Glaucoma Surgery
Number: 0484
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses glaucoma surgery.
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Medical Necessity
Aetna considers the following glaucoma treatments as medically necessary:
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Laser trabeculoplasty or Food and Drug Administration (FDA)-approved aqueous drainage/shunt implants for the treatment of members with refractory primary open-angle glaucoma when first-line drugs (e.g., latanoprost or timolol), and second-line drugs (e.g., brimonidine or dorzolamide) have failed to control intra-ocular pressure (IOP). Currently available implants include:
- Ahmed glaucoma implant
- Baerveldt seton
- Ex-PRESS mini glaucoma shunt
- Glaucoma pressure regulator
- Krupin-Denver valve implant
- Molteno implant
- Schocket shunt;
- One or two iStent Trabecular Micro-Bypass Stents per eye 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;
- Hydrus Microstent 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;
- XEN Glaucoma Treatment System 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;
- Adjunctive use of anti-fibrotic agents (e.g., mitomycin C) for use with the Ex-PRESS mini glaucoma shunt. However, adjunctive use of anti-fibrotic agents (e.g., mitomycin C) or systemic corticosteroids with other shunt implants is considered experimental and investigational because there are no advantages to the adjunctive use of these agents with currently available shunts;
- Combined glaucoma and cataract surgery for persons with a visually signifiant cataract with uncontrolled glaucoma despite maximal medical therapy and/or laser trabeculoplasty.
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Experimental and Investigational
The following glaucoma treatments are considered experimental and investigational because the effectiveness of these approaches has not been established (not an all-inclusive list):
- iStent Trabecular Micro-Bypass Stent System is considered contraindicated for persons with primary angle-closure glaucoma, secondary angle-closure glaucoma (including neovascular glaucoma), retrobulbar tumor, thyroid eye disease, Sturge-Weber Syndrome or any other type of condition that may cause elevated episcleral venous pressure;
- More than two iStents per eye;
- Hydrus Microstent is considered contraindicated for persons with birth defects of the anterior chamber angle of the eye, primary angle-closure glaucoma, secondary angle-closure glaucoma (including neovascular glaucoma), malignant glaucoma, traumatic glaucoma, and uveitic glaucoma;
- More than one Hydrus Microstent per eye;
- Transciliary filtration (Fugo Blade transciliary filtration, Singh filtration) for the treatment of glaucoma or any other indications;
- Suprachoroidal drainage of aqueous humor (suprachoroidal shunt), anterior segment aqueous drainage devices without extra-ocular reservoir inserted by an internal approach, and other shunts (e.g., the DeepLight Gold Micro-Shunt (SOLX, Boston, MA), Eyepass Glaucoma Implant (GMP Companies, Inc., Fort lauderdale, FL) that have not been approved by the FDA for the treatment of glaucoma;
- CyPass Micro-Stent, and the iStent G3 Supra;
- Insertion of a drug-eluting implant, including punctal dilation and implant removal when performed, into the lacrimal canaliculus for the treatment of glaucoma or ocular hypertension;
- Beta radiation for the treatment of glaucoma;
- Ab interno trabeculectomy (trabectome) for the treatment of glaucoma;
- Ab interno Kahook dual blade trabeculectomy for the treatment of primary congenital glaucoma;
- Sub-conjunctival injection of anti-vascular endothelial growth factor agent (e.g., bevacizumab, ranibizumab) for control of wound healing in glaucoma surgery;
- Intra-operative optical coherence tomography in glaucoma surgery;
- Implantation of a drug-eluting implant into lacrimal canaliculus during routine cataract removal;
- Excimer laser trabeculostomy for the treatment of glaucoma;
- Excimer laser trabeculotomy for the treatment of glaucoma;
- Standalone iStent Infinite for the treatment of open-angle glaucoma.
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Related Policies
Background
Glaucoma is an irreversible group of conditions/diseases involving death of the nerve cells in front of the optic nerve. It was once thought that glaucoma was generally due to increased intraocular pressure (IOP); however, the condition is also found in individuals with normal or low eye pressure. Therefore, diagnosis of glaucoma does not rely on increased IOP and may be related to optic nerve damage. Glaucoma is one of the leading causes of blindness with loss of peripheral vision being a hallmark sign of glaucoma.
The majority (about 90 %) of patients with glaucoma have primary open-angle glaucoma (POAG) that is defined as a chronic condition in which the IOP is elevated beyond a level compatible with the continued health and function of the eye, with a gonioscopically open angle, and a decreased facility of outflow. It is a slow progressive, insidious optic neuropathy. Primary open-angle glaucoma is also known as chronic open-angle glaucoma and chronic simple glaucoma. Another form of glaucoma is acute angle-closure glaucoma (AACG), which occurs as a dramatic, violent attack with closure of the entire angle. In contrast to POAG, AACG manifests with symptoms of blurred vision with colored halos around lights, pain, redness, and often nausea and vomiting related to the pain. In AACG, the IOP can rise precipitously to more than 50 mm Hg.
Medication, in the form of eye drops, pills or both, is the most common early treatment for glaucoma. There are numerous medications available for treating glaucoma; all of which must be taken regularly. If medication fails, other interventions may be recommended.
Acute angle-closure glaucoma is treated with oral or intravenous carbonic anhydrase inhibitors (e.g., acetazolamide), topical beta-blockers (e.g. timolol), and miotics (e.g., pilocarpine) to induce miosis. If pharmacotherapies fail, laser iridotomy can be performed to create an opening in the peripheral iris to relieve pupillary block.
Primary open-angle glaucoma is usually treated with ophthalmic medications. The first-line drugs include timolol (a non-specific beta blocker) and latanoprost (a prostaglandin F2a agonist). The second-line drugs entail brimonidine (an alpha agonist) and dorzolamide (a topical carbonic anhydrase inhibitor). The third-line drugs include apraclonidine (an alpha agonist), pilocarpine (a cholinergic agonist), acetazolamide (an oral carbonic anhydrase inhibitor), and epinephrine (a non-specific adrenergic agonist). In a randomized controlled study, Doi et al (2005) concluded that the combination of bimatoprost and latanoprost in POAG increases IOP and should not be considered as a therapeutic option.
An alternative to pharmacotherapies for the treatment of POAG is argon laser trabeculoplasty. Laser Trabeculoplasty is a surgical procedure in which a sharply focused beam of light is used to treat the drainage angle of the eye, enabling fluid to flow out of the front part, decreasing pressure. Although this procedure is frequently used and well- tolerated, there are some concerns regarding its long-term effectiveness. Stein and Challa (2007) stated that laser trabeculoplasty has been reported to be an effective method to lower IOP in patients with primary or secondary OAG, both as an initial therapy or in conjunction with hypotensive medications. These investigators described the proposed mechanisms of action of argon laser trabeculoplasty and selective laser trabeculoplasty, as well as reviewed current studies of the therapeutic effect of these interventions. The exact mechanisms by which argon laser and selective laser trabeculoplasty lower IOP are unclear; the authors discussed the 3 most common theories:- the mechanical theory,
- the cellular (biologic) theory, and
- the cell division theory.
Since both lasers are applied to the same tissue and produce similar results, they most likely produce their effects in comparable ways. These researchers also described the results of several studies comparing these devices. Most show them to be equally effective at lowering IOP; however, there are a few circumstances when selective laser trabeculoplasty may be a better option than argon laser trabeculoplasty. The authors concluded that argon laser and selective laser trabeculoplasty are safe and effective procedures for lowering IOP. They noted that results of ongoing clinical trials will help further define their role in the management of patients with OAG.
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).
When medications and/or laser trabeculoplasty have failed to reduce IOP, the most commonly used surgical intervention for POAG in adults is known as a filtering procedure. In general, there are 4 techniques for filtering surgery:- full-thickness fistulas (e.g., thermal sclerostomy),
- partial-thickness fistulas (e.g., trabeculectomy),
- tubes and setons (e.g., Molteno implant, Krupin-Denver valve implant, or Ahmed glaucoma implant), and
- cyclodestructive procedures (e.g., cyclophotocoagulation or cyclocryotherapy).
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 % confidence interval [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.
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 %.
Filippopoulos and Rhee (2008) reviewed recent advances in penetrating glaucoma surgery with particular attention paid to 2 novel surgical approaches:- ab interno trabeculectomy with the Trabectome, and
- implantation of the Ex-PRESS shunt.
Ab interno trabeculectomy (Trabectome) achieves a sustained 30 % reduction in IOP by focally ablating and cauterizing the trabecular meshwork/inner wall of Schlemm's canal. It has a remarkable safety profile with respect to early hypotonous or infectious complications as it does not generate a bleb, but it can be associated with early post-operative IOP spikes that may necessitate additional glaucoma surgery. The Ex-PRESS shunt is more commonly implanted under a partial thickness scleral flap, and appears to have similar efficacy to standard trabeculectomy offering some advantages with respect to the rate of early complications related to hypotony. The authors concluded that penetrating glaucoma surgery will continue to evolve. The findings of randomized clinical trials will determine the exact role of these surgical techniques in the glaucoma surgical armamentarium.
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".
Two iStents for the Treatment of Open-Angle Glaucoma
Myers and associates (2018) evaluated long-term outcomes of 2 trabecular micro-bypass stents, 1 suprachoroidal stent, and post-operative prostaglandin in eyes with refractory OAG. Prospective, ongoing 5-year study of 80 eligible subjects (70 with 4-year follow-up) with OAG and IOP of greater than or equal to 18 mmHg after prior trabeculectomy and while taking 1 to 3 glaucoma medications. Subjects received 2 iStent trabecular micro-bypass stents, 1 iStent Supra suprachoroidal stent, and post-operative travoprost. Post-operative IOP was measured with medication and annually following medication wash-outs. Performance was measured by the proportion of eyes with greater than or equal to 20 % IOP reduction on 1 medication (the protocol-specified prostaglandin) versus pre-operative medicated IOP (primary outcome); and the proportion of eyes with post-operative IOP of less than or equal to 15 and less than or equal to 18 mmHg on 1 medication (secondary outcome). Additional clinical and safety data included medications, visual field, pachymetry, gonioscopy, AEs, VA, and slit-lamp and fundus examinations. Pre-operatively, mean medicated IOP was 22.0 ± 3.1 mmHg on 1.2 ± 0.4 medications, and mean unmedicated IOP was 26.4 ± 2.4 mmHg. Post-operatively, among eyes without later cataract surgery, mean medicated IOP at all visits through 48 months was less than or equal to 13.7 mmHg (greater than or equal to 37 % reduction), and annual unmedicated IOP was less than or equal to 18.4 mmHg (reductions of greater than or equal to 30 % versus pre-operative unmedicated IOP and greater than or equal; to 16 % versus pre-operative medicated IOP). At all post-operative visits among eyes without additional surgery or medication, greater than or equal to 91 % of eyes had greater than or equal to 20 % IOP reduction on 1 medication versus pre-operative medicated IOP. At month 48, 97 and 98 % of eyes achieved IOP of less than or equal to 15 and less than or equal to 18 mmHg, respectively, on 1 medication; 6 eyes required additional medication, no eyes required additional glaucoma surgery, and safety measurements were favorable throughout follow-up. The authors concluded that IOP control was achieved safely with 2 trabecular micro-bypass stents, 1 suprachoroidal stent, and post-operative prostaglandin; this micro-invasive, ab interno approach introduced a possible new treatment option for refractory disease.
