Five-Year Outcomes of Single Trabecular Microbypass Stent (iStent^®) Implantation with Phacoemulsification in Korean Patients

The Korean National Insurance System (Health Insurance Review & Assessment Service) approved the use of trabecular microbypass stents in 2017. Many studies have been published on the short-term safety and efficacy of first-generation iStent^® implantations [6‐8]. However, there have been few long-term follow-up studies [9‐12], and no studies with long-term follow-up after iStent^® implantation in Korean patients. To the best of our knowledge, this study is the first to investigate 5-year outcomes in Korean patients.

This real-world retrospective study of single trabecular microbypass stent implantation combined with phacoemulsification demonstrated a statistically significant sustained IOP reduction and decreased medication burden among Korean patients with POAG over 5 years. Although the mean medication slightly increased after 2 years postoperatively, the mean medication at year 5 was 0.83 from 2.24 preoperative medications (P < 0.001, paired t test).

In our study, IOP was reduced from 15.8 mmHg with 2.24 medications to 13.8 mmHg with 0.83 medications at 5 years. The proportion of eyes achieving IOP ≤ 18 mmHg with or without medication was 94.4% and 89.3% of eyes, and 52.8% and 46.4% had IOP ≤ 15 mmHg without medication at years 1 and 5 in our study, respectively. A low mean preoperative IOP of 15.8 mmHg might lead to a high success rate; thus, we defined IOP ≤ 15 mmHg without medication as a strict success criterion.

Similar to our report, Fea et al. [16] showed that IOP was decreased from 17.8 mmHg with 1.9 medications to 15.9 mmHg with 0.5 medications at 4 years postoperatively. Ferguson et al. [17] reported outcomes after combination procedure, observing that the mean IOP decreased from 18.8 to 14.9 mmHg. The proportions of IOP ≤ 18 mmHg were 81.0% and 83.0% at 1 year and 6 years, and the proportions of IOP ≤ 15 mmHg were 53.0% and 53.0% at 1 year and 6 years in their study.

In this context, similar long-term outcomes after combined phacoemulsification with first-generation iStent^® implantation have been reported. Arriola-Villalobos et al. reported long-term outcomes in mild-to-moderate open-angle glaucoma, with 11 of 20 patients completing 5 years of follow-up [11]. In their study, the mean IOP reduction at the final visit was 3.16 mmHg (19.42 preoperatively vs. 16.26 final), with a mean reduction of 0.48 (1.32 preoperatively vs. 0.84 final). Ansari [10] reported the 5-year outcomes in 35 eyes with moderately advanced glaucoma. In that study, the mean IOP was reduced from 18.5 mmHg with 2.3 medications to 14.7 mmHg with 2.7 medications at 5 years. Ziaei and Au [9] reported a mean IOP reduction of 4.87 mmHg with 0.59 medications in the Manchester iStent^® study with 7 years of follow-up.

These differences in IOP reduction might have occurred because of different baseline characteristics, including preoperative IOP, etiology of glaucoma, homogeneity, ethnic differences, and decision-making by the surgeon. For example, our study included only POAG cases and a small percentage of previous trabeculoplasty cases (n = 2, 4.8%), whereas the Manchester iStent study [9] included patients with pseudoexfoliation syndrome and mixed-mechanism glaucoma, and another study from the UK included a relatively high number of patients with previous laser procedures (20%) and only moderately advanced glaucoma cases [10]. Moreover, in our study, the operator (S.-H.L.) prescribed additional medications considering the customized target IOP, with reference to the American preferred practice pattern [3] and European guidelines [2]. We did not prescribe medications if eyes with mild POAG achieved IOP ranging from 15 to 18 mmHg without medication. And combination medications were considered as two medications in our dataset. This preference may result in a greater reduction in the number of medications while achieving target IOP.

