Effectiveness and Safety of Xen Gel Stent in Glaucoma Surgery: A Systematic Review of the Literature

Although topical medical therapy and selective-laser-trabeculoplasty represent the treatments of choice to reduce intraocular pressure, many patients do not achieve adequate glaucoma control; therefore, they require further options and eventually surgery. Trabeculectomy is still considered the gold standard, but the surgical management of glaucoma has undergone continuous advances in recent years, XEN-gel-stent has been introduced as a safer and less traumatic means of lowering intraocular pressure (IOP) in patients with open-angle glaucoma (OAG). This study aimed to review the effectiveness and safety of clinical data on XEN-stent in OAG patients with a Synthesis-Without-Meta-analysis (SWiM) methodology. A total of 339 studies were identified following a literature search adhering to PRISMA guidelines and, after evaluation, 96 studies are discussed. XEN63 and XEN45 device data were collected both short and long term. In addition, this document has evaluated different aspects related to the XEN implant, including: its role compared to trabeculectomy; the impact of mitomycin-C dose on clinical outcomes; postoperative management of the device; and the identification of potential factors that might predict its clinical outcomes. Finally, current challenges and future perspectives of XEN stent, such as its use in fragile or high myopia patients, were discussed.


Introduction
The term open-angle glaucoma covers a wide range of chronic and progressive optic neuropathies which have the loss of retinal ganglion cells and their axons in common, as well as the subsequent loss of the visual field [1].
Lowering intraocular pressure (IOP) is currently considered as the main known modifiable risk factor [2]. Topical hypotensive medication and selective laser trabeculoplasty are currently considered as the first treatment approaches in most patients [3]. However, some patients do not achieve adequate glaucoma control; therefore, they require further therapies and eventually surgery [3][4][5], such as trabeculectomy [6], which unfortunately may lead to potential vision-threatening complications [7].
Glaucoma surgery has experienced important advances over the last several years. One of the most important advances in glaucoma surgery in recent years was the development of the minimally or microinvasive glaucoma surgery (MIGS) devices [8]. They

XEN63
The currently available scientific evidence evaluating the clinical outcomes of XEN63 is very limited [18][19][20][21][22][23] (See Table 1), and most of the evidence was generated from a former

XEN63
The currently available scientific evidence evaluating the clinical outcomes of XEN63 is very limited [18][19][20][21][22][23] (See Table 1), and most of the evidence was generated from a former device that was never commercialized; therefore, we will not go into detail analysing the results of those articles [18][19][20][21]. To date, there are two papers evaluating the efficacy and safety of the XEN63 device. Fea et al. [22] evaluated the new XEN63 device and found a mean (95% confidence interval, 95% CI) IOP lowering effect of −14.8 (−20.1 to −9.5) mmHg, p < 0.0001 at month-3, reporting that the mean IOP achieved with XEN63 was consistently lower than that obtained with XEN45. This may be an important point because the larger calibre of the Xen 63 device could by clinically meaningful for patients with high preoperative IOP.
Additionally, Fea et al. [23] evaluated the effectiveness and safety of the new XEN63 device over a follow-up period of 18 months in patients with glaucoma in a real clinical setting. They reported significant IOP lowering and a reduction in the number of ocular hypotensive drugs during a follow-up period of 18 months. Moreover, the incidence rate of adverse events was relatively low and most of them were mild in severity [23]. Table 1 summarizes the main outcomes of XEN63 according to the current evidence.

