is a third generation iStent device under development and is similar in design to the CyPass Micro-Stent. The device is inserted under goinioscopic view through a clear corneal incision into the suprachoroidal space and is proposed for use alone or at the time of cataract surgery.

On June 25, 2012, the FDA approved the iStent Trabecular Micro-Bypass Stent System, Model GTS100R/L.  This is the first device approved for use in combination with cataract surgery to reduce IOP in adult patients with mild or moderate open-angle glaucoma and a cataract who are currently being treated with medication to reduce IOP. The iStent, an anterior segment aqueous drainage device, is a small (approximately 1 mm by 0.5 mm) L-shaped titanium device that is inserted into the trabecular meshwork through the cornea and is designed to create a bypass between the anterior chamber and Schlemm's canal for aqueous humor to flow directly into the canal toward the episcleral drainage system.

In a prospective, non-randomized, interventional case-series study, Buchacra et al (2011) evaluated the mid-term safety and effectiveness of the iStent glaucoma device in patients with secondary open-angle glaucoma.  A total of 10 patients with secondary open-angle glaucoma (traumatic, steroid, pseudoexfoliative, and pigmentary glaucoma) of recent onset who underwent ab interno implantation iStent were included in this analysis.  Patients were assessed following the procedure on days 1, 7, and 15 and months 1, 3, 6, and 12, and examinations included visual acuity, IOP measurement using Goldmann tonometry, number of glaucoma medications, and complications.  Wilcoxon rank-test for data with abnormal distribution was used for the analysis of IOP and glaucoma medications at baseline versus 3, 6, and 12 months following the procedure.  The mean baseline IOP was 26.5 ± 7.9 (range of 18 to 40) mm Hg, and significantly decreased in 10.4 ± 9.2 mm Hg at 3 months (p < 0.05), in 7.4 ± 4.9 mm Hg at 6 months (p < 0.05), and in 6.6 ± 5.4 mm Hg at 12 months (p < 0.05) following iStent implantation.  The mean number of hypotensive medications at baseline was 2.9 ± 0.7 (range of 2 to 4).  Statistically significant reductions in the number of medications of 1.1 ± 1.1 were observed at 3 months (p < 0.05), 1.0 ± 0.7 at 6 months (p < 0.05), and 1.1 ± 0.6 at 12 months (p < 0.05).  No significant changes in visual acuity were noted.  The most common complications comprised mild hyphema in 7 eyes and transient IOP greater than or equal to 30 mm Hg in 3 eyes on post-operative day 1.  Obstruction of the lumen of the stent with a blood clot was seen in 3 eyes, and all instances resolved spontaneously.  The authors concluded that the iStent is a safe and effective treatment option in patients with secondary open-angle glaucoma, and reduces the topical treatment burden in one hypotensive medication.

Francis and Winarko (2012) stated that in POAG, the site of greatest resistance to aqueous outflow is thought to be the trabecular meshwork.  Augmentation of the conventional (trabecular) outflow pathway would facilitate physiologic outflow and subsequently lower IOP.  Ab interno Schlemm's canal surgery including 2 novel surgical modalities, Trabectome (trabeculotomy internal approach) and Trabecular Micro-bypass Stent (iStent), is designed to reduce IOP by this approach.  In contrast to external filtration surgeries such as trabeculectomy and aqueous tube shunt, these procedures are categorized as internal filtration surgeries and are both performed from an internal approach via gonioscopic guidance.  Published results suggest that these surgical procedures are both safe and efficacious for the treatment of open-angle glaucoma.

Augustinus and Zeyen (2012) reviewed the different aspects that influence the choice and sequence of surgical treatment in patients with co-existing open-angle glaucoma and cataract.  The effect of phaco-emulsification on IOP and on a pre-existing bleb was discussed and phaco-trabeculectomy and trabeculectomy were compared.  Moreover, the most recent surgical pressure lowering techniques in combination with phaco-emulsification were reviewed: iStent, Trabectome, Hydrus, Cypass and Canaloplasty.  Medline database was used to search for relevant, recent articles.  The authors concluded that a sustained IOP decrease of 1.5 mm Hg can be expected after a phaco-emulsification in patients with open-angle glaucoma.  The higher the pre-operative pressure, the greater the IOP lowering will be.  A phaco-emulsification on a trabeculectomized eye will often lead to reduced bleb function and an IOP rise of on average 2 mm Hg after 12 months.  Compared to a trabeculectomy, phaco-trabeculectomy will have a less IOP lowering effect and a higher complication rate.  iStent and Trabectome combined with phaco-emulsification can decrease the IOP with 3 to 5 mm Hg, with a low complication rate.  The combination of Cypass and Hydrus with phaco-surgery may have a more significant IOP lowering effect but long-term results are not yet published.  Combining Canaloplasty with phaco-emulsification is a more challenging surgery but if a tension suture can be placed, an IOP decrease around 10 mm Hg might be expected.

