Microinvasive glaucoma surgery (MIGS) is a growing trend, and XEN gel implant is one of the most effective types of MIGS. This study aimed to examine factors associated with the surgical success of XEN gel implants.
Methods
This retrospective cohort study enrolled patients with glaucoma receiving XEN implantation alone or combined with phacoemulsification (PHACOXEN) with a follow-up period of more than 6 months at Hualien Tzu Chi Hospital, Taiwan. If intraocular pressure (IOP) elevated above 20 mmHg during the follow-up, needling or open revision was performed. The primary outcome measures included IOP and the number of glaucoma medications.
Results
Male patients had lower postoperative IOP; male patients and higher preoperative IOP were associated with higher IOP change rates, and older patients had a higher chance of achieving IOP < 18 mmHg and being medication-free at months 12, 24, and 36. The Kaplan–Meier curve showed that the probability of free-of-rescue intervention over the follow-up period was not different between the XEN alone and the PHACOXEN group (P = 0.859). Both needling and open revision were effective rescue interventions, but open revision had a higher chance of achieving IOP ≤ 18 mmHg and being medication-free (P = 0.031) and required less medication afterward (P = 0.044). Older age (P = 0.013) and male patients (P = 0.022) had a lower IOP after rescue interventions. Compared with open revision, needling was associated with higher IOP (P = 0.048) and more required medications (P = 0.048).
Conclusions
XEN alone and PHACOXEN had comparable surgical outcomes, whereas open revision had a better IOP lowering effect than needling as a rescue intervention. Male and older patients had better surgical results in primary XEN implantations and rescue interventions.
Key Summary Points
Why carry out this study?
There is a growing trend toward microinvasive glaucoma surgery (MIGS). XEN gel implant is one of the most effective types of MIGS.
However, which factor might affect the efficacy of XEN is still not known. Our study tried to analyze the possible associated factors.
What was learned from the study?
Our study showed male and older patients had better surgical results in primary XEN implantations and rescue interventions, while preoperative intraocular pressure (IOP) level, preoperative number of medications, or type of glaucoma did not affect the outcome. XEN alone and PHACOXEN had comparable surgical results.
Open revision had a better IOP-lowering effect than needling as a rescue intervention.
Introduction
The prevalence of glaucoma is increasing worldwide. Some patients go blind either due to uncontrolled course or poor compliance from the adverse effects of medication. Traditional filtering surgeries, including trabeculectomy and glaucoma drainage devices, help lower the intraocular pressure (IOP) but might have a challenging postoperative course. Hence, there is a trend toward microinvasive glaucoma surgery (MIGS). XEN45 gel implant is one of the most effective MIGSs. The XEN45 implant reduces intraocular pressure (IOP) by shunting aqueous humor to the subconjunctival space. It is implanted via a small clear cornea wound alone or simultaneously with phacoemulsification cataract surgery. Compared with trabeculectomy, the small wound of the procedure and the 45 nm inside diameter of the XEN implant can reduce the risk of intraoperative and postoperative hypotony and accelerate postoperative visual recovery.
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The reported complete success rate of XEN in open-angle glaucoma ranges from 35.5% to 57.7% by different definitions of surgical success [1‐5]. The rate of medication-free patients after XEN implantation ranges from 33% to 65.5% [3, 6‐8]. If the filtering function is not good, then needling is usually suggested to release the surrounding fibrotic tissue, which might be necessary in 37.0–55.4% of eyes [1‐5]. Open revision is another option or the second step to needling [9, 10].
Herein, a 3-year outcome of XEN implantation in medically uncontrolled glaucoma was reported. The efficacy of XEN alone or simultaneously combined with phacoemulsification was compared. In addition, needling was compared with open revision in the rescue of the poor filtering function. Factors associated with the surgical success of XEN were also analyzed.
Methods
This retrospective study was approved by the Research Ethics Committee of Hualien Tzu Chi Hospital (REC. no.: IRB112-039-B) and performed in accordance with the Declaration of Helsinki. The need for informed consent was waived because of the retrospective nature of the study. The study enrolled patients receiving XEN gel stent (XEN®45, Allergan plc, Dublin, Ireland) implantation surgery with a follow-up period of more than 6 months at Hualien Tzu-Chi Hospital in Taiwan between 2018 and 2022. Patients with glaucoma agde > 20 years, uncontrolled IOP, and visual field progression under maximum tolerable medications received XEN gel stent implantation; while those with previous filtering surgery were excluded. Patients with open angles and without cataracts received XEN implantation (XEN alone). Those with significant cataracts or narrow or close angles underwent combined phacoemulsification and intraocular lens implantation with XEN gel stent implantation (PHACOXEN). All the surgeries were performed by two glaucoma specialists (Yuan-Chieh Lee and Hong-Zin Lin).
Surgical Procedures
XEN alone and PHACOXEN surgeries were performed under topical anesthesia. For XEN alone surgery, a point mark 3 mm away from the limbus for the planned exit site was made. Mitomycin-C (MMC; 0.2 mg/mL, 0.1 mL) was injected subconjunctivally around and posterior to the point mark. After 5 min, a 1.6 mm clear cornea incision, 150°–180° away from the point mark and 0.5 mm anterior to the limbus, was made. A 1% concentration of sodium hyaluronate (Provisc, Alcon) was injected into the anterior chamber. XEN was inserted through the posterior trabecular meshwork to the subconjunctival space about the point mark, and sodium hyaluronate was washed out with BSS using a Simcoe cannula. The wound was sealed via wound hydration or a 10–0 suture.
