A Multicenter Prospective Comparative Study Evaluating Cataract Surgery and Endoscopic Cyclophotocoagulation either with or without iStent inject Implantation in Brazilian Patients with Glaucoma

Abstract

Purpose

Compare 12-month (12M) safety and efficacy of endoscopic cyclophotocoagulation (ECP) + cataract surgery (Group 1) versus ECP + cataract surgery + iStent inject trabecular micro-bypass implantation (Group 2) in Brazilian patients with open-angle glaucoma (OAG).

Methods

This prospective, multicenter, comparative case series included patients with OAG and cataract who were randomized to receive treatment in Group 1 or Group 2. Outcomes included intraocular pressure (IOP); number of glaucoma medications; visual acuity; adverse events; and secondary surgeries.

Results

Preoperatively, Groups 1 and 2 had similar mean IOP (22.1 and 22.0 mmHg, respectively) and medication burden (3.3 and 3.4 medications, respectively). At all follow-up timepoints through 12M, both groups achieved significant IOP and medication reductions versus preoperative (IOP p < 0.001 and meds p < 0.001 for both groups). At 12M, IOP reductions were 24.2% (Group 1) and 43.6% (Group 2) (p < 0.001); medication reductions were 50.2% and 71.5%, respectively. Mean postoperative IOP and medications were higher in Group 1 than Group 2 (IOP p < 0.01 all visits, medication p < 0.01 at 6M and 12M). Adverse events were generally mild and infrequent in both groups.

Conclusion

In this prospective comparative study of ECP + phacoemulsification, either with/without iStent inject implantation, both treatment groups achieved significant and safe reductions in IOP and medications versus preoperative in Brazilian OAG patients. Reductions were significantly greater, and mean postoperative IOP and medications were significantly lower, in the group receiving iStent inject with ECP and phacoemulsification.

Introduction

Glaucoma is the leading cause of irreversible blindness worldwide.¹ A meta-analysis of 50 population-based studies encompassing over a quarter of a million individuals estimated the global prevalence of glaucoma for those aged 40 to 80 years at 3.5%. The number of people in this age group with glaucoma was estimated at 64.3 million in 2013 and is anticipated to increase to 111.8 million in 2040 [1].

Medical and surgical therapies for treating glaucoma focus on lowering intraocular pressure (IOP), currently the only known modifiable risk factor [2]. Although medications are moderately effective and safe, chronic treatment with topical ocular hypotensive agents can be associated with deleterious effects to the ocular surface, issues with patient adherence and persistence to their prescribed regimens, and reduced chance for success with subsequent surgical procedures [3–8].

In the surgical realm, phacoemulsification alone often is associated with modest IOP reduction due to an increase in outflow facility [9]; however, these effects appear to be modest and impermanent [10]. Traditional filtration surgeries (e.g., trabeculectomy and tube implants) can dramatically reduce IOP, but often are associated with considerable morbidity [11–13]. In the past decade, a new class of procedures, micro-invasive glaucoma surgeries (MIGS), has been developed. These procedures provide moderate IOP reduction and have a more favorable safety profile than filtering surgeries. MIGS procedures can be combined with phacoemulsification or with other non-filtering glaucoma procedures, such as endoscopic cyclophotocoagulation (ECP; BVI Endo Optiks, Waltham, MA, USA) [2].

The iStent inject trabecular micro-bypass (Glaukos Corp., San Clemente, CA, USA), often considered the most micro-invasive and safest of the MIGS implant devices, consists of two pre-loaded injectable titanium stents implanted via an ab-interno approach through the trabecular meshwork into Schlemm’s canal [14]. Once in position, the stents facilitate trabecular outflow. The prospective, randomized, multicenter, Phase 3 pivotal trial evaluating the device showed that iStent inject provides a ≥ 20% IOP reduction in 75.8% of OAG eyes at 24 months when used in combination with cataract surgery compared with 61.9% eyes undergoing cataract surgery alone [15]. For the treatment responders, 84% and 67% of the treated and control eyes, respectively, were medication-free at 23 months. Furthermore, an analysis of these iStent inject patients found improvements in quality of life in terms of ocular symptoms and vision-related activities compared with cataract surgery alone [16]. A large real-world cohort of Australian eyes, which included pseudoexfoliative (PXG) and pigmentary (PG) glaucoma, found clinically meaningful reductions in IOP and ocular hypotensive medication use at 1 year and 2 years [17, 18].