In a prospective, non-comparative, uncontrolled, non-randomized, interventional case series study, Arriola-Villalobos and associates (2012) evaluated the long-term safety and effectiveness of combined cataract surgery and Glaukos iStent implantation for co-existent open-angle glaucoma and cataract.  Subjects older than 18 years with co-existent uncontrolled mild or moderate open-angle glaucoma (including pseudoexfoliative and pigmentary) and cataract underwent phaco-emulsification and intra-ocular lens implantation along with ab-interno gonioscopically guided implantation of 1 Glaukos iStent.  The variables recorded during a minimum of 3 years of follow-up were: IOP, number of anti-glaucoma medications and best-corrected visual acuity (BCVA).  The 19 patients enrolled were 58 to 88 years old (mean age of 74.6 ± 8.44 years).  Mean follow-up was 53.68 ± 9.26 months.  Mean IOP was reduced from 19.42 ± 1.89 mm Hg to 16.26 ± 4.23 mm Hg (p = 0.002) at the end of follow-up, indicating a 16.33 % decrease in IOP.  The mean number of pressure-lowering medications used by the patients fell from 1.32 ± 0.48 to 0.84 ± 0.89 (p = 0.046).  In 42 % of patients, no anti-glaucoma medications were used at the end of follow-up.  Mean BCVA significantly improved from 0.29 ± 0.13 to 0.62 ± 0.3 (p < 0.001).  No complications of surgery were observed.  The authors concluded that combined cataract surgery and Glaukos iStent implantation seems to be an effective and safe procedure to treat co-existent open-angle glaucoma and cataract.

In a prospective randomized controlled multi-center (29 sites) clinical trial, Craven et al (2012) evaluated the long-term safety and effectiveness of a single trabecular micro-bypass stent with concomitant cataract surgery versus cataract surgery alone for mild-to-moderate open-angle glaucoma. Eyes with mild-to-moderate glaucoma with an unmedicated IOP of 22 mm Hg or higher and 36 mm Hg or lower were randomly assigned to have cataract surgery with iStent trabecular micro-bypass stent implantation (stent group) or cataract surgery alone (control group).  Patients were followed for 24 months post-operatively.  The incidence of adverse events was low in both groups through 24 months of follow-up.  At 24 months, the proportion of patients with an IOP of 21 mm Hg or lower without ocular hypotensive medications was significantly higher in the stent group than in the control group (p = 0.036).  Overall, the mean IOP was stable between 12 months and 24 months (17.0 mm Hg ± 2.8 [SD] and 17.1 ± 2.9 mm Hg, respectively) in the stent group but increased (17.0 ± 3.1 mm Hg to 17.8 ± 3.3 mm Hg, respectively) in the control group.  Ocular hypotensive medication was statistically significantly lower in the stent group at 12 months; it was also lower at 24 months, although the difference was no longer statistically significant.  The authors concluded that patients with combined single trabecular micro-bypass stent and cataract surgery had significantly better IOP control on no medication through 24 months than patients having cataract surgery alone.  Both groups had a similar favorable long-term safety profile.

Drug-eluting punctual plugs made of resorbable material are inserted into the lacrimal punctum (tear duct) and purportedly emit sustained release medications for a 30 - 60 day period until degrading and exiting via the nasolacrimal system. These devices are currently being studied but have not received FDA approval.

Ocular Therapeutics is currently conducting clinical trials regarding the insertion of a drug-eluting implant, including punctual dilation and implant removal when performed, into the lacrimal canaliculus.  The clinical trials are investigating the use of dexamethasone intracanalicular plugs for the treatment of post-operative inflammation and pain and travoprost intracanalicular plugs for reduction of intraocular pressure in patients with glaucoma or ocular hypertension.  Ocular Therapeutix recently announced that the American Medical Association (AMA) approved a Category III CPT code for the insertion of a drug-eluting implant which could be used in clinical trials to establish use and provide a mechanism for reimbursement for insertion of these intracanalicular plugs following FDA approval.

Munoz-Negrete et al (2015) evaluated the safety and effectiveness of non-penetrating deep sclerectomy (NPDS) in 3 consecutive eyes with pre-existing and uncontrolled glaucoma after Descemet stripping with automated endothelial keratoplasty (DSAEK).  Non-penetrating deep sclerectomy with intra-scleral implant and topical adjunctive intra-operative mitomycin C (0.2 mg/ml 1 minute) was performed.  Intra-ocular pressure and number of glaucoma medication were registered before and after NPDS with at least 1-year follow-up.  Intra-operative and post-operative complications were also registered.  Before NPDS, IOP was 18 mm Hg in 1 patient and 32 mm Hg in the other 2 patients.  Four anti-glaucoma drugs were used in 2 cases and 3 in the other one.  At 1 year after NPDS, all the patients had an IOP less than or equal to 18 mm Hg.  Two patients required post-operative anti-glaucoma medications (1 drug in 1 case and 2 drugs in the other one).  Neodymium-doped yttrium aluminum garnet laser goniopuncture was needed in 2 patients and it had to be repeated in 1 of them.  No complications related to NPDS were observed.  A corneal graft rejection was observed 5 months after NPDS in 1 case that resolved without sequelae with intensive corticosteroid eye-drop therapy.  The authors concluded that NPDS could be a safe and successful alternative to conventional filtration surgery after DSAEK in eyes with uncontrolled glaucoma.  They stated that larger series and a longer follow-up would be needed to set the actual role of surgery in DSAEK patients.