In a prospective, randomized, single-masked, concurrently controlled, multi-center clinical trial, Samuelson and colleagues (2019) examined the safety and effectiveness of the iStent inject Trabecular Micro-Bypass System (Glaukos Corporation, San Clemente, CA) in combination with cataract surgery in subjects with mild-to-moderate POAG. Subject were individuals with eyes with mild-to-moderate POAG and pre-operative IOP of less than or equal to 24 mmHg on 1 to 3 medications, unmedicated diurnal IOP (DIOP) 21 to 36 mmHg, and cataract requiring surgery. After uncomplicated cataract surgery, eyes were randomized 3:1 intra-operatively to ab interno implantation of iStent inject (Model G2-M-IS; treatment group, n = 387) or no stent implantation (control group, n = 118). Subjects were followed through 2 years post-operatively. Annual wash-out of ocular hypotensive medication was performed. Effectiveness end-points were greater than or equal to 20 % reduction from baseline in month 24 unmedicated DIOP and change in unmedicated month 24 DIOP from baseline. Safety measures included best spectacle-corrected visual acuity (BSCVA), slit-lamp and fundus examinations, gonioscopy, pachymetry, specular microscopy, visual fields, complications, and AEs. The groups were well balanced pre-operatively, including medicated IOP (17.5 mmHg in both groups) and unmedicated DIOP (24.8 ± 3.3 mmHg versus 24.5 ± 3.1 mmHg in the treatment and control groups, respectively, p = 0.33). At 24 months, 75.8 % of treatment eyes versus 61.9 % of control eyes experienced greater than or equal to 20 % reduction from baseline in unmedicated DIOP (p = 0.005), and mean reduction in unmedicated DIOP from baseline was greater in treatment eyes (7.0 ± 4.0 mmHg) than in control eyes (5.4 ± 3.7 mmHg; p < 0.001). Of the responders, 84 % of treatment eyes and 67 % of control eyes were not receiving ocular hypotensive medication at 23 months. Furthermore, 63.2 % of treatment eyes versus 50.0 % of control eyes had month 24 medication-free DIOP of less than or equal to 18 mmHg (difference 13.2 %; 95 % CI: 2.9 to 23.4). The overall safety profile of the treatment group was favorable and similar to that in the control group throughout the 2-year follow-up. The authors concluded that clinically and statistically greater reductions in IOP without medication were achieved after iStent inject implantation with cataract surgery versus cataract surgery alone, with excellent safety through 2 years.
Ahmed, Ex-PRESS, or Trabeculectomy for the Treatment of Primary and Secondary Glaucoma
In a systematic review and network meta-analysis, Zhang and colleagues (2022) compared the effectiveness of Ahmed, Ex-PRESS, and trabeculectomy to provide a reference for determining surgical schemes for glaucoma patients undergoing external drainage surgery in clinical practice. These investigators carried out a literature search for studies on the treatment of primary and secondary glaucoma with 3 types of external drainage surgery (Ahmed, Ex-PRESS, and trabeculectomy). As of April 24, 2021, 7 electronic databases were searched for RCTs comparing any 2 of Ahmed, Ex-PRESS, and trabeculectomy in the treatment of glaucoma. The Cochrane tool was also adopted to examine the risk of bias in these trials. The RR with 95 % CI, and WMD were determined and compared indirectly using R software. A total of 14 RCTs were included in this study, involving 866 eyes of 808 patients. As for the IOP after 3 months, trabeculectomy did not contribute to better improvement than Ahmed (WMD = 0.014; 95 % CI: -0.14 to 0.18) and Ex-PRESS (WMD = 0.014; 95 % CI: -0.072 to 0.097). However, there was a significant difference in the IOP 1 year between trabeculectomy and Ex-PRESS (WMD = 0.097; 95 % CI: 0.0080 to 0.18), with the latter achieving a favorable improvement effect. Meanwhile, the complete success (CS) of trabeculectomy was significantly lower than that of Ex-PRESS (RR = 0.73; 95 % CI: 0.57 to 0.93). In addition, Ex-PRESS was superior to Ahmed (WMD = -0.48; 95 % CI: -0.89 to -0.084) in terms of a decreased number of post-operative medications. The authors concluded that for glaucoma patients who are required to receive external drainage surgery, Ex-PRESS could achieve a significant effect on the IOP 1 year and CS, as well as a marked decrease in the number of post-operative medications used, compared with the other 2 types of surgery. In terms of the effectiveness at least 1 year after surgery, Ex-PRESS should be one of the preferred methods for external drainage.
Hydrus Microstent
In a prospective, multi-center, single-masked RCT, Pfeiffer and co-workers (2015) evaluated the safety and effectiveness of the Hydrus Microstent (Ivantis, Inc., Irvine, CA) with concurrent cataract surgery (CS) for reducing IOP in OAG. A total of 100 eyes from 100 patients aged 21 to 80 years with OAG and cataract with IOP of 24 mmHg or less with 4 or fewer hypotensive medications and a washed-out diurnal IOP (DIOP) of 21 to 36 mmHg. On the day of surgery, patients were randomized 1:1 to undergo CS with the microstent or CS alone. Post-operative follow-up was at 1 day, 1 week, and 1, 3, 6, 12, 18, and 24 months. Washout of hypotensive medications was repeated at 12 and 24 months. Response to treatment was defined as a 20 % or more decrease in washed out DIOP at 12 and 24 months of follow-up compared with baseline. Mean DIOP at 12 and 24 months, the proportion of subjects requiring medications at follow-up, and the mean number of medications were analyzed. Safety measures included AEs, change in VA, and slit-lamp observations. The proportion of patients with a 20 % reduction in washed out DIOP was significantly higher in the Hydrus plus CS group at 24 months compared with the CS group (80 % versus 46 %; p = 0.0008). Washed out mean DIOP in the Hydrus plus CS group was significantly lower at 24 months compared with the CS group (16.9 ± 3.3 mmHg versus 19.2 ± 4.7 mmHg; p = 0.0093), and the proportion of patients using no hypotensive medications was significantly higher at 24 months in the Hydrus plus CS group (73 % versus 38 %; p = 0.0008). There were no differences in follow-up VA between groups. The only notable device-related AE was focal peripheral anterior synechiae (1 to 2 mm in length). Otherwise, AE frequency was similar in the 2 groups. The authors concluded that IOP was clinically and statistically significantly lower at 2 years in the Hydrus plus CS group compared with the CS alone group, with no differences in safety.
In a retrospective case-series study, Fea and associates (2017b) examined the safety and efficacy of a new Schlemm canal scaffold microstent (Hydrus) combined with CS in routine clinical practice. Clinical outcomes in patients with POAG who had combined phacoemulsification and microstent implantation were analyzed. Data (IOP, number of glaucoma medications, incidence of complications) were collected pre-operatively and post-operatively through 24 months. A total of 92 eyes were included; 6 patients had previous glaucoma surgeries; 67 patients completed a 2-year follow-up. The mean baseline IOP was 19.4 mm Hg ± 4.4 (SD). The mean IOP was 15.5 ± 2.7 mm Hg at 1 year and 15.7 ± 2.5 mm Hg at 2 years (p < 0.001). The IOP reduction was correlated with the baseline IOP (R2 = 0.72). The mean number of glaucoma medications was 2.1 ± 1.0 pre-operatively, decreasing significantly at 1 year (0.6 ± 1.0) and 2 years (0.7 ± 1.0) (p < 0.001). At 2 years, 64 % of patients were medication-free. In patients with an IOP of 18 mm Hg or higher pre-operatively, the reduction in IOP and in the number of medications was higher; 2 patients required microstent re-positioning intra-operatively; 1 patient was treated with an argon laser for microstent obstruction, and 1 patient had a trabeculectomy at 18 months. The authors concluded that this microstent combined with CS safely and effectively reduced the IOP and medication use in a routine clinical practice setting with results comparable to those in previously published controlled clinical trials.
In a prospective, interventional, case-series study, Fea and colleagues (2017c) compared the reduction of IOP and glaucoma medications following selective laser trabeculoplasty (SLT) versus stand-alone placement of the Hydrus microstent. This trial included a total of 56 eyes (56 patients) with uncontrolled POAG. Patients received either SLT (n = 25) or Hydrus implantation (n = 31) in 2 centers; they were evaluated at baseline and 1, 7 days, 1, 3, 6 and 12 months after surgery. Main outcome measures were IOP and number of glaucoma medications variations inter-groups and intra-groups. There were no significant differences at baseline between groups, but the mean deviation was worse in the Hydrus group (-8.43 ± 6.84 dB, CI: -2.8 to -3.3 versus -3.04 ± 0.65 dB, CI: -6 to -10.8; p < 0.001). After 12 months, there was a significant decrease in IOP and medications in the Hydrus group compared with baseline values. In the SLT group, only the decrease in IOP was significant. There was 3-fold greater reduction in medication use in the Hydrus group compared with SLT (-1.4 ± 0.97 versus -0.5 ± 1.05, p = 0.001); 47 % of patients were medication-free at 12 months in the Hydrus group (4 % in the SLT group). No complications were recorded in the SLT group. In the Hydrus group, 3 patients experienced a temporary reduction of VA post-operatively, and 2 patients had post-operative IOP spikes that resolved within 1 week. The authors concluded that both SLT and Hydrus implantation reduced IOP without serious AEs; and Hydrus implantation led to a significant and further reduction in medication dependence at 12 months.
Al-Mugheiry and co-workers (2017) evaluated learning effects with respect to outcomes of a MIGS inserted during CS in glaucoma patients. This trial was a ingle-surgeon, observational cohort study of 25 consecutive Hydrus microstent insertions, with a minimum follow-up of 12 months. A learning curve analysis was performed by assessing hypotensive effect, AEs, and surgical procedure duration, with respect to consecutive case number. Success was defined with respect to various IOP targets (21, 18, 15 mm Hg) and reduction in required anti-glaucoma medications. Complete success was defined as achieving target IOP without anti-glaucoma therapy. No clinically significant AEs or learning effects were identified, although surgical time reduced with consecutive case number. Mean follow-up was 16.8 months. At final follow-up the mean IOP for all eyes was reduced from 18.1 (± 3.6) mm Hg [and a simulated untreated value of 25.9 (± 5.2) mm Hg] to 15.3 (± 2.2) mm Hg (p = 0.007; p < 0.0001) and the mean number of topical anti-glaucoma medications was reduced from 1.96 (± 0.96) to 0.04 (± 0.20) (p < 0.0001). Complete success (IOP of less than 21 mm Hg, no medications) was 96 % at final follow-up. Complete success (IOP of less than 18 mm Hg, no medications) was 80 % at final follow-up, but only 32 % with a target IOP of less than 15 mm Hg (no medications). The authors concluded that no significant learning curve effects were observed for a trained surgeon with respect to MIGS microstent insertion performed at the time of CS. Adjunctive MIGS surgery was successful in lowering IOP to less than 18 mm Hg and reducing/abolishing the requirement for anti-glaucoma medication in eyes with OAG, but less successful at achieving low IOP levels (less than 15 mm Hg).