Endoscopic cyclophotocoagulation reduces aqueous production, thereby decreasing the inflow component of the inflow/outflow balance that contributes to IOP [19–21]. ECP is performed using an ab-interno approach wherein a power-titratable 810 nm laser probe is inserted through a limbal incision to allow visualization and continuous photocoagulation of the ciliary process epithelium over approximately 270 degrees [19]. Our group previously reported that phacoemulsification with ECP was safe and effective as a primary procedure for combined cataract and glaucoma [22]. A prospective study by Francis et al. showed significant IOP reductions with cataract surgery plus ECP compared with cataract surgery alone [23]. ECP utility has been shown in mild to moderate glaucoma,^19–21 as well as in refractory glaucoma [24].

Both ECP and iStent inject implantation have been shown to be effective at lowering IOP and topical ocular hypotensive medication burdens in OAG [15, 17, 18, 20, 21, 23]. ECP in combination with cataract surgery is a common treatment modality performed by surgeons in Brazil. With the increasing utilization of iStent inject trabecular micro-bypass, the combination of ECP and stent implantation has emerged as a potential treatment option, allowing the surgeon to target both outflow and inflow components of patients’ disease. Further, this study aims to address the paucity of clinical evidence in a Latin American population with glaucoma and cataract.

The present prospective multicenter study compares 1-year outcomes following phacoemulsification + ECP (Group 1) or phacoemulsification + ECP + iStent inject implantation (Group 2) in a Brazilian population The report supplies some of the first data on this treatment combination, with outcomes observed in a Latin American patient population that historically has been under-represented in the literature.

Material And Methods

Results

Discussion

A considerable shift from traditional glaucoma surgeries to MIGS procedures has occurred in recent years [26, 27]. A study from the American Academy of Ophthalmology Intelligent Research in Sight (IRIS®) Registry data found that, from 2013 to 2018, MIGS surgeries rose to comprise nearly half of all glaucoma surgeries in the US. The most common concurrent procedures were ECP and iStent/iStent inject implantation, which accounted for 55.4% of all concurrent glaucoma procedures [26]. These trends underscore the relevance and value of the current study.

The present report provides safety and effectiveness outcomes of phacoemulsification plus ECP or plus ECP + iStent inject implantation in a group of patients from Brazil with cataract and glaucoma. Substantial IOP lowering and reductions in ocular hypotensive medication use were observed for both treatment groups and were sustained for up to 1 year. Both procedures were generally well tolerated with few procedure-related adverse events.

The combination of micro-bypass stent, cataract surgery, and ECP leverages different mechanisms of action in glaucoma management [28]. Not unexpectedly, the eyes receiving the iStent inject in combination with phacoemulsification + ECP demonstrated significantly greater reductions in IOP throughout the 1 year of follow-up (P < 0.01). At Year 1, the difference in percent IOP reductions from preoperative were nearly twice as large for Group 2 than Group 1 (P < 0.001). Overall, the reductions in IOP for eyes with the combined ECP + iStent inject procedure appeared to be maintained with less upward drift over time than for those undergoing the single ECP procedure.

Both treatment groups achieved clinically significant categorical reductions in IOP, with more marked reductions in the group undergoing iStent inject implantation (Group 2). In Group 1, 97.0% and 33.3% of eyes attained IOP ≤ 18 mmHg and ≤ 15 mmHg at Year 1, respectively. In Group 2, from 3 months onward, 100% of eyes achieved both IOP ≤ 18 mmHg and ≤ 15 mmHg through Year 1.