An UpToDate review on “Open-angle glaucoma: Treatment” (Jacobs, 2016) states that “Filtration surgery not uncommonly fails due to excessive scar tissue formation. There are reports of the use of adjuncts before, during, or after surgery, such as beta irradiation and antimetabolites (5-fluorouracil and mitomycin C), to increase the rate of surgical success.  There is great variation in use and choice of adjuncts worldwide, and adjuncts can be associated with a higher complication rate.  For example, beta irradiation at the time of trabeculectomy can minimize scar tissue formation and increase the likelihood that surgery will effectively lower the IOP, but increases the risk of cataract formation”.

Combined Glaucoma and Cataract Surgery

Zhang and colleagues (2015) stated that cataract and glaucoma are leading causes of blindness worldwide, and their co-existence is common in elderly people. Glaucoma surgery can accelerate cataract progression, and performing both surgeries may increase the rate of post-operative complications and compromise the success of either surgery.  However, cataract surgery may independently lower intra-ocular pressure (IOP), which may allow for greater IOP control among patients with co-existing cataract and glaucoma.  The decision between undergoing combined glaucoma and cataract surgery versus cataract surgery alone is complex.  Therefore, it is important to compare the effectiveness of these 2 interventions to aid clinicians and patients in choosing the better treatment approach.  In a Cochrane review, these investigators evaluated the relative safety and effectiveness of combined surgery versus cataract surgery (phacoemulsification) alone for co-existing cataract and glaucoma.  The secondary objectives included cost-analyses for different surgical techniques for co-existing cataract and glaucoma.  These investigators searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 10), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to October 2014), EMBASE (January 1980 to October 2014), PubMed (January 1948 to October 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to October 2014), the metaRegister of Controlled Trials (mRCT), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). They did not use any date or language restrictions in the electronic searches for trials.  They last searched the electronic databases on October 3, 2014.  They checked the reference lists of the included trials to identify further relevant trials.  These researchers used the Science Citation Index to search for references to publications that cited the studies included in the review.  They also contacted investigators and experts in the field to identify additional trials.  The authors included RCTs of participants who had open-angle, pseudoexfoliative, or pigmentary glaucoma and age-related cataract.  The comparison of interest was combined cataract surgery (phacoemulsification) and any type of glaucoma surgery versus cataract surgery (phacoemulsification) alone.  Two review authors independently assessed study eligibility, collected data, and judged risk of bias for included studies.  They used standard methodological procedures expected by the Cochrane Collaboration.  These investigators included 9 RCTs, with a total of 655 participants (657 eyes), and follow-up periods ranging from 12 to 30 months; 7 trials were conducted in Europe, 1 in Canada and South Africa, and 1 in the United States.  These researchers graded the overall quality of the evidence as low due to observed inconsistency in study results, imprecision in effect estimates, and risks of bias in the included studies.  Glaucoma surgery type varied among the studies: 3 studies used trabeculectomy, 3 studies used iStent implants, 1 study used trabeculotomy, and 2 studies used trabecular aspiration.  All of these studies found a statistically significant greater decrease in mean IOP post-operatively in the combined surgery group compared with cataract surgery alone; the MD was -1.62 mmHg (95 % CI: -2.61 to -0.64; 489 eyes) among 6 studies with data at 1 year follow-up.  No study reported the proportion of participants with a reduction in the number of medications used after surgery, but 2 studies found the mean number of medications used post-operatively at 1 year was about 1 less in the combined surgery group than the cataract surgery alone group (MD -0.69, 95 % CI: -1.28 to -0.10; 301 eyes); 5 studies showed that participants in the combined surgery group were about 50 % less likely compared with the cataract surgery alone group to use 1 or more IOP-lowering medications 1 year post-operatively (RR 0.47, 95 % CI: 0.28 to 0.80; 453 eyes).  None of the studies reported the mean change in visual acuity or visual fields.  However, 6 studies reported no significant differences in visual acuity and 2 studies reported no significant differences in visual fields between the 2 intervention groups post-operatively (data not analyzable).  The effect of combined surgery versus cataract surgery alone on the need for re-operation to control IOP at 1 year was uncertain (RR 1.13, 95 % CI: 0.15 to 8.25; 382 eyes).  Also uncertain was whether eyes in the combined surgery group required more interventions for surgical complications than those in the cataract surgery alone group (RR 1.06, 95 % CI: 0.34 to 3.35; 382 eyes).  No study reported any vision-related quality of life data or cost outcome.  Complications were reported at 12 months (2 studies), 12 to 18 months (1 study), and 2 years (4 studies) after surgery.  Due to the small number of events reported across studies and treatment groups, the difference between groups was uncertain for all reported adverse events.  The authors concluded that there is low quality evidence that combined cataract and glaucoma surgery may result in better IOP control at 1 year compared with cataract surgery alone.  The evidence was uncertain in terms of complications from the surgeries.  Furthermore, this Cochrane review has highlighted the lack of data regarding important measures of the patient experience, such as visual field tests, quality of life measurements, and economic outcomes after surgery, and long-term outcomes (5 years or more). They stated that additional high-quality RCTs measuring clinically meaningful and patient-important outcomes are needed to provide evidence to support treatment recommendations.

