Five-Year Outcomes of iStent inject Implantation With or Without Phacoemulsification in Eyes with Open-Angle Glaucoma

Glaucoma is a leading cause of blindness globally, estimated to have caused permanent vision loss in 3.6 million individuals over the age of 50 years in 2020 [1]. With the anticipated growth of the aging population, it has been estimated that 111.8 million people will be affected by glaucoma by 2040 [2]. If untreated, glaucoma results in progressive, permanent and vision loss. The key objective in treatment is lowering intraocular pressure (IOP) as this has demonstrated efficacy in reducing progression in patients with ocular hypertension and open-angle glaucoma (OAG). Most often, topical pharmacotherapy to lower IOP has been the mainstay of treatment for decades, with the aim to delay progression of visual field loss, and this therapy has been shown to be effective and reasonably safe. The use of topical medications to treat glaucoma, however, can be associated with substantial side effects, damage to the ocular surface, ongoing financial burden, and limited effectiveness due to some degree of nonadherence in up to 90% of patients [3‐10].

Recently, the management of OAG utilizing minimally invasive surgical interventions has become more widespread. Such interventions can include selective laser trabeculoplasty (SLT), minimally invasive glaucoma surgery (MIGS), and sustained-release procedural pharmaceuticals. Within the past two decades, MIGS procedures have become recognized as surgical interventions that both deliver improved outcomes and can be employed earlier in the disease process. This interventional management strategy has enhanced the surgeon’s armamentarium for the treatment of mild to moderate glaucoma, and even severe glaucoma. A recent publication of data from the American Academy of Ophthalmology IRIS Registry reported that of > 200,000 eyes receiving glaucoma surgeries in the USA between 2013 and 2018, the iStent® implant (Glaukos Corp., San Clemente, CA, USA) was the most commonly performed MIGS, being used primarily for individuals with normal tension glaucoma (NTG) or primary OAG (POAG) [11].

The iStent® Trabecular Micro-Bypass Stent (containing one stent) was the first MIGS device to be approved by the United States Food and Drug Administration (FDA) and, more recently, the second-generation iStent inject® (containing 2 stents) was also approved for use. Both iterations of the iStent create a patent pathway to bypass the trabecular meshwork and allow for direct aqueous flow into Schlemm’s canal, thus decreasing IOP, and clinical studies conducted in a variety of settings have demonstrated significant reductions in IOP and medication burden and a favorable safety profile. Studies of up to 42 months duration have evaluated the impact on IOP and medication reduction after single and multiple stent placement, performed in a standalone procedure or combined with cataract surgery, and confirmed that although the majority of IOP reduction is the result of the first stent, each additional stent provides further reduction in IOP and medication use [12‐14]. We previously completed a study in which we compared both iStent and iStent inject system and observed significant and safe IOP and medication reductions with both devices, with a trend toward greater efficacy and fewer adverse events with the iStent inject system compared to the iStent system [15].

In Brazil, the iStent inject procedure is approved to be performed in conjunction with cataract surgery or as a standalone procedure. Although it has been shown that cataract surgery may independently lower IOP among patients with co-existing cataract and glaucoma, broad evidence has shown a statistically significant greater decrease in mean IOP postoperatively when cataract surgery is combined with MIGS, compared with cataract surgery alone, and a 50% less likelihood of having to use one or more topical medications postoperatively with a combined procedure [16, 17]. Previous studies have also shown that when cataract surgery is combined with MIGS procedures, it is more cost effective [18, 19]. Specific to the iStent inject combined with cataract surgery compared to cataract surgery alone, Samuelson and colleagues reported the findings of a 2-year randomized multicenter trial, with the results showing that clinically and statistically greater reductions in medication-free IOP were achieved after iStent inject implantation with cataract surgery in eyes with mild to moderate POAG as compared to cataract surgery alone, with excellent safety through the 2-year study period [20]. More recently, Fan Gaskin et al. reported that in their similarly designed 2-year, randomized single-center trial of eyes with mild to moderate POAG, 57% of those undergoing the combined procedure were on no medications at 2 years, compared to 36% of those who had only cataract surgery [21].

