Glaucoma treatment trends: a review

Glaucoma treatment trends: a review Ronan Conlon, MD,* Hady Saheb, MD, MPH, FRCSC,† Iqbal Ike K. Ahmed, MD, FRCSC‡,§,¶ ABSTRACT ● Glaucoma is one of the most common causes of blindness worldwide, and its prevalence is increasing. The aim of the present review is to describe the current medical and surgical treatment trends in the management of open-angle glaucoma. There has been an increase in the availability of glaucoma medications and the use of laser trabeculoplasty over the past decade, with a subsequent decrease in invasive incisional surgery. In addition, a new class of glaucoma procedures, termed microinvasive glaucoma surgery, has emerged, which aims to fill the gap between conservative medical management and more invasive surgery.

GLAUCOMA TREATMENT TRENDS: A REVIEW

MEDICAL THERAPIES

Glaucoma is the number one cause of irreversible vision loss and the second leading cause of blindness worldwide.1 Approximately 66.8 million people worldwide are afflicted with glaucoma. This number is expected to increase to 80 million in 2020 because of both demographic expansion and population aging.2 In Canada, it is estimated that 2.7% of people over the age of 40 years have glaucoma and 11% over the age of 80 years.3 Unfortunately, because of the asymptomatic nature of chronic glaucoma, up to 50% of people in the industrialized world are unaware of their diagnosis and not receiving treatment.4,5 Management of glaucoma focuses on lowering intraocular pressure (IOP), which remains the principal proven method of treatment.6 Target IOP for a particular eye is established from a number of factors, including pretreatment pressure, risk of progression, optic nerve damage, and age. It is recommended by the American Academy of Ophthalmology that initial treatments aim to reduce IOP in primary open-angle glaucoma (OAG) by 25% from baseline.7 The aim of the present review is to describe the current medical and surgical treatment trends in the management of OAG.

The first approach in the management of OAG is usually through topical medications. An array of drops can be used to lower IOP and can be divided into 5 major classes: prostaglandin analogues, beta-blockers, diuretics, cholinergic agonists, and alpha agonists.8 Monotherapy with either prostaglandin analogues or beta-blockers is most often the first line. Prostaglandin analogues decrease IOP by reducing outflow resistance, which results in increased aqueous humor flow through the uveoscleral pathway.9 Beta-blockers, on the other hand, reduce IOP by decreasing aqueous formation. The ocular tolerability of beta-blockers is favourable; however, they may cause cardiac or respiratory side effects.10 In the past, beta-blockers were the most common firstline topical medication.11 Prostaglandin analogues have been shown to reduce IOP more than beta-blockers in several studies,12–14 with fewer systemic side effects. During the 1990s, the use of prostaglandin analogues increased, whereas that of beta-blockers decreased.15 A study conducted in Ontario, Canada, demonstrated an increase in the usage of glaucoma medications between 1992 and 2004, particularly prostaglandin analogues, with a subsequent decrease in the number of glaucoma surgeries.16 In Ontario, the number of glaucoma medications dispensed almost doubled between 1992 and 2004. In addition, the increase in dispensed prostaglandin analogues was strongly correlated (p o 0.001) with a decreasing number of performed trabeculectomies.16 If monotherapy alone is not effective in controlling IOP, other drugs with different mechanisms of action can replace or be added in conjunction with beta-blockers or prostaglandin analogues. Commonly used second-line agents include alpha-agonists and topical carbonic anhydrase inhibitors.17 A major challenge with adding multiple drops is compliance. It has been demonstrated that

METHODOLOGY A literature search was conducted with PubMed using keywords such as OAG, glaucoma treatment trends, laser trabeculoplasty, nonpenetrating glaucoma surgery, trabeculectomy, glaucoma drainage implants (GDIs), and microinvasive glaucoma surgery. Articles dating back a maximum of 50 years were included, with a focus on studies that have influenced current management trends in OAG. In addition, information from the Canadian Ophthalmology Society Guidelines was used.

& 2016 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2016.07.013 ISSN 0008-4182/16 CAN J OPHTHALMOL — VOL. ], NO. ], ] 2016

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Glaucoma treatment trends: a review—Conlon et al. increasing the number of drop bottles to a patient’s treatment regimen negatively affects patient adherence.18 To improve patient adherence and reduce exposure to preservatives, fixed combination therapies have been developed. A number of fixed-combination glaucoma drops are currently available. Some examples are Cosopt (Merck & Co., Inc, Kenilworth, N.Y.), Combigan (Allergan, Irvine, Calif.), Xalacom (Pfizer, New York City, N. Y.), Azarga (Alcon, Fort Worth, Tex.), DuoTrav (Alcon), and Simbrinza (Alcon). Another strategy to increase patient compliance is via injectable sustained release medications. These devices are designed to release a drug over a prolonged time interval. A sustained release implant of bimatoprost (Allergan) was recently developed and is capable of delivering medication for up to 6 months after a single intracameral injection. In a phase 2 trial, in which patients received the implant in 1 eye and topical daily bimatoprost in the other, the efficacy was comparable and the duration of effect was 4–6 months.19 Despite the existence of numerous glaucoma medications, there is currently no agent that targets the most common pathogenic cause of increased IOP, impaired trabecular outflow. Recently, a new class of glaucoma medications, known as rho kinase inhibitors, has emerged. They have been shown to increase trabecular outflow by acting directly on the contractile tone of the trabecular meshwork.20 AR-13324 (Rhopressa; Aerie Pharmaceuticals, Irvine, Calif.) is a rho kinase and norepinephrine transporter inhibitor that is believed to lower IOP by 3 main actions: reducing aqueous production, increasing trabecular outflow, and decreasing episcleral venous pressure. In a recent phase 2 trial, involving 213 subjects, the efficacy of AR13324 was compared to that of latanoprost (Pfizer).21 Mean unmedicated baseline diurnal IOP was 25.8, 25.6, and 25.5 mm Hg in the AR-13324 0.01%, AR-13324 0.02%, and latanoprost groups, respectively. On day 28, a total decrease from unmedicated baseline IOP of 5.5, 5.7, and 6.8 mm Hg was observed. Although AR-13324 0.02% was less effective at lowering IOP by 1 mm Hg, it had a similar efficacy to latanoprost in a prespecified patient subgroup that excluded patients with baseline IOPs of 426 mm Hg.21 Roclatan (Aerie Pharmaceuticals), which is a combination of Rhopressa and latanoprost, demonstrated superior IOP-lowering effects compared with latanoprost. In a phase 2b clinical trial, Roclatan lowered mean diurnal IOP from 25.1 to 16.5 mm Hg on day 29, which was about 2 mm Hg greater than that of latanoprost. The most common complication with Roclatan was hyperemia, which occurred in approximately 40% of patients and was scored as mild in the majority.22 Early clinical trials suggest that rho kinase inhibitors may soon be used more frequently in the medical management of glaucoma, although more data are needed.

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There continues to be interest in drugs that may protect the optic nerve from damage, known as neuroprotection. Although in theory this would be extremely useful in the management of OAG, human trials involving memantine (Namenda; Forest Laboratories, New York, N.Y.) for optic neuroprotection yielded nonsignificant findings.23 Further research into the area of neuroprotection needs to be explored to examine its role, if any, in the management of glaucoma.

LASER THERAPIES Medical management does not reduce IOP to target levels in all patients, and some continue to experience deterioration of the optic nerve despite maximum medical therapy. Argon laser trabeculoplasty was introduced as a treatment modality for OAG by Wise and Witter.24 The mechanism is not well understood, although it is thought to be caused by thermal energy directed toward the trabecular meshwork, which causes focal scarring and thereby opens space in adjacent structures, or attributable to the inflammation of cytokines and phagocytosis, which induces structural changes with improved outflow.25 The overall number of laser trabeculoplasty procedures and bilateral same-day laser treatments increased dramatically in the first half of the 2000s, owing to the advent of selective laser trabeculoplasty (SLT).26–30 In Ontario, Canada, the volume of same-day bilateral laser trabeculoplasties increased from 15.3 per 1000 with OAG in 2000 to 74.7 in 2013.30 In addition, the number of laser iridotomies showed a 1.7-fold increase from 2000 to 2012 in Ontario.29 SLT was introduced by Latina et al. in 1998 and is currently the most widely used and accepted laser therapy for the treatment of OAG.31–35 SLT is less traumatic than ALT and uses a frequency-doubled Q-switched Nd:YAG laser (Selecta 7000; Coherent Medical Group, Santa Clara, Calif.) to achieve similar results without causing visible damage to the trabecular meshwork structures. The exact mechanism by which SLT lowers IOP is not well understood. Minimal structural damage to the trabecular meshwork favours theories that SLT acts on a cellular level without any thermal effects.35,36 This could be either through phagocytosis of trabecular meshwork debris or by stimulating growth of the trabecular meshwork to increase outflow.37,38 In the SLT pilot study by Latina et al., 70% of eyes achieved an IOP reduction of at least 3 mm Hg at 26 weeks.31 Numerous studies have since followed demonstrating the effectiveness of SLT. SLT is effective in reducing IOP Z20% below baseline in 58%–94% of eyes at 12 months 32,39–41 and 40%–85% at 2 years.35,37,42 The IOP-lowering effect of SLT tends to decrease over time and the mean survival time (time 50% of eyes fail) is around 2 years.40,43