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For PHACOXEN surgery, MMC (0.2 mg/mL, 0.1 mL) was injected subconjunctivally around and posterior to the point mark. A 2.2 mm clear cornea incision was made. The soft-shell technique with chondroitin sulfate 4%–sodium hyaluronate 3% (Viscoat) and sodium hyaluronate 1% (Provisc) was used. After phacoemulsification and intraocular lens implantation, carbachol intraocular solution (Miostat) was injected to constrict the pupil. The XEN was inserted, and the viscoelastics were washed out. The wound was closed via hydration or suture.
Postoperative Management
Prednisolone acetate 1.0% and levofloxacin eye drops four times a day were prescribed postoperatively for 4 weeks. Afterward, betamethasone 0.1% eye drops were used once daily. Glaucoma medications were discontinued after the surgery but were re-added once the IOP elevated above 20 mmHg, either temporarily until “rescue interventions” (including needling or open revision) or for long term if patients refused further interventions.
Needling was performed under a slit-lamp biomicroscope at the clinic or under a surgical microscope in the operating room. After sweeping across the subconjunctival fibrotic tissue around the XEN gel stent with a 27- or 30-gauge needle, MMC (0.1 mg/mL, 0.1 mL) was injected around the XEN gel stent.
The open revision was performed in the operation room and referred to peritomy, blunt dissection, and incision or excision of the fibrotic Tenon’s tissue around the XEN gel stent. After completely freeing the XEN gel stent, MMC soaking (0.2 mg/mL, 2 min) with sponges and peritomy closure with 10–0 nylon were performed.
Outcomes and Statistic Analysis
The primary outcome measures included the IOP and the number of glaucoma medications at months 12, 24, and 36. Success was defined as final postoperative IOP ≤ 18 mmHg; a “complete success” where IOP ≤ 18 mmHg was achieved without the use of glaucoma medications or rescue interventions or a “qualified success” where IOP ≤ 18 mmHg was achieved with glaucoma medications but without rescue interventions. Other outcome estimates included the proportion of eyes achieving variant IOP levels (IOP ≤ 18, ≤ 15, and ≤ 12 mmHg), achieving medication-free (meds-free) outcome, requiring rescue interventions, and the number of needed IOP-lowering medications. In the comparison of the XEN alone and PHACOXEN, failure was defined as if a patient required rescue intervention(s) or loss of light perception during the follow-up period.
Data were expressed as frequencies, proportions, or means ± standard deviations depending on the characteristics of each covariate. A chi-squared test was used to evaluate the association between two categorical variables. Independent t-test was used to compare the means of continuous variables between the two groups. Linear regression and logistic regression were adopted to evaluate factors associated with continuous and binary outcomes at different follow-up times (12/24/36 months), respectively. The Kaplan–Meier curve was used to show the probability of achieving free-of-rescue interventions in the XEN alone and PHACOXEN group. Log-rank test was used to compare the survival distributions of the two groups. Generalized estimating equations (GEE) model was adopted to evaluate the associations between risk factors and outcomes after rescue interventions, such as IOP and the number of used eye drops during the follow-up period. P < 0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC) or Stata version 16.0 (Stata Corp., College Station, Texas, USA).
Results
Among the 100 charts reviewed, 15 charts were excluded due to insufficient follow-up periods, and 85 eyes were enrolled in the study. Demographic data of patients receiving XEN surgery are listed in Table 1. A total of 68, 47, and 25 eyes completed 12-, 24-, and 36-month follow-ups, respectively. The IOP decreased from 26.1 ± 10.1 mmHg at baseline to 11.9 ± 0.6 on day 1; 14.7 ± 0.7 at week 1; and 14.2 ± 0.6, 14.6 ± 0.6, 15.3 ± 0.7, 14.0 ± 0.5, 13.0 ± 0.6, and 13.6 ± 0.7 mmHg at month 1, 3, 6, 12, 24, and 36, respectively (P < 0.001 at each time point compared with the baseline). The number of glaucoma medications decreased from 3.5 ± 1.1 at baseline to 0.5 ± 0.1 at month 12, 0.7 ± 1.22 at month 24, and 0.8 ± 1.27 at month 36 (P < 0.001 at each time point compared with the baseline). The rate of rescue interventions was 53%, 55.3%, and 56% at months 12, 24, and 36, respectively. The mean IOP and the mean number of medications in the cohort are demonstrated in Fig. 1A.
Table 1
Demographic data
Total eyes (n)
85
Laterality (n)
Right
47 (55.3%)
Left
38 (44.7%)
Gender (n)
Female
27 (31.8%)
Male
58 (68.2%)
Age (years)
64.0 ± 16.1
Female
60.8 ± 13.1
Male
65.5 ± 17.2
Preoperative IOP (mmHg)
26.1 ± 10.1
Number of medications (class)
3.5 ± 1.1
Glaucoma type (n)
Open-angle glaucoma
46 (54.1%)
Angle-closure glaucoma
23 (27.1%)
Uveitic glaucoma
5 (5.9%)
Normal tension glaucoma
1 (1.2%)
Steroid-induced glaucoma
2 (2.4%)
Neovascular glaucoma
3 (3.5%)
Traumatic glaucoma
5 (5.9%)
Surgery type (n)
XEN alone
39 (45.9%)
PHACOXEN
46 (54.1%)
Follow-up period (month)
26.0 ± 13.5
Data are presented as n (%) or mean ± standard deviation
IOP intraocular pressure
Fig. 1
Mean intraocular pressure (IOP) and mean number of medications in the cohort. A Cohort of the total enrolled patients, including those with needlings and revisions. B Cohort of the XEN alone and PHACOXEN groups, respectively.
