Outcomes of Resident Performed Hydrus, iStent, and Kahook Glaucoma Procedures in a Predominantly African American Population

Précis: This retrospective study characterized the efficacy and safety of 3 different microinvasive glaucoma surgery (MIGS) procedures in a predominantly African American population at the Philadelphia Veterans Affairs Hospital (Hydrus, Kahook, iStent), demonstrating no significant difference in intraocular pressure (IOP) and medication reduction between the 3 at long-term follow-up. Purpose: To compare the efficacy and safety of 3 different MIGS procedures in a predominantly African American population. Methods: Retrospective cohort study of patients undergoing cataract extraction combined with 1 of 3 MIGS procedures (Hydrus, iStent, Kahook) at the Philadelphia Veterans Affairs Medical Center between January 1, 2015 and November 1, 2020. Analysis of variance and regression models were used to compare reduction in IOP and medication use among 3 MIGS types. Results: A total of 123 eyes of 112 patients were included, including 56 (45.5%) eyes for Hydrus, 40 (32.5%) eyes for iStent, and 27 (22.0%) eyes for Kahook. Adjusted mean IOP reduction was greater for Hydrus at postoperative day 1 (−4.49 vs. −1.76 for iStent and −1.69 for Kahook, P=0.05 and greater for Kahook at postoperative week 1 (−2.53 vs. +0.70 for iStent vs. −1.41 for Hydrus, P=0.02), but did not differ significantly between MIGS types at subsequent postoperative visits (all P>0.05). In multivariable analysis, MIGS type was not significantly associated with reduction in IOP or medication use at 9 to 12 months postoperatively. There were no significant differences in complication rates across MIGS types. Conclusion: In this study, the difference in IOP lowering and medication reduction postoperatively between the Hydrus, iStent, and Kahook was not statistically significant after postoperative day 1. More studies are needed to evaluate outcomes of MIGS surgeries in glaucoma populations of different disease severity.

G laucoma is the second leading cause of blindness worldwide, causing an estimated 4.5 million cases and accounting for 12% of global blindness. 1 This disease causes progressive damage to the optic nerve and nerve fiber layer, with potential to progress to severe visual field loss and visual acuity deficits. 2,3 Furthermore, untreated disease carries significant economic burden due to the cost of ocular antihypertensive medications, health care consultations, and glaucoma-related procedures. 4 The mainstay of therapy involves the reduction of intraocular pressure (IOP), with treatment options ranging from medications, which may be limited due to poor compliance 5,6 and tolerability, 7,8 to laser therapy to surgery. 5 Progression to ab-externo filtration surgery has been considered the gold standard for IOP reduction. However, this technique is associated with significant complications including scarring, bleb-related infections, and secondary cataracts. [9][10][11] More recently, microinvasive glaucoma surgeries (MIGS) have become a treatment option with growing evidence of efficacy and safety. 12 With little to no scleral dissection, minimal conjunctival manipulation, good safety profile, rapid recovery, and significant reductions in IOP, certain MIGS procedures are ideal for patients with mild-moderate glaucoma refractory to standard medical therapy. 13 MIGS devices may be classified into trabecular/ Schlemm canal, suprachoroidal, and subconjunctival mechanisms. 14,15 Trabecular/Schlemm canal mechanisms involve increasing outflow through the trabecular meshwork and Schlemm canal. Suprachoroidal mechanisms involve increasing outflow through the uveoscleral pathway. Subconjunctival mechanisms involve shunting aqueous from the anterior chamber to the subconjunctival/sub-Tenon space.
Three commonly used MIGS devices that utilize a trabecular/Schlemm canal mechanism include the Hydrus, iStent, and Kahook. The Hydrus Microstent ("Hydrus," Ivantis Inc., Irvine, CA) is a device designed to be inserted into 90 degrees of the trabecular meshwork to act as a trabecular meshwork bypass stent and scaffold for Schlemm canal. The iStent and iStent inject ("iStent," Glaukos Corporation, San Clemente, CA) are devices designed to be implanted into Schlemm canal to bypass the trabecular meshwork. The Kahook Dual Blade ("Kahook," New World Medical, Rancho Cucamonga, CA) is a goniotomy blade designed to excise a segment of trabecular meshwork to provide direct trabecular bypass.