Effect on Intraocular Pressure Lowering and Reduction in the Number of IOP-Lowering Medications
Multiple studies have evaluated the IOP lowering effect of the XEN device, either alone or in combination with cataract surgery, in patients with glaucoma . Although most of the studies were performed in patients with primary open-angle glaucoma (POAG), other studies were performed in patients with pseudoexfoliative glaucoma (PXG) [40,42,54,72,98] or glaucoma secondary to uveitis [47].
The results of a systematic review and meta-analysis published recently, which used a pooled analysis with a random effects model, have shown a mean (95% CI) IOP lowering from baseline of −7.8 (−7.4 to −8.2) mmHg and −8.4 (−6.9 to −9.8) mmHg in the eyes of patients who underwent XEN-solo and XEN + Phaco, respectively. All patients were treated and followed up as routine clinical practice between May 2013 and February 2020. The mean sample size was 79 ± 67 and the average follow-up time was 17.0 ± 8.1 months [12].
Similarly, Yang et al. [102] did not find significant differences in IOP lowering between XEN-solo and XEN + Phaco (standardized mean difference: −0.01, 95% CI −0.09 to 0.08, p value 0.894). Moreover, Panarelli et al. [103] reported that, on average, successful gel stent surgery achieved a postoperative IOP of approximately 14.0 mm Hg and reduction to fewer than 1 ocular hypotensive medication.

(12.7)
Almendral et al. [   Data about standard deviation was not provided. * Mean (Standard deviation). ** Mean (95% confidence interval). ⁑ Percentage. ⁂ Mean (Standard error). ⁋ 95% Confidence interval. *** All the needling procedures were done between week 1 and month 3. 1 Data calculated from Table 2 of the paper. 2 Postoperative bleb needling or antimetabolite injection. 3 Data from naïve patients. Abbreviations: IOP: intraocular pressure; N: number of eyes; NOHM: number of ocular hypotensive medications. Data about standard deviation was not provided. * Mean (Standard deviation). ** Mean (95% confidence interval). ⁑ Percentage. ⁂ Mean (Sta Confidence interval. *** All the needling procedures were done between week 1 and month 3. 1 Data calculated from Table 2 of the paper. 2 needling or antimetabolite injection. 3 Data from naïve patients. Abbreviations: IOP: intraocular pressure; N: number of eyes; NOHM: number sive medications. 95% Confidence interval. *** All the needling procedures were done between week 1 and month 3. 1 Data calculated from Table 2       Similar results have been published by Yan et al. [102], who found a statistically significant reduction in ocular hypotensive medications (standardized mean difference: 2.11, 95% CI 1.84 to 2.38, p value < 0.001). Furthermore, after adjusting for different covariates, the reduction in the number of ocular hypotensive drugs was significantly lower in the XEN + Phaco group than in the XEN-solo group (Risk ratio: 1.45, 95% CI 1.06 to 1.99, p value 0.019) [102].

IOP Lowering at 12 Months
Thirty-four studies have evaluated the IOP lowering effect of the XEN device over 12 months of follow-up (see Table 2). On average, the results of the different studies pointed in the same general direction, mostly indicating that XEN45 provided IOPs below 15 mmHg after one year of follow-up (Table 2), which is consistent with the most recent meta-analysis published [12,101,102].

IOP Lowering at 24 Months
Twelve studies have evaluated the IOP lowering effect of XEN45 after 24 months of follow-up (See Table 3). The results of the different studies included in this SWiM paper have shown that, after 2 years of follow-up, XEN45 provided a good IOP lowering, with final IOPs ≤15 mmHg and an IOP lowering that ranged between −5 and −10 mmHg (Table 3).

IOP Lowering at 36-Months
Six papers have evaluated the longer-term efficacy of XEN45 in terms of IOP lowering and reducing the number of ocular hypotensive medications, (See Table 4). With the exception of one paper (n = 23 eyes), which reported an IOP of 19.6 ± 2.1 mmHg at 36 months [78], currently available evidence shows good hypotensive effects for XEN45, with IOPs at 36-48 months in the range of 13-14 mmHg, as well as a significant reduction in the number of ocular hypotensive medications [45,61,81,87,88,94,101]. In addition, compared to preoperative values, the reduction in IOP was greater than 30% (Table 4).
Current evidence has demonstrated the efficacy and safety of the XEN45 device in the short, medium, and long term.

