Response to Comments: Micro-Invasive Glaucoma Surgery (MIGS)

The American Glaucoma Society (AGS) recommended coverage of XEN45. They conclude: “At this juncture, based on the data that has been published and reported in the mainstream Ophthalmology Annual meetings, the AGS supports the use of the Xen-45 gel microstent for patients with refractory glaucoma who are in need of glaucoma filtration surgery to lower IOP significantly to save their sight. Without access to the XEN-45, many patients are having riskier surgeries performed because of these noncoverage issues…… The non-coverage of the Xen is a serious patient care issue for members of the AGS who serve thousands of glaucoma patients’ everyday. In light of the accumulating favorable information regarding the gel stent, the AGS urges Medicare carrier medical directors to reconsider and allow coverage for the Xen-45 gel microstent."

NGS agrees there is “accumulating favorable information” in terms of abstracts and society meeting presentations, but the peer-reviewed, published literature is lacking in quality (no RCT), size, and length of follow-up (longer-term follow-up is especially relevant when a device is permanently implanted). Below is a summary of the published studies of XEN45 that NGS has been made aware of to date. There are two case reports, three small, uncontrolled, prospective case series with one-year follow-up, and one retrospective case study comparing XEN and trabeculectomy at least one month after surgery, the only study to have a control group. While the results are uniformly promising, the authors also generally call for longer follow-up and randomized study.

1. A retrospective study of 354 eyes (185 microstent and 169 trabeculectomy) in patients with uncontrolled glaucoma but no prior incisional surgery (1). There was no statistical difference in either risk of failure or safety profiles, at least 1 month after surgery, between the two treatments. The authors conclude that “Further research is warranted to investigate these 2 interventions. A randomized controlled trial (unlikely able to mask) would be welcomed to eliminate confounding.”

2. A prospective case series of 13 eyes treated with XEN for open-angle glaucoma (OAG), 10 with simultaneous phacoemulsification (2). At one year, 42% achieved complete success (>=20% IOP drop without medications), and 66% qualified success (>= 20% IOP drop with medications). Complications included choroidal detachment in 2 eyes, and implant extrusion in 1 eye, and 2 eyes underwent trabeculectomy. The authors conclude: “this new technique needs further assessment for longer follow-up survival.”

3. A prospective case series of 41 eyes treated with combined XEN and cataract surgery for OAG (3). At one year, 80.4% achieved complete success (IOP >=6 and <=17 mmHg without medications), and 97.5% qualified success (IOP >=6 and <=17 mmHg with medications).

4. A prospective case series of 30 eyes treated with combined XEN and cataract surgery for OAG (4). At one year, the preoperative IOP had decreased by approximately 29%. The mean medications required went from 3.07 preoperatively to 0.17 (p<0.001). Complications occurred in 3 eyes, 2 eyes had XEN implantation aborted due to surgical difficulties (subconjunctival hemorrhage and XEN extrusion during preparations), while one eye had filtration bleb failure due to encapsulation 5 months after surgery. The authors conclude: “randomized and controlled studies with higher numbers of patients and longer terms are necessary to confirm the promising results described above.”

5. A case report of a XEN complication and how it was treated (5).

6. A case report of successful XEN implant after descement membrane endothelial keratoplasty (DMEK) (6).

NGS received approximately a dozen comments from clinicians endorsing coverage of XEN45 and describing their experience using it. Several noted it is particularly suited to the Medicare populations. Two representative examples follow:  “As the population grow older (many more individuals in their late 80’s and 90’s) and many more patients on anticoagulation medications, the risk of choroidal hemorrhage rises with trabeculecomy. In several of my more elderly/fragile patients, we have found great success with the XEN Gel stent. Many of these patients repetitively refused trabeculectomy but chose to have the XEN Gel Stent with the hope of not going fully blind.” “The XEN gel stent fills a very particular need in the very elderly with advancing glaucoma.  In many patients over 85 years old, conjunctival surgeries must be avoided due to the serious risk of poor wound healing.  Without a conjunctival incision, the XEN device can control even severe glaucoma without this risk.”