These findings are consistent with the literature on ECP and trabecular micro-bypass. A retrospective consecutive case series by Ferguson et al.[28] demonstrated significantly greater IOP reductions in eyes with mild to severe OAG that received ECP + iStent than those that underwent iStent implantation alone (P < 0.01). Twelve months after surgery the mean IOP reductions were 7.14 mmHg and 4.48 mmHg in the two groups, respectively. Similarly, a longitudinal retrospective 12-month study by Pantalon and colleagues [29] in eyes with early-to-moderate OAG reported significantly larger IOP reductions from baseline of 35% versus 21% for eyes undergoing phacoemulsification + ECP + 2 iStents versus phacoemulsification + 2 iStents (P = 0.03). These results support those of the current study in which the combined procedure provided greater IOP-lowering efficacy than cataract surgery with ECP alone.

Favorable trends also were observed in terms of the reduction in topical ocular hypotensive medications in the current study. The vast majority of eyes in both groups achieved reductions in the number of medications from Month 1 to Year 1. At Year 1, both procedures resulted in substantial mean reductions in medication use (50.2% for Group 1 and 71.5% for Group 2). As with IOP, the medication reductions were significantly greater in the group undergoing iStent inject implantation (Group 2) (P < 0.001). At Year 1, about 73% of eyes were still using 2 medications in Group 1 compared to only 20% in Group 2. Similarly, 24.2% versus 77.1% of eyes in Group 1 and Group 2, respectively, were using 0–1 medication at Year 1. For both groups, at the end of the study, only about 3% of eyes required 3 medications and none required 4 medications. These results represented significant benefits at the level of each patient, given the well-known personal, physical, social, and financial consequences of chronic medication exposure. The benefits were particularly apparent in eyes that underwent iStent inject implantation.

The medication outcomes observed in the present study are aligned with those of Pantalon and colleagues, who reported significantly greater 1-year medication reductions after phacoemulsification + ECP + iStent inject than after phacoemulsification + iStent inject [29]. In contrast, Ferguson et al [28] reported 1-year medication reductions that were less marked in eyes undergoing phacoemulsification + ECP + iStent (38%) than in eyes undergoing phacoemulsification + iStent (63%). This difference may be attributed to differences in baseline characteristics, or to the fact that the Ferguson study involved eyes with 1 stent (iStent) compared to eyes with 2 stents (iStent inject) in the Pantalon study [29] and in our present study. It is also possible that the treatment groups in the Ferguson study were not as well-matched at baseline, since that study was retrospective and non-randomized. Such between-group differences would not be expected in the current dataset, in which patients were prospectively enrolled, randomized, and treated. at 1 year with ECP + iStent compared with iStent and phacoemulsification alone (P = 0.01) [29].

Long-term topical ocular medication use can be associated with substantial downsides. The cost of chronic medication can be a financial burden for patients; not surprisingly, numerous studies have shown the cost effectiveness of the iStent device compared with the use of chronic topical medications [30–36]. Topical ocular hypotensive medications often contain preservatives, such as benzalkonium chloride, which are known to cause adverse effects on the ocular surface [4, 11]. In addition, patient adherence to topical ocular hypotensive drops is typically less than ideal [7, 9, 10, 37, 38]. Barriers to patient adherence also may include complex medication regimens, difficulty with drop instillation, and other factors (patient, provider, social, or environmental) [9]. Poor adherence to glaucoma medication therapy can put a patient at risk for irreversible optic nerve damage and vision loss. Thus the implantation of micro-bypass stents provides a treatment alternative for the surgeon that can reduce preservative load to the ocular surface [18, 39–45] and lessen reliance on patient adherence, thereby helping to preserve visual function.

Both ECP and iStent inject implantation were associated with few intraoperative complications or postoperative adverse events in our study. The majority of events occurred in the initial days following surgery and resolved soon thereafter. Cup:Disc ratios, visual fields, and retinal nerve fiber layer thickness remained stable over the course of the 1-year study in both groups. Best-corrected visual acuity improved dramatically at Year 1 versus preoperative, consistent with what would be expected after cataract surgery alone; there was no indication that the addition of iStent inject or ECP detracted from patients’ overall visual potential.