Can XEN45 Be Safely and Effectively Implanted in Myopic Patients?
Evidence surrounding the use of XEN45 in myopic OAG patients is limited [52,64,[104][105][106]. In fact, there are currently only two studies that specifically evaluated the efficacy and safety of XEN45 in patients with high myopia.
Laborda-Guirao et al. did not find significant differences between OAG eyes with or without high myopia in intraocular pressure (IOP) lowering, success rate, reduction in the number of ocular hypotensive medications, or postoperative complications, which clearly suggested that XEN45 may be safely and effectively used in glaucomatous eyes with high myopia [52].
Chao et al. [64], have retrospectively evaluated the effectiveness and safety of the XEN45 in East Asian patients with primary open angle glaucoma (POAG). Although this study did not specifically evaluate the efficacy and safety of XEN45 in patients with high myopia, the mean spherical equivalent was −5.13 ± 4.44 diopters, with a range of −13.63 to −2.88 diopters and mean axial length of 26.67 ± 1.65 mm (up to 29.34 mm). According to the results of this study, axial length was not significantly associated with success, either complete (odds ratio: 0.082, p = 0.559) or qualified (odds ratio: 0.659; p = 0.186); need of subsequent intervention (odds ratio: 0.959, p = 0.803); or need of additional surgery (odds ratio: 1.382, p = 0.382). Additionally, no major complications were observed [64]. These results suggested that axial length did not have any influence on XEN45 outcomes.
Sacchi et al. [105], in a retrospective study (which included seven eyes followed for 2 years) evaluated the effectiveness and safety of Xen 45 in patients with medically uncontrolled glaucoma and concomitant high myopia (>6 Diopters). Preoperative mean IOP was significantly lowered from 22.1± 4.9 mmHg to 14.8 ± 4.0 mmHg at month-24, p < 0.0001. Regarding safety, two eyes had hypotony (without maculopathy) and one eye had choroidal detachment [106]. According to the results of this study, the XEN implant had a better safety profile than trabeculectomy, with a similar hypotensive profile [105].
Additionally, Fea et al. assessed the effectiveness and safety of XEN in 31 glaucomatous eyes with a refractive error higher than −6 D and an axial length ≥26 mm [106]. Mean preoperative IOP (95% CI) was significantly lowered from 23.5 (20.5-26.4) mm Hg to 13.0 (12.2-13.8) mm Hg, p < 0.0001. Regarding safety, hypotony (an IOP <6 mm Hg) was reported in eight eyes (28.6%) during the first postoperative day and remained for a week [106].
Conversely, one publication described the clinical outcomes of XEN45 in a high myopic eye. The patient required a XEN removal to control IOP, which resulted in loss of the remaining visual field in the eye [104].
Currently available scientific evidence suggests that XEN45 may be effectively and safely implanted in myopic eyes. However, there is a need for a prospective study specifically evaluating the clinical outcomes of XEN45 in eyes with OAG and high myopia.

XEN-Solo Versus XEN + Phaco: Is There a Difference in Terms of IOP Lowering?
This question has brought an increasing interest among glaucoma specialists. Fifteen papers have compared the efficacy of XEN45 solo or in combination with cataract surgery (phacoemulsification). After reviewing the literature, the most plausible conclusion is that there is no agreement regarding the superiority of the solo procedure over the combined procedure with cataract surgery (See Table 5).      According to the results of Chen et al. [12], both XEN alone (mean difference: −7.8 mmHg; 95% CI: −8.21 to −7.38 mmHg, p < 0.001) and XEN + Phaco (mean difference: −8.35 mmHg; 95% CI: −9.82 to −6.88 mmHg, p < 0.001) significantly lowered the IOP.
Similarly, Yang et al. [103], in a systematic review and metanalysis, did not find significant differences between XEN and phaco-XEN surgery in terms of IOP after surgery (standardized mean difference: −0.01, 95% CI −0.09 to 0.08, p value 0.894). Nevertheless, the reduction in the number of ocular hypotensive medications was greater in the XEN solo group (p = 0.019) [102].
However, another systematic review and meta-analysis published by Wang et al. [107] has shown different results. They found better results for XEN alone compared to XEN + Phaco procedures in IOP lowering, but not in reducing ocular hypotensive medications [107].
In light of the available scientific evidence and based on our own experience, the XEN45 device, either alone or in combination with cataract surgery (phacoemulsification), significantly lowers IOP and reduces the number of ocular hypotensive medications. Similar to trabeculectomy, there are no data to support the superiority of the combined surgery over the solo surgery, and vice versa.