While NGS understands that personal experience can be very compelling, and agrees less invasive approaches tend to favor the elderly, coverage must be grounded on the peer-reviewed literature. See response #1. 

NGS received a presentation from Allergen, the manufacturer of XEN45, primarily based on describing the results of the as yet unpublished US Pivotal study (7).

While NGS understands the US Pivotal study has been accepted for publication, only peer-reviewed, published studies are considered. However, even when published, this study won’t fundamentally address the evidentiary deficiencies cited in response #1. It is a relatively small (N=65), non-randomized, non-controlled study, with a follow-up of only 12 months.

NGS received a presentation from a consultant for Allergen, primarily based on personal use experience and a summary of the APEX phase IV XEN45 Study already cited in the draft LCD (8).

This study is also unpublished and similarly doesn’t address existing evidentiary deficiencies (see response #3).

The American Glaucoma Society (AGS) also recommended select off-label coverage of both multiple microstents (“stent dosing”) and as a standalone procedure (i.e., without simultaneous cataract surgery). They argue the concept of “dosing” has an anatomic basis in that “most physiologists believe that canalicular outflow is segmental, and while a single stent improves outflow in that portion of the canal and distal outflow system, placing more than one stent provides access to additional collector channels.”

NGS disagrees. Below is a summary of the published studies provided (all but one involving iStent) in support of either multiple stenting, use as a standalone, or both. There is a case report, three small, uncontrolled, prospective case series with only one-year follow-up, and one small, retrospective case series in pseudophakic subjects. The most important study, an RCT, failed to show a statistical difference in either primary or secondary outcome measures, between one, two, or three standalone iStents. As noted by AGS, there is now over 5 years of experience with iStent since it was FDA approved in 2012. If the evidence accumulated supports dosing and use as a standalone, NGS would encourage application by the manufacturer for expanded labelling. On a separate but related note, there has been more than enough time to petition for a Category 1 CPT code, a move that would also address complaints about variable or deficient pricing by Medicare contractors.

1. A prospective, randomized, controlled evaluation of OAG uncontrolled on two topical hypotensive medications, treated with one (38), two (41), or three (40) iStents (9). There was no significant difference between the three groups on either the primary or secondary outcome measure. Both month 12 IOP reduction >=20% without ocular hypoten­sive medication vs baseline unmedicated IOP, and month 12 unmedicated IOP <=18 mmHg, were achieved by 89.2%, 90.2%, and 92.1% of one-, two-, and three-stent eyes, respectively. While the authors report other measures (e.g., IOP) which were statistically different between groups, these weren’t defined in the protocol prior to the study according to clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT01517477).

2. A pilot prospective, non-controlled study of 39 subjects with OAG treated with two iStents as a standalone procedure (10). The primary efficacy end point (IOP reduction >=20% from baseline to 12 months without medication) and the secondary end point (IOP <=18 mmHg at 12 months without medication) were each achieved by 92.3% of subjects. Three-year follow-up in 30 subjects demonstrated persistent IOP reduction in >=20% in 86.2% and IOP <= 18 mmHg in 89.7%. The authors note: “We also welcome larger, multicenter controlled studies to further corroborate our findings.”

3. A prospective study of 53 eyes with OAG, not controlled on two medications, treated with two iStents as a standalone procedure and postoperative topical prostaglandin (11). The main outcome measure (the proportion of eyes with intraocular pressure reduction ≥ 20% versus medicated baseline intraocular pressure with reduction of one medication at 12 months), was achieved in 91% of the 53 treated eyes.

4. A retrospective, consecutive case series of 42 pseudophakic eyes with mild to moderate glaucoma implanted with a single iStent (12). IOP was significantly reduced at one and two years, but medication use was not.

5. A multi-center, prospective, study of 65 subjects with OAG refractory to medical therapy and treated with a single CyPass device (13). Among the 55 subjects available for follow-up at one year, IOP was reduced by 34.7% (p<0.0001) and medications decreased from 1.4 to 1.3 (p=0.002).