Randomized trials have established the efficacy and safety of the Hydrus, iStent, and iStent Inject, most often comparing combined phacoemulsification-MIGS to phacoemulsification alone. [16][17][18][19] Fewer studies have directly compared the efficacy and safety of such MIGS devices, and to date only 1 randomized trial has compared different MIGS devices (Hydrus vs. 2 iStents, performed as standalone procedures without cataract extraction, demonstrating that standalone Hydrus resulted in a higher surgical success rate and fewer medications compared with the 2 iStent procedure). 20 Furthermore, most retrospective studies and randomized trials involving of glaucoma surgeries including trabeculectomy, Express shunts, laser trabeculoplasty, and tube shunts have been performed in a predominantly white population, limiting the generalizability of results to other patient populations, especially black patients in whom glaucoma is more prevalent, more likely to progress, and more likely to be refractory to treatment. 21 Finally, it is crucial to recognize the importance of evaluation of resident physician performed procedures, especially for surgeries that require utilization of relatively novel devices and techniques. Our study retrospectively compared the efficacy and safety of 3 resident physician performed MIGS procedures-Hydrus, iStent, and Kahook-in a predominantly black Philadelphia Veterans Affairs Medical Center (VAMC) population.

METHODS
This study was a retrospective cohort study of patients at the Philadelphia VAMC who underwent one of three MIGS procedures: Kahook Dual Blade (New World Medical, Rancho Cucamonga, CA), Hydrus Microstent (Ivantis, Irvine, CA), or 2 iStents (Glaukos, Laguna Hills, CA). On this resident physician run service, resident physicians performed all surgeries as the primary surgeons. As the newer versions of iStent were cleared by the FDA, they replaced the prior version moving from 2 original iStents to 2 iStent Injects, then 2 iStent Inject W devices, between 2015 and 2020. Electronic medical records were reviewed to extract baseline data including demographic information, MIGS type, initial glaucoma diagnosis (primary open-angle glaucoma, ocular hypertension, normal tension glaucoma, traumatic glaucoma, or  pigmentary glaucoma), preoperative maximum IOP (Tmax), cup-to-disc ratio, and central corneal thickness. Glaucoma severity was assessed using the mean of the last 3 preoperative and first postoperative Humphrey Visual Field mean deviation (HVF MD) values, which was then categorized into mild, moderate, or severe based on the Hodapp-Anderson-Parrish system (Hodapp et al 22 ). Of note, patients with ocular hypertension at diagnosis were included as chart review demonstrated some level of abnormality in retinal nerve fiber layer and visual fields, making them closer to at least mild open angle glaucoma at time of surgery. In addition, while not a specific indication for MIGS use, traumatic glaucoma was included in order to be inclusive of the unique prevalence of trauma in this Veterans population given that our goal was to guide surgical decisions when treating Veterans with cataracts who were also using glaucoma medications. Postoperative goniotomy confirmed placement of the device.
For each study eye, IOP was measured at the preoperative visit as well as postoperative day 1, week 1, month 1, month 2 to 3, month 6, and month 9 to 12. Most IOP measurements were taken by Goldmann applanation, but some were taken by iCare or Tonopen-which were considered to be equivalent measures when averaged across 3 measurements 23 in 2020 due to infection control policies instituted in response to the COVID-19 pandemic. Preoperative baseline IOP was a standardized measurement, which consisted of the average of 3 measurements. Glaucoma medication burden was assessed with 2 measures: (1) number of glaucoma medication classes and (2) number of total daily drops. For example, a patient using latanoprost once daily at night and timolol twice a day would have 2 medication classes and 3 total daily drops. These measures were obtained at the preoperative visit and each postoperative visit.