CyPass Micro-Stent

Saheb and Ahmed (2012) noted that there is an increasing interest and availability of micro-invasive glaucoma surgery (MIGS) procedures.  It is important that this increase is supported by sound, peer-reviewed evidence.  These researchers defined MIGS, reviewed relevant publications in the period of annual review and discussed future directions.  The results of the pivotal trial comparing iStent combined with phaco-emulsification to phacoemulsification alone showed a significantly higher percentage of patients with unmedicated IOP of less than or equal to 21 mm Hg, and a comparable safety profile.  Initial results were published regarding a second-generation micro-bypass stent (iStent inject, Glaukos Corporation, Laguna Hills, CA), a canalicular scaffold (Hydrus, Ivantis Inc., Irvine, CA) and an ab interno suprachoroidal micro-stent (CyPass, Transcend Medical, Menlo Park, CA), showing a decrease in mean post-operative IOP.  Phaco-Trabectome (Ab interno trabeculectomy Trabectome, NeoMedix Inc., Tustin, CA) was compared to phaco-trabeculectomy and showed less IOP reduction, less post-operative complications, and a similar success rate.  Similar success rates were found with the comparison of excimer laser trabeculostomy (ELT, AIDA, Glautec AG, Nurnberg, Germany) and selective laser trabeculoplasty.  A number of publications reviewed the importance of the location of implantable devices, intra-operative gonioscopy, cost-effectiveness and quality-of-life studies, and randomized clinical trials.  The authors concluded that MIGS procedures offer reduction in IOP, decrease in dependence on glaucoma medications and an excellent safety profile.  Their role within the glaucoma treatment algorithm continues to be clarified and differs from the role of more invasive glaucoma surgeries such as trabeculectomy or glaucoma drainage devices.

Saheb and associates (2014) evaluated the supra-ciliary space (SCS) with anterior segment optical coherence tomography (OCT) imaging after CyPass Micro-Stent implantation.  The SCS was imaged with OCT after micro-stent implantation at 1, 6 months, and 1 year.  Images were graded on a scale of 0 to 4 for morphological features indicative of fluid presence within, or drainage through, the SCS.  A total of 35 patients underwent ab-interno micro-stent implantation.  Mean age was 68.6 ± 10.2 years.  Baseline mean IOP was 21.9 ± 6.1 mm Hg on average of 3.0 topical medications.  At 1 month, the fluid space grade was greater than or equal to 1 for 96 % (24/25) of patients for tenting, 79 % (15/19) for fluid posterior to the micro-stent, and 89 % (8/9) for fluid surrounding the micro-stent.  The mean (composite) score for all features was 2.5 ± 0.99.  The majority of patients maintained aqueous fluid through 12 months.  The authors concluded that OCT imaging provided adequate visualization of the angle, the SCS and aqueous fluid drainage after implantation of a suprachoroidal micro-stent into the SCS.

The drawbacks of this study included its retrospective nature and short-term follow-up (12 months).  Furthermore, while standardized for the purposes of this study, the grading of OCT images did not follow a validated systematic approach due to the lack of such grading scales.  There is a paucity of OCT grading systems in general, and none available for the SCS.  The authors used the size of the micro-stent as a standard measure, since its size was consistent across all subjects and independent of OCT software or print-outs.   The individual measuring the images was masked as to the post-operative time of the image, however, there may have been a bias toward larger measures when the micro-stent was fully visible.  Finally, images were not available for all subjects, with a gradual decrease in available images at later time-points.  There could have been some selection bias in this study for imaging of patients with poorer post-operative outcomes.  This bias needs to be considered as researchers evaluate the grades of the available images, especially at later time-points.