×
Univariate and multivariate regression analyses identified the association between surgical outcomes of XEN implantation and the following factors (Tables 2, 3, and 4). Table 2 shows factors associated with IOP at different time points. Male patients were associated with lower postoperative IOP at months 12, 24, and 36 (except at month 36 by adjusted analysis). Glaucoma other than primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) and higher preoperative baseline eye drop numbers had lower postoperative IOP levels at month 12, which were insignificant at months 24 and 36.
Table 2
Factors associated with the intraocular pressure (IOP) at different follow-up time (12/24/36 months) (n = 85)
Variable
12 months (n = 68)
24 months (n = 47)
36 months (n = 25)
Crude
Adjusted
Crude
Adjusted
Crude
Adjusted
β (95% CI)
P value
β (95% CI)
P value
β (95% CI)
P value
β (95% CI)
P value
β (95% CI)
P value
β (95% CI)
P value
Age
–0.03(–0.10, 0.04)
0.345
–0.03(–0.10, 0.03)
0.31
–0.05(–0.13, 0.03)
0.183
–0.04(–0.11, 0.04)
0.344
–0.01(–0.10, 0.08)
0.814
–0.01(–0.10, 0.09)
0.851
Gender
–
–
–
–
–
–
–
–
–
–
–
–
Male
–3.57(–5.53, –1.60)
0.001*
–3.08(–5.01, –1.16)
0.002*
–3.50(–5.85, –1.16)
0.004*
–3.66(–6.13, –1.19)
0.005*
–2.75(–5.23, –0.27)
0.031*
–2.68(–5.67, 0.32)
0.076
Female
References
NA
References
NA
References
NA
References
NA
References
NA
References
NA
Surgery
–
–
–
–
–
–
–
–
–
–
–
–
XEN
–0.70(–2.73, 1.33)
0.495
0.53(–1.48, 2.54)
0.6
–0.38(–2.73, 1.97)
0.746
0.42(–2.08, 2.93)
0.734
–2.55(–4.97, –0.14)
0.039*
–1.92(–4.66, 0.82)
0.158
PHACOXEN
References
NA
References
NA
References
NA
References
NA
References
NA
References
NA
Glaucoma type
–
–
–
–
–
–
–
–
–
–
–
–
POAG
References
NA
References
NA
References
NA
References
NA
References
NA
References
NA
PACG
–0.85(–3.20, 1.50)
0.473
–0.85(–3.31, 1.62)
0.49
–1.62(–4.42, 1.18)
0.251
–1.34(–4.27, 1.59)
0.361
0.89(–2.28, 4.05)
0.566
–0.62(–3.63, 2.39)
0.671
Others
–3.01(–5.59, –0.42)
0.023*
–2.51(–5.01, –0.01)
0.049*
–1.06(–4.16, 2.04)
0.494
–0.37(–3.47, 2.74)
0.812
1.89(–2.26, 6.04)
0.357
2.75(–0.95, 6.45)
0.135
Pre-IOP
–0.08(–0.17, 0.02)
0.125
–0.02(–0.12, 0.08)
0.7
–0.08(–0.18, 0.03)
0.135
–0.07(–0.17, 0.04)
0.224
0.05(–0.09, 0.20)
0.464
0.14(–0.01, 0.29)
0.060
Pre-meds
–1.12(–2.02, –0.21)
0.016*
–1.15(–2.05, –0.25)
0.013*
–0.29(–1.37, 0.78)
0.584
–0.21(–1.29, 0.88)
0.703
–0.49(–1.68, 0.70)
0.402
–0.83(–2.10, 0.43)
0.183
The bold values represent mean those P values reaching statistical significance of a P value < 0.05
Dependent variable: final IOP
POAG primary open angle glaucoma, PACG primary angle closure glaucoma, IOP intraocular pressure, CI confidence interval
*P value < 0.05 was considered statistically significant after test
Table 3
Factors associated with the change rate of intraocular pressure (IOP) at different follow-up time (12/24/36 months) (n = 85)
Variable
12 months (n = 68)
24 months (n = 47)
36 months (n = 25)
Crude
Adjusted
Crude
Adjusted
Crude
Adjusted
β (95% CI)
P value
β (95% CI)
P value
β (95% CI)
P value
β (95% CI)
P value
β (95% CI)
P value
β (95% CI)
P value
Age
–0.07 (–0.63, 0.50)
0.81
–0.19 (–0.54, 0.17)
0.3
–0.21 (–0.84, 0.42)
0.51
–0.15 (–0.54, 0.24)
0.4
0.19 (–0.64, 1.02)
0.64
–0.44 (–0.91, 0.04)
0.1
Gender
–
–
–
–
–
–
–
–
–
–
–
–
Male
–22.95 (–39.39, –6.51)
0.007*
–18.45 (–28.52, –8.37)
0.001*
–19.39 (–39.70, 0.91)
0.06
–20.68 (–33.15, –8.20)
0.002*
–25.29 (–47.86, –2.72)
0.030*
–17.87 (–32.96, –2.78)
0.023*
Female
References
NA
References
NA
References
NA
References
NA
References
NA
References
NA
Surgery
–
–
–
–
–
–
–
–
–
–
–
–
XEN
–15.04 (–31.05, 0.97)
0.07
1.49 (–9.05, 12.03)
0.8
–10.32 (–29.43, 8.79)
0.28
6.13 (–6.54, 18.80)
0.3
–21.75 (–44.10, 0.60)
0.06
–2.77 (–16.58, 11.04)
0.7
PHACOXEN
References
NA
References
NA
References
NA
References
NA
References
NA
References
NA
Glaucoma type
–
–
–
–
–
–
–
–
–
–
–
–
POAG
References
NA
References
NA
References
NA
References
NA
References
NA
References
NA
PACG
–19.13 (–37.34, –0.91)
0.040*
–4.67 (–17.56, 8.22)
0.5
–21.21 (–43.26, 0.84)
0.06
–7.50 (–22.30, 7.29)
0.3
2.86 (–26.63, 32.36)
0.84
–7.16 (–22.34, 8.03)
0.3
Others
–31.31 (–51.33, –11.28)
0.003*
–9.24 (–22.35, 3.88)
0.2
–22.06 (–46.49, 2.38)
0.08
–3.90 (–19.58, 11.78)
0.6
1.98 (–36.79, 40.74)
0.92
10.14 (–8.52, 28.79)
0.3
Pre-IOP
–2.45 (–2.96, –1.94)
< 0.001*
–2.18 (–2.71, –1.66)
< 0.001*
–2.25 (–2.77, –1.72)
< 0.001*
–2.20 (–2.74, –1.65)
< 0.001*
–2.51 (–3.27, –1.76)
< 0.001*
–2.29 (–3.03, –1.55)
< 0.001*
Pre-meds
–10.10 (–17.31, –2.90)
0.007*
–5.66 (–10.38, –0.94)
0.020*
–5.87 (–14.58, 2.83)
0.18
–2.04 (–7.51, 3.43)
0.5
–12.09 (–21.81, –2.38)
0.017*
–5.31 (–11.70, 1.08)
0.1
Dependent variable: final IOP
POAG primary open angle glaucoma, PACG primary angle closure glaucoma, IOP intraocular pressure, CI confidence interval
*p-value < 0.05 was considered statistically significant after test
Table 4
Factors associated with IOP ≤ 18 + meds-free with or without rescue intervention (n = 85)
12 months (n = 68)
P value
24 months (n = 47)
P value
36 months (n = 25)
P value
IOP ≤ 18 + meds-free
IOP ≤ 18 + meds-free
IOP ≤ 18 + meds-free
OR (95% CI)
OR (95% CI)
OR (95% CI)
Age
1.04 (1.001, 1.09)
0.044*
1.07 (1.01, 1.13)
0.016*
1.11 (1.01, 1.23)
0.040*
Gender
–
–
–
–
–
–
Male
2.05 (0.62, 6.83)
0.242
3.53 (0.79, 15.65)
0.098
1.51 (0.15, 15.67)
0.729
Female
References
NA
References
NA
References
NA
Surgery
–
–
–
–
–
–
XEN
0.29 (0.07, 1.22)
0.092
1.05 (0.20, 5.56)
0.950
2.81 (0.32, 24.80)
0.352
PHACOXEN
References
NA
References
NA
References
NA
Glaucoma type
–
–
–
–
–
–
POAG
References
NA
References
NA
References
NA
PACG
0.40 (0.08, 1.91)
0.248
0.90 (0.14, 5.92)
0.915
0.69 (0.05, 9.28)
0.781
Others
3.07 (0.46, 20.30)
0.245
2.38 (0.28, 19.89)
0.423
2.69 (0.10, 74.44)
0.559
Pre-IOP
1.03 (0.96, 1.10)
0.413
1.00 (0.93, 1.08)
0.906
1.00 (0.88, 1.15)
0.954
Pre-meds
1.47 (0.81, 2.66)
0.200
0.75 (0.38, 1.49)
0.411
0.82 (0.31, 2.22)
0.704
IOP intraocular pressure, POAG primary open angle glaucoma, PACG primary angle closure glaucoma, CI confidence interval, OR odds ratio
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Factors associated with the change rate of IOP at different follow-up times are shown in Table 3. Male patients and higher preoperative baseline IOP were associated with higher IOP change rates at months 12, 24, and 36. The preoperative baseline medications were also positively associated with the change rate of IOP at month 12.
Multivariate analysis (Table 4) showed that older patients had a higher chance of achieving IOP < 18 mmHg and being medication-free at months 12, 24, and 36.
XEN alone versus PHACOXEN
No significant difference in age, gender, or mean follow-up period was observed between the XEN alone and the PHACOXEN groups (Table 5). However, the distribution of glaucoma type was different between the XEN alone and PHACOXEN groups (P = 0.011). Baseline IOP and glaucoma medication numbers were higher in the XEN alone group (P = 0.035 and 0.009, respectively). The number of eyes that completed a 12-, 24-, and 36-month follow-up was 31, 25, and 14 in the XEN group and 35, 22, and 11 in the PHACOXEN group, respectively. The IOP course and glaucoma medication numbers over time in the XEN alone group and the PHACOXEN group are illustrated in Fig. 1B. A proportion of 21/39 (53.8%) in the XEN group and 22/46 (47.8%) in the PHACOXEN group required rescue interventions (including needling or revision) to restore the filtering function. The Kaplan–Meier curve showed that the probability of achieving free-of-rescue intervention over the follow-up period was not significantly different in both groups (P = 0.859, Fig. 2). Although the XEN alone group had lower IOP levels (P = 0.037) and a higher qualified success rate (P = 0.048) at month 36 in Table 5, the differences were not significant by multivariate analysis in Tables 2, 3, and 4.