Statistical Analysis
Baseline characteristics across 3 MIGS groups were compared using analysis of variance for comparisons of means and using χ 2 test or Fisher exact test for comparison of proportions. Preoperative and postoperative IOP, glaucoma medications (classes and total daily drops) at each postoperative visit were compared among 3 MIGS groups using analysis of variance. Change of IOP from baseline at each postoperative visit was compared across the 3 MIGS groups with and without adjustment for baseline IOP. In the adjusted regression model, the dependent variable was the IOP change from baseline (not the baseline IOP), and  the independent variable included baseline IOP, surgery group, etc. In this model, the adjustment by baseline IOP was possible because it was equivalent to the model using the follow-up IOP as a dependent variable and baseline IOP as an independent variable. The mean number of glaucoma medication classes and total daily drops at each postoperative visit were compared across groups in a similar manner. Because eyes with higher IOP at baseline tended to have larger postoperative IOP change from baseline, in our multivariable analysis for determining factors associated with IOP change from baseline, we adjusted for the baseline IOP. Univariable and multivariable regression analyses were performed for risk factors including change in IOP, glaucoma medication classes and total daily drops at the final postoperative visit compared with baseline.

RESULTS
A total of 123 eyes of 112 patients underwent a MIGS procedure between 2015 and 2020 and were followed for a mean of 360 days postoperatively (SD = 60.70, range = 33 to 371). 56 (45.5%) eyes underwent Hydrus, 40 (32.5%) eyes underwent iStent, and 27 (22.0%) eyes underwent Kahook. Baseline characteristics for these 3 groups of eyes are shown in Table 1. Patients with eyes undergoing Hydrus were more likely to have a diagnosis of normal tension glaucoma or ocular hypertension on initial diagnosis (P = 0.004). The 3 groups did not differ significantly in preoperative HVF MD severity, Tmax, cup-to-disc ratio, or central corneal thickness. Table 2 shows the IOP over time by MIGS groups. The mean preoperative IOP was significantly higher among eyes undergoing Hydrus than eyes undergoing iStent or Kahook (P = 0.002). The mean postoperative IOP did not differ significantly among the three groups at any postoperative visit, although there was a trend toward lower IOP at postoperative day 1 in eyes undergoing Hydrus (P = 0.10) and at postoperative week 1 in eyes undergoing Kahook (P = 0.06). The mean number of medication classes and total daily drops did not differ significantly among the 3 groups preoperatively or postoperatively ( Table 2).
At the final postoperative visit, the mean IOP reduction was 2.6 mm Hg for Hydrus, 1.0 mm Hg for iStent, and 1.7 mm Hg for Kahook (Table 3). After adjustment by preoperative IOP, the adjusted mean IOP reduction was significantly greater for eyes undergoing Hydrus (  Table 3). Adjusted mean IOP reductions did not differ significantly among the 3 groups after postoperative week 1.
In both univariable and multivariable analysis, higher preoperative IOP was the only significant predictor of greater IOP reduction at the final postoperative visit (Table 4). At the final postoperative visit, the mean number of medication classes decreased from 1.8 to 1.3 overall. In univariable analysis, higher preoperative Tmax, higher number of preoperative medication classes, and higher number of preoperative total daily drops were significantly associated with greater reduction in number of medication classes at the final postoperative visit. In multivariable analysis, a higher number of preoperative medication classes and a lower number of preoperative total daily drops were associated with a greater reduction in the number of medication classes at the final postoperative visit (Table 5). At the final postoperative visit, the mean number of total daily drops decreased from 3.0 to 2.2 overall. In univariable analysis, glaucoma type (primary open-angle glaucoma), higher preoperative Tmax, higher number of preoperative medication classes, and higher number of preoperative total daily drops were significantly associated with greater reduction in number of total daily drops at the final postoperative visit. In multivariate analysis, only higher number of preoperative medication classes remained significant (Table 6).
Two eyes experienced intraoperative complications (vitrectomy), which were due to the cataract portion of the surgery rather than the placement of the MIGS device. No study eyes experienced complications of persistent iritis, hypotony, changes in visual acuity, slit-lamp findings (conjunctival injection/edema/infection, iritis, scleritis/scleral edema, corneal abrasion/edema/infection, AC cell/flare, retinal tear/hemorrhage/ detachment, optic nerve atrophy), or need for subsequent procedures.