In a prospective, multi-center, single-masked, RCT, Samuelson and colleagues (2019) compared CS with implantation of a Schlemm canal microstent with CS alone for the reduction of IOP and medication use after 24 months. Subjects with concomitant POAG, visually significant cataract, and washed-out modified DIOP (MDIOP) between 22 and 34 mmHg were enrolled in this trial. They were randomized 2:1 to receive a single Hydrus microstent in the Schlemm canal or no stent after uncomplicated phacoemulsification. Comprehensive eye examinations were conducted 1 day, 1 week, and 1, 3, 6, 12, 18, and 24 months post-operatively. Medication washout and MDIOP measurement were repeated at 12 and 24 months. The primary and secondary effectiveness end-points were the proportion of subjects demonstrating a 20 % or greater reduction in unmedicated MDIOP and change in mean MDIOP from baseline at 24 months, respectively. Hypotensive medication use was tracked throughout the course of follow-up. Safety measures included the frequency of surgical complications and AEs. A total of 369 eyes were randomized after phacoemulsification to Hydrus microstent (HMS) and 187 to no microstent (NMS). At 24 months, unmedicated MDIOP was reduced by greater than or equal to 20 % in 77.3 % of HMS group eyes and in 57.8 % of NMS group eyes (difference = 19.5 %, 95 % CI: 11.2 % to 27.8 %, p < 0.001). The mean reduction in 24-month unmedicated MDIOP was -7.6±4.1 mmHg (mean ± standard deviation) in the HMS group and -5.3±3.9 mmHg in the NMS group (difference = -2.3 mmHg; 95 % CI: -3.0 to -1.6; p < 0.001). The mean number of medications was reduced from 1.7 ± 0.9 at baseline to 0.3 ± 0.8 at 24 months in the HMS group and from 1.7 ± 0.9 to 0.7 ± 0.9 in the NMS group (difference = -0.4 medications; p < 0.001). There were no serious ocular AEs related to the microstent, and no significant differences in safety parameters between the 2 groups. The authors concluded that this 24-month multi-center RCT demonstrated superior reduction in MDIOP and medication use among subjects with mild-to-moderate POAG who received a Schlemm canal microstent combined with phacoemulsification compared with phacoemulsification alone.
On August 10, 2018, the FDA approved the Hydrus Microstent for use in conjunction with cataract surgery for the reduction of IOP in adult patients with mild-to-moderate POAG.
The Hydrus Microstent should not be used in patients with the following types of glaucoma:
- Angle closure glaucoma
- Malignant glaucoma
- Neovascular glaucoma
- Traumatic glaucoma
- Uveitic glaucoma.
Furthermore, the Hydrus Microstent should not be used in patients with birth defects of the anterior chamber angle of the eye.
In a prospective, multi-center RCT, Ahmed et al (2022) presented the 5-year results of the HORIZON trial comparing cataract surgery (CS) combined with an intra-canalicular Microstent with CS alone. Patients with cataract and POAG treated with 1 or more glaucoma medications, washed-out diurnal intra-ocular pressure (DIOP) of 22 to 34 mmHg, and no prior incisional glaucoma surgery were included in this trial. Eyes were randomized 2:1 to receive a Hydrus Microstent (HMS) or no stent following successful CS. Main outcome measures included IOP, glaucoma medication use, repeat glaucoma surgery, visual acuity (VA), visual field, procedure-related AEs, and corneal endothelial cell counts. A total of 369 eyes were randomized to HMS treatment, and 187 eyes were randomized to CS only. Study groups were well-matched for pre-operative IOP, medication use, washed-out DIOP, and glaucoma severity. Five-year follow-up was completed in 80 % of patients. At 5 years, the HMS group included a higher proportion of eyes with IOP of 18 mmHg or less without medications than the CS group (49.5 % versus 33.8 %; p = 0.003), as well as a greater likelihood of IOP reduction of 20 % or more without medications than the CS group (54.2 % versus 32.8 %; p < 0.001). The number of glaucoma medications was 0.5 ± 0.9 in the HMS group and 0.9 ± 0.9 in the CS group (p < 0.001), and 66 % of eyes in the HMS group were medication-free compared with 46 % in the CS group (p < 0.001). The cumulative risk of incisional glaucoma surgery was lower in the HMS group (2.4 % versus 6.2 %; p = 0.027, log-rank test). No clinical or statistically significant differences were found in the rate of endothelial cell loss (ECL) from 3 to 60 months between the HMS and CS alone groups (p = 0.261). The authors concluded that the addition of a Schlemm's canal Microstent in conjunction with CS was safe, resulted in lowered IOP and medication use, and reduced the need for post-operative incisional glaucoma filtration surgery compared with CS after 5 years. Furthermore, long-term presence of the implant did not affect the corneal endothelium adversely.
The authors stated that the 5-year HORIZON study findings suggested the following: First, combining HMS implantation with phacoemulsification reduced medication dependence and improved the likelihood of remaining drop-free regardless of pre-operative medication count. Second, the percentage of eyes that were medication-free was durable. Third, combining HMS implantation with CS reduced the need for further incisional glaucoma surgery compared with CS alone. Fourth, no clinically significant differences in safety outcomes existed between the HMS and CS groups, including the long-term rate of ECL. By reducing dependency on topical medications and reducing the risk of further glaucoma surgery without introducing significant complications, HMS treatment has a durable and significant impact on QOL of and the long-term consequences faced by patients with early-stage glaucoma.
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.
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 < 0.0001) 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 (2017) 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 a prospective 12-month study on patients with POAG, Fea and colleagues (2017a) evaluate the safety and efficacy of the Xen Gel Stent and provided a macroscopic as well as microscopic analyses of bleb morphology. Patients underwent implantation of the XEN Gel Stent (Allergan INC, Dublin, Ireland) either alone or combined with a cataract surgery (CS). Biomicroscopy, in-vivo confocal microscopy (IVCM), and anterior segment-optical coherence tomography (AS-OCT) were used to assess bleb morphology. Safety parameters were AEs, BCVA, visual field, and corneal endothelial cell loss. A post-operative IOP less than or equal to 18 mmHg without or on medications was respectively defined as complete and qualified success while an IOP greater than or equal to 18 mmHg was defined as failure. A total of 12 eyes of 11 patients were evaluated. At 1 year, 5 out of 10 patients available achieved a complete success while 5 were qualified success; AS-OCT showed that bleb wall reflectivity was significantly higher in the failure group; IVCM revealed that stromal density was significantly lower in the success group. No safety issues were recorded. The authors concluded that these findings showed that there were statistically significant reductions in both IOP and medication use following implantation of the XEN Gel Stent in this group of POAG patients, and no safety issues related to the procedure or to the study device were observed. They stated that implantation of the XEN Gel Stent appeared to be a safe and effective procedure for the treatment of POAG. It is unclear whether these results provided clinically significant health outcomes.
The authors noted that this study had several drawbacks. It had a small sample size (n = 12 eyes), had a relatively short follow-up (12 months), and lacked an early post-operative evaluation to more stringently monitor the bleb development. A more standardized approach in bleb evaluation with imaging techniques was also needed. The presence of inflammatory cells, indicators of inflammation, and subsequent fibrosis in the conjunctival epithelium was not methodically investigated; however, it could provide a valuable predictive tool and deserved further investigations. It was also possible that AS-OCT may mis-represent bleb structure and artifacts. These researchers stated that larger scale studies with longer follow-up are needed.
In a prospective, interventional study, Galal and associates (2017) evaluated gel microstent (XEN, AqueSys, Inc.) for treatment of POAG. A total of 13 eyes with POAG underwent XEN implantation with subconjunctival mitomycin-C. Of those eyes, 3 were pseudophakic and 10 underwent simultaneous phacoemulsification and XEN. Patients had uncontrolled IOP, had intolerance to therapy, or had maximal therapy but undergoing cataract extraction. Follow-up visits included IOP, number of medications, vision, and complications and lasted for 1 year. Complete success was defined as IOP reduction greater than or equal to 20 % from pre-operative baseline at 1 year without any glaucoma medications while partial success as IOP reduction of greater than or equal to 20 % at 1 year with medications. IOP dropped from 16 ± 4 mmHg pre-op to 9 ± 5, 11 ± 6, 12 ± 5, 12 ± 4, and 12 ± 3 mmHg at 1 week, 1, 3, 6, and 12 months (p = 0.004, 0.026, 0.034, 0.01, and 0.01, Wilcoxon Signed Ranks) consecutively. BCVA (LogMAR) was 0.33 ± 0.34 and improved to 0.13 ± 0.11 at 1 year. Mean number of medications dropped from 1.9 ± 1 pre-operatively to 0.3 ± 0.49 (p = 0.003) at 1 year; 42 % of eyes achieved complete success and 66 % qualified success. Complications included choroidal detachment in 2 eyes, and implant extrusion in 1 eye, and 2 eyes underwent trabeculectomy. The authors concluded that XEN implant was an effective surgical treatment for POAG, with significant reduction in IOP and glaucoma medications at 1 year follow-up. Moreover, they stated that this new technique needed further assessment for longer follow-up survival.
In a single-arm, open-label, multi-center clinical study, Grover and co-workers (2017) evaluated the IOP-lowering performance and safety of an ab interno gelatin stent (XEN 45 Gel Stent, Allergan plc, Irvine, CA) in refractory glaucoma. Following mitomycin C pre-treatment, the stent was placed ab interno in patients who failed prior filtering/cilio-ablative procedure or had uncontrolled IOP on maximum-tolerated medical therapy, with medicated IOP greater than or equal to 20 and less than or equal to 35 mm Hg and visual field mean deviation less than or equal to -3 dB. Primary performance outcomes: patients (%) achieving greater than or equal to 20 % IOP reduction from baseline on the same or fewer medications and mean IOP change from baseline at month 12. Procedure-related complications and ocular AEs were assessed. A total of 65 patients were implanted (intent-to-treat/safety population). At 12 months, 75.4 % (46/61; observed data) reported greater than or equal to 20 % IOP lowering from baseline on the same or fewer medications. Mean IOP change from baseline was -9.1 mm Hg (95 % CI: -10.7 to -7.5) (n = 52; observed data) at 12 months, excluding patients with missing data (n = 4) and those requiring a glaucoma-related secondary surgical intervention (n = 9). Mean medication count decreased from 3.5 (baseline) to 1.7 (12 months). No intra-operative complications or unexpected post-operative AEs were reported. Most AEs were mild/moderate; common AEs included needling (without sight-threatening complications), non-persistent loss of BCVA, and transient hypotony (requiring no surgical intervention). The authors concluded that the gelatin stent reduced IOP and medication use without raising unexpected safety concerns, offering a minimally invasive surgical option for refractory glaucoma patients.
The authors stated that potential study limitations included the absence of comparator and open-label study design, which could have impacted the outcomes. As mentioned in the key studies of the supra-ciliary microstent and trabecular micro-bypass, however, investigator masking was not feasible with this type of treatment. It was also worth noting that potential effects on the study eye of changes in the fellow eye were not considered. In addition, the study population included less than or equal to 5 % Asian patients and less than or equal to 13 % patients with pseudo-exfoliation, pigmentary, or mixed-mechanism glaucoma. Nonetheless, they stated that these findings were generalizable to men and women with refractory glaucoma characterized by uncontrolled IOP on maximum-tolerated medical therapy and open angles.
