DOI: https://doi.org/10.21203/rs.3.rs-1490962/v1
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 mmHg to 9.1 ± 2.9 mmHg in the low IOP group (p < 0.001), and from 22.5 ± 4.8 mmHg 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.
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 mid-teen range [2], which might be the lowest postoperative IOP level that can reasonably be expected. Long tube surgery is also gaining acceptance around the world. However, long tube shunt surgery is 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 [11–14]. 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).
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. 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 maximally tolerated glaucoma medications 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.
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-mm2 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) from a clear temporal cornea was implanted. 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.
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. We counted a compounding agent as two medications. We performed laser suture lysis and needling when the surgeon determined that these treatments were necessary.
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. Our definition of success does not include the use or non-use of glaucoma medications or needling treatment.
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.
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 choloidal hemorrhage. Table 1 summarizes and compares the characteristics of the two groups. No ophthalmic parameters other than preoperative IOP showed any significant difference between the two groups.
| Low IOP Group 26 eyes | High IOP Group 53 eyes | p value | |
|---|---|---|---|
| Gender (male) | 16/26 (61.5%) | 25/53 (47.2%) | 0.230 |
| Age: yrs | 67.6 ± 12.6 | 68.5 ± 9.4 | 0.730 |
| CCT: mm | 519 ± 36 | 527 ± 36 | 0.383 |
| History of trabeculotomy | 6/26 (23.1%) | 11/53 (20.8%) | 0.813 |
| Cataract simultaneously | 9/26 (34.6%) | 21/53 (39.6%) | 0.667 |
| Pre IOP: mmHg | 13.2 ± 2.0 | 22.5 ± 4.8 | < 0.0001 |
| Pre Medications | 3.8 ± 0.6 | 4.1 ± 0.8 | 0.260 |
| IOP; intraocular pressure | |||
| CCT; Central corneal thickness | |||
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.
| Postoperative IOP | Low IOP Group (eyes) | High IOP Group (eyes) | p value |
|---|---|---|---|
| pre IOP | 13.2 ± 2.0 (26) | 22.5 ± 4.8 (53) | < 0.0001 |
| 1 year | 9.3 ± 2.7 (26) | 11.4 ± 5.2 (49) | 0.0705 |
| 2 years | 9.8 ± 2.0 (25) | 11.9 ± 3.8 (47) | 0.0177 |
| 3 years | 9.1 ± 2.9 (23) | 12.5 ± 4.0 (43) | 0.0008 |
| 4 years | 9.4 ± 3.6 (18) | 11.9 ± 4.6 (33) | 0.0461 |
| 5 years | 9.8 ± 3.8 (13) | 11.4 ± 3.9 (24) | 0.2183 |
| Postoperative medications | Low IOP Group (eyes) | High IOP Group (eyes) | p value |
|---|---|---|---|
| Pre medications | 3.8 ± 0.6 (26) | 4.1 ± 0.8 (53) | 0.260 |
| 1 year | 1.3 ± 1.6 (26) | 1.2 ± 1.7 (49) | 0.801 |
| 2 years | 1.7 ± 1.9 (25) | 1.8 ± 1.7 (47) | 0.730 |
| 3 years | 2.0 ± 1.6 (23) | 2.6 ± 1.5 (43) | 0.254 |
| 4 years | 2.1 ± 1.8 (18) | 2.7 ± 1.5 (33) | 0.168 |
| 5 years | 2.6 ± 1.7 (13) | 2.3 ± 1.7 (24) | 0.533 |
The results of our Kaplan-Meier analysis are shown in Fig. 1. The results of surgical outcomes were not significantly different (p = 0.449; log-rank test). The success rates at 1, 2, 3, 4 and 5 years were 84.6%, 76.9%, 65.4%, 65.4% and 57.2%, respectively, in the Low IOP Group, and 88.9%, 83.2%, 77.4%, 74.5% and 63.5% in the High IOP Group.
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, 19–23]. Although definitions of success vary, our surgical outcomes are comparable to those of previous studies.
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 surger include diabetes, non-Caucasian race, and previous glaucoma surgery [24]. We did not define the indications for glaucoma surgery, cataract surgery or additional glaucoma medications. And finally, the number of patients was small, and the follow-up period was short.
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.
Funding statement: No funding was received for this research.
Financial interests and conflict of Interest statement: The authors have no relevant financial or non-financial interests to disclose.
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.
Ethical approval: All procedures were performed in accord with the ethical standards of the Institutional Review Board of the University of Toyama (Toyama, Japan) and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Formal patient consent was not required for the present retrospective analysis.
Consent to participate and publish: Informed consent was obtained from all individual participants included in the study.