Minimally invasive glaucoma surgeries fill a gap that has existed in the treatment algorithm for glaucoma between medical therapy and laser at one end of the spectrum and traditional filtering glaucoma surgeries at the other. Before the advent of minimally invasive glaucoma surgery, a patient who had failed laser treatment and was not adequately controlled on medical therapy was referred for a trabeculectomy procedure. The intraocular pressure–lowering efficacy provided by trabeculectomy comes with known risks of intraoperative (e.g., torn conjunctiva, hemorrhage, choroidal effusion), postoperative (e.g., hypotony, failing or encapsulated bleb, uveitis, endophthalmitis, hyphema), and late postoperative (e.g., leaking bleb, blebitis, cataract) complications.4,53 In situations where intraocular pressure reduction goals are more modest, the glaucoma is newly diagnosed, the optic nerve head damage is only mild to moderate, and/or the medication burden creates the risk of poor adherence, minimally invasive glaucoma surgery is a treatment option that should be considered.54,55 Implantation concomitant with cataract surgery is currently the only Food and Drug Administration–approved indication for both the CyPass supraciliary stent (Alcon Laboratories) and the iStent trabecular stent (Glaukos, Inc., Laguna Hills, CA), although both may be used in standalone procedures in Europe. Cataract surgery alone provides intraocular pressure reduction of up to 15% in the first 12 to 24 months, but the effect seems to diminish over time, averaging 9% at 36 months.55 The Hydrus device currently in premarket approval evaluation is also for use with cataract surgery. The size of the patient population that could benefit from minimally invasive glaucoma surgery is quite large. In a recent retrospective chart review of all cataract surgeries performed in the outpatient setting at three locations in Colorado, approximately 18% of patients had comorbid glaucoma.56 Cataract surgery thus provides a unique opportunity to implant a minimally invasive glaucoma surgery device without the risk of a second surgery, providing the glaucoma patient with the potential for improved quality of life through medication reduction and intraocular pressure control less reliant on individual adherence.
Minimally invasive glaucoma surgery devices approved in the United States for the treatment of glaucoma increase outflow by three distinct mechanisms: subconjunctival outflow, trabecular bypass into Schlemm's canal, and uveoscleral flow into the suprachoroidal space.
The XEN gel stent is indicated for refractory glaucoma in cases where surgical treatment has failed or in cases that are unresponsive to maximum tolerated medical therapy.49 XEN can be placed in phakic or pseudophakic eyes as a standalone procedure. XEN is also implanted with an ab interno surgical approach; however, the mechanism of action is more akin to filtration surgery than to the physiological outflow pathways (Schlemm's canal, uveoscleral). The XEN gel stent is a 6-mm-long tube with a 45-μm bore composed of porcine gelatin crosslinked with glutaraldehyde. It is placed in a scleral tunnel created by the beveled needle applicator and terminating just under the conjunctiva. Aqueous humor flows from the anterior chamber through the stent and forms a filtering bleb under the conjunctiva. The length of the stent coupled with the bore creates outflow resistance titrated to prevent hypotony.57 In the single-arm noncomparative trial supporting U.S. approval, 71% of patients achieved intraocular pressure reductions of 20% or greater from baseline on the same or fewer medications at 12 months of follow-up. The mean medication reduction was 1.8 (baseline, 3.5; 12 months, 1.7) for the 52 subjects (80%) completing 12 months of follow-up.49 XEN implantation is less traumatic and tissue disruptive than traditional trabeculectomy. It was thought that this would result in less fibrosis and therefore decrease the need for bleb manipulations and needling. The rate of needling for XEN procedures is reported to be approximately 32% by 1 year postoperatively, similar to rates seen with conventional filtration procedures.49 Although XEN could conceivably be used with cataract surgery across the spectrum of glaucoma, the presence of a bleb and the potential for bleb complications and maintenance suggest that this device be reserved for more advanced cases. The somewhat more complicated surgical procedure (than for other minimally invasive glaucoma surgery) could limit adoption by cataract surgeons where the ideal concomitant procedure should add minimal time to the cataract extraction, be relatively easy procedurally, and require a minimum of follow-up.
