Xen Glaucoma Treatment System

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Background

Glaucoma is a leading cause of overall blindness, and the number one cause of irreversible blindness, both in the United States and worldwide.[1][2] Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of glaucoma.[3]

The decrease in quality of life associated with glaucoma can be profound and may occur earlier than previous thought, highlighting the importance of early diagnosis and treatment.[4] Reduction of IOP is the only proven method to prevent and treat glaucoma.[5][6][7][8]

Current guidelines from the American Academy of Ophthalmology Preferred Practice Pattern recommend lowering the IOP to a target level, which is a value or range of values at which the rate of disease progression will be slowed sufficiently to avoid functional impairment from the disease.[9]

Glaucoma treatments include various topical and oral medications; cyclodestructive and trabecular meshwork-directed laser procedures; and various surgical techniques designed to improve trabecular meshwork outflow, increase suprachoroidal drainage, or divert aqueous to the subconjunctival space. Subconjunctival drainage of aqueous humor, resulting in bleb formation, has been a cornerstone of glaucoma surgery for more than a century.[10] However, the ‘gold standard’ trabeculectomy[11] has significant short-term risks like near 50% rate of transient perioperative complications[12] as well as long-term risks of failure, reported to be as high as 50% at 5 years.[13] Because of potentially serious complications associated with traditional glaucoma surgeries (e.g trabeculectomy and tube-shunt drainage devices)[3], a wave of less invasive glaucoma surgical devices have emerged in recent years with a goal of safer, earlier surgical intervention. As with all glaucoma surgeries, these devices can offer lower and less variable IOP on fewer medications, thereby addressing both the under-treatment and noncompliance issues.[11]

Minimally invasive glaucoma surgery (MIGS) meets the criteria of minimal tissue disruption, ab-interno implantation, short surgical time, IOP reduction, simple instrumentation, and fast postoperative recovery.[14] Xen Gel Implant is a microstent that lowers IOP via subconjunctival drainage but without the tissue disruption of a trabeculectomy or traditional glaucoma drainage implant.[3] [15]

Xen Gel Implant

XEN GEL Implant (Allergan Inc., CA, USA) is a 6-mm hydrophilic[15] tube of collagen-derived gelatin cross-linked with glutaraldehyde[3], which is non­inflammatory[16] and causes minimal extraocular fibrotic or vascular response to the implant material[11]. The XEN decreases IOP by creating a permanent drainage shunt from the anterior chamber (AC) to the subconjunctival space through a scleral channel.[15] The device hydrates within 1-2 minutes of contact with aqueous humor, bending and conforming to tissue.[3] This flexibility mitigates many of the issues seen with synthetic materials such as migration, erosion and corneal endothelial damage.[16]

The design of the Xen Gel Stent is based upon the principles of laminar fluid dynamics. [15] The Hagen–Poiseuille equation was used to calculate the required internal dimensions of a tube that (1) would prevent hypotony at average aqueous humor production of 2–3 μl/min and (2) would provide a steady-state IOP floor of approximately 6–8 mmHg. In effect, the primary flow resistance of the tube itself is designed to prevent hypotony.[11][17]

Three Xen models were initally designed[11]: 45, 63, and 140 μm internal lumen diameters for varying levels of IOP control. The smallest one, XEN45, was approved by the FDA in 2016 and hereafter is referred to as XEN.[15] The tube length of 6 mm is of suitable length for passage from the AC, through the trabecular meshwork and sclera, and into the subconjunctival space at an optimal distance from the limbus.[3] The external diameter of the XEN is 150 μm and the inner diameter is 45 μm. Implantation of the XEN is performed with a sterilized, single-hand inserter containing a 27G needle that is preloaded with one gelatin stent.[18]

Suitable and Non-suitable Patients

The most suitable patients for Xen implantation are:

  • Patients with uncontrolled glaucoma, primary open-­angle glaucoma, and pseudoexfoliative or pigmentary glaucoma with open angles that are unresponsive to maximum tolerated medical therapy.[7][13]
  • Patients requiring combined phacoemulsification and glaucoma surgery with open angles are also suitable patients for XEN implantation.[19]


The XEN gel stent is generally contraindicated under the following circumstances or conditions:

  • Patients with angle ¬closure glaucoma where the angle has not been surgically opened; previous glaucoma shunt/valve or conjunctival scarring/pathologies in the target quadrant; active iris neovascularization or neovascularization of the iris within 6 months of the surgical date; active inflammation (eg, blepharitis, conjunctivitis, keratitis, and uveitis); anterior chamber intraocular lens; intraocular silicone oil; vitreous in the anterior chamber; impaired episcleral venous drainage (eg, Sturge–Weber or nanophthalmos or other evidence of elevated venous pressure) and known or suspected allergy or sensitivity to drugs required for the surgical procedure or any of the device components (eg, porcine products or glutaraldehyde).[15]

