The uveoscleral outflow pathway was initially described by Anders Bill in 1965.^1,2 Through this pathway, aqueous leaves the anterior chamber across the iris root and the ciliary body to the suprachoroidal space,³ and from there into the scleral vessels, the choriocapillaris, and episclera.⁴

The suprachoroidal space has been an attractive target to lower intraocular pressure (IOP) for several reasons. The large surface area and a negative pressure gradient provide a good driving force for aqueous outflow. In addition, the substantial effect of cyclodialysis in lowering IOP has been shown in clinical experience.

Since 1905 when Dr. Leopold Heine devised the cyclodialysis spatula to reproducibly create a cyclodialysis cleft to lower IOP,⁵ several space-maintaining substances, techniques, and implants have been described to create a reproducible and safe suprachoroidal drainage pathway; these have met with limited success. With advances in device design and biocompatibility, several implants have been developed in recent years targeting the uveoscleral outflow pathway.

The Cypass Microstent

Cypass (Alcon) was the first ab-interno supraciliary microstent that received FDA approval in 2017. It was designed to be placed at the time of cataract surgery. It was constructed of a biocompatible polyimide material, and measured 6.35 mm in length with a 300-µm lumen.

In the COMPASS trial of 505 subjects randomized to cataract extraction with Cypass and cataract extraction alone, at 2 years the mean IOP reduction was 7.4 mmHg in the implant group, and 85% of patients were medication free. In addition, there was little difference in endothelial cell loss after 2 years between the Cypass and cataract surgery-only groups.⁶ The 5-year COMPASS-XT trial showed a higher percentage of subjects in the Cypass group (46%) than in the control group (32.1%) able to achieve an IOP reduction of ≥20% without any medication.⁷ However, longer term data showed that the Cypass microstent group experienced statistically significantly higher endothelial cell loss compared to the control cataract surgery group.

In August 2018, Alcon voluntarily withdrew the device from the market based on results of the COMPASS-XT trial and the FDA officially recalled the device shortly thereafter. In response, the ASCRS Cypass Withdrawal Task Force issued a report on how to manage these patients, which stated the following⁸:

• Patients who received Cypass devices should be notified that the medical implants have been voluntarily withdrawn from the market.
• Patients should continue to be followed by their physician at appropriate intervals.
• Risk assessment includes (1) evaluation of symptoms (eg, morning blurriness or glare); (2) slit lamp examination (eg, evaluation of focal or diffuse corneal stromal edema and/or guttata); and (3) gonioscopy with attention to device position (ie, contact with the corneal endothelium, the position of the device lumen anterior to Schwalbe’s line, and to the number of retention rings visible in the anterior chamber). Although clinical examination alone may be appropriate for monitoring these patients, some other ancillary tests, such as corneal pachymetry and specular microscopy, may be considered. Studies showed that there is a direct association between the percentage of endothelial cell loss per year and the number of retention rings visible in the anterior chamber. The percentages of endothelial cell loss per year were 0.36% in the control group, 1.39% in the no visible ring group, 2.74% in the 1 visible ring group, and 6.96% among eyes with 2 or 3 visible rings. The assessment of endothelial cells was done by specular microscopy.
• According to the Cypass instructions for use (IFU), device adjustment or removal is not recommended in the absence of clinical sequelae.⁹
• According to the Cypass IFU, situations that may be considered for adjustment or removal of the Cypass microstent include, but are not limited to (1) intermittent or persistent contact between the Cypass microstent and the corneal endothelium; (2) significant decrease in endothelial cell density that seems to be associated with Cypass microstent positioning or stability; (3) iris-cornea touch; (4) persistent hypotony; (5) persistent uncontrolled uveitis; (6) recurrent or persistent hyphema with elevated IOP above the target pressure; and (7) any anatomic or functional clinical sequelae of the anterior or posterior segment that may threaten vision.
• In eyes with 0 or 1 ring of the Cypass device visible in the anterior chamber by gonioscopy with no clear evidence of corneal decompensation, no action is recommended other than clinical monitoring.
• Eyes with 2 or 3 rings of the Cypass device visible in the anterior chamber by gonioscopy are at higher risk of corneal endothelial cell loss. However, not all of these eyes will experience clinically significant endothelial cell loss. Therefore, no action is recommended other than clinical monitoring without clinically significant evidence of corneal decompensation. These patients may need more frequent corneal evaluation.
• With evidence of corneal decompensation with more than 1 visible ring on gonioscopy, Cypass repositioning, removal, or trimming of the proximal end may be considered. The consensus is that implant repositioning (ie, deeper implantation) is safest if it is performed within 7 days to 10 days of implantation. Beyond this period of time, there may be higher risk of complications with repositioning of the device because of fibrosis around and/or through the filtration holes of the device. In addition, device removal was not recommended for the same reason. Trimming of the proximal end would be the most preferred procedure if the patient and physician agree. More information about the technical descriptions of the procedures could be found in the Cypass microstent IFU.⁹

There is still some debate surrounding the device and that Alcon acted on the side of caution. It has been argued that the endothelial cell loss could be caused by the glaucoma disease process itself, be caused by treatment alternatives, or be secondary to surgical technique rather than caused by the device itself. In addition, there are limited data about 5-year endothelial cell loss following insertion of other glaucoma surgical devices to serve as a comparator to data generated by the COMPASS-XT study.

Some glaucoma specialists still support the use of Cypass because of its efficacy and relatively good safety profile. There have been some discussions about the possibility of reassigning the device to be used specifically in moderate to severe primary open-angle glaucoma vs mild-to-moderate primary open-angle glaucoma. There is currently no update on the revision of the device.

iStent Supra Microbypass Stent

The iStent Supra (Glaukos) is a suprachoroidal stent that is made from a heparin-coated combination of polyethersulfone and medical-grade titanium. The device is 4 mm long and has a 165-μm lumen. It is inserted by an ab-interno approach through a clear corneal incision, and retention rings provide stability. It could be implanted as a stand-alone procedure in both phakic and pseudophakic eyes or in conjunction with cataract surgery. The device is inserted into the suprachoroidal space using a preloaded disposable injector.

To date, there have been few published studies on this device. One European study assessed the 12-month safety and efficacy of iStent Supra in reducing IOP and medication burden in open-angle glaucoma subjects who had previously uncontrolled glaucoma on 2 topical medications.¹⁰ The mean preoperative medicated diurnal IOP was 20.4 mmHg, and the unmedicated baseline IOP was 24.8 mmHg. Twelve months after uncomplicated placement of the iStent Supra and administration of postoperative travoprost, 98% of 42 subjects met the primary endpoint of the study, which was 20% reduction of IOP with 1 medication.¹⁰ The mean IOP decreased by 47% to 13.2 mmHg. No adverse events were documented during the course of the study.¹⁰

In another prospective study, Myers et al reported 4-year outcomes of the iStent Supra suprachoroidal stent in 80 subjects with open-angle glaucoma and IOP ≥18 mmHg after prior trabeculectomy and while taking 1 to 3 glaucoma medications.¹¹ Participants received 2 iStent trabecular microbypass stents, 1 iStent Supra suprachoroidal stent, and postoperative travaprost. Preoperatively, mean medicated IOP was 22.0±3.1 mmHg with 1.2±0.4 medications, and mean unmedicated IOP was 26.4±2.4 mmHg. Postoperatively, mean medicated IOP at all visits through 48 months was ≤13.7 mmHg (≥37% reduction) in eyes without later cataract surgery; and annual unmedicated IOP was ≤18.4 mmHg (reductions of ≥30% vs preoperative unmedicated IOP and ≥16% vs preoperative medicated IOP).¹¹ Among eyes without additional surgery or medication, ≥91% of eyes had ≥20% IOP reduction on 1 medication vs preoperative medicated IOP at all postoperative visits.¹¹ After 4 years, 97% and 98% of eyes achieved IOP ≤15 mmHg and ≤18 mmHg, respectively, on 1 medication.¹¹ The authors also reported favorable safety measurements throughout follow-up.¹¹

There is currently an ongoing prospective, randomized, single-masked, multicenter clinical trial¹² in the United States that is evaluating the safety and efficacy of the Glaukos suprachoroidal stent model G3 in conjunction with cataract surgery, compared to cataract surgery alone, in subjects with mild-to-moderate primary open-angle glaucoma. The study started in October 2011 and is estimated to be completed in May 2022 with estimated enrollment of 1,200 participants.

iStar Miniject

Miniject is a newly designed suprachoroidal device by iStar Medical for patients with primary open-angle glaucoma. MINIject uses the unique porous structure of its proprietary Star material, which has antifibrotic and anti-inflammatory properties and enhances natural fluid outflow. As a result, it is designed to reduce IOP and medication burden by enhancing uveoscleral outflow, while biointegrating with surrounding tissue and limiting inflammation, fibrosis, and subsequent complications.

The STAR-I trial was a prospective, multicenter, first-in-human, single-arm, interventional study that evaluated the efficacy and safety of standalone, ab-interno implantation of Miniject in 25 patients with open-angle glaucoma uncontrolled by topical medications.¹³ Mean baseline IOP was 23.2±2.9 mmHg on 2.0±1.1 medications, which decreased to 13.8±3.5 mmHg (40.7% reduction) on 1.0±1.3 medications 2 years after implantation.¹³ Complete success (ie, diurnal 5<IOP ≤21 mmHg with an IOP reduction of 20% without any medication) was achieved in 47.6% of patients and qualified success (ie, diurnal 5<IOP ≤21 mmHg with an IOP reduction of 20% with medication) in 100% of patients 2 years after implantation.¹³ All patients achieved a 20% IOP reduction, and 48% of patients were medication free.¹³ No serious ocular adverse events or additional glaucoma surgery were reported. Mean central endothelial cell density decreased from 2,411 cells/mm² to 2,341 cells/mm² at 24 months, representing a 5% decrease for matched eyes. No patient had a ≥30% decrease in central endothelial cell density.¹³

The European STAR-II study is a prospective, interventional, single-arm, multicenter trial evaluating the efficacy and safety of standalone, ab-interno implantation of Miniject in 29 of 31 patients with primary open-angle glaucoma in 8 sites in France, Germany, and Spain.¹⁴ The primary endpoint is success rate >60% (ie, diurnal 5<IOP ≤21 mmHg with ≥20% IOP reduction from baseline, with/without medications). At the 6-month follow-up, 75.9% of subjects achieved the prospectively defined success.¹⁴ The mean IOP was reduced by 40.2% (9.9 mmHg) from 24.6±3.8 mm Hg at baseline to 14.7±6.0 mmHg at 6 months. In addition, the use of medications was reduced by 63.4% to 1.0±1.3 from 2.9±1.2 at baseline.¹⁴ Furthermore, 79.3% of the patients had mean IOP ≤18 mmHg, 82.8% achieved ≥20% IOP reduction, and 55.2% were medication free at 6 months.¹⁴ At the 6-month follow-up, there were no major complications and minimal changes to corneal endothelial cell density. The study will be followed up for 2 years.¹⁵

Conclusion

The accessibility and physical characteristics of the suprachoroidal space, as well as the potential for significant IOP reduction, have made it an attractive target for minimally invasive glaucoma procedures. The preliminary results of different suprachoroidal devices are encouraging. Interestingly, the pathways for FDA approval vary from a combined procedure with cataract extraction in mild-to-moderate glaucoma to a standalone procedure in refractory glaucoma. However, more data from long-term, randomized, controlled trials are needed before approval by the FDA. GP

References

1. Bill A, Hellsing K. Production and drainage of aqueous humor in the cynomolgus monkey (Macaca irus). Invest Ophthalmol. 1965;4(5):920-926.
2. Bill A. The aqueous humor drainage mechanism in the cynomolgus monkey (Macaca irus) with evidence for unconventional routes. Invest Ophthalmol. 1965;4(5):911-919.
3. Emi K, Pederson JE, Toris CB. Hydrostatic pressure of the suprachoroidal space. Invest Ophthalmol Vis Sci. 1989;30(2):233-238.
4. Alm A, Nilsson SF. Uveoscleral outflow – A review. Exp Eye Res. 2009;88(4):760-768.
5. Heine L. Die cyclodialyse, eine neue glaukomoperation. Dtsch Med Wochenschr. 1905;31:824-826.
6. Vold S, Ahmed II, Craven ER, et al; CyPass Study Group. Two-year COMPASS trial results: supraciliary microstenting with phacoemulsification in patients with open-angle glaucoma and cataracts. Ophthalmology. 2016;123(10):2103-2112.
7. Reiss G, Clifford B, Vold S, et al. Safety and effectiveness of CyPass Supraciliary Micro-Stent in primary open-angle glaucoma: 5-year results from the COMPASS XT study. Am J Ophthalmol. 2019;208:219-225.
8. ASCRS CyPass Withdrawal Task Force. Preliminary ASCRS CyPass withdrawal consensus statement. https://ascrs.org/news/ascrs-news/cypass-withdrawl
9. Alcon. Instructions for Use CyPass System REF #CYP-241-S. Accessed November 9, 2021. https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150037d.pdf
10. Junemann A. Twelve-month outcomes following ab interno implantation of suprachoroidal stent and postoperative administration of travoprost to treat open angle glaucoma. Presented at: 31st Congress of the European Society of Cataract and Refractive Surgeons; October 2013; Amsterdam, Netherlands.
11. Myers JS, Masood I, Hornbeak DM, et al. Prospective evaluation of two iStent® trabecular stents, one iStent Supra® suprachoroidal stent, and postoperative prostaglandin in refractory glaucoma: 4-year outcomes. Adv Ther. 2018;35(3):395-407. doi:10.1007/s12325-018-0666-4
12. Multicenter investigation of the Glaukos suprachoroidal stent model g3 in conjunction with cataract surgery. Clinicaltrials.gov identifier: NCT01461278. Accessed October 28, 2021. https://clinicaltrials.gov/ct2/show/NCT01461278
13. Denis P, Hirneiß C, Durr GM, et al. Two-year outcomes of the MINIject drainage system for uncontrolled glaucoma from the STAR-I first-in-human trial [published online ahead of print, 2020 Oct 3]. Br J Ophthalmol. 2020;bjophthalmol-2020-316888. doi:10.1136/bjophthalmol-2020-316888
14. García Feijoó J, Denis P, Hirneiß C, et al. A European study of the performance and safety of MINIject in patients with medically uncontrolled open-angle glaucoma (STAR-II). J Glaucoma. 2020;29(10):864-871. doi:10.1097/IJG.0000000000001632
15. MINIject glaucoma implant in European patients (STAR-II). Clinicaltrials.gov identifier: NCT03624361. Accessed October 28, 2021. https://clinicaltrials.gov/ct2/show/NCT03624361