Table 5
Outcomes of XEN and PHACOXEN in eyes that complete a 12-, 24-, or 36-month follow-up
XEN
PHACOXEN
P value
Total eyes (n)
39
46
Age (years)
61.0 ± 18.4
66.5 ± 13.5
0.113
Sex (n)
0.264
Male
29 (74.4%)
29 (63.0%)
Female
10 (25.6%)
17 (37.0%)
Glaucoma type (n)
0.011*
Primary open-angle glaucoma
23 (59.0%)
23 (50.0%)
Primary angle-closure glaucoma
5 (12.8%)
18 (39.1%)
Others
11(28.2%)
5 (10.9%)
Pre-IOP (mmHg)
28.4 ± 10.8
23.8 ± 9.0
0.035*
Pre-meds numbers (class)
3.8 ± 0.8
3.2 ± 1.2
0.009*
Follow-up months
24.7 ± 11.7
21.8 ± 12.2
0.269
Rescue interventions eye (n)
21 (53.8%)
22 (47.8%)
0.580
Complete follow-up months
12 months
24 months
36 months
12 months
24 months
36 months
12 months
24 months
36 months
Complete follow-up eyes (n)
31
25
14
35
22
11
IOP (mmHg)
13.3 ± 3.7
12.9 ± 3.9
12.4 ± 2.1
14.4 ± 4.4
13.3 ± 4.1
15.0 ± 3.7
0.270
0.734
0.037*
IOP ≤ 18
28
(84.8%)
23
(92.0%)
14
(100.0%)
27
(77.1%)
18
(81.8%)
10
(90.9%)
0.419
0.297
0.250
IOP ≤ 15
23
(69.7%)
19
(76.0%)
12
(85.7%)
21
(60.0%)
16
(72.7%)
4
(36.4%)
0.403
0.797
0.011*
IOP ≤ 12
12
(36.4%)
11
(44.0%)
8
(57.1%)
11
(31.4%)
10
(45.5%)
2
(18.2%)
0.667
0.920
0.048*
IOP change rate (%)
−44.7 ± 28.8
−43.1 ± 33.3
−40.6 ± 26.8
−29.7 ± 35.4
−32.8 ± 31.5
−18.9 ± 26.9
0.065
0.283
0.056
Meds numbers (class)
0.7 ± 1.2
0.7 ± 1.2
0.8 ± 1.2
0.4 ± 1.0
0.6 ± 1.2
0.9 ± 1.4
0.266
0.777
0.849
Eyes with meds numbers (n)
Meds-free 0
23
(69.7%)
17
(68.0%)
9
(64.0%)
28
(80.0%)
17
(77.3%)
7
(63.6%)
0.392
0.908
0.548
1
2
(6.1%)
3
(12.0%)
1
(7.1%)
2
(5.7%)
1
(4.6%)
1
(9.1%)
2
3
(9.1%)
1
(4.0%)
2
(14.3%)
3
(8.6%)
1
(4.6%)
0
(0.0%)
3
5
(15.2%)
3
(12.0%)
2
(14.3%)
1
(2.9%)
2
(9.1%)
3
(27.3%)
≥ 4
0
(0.0%)
1
(4.0%)
0
(0.0%)
1
(2.9%)
1
(4.6%)
0
(0.0%)
Complete success rate (%)
13
(39.4%)
10
(40.0%)
4
(28.6%)
11
(31.4%)
8
(36.4%)
2
(18.2%)
0.492
0.798
0.546
Qualified success rate (%)
17
(51.5%)
13
(52.0%)
8
(57.1%)
12
(34.3%)
8
(36.4%)
2
(18.2%)
0.151
0.282
0.048*
Meds-free + IOP ≤ 18 (n)
22
(66.7%)
16
(64.0%)
8
(57.1%)
26
(74.3%)
15
(68.2%)
5
(45.5%)
0.491
0.763
0.561
Data are presented as n (%) or mean ± standard deviation
Kaplan–Meier curves of the probability of keeping free-of-rescue intervention over the follow-up period for the XEN alone and PHACOXEN groups
×
Needling versus Open Revision
Among 85 eyes, 43 (50.6%) should undergo rescue interventions: 18 (21.2%) eyes received only needling(s), 19 (22.4%) eyes received only open revision(s), and 6 (7.1%) eyes had needling(s) and subsequent open revision. Among these six eyes [receiving needling(s) and subsequent open revision], no flow from the implant and failed stenting were observed in two eyes: one eye had second XEN implantation, and one eye underwent trabeculectomy on the spot. Among 19 eyes receiving pure open revision, one had transluminal XEN stenting by 10–0 prolene on noting no flow from the XEN implant.
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Those receiving needling or open revision only and followed up for more than 12 months were included for comparison. The pre-rescue intervention baseline data and outcomes at 12 months after interventions of the needling group and the open revision group were compared in Table 6. The open revision group had higher baseline medication numbers (P = 0.035), but had a higher proportion reaching IOP ≤ 18 with medication-free patients (P = 0.031) and required less medications at month 12 (P = 0.044). The course of IOP, the number of eyedrops used, and the cumulative times of rescue interventions over the 12-month follow-up are illustrated in Fig. 3.