Surgical Procedure

XEN comes preloaded in an injector (system with a 27 g sharp beveled needle tip)[11] and is designed to be implanted ab interno, meaning from within the AC:

  1. After topical anesthesia, 0.05–0.2 ml MMC (0.1–0.2 mg/ml) is injected with a 30-gauge needle in the superonasal quadrant and massaged over the area of anticipated XEN Gel Implant insertion or a conjunctival flap is made and MMC applied on sponges (off-label use).[3] Administration of MMC also can be performed after XEN implantation.
  2. Cataract surgery, if planned, may be performed before XEN implantation. Following intraocular lens (IOL) implantation, miotic drugs may be used to facilitate XEN implantation.[15]
  3. The intended area of placement in the supero-nasal quadrant, which is 3 mm from the limbus, is marked.[15]
  4. Two small, self-sealing corneal incisions are made, and viscoelastic is used to fill the AC.
  5. Injector tip is placed through an inferotemporal or temporal clear corneal incision (~2mm), while a second instrument is utilized for counter-traction through a superotemporal or superonasal paracentesis (1 mm)
  6. The inserter needle (double-beveled 27 gauge) is directed through the temporal incision and across the AC toward the superonasal quadrant. A mirrored gonioscope can be used to guide this step, but it is not mandatory and can be used at the discretion of the surgeon.[15]
  7. XEN Gel Implant should be placed anterior to Schlemm’s canal between the pigmented and nonpigmented trabecular meshwork to avoid bleeding. This step should be performed under gonioscopic visualization.
  8. The sharp tip is engaged at or slightly anterior to the trabecular meshwork and advanced through the sclera.[11]
  9. The needle is tunneled through the sclera coming out subconjunctivally 2-3 mm from the limbus, as previously marked, using a second instrument to provide countertraction via the side port.
  10. A sliding mechanism is then pushed forward to initially deploy the stent and then to retract the needle into the hub[11], without drawing the implant back.[15]
  11. The injector is then withdrawn, and the XEN placement is confirmed. The ideal stent placement should leave 2.0 mm of exposed implant in the subconjunctival space (preferentially in a more supercial layer than the sub-Tenon space), 1.0 mm in the AC, and 3.0 mm tunneled through sclera.
  12. Viscoelastic is removed from the AC.
  13. Bleb morphology and function may be obtained by forced infusion of fluid through paracentesis at the end of the procedure.[15]

Perioperative Management

Pre-operative:

  • Patients are instructed to stop all glaucoma medications on the day of the operation.

Post-operative:

  • Patients are seen postoperative day 1 and followed up at the physician discretion.
  • Postoperative medication regimen varies, but generally includes topical antibiotic prophylaxis and topical corticosteroids several times each day for at least one month followed by a slow taper.[20][21]
  • XEN implant location and bleb morphology require close biomicroscopic follow-up, which can be complemented by ultrasound biomicroscopy (UBM) or anterior segment optical coherence tomography (AS-OCT).

Morphologic changes to the developing filtering bleb after surgery may help to predict early treatment failure and guide bleb revision and management. Fea et al. reported that maximal height of the bleb and the total area of cystic hypoehoic spaces were significantly higher in the success group.[22] Increased micro-cysts and loosely arranged connective tissue/low stromal reflectivity are suggestive of new or increased alternative outflow induced by the stent implantation. In the other hand, bleb wall reflectivity was significantly higher in the failure group.

Post-operative Needling:

Whenever a XEN bleb becomes flat/fibrotic, bleb needling can be performed as an alternative to surgery. Prospective studies have reported needling rates as high as 46.2% within the first 12 months.[18] XEN needling has been demonstrated to be relatively safe and effective.[23] However, there are reports of XEN fractures and amputations caused by needling.[24] One case series of XEN fractures after needling concluded that because XEN is composed of flexible gelatin, the device can be damaged relatively easily during the bleb needling process.

Higher IOP at post-operative day 1 has been identified as a predictor for future needling following standalone XEN. One prospective study reported that if IOP is greater than 10 mmHg on post-operative day, the probability of needling doubles, and if IOP is greater than 20 mmHg, the probability of needling quadruples to 80%.[25]

Xen Implant Advantages

Xen Implant has some advantages over traditional surgeries such as trabeculectomy and tube shunt surgeries:[26]

  • Soft and flexible when wet
  • Minimally invasive, pre-loaded injector
  • Shorter surgical and recovery times
  • Potentially fewer side effects, e.g. prevention of chronic hypotony by an intrinsic flow-limiting design[11]
  • Retains postoperative options, allowing physicians to use additional IOP-reduction techniques that could be required at a later time [16]

Complications

Most reported Intra- and post-operative complications are minor and inherent to the surgical technique. However, more rare and serious complications have been reported. A critical point is the final placement of the XEN device.