Glaucoma treatment trends: a review—Conlon et al. SLT is being used earlier in the glaucoma treatment algorithm, without waiting for maximal medical management. It has been compared to medication as a primary treatment for OAG and has the advantage of not relying on adherence with glaucoma medications. A meta-analysis of randomized control studies comparing medication to SLT showed that there was no statistically significant difference in IOP reduction or treatment success.44 SLT’s current role is either as primary treatment or as an adjunct to medical therapy. Economic modeling shows that SLT alone as a primary treatment for OAG is cost effective, especially in an aging population.45 A study conducted in Ontario, Canada, demonstrated cost savings with SLT over medical therapy as a primary treatment for OAG over a 6-year period. The study assumed that SLT was repeated every 2–3 years. Using the scenario in which SLT is repeated every 2 years, it produced 6 year cost savings over mono-, bi-, and tridrug therapy of $206.45, $1668.64, and $2992.67 per patient, respectively.46 Although SLT is regarded as less traumatic than ALT, pressure spikes and transient inflammation may still occur. Micropulse laser trabeculoplasty (MLT) is a new laser therapy that uses an 810 nm diode laser Iridex 1Q810 (Iridex Corporation, Mountain View, CA). It delivers energy in repetitive microsecond pulses followed by an intermittent period of rest, which reduces the buildup of thermal energy.47 It has the ability to control thermal elevation and does not cause observable coagulative damage to the trabecular meshwork on scanning electron microscopy.48 Several studies have demonstrated the efficacy of MLT.49,50 In a prospective interventional case series that included a total of 20 patients, MLT was successful in 15 patients (75%) with a mean IOP reduction of around 20% at 12 months.49 The preliminary data of another study comparing MLT with SLT demonstrated comparable results. Twelve eyes underwent MLT and 14 had SLT. MLT achieved a mean IOP reduction of 3.9 mm Hg, whereas the reduction in SLT was 2.6 mm Hg. The mean change in the number glaucoma medications was 0.6 in the MLT group compared with 0.1 in the SLT group.50 MLT has shown promising results in these early clinical studies. Larger multicentre studies are currently underway, which will help define its exact role in the management of OAG. Other new laser modalities, including titanium-sapphire laser trabeculoplasty (TSLT) and pattern scanning trabeculoplasty (PLT), are currently being studied. TSLT is a subtype of laser trabeculoplasty, which uses a SOLX 790 laser (Occulogix, Ont.), emitting near-infrared energy in pulses ranging from 5 to 10 mls. This laser modality is thought to allow deeper penetration into the juxtacanalicular network as well as the inner wall of Schlemm’s canal.51 PLT uses a 577-nm laser with computer-guided scanning technology (Topcon Medical Laser Systems,

Santa Clara, Calif.) to apply a sequence of pattern laser spots onto the trabecular meshwork. This laser modality is thought to achieve a cellular response with less tissue scarring.51 Initial pilot studies have been able to demonstrate the IOP-lowering capabilities of both TSLT and PLT, although larger-scale studies are warranted to determine their long-term safety and efficacy.52,53 Another laser therapy, known as cyclophotocoagulation, has been increasingly used among glaucoma surgeons. In 1 study, which examined the glaucoma procedure rates in the United States, cyclophotocoagulation procedures rose 248%, from 1995 to 2004.26 Cyclophotocoagulation was first introduced in the early 1970s as a last-line surgery to lower IOP. During cyclophotocoagulation, a semiconductor diode laser is used to ablate the ciliary processes. Two techniques are currently used to perform cyclophotocoagulation: transscleral diode cyclophotocoagulation (TCP) and endoscopic diode cyclophotocoagulation (ECP). TCP has traditionally been used as a last resort procedure for cases of refractory glaucoma. ECP is commonly performed in conjunction with cataract surgery.54 Previous studies have demonstrated a wide range of IOP reduction, ranging from 12.3% to 66%, using TCP.55,56 The amount of energy used seems to directly correlate with treatment success. A meta-analysis performed demonstrated a direct linear correlation between the total amount of energy applied to the ciliary body and success rate.57 Although TCP is mainly used in cases of refractory glaucoma, a growing number studies support the use of TCP as a primary procedure.55,58–62 ECP is commonly performed in combination with cataract surgery. Lindfield et al. conducted a retrospective study in which 56 patients who underwent phacoemulsification and ECP were reviewed; mean IOP decreased from 21.5 to 14.4 mm Hg at 24 months postoperatively.63 In another study, 626 phacoemulsification and ECP eyes were compared with a cohort of 81 eyes that underwent phacoemulsification alone. The combined group had a mean reduction in IOP of 3.5 mm Hg, whereas the control group had a mean reduction in IOP of 0.7 mm Hg.64,65

SURGICAL THERAPIES Trabeculectomy

When medication and laser therapy alone is not effective in controlling IOP, more invasive incisional surgery, such as trabeculectomy or GDIs, is indicated. Overall, there has been a reduction in the number of glaucoma surgeries performed in Canada, United States, the Netherlands, Australia, England, Scotland, and Wales.16,26,27,66–71 This decrease can be attributed to the introduction of improved glaucoma pharmacotherapy in the 1990s. In 1 study, which examined the glaucoma surgical procedure rates in Canada, a 29% decrease in the number of trabeculectomies performed was observed CAN J OPHTHALMOL — VOL. ], NO. ], ] 2016

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Glaucoma treatment trends: a review—Conlon et al. Table 1—Overview of 3 landmark tube studies: Tube versus Trabeculectomy (TVT), Ahmed Baerveldt comparison (ABC), Ahmed versus Baerveldt (AVB) TVT.85

ABC.116

AVB.117

Patients with uncontrolled or high-risk Patients who had previous trabeculectomy and/ Patients with previous intraocular surgery or glaucoma refractory to maximal medical refractory glaucoma and IOP Z18 mm Hg in or cataract extraction and uncontrolled therapy were randomized to an Ahmed FP7 whom glaucoma drainage implant (GDI) glaucoma (IOP Z18 on maximal medical glaucoma valve or an Baerveldt-350 implant. therapy) were randomized to either tube shunt surgery was planned were randomized to surgery (350 mm2 Baerveld glaucoma implant) implantation of the Ahmed FP7 glaucoma valve (AGV) or the Baerveldt 101–350 glaucoma or trabeculectomy with mitomycin C implant (BGI) Defined as IOP Z21 mm Hg or less than a 20% Defined as any of the following: IOP outside Criteria for Prospectively defined as IOP 421 mm Hg or target range (5–18 mm Hg, with Z20% reduction below baseline on 2 consecutive failure less than 20% reduction below baseline on reduction from baseline) for 2 consecutive study visits after 3 months, IOP r5 mm Hg on 2 consecutive follow-up visits after 3 months, visits after 3 months, vision-threatening 2 consecutive study visits after 3 months, IOP r5 mm Hg on 2 consecutive follow-up complications, de novo glaucoma reoperation for glaucoma, loss of light visits after 3 months, reoperation for glaucoma, procedures, or loss of light perception perception, or removal of the implant for any or loss of light perception reason Proportion of The cumulative probability of failure was 29.8% The cumulative probability of failure during The cumulative probability of failure at 3 years success in the tube group and 46.9% in the 5 years of follow-up was 44.7% in the AGV was 51% in the AGV group and 34% in the trabeculectomy group at 5 years group and 39.4% in the BGI group BGI group postoperatively

Comparison groups

between 1995 and 2004.27 In another study, conducted in the United States, a 53% decrease in trabeculectomies was observed between 1995 and 2004.26 Not only has there been a reduction in the number of glaucoma surgeries performed, there has also been a decrease in the number of surgeons performing incisional glaucoma surgery.72 In a study conducted in Ontario, Canada, a 47% decline in the percentage of ophthalmologists performing incisional glaucoma surgery between 1995 and 2010 was observed (from 35% in 1995 to 19% in 2010). At the same time, the proportion of incisional glaucoma surgery provided by glaucoma surgeons has more than doubled. A likely explanation for this trend is the expansion in glaucoma fellowship training opportunities, providing general ophthalmologists with easier access to a subspecialist.72 Although trabeculectomy remains the “gold standard” for glaucoma surgery,73–75 it is accompanied by high rates of both short- and long-term complications. In the early postoperative period these complications include choroidal effusions, hypotony, shallow anterior chambers, and hyphema.76–81 Long-term complications are often bleb related and include leakage, blebitis, and endophthalmitis.

