Combined Microinvasive Glaucoma Surgery – A Review of the Literature and Future Directions

ABSTRACT

The use of microinvasive invasive glaucoma surgery (MIGS) in the treatment of glaucoma has increased exponentially over the last 10 years. However, practice patterns vary widely given the relative newness of these technologies. Some surgeons perform two or more MIGS simultaneously, such as those that target aqueous production and those that target aqueous outflow. These combined MIGS (cMIGS) may result in lower intraocular pressure (IOP) and reduced medication burden as compared to single MIGS (sMIGS). Current evidence suggests some cMIGS are more effective in reducing medication burden for at least 12 months versus sMIGS. This review focuses on the current evidence related to the efficacy of cMIGS as well as novel combinations of standalone MIGS, limitations of the current literature, and future directions for research.

KEYWORDS:

• CMIGS
• Combination MIGS
• Combined MIGS
• ICE1
• ICE2
• PEcK

INTRODUCTION

Microinvasive glaucoma surgery (MIGS) has presented an opportunity to lower intraocular pressure (IOP) and reduce medication burden with fewer complications compared to traditional filtering surgery.¹ The term “MIGS” was first coined by Ike Ahmed in 2009 and generally refers to glaucoma procedures with the following characteristics: ab interno with no disruption of conjunctival tissue, minimal disruption of anatomy with biocompatible materials, positive safety profile, good efficacy, and fast recovery time.^1,2 While the iStent inject® (Glaukos Corporation, Laguna Hills, CA, USA) and Hydrus® (Ivantis Medical, Irvine, CA, USA) can be clearly characterized by this definition, other procedures, including the Trabectome® (MicroSurgical Technolology, Redmond, WA, USA), Kahook Dual Blade® (New World Medical, Rancho Cucamonga, CA, USA), Xen Gel Stent® (Allergan, Dublin, Ireland), and cyclodestructive procedures do not meet all these criteria. As such, some authors have referred to these procedures as not truly MIGS, or alternatively by the definition “MIGS-plus”.¹ For the purpose of this review, all the aforementioned procedures will be referred to as “MIGS”, and proposed abbreviations for the purpose of MIGS discussion is provided in Figure 1.

Figure 1. Proposed abbreviations for Microinvasive Glaucoma Surgery (MIGS) discussion.

MIGS procedures have been shown to modestly reduce IOP and medication burden over cataract surgery alone, and certain MIGS devices have been approved by the Food and Drug Administration (FDA) for use only in patients with mild or moderate glaucoma when performed with concurrent phacoemulsification (phaco). Currently, only Trabectome, Kahook Dual Blade (KDB), and endoscopic cyclophotocoagulation (ECP) have been approved for standalone use without concurrent cataract surgery, though other MIGS are actively being investigated or are pending approval by the FDA for this context. Cataract surgery by itself may reduce IOP by a mean of 5 mmHg^1,3,4 and has been shown to have greater, albeit variable, reductions in IOP and medication burden when combined with MIGS.^1,2 The variable magnitude of IOP reduction by MIGS in the literature is likely a result of differences in study type, glaucoma type, glaucoma severity, baseline IOP, and baseline medication burden. Furthermore, efficacy is also subject to surgical parameters, which, for example, include variability in the degrees excised by the KDB or in the energy settings and degrees treated by cyclodestruction.^5–7

There has been growing interest in increasing the efficacy of MIGS by combining procedures with different mechanisms of action, specifically those that increase trabecular outflow with those that decrease aqueous production. By combining procedures to target multiple aspects of aqueous flow and/or production, combined MIGS (cMIGS) may offer an additive reduction in IOP and medication burden. In practice, according to the IRIS registry, 8,089 concurrent glaucoma procedures with phaco were performed between 2013 and 2018. These included predominantly phaco/iStent/ECP (55.4%) and phaco/KDB/ECP (9.6%).⁸ Despite the increasing popularity of cMIGS, few studies have compared the efficacy, safety, or cost-effectiveness of cMIGS with that of single MIGS combined with phaco (sMIGS). This review will discuss the current literature investigating the efficacy and safety of cMIGS as well as propose future directions for further investigation.