Intra-operative complications:

  • Incorrect placement of the XEN;
  • Posterior placement of the implant, especially through ciliary body, resulting in bleeding and/or hypotony;
  • Subconjunctival or AC bleeding during the implantation.
  • Stent breaking into multiple pieces during placement into the subconjunctiva[27]
  • Limbal-based conjunctival dissection[27]
  • Cyclodialysis cleft secondary to XEN insertion[28]

Post-operative complications:

  • Complications of relocation or reimplantation;
  • Hyphema
  • Wound leak[13]
  • Transient hypotony, AC shallowing, and choroidal detachment
  • Suprachoroidal hemorrhage[29]
  • Malignant glaucoma[30]
  • Internal ostium occlusion by retained viscoelastic, blood clot, or inflammatory fibrin leading to bleb failure and raised IOP

Late complications:

  • Device erosion and exposure of implant[31]
  • Implant migration: Dislocation into AC, XEN-iris touch[13][27]
  • Bleb leak or dehiscence (may be due to thin or ischemic bleb with overfiltration)
  • Reported cases of blebitis and persistent hypotony,[32] suprachoroidal bleeding,[33] conjunctival perforation and late seidel.[34]
  • Endophthalmitis[28][35]

Efficacy and Safety Profile

The XEN was introduced relatively recently, thus long-term results are yet to be published. Studies with 1-year follow-up have found it to be efficacious in lowering IOP significantly and reducing the number of hypotensive medications used, with minimal complications or serious side effects.[3] Most studies document an IOP reduction of >29% (greater than the reduction demonstrated by isolated phacoemulsification in patients with primary open-angle glaucoma) and a significant reduction in the number of IOP-lowering medications.

Grover et al. evaluated the IOP-lowering effect and safety of the XEN Gel Implant patients with refractory glaucoma (previously failed filtering or cycloablative procedure and/or uncontrolled IOP on maximally tolerated medical therapy).[36] In 76.3% of patients there was ≥20% reduction of IOP on same or fewer medications. The mean (SD) medication use reduced from 3.5 (1) at baseline to 1.7 (1.5) at 12-month follow-up. There was 75% probability of success reported at 12 months (Kaplan–Meier analysis). Visual recovery post-surgery was rapid with most patients experiencing either no change in vision or improvement in BCVA. This study clearly demonstrates the effectiveness and good safety profile of XEN Gel Implant in refractory glaucoma.

In Galal et al evaluated 13 eyes with primary open angle glaucoma underwent XEN implantation with subconjunctival mitomycin C (MMC).[37] Complete success (IOP reduction ≥20% from preoperative baseline at 1 year without any glaucoma medications) was achieved on 41.7% of patients, while qualified success rate (IOP reduction of ≥20% at 1 year with medications) was 66.7%. IOP reduction at 12 months was 16 ± 4 to 12 ± 3 mmHg (p ≤ 0.01) and medication’s reduction at 12 months was 1.9 ± 1 to 0.3 ± 0.49 (p = 0.003).

In a prospective, non-RCT by De Gregorio et al, 41 eyes of 33 patients underwent a XEN Gel Implant procedure combined with cataract surgery.[38] Outcomes of this study show that XEN45 implant is statistically effective in reducing IOP and medications even after 12 months. The complete success rate (≤18 mmHg without medications) after 12 months was achieved in 80.4% (33 of 41 eyes) and a qualified success (≤18 mmHg with medications) in 97.5% (40 of 41 eyes). IOP reduction at 12 months was 22.5 ± 3.7 to 13.1 ± 2.4 mmHg (p < 0.05) and medication’s reduction at 12 months was 2.5 ± 0.9 to 0.4 ± 0.8 (p < 0.05).

In a prospective, multicenter, non-RCT, Reitsamer et al reported 24 months follow-up of 174 eyes (79.8% of 218 total eyes initially enrolled).[39] Of these, 65.8% achieved complete success, defined as ≥20% reduction in IOP without secondary surgical intervention. 48.4% achieved ≥30% reduction in IOP without secondary surgical intervention. 41.1% of eyes underwent at least one needling. This study included both standalone XEN implantations and those that combined phacoemulsification with XEN implantation, and the results were similar for both of these treatment arms.