XEN Versus Trabeculectomy: Is There a Difference in Terms of IOP Lowering?
Due mainly to its well-stablished IOP lowering effect, trabeculectomy is currently considered as the gold standard in glaucoma surgery [5]. However, it may lead to potential vision-threatening complications [6].
The Gold-Standard Pathway Study (GPS) [108] was the first multicenter, prospective, and randomized study comparing the effectiveness and safety of XEN45 versus trabeculectomy in glaucoma that was poorly controlled with topical IOP-lowering therapy. The results of this study showed that the mean IOP change from baseline was significantly greater at month 12 in the trabeculectomy group (0.024), although both treatments significantly lowered IOP from preoperative values (p < 0.001). XEN and trabeculectomy significantly reduced the preoperative mean number of ocular hypotensive medications, without significant differences between them (p = 0.068).
In addition, XEN was noninferior to trabeculectomy, regarding the prespecified primary endpoint (62.1% and 68.2% achieved the primary endpoint, respectively; p = 0.487), namely the percentage of patients achieving ≥20% IOP reduction from baseline at Month 12 without medication increase, clinical hypotony, vision loss to counting fingers, or secondary surgical intervention. Finally, XEN resulted in less need for in-office postoperative interventions (p = 0.024 after excluding laser suture lysis), faster visual recovery (p < 0.05), and greater 6-month improvements in visual function problems (p ≤ 0.022) [108].
Similarly, Marcos-Parra et al. [48] compared the IOP lowering effect and the reduction in ocular hypotensive medications between the XEN device and trabeculectomy in OAG patients. They reported a significantly greater IOP lowering in the trabeculectomy group than in the XEN group (p = 0.001), with a similar reduction in the ocular hypotensive drugs [48]. However, this difference was mainly due to the combined surgery (glaucoma + cataract). When comparing the IOP lowering effect between XEN + Phaco and Trabeculectomy + Phaco, IOP lowering from preoperative values was found to be significantly greater in the Trabeculectomy + Phaco group at day 1, week 1, and months 1 and 3. While comparing XEN alone versus trabeculectomy alone, the only significant differences were observed in month 6. Moreover, in terms of success rates, there were no differences in the proportion of eyes who achieved a final IOP ≥6 and ≤16 mmHg (p = 0.1317), although it was slightly lower in the XEN (66.2%) than in the trabeculectomy group (78.6%) [48].
Additionally, Schlenker et al. [109] observed similar rates of complete and qualified success for both interventions.
Wang et al. [102], in a systematic review and meta-analysis, reported no significant differences between XEN gel implant and trabeculectomy on lowering IOP, although the analysis showed a high heterogeneity (I2:60%). However, after a sensitive analysis that excluded the Schenkler et al. study [109] and reduced the heterogeneity (I2:0%), the results showed that trabeculectomy was more effective in lowering IOP, without significant differences in terms of the reduction in ocular hypotensive medications [102]. Table 6 shows a comparison of the clinical outcomes of XEN45 and Trabeculectomy. Compared to trabeculectomy, XEN45 has been associated with several advantages, including less conjunctival manipulation, less postoperative inflammation, and lower incidence of postoperative adverse events. Moreover, the rates of postoperative interventions seem to be lower with XEN45 than with trabeculectomy. Therefore, XEN45 could be considered as the first-choice surgery in certain types of patients.