METHODS

Utilizing a PubMed search, the following terms were used to identify relevant literature: endocyclophotocoagulation, goniotomy, iStent, Hydrus, minimally invasive glaucoma surgery, microinvasive glaucoma surgery, sequential minimally invasive glaucoma surgery, combined minimally invasive glaucoma surgery, combined microinvasive glaucoma surgery, phaco/ECP/KDB (PEcK), iStent/cataract extraction/ECP (ICE-1 or ICE1), iStent inject/cataract extraction/ECP (ICE-2 or ICE2). A total of four original studies were found looking at the effectiveness of combined first-generation iStent with ECP and phaco, phaco with ECP and goniotomy (Kahook Dual Blade), and second-generation iStent inject combined with phaco and ECP. No comparative studies of phaco/Hydrus/ECP were identified. To our knowledge, no other MIGS procedures besides the first-generation iStent, iStent inject, and KDB have been reported in peer-reviewed literature in combination with ECP, although other combinations have been reported through case series reported in conference abstracts,^9,10 which are included and discussed separately. This review will briefly describe the research on cMIGS components (ECP, iStent, KDB) when employed independently and then discuss the existing literature on cMIGS.

CMIGS COMPONENT: ENDOCYCLOPHOTOCOAGULATION

ECP was first described by Uram in 1992 as a potential treatment option for neovascular glaucoma.¹¹ In this method, an ab interno approach is utilized to ablate the ciliary processes under direct visualization. The mechanism of action involves destruction via energy absorption by melanin in the ciliary body pigmented epithelium with energy transfer to the nonpigmented epithelium. Pathological studies have shown that the tissue damage from ECP is confined to the ciliary processes and associated capillary beds, thereby reducing damage to adjacent structures.¹² A recent systematic review, which looked at ECP studies from 2007 to 2018, found that the IOP reduction varied significantly (from 18 to 72% reduction) in response to ECP. It should be noted that the IOP reduction varied depending on baseline IOP, type of glaucoma, the degrees of ciliary processes treated, and whether other procedures were combined with ECP.^5,6 Standalone ECP is effective in reducing medication burden and has been shown to reduce medications by 0.4–1.7 in primary open angle glaucoma (POAG) patients and by 1.5–1.7 in refractory glaucoma patients.⁵ Current evidence suggests ECP sMIGS more effectively reduces IOP than phaco alone. Several studies have demonstrated a 17–23% IOP reduction after ECP sMIGS versus a 6–11% reduction after phaco alone after a 12-month follow-up interval.^13,14 In terms of ECP sMIGS complications, the ECP Collaborative Study Group reported the following complications after surgery in 5000 eyes: IOP increase (14.5%), hyphema (3.8%), visual acuity decline (1.03%), CME (0.7%), and choroidal detachment (0.36%).¹⁵ In summary, ECP is effective in reducing IOP and medication burden, while maintaining an acceptable safety profile.

CMIGS COMPONENT: ISTENT

The first generation iStent® was approved by the FDA in 2012 in conjunction with cataract surgery for patients with a diagnosis of mild-to-moderate open-angle glaucoma (OAG) and who are currently being treated with topical medication.¹ The proposed mechanism of action is via stenting of the potentially diseased trabecular meshwork and allowing aqueous to egress into Schlemm’s canal through the stent.

Current literature suggests that sMIGS consisting of iStent and phaco is more efficacious than phaco alone, with regard to both IOP lowering and medication reduction. In the iStent pivotal trial, iStent sMIGS was shown to be more efficacious in reducing IOP and medication burden compared to phaco alone.¹⁶ In a pivotal trial of the second-generation iStent (iStent inject), Samuelson et al. found that iStent inject sMIGS produced greater reductions in IOP and number of required glaucoma medications compared to phaco alone after 24 months of follow-up.¹⁷ The iStent inject sMIGS group did not show a difference in postoperative adverse events compared to the phaco only control group. There were no cases of stent migration or dislocation and no reports of hyphema greater than 10% of anterior chamber diameter. Both the iStent inject sMIGS and phaco only groups showed decreased endothelial cell density, 12.5% and 11.6% respectively, in the first 3 months following surgery with minimal decline thereafter. Rates of intraocular inflammation, loss of vision, and secondary surgical intervention were similar between the two groups. In summary, sMIGS involving the iStent and the iStent inject have been demonstrated to lower IOP and reduce medication burden more than phaco alone, and the safety profile is acceptable.