Glaucoma Drainage Implants

In recent years, there has been an increased interest in GDIs.26,29,72 Traditionally, GDIs were used in more refractory glaucoma, although they have been gaining favour, even in cases of nonrefractory glaucoma. In 1 study, which examined the glaucoma surgical procedure rates in the United States, a 184% increase in the use of GDIs, from 2728 in 1995 to 7744 in 2004, was observed. Surveys of the membership of the American Glaucoma Society performed in 1996, 2002, and 2008 have also shown a significant increase in the use of GDIs compared with trabeculectomy.82–84 The shift in practice pattern toward increased use of GDIs even in cases of nonrefractory glaucoma was

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validated by the results of the Tube versus Trabeculectomy (TVT) Study (Table 1).85 In this study, patients who had previous trabeculectomy and/or cataract extraction and uncontrolled glaucoma (with IOP Z18) were randomized to either tube shunt surgery (350 mm2 Baerveld glaucoma implant) or trabeculectomy with mitomycin C (Mutamycin; Bristol-Myers Squibb, New York City, N.Y.). It was found that patients who underwent tube shunt surgery had a higher success rate compared with trabeculectomy during 5 years of follow-up. The cumulative probability of failure was 29.8% in the tube group and 46.9% in the trabeculectomy group at 5 years postoperatively.85 Previously reported data also demonstrated a higher failure rate with trabeculectomy with mitomycin C at both 1 and 3 years.86,87 The trabeculectomy failure rate in the TVT study was similar to other studies88–99; however, the failure rate of tube shunts was lower than previously reported.100–109 A probable explanation for this difference is that the TVT study enrolled eyes at lower risk of failure than eyes that have traditionally underwent tube shunt surgery. It is important to note that the TVT study included only patients who had a previous failed trabeculectomy or cataract extraction. The goal of the study was not to compare 2 surgical techniques on previously unoperated eyes. Currently, there is a primary TVT study underway that will address this question. All GDIs share a similar design and consist of a tube that is used to divert aqueous humor from the anterior chamber of the eye to an external reservoir. The devices differ with respect to the presence or absence of valves, size, and composition of the end plate. Two of the most commonly used GDIs are the Ahmed valve (New World Medical, Inc, Rancho Cucamonga, Calif.) and Baerveldt implant (Abbott Medical Optics, Inc, Santa Ana, Calif.). The Ahmed implant has a venturi-based flow restrictor, designed to reduce postoperative hypotony, although it has been associated with high rates of encapsulation and inadequate IOP reduction.107,110–113 The Baerveldt

Glaucoma treatment trends: a review—Conlon et al. implant is nonvalved and requires intraoperative mechanical flow restriction to allow adequate time for a capsule to form. Aqueous drainage begins only after the flow restriction reverses, usually 4–6 weeks postoperatively. This delay in aqueous drainage has been reported to cause early postoperative IOP volatility.114,115 The Ahmed Baerveldt Comparison (ABC) was a prospective, randomized study initiated to compare the safety and efficacy of the Ahmed FP7 glaucoma valve (AGV) and the Baerveldt 101–350 glaucoma implant (BGI) (Table 1).116 Patients with refractory glaucoma and an IOP Z18 in whom GDI surgery was planned were enrolled in the study and randomly assigned to implantation of an AGV or BGI. The primary outcome in the ABC study was cumulative failure rate. The probability of failure at 5 years was 44.7% in the AGV group compared with 39.4% in the BGI group (p ¼ 0.65), although the reasons for failure were different. Failure with the AGV was mainly attributable to high IOP end points, whereas failure with the BGI was most often related to safety end points (hypotony, loss of light perception, and implant explantation).116 At 5 years, mean IOP decreased from baseline averages of 31 to 32 mm Hg to 14.7 mm Hg in the AGV group and 12.7 mm Hg in the BGI group (p ¼ 0.015). Although the BGI decreased IOP to a greater extent in the long-term, AGV decreased IOP more in the early postoperative period compared with the BGI. In addition, the BGI group required fewer adjunctive medications at 5 years (2.2 in the AGV group vs 1.8 in the BGI group).116 The results of the ABC study were supported by a similar study, the Ahmed versus Baerveldt Study (AVB), which also compared the AGV to BGI (Table 1).117 Again, lower failure rates and a reduction in the need for glaucoma medications were observed with the BGI, although there were more vision-threatening complications and hypotony in the BGI group.117 The ABC and AVB studies do not demonstrate superiority of 1 GDI. Other important considerations, such as individual patient characteristics and surgeon experience, are critical in selecting an implant. For example, if the surgeon’s goal is to lower pressure as much as possible to prevent progression, it may be more advantageous to use a BGI. On the other hand, if the target pressure is higher and the goal is to obtain an IOP within normal limits, the AGV may be more suitable given its superior safety profile. After 5 years of follow-up more reoperations for implant-related complications occurred in the BGI group in the ABC study.118

Nonpenetrating Glaucoma Surgery

Nonpenetrating glaucoma surgery (NPGS), such as deep sclerectomy (DS) and viscocanalostomy (VC), were popularized in the 1990s as an alternative to

trabeculectomy, with fewer complications.119 The main difference between NPGS and trabeculectomy is that the procedures involve the creation of a filtration membrane (the Trabeculo-Descemet’s membrane) rather than a sclerostomy. Most studies agree that NPGS has a lower complication rate than trabeculectomy,120–125 although their efficacy in terms of lowering IOP remains a subject of debate. Some studies suggest that NPGS techniques have comparable IOP-lowering capabilities as the standard trabeculectomy,124,126 whereas others suggest that NPGS is inferior at lowering IOP.122–132 Randomized prospective studies have found success rates of DS and trabeculectomy to be similar.133–136 Cillino et al. found no significant difference in outcomes between the 2 techniques, but concluded that trabeculectomy was more suitable with patients with higher IOPs.136 A meta-analysis of 10 randomized control trials comparing trabeculectomy and VC concluded that trabeculectomy had a greater pressure-lowering effect than VC, but a higher risk profile.137 In 1 prospective randomized study of 50 eyes, 42% of patients in the trabeculectomy group had a successful outcome compared with 21% in the VC group.125 The main benefit of using NPGS is its increased safety profile. The avoidance of full-thickness penetration and its potential for sudden hypotony is an enticing option for patients at high risk for complications with trabeculectomy. One of the main limitations to their widespread use is their surgical difficulty.

Microinvasive Glaucoma Surgery

Recently, a new class of glaucoma procedures, termed “microinvasive glaucoma surgery” (MIGS), has emerged. MIGS procedures are used earlier in the glaucoma treatment algorithm and aim to fill the gap between medication and more invasive surgeries such as trabeculectomy or GDIs. Many MIGS procedures are performed in conjunction with cataract surgery, where the patient has already accepted the risks of intraocular surgery. In contrast with more invasive glaucoma surgeries, MIGS procedures use an ab interno approach and are relatively low risk. MIGS procedures target 3 main outflow channels: Schlemm’s canal through trabecular outflow; the suprachoroidal space via the uveoscleral pathway; and the subconjunctival space, by creating an alternative outflow pathway for aqueous humor (Table 2). In general, MIGS procedures share 5 important features: ab interno approach, minimal trauma, ability to lower IOP, extremely high safety profile, and rapid recovery.138 The definition of MIGS is subject to debate, and was initially termed minimally invasive glaucoma surgery (Ahmed I.K., personal communication, 2016). It is the opinion of the authors that the term micro is more representative of MIGS, as it truly differentiates MIGS from other CAN J OPHTHALMOL — VOL. ], NO. ], ] 2016

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Glaucoma treatment trends: a review—Conlon et al. Table 2—Classification of microinvasive glaucoma surgery (MIGS) devices by outflow channel Outflow channel

MIGS device

Schlemm’s canal

iStent (Glaukos Corporation, Laguna Hills, Calif.) iStent inject (Glaukos Corporation) Hydrus (Ivantis, Irvine, Calif.) Trabectome (Neomedix, Inc, Tustin, Calif.) iStent supra (Glaukos Corporation) CyPass (Transcend Medical, Menlo Park, Calif.) Xen Gel Stent (Allergan, Irvine, Calif.)

