Risk factors for Ex-Press® surgery failure

To investigate the risk factors for Ex-Press® (EXP) surgery failure. This was a retrospective non-randomized study of 98 patients who had undergone EXP and were followed up ≥ 5 years. We investigated the following nine risk factors: age, gender, hypertension, diabetes mellitus (DM), previous glaucoma surgery, type of glaucoma (primary open-angle glaucoma vs. pseudo-exfoliation glaucoma), surgical methods (EXP alone vs. EXP + cataract surgery simultaneously), central corneal thickness (CCT), and preoperative intraocular pressure (IOP). We defined a successful surgery as a postoperative reduction in the IOP ≥ 20% from the preoperative IOP and ≤ 18 mmHg. We determined the risk factors using multivariate cox regression models. Performing EXP significantly decreased the IOP (preoperative: 25.2 ± 8.7, at 5 years: 11.1 ± 4.1). The success ratio of EXP was 67.4% at 5 years. We found no significant risk factors for EXP surgery failure. The p values of the factors were age (p = 0.936), gender (p = 0.0587), hypertension (p = 0.409), DM (p = 0.967), previous glaucoma surgery (p = 0.940), type of glaucoma (p = 0.435) surgical methods (p = 0.521), CCT (p = 0.091), and preoperative IOP (p = 0.082). No preoperative factors that could be used to predict the failure of EXP surgery were identified. EXP can be safely performed for primary open-angle glaucoma and pseudo-exfoliation glaucoma.


Introduction
Filtration surgery using the Ex-Press ® shunt (EXP) (Alcon Laboratories, Fort Worth, TX, USA) is prevalent worldwide and was approved in Japan in December 2011. The EXP surgery is performed to reduce the intraocular pressure (IOP) of patients with glaucoma. The Ex-Press ® is a stainless steel filtration device designed to shunt the aqueous humor from the anterior chamber to the subconjunctival space. EXP surgery is similar to a trabeculectomy (Trab), but EXP surgery does not require the removal of trabecular meshwork (TM) or a peripheral iris resection. In light of these advantages, EXP surgery has less risk of complications such as hyphema and suprachoroidal hemorrhage compared to a Trab [1,2]. EXP surgery is also a less invasive surgical method than a Trab [3]. Several research groups have demonstrated that the surgical outcomes of EXP surgery are comparable to those of Trab [2][3][4][5][6][7].

Patients
This was a retrospective single-facility study. The patients had already used maximally tolerated glaucoma medications but required further treatment to lower their IOP due to the progression of their visualfield disorder. The surgical indications were judged by one glaucoma specialist (N.T.). We performed EXP surgeries for 182 eyes during the period from April 2013 to May 2017 at our hospital. Twenty-five patients underwent surgery for both eyes; we used the unilateral data of the eye that was operated earlier. We excluded the patients who were followed for < 5 years. We analyzed the cases of a final total of 98 patients who underwent EXP for the first time at Toyama University Hospital.
We included both patients who underwent EXP surgery alone and patients who underwent simultaneous cataract surgery. We included the patients who had undergone a trabeculotomy, including minimum invasive glaucoma surgery (MIGS). We included only the cases of patients with primary open-angle glaucoma (POAG) or pseudo-exfoliation glaucoma (PEXG). Two glaucoma specialists (N.T. and A.H.) diagnosed the type of glaucoma. We also excluded patients who had undergone a Trab or tube shunt surgery.
All of the patients had undergone 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), measurement with optical coherent tomography (OCT) (RS-3000, Nidek; Aichi, Japan), the measurement of central corneal endothelial cell density (ECD) with a specular microscope (EM-4000, Tomey; Nagoya, Japan), and the measurement of the central corneal thickness (CCT) with anterior segment (AS)-OCT (CASIA SS-1000; Tomey, Nagoya, Japan). The IOP was measured by GAT. We did not fix the time point for the measurement of IOP.
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, written informed consent was obtained from all individual participants included in the study.