The iStent inject has demonstrated greater efficacy in reducing medication burden and IOP control than the first-generation stent.¹⁸ This observation, combined with greater ease of use, has resulted in the iStent falling out of favor over the last several years. This change is of critical importance, as several of the earliest studies of trabecular microbypass stents looked at iStent efficacy, rather than that of the iStent inject. This change in practice pattern is important to note, as future cMIGS studies will likely look at the efficacy of the ICE2 procedure, rather than ICE1, which will be discussed further in the section ICE: cMIGS with iStent or iStent inject/Cataract Extraction/ECP below.

CMIGS COMPONENT: KAHOOK DUAL BLADE

The KDB is a standalone MIGS procedure that involves ab interno trabecular excision. It is thought to lower IOP by removing diseased trabecular meshwork and by enhancing aqueous outflow via remodeling of the extracellular matrix near Schlemm’s canal. Multiple studies have evaluated the efficacy of KDB as a standalone procedure. KDB has been shown to be effective in severe or refractory POAG or angle closure glaucoma (ACG), with reported IOP reduction of up to 24% over 6 months.¹⁹ Studies have shown that higher baseline IOP has been predictive of larger IOP reductions by KDB regardless of glaucoma severity or subtype.^1,19–21

A review by Birnbaum et al.¹ reported IOP reductions between 14.5% and 24% following KDB sMIGS in retrospective studies of OAG patients followed 6–12 months post-operatively. Additionally, KDB sMIGS was associated with medication reduction of 0.1–2.1 in glaucoma of all types and severities over 6–12 months. Despite the large body of literature supporting the effectiveness of KDB and goniotomy in reducing IOP, there are relatively few head-to-head studies comparing KDB sMIGS directly to phaco alone. This gap in the literature may be a result of KDB not undergoing pivotal trials in the same manner as implantable MIGS devices. A retrospective study by Sieck et al. compared the KDB sMIGS to phaco alone, reporting that 72% of the KDB sMIGS group experienced an IOP reduction of greater than 20% over 12 months. Interestingly, this was not statistically significant from phaco alone, after which 69% experienced an IOP reduction of greater than 20% over 12 months.²⁰ In contrast, Kim et al²² demonstrated that combined phaco/goniotomy (not specifically KDB) was more effective at reducing IOP and medication use from baseline versus phaco alone (−3.1 ± 2.9 mmHg versus −1.3 ± 2.4 mmHg and −1.2 ± 0.9 vs −0.7 ± 0.9, respectively, both p < .05). The most common complication of KDB is hyphema, which has been reported to occur in 6–19% of cases, with the majority resolving by post-operative month one.¹ Other reported complications such as IOP spike (1–18%) and cystoid macular edema (2–6%) have remained within ranges reported after phaco alone. In summary, standalone KDB is effective in reducing IOP and medication burden with an acceptable safety profile. Future studies directly comparing KDB sMIGS versus phaco are needed to clearly define the degree of benefit.

ICE: CMIGS WITH ISTENT OR ISTENT INJECT/CATARACT EXTRACTION/ECP

A summary of the current cMIGS literature is found in Table 1. Ferguson et al. introduced the term ICE in 2017 when studying the effectiveness of phaco/iStent versus phaco/ECP/iStent (ICE1).²³ Using a retrospective review of charts from a single surgeon, they found that despite equivalent baseline IOP, the ICE1 procedure offered greater IOP reduction than phaco/iStent. However, they found that the phaco/iStent group required a lower mean number of topical medications compared to the ICE1 group (0.62 versus 1.10; p < .01) after one year, despite having similar baseline IOP and number of preoperative medications. Of importance, the study and control groups were not equivalent with regard to glaucoma severity at baseline. About 51% of the ICE1 group patients had severe glaucoma while only 10% of patients in the phaco/iStent group had severe glaucoma, which may explain why the ICE1 group required more medications postoperatively. The greater IOP lowering seen in the ICE1 group, although statistically significant, should therefore be interpreted in the context of greater medication use. Despite its limitations, this retrospective study laid the groundwork for subsequent studies, as it suggested a greater IOP-lowering effect with the addition of ECP to phaco/iStent versus iStent sMIGS. Notably, this study did not include a detailed report of postoperative complications, although rates of IOP spike and secondary glaucoma surgery in the cMIGS group were described as similar to the sMIGS group (no p value reported). It also did not include an ECP sMIGS arm, and therefore it is difficult to fully conclude that combining iStent and ECP is more effective than either surgery alone when performed with phaco.