In a multi-center, prospective, consecutive case-series study, Hoh and co-workers (2014) evaluated through 2 post-operative years the clinical outcomes associated with a novel SCS micro-stent for the surgical treatment of OAG when implanted in conjunction with cataract surgery.  A total of 136 subjects (136 eyes) with OAG and requiring cataract surgery with 24-month post-operative data were included.  A combined phacoemulsification procedure, with intra-ocular lens insertion and CyPass Micro-Stent implantation into the SCS of the study eye, was performed.  At baseline, all subjects were on glaucoma medication with either uncontrolled IOP (greater than or equal to 21 mmHg, Cohort 1, n = 51) or controlled IOP (less than 21 mmHg, Cohort 2, n = 85).  Glaucoma medications were stopped post-operatively, but could be re-started if needed, at the investigator's discretion.  Device-related adverse events (AEs), post-operative IOP, best corrected distance visual acuity (BCDVA), and number of IOP-lowering medications were recorded.  The micro-stent was successfully implanted in all eyes.  At 24 months, 82 subjects remained in the study.  No sight-threatening AEs occurred.  The most common AEs were transient hypotony (15.4 %) and micro-stent obstruction (8.8 %), typically due to iris tissue over-growth; 15 subjects (11 %) required secondary incisional glaucoma surgery.  For Cohort 1 (n = 23), mean ± SD IOP was 15.8 ± 3.8 mmHg after 24 months (change, -37 % ± 19 %).  Mean IOP decrease from baseline was statistically significant (p < 0.0001) at months 6, 12, and 24.  For Cohort 2 (n = 59), mean ± SD IOP at 24 months was 16.1 ± 3.2 mmHg (change, 0 % ± 28 %).  Mean decrease from baseline was statistically significant at months 6 (p = 0.0188) and 12 (p = 0.0356).  At 24 months, the mean ± SD number of medications was 1.0 ± 1.1 in Cohort 1 and 1.1 ± 1.1 in Cohort 2.  Mean decrease from baseline medication use was statistically significant at months 6 (p < 0.001), 12 (p < 0.001), and 24 (p = 0.0265) in Cohort 1, and at months 6, 12, and 24 (all p < 0.0001) in Cohort 2.  The authors concluded that CyPass Micro-Stent implantation, in combination with cataract surgery, was associated with minimal complications while substantially lowering IOP and/or use of IOP-lowering medications.

In a multi-center RCT, Void and colleagues (2016) evaluated 2-year safety and effectiveness of SCS micro-stenting for treating mild-to-moderate POAG in patients undergoing cataract surgery.  Subjects were enrolled beginning July 2011, with study completion in March 2015.  Subjects had POAG with mean diurnal un-medicated IOP 21 to 33 mmHg and were undergoing phacoemulsification cataract surgery.  After completing cataract surgery, subjects were intra-operatively randomized to phacoemulsification only (control) or SCS micro-stenting with phacoemulsification (micro-stent) groups (1:3 ratio).  Micro-stent implantation via an ab interno approach to the SCS allowed concomitant cataract and glaucoma surgery.  Outcome measures included percentage of subjects achieving greater than or equal to 20 % un-medicated diurnal IOP lowering versus baseline, mean IOP change and glaucoma medication use, and ocular AE incidence through 24 months.  Of 505 subjects, 131 were randomized to the control group and 374 were randomized to the micro-stent group.  Baseline mean IOPs in the control and micro-stent groups were similar: 24.5 ± 3.0 and 24.4 ± 2.8 mmHg, respectively (p > 0.05); mean medications were 1.3 ± 1.0 and 1.4 ± 0.9, respectively (p > 0.05).  There was early and sustained IOP reduction, with 60 % of controls versus 77 % of micro-stent subjects achieving greater than or equal to 20 % un-medicated IOP lowering versus baseline at 24 months (p = 0.001; per-protocol analysis).  Mean IOP reduction was a decrease of 7.4 mmHg for the micro-stent group versus a decrease of 5.4 mmHg in controls (p < 0.001), with 85 % of micro-stent subjects not requiring IOP medications at 24 months.  Mean 24-month medication use was 67 % lower in micro-stent subjects (p < 0.001); 59 % of control versus 85 % of micro-stent subjects were medication free.  Mean medication use in controls decreased from 1.3 ± 1.0 drugs at baseline to 0.7 ± 0.9 and 0.6 ± 0.8 drugs at 12 and 24 months, respectively, and in the micro-stent group from 1.4 ± 0.9 to 0.2 ± 0.6 drugs at both 12 and 24 months (p < 0.001 for reductions in both groups at both follow-ups versus baseline).  No vision-threatening micro-stent-related AEs occurred; VA was high in both groups through 24 months; greater than 98 % of all subjects achieved 20/40 BCVA or better.  The authors concluded that the findings of this RCT demonstrated safe and sustained 2-year reduction in IOP and glaucoma medication use after micro-stent surgical treatment for mild-to-moderate POAG.