Table 6
Comparisons of baseline data and outcomes at 12 months after rescue interventions between needling and open revision (N = 37)
Needling
Open revision
P value
Numbers of eyes (n)
18
19
Pre-rescue intervention IOP (mmHg)
23.7 ± 5.7
27.1 ± 7.4
0.128
Pre-rescue intervention meds numbers (class)
0.2 ± 0.4
0.95 ± 1.4
0.035*
Timing of first rescue intervention (months)
2.9 ± 2.9
6.5 ± 7.4
0.062
(Range: 0.5–10)
(Range: 1–25.6)
Numbers of rescue intervention (times)
1.8 ± 1.6
1.4 ± 0.9
0.352
Eyes with different times of rescue interventions (n)
0.239
1
12
16
2
3
0
3
1
2
≥ 4
2
1
IOP ≤ 18 with meds-free eyes (n)
8 (44.44%)
15 (78.95%)
0.031*
IOP ≤ 18 with/without meds eyes (n)
13 (72.2%)
15 (78.9%)
0.634
Post-rescue intervention IOP (mmHg)
14.1 ± 4.39
14.1 ± 5.21
0.708
(Range 8.5–24.0)
(Range 3–24.5)
Eyes at different IOP level (n)
IOP ≤ 18
13
15
0.634
IOP ≤ 15
12
12
0.823
IOP ≤ 12
7
6
0.642
Post-rescue intervention meds numbers (class)
0.9 ± 1.16
0.4 ± 1.12
0.191
Meds-free eyes (n)
10 (55.6%)
16 (84.2%)
0.057
Eyes with different meds numbers (n)
0.044*
0
10
16
1
1
1
2
5
0
3
2
1
4
0
1
Data are presented as n (%) or mean ± standard deviation
*P value < 0.05 was considered statistically significant after test
Fig. 3
Mean intraocular pressure (IOP), mean number of medications, and mean cumulative frequency (CF) of rescue interventions along the cohort for the needling and open revision groups
×
Factors associated with IOP or medication numbers after rescue interventions were evaluated using the GEE (Tables 7, 8). Both results showed older age (P = 0.013) and male patients (P = 0.022) had a lower IOP after rescue interventions. The type of surgery (XEN alone or PHACOXEN), the IOP level before rescue interventions, and the interval from primary XEN implantation to rescue interventions were not significantly associated with final IOP or the number of required medications (Tables 7 and 8). Compared with open revision, needling was associated with higher IOP (P = 0.048) and more required medications (P = 0.048).
Table 7
Multivariable analysis for associations between the IOP after rescue interventions and covariates, performed by generalized estimating equations (GEE)
Predictor
Model 1
Model 2
β
95% CI
P value
β
95% CI
P value
Intercept
18.965
(12.084, 25.845)
< 0.001*
18.222
(11.226, 25.219)
< 0.001*
Age
–0.074
(–0.132, –0.016)
0.013*
–0.073
(–0.131, –0.016)
0.013*
Gender
–
–
–
–
–
–
Female
References
References
NA
References
References
NA
Male
–2.518
(–4.599, –0.436)
0.018*
–2.423
(–4.495, –0.351)
0.022*
Type of primary surgery
–
–
–
–
–
–
PHACOXEN
References
References
NA
References
References
NA
XEN
0.454
(–1.657, 2.565)
0.674
0.475
(–1.631, 2.58)
0.659
Pre-rescue intervention IOP
0.094
(–0.067, 0.254)
0.252
0.091
(–0.071, 0.253)
0.273
Post-rescue intervention meds
1.11
(–0.120, 2.340)
0.077
1.149
(–0.041, 2.339)
0.058
Interval from primary surgery
–0.005
(–0.029, 0.019)
0.678
–0.003
(–0.028, 0.021)
0.787
Type of rescue intervention
–
–
–
–
–
–
Revision
References
References
NA
References
References
NA
Needling
1.743
(–0.557, 4.044)
0.138
3.254
(0.032, 6.475)
0.048*
Time
–0.06
(–0.111, –0.010)
0.020*
–0.021
(–0.088, 0.047)
0.549
Time × rescue intervention
–
–
–
–
–
–
Revision
–
–
–
References
References
NA
Needling
–
–
–
–0.086
(–0.181, 0.009)
0.076
Data are presented as β (95% CI)
IOP intraocular pressure, meds antiglaucoma medications, CI confidence interval
*P value < 0.05 was considered statistically significant after test
Table 8
Multivariate analysis for associations between the number of the final meds and possible variates, performed by generalized estimating equations (GEE)
Predictor
Model 1
Model 2
β
95% CI
P value
β
95% CI
P value
Intercept
–0.431
(–1.596, 0.735)
0.469
–0.404
(–1.573, 0.764)
0.498
Age
0.005
(–0.01, 0.02)
0.491
0.005
(–0.009, 0.020)
0.483
Gender
–
–
–
–
–
–
Female
References
References
NA
References
References
NA
Male
–0.146
(–0.590, 0.298)
0.519
–0.148
(–0.593, 0.298)
0.515
Type of primary surgery
–
–
–
–
–
–
PHACOXEN
References
References
NA
References
References
NA
XEN
0.058
(–0.404, 0.52)
0.806
0.055
(–0.409, 0.519)
0.816
Pre-rescue intervention Meds
0.082
(–0.122, 0.287)
0.430
0.083
(–0.121, 0.286)
0.425
Post-rescue intervention IOP
0.023
(–0.009, 0.055)
0.156
0.025
(–0.007, 0.057)
0.127
Interval from primary surgery
–0.001
(–0.005, 0.004)
0.768
–0.001
(–0.005, 0.004)
0.725
Type of rescue intervention
–
–
–
–
–
–
Revision
References
References
NA
References
References
NA
Needling
0.512
(0.063, 0.96)
0.025*
0.399
(0.004, 0.794)
0.048*
Time
0.008
(0.002, 0.015)
0.013*
0.006
(–0.002, 0.013)
0.137
Time × rescue intervention
–
–
–
–
–
–
Revision
–
–
–
References
References
NA
Needling
–
–
–
0.006
(–0.008, 0.021)
0.404
Data are presented as β (95% CI)
IOP intraocular pressure, meds antiglaucoma medications, CI confidence interval
*P value < 0.05 was considered statistically significant after test
Discussion
Studies primarily reported the efficacy of XEN implants mainly in open-angle glaucoma rather than angle-closure glaucoma. The prevalence of PACG was higher in Taiwan and Asia than in western populations [11‐13]. In the present study, XEN surgery was performed in various types of glaucoma, including POAG, PACG, and other forms of glaucoma.