Regarding glaucoma severity, according to the Hodapp-Anderson criteria [2], our patients were heterogeneous (early, 33.3%; moderate, 33.3%; severe-end stage, 33.3%). In addition, 45.2% (19/42 eyes) of the eyes received three or more preoperative medications. These patients were considered high-risk cases as defined in the Manchester iStent study [9]. On the basis of our results, patients with more preoperative medications or more advanced stages of the disease might show a higher risk of surgical failure in the Kaplan–Meier survival analysis. The long-term survival rate (decrease in the medication number of one or more) was significantly lower in the higher medication group (≥ 3 preoperative medications, 68.8%; 4 preoperative medications, 50.0%) than in the lower medication group (1–2 preoperative medications, 95.0%; 1–3 preoperative medications, 92.6%) at year 5. In our previous study, we postulated reasons for the higher surgical failure rate in the higher medication group [8]; possible explanations include post-trabecular outflow resistance (distal outflow resistance), properties of the SC and lymphatics [18], and biomechanical changes in the SC and cytoskeleton-induced long-term use of glaucoma medication [8, 19].

Although our study did not include pigment dispersion syndrome and pseudoexfoliative glaucoma, previous studies have reported a relatively good IOP reduction [20, 21]. Secondary open-angle glaucoma, including pseudoexfoliation syndrome and pigment dispersion syndrome, obstruction, and consequent increased resistance to the outflow of aqueous humor through the conventional outflow pathway, causes increased IOP. Buchacra et al. reported that performing a bypass of the trabecular meshwork between the anterior chamber and Schlemm’s canal and restoring the physiologic aqueous outflow might be an effective treatment option for these types of glaucoma [21].

Four patients (9.5%) required additional glaucoma surgery; all had maximal antiglaucoma topical medication and were at advanced-stage disease. Indeed, they required a lower target IOP to avoid progression, according to the European Glaucoma Society guidelines [2]. Similarly, Ziaei and Au [9] reported that 12% of patients underwent further glaucoma surgeries over 7 years, and Salimi et al. [22] also reported a 10% reoperation rate over 8 years after two first-generation iStent^® implantations. This low reoperation rate, along with sustained IOP reduction throughout the follow-up period, supports the long-term efficacy of iStent^® in contrast to the short-term IOP reduction achieved by laser trabeculoplasty or cataract surgery [22‐25].

In patients with greater preoperative medication use, more aggressive or traditional glaucoma surgery, such as trabeculectomy or implantation of glaucoma drainage devices, may yield more favorable results [8]. In terms of MIGS, combination approaches using different techniques and more stents are being explored, such as a combination of iAccess precision blade goniotomy [26] or Kahook dual blade [27], titrated IOP control using multiple iStent^® implantations (two or three first-generation iStent^® implants) as suggested by Katz et al. [12], two or three multiple mixed-generation trabecular stents (iStent inject^® ± iStent^®) [28], newest-generation three-stent, iStent infinite^® [29], or other subconjunctival MIGS. Multiple stents could achieve a lower IOP, with previous results showing incrementally greater and more sustained reductions in multi-iStent^® eyes [12] or more three-stent eyes (iStent inject^® + iStent^®) than in two-stent eyes achieving the target IOP [28]. Recently, multicenter prospective studies have reported that iStent infinite^® achieved clinically significant IOP reduction in patients with medically uncontrolled OAG with prior therapy [29].

The main limitation of this study was the lack of control of phacoemulsification alone due to the retrospective case-series study design. These major limitations are commonly found in other MIGS studies [8, 9, 17, 30]. Many previous studies including ocular hypertension study have suggested that cataract surgery has clinical benefit to reduce IOP in eyes with glaucoma or ocular hypertension [24, 31, 32]. Thus, our results should be interpreted carefully in terms of magnitude of IOP reduction and number of glaucoma medications. There are some considerations for the interpretation of our dataset regarding the additive effect of cataract surgery on IOP control.

First, we tried to minimize these confounding factors and referenced our previous study that compared combined phaco-iStent^® inject and phacoemulsification alone [13]. In our previous study, mean IOP decreased 14.3 ± 2.7 to 13.1 ± 2.1 mmHg after phacoemulsification in 100 Korean non-glaucomatous eyes with cataract (data not shown in this manuscript) [13]. Second, angle status and preoperative baseline IOP are important factors for IOP reduction after cataract surgery alone. The amount of IOP reduction after phacoemulsification in glaucomatous eye has been reported from 1.0 to 5.5 mmHg [24, 31, 33]. The single most-common significant factor associated with greater IOP reduction after phacoemulsification is higher IOP before phacoemulsification [31]. And, IOP reduction after cataract surgery is much more prominent in patients with closed-angle glaucoma than in those with open-angle glaucoma. In our study, we included controlled POAG only, with a baseline IOP of 15.8 mmHg, whereas previous studies mainly had the majority of eyes with high IOP and various glaucoma subtypes. Thus, we postulated that the IOP-lowering efficacy of phacoemulsification might be limited in our study participants. Our hypothesis was supported by the results of previous studies. In one Korean study [31] of a total 106 controlled patients with glaucoma who received phacoemulsification, IOP decreased from 14.25 ± 3.35 to 13.17 ± 2.90 (1 year), 13.89 ± 2.66 (2 years), and 14.17 ± 4.21 mmHg (3 years), respectively. Majstruk et al. [34] also reported that IOP decreased by a mean of 1.15 ± 3 mmHg and the number of glaucoma medications remained unchanged (17 ± 2.7 mmHg with 1.5 ± 0.8 medications, preoperatively). In this context, the authors thought that IOP reduction was minimal after phacoemulsification in eyes with IOP in the low- or mid-teens. However, there are controversies still abound. Poley et al. [24] reported a mean IOP decrease of 1.6 mmHg in patients with a preoperative IOP of 15–17 mmHg, a range closely corresponding to that in our study, whereas Baek et al. [31] reported that IOP changes are nearly zero in patients with a preoperative IOP of 15 or 16 mmHg. Third, all enrolled patients in our study underwent phacoemulsification with MIGS between 2018 and 2019, reflecting glaucoma treatment preference trends choosing combined phaco-MIGS surgery as the primary procedure. In American Glaucoma Society reports [35], phaco alone was the most preferred surgical approach in 44% of patients with POAG, phaco-trabeculectomy in 24%, with MIGS in 22%, and with glaucoma drainage device (GDD) in 9% in March 2016. In 2020 Japanese Glaucoma Society reports [36], the frequency of MIGS with phacoemulsification remarkably increased (79.0%) for non-operated eyes with mild open-angle glaucoma associated with cataract. Finally, we could get the beneficial effects for reducing medication burden and decreasing the risk of IOP spike during the early postoperative period. Previous studies have also shown IOP spikes above 30 mmHg in up to 27% of patients with POAG in the first operative days after phacoemulsification alone [31, 37]. A higher risk of IOP spikes in the early postoperative period exposes patients to additional optic nerve damage to their already compromised optic disc [38].

In summary, phacoemulsification itself may have strengthened the IOP-lowering effects observed in the Ocular Hypertension Treatment Study [32]. Despite these drawbacks, this is the first study to evaluate the long-term IOP-lowering efficacy and safety profiles of iStent^® in Korean eyes, representing real-world clinical outcomes. The scope of detailed conclusions that may be drawn for specific patient groups provides valuable insights into the natural history of disease progression following this intervention in the real world [8, 9].

Our study has some other limitations. First, the number of participants was relatively small and heterogeneous, and the study was a retrospective design with a relatively high loss to follow-up. To overcome these major limitations, future comparative studies with larger sample sizes would be valuable in confirming our results. Second, the analysis included both eyes without adjustments or corrections. Although many previous studies included both eyes for analysis, the mean IOP in contralateral eyes decreased independently of whether contralateral eyes were undergoing topical ocular hypotensive therapy or not after trabeculectomy [39]. Thus, a careful interpretation is required. And we also that consider regression to the mean usually occurs in non-randomized studies [40]. Third, routine specular microscopy was not performed to check for corneal endothelial cell loss; however, clinically significant corneal edema or severe endothelial cell loss of greater than 30% [41] was not observed in our study.