Ozal and co-workers (2017) reported follow-up data for patients who underwent XEN45 gel stent implantation. A total of 15 eyes in 15 patients who underwent XEN45 gel stent implantation surgery were examined in the study. All patients were examined pre-operatively and at the following post-operative time points: 1 day; 1 and 2 weeks; and 1, 2, 3, 6, and 12 months; IOP was measured via Goldmann applanation tonometry. Combined surgical procedures (XEN45 + phacoemulsification + intraocular lens) were performed in patients who that had cataracts in addition to glaucoma. The mean IOP values were significantly lower than the pre-operative values at all post-operative visits (p < 0.001). In 2 patients, the IOP exceeded 20 mmHg 12 months after surgery. These IOP increases were controlled by medical therapy, and none of the patients needed another surgical procedure. The authors concluded that the results of this study were promising, and XEN45 gel stent implantation presented a valuable contribution to glaucoma surgery. Using XEN45 gel stents, these investigators reduced IOP and medication use without significant complications in patients with different forms of glaucoma. They believed that this new surgical procedure would play an important role in glaucoma surgery in the future. Moreover, they stated that further studies with greater numbers of patients and longer follow-up periods are needed to clarify certain points.
The authors stated that this study had several drawbacks; in particular, the small number of patients (n = 15) and the lack of control group limited their comparisons. Thus, it has not been evaluated whether the efficacy of XEN45 gel implantation differs between patients according to prior glaucoma surgery. Furthermore, the mild IOP-reducing effect of phacoemulsification alone was not evaluated. In addition, these researchers could not evaluate in which glaucoma type this surgical method is most effective. They noted that clinical trials (NCT02006693, NCT02036541) are ongoing for XEN gel stents; these researchers think that after the results of these studies have been published, new aspects of XEN gel stent implantation will be revealed.
Sng and associates (2018) noted that the XEN-45 implant (a hydrophilic collagen implant that drains aqueous to the subconjunctival space) has not been studied in the context of uveitic glaucoma. In an exploratory, prospective, case-series study, these researchers determined the safety and efficacy of the XEN-45 collagen implant in eyes with uveitic glaucoma. A total of 24 consecutive patients with medically uncontrolled uveitic glaucoma (mean age ± standard deviation [SD] = 45.3 ± 18.1 years) were implanted with the XEN-45 implant. The primary outcome measure was IOP reduction at 12 months as compared to baseline. Secondary outcome measures included ocular hypotensive medication use at 12 months, the requirement for further glaucoma surgery and failure. Intra-operative and post-operative complications were documented. The baseline mean ± SD IOP was 30.5 ± 9.8 mmHg and the mean ± SD number of glaucoma medications required was 3.3 ± 0.8. In 20 eyes (83.3 %) in whom conventional glaucoma surgery was originally perceived to be inevitable, further surgery was not required after XEN-45 implantation. The mean IOP was reduced by 60.2 % from baseline to 12.2 ± 3.1 mmHg and mean medication usage was reduced to 0.4 ± 0.9 at 12 months (both p < 0.001); 1 patient had hypotony persisting beyond 2 months that required surgical revision, and 1 patient developed blebitis. The 12-month cumulative Kaplan-Meier survival probability was 79.2 %. The authors concluded that the XEN-45 implant was effective for the treatment of patients with medically uncontrolled uveitic glaucoma. Moreover, they stated that potentially sight-threatening complications, including bleb-related ocular infection and persistent hypotony, may occur. These researchers noted that these preliminary findings from an exploratory study need to be validated by well-designed studies.
In an international, multi-center, retrospective, interventional cohort study, Schlenker and colleagues (2017) compared the safety, efficacy, and risk factors for failure of standalone ab interno gelatin microstent implantation with mitomycin C (MMC) versus trabeculectomy with MMC. A total of 354 eyes of 293 patients (185 microstent and 169 trabeculectomy) with no prior incisional surgery were included in this trial. Consecutive eyes with uncontrolled glaucoma underwent microstent or trabeculectomy surgery from January 1, 2011 through July 31, 2015 at 4 academic ophthalmology centers. Primary outcome measure was HR of failure, with failure defined as 2 consecutive IOP readings of less than 6 mmHg with vision loss or greater than 17 mmHg without glaucoma medications (complete success) at least 1 month after surgery despite in-clinic interventions (including needling). Secondary outcome measures included IOP thresholds of 6 to 14 mmHg and 6 to 21 mmHg and same thresholds allowing for medications (qualified success), interventions, complications, and re-operations. Baseline characteristics were similar, except more men (56 % versus 43 %), younger patients (average, by 3 years), better pre-operative VA (22 % versus 32 % with 0.4 logarithm of the minimum angle of resolution vision or worse), and more trabeculoplasty (52 % versus 30 %) among microstent eyes. The adjusted HR of failure of the microstent relative to trabeculectomy was 1.2 (95 % CI: 0.7 to 2.0) for complete success and 1.3 (95 % CI: 0.6 to 2.8) for qualified success, and similar for other outcomes. Time to 25 % failure was 11.2 months (95 % CI: 6.9 to 16.1 months) and 10.6 months (95 % CI: 6.8 to 16.2 months) for complete success and 30.3 months (95 % CI: 19.0 to infinity months) and 33.3 months (95 % CI: 25.7 to 46.2 months) for qualified success. Overall, white ethnicity was associated with decreased risk of failure (adjusted HR, 0.49; 95 % CI: 0.25 to 0.96), and diabetes was associated with increased risk of failure (adjusted HR, 4.21; 95 % CI: 2.10 to 8.45). There were 117 and 165 distinct interventions: 43 % and 31 % underwent needling, respectively, and 50 % of trabeculectomy eyes underwent laser suture lysis. There were 22 and 30 distinct complications, although most were transient; 10 % and 5 % underwent re-operation (p = 0.11). The authors concluded that there was no detectable difference in risk of failure and safety profiles between stand-alone ab interno microstent with MMC and trabeculectomy with MMC.
In a retrospective analysis, Hengerer and associates (2017) evaluated the IOP-lowering effects and complication management of an ab interno gel implant for the treatment of patients refractory to anti-glaucoma medication or glaucoma surgery. These investigators examined medical records of 242 consecutive eyes of 146 patients with uncontrolled IOP despite maximum tolerated medical therapy or prior surgical intervention that underwent XEN45 implantation (as sole procedure or in combination with CS) between March 2014 and June 2015. Data included IOP, number of glaucoma medications, the need for additional surgery, needling, and complications. During the study period, mean IOP had decreased by 54.1 % from 32.19 (± 9.1) mm Hg to 14.24 (± 4.0) mm Hg (p = 0.00; Wilcoxon test). The number of anti-glaucoma medications had decreased from a mean of 3.13 ± 1.0 to 0.3 ± 0.7 (p = 0.00; Wilcoxon test). Needling was required between week 1 and months 3 in 27.7 % of all eyes to enhance the outflow. Hypotony (IOP less than 6 mm Hg) was observed in 9 eyes (4.0 %) at 1 month but normalized in all eyes at 12 months post-operatively; 2 eyes experienced hypotony requiring the refill of the anterior chamber. The authors concluded that these findings indicated that the XEN45 gel implant had a favorable safety profile and was an effective therapeutic option for controlling IOP in glaucoma patients with unregulated IOP despite IOP-lowering medical therapy or prior surgical intervention. It offered an effective approach, both as sole procedure and in combination with CS.
In a prospective, non-randomized, clinical study, De Gregorio and co-workers (2018) examined the efficacy in IOP reduction and safety of the smallest gel stent (XEN 45 Gel Stent) micro-incisional glaucoma surgery combined with micro-incisional CS (MICS). A total of 41 eyes of 33 patients with OAG underwent a XEN 45 Gel Stent implantation combined with MICS. Treatment outcomes analyzed included: IOP, medication use, intra- and post-operative complications. At the end of the follow-up, these researchers evaluated the complete success, defined as a post-operative IOP of greater than or equal to 6 and less than or equal to 17 mmHg without glaucoma medications and the qualified success defined as a post-operative IOP greater than or equal to 6 and less than or equal to 17 mmHg, with glaucoma medications. The mean pre-operative IOP was 22.5 ± 3.7 mmHg on 2.5 ± 0.9 medication classes. After 12 months, the mean post-operative IOP was 13.1 ± 2.4 mmHg (mean IOP reduction of 41.82 %) with a mean of 0.4 ± 0.8 medication classes (p < 0.05 for IOP and medications). The complete success rate was achieved in 80.4 % and a qualified success in 97.5 %. There were no major intra- and post-operative complications during the 1st year of follow-up. The authors concluded that this study demonstrated that the smaller diameter XEN 45 gel implant was statistically effective in reducing IOP and medications in glaucoma patients with a low rate of complications. The main drawbacks of this study were its small sample size (n = 33 patients), relatively short-term follow-up (12 months), and its non-randomized design.
In a prospective, interventional study, Mansouri and colleagues (2018) evaluated the safety and efficacy of XEN gel implant as a stand-alone treatment versus combined XEN-phacoemulsification surgery (XEN + CS) in glaucoma patients. A total of 149 eyes (113 patients) with OAG and uncontrolled (IOP despite medical treatment were enrolled at a tertiary glaucoma center and followed-up for a minimum of 1 year. Approximately 2/3 of patients underwent combined XEN + CS, while the remainder had XEN alone surgery. Primary outcome was a 20 % or more decrease in IOP from medicated baseline at 1 year. Mean IOP, mean number of medications at last follow-up, and incidence of AEs were analyzed. Of 149 enrolled eyes, data of 87 (58 %) were available at 1 year. A total of 109 (73.2 %) eyes underwent XEN + CS and 40 (26.8 %) XEN alone surgery. Mean medicated IOP was 20.0 ± 7.1 at baseline and 13.9 ± 4.3 mm Hg at 1 year (p < 0.01), a 31 % IOP reduction. Mean medications dropped from 1.9 ± 1.3 pre-operatively to 0.5 ± 0.8 at 1 year (p < 0.001). In total, 62.1 % of patients achieved a greater than or equal to 20 % IOP reduction; this proportion was higher in the XEN alone group; 57.7 % of eyes achieved complete success (without any anti-glaucoma medications) and 71.1 % qualified success (with or without medications) when IOP of less than 16 mm Hg was considered as the definition of success. In all, 37 % of patients required needling intervention; AEs included bleb revision in 5 eyes, choroidal detachment in 2 eyes, and 2nd glaucoma surgery in 9 eyes. The authors concluded that the XEN gel implant as a stand-alone procedure or combined with CS demonstrated safe and sustained IOP reduction after 1 year. This study had 2 main drawbacks: First, only 58 % (87) of the 149 enrolled eyes were available at 1 year follow-up; and second, follow-up was short-term (1 year).
Widder and colleagues (2018) examined the IOP-lowering potential, the risk profile, and the success rate of the XEN45 Gel Stent. A total of 261 eyes underwent surgery. The mean follow-up time was 8.5 months. The aim of the treatment was to achieve adequate IOP reduction without medication. Therefore, all patients who did not show sufficiently reduced IOP underwent a surgical revision with opening of the conjunctiva. To determinate the success rate, these researchers performed 2 kinds of analysis: the primary success rate – eyes with appropriate IOP control without medication or surgical revision, and overall success rate – 1 surgical revision was allowed; IOP was lowered from 24.3 mmHg (SD 6.6) to 16.8 mmHg (SD 7.6), and the medication score was lowered from 2.6 (SD 1.1) to 0.2 (SD 0.7). Revisional surgery was performed in 80 eyes (34 %). After a 1st revision, IOP was lowered to 14.0 mmHg (SD 5.1), and the medication score was lowered to 0.2 (SD 0.6). The primary success rate was 66 % and the overall success rate 90 %. The primary success rate was higher in pseudophakic eyes (73 %) than in phakic eyes (53% ) or combined surgery (55 %). The authors concluded that the XEN45 Gel Stent had an IOP-lowering potential and few side-effects; pseudophakic eyes appeared to have a better primary prognosis compared to combined surgery or surgery in phakic eyes.
