Surgeons explore suprachoroidal space as alternative aqueous outflow target

Microinvasive glaucoma surgery, an alternative to trabeculectomy and tube shunt implantation, is designed to improve aqueous outflow by using stents to direct aqueous humor into the uveoscleral pathway, subconjunctival space or suprachoroidal space.

Ab interno MIGS with the Trabectome (NeoMedix) or the iStent (Glaukos) has been shown to reduce IOP without bleb-associated risks and is often performed in conjunction with cataract surgery.

Some surgeons are starting to embrace MIGS in the suprachoroidal space. The suprachoroidal space has certain anatomic features that increase aqueous outflow and reduce the risk of complications, proponents say.

Suprachoroidal stents are not approved in the U.S., but two ab interno devices are undergoing clinical trials in the U.S.: the iStent Supra (Glaukos) and the CyPass suprachoroidal micro-stent (Transcend Medical). Both devices are indicated for combined cataract and glaucoma surgery. Transcend Medical plans to submit a premarket approval application to the FDA later this year, according to correspondence from the company.

“With regard to the technique, it seems very reasonable. I think that the transition period or learning period for anyone who’s looking to incorporate that, provided that these get approved, will be fairly rapid. I’m optimistic about its ability to proliferate among our colleagues,” Douglas J. Rhee, MD, OSN Glaucoma Board Member, said. “In terms of the initial data, it’s pretty impressive. The Transcend device has closed their enrollment.”

Image: Shari Fleming Photography

Transcend has published 24-month data on the CyPass.

“There’s not a ton of published information out on the Glaukos device, but what is out there is also very impressive. I’m very optimistic about this technology,” Rhee said.

Why the suprachoroidal space?

According to a report by Steven Vold, MD, suprachoroidal outflow has the potential for best IOP-lowering efficacy. In addition, he said, preliminary safety results for suprachoroidal shunts are comparable to results obtained with other MIGS implants.

“The suprachoroidal space is a very absorptive space,” Ike K. Ahmed, MD, FRCSC, OSN Glaucoma Board Member, said. “It has a lot of potential in terms of its ability to lower pressures. It’s a very large absorptive surface area that potentially can take a lot of aqueous and facilitate its drainage.”

MIGS is safer in the suprachoroidal space than the subconjunctival space, according to Reay Brown, MD.

“I think safety is No. 1. I think that’s the whole thing. If it weren’t safer, then it may not be so appealing. But it is safer,” Brown said. “The suprachoroidal space has not really been targeted very much before. Although people have done cyclodialysis, which is one way to approach the suprachoroidal space, that procedure was very primitive and too often you would get low pressures or no effect, so it was hard to reach a middle ground. But the CyPass has been able to achieve pressures that are very good, and it has not had much, if any, hypotony.”

Ahmed elaborated on the reduction of risk and anatomic advantages of suprachoroidal drainage.

“[We avoid] an external bleb,” Ahmed said. “The ability to redirect aqueous to a physiologic outflow pathway to the suprachoroidal space reduces the need to go subconjunctivally, which is the goal of this procedure.”

According to Nils A. Loewen, MD, PhD, targeting the suprachoroidal space prevents exposure and consequences such as endophthalmitis and hypotony.

“The advantage of the suprachoroidal space is that any device that is placed into the suprachoroidal space is not going to erode through the conjunctiva and cause exposure,” Loewen said. “Exposure on the conjunctiva side of any device can cause endophthalmitis because it’s basically an open eye. Traditional trabeculectomy can also cause early and late very low eye pressure, called hypotony, that is almost unheard of with suprachoroidal devices.”

In addition, the suprachoroidal space is somewhat less prone to fibrosis than other areas, but it also exists here to some extent, Loewen said.

“Our eye is designed to inhibit exuberant inflammatory responses. If you think about how this might have made sense from an evolutionary perspective, when we were hunters and gatherers, preserving an eye after injury was very important. Suppressing an immune response is important so you can still see,” he said.

Thomas W. Samuelson, MD, OSN Glaucoma Section Editor, said there are anatomic advantages of targeting the suprachoroidal space for aqueous outflow.

“I would say that an opportunity to keep all of the outflow within the eye is favorable because any time you have a direct communication from outside the eye to inside the eye, you introduce an infection risk that you don’t have if you keep everything within the sclera,” Samuelson said. “Anytime you create a direct conduit, whether it be a trabeculectomy, an aqueous drainage device or even the new, less invasive subconjunctival devices such as the Xen (AqueSys) or the InnFocus (InnFocus), you introduce the potential risk for bleb-related infections. Although, to the best of my knowledge, there have been no reported infections with Xen or InnFocus.”

In addition, using the suprachoroidal space is a good alternative for patients with angle-closure glaucoma or failed transscleral procedures, