Newly Diagnosed Primary Open-Angle Glaucoma Randomized to 2 Trabecular Bypass Stents or Prostaglandin: Outcomes Through 36 Months

Purpose To examine outcomes through 36 months in phakic eyes with newly diagnosed primary open-angle glaucoma (POAG) naïve to therapy randomized to treatment with two trabecular micro-bypass stents or topical prostaglandin. Methods Subjects with POAG naïve to therapy, with intraocular pressure (IOP) ≥21 and ≤40 mmHg, were randomized to implantation of two stents or travoprost. Additional medication was to be prescribed post-treatment for elevated IOP or glaucomatous optic nerve findings. Of 101 randomized subjects, 100 subjects were followed for 24 months and 73 subjects were followed for 36 months. Follow-up on all subjects is ongoing. Results In this randomized cohort of 101 POAG subjects, 54 subjects underwent 2-stent surgery and 47 received topical travoprost. Mean pre-treatment IOP was 25.5 ± 2.5 mmHg in stent-treated eyes and 25.1 ± 4.6 mmHg in medication-treated eyes. By 3 years, mean IOP was 14.6 mmHg in stent eyes (with medication added in 6 eyes) and 15.3 mmHg in travoprost eyes (with a second medication added in 11 eyes). In the subset of eyes that did not require additional medical therapy, mean IOP was 14.5 mmHg and 15.7 mmHg in the respective groups. Ninety-one percent of stent eyes had 3-year IOP ≤18 mmHg without additional therapy (62% ≤ 15 mmHg) and 79% of travoprost eyes had 3-year IOP ≤18 mmHg (21% ≤ 15 mmHg). Safety was favorable in both groups. Conclusions In this prospective, randomized comparison of subjects with newly diagnosed POAG naïve to therapy, substantial IOP reduction with a favorable low complication rate was shown through 3 years after either 2 trabecular stents implanted as the sole procedure or topical travoprost therapy. These data suggest 2-stent implantation may be a viable initial treatment option comparable to topical prostaglandin in newly diagnosed POAG patients. Trial registration: ClinicalTrials.gov identifier, NCT01443988. Funding Glaukos Corporation, Laguna Hills, CA. Electronic supplementary material The online version of this article (doi:10.1007/s40123-016-0065-3) contains supplementary material, which is available to authorized users.

added in 6 eyes) and 15.3 mmHg in travoprost eyes (with a second medication added in 11 eyes). In the subset of eyes that did not require additional medical therapy, mean IOP was 14.5 mmHg and 15.7 mmHg in the respective groups. Ninety-one percent of stent eyes had 3-year IOP B18 mmHg without additional therapy (62% B 15 mmHg) and 79% of travoprost eyes had 3-year IOP B18 mmHg (21% B 15 mmHg). Safety was favorable in both groups.
Conclusions: In this prospective, randomized comparison of subjects with newly diagnosed POAG naïve to therapy, substantial IOP reduction with a favorable low complication rate was shown through 3 years after either 2 trabecular stents implanted as the sole procedure or topical travoprost therapy. These data suggest 2-stent implantation may be a viable initial treatment option comparable to topical prostaglandin in newly diagnosed POAG patients.

INTRODUCTION
Traditionally, treatment for newly diagnosed open-angle glaucoma (OAG) has started with topical ocular hypotensive medical therapy, followed by laser trabeculoplasty. These approaches have a lower risk profile than filtering or drainage device surgery. Further, these modalities preserve ocular tissues in case more invasive surgery is eventually required.
Despite these advantages, the efficacy of medical and laser therapy is limited. Various factors may hinder the proper use of topical medications, such as side effects (e.g., ocular hyperemia, iris hyperchromia, and periorbital atrophy), cost, intolerance to topical medications, and difficulty with drop instillation [1,2]. In addition, patient adherence to medical therapy is frequently documented to be low [3][4][5][6]. In one study of 28,741 patients are naïve to glaucoma therapy, for example, 70% of patients discontinued their therapy after 1 year [3]. Such non-compliance limits the actual vs. expected effect of medical therapy and can increase the risk of disease progression, cost to patients, and cost to providers [7]. Laser procedures do not share the same challenges as topical medications, but their efficacy may be limited by short-term inflammation and long-term attrition [8].  [18][19][20][21]. MIGS with trabecular micro-bypass stents offers a highly favorable safety profile compared to more invasive traditional incisional glaucoma surgery or more recent suprachoroidal stent procedures [22][23][24].
To date, reports of trabecular micro-bypass stent implantation have focused on patients with mild to moderate OAG who have received prior medical or surgical treatment for their disease [11][12][13][14][15][16][17][18][19][20][21][22]. Due to its favorable safety and clinical effectiveness, however, it is possible that iStent implantation may be a suitable treatment option for patients with newly diagnosed glaucoma who are naïve to therapy and who require treatment long before they undergo cataract surgery.
To address the potential utility of iStent as initial therapy in these patients, we conducted a prospective, randomized study to evaluate the IOP-lowering effect and complication rates of implanting two iStents as a standalone procedure compared to primary medical therapy in patients recently diagnosed with OAG who had not undergone prior glaucoma treatment. An earlier report showed IOP control and favorable safety through 2 years [25]. The present report covers outcomes through 3 years.