Given the different definitions of success and varied follow-up periods among various studies, the comparison among studies is difficult. Mansouri et al. reported a 12-month prospective study of 87 open-angle glaucoma eyes receiving XEN implants [2]. Complete success (IOP of < 16 mmHg, without medications) and qualified success (IOP of < 16 mmHg, with or without medications) were achieved in 57.7% and 71.1% of eyes at 12 months, respectively, with needling intervention in 37% of patients [2]. The XEN alone or XEN + cataract group had similar success probabilities and needling rates [2].
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Karimi et al. conducted a multicenter, 18-month study of 259 eyes that underwent XEN implantation. They reported a 37.4% complete success (the postoperative IOP ≤ 21 mmHg with a 20% reduction from preoperative IOP without medications and significant complications but needling allowed) and a 24.2% partial success (the same criteria but with glaucoma medications) at 12 months [3]. A proportion of 40.9% of eyes required needling or antimetabolite injection. Proportions of 51.1% and 51.6% eyes were medication-free at 12 months and 18 months [3]. XEN and PHACOXEN had similar outcomes [3].
Reitsamer et al. reported a 67.6% clinical success (achieving ≥ 20% IOP reduction from baseline on the same or fewer medications without glaucoma-related secondary surgical intervention but with needling) at 12 months and 65.8% at 24 months of 218 implanted in 202 POAG eyes [6]. Proportions of 51.1% and 44.7% eyes were medication-free at 12 and 24 months, respectively. Later, they reported the 3-year results of 212 eyes and slightly changed the definition [4]. Complete success (≥ 20% IOP reduction from medicated baseline without medications and secondary surgery but with needling) was 42.6%, 39.6%, and 35.5% at 12, 24, and 36 months. Qualified success (≥ 20% IOP reduction from medicated baseline while remaining on the same number or fewer medications) was 62.4%, 63.1%, and 65.8% at 12, 24, and 36 months, respectively. The rate of eyes requiring needling was 37%, 42%, and 43% by months 12, 24, and 36, respectively [4]. The results appeared comparable either with or without phacoemulsification [4, 6].
In our study, the complete success rate was 35.3%, 38.3%, and 24.0%; the qualified success rate was 42.6%, 44.7%, and 40.0% at months 12, 24, and 36, respectively. With rescue interventions, the rate of IOP ≤ 18 mmHg with medication-free eyes increased to 70.6%, 66.0%, and 52.0% at months 12, 24, and 36, respectively. Like most studies [2‐6], our study also demonstrated that XEN alone and PHACOXEN surgery had comparable efficacy in lowering IOP and similar rates of rescue intervention. However, patients with PACG were enrolled in our study. As cataract extraction alone had an IOP-lowering effect in medically uncontrolled chronic PACG eyes [14], the association between follow-up IOP level or change rate of IOP and glaucoma types or the types of surgery (XEN alone or PHACOXEN) was evaluated by multivariate analysis. The results still showed no significant difference in IOP-lowering effects between XEN alone and PHACOXEN.
The ever-reported rate of needling after XEN implantation ranged from 37.0% to 55.4% [1‐5], and the rate of open revision after failed needling was between 6.0% and 27.5% [2, 3, 9, 15]. Mansouri et al. reported a needling rate of 37% and a bleb revision rate of 6% [2]. Steiner et al. reported a similar rescue intervention rate of 49.6% in 268 eyes [10]. In this study, the rate of rescue intervention (including needling and open revision) after XEN implantation was 50.6%, which was comparable to previous reports. About half of the XEN-implanted eyes required needling or open revision.
Needling and open revision rescued the surgical outcomes of XEN implantation, but only limited studies discussed needling and open revision. Arnljots et al. defined success at IOP levels ≤ 21 mmHg and reported a complete and qualified success rate of 37% and 90% after needling, respectively, but only 19 eyes were included and followed for 6 months in their study [16]. José et al. reported a 61% and 72% complete and qualified success rate, respectively, in their 18-patient 1-year study, using IOP levels ≤ 18 mmHg with IOP reduction ≥ 20% as the definition of success [17]. Steiner et al. reported a better Kaplan–Meier success rate in open revision than in needling (50.7% ± 6.1% versus 24.3% ± 7.8%, P = 0.015), and fewer additional interventions were required in open revision than in needling (17.1% versus 54.5%, P < 0.001) [10]. Their success was defined as postoperative IOP ≤ 21 mmHg or ≤ 18 mmHg and an IOP reduction ≥ 20% with medications allowed. In our study, the patients receiving open revision tended to have longer intervals from primary XEN implantation (P = 0.062), higher pre-rescue intervention IOP (P = 0.128), and more pre-rescue intervention medications (P = 0.035). Interestingly, at 12 months post-rescue intervention, the open revision group had a higher rate of achieving IOP ≤ 18 with medication-free eyes (P = 0.031), less medication needed (P = 0.044), and equal rate of IOP ≤ 18 with/without medications, compared with the needling group. GEE analysis also showed open revision was associated with lower IOP (P = 0.048) and less required medications (P = 0.048).