Several studies have also demonstrated longer-term safety and preservation of structure and function following iStent inject implantation with phacoemulsification. In a study conducted in Canada, Salimi and colleagues reported that significant and sustained reductions in IOP and medication burden were achieved across 3 years in their real-world cohort of 124 eyes with different subtypes of glaucoma, ranging from mild to severe, while structural and functional parameters remained stable [22]. Clement et al. also reported similar findings in a 3-year-long multicenter study in 273 eyes from Australia. In addition, Hengerer and colleagues confirmed favorable efficacy and safety over a 7-year period in their 125-eye study, which is the longest follow-up of any iStent inject implantation published to date [24].

Here, we report the efficacy and safety outcomes of iStent inject implantation with and without combined phacoemulsification over a 5-year follow-up period in eyes with mild to moderate OAG. Our hypothesis was that this intervention would provide meaningful reductions in IOP and topical medication burden, and that these reductions would be seen across all subgroups. This study is current one of the longest-term iStent inject studies available, and the longest-term study performed outside of Europe or North America to date.

Main study outcomes included the changes versus baseline in mean IOP and number of medications used over time. Additional outcomes included the proportion of eyes achieving IOP ≤ 12 mmHg, ≤ 15 mmHg, and ≤ 18 mmHg over the study period and the proportion of eyes using zero, one, two, three, or more topical medications over the same study period.

Eligible patients in the Combined subgroup were ≥ 18 years of age and had mild or moderate OAG, cataract requiring surgery, and the need for IOP and/or medication reduction. The only difference between the Combined subgroup and Standalone subgroup was that those in the Standalone subgroup were already pseudophakic in the study eye. Any eyes presenting with significant coexisting ocular diagnoses that could confound the outcomes of the surgery were excluded. The staging of glaucoma was classified using the Hodapp–Parrish–Anderson visual field criteria that are commonly used in clinical studies, with mild glaucome defined as mean deviation [MD] no worse than − 6 dB; moderate glaucome as MD worse than − 6 dB but no worse than − 12 dB; and severe glaucome as MD worse than − 12 dB [25].

Each patient in the Combined subgroup underwent phacoemulsification and intraocular lens implantation using the standard technique through a clear corneal incision. Prior to proceeding to the iStent inject procedure, and for those receiving iStent inject as the sole procedure, the patient’s head and surgical microscope were positioned to confirm an appropriate gonioscopic view of the trabecular meshwork and nasal angle. Viscoelastic with or without intracameral miotic was injected into the anterior chamber to deepen the angle, enhance visualization of Schlemm’s canal and maintain the anterior chamber. The iStent inject inserter was inserted through the existing temporal corneal incision used for phacoemulsification, then advanced across the anterior chamber to the nasal angle, where the first stent was implanted into Schlemm’s canal. Then, without withdrawing the inserter from the eye, the surgeon laterally repositioned the injector tip to implant the second stent, approximately 2 to 3 clock hours away from the first stent. Following confirmation of proper stent placement and seating after implantation, viscoelastic was removed and proper sealing of the corneal incision was ensured [27].

All procedures were performed under local anesthesia. Patients were prescribed postoperative topical antibacterial medication (moxifloxacin 4 times/day for 10 days) and topical anti-inflammatory medication (dexamethasone 4 time/day for 10 days, with tapering to 3 time/day for 5 days, 2 time /day for 5 days, 1 time/day for 5 days, then stop), as per the surgeon’s standard practice.