The iStent was the first minimally invasive glaucoma surgery device to receive a marketing authorization in the United States (in 2012). It is an L-shaped stent that is approximately 1.0 mm long and is made of heparin-coated titanium (Fig. 2). It has an internal bore of 120 μm. Properly placed, the long leg of the L resides in Schlemm's canal with the short leg or snorkel protruding into the anterior chamber. There are numerous publications for the iStent; however, most are relatively small or case series or both and thus of relatively low-quality evidence.58 A randomized controlled trial with a sample size providing appropriate statistical power to test the hypothesis (N = 240) compared 1- and 2-year outcomes for the iStent + phacoemulsification versus phacoemulsification alone.45,46 At 1 year, 72% of patients randomized to the stent met the primary end point (intraocular pressure ≤21 mmHg) versus 50% for the control group. The difference between groups narrowed at 2 years (61% stent, 50% control). The proportion of patients achieving 20% reduction or greater from baseline intraocular pressure was 66% stent and 48% control at 1 year and 53% stent and 44% control at 2 years. Use of ocular hypotensive medications at 1 year postoperatively was reduced by an average of 1.4 (stent) or 1.1 (control) medications.
Several studies with the original iStent indicated that placement of a second or even third stent in the eye provided superior outcomes.59,60 This has been ascribed to a theoretical incremental increase in outflow facility with each additional stent.61 Alternatively, there may be a chance element involved in stent placement; Schlemm's canal is interrupted circumferentially by occasional septa, and not all collector channels are active; therefore, a second stent not only increases the potential volume of aqueous egress, but it also increases the likelihood of proximity to active collector channels.4,62 The second-generation trabecular bypass (iStent inject) from Glaukos has recently completed a randomized controlled trial to support a premarket approval submission (ClinicalTrials.gov identifier NCT01461291). Like the first generation, the new device is heparin-coated titanium but is much smaller (360 × 230 μm) with radial symmetry (Fig. 2) and is injected through the trabecular meshwork into Schlemm's canal. In contrast to the first generation, and presumably directed by findings from the multiple-stent studies cited above, it is intended that treatment consists of implantation of two stents. These are placed into the nasal aspect of Schlemm's canal at approximately two clock-hours apart.47 Results from the pivotal premarket approval trial are not yet public; however, one randomized controlled trial has been published enrolling 192 patients, randomized 1:1 to either two iStent inject stents or latanoprost/timolol fixed combination.47 At 12 months, the proportion of eyes with a 20% reduction or greater from baseline was 95% for the stent group and 92% for the medication group. Mean intraocular pressure reductions at 12 months were 8.1 and 7.3 mmHg, respectively.47 A second small randomized controlled trial listed on ClinicalTrials.gov (NCT00721968) comparing iStent inject plus cataract surgery with cataract surgery alone was completed in 2012, although it has not been published; 18 (67%) of 27 stent patients had intraocular pressure of 18 mmHg or less at month 12 versus 24% for the cataract surgery–only group.