DISCUSSION
In this retrospective study, we examined the efficacy and safety of Hydrus, iStent, and Kahook procedures combined with cataract surgery in the Philadelphia VA population. We found that while there were significantly greater short-term adjusted IOP reductions for specific MIGS types (Hydrus at postoperative day 1 and Kahook at postoperative month 1), IOP reduction did not differ significantly among the Hydrus, iStent, and Kahook after postoperative month 1 in the multivariable analysis with adjustment by baseline IOP. Instead, higher preoperative IOP was the only significant predictor of greater IOP reduction. Similarly, the number of preoperative medication classes, rather than MIGS type, was a significant predictor of reduction in medication classes and total daily drops.
A number of randomized trials have established the efficacy of various MIGS procedures (specifically Hydrus and iStent) when combined with phacoemulsification compared with phacoemulsification alone. [16][17][18][19] However, to date only one randomized trial has compared the efficacy of different standalone MIGS procedures. The COMPARE study was a prospective randomized trial comparing standalone implantation of 1 Hydrus device to 2 iStent (generation 1) devices. It found that Hydrus was associated with greater medication reduction compared with 2 iStent devices at 12 months, but found no significant difference in IOP reduction. 20 Another registered trial is underway comparing cataract extraction combined with Hydrus versus iStent implantation (NCT02024464). In contrast to the findings of COMPARE study, our retrospective study found that MIGS type (eg, Hydrus, iStent, Kahook) was not a significant predictor of IOP or medication reduction. There are a number of possible reasons for this difference. Our study examined combined phacoemulsification-MIGS procedures, while the COM-PARE study examined standalone MIGS procedures. Our study population was predominantly male and black, while the COMPARE study population was 42% to 45% male and only 1% to 4% African ancestry. Furthermore, our study did not involve a medication washout period, so the mean preoperative IOP was lower than the mean preoperative IOP in COMPARE (15.7 vs. 19.0 to 19.1 mm Hg).
Our findings are similar to prior retrospective studies comparing Hydrus, iStent, and Kahook procedures. Lee and colleagues retrospectively compared eyes undergoing phacoemulsification alone, phacoemulsification-Hydrus, and phacoemulsification-iStent over 24 months, and found greater IOP and medication reduction in the 2 MIGS groups compared with the phacoemulsification alone group, but no significant differences between the 2 MIGS groups. 24 Two retrospective studies compared phacoemulsification combined with Kahook or one iStent (generation 1) with 12 months' follow-up. One found no significant differences in IOP or medication reduction. 23 The other found that Kahook was associated with greater IOP reduction but not greater medication reduction; however, the Kahook group had higher baseline IOP than the iStent group (18.2 vs. 16.7), which may have permitted greater IOP reduction in the Kahook group. 17 Our findings highlight the importance of adjusting for baseline IOP when comparing MIGS procedures, specifically Hydrus, iStent, and Kahook, in a retrospective analysis. In our study, eyes undergoing Hydrus had higher baseline IOP than eyes undergoing iStent or Kahook, suggesting that clinicians may have preferentially chosen to use Hydrus for eyes with greater baseline IOP. After controlling for baseline IOP, all 3 MIGS procedures appeared equally efficacious in reducing IOP and medication use. In addition, our study's suggestion that higher preoperative IOP was the only significant predictor of greater IOP reduction falls in the context of past cataract surgery research. Prior studies support the observation that the IOP lowering effect of cataract surgery is likely to be the greatest in those with high  17,25 At 1 year postoperatively, the cataract extraction arm alone had a mean IOP reduction of 8.5 mm Hg, at 2 years postoperatively, the cataract extraction arm alone had a sustained mean IOP reduction of 7.4 mm Hg. 17,25 Therefore, it is important to note the possibility that differences in change in IOP are not related to MIGS devices and may be secondary to cataract surgery alone, although a contribution from the MIGS devices are more likely. In addition, in this study it is possible that intraoperative complications potentially contributory to IOP such as initial Hydrus misplacement were not noted in the operative notes, as attending surgeons were able to assist the resident physicians to correct the issue intraoperatively. Therefore, future study clarifying all components of each surgical step and decision in the OR would be helpful. Finally, it is also important to mention the potential contribution of miochol/miostat use intraoperatively, and Diamox use postoperatively. The impact of this medication usage on assessing IOP spikes are important to investigate in future studies.