Table 1. Summary of cMIGS studies from 2017 to 2021.

	Study	Design	Intervention	Population	Number of Eyes	Baseline IOP (mmHg)	Mean IOP Reduction (mmHg)	Final IOP (mmHg)	Baseline # of Medications	Mean Medication Reduction	Final # of Medications	Patients Off Medications By End of Follow-up Period (%)	LaserSettings (W)/° Processes Treated	Most Common Complications (%)	Eyes Requiring Additional Surgery (%)	Follow-up Period (months)
cMIGS versus sMIGS	Izquierdo et al., 2021	P	PEcK■ versus phaco/ECP□	Mild and advanced POAG on 2 or more medications	27■	16.96 ± 3.66■	5.52 (33% reduction)■	11.44 ± 2.15■	2.0 ± 1.4■	1.2 (60% reduction)■	0.8 ± 1.0■	59■	0.2/360	hyphema (37.0); corneal edema (25.9); IOP spike (11.1); PCO (4.5)	7.4■	12
					22□	15.64 ± 4.88□	3.19 (20% reduction)□	12.45 ± 1.90□	1.5 ± 1.3□	0.5 (33% reduction)□	1.0 ± 1.5□	44.1□		IOP spike (31.8); corneal edema (18.2); PCO (18.2)	9□
	Pantalon et al., 2020	R	ICE2★ versus phaco/iStent inject®☆	OHT or early-to-moderate OAG	63★	19.97 ± 4.31★	6.92 (65% reduction)★	13.05 ± 2.18★	2.22 ± 1.85★	0.98 (45% reduction)★	1.24 ± 1.05★	31.7★	0.2/270★	IOP spike (1.8); CME (1.8)	0★	12
					46☆	17.63 ± 3.86☆	3.54 (20% reduction)☆	14.09 ± 1.86☆	2.07 ± 1.02☆	0.68 (33% reduction)☆	1.39 ± 1.03☆	19.6☆	NA	CME (4.3)	0☆
	Heersink et al., 2019	R	Phaco/iStent®/ab interno canaloplasty● versus phaco/iStent®Δ	POAG only; no h/o SLT within 6 months or previous ALT	86●	16.6 ± 3.4●	2.9 ± 3.6 (17% reduction)●	13.7●	1.4 ± 1.0●	0.9 (64% reduction)●	0.5●	56●	NA	inflammation for 1 month (6); VA loss >2 lines (3); dry eye exacerbation (3); hyphema (1); foreign body sensation (1); SCH (1); anisometropia (1)	0●	6
					100Δ	15.1 ± 3.0Δ	1.7 ± 3.1 (11% reduction)Δ	13.4Δ	1.2 ± 0.9Δ	0.7 (58% reduction)Δ	0.5Δ	48Δ	NA	VA loss >2 lines (8); inflammation for 1 month (4); dry eye exacerbation (2); corneal edema (2); foreign body sensation (2); anisometropia (1)	0Δ
	Ferguson et al., 2017	R	ICE1▲ versus phaco/iStent®Δ	Any stage OAG	51▲	21.49 ± 9.56▲	7.14 (33% reduction)▲	14.35 ± 3.5▲	1.75 ± 1.00▲	0.65 (38% reduction)▲	1.10 ± 1.00▲	40.5▲	0.2/270▲	IOP spike (~8)	4▲	12
					50Δ	20.66 ± 3.23Δ	4.48 (22% reduction)Δ	16.18 ± 4.14Δ	1.68 ± 1.00Δ	1.06 (63% reduction)Δ	0.62 ± 1.00Δ	NR	NA	IOP spike (~8)	4Δ
cMIGS versus cMIGS	Klug et al., 2021	R	ICE1▲ versus PEcK■	Any stage POAG, NTG, PXG, MMG, PG, traumatic or secondary glaucoma, and OHT	23▲	14.7 ± 4.3▲	2.3 ± 4.0 (16% reduction)▲	12.4▲	1.7 ± 0.93▲	0.97 ± 0.66 (57% reduction)▲	0.73▲	NR	0.25–0.50/120-360▲	NR	0▲	12
					53■	18.3 ± 5.9■	5.1 ± 4.4 (28% reduction)■	13.2■	3.3 ± 1.3■	1.6 ± 1.5 (48% reduction)■	1.7■	NR	0.25–0.50/180-270■	PCO requiring YAG capsulotomy (5.7)	7.5■

Abbreviations: P = prospective; R = retrospective; NA = not applicable; NR = not recorded; PCO = posterior capsular opacification; PG = pigmentary glaucoma; MMG = mixed-mechanism glaucoma; PXG = pseudoexfoliative glaucoma; POAG = primary open angle glaucoma; OAG = open angle glaucoma; OHT = ocular hypertension; CME = cystoid macular edema; IOP = intraocular pressure; ALT = argon laser trabeculoplasty; SLT = selective laser trabeculoplasty; SCH = subconjunctival hemorrhage.