In a prospective, non-randomized, open-label, multi-center, 2-year study, Reitsamer and colleagues (2019) examined the effectiveness of an ab interno subconjunctival gelatin implant (the AqueSys XEN Implant) as primary surgical intervention in reducing IOP and IOP-lowering medication count in medically uncontrolled moderate POAG. Eyes with medicated baseline IOP 18 to 33 mmHg on 1 to 4 topical medications were implanted with (phaco + implant) or without (implant alone) phacoemulsification. Changes in mean IOP and medication count at months 12 (primary outcomes) and 24, clinical success rate (eyes [%] achieving greater than or equal to 20 % IOP reduction from baseline on the same or fewer medications without glaucoma-related secondary surgical intervention), intra-operative complications, and post-operative AEs were assessed. The modified intent-to-treat population included 202 eyes (of 218 implanted). Changes (S.D.) in mean IOP and medication count from baseline were - 6.5 (5.3) mmHg and - 1.7 (1.3) at month 12 and - 6.2 (4.9) mmHg and - 1.5 (1.4) at month 24, respectively (all p < 0.001). Mean medicated baseline IOP was reduced from 21.4 (3.6) to 14.9 (4.5) mmHg at 12 months and 15.2 (4.2) mmHg at 24 months, with similar results in both treatment groups. The clinical success rate was 67.6 % at 12 months and 65.8 % at 24 months. Overall, 51.1 (12 months) and 44.7 % (24 months) of eyes were medication-free. The implant safety profile compared favorably with that published for trabeculectomy and tube shunts. The authors concluded that the gelatin implant effectively reduced IOP and medication needs over 2 years in POAG uncontrolled medically, with an acceptable safety profile.
Ab Interno Kahook Dual Blade Trabeculectomy for the Treatment of Primary Congenital Glaucoma
Harvey and Schmitz (2020) noted that primary congenital glaucoma is a rare ocular disorder that is responsible for 0.01 % to 0.04 % of total blindness worldwide. The goal of congenital glaucoma management is to allow for proper development of the immature visual system by controlling IOP. Medical therapy usually provides a supportive role to temporarily reduce IOP, however, patients typically require irido-corneal angle surgery to facilitate aqueous humor outflow. These researchers described the use of minimally invasive ab interno Kahook dual blade trabeculectomy for the treatment of primary congenital glaucoma. The subject was a 13-month old infant with bilateral primary congenital glaucoma due to a loss of function TEK mutation. He had bilateral findings of elevated IOP, buphthalmos, Haab's striae, photophobia, and myopia. Over the course of 6 weeks, 3 ab interno trabeculectomies with a Kahook dual blade were performed in the patient's left eye and 1 in the patient's right eye. After 3 months, IOP while receiving pressure reducing ophthalmic drops bilaterally reduced from 43 to 21 mmHg in the right eye after a single surgery and from 44 to 34 mmHg in the left eye after 3 surgeries, eventually requiring glaucoma drainage implant placement. There were no complications. The authors concluded that ab interno Kahook dual blade trabeculectomy is a minimally invasive and potentially successful procedure for the treatment of congenital glaucoma. These researchers stated that the safety profile of minimally invasive glaucoma surgery warrants consideration for congenital glaucoma patients, as they usually require irido-corneal angle surgery because pharmacologic therapy is usually inadequate. These preliminary findings need to be validated by further investigation.
Ab Interno Supraciliary Microstent Surgery for the Treatment of Open-Angle Glaucoma
Sandhu and colleagues (2021) noted that glaucoma is the leading cause of global irreversible blindness, often associated with elevated IOP. Where medical or laser treatment has failed or is not tolerated, surgery is often required. Minimally-invasive surgical approaches have been developed in recent years to reduce IOP with lower surgical risks. Supraciliary microstent surgery for the treatment of OAG is one such approach. In a Cochrane review, these investigators examined the safety and effectiveness of supraciliary microstent surgery for the treatment of OAG, and compared with standard medical, laser or surgical treatments. They searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2020, Issue 8); Ovid Medline; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was August 27, 2020. These investigators searched for RCTs of supraciliary microstent surgery, alone or with cataract surgery, compared to other surgical treatments (cataract surgery alone, other minimally invasive glaucoma device techniques, trabeculectomy), laser treatment or medical treatment. Two review authors independently screened titles and abstracts from the database search to identify studies that met the selection criteria. Data extraction, analysis, and evaluation of risk of bias from selected studies was carried out independently and according to standard Cochrane methodology. One study met the inclusion criteria of this review, examining the safety and effectiveness of the Cypass supraciliary microstent surgery for the treatment of OAG, comparing phacoemulsification + supraciliary microstent surgery with phacoemulsification alone over 24 months. This study comprised 505 eyes of 505 participants with both OAG and cataract, 374 randomized to the phacoemulsification + microstent group. In this study, the perceived risk of bias from random sequence generation, allocation concealment and selective reporting was low. However, these researchers considered the study to be at high risk of performance bias as surgeons/investigators were unmasked. Attrition bias was unclear, with 448/505 participants contributing to per protocol analysis. Insertion of a Cypass supraciliary microstent combined with phacoemulsification probably increased the proportion of participants who were medication-free (not using eye-drops) at 24 months compared with phacoemulsification alone (85 % versus 59 %, RR 1.27, 95 % CI: 1.09 to 1.49, moderate-certainty evidence). There was high-certainty evidence that a greater improvement in mean IOP occurs in the phacoemulsification + microstent group - mean (SD) change in IOP from baseline of -5.4 (3.9) mmHg in the phacoemulsification group, compared to -7.4 (4.4) mmHg in the phacoemulsification + microstent group at 24 months (MD -2.0 mmHg, 95 % CI: -2.85 to -1.15). There was moderate-certainty evidence that insertion of a microstent was probably associated with a greater reduction in use of IOP-lowering drops (mean reduction of 0.7 medications in the phacoemulsification group, compared to a mean reduction of 1.2 medications in the phacoemulsification + microstent group). Insertion of a microstent during phacoemulsification may reduce the requirement for further glaucoma intervention to control IOP at a later stage compared to phacoemulsification alone (RR 0.26, 95 % CI: 0.07 to 1.04, low-certainty evidence). There was no evidence relating to the rate of visual field progression, or proportion of participants whose visual field loss progressed in this study. There was moderate-certainty evidence showing little or no difference in the proportion of participants experiencing post-operative complications over 24 months between participants in the microstent group compared to those who received phacoemulsification alone (RR 1.1, 95 % CI: 0.8 to 1.4). Five-year post-approval data regarding the safety of the Cypass supraciliary microstent showed increased endothelial cell loss, associated with the position of the microstent in the anterior chamber. There were no reported health-related QOL (HR-QOL) outcomes in the included study. The authors concluded that data from this single RCT showed superiority of supraciliary microstent surgery when combined with phacoemulsification compared to phacoemulsification alone in achieving medication-free control of OAG. However, there are long-term safety concerns with the device used in this trial, relating to the observed significant loss of corneal endothelial cells at 5 years following device implantation. At the time of this review, this device has been withdrawn from the market. This review has found that few high-quality studies exist comparing supraciliary microstent surgery to standard medical, laser or surgical glaucoma treatments. This should be addressed by further appropriately designed RCTs with sufficient long-term follow-up to ensure robust safety data are obtained. Consideration of health-related QOL outcomes should also feature in trial design.
Ab Interno Trabecular Bypass Surgery with Trabectome for Open-Angle Glaucoma
Hu and colleagues (2021) noted that glaucoma is the leading cause of irreversible blindness. Minimally invasive surgical techniques, such as ab interno trabecular bypass surgery, have been introduced to prevent glaucoma from progressing. In light of the potential benefits for patients with OAG and the widespread uptake of the technique, it is important to examine the evidence of treatment with ab interno trabecular bypass surgery with Trabectome. These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2020, Issue 7); Ovid Medline; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was July 17, 2020. They searched for RCTs of ab interno trabecular bypass surgery with Trabectome compared to other surgical treatments (other minimally invasive glaucoma device techniques, trabeculectomy), laser treatment, or medical treatment. These researchers also included trials in which these devices were combined with phacoemulsification compared to phacoemulsification in combination with other glaucoma surgery or alone. They used the standard methodological procedures expected by Cochrane. The primary outcome was proportion of subjects who were medication-free (not using eye-drops). Secondary outcomes included mean change in IOP, proportion of subjects who needed further glaucoma surgery, mean change in QOL, proportion of subjects who achieved an IOP of 21 mmHg or less, 17 mmHg or less, or 14 mmHg or less and rate of visual field progression. Adverse effects were the proportion of subjects experiencing intra- and post-operative complications. All outcomes were measured in the short-term (6 to 18 months), medium-term (18 to 36 months), and long-term (36 months or longer). In this update, these researchers included 1 RCT which had previously been identified as an ongoing study in the 2016 publication. This trial was a single-center, single-surgeon RCT set in Canada with 19 subjects; they were adults who had OAG, open angles, and had inadequately controlled IOP that needed surgical intervention. The study was terminated before the intended sample size was reached due to slow recruitment and increasing lack of clinical equipoise over time. This reduced the power of the study to detect clinically important effects. These investigators evaluated the trial as being at high risk of attrition, reporting, and other potential sources of biases. The risks of performance and detection bias are unclear. The intervention group of 10 individuals had Trabectome ab interno trabeculotomy combined with cataract extraction (phaco-AIT) and the comparator group of 9 individuals had trabeculectomy with mitomycin C combined with cataract extraction (phaco-Trab), 1 of whom was lost to follow-up; 7 of 10 subjects in the phaco-AIT group and 4 of 8 in the phaco-Trab group were medication-free (not using eye-drops) at 12 months (OR 2.33, 95 % CI: 0.34 to 16.2; very low-certainty evidence). At 12 months, the mean change in IOP was worse for phaco-AIT than for phaco-Trab, but this evidence was very uncertain (MD 3.70 mmHg, 95 % CI: -1.44 to 8.84; very low-certainty evidence) in the phaco-AIT group, as was the difference in the mean number of IOP-lowering eye-drops taken per day (MD -0.41, 95 % CI: -1.22 to 0.40; very low-certainty evidence). Only 1 subject in the phaco-AIT group needed further glaucoma surgery. The study protocol declared that QOL and visual field progression were measured, but they were not reported. All 8 subjects with complete data in the phaco-Trab group and 8 of 10 in the phaco-AIT had at least 1 early or late post-operative complication (e.g., day 1 IOP spike, hypotony, choroidal effusion, bleb leak or encapsulation, uveitis, or peripheral anterior synechiae). The evidence was very low-certainty due to high risk of bias for several domains for this study and for large imprecision of all estimates. These researchers also identified 1 ongoing study, identified from the International Clinical Trials Registry Platform (ICTRP): an open, multi-center, RCT comparing Trabectome to ab interno trabeculectomy using microhook. The study investigators plan to recruit 120 adults between 20 and 90 years of age. The primary outcome is duration of treatment success; and secondary outcomes include post-operative IOP, number of anti-glaucoma medications, and AEs. The authors concluded that there is currently no high-quality evidence for the outcomes of ab interno trabecular bypass surgery with Trabectome for OAG. These researchers stated that properly designed RCTs are needed to examine the long-term safety and efficacy of this technique.