6. A case report of 2 iStents implanted into a patient with recurrent OAG 5 years after Ahmed valve implantation (14). They report a decrease in the IOP from a pre-operative baseline of 28 mm Hg to 17 mm Hg at two year follow-up.

  References 

1. Schlenker MB, Gulamhusein H, Conrad-Hengerer I, et al. Efficacy, safety, and risk factors for failure of standalone ab interno gelatin microstent implantation versus standalone trabeculectomy. Ophthalmology. 2017:1-10. http://dx.doi.org/10.1016/j.ophtha.2017.05.004. 

2. Galal A, Bilgic A, Eltanamly R, Osman A. Xen Glaucoma implant with mitomycin c 1-year follow-up: result and complications. Journal of Ophthalmology. 2017:1-5. https://doi.org/10.1155/2017/5457246.

3. De Gregorio A,  Pedrotti E, Russo L, Morselli S. Minimally invasive combined glaucoma and cataract surgery: clinical results of the smallest ab interno gel stent. Int Ophthalmol. 2017:1-6. doi: 10.1007/s10792-017-0571.

4. Pérez-Torregrosa VT, Olate-Pérez Á, Cerdà-Ibáñez M. et al. Combined phacoemulsification and Xen 45 surgery from a temporal approach and 2 incisions. Arch Soc Esp Oftalmol. 2016;91(9):415-421.

5. Pinto Ferreira N, Abegã Pinto L, Marques-Neves C. Xen gel stent internal ostium occlusion: ab-interno revision. J Glaucoma. 2017;26(4):e150–e152.

6. Hohberger B,  Welge-LüBen UC, Lämmer R. ICE-Syndrome: A case report of implantation of a microbypass Xen gel stent after DMEK transplantation. J Glaucoma.  2017;26(2):e103–e104.

7. Grover DS, Flynn WJ, Bashford KP, Lewis RA, Duh Y-J, Nangia RS, Niksch B, Performance and safety of a new ab interno gelatin stent in refractory glaucoma at 12 months, American Journal of Ophthalmology (2017), doi: 10.1016/j.ajo.2017.07.023.

8. Stalmans I, Vera, V. Evaluation of the XEN implant in patients with moderate primary open-angle glaucoma: 1-year results. Abstract presented at the European Glaucoma Society 2016 Congress (EGS), June 19-22, 2016, Prague, Czech Republic.

9. Katz, LJ, Erb C, Carceller GA, et al. Prospective, randomized study of one, two, or three trabecular bypass stents in open-angle glaucoma subjects on topical hypotensive medication. Clinical Ophthalmology (Auckland, NZ) 9 (2015): 2313.

10. Donnenfeld ED, Solomon KD, Voskanyan L, et al. A prospective 3-year follow-up trial of implantation of two trabecular microbypass stents in open-angle glaucoma. Clinical Ophthalmology (Auckland, NZ) 9 (2015): 2057.

11. Berdahl J, Voskanyan L, Myers JS, et al. Implantation of two second-generation trabecular micro-bypass stents and topical travoprost in open-angle glaucoma not controlled on two preoperative medications: 18-month follow-up. Clinical & Experimental Ophthalmology (2017).

12. Ferguson, Tanner J, Berdahl JP, Schweitzer JA et al. Evaluation of a trabecular micro-bypass stent in pseudophakic patients with open-angle glaucoma. Journal of glaucoma 25.11 (2016): 896-900.

13. Garcia-Feijoo J, Rau M, Grisanti S, et al. Supraciliary micro-stent implantation for open-angle glaucoma failing topical therapy: 1-year results of a multicenter study. Am J Ophthalmol 2015;159(6):1075–1081.

14. Roelofs K, Arora S, Dorey MW. Implantation of 2 trabecular microbypass stents in a patient with primary open-angle glaucoma refractory to previous glaucoma-filtering surgeries. Journal of Cataract & Refractive Surgery 40.8 (2014): 1322-1324.