These visual acuity findings are consistent with prior evaluations of phacoemulsification + ECP and/or iStent implantation [22, 29, 46–51]. For example, a previous study from our group demonstrated improvements in the logMAR visual acuity (P = 0.01) for up to 2 years in eyes receiving phacoemulsification + ECP [22]. Morales and colleagues [50] found improvements in corrected distance visual acuity of 2 Snellen lines or more at 1 year in 73% of patients undergoing ECP and phacoemulsification. In another study of eyes undergoing ECP with phacoemulsification, Clement et al. [47] reported 94% of eyes achieved stable or improved vision after 1 year. Kang et al. [48] demonstrated maintenance or improvement in visual acuity for 95% of their ECP + phacoemulsification group with a mean follow-up of 21 months. Several studies have shown improvements in visual acuity 1 year or more following iStent implantation, either as a stand-alone procedure,⁵¹ or when combined with cataract surgery [46, 49]. Finally, Pantalon et al. [29] reported similar 1-year BCVA results in eyes undergoing phacoemulsification plus either iStent inject + ECP or iStent inject. All of these studies, as well as the current one, demonstrate favorable outcomes with ECP, iStent inject implantation, or the combination of the two procedures in combination with phacoemulsification in terms of preserving the visual improvements expected after cataract surgery alone.

This study is limited by its modest sample size, 1-year follow-up duration, and inclusion of data from 2 surgeons at 2 sites. Patients with other forms of glaucoma than OAG were excluded, as well as those who had undergone previous glaucoma filtration surgery. Not all data were available for all parameters at all time points. A future study could include a greater number of patients, longer duration of follow-up, data from more sites, or a broader range of glaucoma subtypes.

Conclusion

When combined with cataract surgery, both ECP and ECP + iStent inject implantation procedures were safe and effective in lowering IOP, reducing topical ocular hypotensive medication use, and preserving the visual improvements experienced after cataract surgery. The IOP and medication reductions were greater in the group undergoing iStent inject implantation alongside phacoemulsification + ECP than in the group receiving phacoemulsification + ECP only. Thus the results demonstrate favorable outcomes with these two procedures when combined with cataract surgery, as well as confirmation of the additional benefit of stent implantation, through one year postoperative in a Brazilian patient cohort.

Declarations

Funding

No funding was provided for the work in this study.

Ethics Compliance

The study was performed according to the tenets of the Declaration of Helsinki; all participants provided their informed consent for enrollment into the study. The study was reviewed and approved by the Ethics Committees of both hospitals involved: Centro Brasileiro De Cirurgia De Olhos (CBCO), Goiânia, GO, Brazil; and Centro Brasileiro Da Visão (CBY), Brasília, DF, Brazil. The study was registered in the Clinical Trial Database of the Federal University of Goiás, Brazil (CAAE ID# 20053019.5.0000.5078, Protocol #3.587.147, registered September 19, 2019).

Data Integrity

All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Editorial Support

Medical writing and editorial support were provided by Julie Crider, PhD (Collaborative Medical Writing, LLC), and Dana Hornbeak, MD, MPH (Glaukos Corporation).

Competing Interest

F.L.: None

J.G.: None

M.A.: None

Funding/Support

No monetary nor product support was received for the work in this study. Editorial assistance (Dana M. Hornbeak, MD, MPH) and publication fees were provided by Glaukos Corporation.

Author Contribution

All authors (F.L., J.G., M.A.) guided study design and wrote protocol.

All authors (F.L., J.G., M.A.) completed data collection.

All authors (F.L., J.G., M.A.) contributed to data analysis and manuscript preparation (including text, figures, and tables).

All authors (F.L., J.G., M.A.) reviewed and approved the manuscript.

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