Ab Interno Trabeculectomy with the Dual Blade in Juvenile Open-Angle Glaucoma
Khouri and colleagues (2021) introduced the use of the Kahook Dual Blade in the treatment of juvenile OAG. A 14-year old boy was presented with juvenile OAG in the left eye. Ab interno trabeculectomy was performed using a dual-blade device; IOP was reduced from 28 to 15 mmHg in the left eye after 18 months. There were no complications. The authors concluded that dual blade ab interno trabeculectomy is a promising alternate to goniotomy in the treatment of juvenile OAG.
Anti-Inflammatory Treatment on the Effectiveness of Selective Laser Trabeculoplasty
Chen and colleagues (2021) noted that selective laser trabeculoplasty (SLT) can lower IOP in cases of OAG. Several studies had examined the effectiveness of anti-inflammatory treatment to relieve discomfort following SLT; however, whether such treatments affect the response of SLT remains uncertain. These investigators systematically searched PubMed, Embase, Web of Science, and Cochrane Library for relevant studies published before March 31, 2021. The major outcomes were the effectiveness of post-SLT anti-inflammatory treatment on IOP reduction, incidence of discomfort, and anterior chamber inflammation compared with those of placebo agents. A total of 5 RCTs with 235 eyes receiving anti-inflammatory treatment and 170 eyes receiving placebo agents were included in the meta-analysis. Compared with placebo, no significant differences were present in IOP reduction effects upon using topical non-steroidal anti-inflammatory drugs (NSAIDs) or steroid post-SLT. The results were consistent from 1 to 6 months during follow-up. Furthermore, anti-inflammatory treatment had no significant effects on pain or discomfort or the presence of anterior chamber cells 1 hour to 1 week following SLT. The authors concluded that topical anti-inflammatory treatment following SLT for patients with glaucoma neither significantly affected IOP reduction nor remarkably relieved clinical discomfort and anterior chamber inflammation. These investigators stated that regular use of post-SLT anti-inflammatory treatment may be unnecessary.
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.
McCartney and Phagura (2020) stated that microinvasive glaucoma surgery and its associated devices remain a field of continued interest and innovation in the management of patients with glaucoma. While a range of outflow optimization devices have been designed, the safety and efficacy of these devices remains to be proven, especially in the long-term. These investigators presented the 1st reported case of bilateral hypertensive crisis associated with CyPass Micro-stent insertion 2 months post-operation and its resultant management. The authors concluded that despite the recall of the CyPass Micro-stent, further clinical experience in the use of these and similar stents is needed. These researchers presented possible hypotheses explaining this phenomenon, the most likely being sudden closure of the suprachoroidal space.
Drug-Eluting Implant into Lacrimal Canaliculus During Routine Cataract Removal
An UpToDate review on “Cataract in adults” (Jacobs, 2021) does not mention the use of drug-eluting implant as a management option.
Drug-Eluting Ocular Insert
Bhagav et al (2011) stated that pathology of eye, especially in the case of glaucoma, requires optimal therapeutically effective concentration of the drug in the ocular tissues for prolonged period of time with decreased dosing frequency and improved patient compliance. In the present study, brimonidine tartrate (BRT) ocular inserts were designed based on hydrophilic and/or inert/zwitterionic polymer matrix to design muco-adhesive and extended release ocular inserts. Designed inserts were evaluated for their physicochemical properties such as crushing strength/hardness, friability, drug content and muco-adhesion, and erosion and in-vitro drug release characteristics. The selected optimized formulations were compared with marketed preparation for in-vivo ocular irritation in healthy rabbits and for in-vivo pharmacodynamic efficacy on alpha-chymotrypsin-induced glaucomatous rabbits. The developed formulations showed good physicochemical properties and muco-adhesive strength, and a good correlation was seen between rate of erosion or swelling with drug release rate in case of formulations with higher proportion of polyethylene oxide (PEO). Modulation of drug release was achieved by incorporating Eudragit in PEO matrix. Addition of Eudragit resulted in shifting of drug release mechanism from erosion-controlled to diffusion-controlled mechanism. The authors concluded that in-vivo ocular irritation studies confirmed the absence of any irritation upon administration in rabbits; and intra-ocular pressure (IOP) measurement studies showed an improved IOP-lowering ability of ocular insert of BRT in comparison to eye drops.
Franca et al (2014) developed and evaluated a novel sustained-release drug delivery system of bimatoprost (BIM). Chitosan polymeric inserts were prepared using the solvent casting method and characterized by swelling studies, infrared spectroscopy, differential scanning calorimetry, drug content, scanning electron microscopy and in-vitro drug release. Bio-distribution of 99mTc-BIM eye drops and 99mTc-BIM-loaded inserts, after ocular administration in Wistar rats, was accessed by ex-vivo radiation counting. The inserts were evaluated for their therapeutic efficacy in glaucomatous Wistar rats. Glaucoma was induced by weekly intra-cameral injection of hyaluronic acid. BIM-loaded inserts (equivalent to 9.0 µg BIM) were administered once into conjunctival sac, after ocular hypertension (OHT) confirmation. BIM eye drop was topically instilled in a second group of glaucomatous rats for 15 days, while placebo inserts were administered once in a third group. An untreated glaucomatous group was used as control; IOP was monitored for 4 consecutive weeks after treatment began. At the end of the experiment, retinal ganglion cells and optic nerve head cupping were evaluated in the histological eye sections. Characterization results revealed that the drug physically interacted, but did not chemically react with the polymeric matrix. Inserts released continually BIM in-vitro during 8 hours. Bio-distribution studies showed that the amount of 99mTc-BIM that remained in the eye was significantly lower after eye drop instillation than after chitosan insert implantation. BIM-loaded inserts lowered IOP for 4 weeks, after 1 application, while IOP values remained significantly high for the placebo and untreated groups. Eye drops were only effective during the daily treatment period; IOP results were reflected in retinal ganglion cells counting and optic nerve head cupping damage. The authors concluded that BIM-loaded inserts provided sustained release of BIM and appeared to be a promising system for glaucoma management.
In a phase II, parallel-arm, multi-center, double-masked, randomized controlled trial (RCT), Brandt et al (2016) compared topical BIM ocular insert with twice-daily timolol (TIM) eye drops in patients with open-angle glaucoma (OAG) or OHT treated for 6 months. A total of 130 adult OAG or OHT patients were included in this study. Eligible patients were randomized 1:1 to receive a BIM insert plus artificial tears twice-daily or a placebo insert plus TIM (0.5 % solution) twice-daily for 6 months after a screening wash-out period. Diurnal IOP measurements (at 0, 2, and 8 hours) were obtained at baseline; weeks 2, 6, and 12; and months 4, 5, and 6. Key eligibility included wash-out IOP of 23 mmHg or more at time 0, IOP of 20 mmHg or more at 2 and 8 hours, and IOP of 34 mmHg or less at all time-points; no prior incisional surgery for OAG or OHT; and no known non-responders to prostaglandins. The primary efficacy end-point examined the difference in mean change from baseline in diurnal IOPs (point estimate, 95 % CI] across 9 co-primary end-points at weeks 2, 6, and 12 comparing the BIM-arm with the TIM-arm using a non-inferiority margin of 1.5 mmHg. Secondary end-points were diurnal IOP measurements at months 4, 5, and 6 and adverse events (AEs). A mean reduction from baseline IOP of -3.2 to -6.4 mmHg was observed for the BIM group compared with -4.2 to -6.4 mmHg for the TIM group over 6 months. The study met the non-inferiority definition at 2 of 9 time-points but was under-powered for the observed treatment effect. Adverse events were consistent with BIM or TIM exposure; no unexpected ocular AEs were observed. Primary retention rate of the insert was 88.5 % of patients at 6 months. The authors concluded that clinically relevant reduction in mean IOP was observed over 6 months with a BIM ocular insert and appeared to be safe and well-tolerated. They stated that the topically applied BIM insert may provide an alternative to daily eye drops to improve adherence, consistency of delivery, and reduction of elevated IOP.
Excimer Laser Trabeculostomy
Durr and colleagues (2020) state that excimer laser trabeculostomy (ELT) is a microinvasive glaucoma surgery (MIGS) that creates multiple laser channels through the trabecular meshwork using a cold laser system, which minimizes tissue fibrosis and aids in bypassing the main area of resistance to aqueous outflow. These researchers examined the available evidence regarding ELT in terms of efficacy and reviewed the safety profile of the procedure. Studies screened had to show clear inclusion and exclusion criteria as well as well-defined outcome measures. PubMed, Medline, Embase and the Cochrane Controlled Trial Database were searched. Preferred Reporting Items of Systematic Reviews (PRISMA) guidelines were used to evaluate for study quality and for any bias. A total of 64 articles were initially identified with 18 meeting preliminary screening criteria. A total of 8 studies met inclusion criteria and 2 additional non-referenced publications were also included: 1 RCT, 4 prospective case-series studies and 5 retrospective studies. Overall studies showed moderate IOP lowering of between 20 % and 40 % from baseline without medication washout and mostly a decrease in glaucoma medications with few complications. The authors concluded that current available evidence showed an IOP-lowering effect from ELT alone or in combination with cataract surgery with encouraging results across different studies and patient populations, notably without washout IOP, and a favorable safety profile. Multiple studies, albeit with small sample sizes and variable loss to follow-up, have shown a long-lasting response up to 8 years after the initial surgery. The potential advantages of this procedure are less scarring than results from traditional thermal lasers, repeatability in different quadrants, ease of use, no device left in the angle and, with lower hyphema risks compared to ablative procedures, potentially less secondary synechia to the angle. Moreover, these researchers stated that the procedure also appears to have a favorable safety profile with few intra-operative or post-operative risks; however, like any new technology, more studies are needed to better characterize ELT and further substantiate these promising findings. These investigators noted that drawbacks to these studies included the lack of controls and washout IOP.
Furthermore, an UpToDate review on “Open-angle glaucoma: Treatment” (Jacobs, 2021) does not mention excimer laser trabeculostomy as a therapeutic option.
Excimer Laser Trabeculotomy
Lavia and associates (2017) noted that micro-invasive glaucoma surgery (MIGS) have been developed as a surgical alternative for glaucomatous patients. These researchers analyzed the change in intraocular pressure (IOP) and glaucoma medications using different MIGS devices (Trabectome, iStent, excimer laser trabeculotomy (ELT), iStent Supra, CyPass, XEN, Hydrus, Fugo Blade, Ab interno canaloplasty, Goniscopy-assisted transluminal trabeculotomy) as a solo procedure or in association with phaco-emulsification; RCTs and non-RCTs (non-randomized comparative studies, non-randomized study of intervention [NRS], and before-after studies) were included. Studies with at least 1 year of follow-up in patients affected by POAG, pseudo-exfoliative glaucoma or pigmentary glaucoma were considered. Risk of bias assessment was carried out using the Cochrane Risk of Bias and the ROBINS-I tools. The main outcome was the effect of MIGS devices compared to medical therapy, cataract surgery, other glaucoma surgeries and other MIGS on both IOP and use of glaucoma medications 12 months after surgery. Outcomes measures were the mean difference in the change of IOP and glaucoma medication compared to baseline at 1 and 2 years and all ocular AEs. Over a total of 3,069 studies, 9 RCTs and 21 case-series studies with a total of 2,928 eyes were included. Main concerns regarding the risk of bias in RCTs were lack of blinding, allocation concealment and attrition bias while in non-RCTs they were represented by patients' selection, masking of participants and co-intervention management. Limited evidence was found based on both RCTs and non RCTs that compared MIGS surgery with medical therapy or other MIGS. In before-after series, MIGS surgery appeared effective in lowering both IOP and glaucoma drug use. MIGS showed a good safety profile: IOP spikes were the most frequent complications and no cases of infection or BCVA loss due to glaucoma were reported. The authors concluded that although MIGS appeared effective in lowering IOP and glaucoma medication and showed good safety profile, this evidence was mainly derived from non-comparative studies and further, good quality RCTs are needed. They stated that future research should be comparative, ideally randomized, including patients and alternative treatments that are relevant to clinical settings.