Suprachoroidal space Subconjunctival space

minimally invasive procedures in nonophthalmic specialties.139 Either way, MIGS is understood as per the above definition. The iStent (Glaukos Corporation, Laguna Hills, Calif.) is one of the most widely used and studied MIGS devices. The microstent is manufactured from heparin-coated titanium and can be implanted into Schlemm’s canal using a preloaded inserter.140 A randomized clinical trial of 240 OAG eyes compared cataract surgery alone to iStent implantation and cataract surgery combined. The primary outcome measure was the percent of patients who achieved an IOP r21 mm Hg without the use of ocular hypotensive medications. Seventy-two percent of participants achieved an unmedicated IOP of r21 in the combined surgery group versus 50% in the cataract surgery group at 1 year, with no substantial differences in adverse events.140 After 2 years, a 61% success rate was observed in the combined surgery group versus 50% in the cataract surgery group.141 Preliminary evidence suggests that the implantation of multiple iStents may be advantageous. Belovay et al.142 demonstrated a significant reduction in IOP and glaucoma medications with the use of 2–3 iStents. Mean preoperative IOP decreased from 18 mm Hg to 14.4 mm Hg at 1 year postoperatively (p o 0.001). In addition, mean topical hypotensive medications decreased from 2.7 to 0.7 at 1 year (p o 0.001).142 A second-generation iStent, known as iStent inject (Glaukos Corporation), was recently developed. The device is smaller and designed for more direct implantation in Schlemm’s canal. In addition, the device is a 2stent system.143 Voskanyan et al. evaluated the safety and efficacy of the device on 99 patients with OAG. Participants enrolled in the study were on at least 2 topical ocular hypotensive medications and required additional IOP lowering. Mean preoperative IOP decreased from 26.3 mm Hg (after medication washout) to 15.7 mm Hg at 1 year postoperatively. In addition, 65% of participants were medication-free at 1 year.144 Fea et al. conducted a randomized study comparing the iStent inject to ocular hypotensive agents and found the device to be at least as effective as medications in controlling IOP in patients with OAG, with an excellent safety profile.145 A third-generation iStent (iStent supra), made of heparin-coated polyethersulfone and a titanium sleeve, was recently developed. The device is designed for

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implantation in the suprachoroidal space. Clinical trials are currently underway. Auffarth and Kretz implanted the device in 80 eyes with mild to moderate OAG uncontrolled on 2 topical medications and demonstrated a significant reduction in IOP and medication burden at 18 postoperatively as well as a favourable safety profile.146 The Hydrus (Ivantis, Irvine, Calif.) is another MIGS device that targets Schlemm’s canal to increase aqueous outflow. The device is an 8-mm-long nitinol (nickel– titanium alloy) Schlemm’s canal scaffold with 3 openings.147 It is implanted through the trabecular meshwork using a manual inserter. A preclinical study was able to demonstrate the long-term biocompatibility of the device in animal models.148 Randomized controlled trials are underway, and the results have been promising. Pfeiffer et al. compared the efficacy of the microstent in conjunction with cataract surgery to cataract surgery alone in patients with OAG. The proportion of patients achieving a 20% reduction in IOP was significantly higher in the Hydrus plus cataract surgery group at 24 months postoperatively (80% vs 46%; p ¼ 0.008). In addition, the proportion of patients using no hypotensive medication at 24 months was significantly higher in the Hydrus plus cataract surgery group (73% vs 38%; p ¼ 0.008), and adverse event frequency was similar in the 2 groups.149 The Trabectome (Neomedix, Inc, Tustin, Calif.) is an instrument that uses microelectrocautery to ablate a strip of tissue from the trabecular meshwork, leaving the inner wall of Schlemm’s canal intact to preserve collector channel drainage. Studies have demonstrated an acceptable safety profile.150,151 In 2010, a study that compared 539 Trabectome and 290 combined cataract surgery and Trabectome procedures revealed a 1-year success rate (IOP r21) of 64.9% in the Trabectome group and 86.9% in the combined procedure group.150 Francis and Winarko prospectively compared eyes undergoing cataract and Trabectome surgery to eyes undergoing cataract and trabeculectomy surgery. A decrease in IOP from 22.1 to 15.4 mm Hg was observed in the cataract and Trabectome surgery group, and a reduction in IOP from 23.0 to 11.0 mm Hg was seen in the cataract and trabeculectomy surgery group. Although the IOP-lowering effect was greater in the cataract and trabeculectomy surgery group, a higher rate of postoperative complications was observed.151 Another study demonstrated that a previously failed Trabectome procedure does not negatively impact the outcomes of a subsequent trabeculectomy.152 This study highlights an important feature of the majority of MIGS devices; conventional glaucoma surgery can be performed if necessary. Another MIGS pathway to decrease IOP is via the suprachoroidal space. The CyPass implant (Transcend Medical, Menlo Park, Calif.) is a suprachoroidal shunt made of a polyamide material. The device can be inserted ab interno into the suprachoroidal space using a manual inserter.138 Early clinical studies have shown that

Glaucoma treatment trends: a review—Conlon et al. implantation of the device at the time of cataract surgery or as a standalone procedure leads to significant reduction in IOP and glaucoma medications.153,154 Hoeh et al. reported their initial surgical experience with the microstent when combined with cataract surgery. Two analysis cohorts were prespecified based on medicated IOP: Z21 mm Hg (cohort 1, n ¼ 65) or o21 mm Hg (cohort 2, n ¼ 102). At 1 year, cohort 1 showed a 35% decrease in mean IOP and a 49% reduction in glaucoma medication usage. Cohort 2 had a 75% reduction in mean medication use, while maintaining an IOP o21 mm Hg.153 GarciaFeijoo et al. evaluated the efficacy of the device in patients refractory to topical medications. Patients with OAG and uncontrolled medicated IOPs of 421 were enrolled. Baseline IOP was reduced from 24.5 to 16.4 mm Hg (p o 0.0001) at 12 months. In addition, the mean number of medications was reduced from 2.2 to 1.4 (p ¼ 0.002). No secondary surgery was performed in 83% (53/64) of patients, precluding them for more invasive glaucoma surgery.154 The XEN Gel Stent (Allergan) targets the subconjunctival space for aqueous drainage via an ab interno approach. The device is 6 mm in length and is composed of cross-linked gelatin. It is designed to swell at the time of implantation to secure the device in place. Initial results suggest that, when combined with antimetabolites, IOPlowering effects are similar to that of trabeculectomy, although the risks may be slightly higher than typical MIGS procedures.155,156 In a recent prospective, nonrandomized study, mean IOP decreased from 20.8 mm Hg preoperatively to 14.4 mm Hg at 6 months and 13.1 mm Hg at 12 months. In addition, glaucoma medications decreased from 2.7 to 0.9 at 12 months.155 Another study demonstrated similar results, with a mean preoperative IOP decreasing from 22.7 to 13.4 mm Hg at 12 months and glaucoma medication usage decreasing by 64%.156 Long-term data are still needed to assess the devices sustained IOP-lowering effect.

RELATIONSHIP

WITH

OPTOMETRISTS

Not only has the medical and surgical management of glaucoma evolved, but also so has the role of optometrists, as the scope of their practice expands. In 2008, the membership of the Canadian Glaucoma Society (CGS) created a committee to develop a model of interprofessional collaboration between optometrists and ophthalmologists in the care of glaucoma patients and glaucoma suspects. A general principle of this model is that ophthalmologists should evaluate patients early in the course of their disease.157 According to the model set forth by the CGS, glaucoma suspects with low/moderate risk can initially be assessed by optometrists and do not require referral to an ophthalmologist. High-risk glaucoma suspects can also be monitored by optometrists, with periodic consultation to an

ophthalmologist (every 3–4 years). Stable early glaucoma patients should be referred to an ophthalmologist in a timely fashion. Once stable, these patients can be returned to the optometrist for monitoring, although they should be reassessed by an ophthalmologist at least every 2–3 years. Patients with moderate and advanced disease should primarily be managed by an ophthalmologist.157

CONCLUSIONS Glaucoma remains one of the most common causes of blindness worldwide and with the aging population there is an increasing prevalence.158 The present review outlines the treatment trends in the early management of glaucoma (which involves topical medications or laser therapy), NPGS, invasive glaucoma surgeries, and the newer MIGS procedures. Overall, there has been an increase in the use of topical medications and laser trabeculoplasty, and a decrease in invasive incisional glaucoma surgery. Fewer ophthalmologists are performing incisional glaucoma surgery (more restricted to fellowship-trained glaucoma subspecialists), while general ophthalmologists have increased responsibility for clinical care and laser therapy.159 In addition, there has been increased use of and reliance on optic nerve imaging and reduction in visual field testing. Previously, there was a gap between conservative medical management and more invasive glaucoma surgery. The newer MIGS procedures aim to fill this gap and early studies have demonstrated their ability to lower IOP with minimal risk in patients with mild to moderate glaucoma. More data and longer follow-up are still needed to determine their exact role in the glaucoma treatment algorithm.