Notes: ▲ = ICE-1; Δ = phaco/iStent® (generation 1); ■ = PEcK; □ = phaco/ECP; ★ = ICE-2; ☆ = phaco/iStent inject®; ● = phaco/iStent®/ab interno canaloplasty.

Although the previous study investigated the ICE1 procedure, which analyzed the iStent, placement of two iStent injects became more commonplace after a meta-analysis suggested superior IOP control and medication reduction as compared to the first-generation model.²⁴ Pantalon et al.²⁵ performed the first study of the ICE2 procedure, in which two iStent inject devices are inserted along with ECP at the time of cataract surgery. In this retrospective, unmasked, unblinded study at a single center, they found the ICE2 procedure conferred greater absolute IOP reduction at 12 months versus phaco/iStent inject (6.92 versus 3.54 mmHg; p = .03). The most common postoperative complications reported in the ICE2 group (IOP spike and CME) occurred in only 1.8% of cases, suggesting a safety profile similar to cataract surgery alone. However, in similar fashion to the ICE1 study reported by Ferguson et al., the baseline characteristics of the two groups were not equivalent, with the ICE2 group having a statistically significantly higher baseline IOP, worse visual fields, and shorter axial length/anterior chamber depth. In addition, the study also lacked an ECP sMIGS arm. Another notable finding was the reduction in number of glaucoma medications, and more specifically, the increased likelihood of being medication-free at 12 months in the ICE2 group. Despite a similar number of baseline medications (2.22 versus 2.07, p = .442), at 12 months postoperatively, 31.7% of eyes in the ICE2 group did not require any topical medications to control IOP compared to 19.6% in the control group (p = .001). A similar number required two or more medications in each group to control IOP (41.2% ICE2 group versus 39% control group). Taken together, these data suggest that the ICE2 procedure results in an increased likelihood of being drop-free 12 months after the procedure in some patients but does not seem to impact medication burden in others. Therefore, a subset of patients may be “responders” to cMIGS, while others receive no medication-lowering benefit with cMIGS versus sMIGS. Identifying the factors that make some patients responders to cMIGS may help providers individualize MIGS treatment for their patients.

PECK: CMIGS WITH PHACOEMULSIFICATION/ENDOCYCLOPHOTOCOAGULATION/KAHOOK DUAL BLADE

In contrast to the ICE1 and ICE2 procedures, the PEcK procedure offers the opportunity to perform cMIGS without the placement of a permanent implant. To our knowledge, the first investigation of the PEcK procedure’s efficacy was published by Izquierdo et al in 2021.²⁶ In this randomized, prospective, unblinded study of 49 eyes with uncontrolled POAG, the investigators compared the PEcK procedure (study group) to phaco/ECP with 360 degrees of treatment applied to the ciliary processes in both groups. In the PEcK group, four clock hours of goniotomy was performed. Surgical success was defined as IOP less than or equal to 12 mmHg and greater than or equal to 6 mmHg or at least a 20% reduction in IOP from baseline. Success was considered “complete” if the primary outcome was obtained without medications and “qualified” if the criteria were met with medications. After 12 months, IOP was reduced by 32.5% in the PEcK group compared to a 20.3% reduction in the phaco/ECP group (p = .031). Complete success was observed in 37% of eyes in the PEcK group versus 31% of eyes in the phaco/ECP only group (no p value provided). Qualified success was observed in 74% of eyes in the PEcK group versus 50% of eyes in the phaco/ECP group (no p value provided). Finally, 59% of patients in the PEcK group were medication free after 12 months versus 44.1% in the phaco/ECP group (no p value provided). Adverse events, such as corneal edema, IOP spikes, and hyphema resolved with or without treatment in both groups. No adverse events required additional treatment or surgery after 12 months of follow up. Strengths of this study include a prospective randomized design, more stringent inclusion and exclusion criteria, and pre-defined criteria for treatment success. However, significant limitations of this study include a relatively small sample size (49 eyes) and inconsistent reporting of p values. Of particular importance, no p values were reported for complete or qualified success rates. It should also be noted this study specifically evaluated patients with mild-to-advanced POAG on two or more medications only (excluding patients on one medicine). Patients with more common types of secondary open-angle glaucoma, such as pseudoexfoliation and pigmentary glaucoma, were also excluded. In summary, the work by Izquierdo et al. suggests that the PEcK procedure may be modestly more effective at reducing IOP and reducing medication burden in patients with uncontrolled POAG on two or more medications compared to phaco/ECP alone.