In a prospective multi-centered study, Lenzhofer et al reported 4-year results of 64 eyes that received XEN63 Gel Microstent for treatment of uncontrolled open angle glaucoma.[40] The average baseline IOP with optimal medical before the XEN implantation was 22.5 ± 4.2 mmHg (n = 34, p <0.001). 4 years after XEN implantation, the average IOP was reported to be 13.4 ± 3.1 mmHg, a 40% decrease from baseline. 25% (12/53) eyes achieved complete surgical success after 4 years and 53% (28/53) achieved qualified success. 53.1% of eyes underwent needling. Notably, the generalizability of the results is limited because MMC was not used and the device under investigation is longer than the FDA-approved XEN45.

XEN Gel Implant Vs. Trabeculectomy

An international multicenter retrospective study has been published that compares the efficacy, safety, and risk factors for failure of standalone XEN gel stent implantation versus trabeculectomy. In this study, 354 eyes with uncontrolled glaucoma and no prior incisional filtering surgery underwent microstent implantation (n = 185) or trabeculectomy (n = 169), both with adjunctive MMC. The results failed to demonstrate any difference in efficacy, risk of failure, and safety profile between the 2 surgical procedures.[15]

Schlenker et al reported a median preoperative IOP of 24 mmHg on three medications for both the Xen45 and trabeculectomy groups.[41] At 12 months, the IOPs in both groups decreased to 13.0 mmHg off all IOP-lowering medications, without any statistically significant difference between groups. There was no difference in the HRs of failure between the two procedures. At last follow-up, a larger proportion of Xen45 patients were completely off medications (75.7 versus 67%), but this was not statistically significant.[11] The trabeculectomy group had more postoperative interventions (mostly laser suture lysis) and complications (bleb leak or dehiscence). Bleb needling was slightly higher for the XEN Gel Implant group (43% vs 31%), but this difference was not statistically significant.

XEN Solo vs XEN Combo

Multiple studies have been published to assess the safety of XEN implantation as a standalone (XEN solo) vs in combination with phacoemulsification (XEN combo). The findings are mixed and appear to vary at least in part due to differences in data analysis methodology.

In the previously mentioned prospective study by Reitsamer et al, XEN solo and Xen combo treatment groups had similar IOP-lowering results at 24 months.[39]

In one retrospective study comparing 200 XEN solo eyes and 39 XEN combo eyes at 12 months follow-up, the IOP in the Xen solo group improved from a baseline of 31.5 ± 8.4 mmHg to 14.3 ± 4.2 mmHg. In comparison, the IOP in the XEN combo group similarly improved from a baseline of 35.7±12.0 mmHg to 13.9±2.5. Additionally, the glaucoma medication for the XEN Solo group dropped from 3.1± 1.0 to 0.3 ± 0.7 while the XEN combo group dropped from 3.3 ± 1.0 to 0.4 ± 0.7. There was no statistical difference between XEN solo and XEN combo.[42]

In a prospective interventional case series comparing Xen solo with Xen combo at 12 months, Mansouri et al reported a median IOP reduction of 40% in the Xen solo treatment arm compared to 22.9% in the Xen combo arm. 81% of Xen solo eyes achieved IOP reduction ≥20% from medicated baseline IOP, whereas 56.1% of Xen combo eyes achieved IOP reduction ≥20% (p= 0.04). At 12 months, 57.7% of all eyes achieved IOP < 16 on no medications, and there was no difference between the Xen solo and Xen combo groups. 37% of all eyes required needling.[43]

In a prospective multicenter trial, Fea et al reported that the mean IOP in Xen solo eyes improved from 21.4 mmHg to 15.8 mmHg at 12-month follow-up, whereas Xen combo eyes’ mean IOP improved from 25.0 to 15.4 mmHg. There was no statistical difference between the two groups’ IOP improvement at any time after post-operative week 1.[30]

XEN in Pediatric Glaucoma

In 2020, an interventional case series reported three eyes of three pediatric patients with congenital glaucoma who received XEN gel stent implant. Two of the eyes failed trabeculotomy and the third eye was a primary gel stent implantation. All three eyes post-operation had controlled IOP without the use of topical medication up to 24 months of follow-up.[44] An additional retrospective study on childhood glaucoma and XEN looked at XEN-augmented Baerveldt implantation that also found encouraging results for refractory pediatric glaucoma.[45]

Conclusion

In the rapidly evolving era of less invasive glaucoma surgeries, Xen Gel Stent offers a new means of lowering IOP for patients with advanced open-angle glaucoma. Most published studies are reporting early follow-up, so the long-term efficacy and safety are yet to be demonstrated. However, many trials with a 1- year follow-up have reported acceptable safety and good efficacy in comparison to traditional filtering surgery.[3][18] Longer follow-up periods will be needed to assess the durability and long-term safety of Xen, especially in comparison with existing traditional glaucoma surgeries.[11]

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