Data were analyzed preoperatively and at annual time points following the procedure. Data collected included IOP, number of medications, visual fields, adverse events, and secondary glaucoma procedures. Statistical analysis was performed using SPSS statistical software (SPSS IBM Corp., Armonk, NY, USA) and a p value of 0.05 was defined as the threshold for statistical significance. Four analysis populations were assessed: (1) the ‘Observed cohort’ of all eyes at each time point (n = 271 at baseline, n = 102 at 5 years); (2) ‘Last-follow-up analysis’ (LFU), including data from all visits, regardless of patients’ length of follow-up (n = 271 at baseline, n = 271 at last follow-up); (3) Mild/Moderate glaucoma subgroups; (4) and Combined/Standalone subgroups. Analyses of mean IOP and medications were performed across the 5 years of follow-up in the Observed cohort and in the Mild/Moderate and Combined/Standalone subgroups. LFU analyses of mean and proportional outcomes of IOP and medications were performed in the Observed cohort, Mild/Moderate subgroups, and Combined/Standalone subgroups. As this was a retrospective study, sample size was determined empirically, rather than via formal sample size calculation. The number of cases was determined by the number of iStent inject surgeries completed over a given time period (January 2018 to January 2024).

The study enrolled 271 eyes of 271 subjects (Observed cohort n = 271) and the mean follow-up period was 40 months (range 10–79 months). At baseline, the mean age was 69 (range 27–88) years, 55% were female, and most subjects were of European or Hispanic descent (83%). Subject characteristics are summarized in Table 1.

The majority of eyes in the cohort were diagnosed with POAG (93%), and the mean (± SD) number of medications at baseline was 2.24 ± 0.90. The stage of glaucoma at baseline was mild for 86% of eyes and moderate for 14%, with a mean preoperative Humphrey Visual Field mean deviation (HVF MD) of − 3.49 ± 2.18 dB. Overall, at baseline the mean IOP was 16.4 ± 3.4 mmHg, including those eyes in the Mild subgroup with a mean IOP of 16.2 ± 3.4 mmHg, and 17.8 ± 3.2 mmHg for those in the Moderate subgroup (Table 1).

The majority of eyes (n = 214, 79%) received iStent inject in combination with cataract surgery (Combined subgroup), while 21% of eyes (n = 57) underwent iStent inject implantation alone (Standalone subgroup). The preoperative mean IOP was 16.0 ± 3.3 mmHg in the Combined subgroup and 17.8 ± 3.4 mmHg in the Standalone subgroup.

This real-world longitudinal study of patients who received the iStent inject stent with or without cataract surgery showed favorable efficacy and safety for up to 5 years. Statistically significant reductions in IOP and the number of medications were observed for the entire cohort for the duration of the study period, and these reductions were observed across the subgroup analyses (Combined/Standalone and Mild/Moderate) and in the last follow-up analysis. Safety was favorable, including relatively few adverse events or secondary procedures. Visual field MD improved slightly, although this could have been due to cataract extraction and/or increased familiarity with the test. The findings of this study (e.g., 16.5% IOP reduction and 72.3% reduction in number of medications at the last follow-up) are relatively consistent with prior literature on the iStent inject® system. For example, in the Canadian 3-year study by Salimi et al., mean IOP was reduced by 22%, mean medication burden was reduced by 51%, and favorable safety included stable best-corrected visual acuity (BCVA), visual field (VF), retinal nerve fiber layer (RNFL) thickness, and ganglion cell inner plexiform layer (GCIPL) thickness after iStent inject implantation with cataract surgery [22]. The 3-year Australian multicenter study by Clement et al., which also included concomitant cataract surgery, reported a mean IOP reduction of 15.5% and a mean medication reduction of 68.5%, with 71.4% of eyes being fee of medication at 3 years [23]. In that study, safety was favorable across glaucoma subtypes, severities, and surgeons, with few adverse events, stable VF, RNFL, and central corneal thickness (CCT); and over the 3-year period, filtering surgery was required in only 2.9% of eyes [23].