Although not yet approved in the United States, the Hydrus device (Ivantis, Inc., Irvine, CA) has recently completed a large premarket approval trial to obtain marketing authorization (ClinicalTrials.gov identifier NCT01539239). Hydrus is a Schlemm's canal scaffold composed of a nickel-titanium alloy. It is an 8-mm-long crescent tube with multiple windows along its length. The device is advanced into the canal leaving, 1 to 2 mm of the inlet segment in the anterior chamber. The device is intended to dilate and stent the canal facilitating aqueous outflow. While data are not yet available from the registration study, a smaller randomized controlled trial comparing Hydrus + cataract surgery with cataract surgery alone found that at 12 months 88% of Hydrus patients had at least a 20% reduction in intraocular pressure from baseline versus 74% for cataract surgery alone.48 The response rate was 80 and 46%, respectively, at 24 months. Mean intraocular pressure reductions from baseline at 12 months were 9.7 (Hydrus) and 9.2 mmHg (cataract surgery only). However, at 24 months, these were 9.4 (Hydrus) and 7.4 mmHg (cataract surgery only). Medication reduction was essentially similar to that reported for iStent (above) with an average decrease from baseline of 1.5 medications at both 12 and 24 months.48
The safety profile for the trabecular bypass devices seems to be very good, although comparisons across studies and with other minimally invasive glaucoma surgery interventions should be made with caution because of variability in the adverse event collection methodology.45 Most of the adverse events reported are those that would be expected for cataract surgery whether or not a stent was placed. Notably, best corrected visual acuities measured at follow-up visits 1 month and greater postoperatively were not different between stent and cataract surgery–only groups.48 In the Hydrus study, it was reported that peripheral anterior synechiae formed at or near the inlet of the device in 12% of patients but did not affect efficacy of the device. Hyphema or blood reflux into the anterior chamber has been reported at a high incidence (>90%) in some iStent studies63,64 and not reported at all in others.45–47,60,65
The second major physiological route for aqueous outflow is the uveoscleral route. Indeed, given that pathologic changes to the trabecular pathway are acknowledged to be the proximal cause of elevated intraocular pressure in open-angle glaucoma, the uveoscleral pathway has been exploited both pharmacologically (i.e., prostaglandin analogs) and surgically (e.g., cyclodialysis; ab externo shunts) as an independent means of lowering intraocular pressure. The supraciliary space is a virtual space lying between the ciliary body and the sclera. Posteriorly, it is continuous with the suprachoroidal space. Supraciliary stents are placed in the anterior chamber angle with the device and applicator, making a blunt dissection between the scleral spur and the iris/ciliary body. A supraciliary stent essentially provides a controlled cyclodialysis. With proper insertion, the size of the cleft is dictated by the dimensions of the stent, which greatly minimizes the risks of uncontrolled hypotony or bleeding. Placement of the stent provides a means of maintaining the cleft and allowing continued outflow.
Currently, the only commercially available supraciliary stent is the CyPass Micro-Stent. A second device, the iStent Supra, is currently in an Investigational Device Exemption clinical trial (NCT01461278) to support U.S. Food and Drug Administration approval. CyPass has been available in Europe since 2008. Marketing approval in the United States (2016) was based on the COMPASS trial, at the time the largest randomized clinical trial comparing a minimally invasive glaucoma surgery device with cataract surgery to cataract surgery alone. In COMPASS, 505 patients were randomized in a 3:1 allocation ratio to CyPass with phacoemulsification or to phacoemulsification alone. One and 2 years after surgery, 82 and 77% of the CyPass group had achieved a 20% reduction in intraocular pressure from baseline compared with 66 and 60% for phacoemulsification alone. Mean intraocular pressure reductions from baseline were 7.9 and 6.2 mmHg at 1 year and 7.4 and 5.4 mmHg at 2 years for the CyPass and phacoemulsification groups, respectively, showing that the intraocular pressure–lowering effect of the stent was sustained over this interval.50 Elimination of medications or simplification of dosing regimen is a critical measure of an intervention such as CyPass that is relevant to improving adherence. In COMPASS, the mean numbers of medications at baseline were 1.4 for CyPass and 1.3 for phacoemulsification only. By 2 years, these were 0.2 for CyPass and 0.6 for the control group. The number of patients on no medications at 2 years was 85% for CyPass and 59% for the phacoemulsification control compared with baseline of 17 and 20%.50 Similarly, Hoh showed that in a cohort of patients controlled at baseline on two medications following CyPass implantation (with or without cataract surgery), an average of 1.5 medications were discontinued at 12 months and 0.9 medication through 3 years while maintaining intraocular pressure control at baseline levels.70,71