The authors stated that findings from this study were generalizable to men and women aged over 45 years, with Shaffer grade greater than or equal to 3 POAG and baseline un-medicated IOP 21 to 33 mmHg, and demographics typical of the enrolled US subpopulation.  They noted that the Latino/Hispanic ethnicity category constituted only 4 % of the cohort and may be under-represented.  These investigators also noted that another drawback of this study was that the principal investigator at each study site was not masked to treatment randomization during patient follow-up examinations.

The AAO Preferred Practice Pattern Glaucoma Panel (Prum et al, 2015) stated that “Several other glaucoma surgeries exist as alternatives to trabeculectomy and aqueous shunt implantation.  The precise role of these procedures in the surgical management of glaucoma remains to be determined”.  Trabecular micro-bypass stent (or iStent) is listed as one of these procedures. 

The XEN Glaucoma Treatment System (XEN45 Gel Stent and XEN Injector)

In a pilot, non-randomized, prospective clinical trial, Sheybani and colleagues (2015) examined the effect on IOP of implanting a new gelatin stent at the time of cataract surgery in the treatment of OAG.  The implantation of 2 models of a gelatin stent (Xen140 and Xen63) was performed at the time of cataract surgery without mitomycin-C.  Complete success was defined as a post-operative IOP of less than 18 mm Hg and more than a 20 % reduction in IOP at 12 months without glaucoma medication.  Failure was defined as loss of light perception vision or worse, a need for additional glaucoma surgery, or less than a 20 % reduction in the IOP from baseline.  The study included 37 eyes of 37 patients.  The mean pre-operative IOP was 22.4 mm Hg ± 4.2 (SD) on 2.5 ± 1.4 medication classes.  The mean IOP was reduced to 15.4 ± 3.0 mm Hg on 0.9 ± 1.0 medication classes (p < .0001) 12 months post-operatively.  This resulted in a qualified success of 85.3 % and a complete success rate off medications of 47.1 %.  There were no failures.  The authors concluded that cataract surgery combined with implantation of the gelatin stent resulted in a significant reduction in IOP in eyes with OAG.

Sheybani and associates (2016) evaluated the IOP-lowering effect of the XEN140 micro-fistula gel stent implant for the surgical treatment of OAG.  A total of 49 eyes (49 patients) with an IOP of greater than 18 mm Hg and less than or equal to 35 mm Hg were studied in a prospective non-randomized multi-center cohort trial of the surgical implantation of the XEN140 implant in patients with OAG.  Complete success was defined as a post-operative IOP less than or equal to 18 mm Hg with greater than or equal to20 % reduction in IOP at 12 months without any glaucoma medications.  Failure was defined as vision loss of light perceptions vision or worse, need for additional glaucoma surgery, or less than 20 % reduction of IOP from baseline.  The average age was 64.3 (28.1 to 86.9) years old; 21 eyes had prior failed trabeculectomy with mitomycin C surgery; IOP at 12 months decreased from a mean of 23.1 (± 4.1) mm Hg to 14.7 (± 3.7) mm Hg for a 36.4 % reduction in IOP from baseline.  The number of patients at 12 months who achieved an IOP of less than or equal to 18 mm Hg and greater than or equal to 20 % reduction in IOP was 40 (89 %).  The number of patients who achieved an IOP of less than or equal to 18 mm Hg and greater than or equal to 20 % reduction in IOP without anti-glaucoma medications was 18 (40 %).  The authors concluded that XEN140 gel stent lowered IOP with few complications when implanted for the surgical treatment of OAG.

Dupont and Collignon (2016) noted that POAG is a progressive ocular disease affecting adults and associated with visual field defect.  The aim of its treatment is to lower the IOP by means of ocular drops, laser or surgery.  To-date, traditional surgical techniques still remain quite invasive, but recent research efforts have been made with a view to develop minimally invasive techniques.  The XEN Gel Stent is one of them.  It allows a safe and efficient lowering of IOP by creating a sub-conjunctival flow, following an ab interno procedure that highly preserves the architecture of the treated eye.

On November 21, 2016, the FDA cleared the XEN Glaucoma Treatment System for the management of refractory glaucoma, including cases where previous surgical treatment has failed, cases of POAG, and pseudoexfoliative glaucoma (PXG) or pigmentary glaucoma with open angles that are unresponsive to maximum tolerated medical therapy. In the U.S. pivotal trial conducted in refractory glaucoma patients, XEN reduced IOP from a mean medicated baseline of 25.1 (+ 3.7) mmHg to 15.9 (+ 5.2) mmHg at the 12 month visit (n=52). The mean baseline number of IOP-lowering medications was 3.5 (± 1.0) versus an average use of 1.7 (± 1.5) medications at 12 months. The most common postoperative adverse events included BCVA loss of > 2 lines (< 30 days 15.4%; > 30 days 10.8%; 12 months 6.2%), hypotony IOP < 6 mm Hg at any time (24.6%; no clinically significant consequences were associated, no cases of persistent hypotony, and no surgical intervention was required), IOP increase > 10 mm Hg from baseline (21.5%), and needling procedure (32.3%).

