Comparison of the results of Ex-PRESS® surgery for primary open-angle glaucoma between high and low preoperative intraocular pressure

To compare surgical outcomes of Ex-PRESS® (EXP) surgery for primary open-angle glaucoma (POAG) between low preoperative intraocular pressure (IOP) and high preoperative IOP. This was a retrospective non-randomized study. Seventy-nine POAG patients who underwent EXP surgery and were followed for > 3 years were included. Patients with a preoperative IOP of ≦ 16 mmHg and > 16 mmHg with tolerant glaucoma medications were defined as the low IOP group and the high IOP group, respectively. We compared the surgical outcomes, postoperative IOP and number of glaucoma medications. Success was defined as a postoperative IOP of ≦ 15 mmHg and a reduction of > 20% from the preoperative IOP to the postoperative IOP. EXP surgeries significantly decreased IOPs from 13.2 ± 2.0 to 9.1 ± 2.9 mmHg in the low IOP group (p < 0.001), and from 22.5 ± 4.8 to 12.5 ± 4.0 mmHg in the high IOP group (p < 0.001). The mean postoperative IOP was significantly low in the low IOP group at 3 years (p = 0.0008). Success rates compared using the Kaplan–Meier survival curve were not significantly different (p = 0.449). EXP surgery was useful for POAG patients with a low preoperative IOP.


Introduction
Minimally invasive glaucoma surgery (MIGS) devices are novel devices that have been introduced to target potential new sites on the outflow pathway for lowering intraocular pressure (IOP) [1]. Many MIGS procedures result in mmHg levels in the midteen range [2], which might be the lowest postoperative IOP level that can reasonably be expected. Glaucoma implant surgeries with a plate such as Baerveldt glaucoma implant or Ahemed glaucoma valve are also gaining acceptance around the world. However, these implant glaucoma surgeries with plate are difficult to perform in patients with a low preoperative IOP due to the risk of hypotony [3]. For these reasons, the surgical method is limited to glaucoma patients with a low preoperative IOP. For patients with a preoperative IOP of 16 mmHg, the target IOP becomes 12.8 mmHg if the reduction rate from the preoperative IOP is above 20%. Patients with progressive visual field impairment despite low IOP are quite common in Japan [4].
Trabeculectomy (Trab) is the most common glaucoma surgery for low IOP patients. In Trab, a bleb is formed in the sub-tenon space to receive the outflow of aqueous humor, thereby lowering IOP. It has been reported that Trab is effective for low IOP glaucoma, and that it improves deterioration of the visual field [5,6]. However, Trab requires excision of the trabecular meshwork and peripheral iris, and is therefore highly invasive compared to MIGS. Trab also has a higher risk of bleeding, vitreous prolapse and choroidal hemorrhage. Another opinion is surgery using Ex-PRESS (EXP; Alcon Laboratories, Fort Worth, TX, USA), a stainless-steel filtration device designed to shunt the aqueous humor from the anterior chamber to the sub-tenon space. EXP has the merit of a low risk of hypotonic maculopathy, choroidal detachment, and shallow anterior chamber because the amount of aqueous humor exiting the bleb from the anterior chamber is limited [7]. EXP surgery is less invasive and has a lower risk of complications [8,9]. Some studies have reported that visual acuity recovered more quickly in EXP than in Trab [8,10].
Many reports have found that EXP surgery is as useful as Trab for patients with high preoperative IOP [11][12][13][14]. However, there have been few reports on the usefulness of EXP surgery for patients with low preoperative IOP [15]. We compared the surgical results of EXP surgery between patients with low preoperative IOP (≦ 16 mmHg) and those with high preoperative IOP group (> 16 mmHg).

Patients
This was a retrospective, non-randomized observational study. We analyzed the cases of 79 consecutive primary open-angle glaucoma (POAG) patients who underwent EXP for the first time at Toyama University Hospital and were followed for > 3 years. We used the unilateral data of the eye that was operated on earlier in patients who underwent binocular surgery. We defined the preoperative IOP as the mean IOP of two visits just before surgery while under preoperative treatment. We divided our subjects into two groups: the low preoperative IOP group (Low IOP Group; n = 26), with a mean preoperative IOP of ≦ 16 mmHg, and the high preoperative IOP group (High IOP Group; n = 53), with a mean preoperative IOP of > 16 mmHg. This study is a retrospective study and there is no clear reason why we divided at 16 mmHg. We compared surgical outcomes between the two groups.
All subjects were recruited during the period from April 2013 to May 2018. All patients underwent a comprehensive ophthalmic examination including refraction, Goldmann gonioscopy, Goldmann applanation tonometry (GAT), a fundus examination, automated perimetry (Humphrey Field Analyzer; Carl Zeiss Meditec, Dublin, CA, USA), measurement with optical coherent tomography (OCT; RS-3000; Nidek, Aichi, Japan) and measurement of the central corneal thickness (CCT) with AS-OCT (CASIA SS-1000; Tomey, Nagoya, Japan). The IOP was measured using GAT. We did not fix the time for measuring IOP.
Two glaucoma specialists (N.T and A.H) diagnosed the cases of POAG. The exclusion criteria were: glaucoma other than POAG, history of ocular trauma, retinal disease and ocular inflammatory disease. We included patients who had undergone prior laser trabeculoplasty, cataract surgery or trabeculotomy. We also included patients who underwent cataract surgery simultaneously.
The patients had already used glaucoma medications as much as possible but required further treatment to lower their IOP due to the progression of their visual field disorder. The surgical indication was determined by a single glaucoma specialist (N.T). The research protocol was approved by the Institutional Review Board of the University of Toyama, and the procedures used conformed to the tenets of the Declaration of Helsinki. After the nature and possible consequences of the study were explained to the patients, each participant in the study provided his or her written informed consent.

Surgical technique
All patients were operated on by the same surgeon (N.T.), who has abundant experience in EXP surgery. Retrobulbar anesthesia was administered. A standard fornix-based conjunctival incision was made to gain exposure to the scleral bed adjacent to the limbus. A single 3.5 × 3.5 mm square scleral flap was created. Mitomycin C (MMC) solution (0.04 mg/ml) was applied below the conjunctiva and below the scleral flap for 4 min. At this point, the eye was a completely enclosed space, and thus the MMC solution could not flow into the anterior chamber. The treated area was then irrigated with approximately 100 ml of balanced salt solution. If the patient needed simultaneous cataract surgery, the cataract surgery was performed at this time. Phacoemulsification was performed with a WhiteStar Signature system (Abbott Medical Optics, Santa Ana, CA, USA), and an intraocular lens (IOL) was implanted from corneal incision. Regarding the surgical indications for cataract surgery, since this was a retrospective study, no clear criteria, such as Veterans Affairs (VA) rating, Emery-Little classification or age, were established and cataract surgery was performed according to the judgment of the surgeon.
The scleral flap was lifted, and a 25-gauge needle was horizontally inserted into the anterior chamber at the surgical limbus to create a path for the Ex-PRESS (model P50); the needle was inserted into the anterior chamber from the sclera-cornea transition zone parallel with the iris. The Ex-PRESS shunt was then inserted into the anterior chamber. The scleral flap was sutured using 10-0 nylon while the tension on the sutures was adjusted to maintain the anterior chamber depth with a slow flow of aqueous humor around the margins of the scleral flap. Most cases were sutured with 2 stitches. The conjunctiva was meticulously closed with 10-0 nylon sutures. We confirmed that there was no leakage from the blebs.

Postoperative treatment
The postoperative treatment protocol was the same in both groups and consisted of topical steroids, antibiotics, and non-steroidal anti-inflammatory drugs (NSAIDs). Antibiotics were applied for 4-6 weeks. The steroids and NSAIDs were reduced over a 12-week period after intervention. After surgery, glaucoma medications were stopped in all cases. Glaucoma medications were added at the discretion of the physician. With regard to the number of glaucoma medications, we counted a compounding agent, as two medications. We performed laser suture lysis and needling when the surgeon determined that these treatments were necessary.

Definition of success
Success was defined as a reduction of ≧ 20% from preoperative IOP to postoperative IOP and a postoperative IOP of ≦15 mmHg. In the Low IOP Group, if the postoperative IOP showed a decrease of 20% or more, the final value would inevitably be less than 15 mmHg. We defined failure as meeting one of the following conditions: (1) postoperative IOP reduced by < 20% from the preoperative IOP on two consecutive visits after the first postoperative month; (2) postoperative IOP of > 15 mmHg or IOP of < 5 mmHg on two consecutive visits after the first postoperative month; (3) additional glaucoma surgery required; (4) phthisis or loss of light perception. We included both cases with additional glaucoma medications and those with needling as successful if the IOP was reduced ≦ 15 mmHg and reduction of ratio ≧ 20%.
We might use the World Glaucoma Association recommended definition of "IOP≦12, 15, 18 or 21 mmHg". In Low IOP group, the mean of preoperative IOP was 13.2 mmHg, cases with preoperative IOP below 12 mmHg were included. Considering target IOP were different, it is difficult to say whether it is better to use the definition of below 12 mmHg. We have also compared, as a point of reference, when success is defined IOP ≦ 12 mmHg.

Statistical analysis
A Wilcoxon signed-rank test and Student's t-test were used. A log-rank test was used to compare the results of a Kaplan-Meier survival analysis. All statistical analyses were performed with JMP Pro 14 software (SAS, Cary, NC, USA). Significance was defined as p-values of < 0.05.