XEN Implant: What Dose of Mitomycin-c Is the Most Effective?
Mitomycin-c (MMC) and 5-fluorouracil (5-FU) have been commonly used in traditional glaucoma filtration surgery, with good evidence suggesting a significant increase in surgery success; however, there is also an increase in the risk of complications [112].
Although MMC was not initially used in all studies [17,19,21], the use of intraoperative MMC has become a common practice of the XEN implant surgical technique .
Regarding XEN45, MMC concentration may influence clinical outcomes. It has been suggested that the success rate may be related to the MMC dose, although other studies have shown a lack of correlation between MMC dosage and the surgical outcomes [113]. In general terms, the use of MMC seemed to increase the therapeutic success rate after XEN45 gel stent implantation, although the ideal dose has not been stablished yet.
Selection of MMC concentration is based on a patient-tailored approach. This may entail an important bias because surgeons will use higher concentrations of MMC in more complicated cases in which they anticipate that the possibility of surgical failure is greater.
A study comparing the efficacy and safety of two MMC doses (0.01% versus 0.02%) in eyes who underwent a XEN45 device implant, either alone or in combination with phacoemulsification, was recently published [95]. The results of this study found that IOP lowering, number of hypotensive medication reduction, or incidence of adverse events were not related to MMC concentration [95]. The lack of significant differences, in terms of IOP lowering or reducing hypotensive medications, between MMC 0.01% and MMC 0.02% raises the possibility of using lower doses of MMC. However, it should be mentioned that MMC 0.01% was not associated with lower incidence rates of adverse events [95].
So far, there is no evidence to recommend the use of a specific MMC concentration. It seems that MMC dose does not significantly impact either the IOP lowering or the reduction in the number of ocular hypotensive medications, so it would seem prudent to recommend "the lowest dose of MMC that, in the surgeon's opinion, may be effective in that patient". However, new studies will be necessary to clarify this issue.
3.3.6. XEN 45 Device Implant: Postoperative Bleb Management Bleb fibrosis is a common complication that may occur after a XEN implant, with rates as high as 45% [114]. Needling is a minimally invasive procedure that is commonly used for restoring the functionality of failed filtering blebs [115].
The most frequently reported postoperative intervention in eyes who underwent a XEN device is needling of the conjunctival bleb, which ranges from 5% to 62% [12] ( Tables 2-4 show the needling rates reported in the different studies).
Needling is not currently considered as an additional procedure, but rather as part of the normal bleb management in XEN implant surgery (similarly to laser suture lysis in trabeculectomy). In most cases, needling is required within the first month postoperatively.
However, in most studies, needling has been used as a rescue strategy once bleb failure has occurred.
Primary needling, at the time of ab interno XEN implantation, has been recently proposed as a technique that may reduce the number of postoperative interventions [96,116].
In a retrospective study, Kerr et al. [116] reported that primary needling at the time of XEN insertion was associated with a significant reduction in the number of bleb interventions (p = 0.003) and, consequently, the subsequent postoperative visits (p = 0.043). Additionally, compared to preoperative values, this technique has provided a significant reduction in both IOP and ocular hypotensive medication [116].
More recently, Buenasmañanas-Maeso et al. [96] performed a retrospective study that assessed the efficacy and safety of primary needling in eyes who underwent a XEN45 implant, either alone or in combination with phacoemulsification. According to the results of this study, primary needling was associated with fewer postoperative interventions. Nevertheless, these eyes were not associated with greater IOP lowering or a greater reduction in ocular hypotensive therapy [96].
Regarding the use of primary needling, there is not enough evidence to recommend its use on a routine basis. Therefore, from a clinical point of view, its use was reserved for those cases in which the XEN implant was twisted, trapped, or did not appear free and mobile in the subconjunctival space. Additionally, it may eventually be used in eyes with previously failed glaucoma surgery or in eyes with pathologies that may be associated with an increased risk of conjunctival fibrosis.