XEN Gel Stent is contraindicated in angle-closure glaucoma where angle has not been surgically opened, previous glaucoma shunt/valve or conjunctival scarring/pathologies in the target quadrant, active iris neovascularization, anterior chamber IOL, intraocular silicone oil, and vitreous in the anterior chamber.

XEN Gel Stent complications may include choroidal effusion, hyphema, hypotony, implant migration, implant exposure, wound leak, need for secondary surgical intervention, and intraocular surgery complications. Safety and effectiveness in neovascular, congenital, and infantile glaucoma has not been established. The product labeling recommends avoiding digital pressure following implantation of the XEN Gel Stent to avoid implant damage.

Kerr and associates (2016) stated that recently, many new devices and procedures have been developed to lower IOP in a less invasive and purportedly safer manner than traditional glaucoma surgery.  These new devices might encourage an earlier transition to surgery and reduce the long-term commitment to topical glaucoma medications with their associated compliance and intolerance issues.  Although often seen as an adjunct to cataract surgery, a growing body of evidence suggested that primary MIGS may be a viable initial treatment option.  New studies have shown that primary ab interno trabeculectomy (Trabectome, NeoMedix Inc., Tustin, CA), trabecular micro-bypass stent insertion (iStent and iStent Inject, Glaukos Corporation, Laguna Hills, CA), canalicular scaffolding (Hydrus, Invantis Inc., Irvine CA), the ab interno gel Implant (XEN, Allergan, Dublin, Ireland) or SC stenting (CyPass Micro-Stent, Alcon, Fort Worth, TX) may lower the lowering IOP and/or topical medication burden in phakic or pseudophakic patients with glaucoma.  This effect appeared to last at least 12 months, but reliable cost-effectiveness and quality of life (QOL) indicators have not yet been established by investigator-initiated randomized trials of sufficient size and duration.

Richter and Coleman (2016) stated that MIGS aims to provide a medication-sparing, conjunctival-sparing, ab interno approach to IOP reduction for patients with mild-to-moderate glaucoma that is safer than traditional incisional glaucoma surgery.  The current approaches include: increasing trabecular outflow (Trabectome, iStent, Hydrus stent, gonioscopy-assisted transluminal trabeculotomy [GATT], Excimer laser trabeculotomy); suprachoroidal shunts (Cypass micro-stent); reducing aqueous production (endocyclophotocoagulation); and subconjunctival filtration (XEN gel stent).  

These investigators noted that MIGS technology has the potential to solve a variety of problems in current glaucoma management.  These include minimizing patient adherence problems, increasing QOL for patients with ocular toxicity, and potentially reducing lifetime costs of expensive glaucoma medications, all while preserving the conjunctiva if additional, more invasive glaucoma surgeries are necessary in the future.  Non-adherence rates in glaucoma have been reported to vary from 24 % to 59 %, and patient reasons for non-adherence include forgetfulness, side effects, lack of affordability, difficulty administering drops, complicated medication schedules, poor understanding of the disease, and poor patient-doctor communication.  Moderate-to-severe ocular surface disease is present in 71 % of patients receiving triple-drop therapy, and in these patients, implementing preservative-free alternatives may help but present additional cost and/or logistical insurance coverage barriers.  Stein et al recently reported that laser trabeculoplasty is more cost-effective than a prostaglandin analog for newly diagnosed POAG when taking into account realistic patient adherence rates. Meanwhile, Kaplan et al recently reported that both Baerveldt implant and trabeculectomy with mitomycin C are more cost-effective than maximal medical treatment.  While there are no data on cost-effectiveness of MIGS yet, if long-term efficacy of MIGS is demonstrated in future clinical studies, MIGS may also prove more cost-effective than medical treatment.

Nonetheless, there are several limitations to the current state of MIGS.  These include limited quality and duration of evidence, lack of study standardization, lack of cost-effectiveness data, and incomplete knowledge of ideal patient selection.  MIGS evidence is currently limited by the retrospective and non-masked nature in the majority of cases.  Directly comparing the evidence of each MIGS type is difficult due to the varied study designs, patient populations, and outcome measures.  Long-term outcomes over several years are mostly unknown.  In evaluating current MIGS data, because most trials have included cataract surgery, it is important for clinicians to recognize the IOP-lowering ability of cataract surgery alone.  According to a recent review by the AAO, cataract surgery results in a small, moderate, and marked reduction in IOP and medications for POAG, PXG, and PACG, respectively.  In studies where MIGS surgery has only been reported in combination with cataract surgery, clinicians cannot assume that IOP-lowering abilities will be similar when cataract surgery is not also performed.  Additionally, nearly all of the current MIGS procedures have the potential risk of late failure due to scarring, and longer follow-up periods in future studies are needed to determine how the longevity of these MIGS procedures compares to the less than ideal longevity of selective laser trabeculoplasty.