Similar to the trabecular stents, adverse events for CyPass attributable to the device or procedure were infrequent and nonserious.50 The most common event was best corrected visual acuity loss of 10 or more letters, which occurred almost twice as frequently in the phacoemulsification-only group than for CyPass (15.3 vs. 8.8%) and was transient, with more than 98% in both groups having best corrected visual acuity better than 20/40 by the end of the study. Other adverse events were iritis (7.8%), intraocular pressure elevation (4.0%), and corneal edema (3.2%); all were transient, and incidences were not statistically significantly different between stent and control groups.50 There were 11 adverse events (2.9%) for numerical hypotony (pressure at or <6 mmHg), which was, again, transient, did not affect functional outcomes such as visual acuity, and resolved without sequela (e.g., maculopathy, choroidal effusion).50
The present work is not intended to be a comprehensive and systematic review of all currently and historically available treatments for elevated intraocular pressure. It is instead focused primarily on minimally invasive glaucoma surgery. Earlier treatment modalities and other approaches aimed at accomplishing similar ends, that is, reduction in the medication burden and as a consequence better adherence, are also discussed in order to place minimally invasive glaucoma surgery in the proper historical context. Treatments reserved for advanced and refractory glaucoma such as filtration surgery, tubes and shunts (e.g., Ahmed Valve), and cyclodestructive techniques are therefore out of scope. There are also limitations in the published literature on minimally invasive glaucoma surgery. Follow-up providing safety and effectiveness data beyond 2 years is generally not available. This is because the devices are relatively new, and the longer-term data are still being collected in postmarket studies. Data on 3-, 4-, and 5-year outcomes should be forthcoming in the future. Head-to-head comparisons of effectiveness and safety are also missing from the literature with a few exceptions.72 This gap will also be filled as ongoing studies are completed and results published (e.g., iStent and Hydrus study, ClinicalTrials.gov identifier NCT02024464). The potential to use devices with different mechanisms of action is yet to be explored as is, with some exceptions, the utility of these devices in more refractory cases.70
The vision and mission of the World Council of Optometry include the following statement: “Our objectives… the worldwide improvement and conservation of human vision.”73 Two decades ago, Spaeth74 opined that noncompliance was not so much a patient problem as it was indicative of poor understanding and communication between doctor and patient. As the point personnel in the effort for improvement and conservation of vision, optometrists are uniquely positioned to take a holistic view of the glaucoma patient including emotional, physical, and social characteristics potentially affecting the patient's ability to adhere to treatment. Patient adherence is the wild card in the deck for controlling glaucoma progression. Patients with glaucoma tend to be older and have systemic comorbidities that can affect ability to adhere to treatment, but there may be non–age-dependent psychosocial factors as well.74 The burden of medication not only includes cost and unwanted adverse effects, but also demands that the patient take them as directed. Older individuals may have difficulties with instillation, and if arthritic, simply removing caps and squeezing drops can be challenging. They may have memory loss. They may be taking multiple other medications. The barriers to good compliance are many and significant. Innovations ranging from drug depots and implants, to laser technology, to minimally invasive glaucoma surgery, are all directed at addressing this very real gap between prescribed treatment and that which is actually delivered. Minimally invasive glaucoma surgery has been shown to provide a safe surgical approach, particularly in combination with cataract surgery, and may provide good intraocular pressure–lowering effectiveness and the opportunity to reduce or eliminate ocular hypotensive medications. Identifying those patients who could benefit from minimally invasive glaucoma surgery through decreased dependence on medications and the potential for better control of their glaucoma is in alignment with the overall goals of optometric practice. In the future, minimally invasive glaucoma surgery devices may find utility beyond mild to moderate glaucoma and in conjunction with cataract surgery. Further studies for many of these devices aimed at expanding the indications are underway including more severe glaucoma and as standalone procedures.
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