REFERENCES 1. Resnikoff S, Pascolini D, Etaya’ale D, et al. Global data on visual impairment in the year 2002. Bull WHO. 2004;82:844-51. 2. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262-7. 3. Perruccio AV, Badley EM, Trope GE. Self-reported glaucoma in Canada: findings from population-based surveys, 1994–2003. Can J Ophthalmol. 2007;42:219-26. 4. Sommer A, Tielsch JM, Katz J, et al. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol. 1991;109:1090-5. 5. Mitchell P, Smith W, Attebo K, Healey PR. Prevalence of open angle glaucoma in Australia–The Blue Mountains Eye Study. Ophthalmology. 1996;103:1661-9. 6. Boland MV, Ervin AM, Friedman DS, et al. Comparative effectiveness of treatments for open angle glaucoma: a systematic review for the US Preventive Services Task Force. Ann Intern Med. 2013;158:271-9. 7. AAO. American Academy of Ophthalmology Glaucoma Panel, Primary Open Angle GlaucomaSan Francisco, CA: AAO PPP Glaucoma Panel, Hoskins Center for Quality Eye Care; 2010; Available from: 〈http://www.aao.org/ppp〉. 8. Narayanaswamy A, Neog A, Baskaran M, et al. A randomized, crossover, open label pilot study to evaluate the efficacy and safety of Xalatan in comparison with generic Latanoprost (Latoprost) in CAN J OPHTHALMOL — VOL. ], NO. ], ] 2016

7

Glaucoma treatment trends: a review—Conlon et al.

9.

10. 11. 12. 13.

14.

15. 16. 17. 18.

19.

20.

21.

22.

23. 24. 25. 26.

27. 28. 29.

8

subjects with primary open angle glaucoma or ocular hypertension. Indian J Ophthalmol. 2007;55:127-31. Gaton DD, Sagara T, Lindsey JD, Gabelt BT, Kaufman PL, Weinreb RN. Increased matrix metalloproteinases 1, 2, and 3 in monkey uveoscleral outflow pathway after topic prostaglandin F(2 alpha)-isopropyl ester treatment. Arch Ophthalmol. 2001;119: 1165-70. Lee DA, Higginbotham EJ. Glaucoma and its treatment: a review. Am J Health Syst Pharm. 2005;62:691-9. Realini T. A history of glaucoma pharmacology. Optom Vis Sci. 2011;88:36-8. Netland PA, Landry T, Sullivan EK, et al. Travoprost compared with latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2001;132:472-84. Sherwood M, Brandt J. Bimatoprost Study Groups 1 and 2. Sixmonth comparison of bimatoprost once-daily and twice-daily with timolol twice-daily in patients with elevated intraocular pressure. Surv Ophthalmol. 2001;45:S361-8. Hedman K, Alm A, Gross RL. Pooled-data analysis of three randomized, double-masked, six-month studies comparing intraocular pressure-reducing effects of latanoprost and timolol in patients with ocular hypertension. J Glaucoma. 2003;12:463-5. Stein JD, Ayyagari P, Sloan FA, Lee PP. Rates of glaucoma medication utilization among persons with primary open-angle glaucoma, 1992 to 2002. Ophthalmology. 2008;115:1315-9. Rachmiel R, Trope GE, Chipman ML, Gouws P, Buys YM. Effect of medical therapy on glaucoma filtration surgery rates in Ontario. Arch Ophthalmol. 2006;124:1472-7. Schwartz GF, Reardon G, Mozaffari E. Persistency with latanoprost or timolol in primary open-angle glaucoma suspects. Am J Ophthalmol. 2004;137:S13-6. Hollo G, Topouzis F, Fechtner RD. Fixed combination intraocular pressure-lowering therapy for glaucoma and ocular hypertension: advantages in clinical practice. Expert Opin Pharmacother. 2014;15:1737-47. Business Wire. Allergan announces R&D pipeline update and US FDA approval. June 30, 2014. Available from: 〈www.businesswire. com/news/home/20140630005687/en/Allergan-Announces-Pipeli ne-Update-U.S.-FDA-Approval〉. VafwQkVFCjw. Accessed November 8, 2015. Pattabiraman PP. Effects of Rho kinase inhibitor AR-13324 on the actin cytoskeleton and on TGFβ2- and CTGF-induced fibrogenic activity in Human Trabecular Meshwork Cells. AOPT 2015 Poster 43. Charleston, SC, February 2015. Bacharach J, Dubiner HB, Levy B, Kopczynski CC, Novack GD. AR-13324-CS202 Study Group. Double-masked, randomized, dose-response study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. Ophthalmology. 2015;122: 302-7. Aerie Pharmaceuticals Reports Roclatan Phase 2b Results Achieve All Clinical Endpoints. Available at: 〈http://investors.aeriepharma. com/releases.cfm?Year=&ReleasesType=&PageNum=2〉. Accessed November 8, 2015. Sena DF, Ramchand K, Lindsley K. Neuroprotection for treatment of glaucoma in adults. Cochrane Database Syst Rev 2010: CD006539. Wise JB, Witter SL. Argon laser therapy for open-angle glaucoma. A pilot study. Arch Ophthalmol. 1979;97:319-22. Samples JR, Singh K, Lin SC, et al. Laser trabeculoplasty for openangle glaucoma: a report by the american academy of ophthalmology. Ophthalmology. 2011;118:2296-302. Ramulu PY, Corcoran KJ, Corcoran SL, Robin AL. Utilization of various glaucoma surgeries and procedures in Medicare beneficiaries from 1995 to 2004. Ophthalmology. 2007;114: 2265-70. Campbell RJ, Trope GE, Rachmiel R, Buys YM. Glaucoma laser and surgical procedure rates in Canada: a long-term profile. Can J Ophthalmol. 2008;43:449-53. Jampel HD, Cassard SD, Friedman DS, et al. Trends over time and regional variations in the rate of laser trabeculoplasty in the Medicare population. JAMA Ophthalmol. 2014;132:685-90. Szigiato AA, Trope GE, Jin Y, Buys YM. Trends in glaucoma surgical procedures in Ontario: 1992–2012. Can J Ophthalmol. 2015;50:338-44.