Ophthalmic data
We analyzed a total of 79 patients, divided into 2 groups: the Low IOP Group (n = 26) and the High IOP Group (n = 53). We experienced no intraoperative complications such as choroidal hemorrhage. Table 1 summarizes and compares the characteristics of the two groups. We used the value of C/D ratio measured with OCT. There were 6 patients in Low IOP group, and 11 patients in High IOP group who had underwent trabeculotomy previously. In Low IOP group, 2 patients had undergone trabeculotomy with the metal probe, and 4 patients with Trabecutome. In High IOP group, 11 of 3 patients had undergone trabeculotomy with the metal probe, and 8 patients with Trabecutome. No ophthalmic parameters other than preoperative IOP showed any significant difference between the two groups.

Postoperative IOP
Postoperative IOP values are summarized in Table 2. We excluded the IOP data of patients who underwent additional glaucoma surgery after EXP surgery. The means of postoperative IOPs at 2, 3 and 4 years were significantly lower in the Low IOP Group than in the High IOP Group. The means of the numbers of postoperative medications are summarized in Table 3.
The mean numbers of glaucoma medications were not significantly different between the two groups at any point in time.

Success rate
The results of our Kaplan-Meier analysis are shown in Fig. 1 We also compared Kaplan-Meier curves when postoperative IOP ≦ 12 mmHg were defined as successful. The Result were significantly better in the Low IOP group, as shown in Fig. 2 (p = 0.0012; log-rank test).

Complications
The postoperative complications are summarized in Table 4. There was no significant difference in complications between High and Low IOP group.

Discussion
EXP surgery could significantly reduce IOP even in cases of low preoperative IOP. It is difficult to compare surgical outcomes between patients with low and high preoperative IOP values. When the cut-off value for success is lowered, the Low IOP Group tends to show better surgical results, and when the IOP reduction rate for success is set higher, the High IOP Group tends to show better surgical results. There are many definitions of success in glaucoma surgery [16]. The definition, therefore, might affect the interpretation of surgical outcomes.
There have been few reports on the usefulness of EXP surgery for low IOP glaucoma. Aihara et al. report that EXP surgery could lower IOP from 14.8 to 10.0 mmHg in one year, achieving a 31.1% reduction in IOP [15]. A collaborative normal-tension glaucoma (NTG) study reports that a 30% reduction is recommended for NTG [17]. Oie et al. found a correlation between the IOP reduction ratio and the speed of visual field progression [18]. Nevertheless, in the present study, in patients with a very low preoperative IOP (the mean was 13.2 mmHg), the IOP reduction ratio was 31.0% 3 years after surgery, while in the high IOP group, the reduction rate was 44.4%.
In the present study, the success rate at 3 years was 65.4% in the Low IOP Group and 77.4% in the High IOP Group. Previous studies have reported successful surgical outcomes of 53.0-73.1% at 3 years after EXP surgery [14,[19][20][21][22][23]. Although definitions of success vary, our surgical outcomes are comparable to those of previous studies.
There was no significant difference in postoperative complications between High and Low IOP groups. There were no additional glaucoma  surgeries in Low IOP group. This is a retrospective study and it is possible that lower IOP might hesitate additional glaucoma surgery. There are some limitations to this study. This is a retrospective and single-facility study. There is a risk that the results would vary greatly depending on the preoperative IOP value. We did not consider IOP fluctuations. Our study included cases of simultaneous cataract surgery. It has been reported that simultaneous cataract surgery yields poorer surgical results [20]. We included a case who had previously undergone trabeculotomy. Mariotti et al. report that identifiable risk factors for failure of EXP surgery include diabetes, non-Caucasian race, and previous glaucoma surgery [24]. We did not test for diabetes. We did not define the indications for glaucoma surgery, cataract surgery or additional glaucoma medications. There is no clear definition for surgery, especially for low preoperative IOPs. We have not been able to evaluate comparative surgical outcomes with visual field test data. And finally, the number of patients was small, and the follow-up period was short. We defined success as either enforcing needling or adding glaucoma medications.
Even in an era when many glaucoma devices have been developed, surgical methods for patients with low preoperative IOP might be limited. EXP surgery is effective for low preoperative IOP patients.
Author contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Mitsuya Otsuka, Noriko Katayama and Naoki Tojo. The first draft of the manuscript was written by Noriko Katayama and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Declarations
Competing interests The authors declare no competing interests.

Conflict of interest
The authors have no relevant financial or non-financial interests to disclose.

Employment
No employment by any organization that may gain or lose financially through publication of this manuscript.
Ethical approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Toyama University.

Consent to participate Informed consent was obtained from all individual participants included in the study.
Content and publish Our manuscript do not contain any individual person's data in any form.