Prospective, Non-randomized, 36-Month Study of Second-Generation Trabecular Micro-Bypass Stents with Phacoemulsification in Eyes with Various Types of Glaucoma

Although filtering surgeries such as tube shunt implantation and trabeculectomy are the procedures most broadly utilized for glaucoma worldwide, the possibility of long-term complications remains a valid concern for both patients and physicians [1]. Since life expectancy and glaucoma prevalence are increasing in the US and globally [2, 3], and the cumulative risk of many complications increases over time, any given complication introduces its own years- or decades-long risk profile. For patients needing a dramatic reduction in intraocular pressure (IOP), these risks may be appropriate and necessary. However, for patients in earlier stages of the disease, and often even for patients with moderate and severe disease, a lower-risk trabecular microinvasive glaucoma surgery (MIGS) may offer sufficient and substantial reductions in IOP and medication burden while also maintaining consistent safety (and hence a desirable benefit–risk profile) over the long term [4].

Available MIGS treatment options have expanded greatly since the first MIGS device was introduced, the iStent^® trabecular micro-bypass (Glaukos Corporation, San Clemente, CA, USA; FDA 2012; CE 2004). This stent is implanted ab interno with or without cataract surgery in accordance with the relevant country’s approved indication. A significant body of evidence has shown meaningful long-term IOP and medication reductions after implanting one or multiple iStent devices, with excellent safety [5‐22]. More recent years have seen the development and increasing surgical use of the second-generation iStent^® inject trabecular micro-bypass (Glaukos; FDA 2018; CE 2010), which includes two trabecular stents implanted ab interno through the trabecular meshwork into Schlemm’s canal in order to increase aqueous outflow and decrease IOP. A growing body of research has documented iStent inject performance and safety for mild to moderate OAG. The majority of these studies have evaluated stent implantation as a standalone procedure [23‐27], while a smaller number of studies have assessed implantation combined with phacoemulsification [28‐33]. In both settings, IOP and medication burden have shown clinically meaningful reductions and long-term durability, and the stent has presented favorable long-term safety.

The current report presents a single surgeon’s experience of the 36 months following the implantation of two second-generation trabecular micro-bypass stents in eyes with various glaucoma diagnoses and a considerable preoperative medication and surgical burden. Safety and effectiveness outcomes are reported for the overall cohort and for the primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEX) subgroups. As such, this report aims to provide practical, clinically relevant information for patients and surgeons who are deciding upon treatment for glaucoma.

In these 81 eyes with POAG, PEX, appositional NAG, PG, or neovascular (secondary) glaucoma, substantial reductions in both IOP and medication use were observed for 36 months postoperatively following the implantation of two second-generation trabecular micro-bypass stents with cataract surgery. These favorable results are consistent with those of numerous previous studies of first-generation trabecular micro-bypass stent implantation in conjunction with cataract surgery for mild to moderate glaucoma [5‐16]. The results also corroborate previous reports of IOP and medication reduction after implantation of two iStent devices in a standalone procedure [17‐22]. In addition, the findings support prior research on second-generation iStent inject implantation either with or without cataract surgery in subjects with predominantly mild to moderate levels of IOP elevation or medication burden [23‐33].

In the overall cohort, preoperative disease burden (as indicated by number of medications and history of prior glaucoma surgery) was relatively substantial. Over half of the eyes were being treated with 3-4 medications preoperatively, nearly one-third of the eyes had undergone prior glaucoma surgery (or surgeries), and only one eye was medication-free. In such previously operated eyes, remodeling and fibrosis of the trabecular meshwork and juxtacanalicular tissue have been shown to occur, thereby producing outflow resistance and contributing to glaucoma [34, 35]. The difficulty involved in achieving favorable outcomes in such eyes is widely acknowledged [1, 34], and is thought to depend on the patency of each eye’s outflow network [35]. Our study showed that there were significant IOP and medication reductions in previously operated eyes, suggesting that trabecular micro-bypass stents could potentially circumvent the diseased portions of the outflow pathway to restore normal aqueous dynamics in the remaining healthy parts.

Given that stent implantation was completed in conjunction with cataract surgery, it is important to acknowledge the widely known impact that cataract surgery alone can have in reducing IOP [36‐38]. Post-phacoemulsification IOP reduction is expected to be modest: less than 2 mmHg on average [36, 37], or a reduction versus baseline of 16.5% three years after cataract extraction, as shown in the Ocular Hypertension Treatment Study (OHTS) [38]. Less dramatic IOP reductions are expected in the setting of lower baseline IOP (e.g., IOP ≤ 20 mmHg) [39, 40]. In the present cohort, IOP decreased by over 8 mmHg, a reduction of 37%; this reduction is approximately two to four times greater than the reduction expected with cataract surgery alone. This is consistent with clinical studies showing significantly greater reductions in IOP and medication use in patients with iStent and iStent inject implantation plus cataract surgery compared to cataract surgery alone [2‐4, 31, 41‐43]. It also aligns with the work of Fernandez-Barrientos et al. [2], who demonstrated significant increases in trabecular outflow facility at 12 months in eyes implanted with iStent in combination with cataract surgery compared to eyes with cataract surgery alone.

With regards to the POAG and PEX subgroups, preoperative characteristics were generally consistent with what has been reported in the literature. In particular, eyes with PEX had slightly higher preoperative IOP and medication burden than eyes with POAG, consistent with the more aggressive and treatment-recalcitrant nature of this glaucoma type [44]. Postoperatively, the outcomes in PEX eyes were similarly favorable to those in POAG eyes, thereby corroborating prior studies showing iStent technology to be a highly suitable and effective treatment option in PEX eyes [12, 14].

We acknowledge several limitations of this unmasked, single-arm study. Subjects comprised a consecutive series of patients in the surgeon’s clinical practice, and thus were not required to meet narrow inclusion criteria for enrollment. Subjects also did not complete preoperative and postoperative medication washouts, since these are not usually part of standard clinical practice and could potentially cause harm to subjects who have moderate to advanced glaucoma. As is the case in most real-world clinical studies, there was no formal control group with which to compare the treatment group; however, we considered preoperative IOP and number of medications to be valid comparators given that they are numeric measures. Potential additional confounders include the absence of diurnal IOP measurements, regression to the mean, and the inability to separate the IOP effects of cataract extraction and stent implantation. In order to avoid misleading conclusions due to the limited number of eyes with complete follow-up through 36 months, subgroup analyses for PEX and POAG were performed at 12 months instead. Future reports based on this dataset could include analyses through 36 months or longer for these subgroups as well as for the overall cohort. Other directions for future work could include stratifying outcomes by type of prior glaucoma surgery and/or number of preoperative medications; examining long-term RNFL data (via OCT measures) as a structural correlate for disease control; and comparing postoperative 3- or 6-month refractive data with expected preoperative values.

In conclusion, this series demonstrated substantial reductions in both IOP and medication burden through 36 months postoperatively following the implantation of two second-generation trabecular micro-bypass stents with cataract surgery, along with favorable safety. Importantly, these outcomes were observed in a clinically heterogeneous patient population with a considerable preoperative medication burden and prevalence of prior glaucoma surgery. This diversity and real-world setting could make the data more representative of real-life clinical populations than many product registration trials. Thus, the study provides a useful reference for both clinicians and patients who are evaluating their glaucoma treatment options.