Can XEN45 Device Be Considered a Safe Procedure?
Although XEN has emerged as a safer and less traumatic approach for lowering IOP in patients with glaucoma, it is not free of complications.
According to the currently available scientific evidence, transient hypotony (defined as IOP <6 mmHg) is the most commonly reported complication of XEN45, with an incidence rate of 9.59%. In the vast majority of patients, hypotony is successfully resolved without additional surgery interventions and the rate of chronic hypotony is very low [12].
The second most common adverse event is hyphema (5.53%). Most of patients have grade I hyphema (less than 1/3 of anterior chamber), which had resolved spontaneously by the first week after surgery [12]. The third most commonly reported adverse event is the incidence of transient IOP spikes, which have been reported in 2.11% of eyes (in most cases associated with hyphema) [12]. Figure 2 shows an overview of the incidence of different adverse events reported after XEN implantation. Regarding the number of corneal endothelial cells, trabeculectomy and glaucoma drainage device implantation can damage corneal endothelial cells [117][118][119][120]. With regards to the impact of XEN on the corneal endothelial cells' loss, there were no significant differences between XEN + phacoemulsification and phacoemulsification alone [121][122][123]. Additionally, the corneal endothelial cell density reduction after XEN implantation as a solo procedure was low [122]. Figure 2. Incidence rate of adverse events reported after XEN implantation (n = 4410). Adapted from Chen et al. [12]. * ≥2 Snellen lines vison loss lasting >1 month. IOP: intraocular pressure; AC: anterior chamber; VA: visual acuity.
The results of a prospective, cross-sectional, and non-randomized clinical trial suggested that, in eyes who underwent a XEN standalone procedure, there were no significant changes in endothelial cell counts over the follow-up period (5 years). However, a statistically significant reduction in the central endothelial cell count was observed in the eyes who underwent a combined procedure (XEN + phacoemulsification) at different timepoints. This clearly suggests that the loss of corneal endothelial cells seems to be related with the cataract surgery, rather than with the XEN implant [123].
Both the experience of the panel and the scientific evidence have shown an acceptable safety profile of the XEN implant. The rate of serious complications (endophthalmitis, hypotonus maculopathy, corneal or macular edema) is low. Moreover, compared to trabeculectomy, the XEN implant has provided a be er safety profile [93].
Three studies [42,50,70] found that none of the evaluated factors were significantly associated with surgery failure, whereas two studies reported that the risk of failure is greater in men than in women [19,98]. However, Gabbay et al. [87] reported that women were more likely to fail. Gillmann et al. [98] observed that eyes with a primary OAG diagnosis and those requiring needling are more likely to fail.
Fea et al. [70] suggested that patients with lower IOP at day 1 and month 1 had a higher chance of success. The same was true if the difference between month 1 and week 1 IOP was lower than 6 mmHg.
Chao et al. [64] reported that surgical success was more likely for eyes with a be er preoperative visual field mean deviation and lower IOP at day 1, week 2, and month 1.
Conversely, Ibáñez-Muñoz et al. [116] found that none of the analysed factors were statistically associated with success.
The question of whether patient ethnicity impacts the XEN clinical outcomes has not been fully elucidated. Success rates appear to be lower in Black and Afro-Latino patients than in Caucasian populations [12,51,56]. Similarly, it has been observed that the ethnic Chinese group presents a reoperation rate as high as 45.9% [64]. However, other studies The results of a prospective, cross-sectional, and non-randomized clinical trial suggested that, in eyes who underwent a XEN standalone procedure, there were no significant changes in endothelial cell counts over the follow-up period (5 years). However, a statistically significant reduction in the central endothelial cell count was observed in the eyes who underwent a combined procedure (XEN + phacoemulsification) at different timepoints. This clearly suggests that the loss of corneal endothelial cells seems to be related with the cataract surgery, rather than with the XEN implant [123].
Both the experience of the panel and the scientific evidence have shown an acceptable safety profile of the XEN implant. The rate of serious complications (endophthalmitis, hypotonus maculopathy, corneal or macular edema) is low. Moreover, compared to trabeculectomy, the XEN implant has provided a better safety profile [93].
Three studies [42,50,70] found that none of the evaluated factors were significantly associated with surgery failure, whereas two studies reported that the risk of failure is greater in men than in women [19,98]. However, Gabbay et al. [87] reported that women were more likely to fail. Gillmann et al. [98] observed that eyes with a primary OAG diagnosis and those requiring needling are more likely to fail.
Fea et al. [70] suggested that patients with lower IOP at day 1 and month 1 had a higher chance of success. The same was true if the difference between month 1 and week 1 IOP was lower than 6 mmHg.
Chao et al. [64] reported that surgical success was more likely for eyes with a better preoperative visual field mean deviation and lower IOP at day 1, week 2, and month 1.
Conversely, Ibáñez-Muñoz et al. [116] found that none of the analysed factors were statistically associated with success.
The question of whether patient ethnicity impacts the XEN clinical outcomes has not been fully elucidated. Success rates appear to be lower in Black and Afro-Latino patients than in Caucasian populations [12,51,56]. Similarly, it has been observed that the ethnic Chinese group presents a reoperation rate as high as 45.9% [64]. However, other studies have suggested that there is no relationship between the ethnic origin of the patients and the clinical outcomes of XEN [39,62].