Excimer laser trabeculotomy (ELT) is a minimally invasive procedure used to lower the intraocular pressure (IOP) via a photo-ablative laser that is applied to the trabecular meshwork of the eye. The trabecular meshwork is one of the main outflow barriers in glaucoma, and the goal of ELT treatment aims to increase the outflow of the aqueous humor. However, there are limited number of studies examining mostly relatively small sample sizes with midterm follow-up available in published peer-reviewed literature. Thus, Deubel et al (2021) present the analysis of a large ELT cohort in a long-term follow-up. The authors conducted a retrospective cohort study of recorded data from 580 patients who underwent ELT (using the XeCl Excimer Laser AIDA via clear cornea incisions) or combined ELT with cataract surgery at a single-center institution in Germany from November 2000 until March 2011. A total of 512 patients with primary open angle glaucoma (POAG), pseudoexfoliation glaucoma (PEX), and ocular hypertension (OHT) were included in the analysis. At every follow-up examination, the usage of IOP-lowering medication and the IOP were recorded. Failure criteria were defined as the need for another surgical glaucoma procedure, when the IOP was not 21 mmHg or less and a reduction of 20% from the baseline was not achieved with (qualified success) or without (absolute success) additional medication. Statistical analysis was done using Kaplan-Meier analysis and Cox regression. Four hundred twenty-eight patients underwent combined cataract and ELT surgery, and 84 underwent solitary ELT surgery. After a median follow-up time of 656 days, 87% (combined surgery) and 66% (ELT) of the patients did not have to undergo another IOP-lowering intervention; 47/31% were classified as a qualified success and 31/11% as a complete success. The IOP-lowering medication, however, could not be significantly reduced within that time period. The authors concluded that ELT is a feasible minimally invasive procedure to lower the IOP on a mid- to long-term basis, especially when combined with cataract surgery. However, over the long term, IOP-lowering medication could not be reduced.
Fornix-Based Versus Limbal-Based Conjunctival Trabeculectomy Flaps for Glaucoma
Theventhiran and colleagues (2021) stated that glaucoma is one of the leading, but largely preventable causes of blindness. It is usually managed first medically with topical IOP-lowering drops or by laser trabeculoplasty. In cases where such treatment fails, glaucoma-filtering surgery such as trabeculectomy, is commonly considered. Surgeons can differ in their technique when carrying out trabeculectomy, for example, the choice of the type of the conjunctival flap (fornix- or limbal-based). In a fornix-based flap, the surgical wound is performed at the corneal limbus; while in a limbal-based flap, the incision is further away. Many studies compared fornix- and limbal-based trabeculectomy with respect to outcomes and complications. In a Cochrane review, these investigators compared the effectiveness of fornix- versus limbal-based conjunctival flaps in trabeculectomy for adult glaucoma, with a specific focus on IOP control and complication rates (adverse effects). They searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2021, Issue 3); Ovid Medline; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was March 23, 2021. There were no restrictions to language or year of publication. These researchers included RCTs comparing the benefits and complications of fornix- versus limbal-based trabeculectomy for glaucoma, irrespective of glaucoma type, publication status, and language. They excluded studies on children less than 18 years of age, since wound healing is different in this age group and the rate of bleb scarring post-operatively is high. These investigators used standard methodological procedures as per Cochrane criteria. They did not identify any new eligible studies for this review update. As presented in the original review, these researchers included 6 trials with a total of 361 participants; 2 studies were conducted in the U.S., and 1 each in Germany, Greece, India, and Saudi Arabia. The participants of 4 trials had OAG; 1 study included participants with primary OAG or primary closed-angle glaucoma, and 1 study did not specify the type of glaucoma; 3 studies used a combined procedure (phacotrabeculectomy). Trabeculectomy with mitomycin C (MMC) was carried out in 4 studies, and trabeculectomy with 5-fluorouracil (5-FU) was conducted in only 1 study. None of the included trials reported trabeculectomy failure at 24 months. Only 1 trial reported the failure rate of trabeculectomy as a late complication. Failure was higher among participants randomized to the limbal-based surgery: 1/50 eyes failed trabeculectomy in the fornix group compared with 3/50 in the limbal group (Peto OR 0.36, 95 % CI: 0.05 to 2.61)); thus, these researchers were very uncertain as to the relative effect of the 2 procedures on failure rate; 4 studies including 252 participants provided measures of mean IOP at 12 months. In the fornix-based surgeries, mean IOP ranged from 12.5 to 15.5 mmHg and similar results were noted in limbal-based surgeries with mean IOP ranging from 11.7 to 15.1 mmHg without significant difference. Mean difference was 0.44 mmHg (95 % CI: -0.45 to 1.33; 247 eyes) and 0.86 mmHg, (95 % CI: -0.52 to 2.24; 139 eyes) at 12 and 24 months of follow-up, respectively. Neither of these pooled analyses showed a statistically significant difference in IOP between groups (moderate certainty evidence); 1 trial reported number of anti-glaucoma medications at 24 months of follow-up with no difference noted between surgical groups. However, 3 trials reported the mean number of anti-glaucoma medications at 12 months of follow-up without significant difference in the mean number of post-operative IOP-lowering medications between the 2 surgical techniques. Mean difference was 0.02, (95 % CI: -0.15 to 0.19) at 12 months of follow-up (high certainty evidence). Because of the small numbers of events and total participants, the risk of many reported AEs was uncertain and those that were found to be statistically significant may have been due to chance. For risk of bias assessment: although all 6 trials were randomized, selection bias was mostly unclear, with unclear random sequence generation in 4 of the 6 studies and unclear allocation concealment in 5 of the 6 studies. Attrition bias was encountered in only 1 trial, which also suffered from reporting bias. All other trials had an unclear risk of reporting bias as there was no access to study protocols. All included trials were judged to have high risk of detection bias due to lack of masking of the outcomes. These researchers noted that trabeculectomy is quite a standard procedure and unlikely to induce bias due to surgeon “performance”, hence performance bias was not evaluated. The authors concluded that the main result of this review was that there was uncertainty as to the difference between fornix- and limbal-based trabeculectomy surgeries due to the small number of events and CIs that crossed the null hypothesis. This also applied to post-operative complications, but without any impact on long-term failure rate between the 2 surgical techniques.
Gonioscopy-Assisted Transluminal Trabeculotomy (GATT)
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.
Intra-Operative Optical Coherence Tomography in Glaucoma Surgery
In a pilot study, Kumar and associates (2015) reported on the use of a spectral-domain OCT (SDOCT) integrated surgical microscope in glaucoma surgery. An SDOCT system was used to interface directly with an ophthalmic surgical microscope, to allow real-time intra-operative SDOCT (iOCT) imaging during glaucoma procedures like phaco-trabeculectomy, Ahmed glaucoma valve (AGV) implantation, gonio-synechiolysis, and bleb needling. The various surgical steps during glaucoma surgeries where iOCT can be of potential help in guiding the surgeon were recorded. High-resolution, cross-sectional images of the relevant structures were achieved with the iOCT system in all procedures. The surgeon could determine the depth of the scleral dissection, the intra-stomal bed, the path of the AGV tube in the eye, the release of peripheral anterior synechiae and the efficacy of needling with respect to breakage of loculations; most of these were technically "blind" procedures, where the outcomes were determined post-operatively. Metallic instruments cast a shadow on tissues below, thereby restricting the use of the device in its current state. The authors concluded that the iOCT system provided high quality, intra-operative, real-time imaging, which could possibly improve the safety and efficacy of the surgical procedures in glaucoma. Moreover, these researchers stated that further studies and modifications to the iOCT are needed to better understand and increase the uptake of this technology in daily practice.
The authors stated that as with every new technology, the iOCT has got limitations. The majority of the limitations of this tool were surgeon- and machine-related. The restricted scanning area and the need to move the scanning zone to target the instrument tip required a rather cumbersome coordination between the surgeon and assistant/technician manning the scanner; re-focusing to the region of interest (ROI) was constantly required to achieve good quality images. Distortion of images during eye or microscope movements also causes motion artefacts. There was a learning curve for focusing and aligning the ROI and the inconvenience of simultaneously looking at both the surgical field and the OCT image simultaneously. The synchronization between the 2 areas under observation had a definite learning curve. The other major limitation was the shadowing effect caused by the metallic instruments currently used, that rendered the underlying tissues invisible. These investigators noted that the integration of real-time in-vivo OCT imaging with the operating microscope is still in its infancy; and improvements in the resolution of the integrated OCT and possible color coding to determine tissue thickness could be other potential areas that need to be addressed. They stated that the iOCT, with further advancements in its technology, could potentially provide the surgeon both quantitative and qualitative, real-time depth and tissue proximity details, thus improving the safety and accuracy of glaucoma surgery.
Ang and colleagues (2020) noted that the application of the OCT in clinical ophthalmology has expanded significantly since its introduction more than 20 years ago. There has been recent growing interest in the application of iOCT. The iOCT's ability to enhance visualization and depth appreciation has the potential to be further exploited in glaucoma surgery, especially with the emergence of minimally invasive glaucoma surgery (MIGS) – to facilitate targeted device placement and fine surgical maneuvers in the angles, the sub-conjunctival layer and the suprachoroidal space. These investigators examined the current literature on the applications of iOCT in glaucoma surgery. A total of 79 studies were identified following a literature search adhering to PRISMA guidelines. After full text evaluation, 10 studies reporting on iOCT use in glaucoma surgery were included. Traditional glaucoma filtering procedures reviewed included trabeculectomy surgery, gonio-synechiolysis, bleb needling and glaucoma drainage device implantation. MIGS procedures reviewed included canaloplasty, trabecular aspiration, ab-interno trabectome and the XEN45 gel stent. iOCT use in ophthalmic surgery is becoming increasingly prevalent and has already been applied in various surgeries and procedures in the field of glaucoma. The authors concluded that with the greater adoption of MIGS, iOCT may further contribute in facilitating surgical techniques and improving outcomes. These researchers stated that while iOCT offers many advantages, there are still limitations to be overcome – iOCT technology continues to evolve to optimize imaging quality and user-experience.