COMPARING CMIGS: PECK VERSUS ICE1

Klug et al. sought to compare the outcomes of PEcK versus the ICE1 procedure.²⁷ In contrast to the prior study of PEcK by Izquierdo et al. that looked only at POAG patients, this study included multiple types of OAG, such as pigmentary and pseudoexfoliation glaucoma patients. The main outcome measures in this retrospective study were Kaplan–Meier survival probabilities with treatment failure defined in two ways. The first criteria for treatment failure were continued uncontrolled IOP greater than 21 mmHg, IOP reduction less than 20% from preoperative baseline, the addition of glaucoma medications from baseline on two consecutive follow-up visits, or need for additional glaucoma surgery. The second set of criteria for treatment failure were inability to reach a preoperatively designated goal IOP set by the surgeon, or if patients were at goal IOP preoperatively on glaucoma medication, failure to maintain goal IOP while reducing glaucoma medication burden on two consecutive follow-up visits after 30 days or need for additional glaucoma surgery. The study showed no significant differences in the Kaplan–Meier analysis of treatment success between PEcK and ICE1 at 6 and 12 months. A greater reduction in IOP was observed in the PEcK group, however the baseline IOP in the PEcK group was higher than the ICE1 group (18.3 vs 14.7 mmHg p = .004), potentially explaining the discrepancy in IOP reduction. Interestingly, despite the PEcK group having more severe glaucoma at baseline (39.6% classified as moderate-to-severe or severe versus 0% in the ICE1 group), the mean reduction in medications in the PEcK group was noninferior to the ICE1 group suggesting PEcK may have more of a role in the treatment of severe glaucoma patients. Hispanic ethnicity was associated with treatment failure in both arms of this study, increasing the risk of failure by 523% in the PEcK group and 356% in the ICE1 group. The significance of this finding is unclear, but it may reflect underlying healthcare disparities related to glaucoma treatment and/or differences in genetics. Finally, it should be emphasized the PEcK procedure was compared exclusively to ICE1. At the time of the study, the surgeon had not performed enough iStent inject procedures to power a study comparing ICE2 to PEcK, but this is an area of active investigation.

OTHER REPORTED CMIGS OR COMBINATIONS OF STANDALONE MIGS

Other described cMIGS often adopt the approach of ICE and PEcK by combining phaco with multiple MIGS, though there have also been early reports of combining standalone MIGS without phaco.

Heersink et. al.²⁸ were the first to describe a cMIGS that targeted the same mechanism of aqueous outflow, rather than targeting both aqueous production and outflow as in ICE and PEcK. They report a cMIGS utilizing phaco, iStent, and VISCO360™ ab interno CanaloPlasty (CP) [Viscosurgical System, Sight Sciences, Inc. Menlo Park, CA, USA]. In the retrospective study funded by Sight Sciences, surgical outcomes of phaco/iStent/CP are compared to those of the iStent sMIGS. The study population included eyes with POAG that underwent phaco/iStent/CP (n = 86) with a mean preoperative IOP of 16.6 mmHg on 1.4 medications or that underwent phaco/iStent (n = 100) with a mean preoperative IOP of 15.1 mmHg on 1.2 medications. The phaco/iStent/CP group achieved a mean IOP reduction of 2.9 mmHg on 0.5 fewer medications (56% of patients off all medications), and the phaco/iStent group achieved a mean IOP reduction of 1.7 mmHg on 0.5 fewer medications (48% of patients off all medications). Statistically greater reductions in mean IOP were achieved by the phaco/iStent/CP group at one, three, and six months post-operatively as compared to phaco/iStent (p < .05). This comparison of phaco/iStent/CP cMIGS, which augments the same mechanism of action of increasing aqueous outflow, can offer additional efficacy when compared to iStent sMIGS throughout six months. A limitation of this study was the lack of a phaco/CP arm, making it difficult to conclude that combining iStent and CP with phaco is more efficacious than either surgery alone when performed with phaco. Additionally, the magnitude of reduction was modest in both groups, though this may have been impacted by the study’s baseline characteristics, as patients had normal mean pre-operative IOPs on relatively few medications. Additional research, ideally with independent funding and longer follow up is needed to fully assert utility from phaco/iStent/CP. Nevertheless, Heersink et. al. offers the first insight into cMIGS that combine procedures targeting the same mechanism of IOP reduction, rather than targeting aqueous production and outflow separately.