CAN J OPHTHALMOL — VOL. ], NO. ], ] 2016

30. Szigiato AA, Trope GE, Jin Y, Buys YM. Same-day bilateral glaucoma laser treatments in Ontario: 2000 to 2013. J Glaucoma. 2016;25:339-42. 31. Latina MA, Sibayan SA, Shin DH, Noecker RJ, Marcellino G. Qswitched 532-nm Nd:YAG laser trabeculoplasty (selective laser trabeculoplasty): a multicenter, pilot, clinical study. Ophthalmology. 1998;105:2082-8. discussion 2089–90. 32. Juzych MS, Chopra V, Banitt MR, et al. Comparison of long-term outcomes of selective laser trabeculoplasty versus argon laser trabeculoplasty in open-angle glaucoma. Ophthalmology. 2004;111: 1853-9. 33. Kent SS, Hutnik CM, Birt CM, et al. A randomized clinical trial of selective laser trabeculoplasty versus argon laser trabeculoplasty in patients with pseudoexfoliation. J Glaucoma. 2015;24: 344-7. 34. Holló G. Argon and low energy, pulsed Nd:YAG laser trabeculoplasty. A prospective, comparative clinical and morphological study. Acta Ophthalmol Scand. 1996;74:126-31. 35. Kramer TR, Noecker RJ. Comparison of the morphologic changes after selective laser trabeculoplasty and argon laser trabeculoplasty in human eye bank eyes. Ophthalmology. 2001;108:773-9. 36. Stein JD, Challa P. Mechanisms of action and efficacy of argon laser trabeculoplasty and selective laser trabeculoplasty. Curr Opin Ophthalmol. 2007;18:140-5. 37. Damji KF, Shah KC, Rock WJ, Bains HS, Hodge WG. Selective laser trabeculoplasty v argon laser trabeculoplasty: a prospective randomised clinical trial. Br J Ophthalmol. 1999;83:718-22. 38. Dueker DK, Norberg M, Johnson DH, Tschumper RC, FeeneyBurns L. Stimulation of cell division by argon and Nd:YAG laser trabeculoplasty in cynomolgus monkeys. Invest Ophthalmol Vis Sci. 1990;31:115-24. 39. Gracner T, Falez M, Gracner B, Pahor D. [Long-term follow-up of selective laser trabeculoplasty in primary open-angle glaucoma]. Klin Monbl Augenheilkd. 2006;223:743-7. In German. 40. Weinand FS, Althen F. Long-term clinical results of selective laser trabeculoplasty in the treatment of primary open angle glaucoma. Eur J Ophthalmol. 2006;16:100-4. 41. Nagar M, Ogunyomade A, O’Brart DP, Howes F, Marshall J. A randomised, prospective study comparing selective laser trabeculoplasty with latanoprost for the control of intraocular pressure in ocular hypertension and open angle glaucoma. Br J Ophthalmol. 2005;89:1413-7. 42. McIlraith I, Strasfeld M, Colev G, Hutnik CM. Selective laser trabeculoplasty as initial and adjunctive treatment for open-angle glaucoma. J Glaucoma. 2006;15:124-30. 43. Bovell AM, Damji KF, Hodge WG, Rock WJ, Buhrmann RR, Pan YI. Long term effects on the lowering of intraocular pressure: selective laser or argon laser trabeculoplasty? Can J Ophthalmol. 2011;46:408-13. 44. Wong MO, Lee JW, Choy BN, Chan JC, Lai JS. Systematic review and meta-analysis on the efficacy of selective laser trabeculoplasty in open-angle glaucoma. Surv Ophthalmol. 2015;60: 36-50. 45. Dirani M, Crowston JG, Taylor PS, et al. Economic impact of primary open-angle glaucoma in Australia. Clin Exp Ophthalmol. 2011;39:623-32. 46. Lee R, Hutnik CM. Projected cost comparison of selective laser trabeculoplasty versus glaucoma medication in the Ontario Health Insurance Plan. Can J Ophthalmol. 2006;41:449-56. 47. Vujosevic S, Bottega E, Casciano M, et al. Microperimetry and fundus autofluorescence in diabetic macular edema: subthreshold micropulse diode laser versus modified early treatment diabetic retinopathy study laser photocoagulation. Retina. 2010;30:908-16. 48. Fudemberg SJ, Myers JS, Katz LJ. Trabecular meshwork tissue examination with scanning electron microscopy: a comparison of MicroPulse Diode Laser (MLT), Selective Laser (SLT), and Argon laser (ALT) Trabeculoplasty in human cadaver tissue. Invest Ophthalmol Vis Sci. 2008;49:1236. 49. Fea AM, Bosone A, Rolle T, et al. Microdulse diode laser trabeculoplasty (MDLT): a phase II clinical study with 12 months follow-up. Clin Ophthalmol. 2008;2:247-52. 50. Coombs P, Radcliffe NM. Outcomes of micropulse laser trabeculoplasty vs. selective laser trabeculoplasty. ARVO 2014. Orlando, FL, May 2014.

Glaucoma treatment trends: a review—Conlon et al. 51. Tsang S, Cheng J, Lee JW. Developments in laser trabeculoplasty. Br J Ophthalmol. 2016;100:94-7. 52. Goldenfeld M, Melamed S, Simon G, Ben Simon GJ. Titanium: sapphire laser trabeculoplasty versus argon laser trabeculoplasty in patients with open-angle glaucoma. Ophthalmic Surg Lasers Imaging. 2009;40:264-9. 53. Turati M, Gil-Carrasco F, Morales A, et al. Patterned laser trabeculoplasty. Ophthalmic Surg Lasers Imaging. 2010;41:538-45. 54. Ishida K. Update on results and complications of cyclophotocoagulation. Curr Opin Ophthalmol. 2013;24:102-10. 55. Egbert PR, Fiadoyor S, Budenz DL, et al. Diode laser transscleral cyclopho- tocoagulation as a primary surgical treatment for primary open-angle glaucoma. Arch Ophthalmol. 2001;119: 345-50. 56. Gupta V, Agarwal HC. Contact trans-scleral diode laser cyclophotocoagulation treatment for refractory glaucomas in the Indian population. Indian J Ophthalmol. 2000;48:29-300. 57. Hauber FA, Scherer WJ. Influence of total energy delivery on success rate after contact diode laser transscleral cyclophotocoagulation: a retrospective case review and meta-analysis. J Glaucoma. 2002;11:329-33. 58. Lai JS, Tham CC, Chan JC, Lam DS. Diode laser transscleral cyclophoto- coagulation as primary surgical treatment for medically uncontrolled chronic angle closure glaucoma: long-term clinical outcomes. J Glaucoma. 2005;14:114-9. 59. Kramp K, Vick HP, Guthoff R. Transscleral diode laser contact cyclophoto-coagulation in the treatment of different glaucomas, also as primary surgery. Graefes Arch Clin Exp Ophthalmol. 2002;240:698-703. 60. Grueb M, Rohrbach JM, Bartz-Schmidt KU, Schlote T. Transscleral diode laser cyclophotocoagulation as primary and secondary surgical treatment in primary open-angle and pseudoexfoliative glaucoma. Long-term clinical outcomes. Graefes Arch Clin Exp Ophthalmol. 2006;244:1293-9. 61. Manna A, Foster P, Papadopoulos M, Nolan W. Cyclodiode laser in the treatment of acute angle closure. Eye. 2012;26:742-5. 62. Preussner PR, Ngounou F, Kouogan G. Controlled cyclophotocoagulation with the 940 nm laser for primary open angle glaucoma in African eyes. Graefes Arch Clin Exp Ophthalmol. 2010;248:1473-9. 63. Lindfield D, Ritchie RW, Griffiths MF. ‘Phaco-ECP’: combined endoscopic & cyclophotocoagulation and cataract surgery to augment medical control of glaucoma. BMJ Open. 2012;2:1-6. 64. Barke SJ, Sturm RT, Caronia RM, et al. Phacoemulsification combined with endoscopic cyclophotocoagulation (ECP) in the management of cataract and medically controlled glaucoma: a large, long term study. In: American Glaucoma Society 16th Annual Meeting; 2–5 March 2006; Charleston, SC; 2006. Abstract 22:47. 65. Berke SJ. Endolaser cyclophotocoagulation in glaucoma management. Tech Ophthalmol. 2006;4:74-81. 66. Strutton DR, Walt JG. Trends in glaucoma surgery before and after the introduction of new topical glaucoma pharmacotherapies. J Glaucoma. 2004;13:221-6. 67. van der Valk R, Schouten JS, Webers CA, et al. The impact of a nationwide introduction of new drugs and a treatment protocol for glaucoma on the number of glaucoma surgeries. J Glaucoma. 2005;14:239-42. 68. Walland MJ. Glaucoma treatment in Australia: changing patterns of therapy 1994–2003. Clin Exp Ophthalmol. 2004;32:590-6. 69. Keenan TD, Salmon JF, Yeates D, Goldacre MJ. Trends in rates of trabeculectomy in England. Eye (Lond). 2009;23:1141-9. 70. Macleod SM, Clark R, Forrest J, Bain M, Bateman N, AzuaraBlanco A. A review of glaucoma treatment in Scotland 1994– 2004. Eye (Lond). 2008;22:251-5. 71. Murphy C, Ogston S, Cobb C, MacEwen C. Recent trends in glaucoma surgery in Scotland, England and Wales. Br J Ophthalmol. 2015;99:308-12. 72. Campbell RJ, Bell CM, Gill SS, et al. Subspecialization in glaucoma surgery. Ophthalmology. 2012;119:2270-3. 73. Razeghinejad MR, Fudemberg SJ, Spaeth GL. The changing conceptual basis of trabeculectomy: a review of past and current surgical techniques. Surv Ophthalmol. 2012;57:1-25.