Furthermore, UpToDate reviews on "Open-angle glaucoma: Treatment" (Jacobs, 2020), "Angle-closure glaucoma" (Weizer, 2020), "Primary infantile glaucoma" (Reynolds and Reynolds, 2020a), and "Overview of glaucoma in infants and children" (Reynolds and Reynolds, 2020b) do not mention intra-operative OCT as an adjunctive surgical option.
iStent Infinite
In an open-label, unmasked, single-center study, Katz et al (2018) examined the long-term outcomes following implantation of 1, 2, or 3 trabecular micro-bypass stents in a standalone procedure in eyes of patients with OAG taking ocular hypotensive medication. Prospective randomized ongoing study of 119 subjects (109 with 42-month follow-up) with OAG, pre-operative IOP of 18 to 30 mmHg on 1 to 3 glaucoma medications, and unmedicated (post-washout) IOP of 22 to 38 mmHg were included in this study. Subjects were randomized to receive 1 (n = 38), 2 (n = 41), or 3 (n = 40) iStent trabecular micro-bypass stents in a standalone procedure. Post-operatively, IOP was measured with medication and annually following washout. Data included IOP, medications, gonioscopy, pachymetry, visual field, visual acuity (VA), AEs, and slit-lamp and fundus examinations. Pre-operative mean medicated IOP was 19.8 ± 1.3 mmHg on 1.71 medications in 1-stent eyes, 20.1 ± 1.6 mmHg on 1.76 medications in 2-stent eyes, and 20.4 ± 1.8 mmHg on 1.53 medications in 3-stent eyes. Post-washout IOP before stent implantation was 25.0 ± 1.2, 25.0 ± 1.7, and 25.1 ± 1.9 mmHg in the 3 groups, respectively. Post-operatively, month 42 medicated IOP was 15.0 ± 2.8, 15.7 ± 1.0 and 14.8 ±1 .3 mmHg in the 3 groups, and post-washout IOP (months 36 to 37) was 17.4 ± 0.9, 15.8 ± 1.1 and 14.2 ± 1.5 mmHg, respectively. IOP reduction of 20 % or more without medication was achieved in 89 %, 90 %, and 92 % of 1e-, 2-, and 3-stent eyes, respectively, at month 12; and in 61 %, 91 %, and 91 % of eyes, respectively, at month 42. The need for additional medication remained consistent at months 12 and 42 in multi-stent eyes (4 2-stent eyes and 3 3-stent eyes at both time-points), whereas it increased in 1-stent eyes (4 eyes at month 12 versus 18 eyes at month 42). Safety parameters were favorable in all groups. The authors concluded that the standalone implantation of either single or multiple iStent device(s) produced safe, clinically meaningful IOP and medication reductions through 42 months post-operatively, with incrementally greater and more sustained reductions in multi-stent eyes.
The authors stated that this study had several drawbacks. This trial was an open-label, unmasked, single-center study in a solely Caucasian patient population. Baseline and post-operative IOPs were not measured at multiple time-points, leaving open the possibility of regression to the mean. No standardized cataract grading system nor threshold for completing cataract surgery was employed. One may notice the relatively low values for IOP variance in this study; these appeared consistent with variance in previous studies. Finally, this trial entailed data through 42 months; a future report will be able to examine even longer-term outcomes through study completion at 60 months.
Healey et al (2021) noted that standalone trabecular micro-bypass glaucoma surgery with the iStent devices is associated with clinically relevant reductions in IOP sustained over a reasonably long-term while simultaneously reducing medication burden and a relatively favorable safety profile. While there is a relatively large body of evidence supporting the implantation of the iStent trabecular micro-bypass devices during phacoemulsification in patients with OAG, its effectiveness as a standalone procedure has been less widely reported. In a systematic review and meta-analysis, these investigators examined evaluate the effectiveness of iStent devices (iStent and iStent inject) when performed independently of cataract surgery in patients with OAG. They carried out a systematic review of the literature in August 2019 to identify studies of standalone trabecular micro-bypass glaucoma surgery with iStent devices in patients with OAG. All randomized trials were considered as well as non-randomized studies that included at least 6 months of follow-up or more than 10 eyes. Key effectiveness analyses included post-operative IOP and medication use, which were used to examine WMDs from baseline, and the proportion of eyes free of ocular medication. Post-operative AEs were descriptively summarized. A total of 13 studies were identified including 4 RCTs and 9 non-randomized or single-arm studies providing data for 778 eyes. In eyes implanted with iStent devices, a weighted mean IOP reduction of 31.1 % was observed at 6 to 12 months. In studies reporting longer-term outcomes (36 to 48 months or 60 months), the weighted mean IOP reduction was 30.4 % and 32.9 %, respectively. The pooled weighted mean reduction in IOP from baseline across all studies at 6 to 12 months and 36 to 60 months post-stent implantation was 7.01 mm Hg (95 % CI: 5.91 to 8.11) and 6.59 mm Hg (95 % CI: 5.55 to 7.63), respectively. Medication burden was reduced by approximately 1.0 medication at 6 to 18 months and 1.2 medications at 36 to 60 months. AEs reported in more than 5 % of participants were progression of pre-existing cataract/cataract surgery and loss of BCVA; however, these rates were no different to those reported in comparator medical therapy study arms. The authors concluded that the findings from these studies supported the independent effect of the iStent trabecular bypass devices on IOP and medication burden over a duration of follow-up of up to 5 years.
The authors stated that this study had several drawbacks. First, the control groups from controlled studies were not considered in the primary effectiveness analysis. This was to allow the incorporation of non-randomized studies. In this context, these researchers considered it reasonable to use pre-operative baseline measurements as a proxy for a control arm. Second, medication use at endpoint was not reported consistently in the included studies, which limited the ability to carry out robust statistical meta-analyses. Third, studies were not evaluated for bias and were not excluded for reasons other than inadequate sample size (10 eyes or less) and follow-up (less than 6 months) to allow a comprehensive review of the available evidence. While this resulted in substantial heterogeneity between the included studies in terms of study design, treatment protocols, outcome measures, severity of disease, prior treatment exposure and surgeon experience, it provided a much more inclusive study population that better reflected the patients for whom clinicians need to make treatment decisions.
In a retrospective, single-center study, Guedes et al (2022) compared standalone implantation of multiple (2 to 3) trabecular micro-bypass stents (iStent inject ± iStent) (Multi-Stent group) versus trabeculectomy + mitomycin C (Trab group) in moderate-to-severe OAG. Eligible patients underwent Multi-Stent or Trab surgery from 2018 to 2020 and had at least 3-month follow-up; visual field mean deviation (VF MD) -6 dB or worse; inadequate prior response to maximum medications ± laser procedures; and had trabeculectomy as their next planned intervention. Primary effectiveness, safety-adjusted treatment success, was defined as 20 % or higher IOP reduction on the same or fewer medications, without clinically significant safety events (severe complications, secondary surgeries, re-interventions). Secondary effectiveness included mean IOP and medications; qualified and complete attainment of target IOP (21/18/15/12 mmHg or less and higher than 6 mmHg); health-economic and QOL measures; and 2-versus-3-stent subgroup analysis. The baseline groups (n = 70 Multi-Stent/40 Trab) were similar: mean IOP (21.1 mmHg/22.3 mmHg); medications (2.87/3.10 medications); disease stage (30 %/35 % severe); VF MD (-10.1 dB/-10.4 dB); and mean last follow-up (LFU, 13.1 months/15.7 months) (all differences non-significant). Primary effectiveness: treatment success at LFU was 62.9 % versus 30.0 % in Multi-Stent versus Trab eyes, respectively (p = 0.001). Secondary effectiveness: At LFU in Multi-Stent versus Trab groups, respectively: mean IOP decreased by 31 % to 14.2 mmHg (p < 0.001) versus by 43 % to 12.5 mmHg (p < 0.001); mean medications decreased by 51 % to 1.31 medications (p < 0.001) versus by 84 % to 0.43 medications (p < 0.001). Multi-Stent eyes, compared to Trab eyes, had fewer visits ± re-interventions within 3 months (3.6 versus 6.1, p < 0.001); longer time to 1st re-intervention (12.2 months versus 4.5 months, p = 0.01); fewer total re-interventions (0.26 versus 0.75, p = 0.006); and earlier lifting of post-operative restrictions (12.6 versus 32.1 days, p < 0.001). In 2-versus-3-stent analysis, there was a trend toward more 3-stent eyes achieving target IOP than 2-stent eyes. Visual fields remained stable in both Multi-Stent and Trab eyes. The authors concluded that implanting 2 to 3 trabecular micro-bypass stents was a viable alternative to trabeculectomy for moderate-to-severe OAG, with clinically appropriate IOP/medication reductions and higher safety-adjusted treatment success versus trabeculectomy. They stated that these findings reported a highly favorable risk-benefit balance. They demonstrated that standalone implantation of 2 or 3 trabecular bypass stents (iStent or iStent inject) may be a viable and safe therapeutic option for patients with moderate-to-severe treatment-resistant glaucoma.
The authors stated that this study had several drawbacks. First, given the retrospective nature of data collection, it was not possible to perfectly match baseline characteristics of the 2 groups; and these researchers could not rule out the possibility of non-quantifiable patient differences between the 2 groups. Despite this constraint, the groups were well-matched for baseline characteristics, including for the most clinically relevant measures such as pre-operative IOP, medication burden, glaucoma type, disease severity, and visual field. The only data point differing between the groups was lens status, with more pseudo-phakic eyes in the Multi-Stent group than in the Trab group. Second, these investigators acknowledged that their standard protocol for post-operative restrictions was cautious and comprehensive, and that some clinicians may advocate earlier resumption of unrestricted activity. However, the same restrictions were applied to both groups in this study; thus, the significant between-group differences were still meaningful. Third, there were no pre-operative or post-operative medication washouts, as these would not be appropriate in this real-world clinical population. Fourth, visual field outcomes were stable in both groups through up to 24 months post-operative; however, longer monitoring are needed to confirm that patients’ glaucoma remains controlled.
In a prospective, open-label, single-arm, multi-center study, Sarkisian et al (2023) examined the safety and effectiveness of the iStent infinite Trabecular Micro-Bypass System in patients with OAG uncontrolled by prior surgical or medical therapy. Implantation of iStent infinite (3 iStent inject W stents) was carried out as a stand-alone surgical procedure in eyes with OAG uncontrolled by prior incisional or cilio-ablative surgeries or maximum tolerated medical therapy (MTMT). Prospectively declared effectiveness endpoints were proportion of eyes achieving 20 % or greater mean diurnal IOP (MDIOP) reduction from baseline at month 12 on the same or fewer IOP-lowering medication classes (responder endpoint) and mean change in MDIOP from baseline at month 12. Safety parameters included AEs, VA, slit-lamp and fundus examinations, gonioscopy, perimetry, and surgical complications. A total of 72 eyes of 72 patients (mean age of 71.9 years) with pre-operative mean medicated MDIOP of 23.4 ± 2.8 mm Hg on a mean of 3.1 ± 0.9 IOP-lowering medication classes were enrolled: 61 eyes with failed prior surgery/ies (Failed-Surgery subgroup) and 11 eyes uncontrolled on MTMT (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) mm Hg [5.5 (0.7) mm Hg Failed-Surgery subgroup, 8.1 (0.9) mm Hg MTMT subgroup]. For patients on the same or fewer medication(s) as baseline, 53.0 % achieved 30 % or greater MDIOP reduction without surgical interventions/other events. Safety was favorable, with no explants, infection, or device-related interventions or hypotony. The authors concluded that iStent infinite stand-alone surgery achieved clinically significant IOP reduction and favorable safety in patients with OAG uncontrolled by prior therapy.
The authors stated that this study had several drawbacks. This was an open-label, single-arm study, consistent with FDA standards for registration submission for a 510(k) device. Although the follow-up period of 12 months was of relatively short duration, the iStent infinite has the same mechanism of action and treatment approach as the 1st-generation iStent and 2nd-generation iStent inject devices, which have shown consistent durability in maintaining IOP and medication reductions for up to 8 years postoperative. Thus, long-term studies with iStent infinite would be expected to show similarly consistent safety and effectiveness over time. No medication washout was carried out, as this might have placed the enrolled glaucoma patients at undue risk for optic nerve damage. However, this trial design was consistent in this regard with similar studies on patients at high risk for glaucoma progression.
References
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