Combinations of standalone MIGS, without concurrent phacoemulsification, have only been reported in a longitudinal case series with pooled outcomes at the American Glaucoma Society (AGS) 2019 and 2020 annual meetings.^9,10 Two abstracts presented by Buttram and Oguntoye et al. describe three combinations of standalone MIGS:¹ Trabecular MicroBypass/CycloPhotoCoagulation (TMB/CPC),² Ab Interno Trabeculectomy/Ab Interno CanaloPlasty (AIT/AICP), and³ Trabecular MicroBypass/SupraCiliary MicroBypass stent (TMB/SCMB). The combined standalone MIGS were performed in patients with a history of refractory glaucoma and prior failed glaucoma surgery. The first group of cases (TMB/CPC) underwent a cyclodestructive component [ECP or MicroPulse transscleral cyclophotocoagulation (IRIDEX Corp., Mountain View, CA)] combined with a trabecular microbypass component via either stenting (iStent, iStent inject, or Hydrus), ab interno canaloplasty [iTrack (Nova Eye Medical, Fremont, USA)], or ab interno trabeculectomy [KDB, Trabectome, lighted microcatheter, Trab 360 (Sight Sciences, Inc. Menlo Park, CA, USA), or OMNI system (Sight Sciences, Inc. Menlo Park, CA, USA)]. Compared to a mean baseline IOP of 33.4 mmHg on 3.4 medications, patients who underwent TMB/CPC (n = 41) achieved significantly lower mean IOP at 12 months (12.8 mmHg, p = .007) and 24 months (12.2 mmHg, p = .010).⁹ There was no significant change in medication burden at 12 months (p = .109) or 24 months (p = .562) following a TMB/CPC procedure compared to baseline. Additionally, the TMB/CPC cases are notable for a 27% incidence of complications, predominantly rebound iritis (12%). The second group of cases (AIT/AICP) underwent ab interno trabeculectomy (KDB, Trabectome, Trab 360, or OMNI system) combined with canaloplasty (iTrack). This combination resulted in a mean IOP reduction of 37.8% on 0.84 fewer medications at 12 months postoperatively.¹⁰ Similarly at 12 months postoperatively, the third group of cases (TMB/SCMB), which underwent trabecular microbypass stenting (iStent, iStent inject, or Hydrus) combined with supraciliary stenting (Cypass, Micro-Stent, Transcend Medical, Inc., Menlo Park, CA – author’s note: study performed prior to Cypass removal from market), resulted in a mean IOP reduction of 44.3% on 1.23 fewer medications.¹⁰ Given the lack of comparison groups, it remains unclear whether combined standalone MIGS offer greater efficacy than single standalone MIGS. Both series are limited by the pooling of outcomes of different types of standalone MIGS into varied groups, a high attrition rate, and analysis of results from only a single site and single surgeon. In summary, these case series offer preliminary evidence for combining standalone MIGS in refractory glaucoma patients and warrants further investigation.

DISCUSSION

cMIGS has been suggested in several retrospective studies to reduce IOP more than sMIGS up to 12 months postoperatively. In addition to the IOP-lowering effect, the use of cMIGS, such as PEcK and ICE2, resulted in a higher proportion of patients being medication free at 12 months versus sMIGS. The literature previously described suggests an acceptable safety profile that is better than standard filtering surgery. The most common complications, notably of hyphema and cystoid macular edema, were transient and typically resolved with standard conservative measures.