While the current MIGS procedures are generally designed to treat patients with mild-to-moderate OAG, clinicians will need to learn which specific patients will or will not benefit from a particular MIGS procedure.  The specific clinical indications that have been learned to-date were discussed under the “Adverse events and clinical considerations” sections for each procedure.  In general, the trabecular procedures will not benefit patients with elevated episcleral venous pressure.  Patients with a bleeding predisposition are less ideal for GATT and possibly for Trabectome as well.  It is also interesting to note that in the trabecular procedures, patients with higher baseline IOPs appeared to demonstrate the greatest IOP-lowering effects.  These data are not yet available for the non-trabecular procedures.  Future data will also help clinicians to individualize their management strategy for each patient.  Advances in aqueous angiography imaging will allow clinicians to localize the most active collector channels pre-operatively, before deciding where to place a particular trabecular stent.  Such imaging modalities may also assess the activity of uveo-scleral flow, thus informing placement location for uveo-scleral stents.  Perhaps in the future, these diagnostic studies will determine which class of MIGS procedure would be most effective for a particular patient.  Because future trials will follow more standardized clinical trial protocols, the ability to select appropriate patients for each MIGS type will become more optimized.  Future-generation MIGS devices will aim to surpass current MIGS outcomes, and these devices have the ever-increasing potential to improve the lives of patients with glaucoma worldwide.

Hohberger and co-workers (2017) stated that treatment of glaucoma eyes with irido-corneal endothelial syndrome is complex; MIGS, such as one that implements a novel, micro-invasive device, known as XEN gel stents, has shown promise in surgical glaucoma treatment and offers a new therapeutic option.  In a case report, these investigators reported the successful implantation of XEN45 gel stent in a woman with secondary glaucoma due to unilateral irido-corneal endothelial syndrome after descement membrane endothelial keratoplasty (DMEK) operation, and the follow-up were presented.  The authors concluded that implantation of XEN gel stents may be a promising option for minimally invasive glaucoma surgery in difficult situations, as low adverse events (AEs), good post-surgery VA and sufficient regulation of IOP can be seen.

Pinto Ferreira and colleagues (2017) noted that MIGS aims to provide a safer and less-invasive means of reducing IOP compared with traditional surgery, with the goal of reducing the need for topical medications.  The XEN gel stent is an ab-interno minimally invasive glaucoma surgery device that approaches IOP reduction by creating a sub-conjunctival drainage pathway.  As with any new device there is lack of experience and knowledge about its long-term results in terms of effectiveness, technique, and complications.  These investigators reported a clinical case of a XEN blood clot internal ostium obstruction and how it was managed.  The ab-interno approach with micro-forceps appeared a minimally invasive, safe, and effective procedure.

Vinod and Gedde (2017) reviewed recent studies evaluating the effectiveness and complication profiles of novel glaucoma procedures promoting aqueous outflow.  Literature from the 2015 to 2016 review period included abundant data regarding new and emerging glaucoma procedures.  Notable findings from recent RCTs include titratability of IOP with multiple trabecular micro-bypass stents (iStent; Glaukos, Laguna Hills, CA) and greater reduction in IOP and medication usage following intra-canalicular scaffolding (Hydrus Microstent; Ivantis Inc., Irvine, CA) combined with phacoemulsification versus phacoemulsification alone.  A SC micro-stent (CyPass Micro-Stent; Transcend Medical, Inc., Menlo Park, CA) received approval from the FDA after a pivotal trial demonstrated its safety and effectiveness.  Early studies of investigational sub-conjunctival filtering devices (XEN Gel Stent; AqueSys, Inc., Aliso Viejo, CA and InnFocus MicroShunt; InnFocus Inc., Miami, FL) offer promising evidence, but late complications are as yet unknown.  The authors concluded that newer glaucoma procedures targeting different aqueous outflow pathways have improved the safety profile of glaucoma surgery while preserving modest effectiveness.  Most can be combined with phacoemulsification, allowing for simultaneous treatment of co-morbid cataract and glaucoma.  Moreover, they stated that well-designed RCTs with extended follow-up are needed to evaluate the long-term effectiveness and late complications of these novel procedures.

Furthermore, UpToDate reviews on “Open-angle glaucoma: Treatment” (Jacobs, 2017) and “Angle-closure glaucoma” (Weizer, 2017) do not mention stenting as a therapeutic option.

In summary, further investigation with RCTs are needed on the XEN Glaucoma Treatment System, especially with its long-term effectiveness as well as cost-effectiveness.