74. Netland PA; Ophthalmic Technology Assessment Committee Glaucoma Panel, American Academy of Ophthalmology. Nonpenetrating glaucoma surgery. Ophthalmology. 2001;108:416-21. 75. Cairns JE. Trabeculectomy: preliminary report of a new method. Am J Ophthalmol. 1968;66:673-9. 76. Kao SF, Lichter PR, Musch DC. Anterior chamber depth following filtration surgery. Ophthalmic Surg. 1989;20:332-6. 77. Stewart WC, Shields MB. Management of anterior chamber depth after trabeculectomy. Am J Ophthalmol. 1988;106:41-4. 78. Brubaker RF, Pederson JE. Ciliochoroidal detachment. Surv Ophthalmol. 1983;27:281-9. 79. Gressel MG, Parrish RK II, Heuer DK. Delayed nonexpulsive suprachoroidal hemorrhage. Arch Ophthalmol. 1984;102:1757-60. 80. Ruderman JM, Harbin TS Jr, Campbell DG. Post-operative suprachoroidal hemorrhage following filtration procedures. Arch Ophthalmol. 1986;104:201-5. 81. Freedman J, Gupta M, Bunke A. Endophthalmitis after trabeculectomy. Arch Ophthalmol. 1978;96:1017-8. 82. Chen PP, Yamamoto T, Sawada A, et al. Use of antifibrosis agents and glaucoma drainage devices in the American and Japanese Glaucoma Societies. J Glaucoma. 1997;6:192-6. 83. Joshi AB, Parrish RK II, Feuer WF. 2002 survey of the American Glaucoma Society: practice preferences for glaucoma surgery and antifibrotic use. J Glaucoma. 2005;14:172-4. 84. Desai MA, Gedde SJ, Feuer WJ, et al. Practice preferences for glaucoma surgery: a survey of the American Glaucoma Society in 2008. Ophthalmic Surg Lasers Imaging. 2011;42:202-8. 85. Gedde SJ, Schiffman JC, Feuer WJ, Herndon LW, Brandt JD, Budenz DL. Treatment outcomes in the Tube Versus Trabeculectomy (TVT) study after five years of follow-up. Am J Ophthalmol. 2012;153:789-803. 86. Gedde SJ, Schiffman JC, Feuer WJ, et al. Treatment outcomes in the Tube Versus Trabeculectomy Study after one year of followup. Am J Ophthalmol. 2007;143:9-22. 87. Gedde SJ, Schiffman JC, Feuer WJ, et al. Three-year follow-up of the Tube Versus Trabeculectomy Study. Am J Ophthalmol. 2009;148:670-84. 88. The Fluorouracil Filtering Surgery Study Group. Five-year followup of the fluorouracil filtering surgery study. Am J Ophthalmol. 1996;121:349-66. 89. The Fluorouracil Filtering Surgery Study Group. Fluorouracil filtering surgery study one-year follow-up. Am J Ophthalmol. 1989;108:625-35. 90. The Fluorouracil Filtering Surgery Study Group. Three-year follow-up of the fluorouracil filtering surgery study. Am J Ophthalmol. 1993;115:82-92. 91. Heuer DK, Parrish RK, Gressel MG, Hodapp E, Palmberg PF, Anderson DR. 5-fluorouracil and glaucoma filtering surgery: II. A pilot study. Ophthalmology. 1984;91:384-94. 92. Heuer DK, Parrish RK, Gressel MG, et al. 5-fluorouracil and glaucoma filtering surgery: III. Intermediate follow-up of a pilot study. Ophthalmology. 1986;93:1537-46. 93. Weinreb RN. Adjusting the dose of 5-fluorouracil after filtration surgery to minimize side effects. Ophthalmology. 1987;94:564-70. 94. Palmer SS. Mitomycin as adjunct chemotherapy with trabeculectomy. Ophthalmology. 1991;98:317-21. 95. Prata JA, Minckler DS, Baerveldt G, Lee PP, LaBree L, Heuer DK. Trabeculectomy in pseudophakic patients: postoperative 5-fluorouracil versus intraoperative mitomycin C antiproliferative therapy. Ophthalmic Surg. 1995;26:73-7. 96. Chen CW, Huang HT, Bair JS, Lee CC. Trabeculectomy with simultaneous topical application of mitomycin-C in refractory glaucoma. J Ocular Pharmacol. 1990;6:175-82. 97. Singh J, O’Brien C, Chawla HB. Success rate and complications of intraoperative 0. 2 mg/ml mitomycin C in trabeculectomy surgery. Eye. 1995;9:460-6. 98. Andreanos D, Georgopoulos GT, Vergados J, Papaconstantinou D, Liokis N, Theodossiadis P. Clinical evaluation of the effect of mitomycin-C in re-operation for primary open angle glaucoma. Eur J Ophthalmol. 1997;7:49-54. 99. You YA, Gu YS, Fang CT, Ma XQ. Long-term effects of simultaneous and subscleral mitomycin C application in repeat trabeculectomy. J Glaucoma. 2002;11:110-8.

CAN J OPHTHALMOL — VOL. ], NO. ], ] 2016

9

Glaucoma treatment trends: a review—Conlon et al. 100. Minckler DS, Heuer DK, Hasty B, Baerveldt G, Cutting RC, Barlow WE. Clinical experience with the single-plate Molteno implant in complicated glaucomas. Ophthalmology. 1988;95:1181-8. 101. Freedman J, Rubin B. Molteno implants as a treatment for refractory glaucoma in black patients. Arch Ophthalmol. 1991; 109:1417-20. 102. Lloyd MA, Sedlak T, Heuer DK, et al. Clinical experience with the single plate Molteno implant in complicated glaucomas. Update of a pilot study. Ophthalmology. 1992;99:679-87. 103. Heuer DK, Lloyd MA, Abrams DA, et al. Which is better? One or two? A randomized clinical trial of single-plate versus double-plate Molteno implantation for glaucomas in aphakia and pseudphakia. Ophthalmology. 1992;99:1512-9. 104. Hodkin MJ, Goldblatt WS, Burgoyne CF, Ball SF, Insler MS. Early clinical experience with the Baerveldt implant in complicated glaucomas. Am J Ophthalmol. 1995;120:32-40. 105. Mills RP, Reynolds A, Emond MJ, Barlow WE, Leen MM. Longterm survival of Molteno glaucoma drainage devices. Ophthalmology. 1996;103:299-305. 106. Huang MC, Netland PA, Coleman AL, Siegner SW, Moster MR, Hill RA. Intermediate-term clinical experience with the Ahmed glaucoma valve implant. Am J Ophthalmol. 1999;127:27-33. 107. Broadway DC, Iester M, Schulzer M, Douglas GR. Survival analysis for success for Molteno tube implants. Br J Ophthalmol. 2001;85:689-895. 108. Roy S, Ravinet E, Mermoud A. Baerveldt implant in refractory glaucoma: long-term results and factors influencing outcomes. Int Ophthalmol. 2001;24:93-100. 109. Minckler DS, Francis BA, Hodapp EA, et al. Aqueous shunts in glaucoma: a report by the American Academcy of Ophthalmology. Ophthalmology. 2008;115:1089-98. 110. Nouri-Mahdavi K, Caprioli J. Evaluation of the hypertensive phase after insertion of the Ahmed Glaucoma Valve. Am J Ophthalmol. 2003;136:1001-8. 111. Tsai JC, Johnson CC, Dietrich MS. The Ahmed shunt versus the Baerveldt shunt for refractory glaucoma: a single-surgeon comparison of outcome. Ophthalmology. 2003;110:1814-21. 112. Tsai JC, Johnson CC, Kammer JA, Dietrich MS. The Ahmed shunt versus the Baerveldt shunt for refractory glaucoma II: longerterm outcomes from a single surgeon. Ophthalmology. 2006;113: 913-7. 113. Ayyala RS, Zurakowski D, Smith JA, et al. A clinical study of the Ahmed glaucoma valve implant in advanced glaucoma. Ophthalmology. 1998;105:1968-76. 114. Krishna R, Godfrey DG, Budenz DL, et al. Intermediate-term outcomes of 350-mm(2) Baerveldt glaucoma implants. Ophthalmology. 2001;108:621-6. 115. Britt MT, LaBree LD, Lloyd MA, et al. Randomized clinical trial of the 350-mm2 versus the 500-mm2 Baerveldt implant: longer term results: is bigger better? Ophthalmology. 1999;106:2312-8. 116. Budenz DL, Barton K, Gedde SJ, et al. Five-year treatment outcomes in the Ahmed Baerveldt comparison. Ophthalmology. 2015;122:308-16. 117. Christakis PG, Tsai JC, Kalenak JW, et al. The Ahmed Versus Baerveldt Study: three-year treatment outcomes. Ophthalmology. 2013;120:2232-40. 118. Budenz DL, Feuer WJ, Barton K, Schiffman J, Costa VP, Godfrey DG, Buys YM. Ahmed Baerveldt Comparison Study Group. Postoperative complications in the Ahmed Baerveldt comparison study during five years of follow-up. Am J Ophthalmol. 2016;163:75-82. 119. Sanchez E, Schnyder CC, Sickenberg M, Chiou AG, Hediguer SE, Mermoud A. Deep sclerectomy: results with and without collagen implant. Int Ophthalmol. 1996;20:157-62. 120. Carassa RG, Bettin P, Fiori M, Brancato R. Viscocanalostomy versus trabeculectomy in white adults affected by open-angle glaucoma: a 2-year randomized, controlled trial. Ophthalmology. 2003;110:882-7. 121. Cillino S, Di Pace F, Casuccio A, Cillino G, Lodato G. Deep sclerectomy versus trabeculectomy with low-dosage mitomycin C: four-year follow-up. Ophthalmologica. 2008;222:81-7. 122. O’Brart DP, Rowlands E, Islam N, Noury AM. A randomised, prospective study comparing trabeculectomy augmented with antimetabolites with a viscocanalostomy technique for the

10

CAN J OPHTHALMOL — VOL. ], NO. ], ] 2016

123. 124.