Several potential benefits of cMIGS or combinations of standalone MIGS remain speculative and require additional investigation. First, preserving conjunctival tissue for later surgery is one of the more promising aspects of combining MIGS. This aspect could be especially advantageous for relatively younger patients with glaucoma whose lifetime risk of trabeculectomy and tube failure could be high if life expectancy continues to increase. Combining MIGS earlier in the treatment pathway may minimize the number of years a patient is exposed to the post-operative risks of filtering surgery, such as bleb leak, tube exposure, endophthalmitis, blebitis, dysesthesia, and fibrosis. Another possible role for cMIGS or combination of standalone MIGS could be in the management of refractory glaucoma following failed trabeculectomy and/or tube shunt surgery. However, evidence for this idea is currently limited to retrospective case series.^9,10 Future studies should prospectively compare these novel approaches versus current approaches to refractory disease (single standalone MIGS, bleb needling, medical therapy or cyclophotocoagulation). Finally, cMIGS or combinations of standalone MIGS can potentially reduce medication costs and improve quality of life by reducing medication burden, although the literature to date has not investigated whether the upfront costs of combining MIGS are balanced by a sustained reduction in medication costs over the long term.

Despite promising initial findings, results of the available cMIGS literature should be interpreted with discretion. First, much of the current literature is retrospective, nonrandomized, and unmasked. In several studies, a higher proportion of patients were noted to have more severe glaucoma at baseline in the cMIGS groups, likely reflecting a selection bias toward using cMIGS in patients with more advanced visual field loss and higher baseline IOPs to attempt delaying more invasive surgery. Although a greater percentage reduction in IOP was noted with cMIGS as compared to iStent or iStent inject sMIGS in several studies, this may have been attributable to the greater potential for IOP reduction in the setting of higher baseline IOP, a finding noted in prior sMIGS studies.^3,29,30 Furthermore, the lack of a designated ECP sMIGS arm in both the Ferguson and Pantalon studies makes it difficult to infer a benefit from the addition of the iStent or iStent inject. Additionally, the relatively short follow-up intervals, although standard for many MIGS trials,³¹ do not allow enough time to determine sustained efficacy or adverse event profiles in the long term. Additional studies are needed to determine if IOP decreases reported in studies of cMIGS, sMIGS, or combination of standalone MIGS are durable over a longer follow-up period.

A significant limitation of evaluating the current MIGS literature is the many nuances and variability in reported baseline characteristics and outcome measures. In 2009, the World Glaucoma Association proposed a set of guidelines to help standardize the design, conduct, and reporting of glaucoma clinical trials to facilitate comparison between studies.³¹ A cross-sectional literature review performed by Mathew et al.³¹ showed that as of 2019, only 45.6% of reviewed randomized controlled trials (RCTs) and non-RCTs related to MIGS adhered to the WGA guidelines. A discussion of the reasons for non-adherence to the WGA guidelines is beyond the scope of this review. However, MIGS research and glaucoma surgical research in general would benefit from the formation of a standardized registry to facilitate comparative effectiveness research. This registry may help codify best practices for how MIGS outcomes and metrics should be reported. The information collected in the registry would be particularly beneficial to address some of the questions posed in this review, such as patient characteristics that predict treatment success or failure with sMIGS, cMIGS or combinations of standalone MIGS.

CONCLUSIONS

Greater reductions in IOP and medication burden may be achieved by cMIGS or combinations of standalone MIGS when compared to sMIGS or single standalone MIGS. The future holds numerous opportunities for combining newer devices, and we must employ a cautious optimism as we systematically study these device combinations to offer the best possible care for our patients. Future randomized controlled trials or larger prospective studies, ideally with standardization of design and reported outcome measures adhering to WGA guidelines, are needed to determine the long-term role for all combinations of MIGS in the surgical treatment paradigm for glaucoma.

DISCLAIMER

The identification of specific products or scientific instrumentation is considered an integral part of the scientific endeavor and does not constitute endorsement or implied endorsement on the part of the author, the Department of Defense, or any component agency. The views expressed in this review are solely those of the author and do not reflect the official policy of the United States Army, US Army Medical Command, or the Department of Defense.

DISCLOSURE STATEMENT

Solá-Del Valle - Allergan, Abbvie (lecturer)

Additional information

Funding

We gratefully appreciate Mr. Joseph Leitch, Mrs. Cathey S. Leitch, Mr. Chad Gifford, and Mrs. Anne Gifford for their philanthropic support of this work.