Open revision included peritomy and sacrificed the naïvety of conjunctiva, which usually had to be performed in the operating room. Given the hesitation or schedule for entering the operating room, patients might ask for medication usage and delayed open revision. Thus, patients in the open revision group might have longer intervals from primary XEN implantation, higher pre-rescue intervention IOP, and more pre-rescue intervention medications in our study. Despite these drawbacks, open revision had several advantages when compared with needling. First, the tiny external ostium of XEN can be covered and obstructed by Tenon’s tissue. XEN might be obscured by thick fibrosis and prevent needling. Blind needling was too risky for XEN amputation. Even a thin Tenon’s capsule around XEN might be tough during needling. Open revision avoided these problems. Second, during open revision, the function of XEN could be checked directly with a sponge to evaluate the outflow. If there was no flow, then the obstructed XEN could be transluminally stented with a 10–0 prolene. If stenting failed, a second XEN implantation or other filtering surgeries could be performed on the spot. By contrast, needling would fail to lower the IOP when the XEN itself was obstructed. Third, if needed, antimetabolite drugs (MMC or 5-fluorouracil) could only be injected during needling. The injected drugs might diffuse far away from XEN, leading to insufficient effects around the XEN but unwanted side effects to other tissue (such as limbus or sclera) away from XEN. During open revision, these antimetabolite drugs could be applied via a soaked sponge to the Tenon tissue at the exact plane and only around the XEN. Fourth, in our study, 6 of 24 (25%) eyes receiving needling still had high IOP after needling and required open revision eventually. Notably, some post-XEN implantation IOP could rise to a high level during follow-up, even higher than the preoperative baseline IOP. Once the needling fails to lower the IOP, the elevated IOP could threaten the residual poor vision for advanced glaucoma eyes. During open revision, we could ensure the filtering function and reduce the risk of further axon damage. Therefore, open revision might be the rescue intervention of choice, especially in high IOP and advanced glaucoma eyes.
Gillmann et al. found male gender a risk factor for XEN failure [5], and they surmised that it was due to the reduced postoperative compliance in male patients. Steiner et al. reported that male gender was not a risk factor for failure to achieve postoperative IOP < 21 mmHg with ≥ 20% IOP reduction after primary XEN implantation but a risk factor after needling or open revision [10]. However, our study showed that male patients had a better IOP result than female patients after XEN implantation and after needling or open revision. This finding might be explained by sex hormone-related wound healing. Estrogens enhance healing, whereas androgenic species retard repair and interfere with the accumulation of structural proteins [18, 19]. The healing of an acute wound is found more slowly in male patients than in women, particularly in older men [20]. Considering that excessive wound healing to fibrosis leads to failure of traditional filtering surgery [21, 22], slow healing in male patients enhances the filtering function of XEN.
Our study also found that older age was significantly associated with medication free after XEN implantation and lower IOP levels after rescue interventions. Aging was related to altered and delayed wound healing [23, 24]. An in vivo study by swept-source optical coherence tomography showed that conjunctival and Tenon’s capsule thickness decreased with age [25]. Thinner Tenon’s capsule and less vigorous wound healing in the elderly might lead to better bleb formation and surgical outcomes of XEN implantations and rescue interventions.
This study has some limitations. First, this study is retrospective rather than prospective and randomized. Hence, some between-group differences were observed at baseline, such as more eyes with PACG in the PHACOXEN group than in the XEN alone group. Therefore, multivariate analysis was used to evaluate these factors. Second, some aspects were not considered. For example, the condition of fibrosis or visibility of the external portion of XEN prior to rescue interventions might differ between the needling and open revision groups. Those who need rescue intervention but have poor visibility of XEN might go to the open revision group and vice versa. Third, as patients might have respective severity of glaucoma or distinct willingness for rescue interventions, the interval from noting IOP elevation or poor XEN function to rescue interventions varied from days to weeks. The baseline IOP and the number of glaucoma medications before rescue interventions might also differ. The clinical situation of each patient might be diverse.
Conclusions
Our study reflected a real-world scenario. XEN implant effectively lowered the IOP and medications over three years. XEN alone and PHACOXEN had comparable surgical outcomes, whereas open revision had a better IOP-lowering effect than needling as a rescue intervention. Male and older patients had better surgical results in primary XEN implantations and rescue interventions.
Acknowledgements
We thank all the study participants. We also appreciated the help from Yi-Jhen Hong and Chin-Chi Chen for administrative procedures and data collection.
Declarations
Conflict of Interest
Hong-Zin Lin, Jen-Hung Wang, and Yuan-Chieh Lee have nothing to disclose.
Ethical Approval
This study was approved by the Research Ethics Committee of Hualien Tzu Chi Hospital (REC. No.: IRB112-039-B) and performed in accordance with the Helsinki Declaration. The need for informed consent was waived because of the retrospective nature of the study.
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