METHODS
This study was designed to enroll phakic subjects with newly diagnosed primary OAG One-hundred qualified subjects were to be randomized in a 1: The iStent device and implantation technique have been described in detail in previous work [12]. In brief, this single-piece, titanium, heparin-coated device has an L-shaped structure with a snorkel (inlet) on the short side which resides in the anterior chamber. The inlet opens to the half-pipe body which resides in Schlemm's canal.  Demographics and pre-treatment parameters are shown in Table 1. The stent and travoprost groups were similar in age (64.5 ± 11.1 vs.

Efficacy
Subjects experienced notable reduction of IOP following implantation of two iStent trabecular micro-bypass devices or administration of topical travoprost (Fig. 1) (Fig. 2).
Proportional analyses showed that 94%, 90%, and 91% of stent-treated eyes had IOP B18 mmHg without the need for postoperative medication at 1, 2 and 3 years, respectively, while 89%, 87% and 79% of eyes in the travoprost group achieved IOP B18 mmHg at these timepoints without requiring additional medical therapy. The majority (62%) of stent eyes maintained IOP B15 mmHg through 3 years, while a decreasing percentage (21%) of travoprost eyes maintained IOP B15 mmHg over the 3-year follow-up period (Fig. 3).

Safety
Safety was favorable in both groups. Two complications were reported during stent insertion in the surgery group, both of which were attributed to subject movement during surgery: one of these subjects had hyphema which resolved by day 1 and one subject had a small iridodialysis which resulted in no postoperative ocular sequelae. No other operative complications were reported.
In general, BCVA was stable over time for both groups (Fig. 4). Progression of cataract over   As shown in Table 3  iStent implantation as initial therapy may offer several benefits over topical medications, whose utility may be limited by issues such as side effects and patient compliance [1][2][3][4][5][6][7][27][28][29][30]. Furthermore, the cost of both brand-name and generic medications places a considerable financial burden on the newly diagnosed glaucoma patient [31], thus making a longstanding surgical solution even more appealing. This may be particularly important in glaucoma patients, the majority of whom have at least one additional chronic condition requiring medication [32].
In this study, the IOP decrease in the travoprost group was greater than the 25-35% IOP reductions reported in prior work [33][34][35].
This may be due to medication-naïve eyes, high compliance due to study participation, and/or regression to the mean. The greater IOP  [35,36].
There are several limitations to this study. Given the surgical vs. medical therapy study design, neither subjects nor clinicians were masked to treatment. Diurnal measurements of IOP were not performed. A pre-treatment grading of the crystalline lens was not used, and guidelines for when to perform cataract surgery were not standardized. Future work could incorporate such measures to address these study limitations, and also could encompass postoperative follow-up past 3 years. In addition, future analyses may examine the long-term cost effectiveness of

CONCLUSIONS
In summary, data from this prospective, randomized, controlled study provide a direct comparison of two trabecular micro-bypass stents vs. prostaglandin medical therapy in newly diagnosed POAG. In both groups, patients showed substantial IOP reduction and favorable safety through 3 years. These findings support the viability of multiple iStent implantations as an initial treatment option comparable to topical prostaglandin in newly diagnosed POAG.

ACKNOWLEDGMENTS
The sponsor, Glaukos Corporation, Laguna Hills, CA, provided study devices, sponsorship for performing this study, publication charges, data collection, data management, data analysis, and editorial assistance in the