Discussion
The objective of this article was to address, in the most practical way possible, different aspects related to the XEN device that may generate doubts, mainly for specialists who are beginning to use this technique.
Based on currently available evidence, the XEN45 device, either alone or in combination with cataract surgery, significantly lowers IOP and reduces the number of ocular hypotensive medications in patients with glaucoma [12,108,110,111,116]. There are promising results with the new XEN63, but the evidence is very limited [22,23].
Regarding its implantation technique, XEN has usually been delivered using an ab interno approach through a corneal incision . However, as surgeons have been gaining experience with the device, different changes that aim to provide better clinical outcomes have been introduced in the implantation technique [24][25][26].
High myopia represents a challenging scenario in glaucoma patients who need surgical treatment. There are two studies that assessed the efficacy and safety of XEN in patients with high myopia. The results of both studies have pointed in the same direction, clearly indicating that the XEN device is an effective and safe option in patients with high myopia [105,106].
Trabeculectomy is still considered as the gold standard in glaucoma surgery [5]. It effectively lowers IOP and reduced the need of ocular hypotensive medications [6]. However, it requires a close postoperative follow-up to prevent potential complications that may lead to severe vision loss [7,[124][125][126].
Nevertheless, XEN has been associated with lower conjunctival manipulation and incidence of postoperative complications and adverse effects [12,48,93,100].
For precisely this reason, this need for postoperative conjunctival manipulation has been one of the main points of discussion of XEN. The vast majority of the studies show a rate of needling which ranges from approximately 20 to 40% (See Tables 2 and 3).
Primary needling (at the time of ab interno XEN implantation) has emerged as a valuable option to reduce the number of postoperative interventions [96,116].
Regarding the existence of predictive factors of the XEN clinical outcomes, current evidence does not show conclusive results.
Finally, regarding the impact of the XEN device on the corneal endothelium, current evidence suggests that XEN does not have a significant impact on corneal endothelial cell loss [121][122][123], unlike what occurs with trabeculectomy or other drainage devices [117][118][119][120].

Conclusions
According to published evidence, the XEN45 device lowers IOP by approximately 35% from preoperative values, obtaining a mean IOP value of ≤15 mmHg, as far as 4 years after surgery. In addition, XEN significantly reduced the need for ocular hypotensive medication, with a mean number of postoperative hypotensive medications ≤ 1 drug.
Based on the evidence and panel's opinion, the XEN device may be considered as the first surgical option in patients who require a target IOP in the mid to low teens. Even though trabeculectomy seems to have a better IOP-lowering effect, the XEN device has been shown to have a better safety profile.
Although XEN device implantation is a relatively new procedure, a large number of studies have been published in recent years, pointing to its long-term potential in the treatment of glaucoma.
Several issues related to XEN clinical outcomes remain to be clarified, such as the role of ethnicity, factors influencing the outcomes, needling rates and the role of primary needling, the impact of high myopia, and the use of XEN in different types of glaucoma, including narrow-angle and angle-closure glaucoma.
Data from randomized and multicentre clinical trials will help surgeons develop patient-tailored management strategies. Funding: The medical writer and editorial assistance for this manuscript was supported by AbbVie with no input into the preparation, review, approval, and writing of the manuscript. The authors maintained complete control over the manuscript content, and it reflects their opinions.
Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.