In terms of study design, among all previously published studies, our study is most similar to the 7-year study by Hengerer and colleagues, which examined outcomes of iStent inject implantation with or without phacoemulsification in eyes with relatively high preoperative disease burden [24]. In these eyes, iStent inject implantation with or without phacoemulsification resulted in significant and durable reductions in IOP (up to 44%) and medication burden (up to 76%) over the 7-year period. No filtration surgeries were required over the follow-up period, and only 4.84% of eyes experienced clinically significant VF loss. In comparison, the present study, completed in a patient population with a relatively lower disease burden at baseline, exhibited a lower percentage reduction in IOP (16.5% at last follow-up) and a similar percentage reduction in medications (72.3%). The lesser IOP reduction can be attributed to the well-recognized pattern of higher preoperative IOP yielding greater absolute and percentage reductions in IOP postoperatively. Safety in the current study was similarly favorable as that in the Hengerer et al. study [24], with filtering surgery in only two eyes (< 1% of total) and stable visual fields through last follow-up.

Reduction in mean medication use was particularly noteworthy in the present study, with two thirds of eyes not requiring any topical medication at their last follow-up compared to only 1.8% preoperatively. Adherence to a daily topical treatment regimen can be very challenging and complex for patients as they are required to successfully self-administer one or more medications, potentially several times per day, for a lifetime. Studies have demonstrated that non-adherence is a key risk factor for glaucoma progression and poor functional outcomes [27, 28]. Beyond adherence, identified challenges of topical therapy include associated costs, inadequate penetration of the corneal surface, ocular surface disease, fluctuations in IOP, and diminished quality of life [29]. Additionally, some patients are unable to use topical medications due to certain comorbidities or dangerous interactions with systemic medications [30].

The broader use of an interventional glaucoma approach to glaucoma management to reduce or eliminate medication burden in patients with glaucoma, especially at earlier stages of the disease, has a range of well-recognized benefits, both clinically and for the patient [29‐35]. These include more consistent IOP control and prevention of disease progression, reduced long-term costs, reduced incidence of medication-related side-effects, and reduction or elimination of the need for patient adherence [29, 36]. Additionally, IOP fluctuations can occur with topical therapies, and they have been identified as a significant and independent risk factor for glaucomatous progression, but are reduced with interventional management [37, 38]. Studies have also documented significant improvement in quality of life with reduced topical medication use, associated with freedom from strict and complex medication regimens, reduced side effects, and significant improvement in ocular surface health [26, 39].

The majority of patients in the present study received the combined phacoemulsification and iStent inject procedure. Other studies of iStent inject used in combination with cataract surgery in the treatment of mild to moderate POAG have similarly shown good efficacy and safety profiles and limited postoperative sequelae [15, 22‐24, 40‐53]. These studies have consistently demonstrated clinically important reductions in IOP and medication burden, with follow-up duration ranging from 6 months to 7 years. The current study reports on patients with a follow-up of 5 years post-procedure, allowing for assessment of the durability of iStent inject in reducing IOP and medication burden. This is particularly important due to the increasing longevity of the population and the chronic nature of glaucoma.

Certain limitations should be discussed in this study. The study was retrospective, occurred at a single center, had no medication washout period, and was limited to mild/moderate glaucoma. Additionally, reported medication use was based on routine clinical practice, rather than on a controlled protocol, and diurnal IOP measurements were not assessed, as these were not done in normal clinical care. Although VFs were measured and analyzed, RNFL thickness was not, so this could be the subject of future analyses. An additional subject of future research could be a prospective study comparing iStent inject and cataract surgery versus cataract surgery alone. These limitations notwithstanding, we believe this population to be highly representative of those patients presenting to real-world practice.

In conclusion, these long-term real-world results demonstrate significant reductions in IOP and in the number of topical glaucoma medications required following iStent inject Trabecular Micro-bypass implantation with or without cataract surgery. This study represents one of the longest-term follow-up periods for iStent inject, providing 5 years of safety and efficacy results in both combined and standalone surgical settings, and in eyes of both mild and moderate glaucoma severities.

The present study also could be a promising springboard for future research. For example, further studies could include a detailed analysis of VF outcomes, inclusion of RNFL measurements, and completion of diurnal IOP measurements. A prospective study comparing iStent inject implantation with cataract surgery versus cataract surgery alone also may be informative.