In this retrospective study, we found that combined phacoemulsification and Hydrus/iStent/Kahook procedures were associated with a mean IOP reduction of 1.7 mm Hg at 9 to 12 months postoperatively, ranging from 1.0 mm Hg (iStent) to 2.6 mm Hg (Hydrus). These are lower in magnitude than prior randomized trials, which involved medication washouts (Hydrus 7.6 to 9.4 mm Hg; iStent 7.0 to 8.4 mm Hg; no randomized trials available for Kahook), but are in line with prior retrospective studies (Hydrus 0.8 to 4.5 mm Hg; iStent 1.7 to 4.2 mm Hg; Kahook 2.4 to 5.0 mm Hg). [16][17][18][19]24,[26][27][28][29] Our study has a number of strengths. First, it is based on real-world data utilizing Hydrus, iStent, and Kahook combined with phacoemulsification, which is part of the current US FDA approval for both the Hydrus and the iStent. MIGS procedures have generally produced lower IOP reductions in real-world settings than randomized trial settings for a number of possible reasons (no preoperative medication washout, more diverse patient demographics, variable surgeon experience), and real-world data can better capture the anticipated effect of using MIGS procedures in clinical practice. Second, our study population was 70% black, a higher proportion than in COMPARE and many other clinical trials, providing data on a patient population that is often underrepresented in clinical trials. This is especially important given evidence that surgical interventions for glaucoma may be less effective in patients of African ancestry. 30 Our study has a number of limitations. First, this study was based at a single Veterans Affairs hospital, and therefore may not be representative of other clinical practice settings. Second, some years of this study were affected by the COVID-19 pandemic, which led to more patients being lost to follow-up and IOP measurements being taken by Tonopen or iCare rather than Goldmann applanation tonometry due to infection control policies. However, the pandemic would be expected to affect all 3 treatment groups equally. Third, the 3 MIGS procedures examined in this study were not equally represented, with more patients undergoing Hydrus than Kahook or iStent. Fourth, the iStent group included patients receiving the generation 1 iStent device before 2018 and the generation 2 iStent Inject device after FDA approval in 2018, as well as the iStent Inject W, creating heterogeneity in the intervention within this treatment group. Fourth, the preoperative IOP was higher in eyes undergoing Hydrus than iStent or Kahook, suggesting providers may have preferentially chosen Hydrus for eyes they deemed had more severe baseline glaucoma. This supports the idea that the Hydrus is thought to have greater efficacy in patients with greater glaucoma severity. This could potentially bias our comparison of treatment responses among three groups. However, we found no significant differences in glaucoma severity as measured by HVF MD, Tmax, or cup-to-disc ratio across the 3 groups, and we controlled for preoperative IOP in multivariate analyses. It is also important to note that if the patients with higher baseline preoperative IOP had undergone iStent and or Kahook as the preferred surgery, a bigger difference in IOP lowering may have been observed. In addition, it is important to recognize a potential differential bias in our results due to the lack of randomization, which may have occurred considering the predilection of Hydrus for "normal tension glaucoma." In addition, due to the COVID-19 pandemic, not all IOP were measured by the Goldmann applanation, which could bias the evaluation of IOP change over time. Finally, unlike the COMPARE trial, there were multiple independent surgeons performing the surgeries, limiting the ability to control for individual iterations on surgical techniques. Similarly, due to the retrospective nature of this study we were unable to confirm correct surgical placement of the Stent and Hydrus for optimal effect. Furthermore, this study uniquely examines outcomes of resident physician performed surgeries, which could also have impacted the IOP changes found. Past studies have shown that resident physician performed cataract surgery has a significantly higher incidence of IOP spikes; however, long-term effect of those spikes in outcomes are unclear. 31,32 In addition, since resident physicians performed the surgeries for all 3 types of MIGS, we would not expect this effect to affect our comparative results.
In conclusion, our study found that eyes undergoing combined cataract extraction-MIGS procedures with Hydrus, iStent, or Kahook did not significantly differ in IOP or medication reduction over 9 to 12 months after MIGS. Rather, preoperative IOP and preoperative number of medication classes were the only significant predictors of IOP reduction and medication reduction, respectively.