Surgical techniques
All patients were operated on by one surgeon (N.T.) who has abundant experience performing EXP. The EXP surgical technique in all cases was as follows. 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 2 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 approx. 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 (Johnson & Johnson Vision, Santa Ana, CA), and an intraocular lens (IOL) was implanted from the clear temporal cornea. Regarding the surgical indications for cataract surgery, since the present study was a retrospective analysis, no clear criteria were established for visual acuity, the Emery grade, or patient age; cataract surgery was performed based on the surgeon's judgment.
The scleral flap was lifted, and a 25-ga. needle was horizontally inserted into the anterior chamber at the surgical limbus to create a path for the Ex-Press ® device (model P50, Alcon Laboratories, Fort Worth, TX); the 25-ga. needle was inserted into the anterior chamber from the sclera-cornea transition zone parallel with the iris. The EXP 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 of the cases were sutured with two stitches. The conjunctiva was meticulously closed with 10-0 nylon sutures. The absence of leakage from the blebs was confirmed in each case.

Postoperative medication
The postoperative treatments consisted of topical steroids, antibiotics, and non-steroidal anti-inflammatory drugs (NSAIDs). The antibiotics were applied for 4-6 weeks after the surgery. The steroid and NSAIDs were reduced over a 12-week period after the interventions. After the surgeries, the patients' glaucoma medications were stopped in all cases. Glaucoma medications were added at the discretion of the patients' physicians. We counted a compounded agent as two medications.

Evaluation of the factors
We defined a successful surgery as a postoperative IOP value ≤ 18 mmHg and postoperative IOP reduction ratio ≥ 20% from the preoperative IOP. We defined failure as meeting one of the following conditions: (1) postoperative IOP > 18 mmHg on two consecutive visits after the first postoperative month; (2) postoperative IOP reduced < 20% from the preoperative IOP on two consecutive visits after the first postoperative month; (3) postoperative IOP < 5 mmHg on two consecutive visits after the first postoperative month; (4) requiring additional glaucoma surgery; or (5) phthisis or loss of light perception. The definition of success did not include the use or non-use of glaucoma medications.
We evaluated the following nine factors to determine whether they could be used to predict the failure of EXP surgery: age, gender, hypertension, DM, previous glaucoma surgery, type of glaucoma (POAG vs. PEXG), surgical methods (EXP alone vs. EXP + cataract surgery simultaneously), CCT, and preoperative IOP. The presence or absence of hypertension and DM was based on the patients' self-reports. The patients' blood pressure was not measured by a sphygmomanometer, and blood samples were not collected regarding DM.

Statistical analyses
The Wilcoxon signed-rank test was used for the comparison of pre-and postoperative IOP values. A log rank test was used to compare the results of a Kaplan-Meier analysis. We performed a Cox regression analysis of the factors for the prediction of EXP surgery failure. All of the statistical analyses were performed with JMP Pro 16 software (SAS, Cary, NC).

Postoperative IOP and the success rate of the EXP surgeries
We analyzed the cases of 98 Japanese patients with glaucoma. Their characteristics are summarized in Table 1. In patients who had additional glaucoma surgery, we only used data from before the additional glaucoma surgery. The mean postoperative IOP and the number of drops of glaucoma medications are summarized in Table 2. The mean postoperative IOP and the mean number of drops of glaucoma medications were both significantly decreased at all of the measurement time points (p < 0.001).

Risk factors for EXP surgery failure
The results of the Cox regression analysis are provided in Table 3. There were no factors that showed significance for EXP surgery failure; all of the factors' p values were > 0.05.

Discussion
Our present findings confirm that the Ex-Press surgery can significantly reduce the IOP of individuals with glaucoma. The success rate at 5 years was 67.4%, which is almost the same rate as in a previous report [15]. The present analyses revealed that none of the nine factors examined could be used to predict EXP surgery failure.
There are several reports that younger age is a risk factor for Trab failure [8,10], whereas Mariotti et al. reported that the success rate of EXP surgery was not affected by the patients' age [15]. The reason why the surgical outcomes were not significantly different depending on the patients' age is unknown. EXP is minimally invasive surgery, so it might be less inflammatory even for younger patients.
Hashimoto et al. reported that male sex was a risk factor for surgical failure [16]. Regarding the role of gender, several investigations indicated that sex hormones such as estrogen and progestin might play a  role in protection of the optic nerve [17,18]. Our present findings suggest that there was no significant difference between male and female. Hypertension is a risk factor for glaucoma [19]. Hypertension affects the ocular blood flow. The presence of hypertension in our present patient series did not affect surgical outcomes.
Diabetes mellitus is reported to be a risk factor for failure of both Trab and EXP surgeries [10,[12][13][14][15]. Diabetic patients have an altered postoperative healing process because of their high aqueous concentrations of transforming growth factors (TGFs) [20]. The TGFs have a major role in scar tissue formation in the eye, and excessive scar formation after glaucoma surgery can lead to surgery failure.
Mariotti et al. reported that previous failed glaucoma surgery is a risk factor for failure of EXP surgery [15]. In our present investigation, preoperative glaucoma surgery was limited to the Trab cases. Trabeculotomy is one of the MIGSs. Since performing a trabeculotomy can conserve the conjunctiva, trabeculotomy might not affect surgical outcomes in this study.
PEXG was reported as a risk factor for Trab failure [9,21]. Djordjević-Jocić et al. reported that inflammatory cytokines are involved in PEXG, and these cytokines might contribute to a reduction in the volume of blebs [22]. EXP is minimally invasive surgery and thus results in low levels of inflammatory cytokines, and it might therefore have less of an effect on the rate of surgical failure. There was a report that surgical outcomes of Trab were not different between POAG and PEXG, and Trab was effective for POAG and PEXG [23]. In our study, surgical outcomes of EXP were not significantly different between POAG and PEXG. EXP surgery was effective for both POAG and PEXG.
Combining a Trab and cataract surgery was reported to adversely affect the cumulative probability of success [8,24]. The cause was attributed to the cytokine MCP-1 (monocyte chemotactic protein-1) that increased after cataract surgery [25]. There are also some reports that there was no difference in surgical outcomes between Trab alone and Trab with simultaneous cataract surgery [26][27][28]. Regarding EXP surgery, there are some reports that surgical outcomes were not significantly different between EXP alone and EXP with simultaneous cataract surgery. Our results agree with those of previous reports [15,29]. EXP is a minimally invasive surgery that produces low amounts of inflammatory cytokines, and it might therefore be less susceptible to cataract surgery. In our study, surgical outcomes of EXP were not significantly different between EXP alone and EXP with simultaneous cataract surgery. EXP surgery might be effective even for simultaneous cataract surgery.
The thickness of CCT was not significantly risk factor. Corneal hysteresis might affect the surgical outcomes; however, we did not measure hysteresis of cornea.
Arimura et al. reported that low preoperative IOP was a risk factor for Trab failure in their patient series [8]. Regarding the definition of a successful surgical outcome of Trab surgery, many reports have defined a > 20% reduction compared to the preoperative IOP as success. Generally, it is difficult to achieve a > 20% reduction in the IOP when the preoperative IOP is low. In our present patients, the mean postoperative IOP was 11.1 ± 4.0 mmHg, confirming that EXP surgery can adequately reduce IOP.
There are some study limitations to address. This was a retrospective analysis. We did not consider IOP fluctuations. We did not define the indications for glaucoma surgery, cataract surgery, and additional glaucoma medications. The definitions of hypertension and DM were not clear. The number of patients was relatively small (n = 98).
Postoperative inflammatory cytokines have been reported to play an important role in scar tissue formation, and it is known that scar tissue formation can affect the outcomes of filtration surgeries. Since the EXP surgery involves less inflammation compared to a Trab surgery, the factors of EXP failure might differ from those of Trab. Our present findings indicate that is difficult to predict preoperatively whether EXP surgery will fail.