125.

126. 127.

128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140.

141.

142. 143.

144. 145.

management of open angle glaucoma uncontrolled by medical therapy. Br J Ophthalmol. 2002;86:748-54. Yarangumeli A, Gureser S, Koz OG, Elhan AH. Kural viscocanalostomy versus trabeculectomy in patients with bilateral hightension glaucoma. Int Ophthalmol. 2004;25:207-13. Zimmerman TJ, Kooner KS, Ford VJ, et al. Trabeculectomy vs. nonpenetrating trabeculectomy: a retrospective study of two procedures in phakic patients with glaucoma. Ophthalmic Surg. 1984;15:734-40. Gilmour DF, Manners TD, Devonport H, Varga Z, Solebo AL, Miles J. Viscocanalostomy versus trabeculectomy for primary open angle glaucoma: 4-year prospective randomized clinical trial. Eye (Lond). 2009;23:1802-7. Mermoud A, Schnyder CC, Sickenberg M, et al. Comparison of deep sclerectomy with collagen implant and trabeculectomy in open-angle glaucoma. J Cataract Refract Surg. 1999;25:323-31. Jonescu-Cuypers C, Jacobi P, Konen W, et al. Primary viscocanalostomy versus trabeculectomy in white patients with open-angle glaucoma: a randomized clinical trial. Ophthalmology. 2001;108: 254-8. Krieglstein GK. Non-penetrating glaucoma surgery. J Glaucoma. 2001;10:S88-90. Khaw PT, Siriwardena D. “New” surgical treatments for glaucoma. Br J Ophthalmol. 1999;83:1-2. Chiselita D. Non-penetrating deep sclerectomy versus trabeculectomy in primary open-angle glaucoma surgery. Eye. 2001;15: 197-201. Luke C, Dietlein TS, Jacobi PC, et al. A prospective randomized trial of viscocanalostomy versus trabeculectomy in open-angle glaucoma: a 1-year follow-up study. J Glaucoma. 2002;11:294-9. Drusedau MU, von Wolff K, Bull H, et al. Viscocanalostomy for primary open-angle glaucoma: the Gross Pankow experience. J Cataract Refract Surg. 2000;26:1367-73. Mielke C, Dawda VK, Anand N. Deep sclerectomy and low dose mitomycin C: a randomised prospective trial in West Africa. Br J Ophthalmol. 2006;90:310-3. El Sayyad F, Helal M, El-Kholify H, Khalil M, El-Maghraby A. Nonpenetrating deep sclerectomy versus trabeculectomy in bilateral primary open-angle glaucoma. Ophthalmology. 2000;107:1671-4. Ambresin A, Shaarawy T, Mermoud A. Deep sclerectomy with collagen implant in one eye compared with trabeculectomy in the other eye of the same patient. J Glaucoma. 2002;11:214-20. Cillino S, Di Pace F, Casuccio A, et al. Deep sclerectomy versus punch trabeculectomy with and without phacoemulsification: a randomised clinical trial. J Glaucoma. 2004;13:500-6. Chai C, Loon SC. Meta-analysis of viscocanalostomy versus trabeculectomy in uncontrolled glaucoma. J Glaucoma. 2010;19:519-27. Saheb H, Ahmed IK. Micro-invasive glaucoma surgery: current prospectives and future directions. Curr Opin Ophthalmol. 2012;23:96-104. Ahmed II. MIGS and the FDA: what’s in a name? Ophthalmology. 2015;122:1737-9. Samuelson TW, Katz LJ, Wells JM, et al. Group UIS. Randomized evaluation of the trabecular micro-bypass stent with phacoemulsification in patients with glaucoma and cataract. OPHTHA. 2011;118:459-67. Craven ER, Katz LJ, Welss MW, et al. Cataract surgery with trabecular micro-bypass stent implantation in patients with mildtomoderate open-angle glaucoma and cataract: two-year follow-up. J Cataract Refract Surg. 2012;38:1339-45. Belovay GW, Naqi A, Chan BJ, Rateb M, Ahmed II. Using multiple trabecular micro-bypass stents in cataract patients to treat open-angle glaucoma. J Cataract Refract Surg. 2012;38:1911-7. Bahler CK, Hann CR, Fjield T, Haffner D, Heitzmann H, Fautsch MP. Second-generation trabecular meshwork bypass stent (iStent inject) increases outflow facility in cultured human anterior segments. Am J Ophthalmol. 2012;153:1206-13. Voskanyan L, García-Feijoó J, Belda JI, et al. Prospective, unmasked evaluation of the iStent s inject system for openangle glaucoma: Synergy trial. Adv Ther. 2014;31:189-201. Fea AM, Belda JI, Rekas M, et al. Prospective unmasked randomized evaluation of the iStent inject (s) versus two ocular hypotensive agents in patients with primary open-angle glaucoma. Clin Ophthalmol. 2014;8:875-82.

Glaucoma treatment trends: a review—Conlon et al. 146. Auffarth G, Kretz F. Open-angle glaucoma in phakic or pseudophakic OAG subjects treated with ab interno suprachoroidal stent and postoperative travoprost. Boston, Massachusetts: American Society of Cataract and Refractive Surgery Annual Meeting; 2014 . 147. Camras LJ, Yuan F, Fan S, et al. A novel Schlemm’s Canal scaffold increases outflow facility in a human anterior segment perfusion model. Invest Ophthalmol Vis Sci. 2012;53:6115-21. 148. Grierson I, Saheb H, Kahook MY, et al. A novel Schlemm’s canal scaffold: histologic observations. J Glaucoma. 2015;24:460-8. 149. Pfeiffer N, Garcia-Feijoo J, Martinez-de-la-Casa J, et al. A randomized trial of a Schlemm’s canal microstent with phacoemulsification for reducing intraocular pressure in open-angle glaucoma. Ophthalmology. 2015;122:1283-93. 150. Mosaed S, Rhee DJ, Filippopoulos T, et al. Trabectome outcomes in adult open-angle glaucoma patients: one year follow-up. Clin Surg Ophthalmol. 2010;28:5-9. 151. Francis BA, Winarko J. Combined trabectome and cataract surgery versus combined trabeculectomy and cataract surgery in open-angle glaucoma. Clin Surg Ophtalmol. 2011;29:4-10. 152. Jea SY, Mosaed S, Vold SD, Rhee DJ. Effect of a failed Trabectome on subsequent trabeculectomy. J Glaucoma. 2012;21: 71-5. 153. Hoeh H, Vold SD, Ahmed IK, et al. Initial clinical experience with the CyPass Micro-Stent: safety and surgical outcomes of a novel supraciliary MicroStent. J Glaucoma. 2016;25:106-12. 154. Garcia-Feijoo J, Rau M, Grisanti S, et al. Supraciliary micro-stent implantation for open-angle glaucoma failing topical therapy: 1-year results of a multicenter study. Am J Ophthalmol. 2015;159:1075-81. 155. Sheybani A, Ahmed IK. Ab interno gelatin stent with mitomycin-c combined with cataract surgery for treatment of open-angle glaucoma: 1-year results. American Society of Cataract and Refractive Surgery Annual Meeting, San Diego, California; 2015 . 156. Grover D. Ab-Interno gelatin stent procedure in combination with mitomycin-C for treatment of glaucoma: 12-month results.

American Society of Cataract and Refractive Surgery Annual Meeting, San Diego, California; 2015 . 157. Canadian Glaucoma Society Committee on Interprofessional Collaboration in Glaucoma Care. Model of interprofessional collaboration in the care of glaucoma patients and glaucoma suspects. Can J Ophthalmol. 2011;46:S1-21. 158. Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014;121:2081-90. 159. Campbell RJ, Bell CM, Gill SS, et al. Clinic-based glaucoma care in the era of surgical subspecialization. Am J Ophthalmol. 2014;157 631–9.e1–2.

Footnotes and Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article. From the *University of Ottawa, Ottawa, Ont; †McGill University, Montreal, Que.; ‡University of Toronto, Toronto, Ont.; §Trillium Health Partners, Mississauga, Ont.; ¶Prism Eye Institute, Mississauga, Ont. Originally received Feb. 8, 2016. Final revision May. 19, 2016. Accepted Jul. 28, 2016. Correspondence to Hady Saheb, MD, MPH, FRCSC, McGill University Health Center Research Institute, 5252 de Maisonneuve, Montreal, Que. H4A 3S5; [email protected]

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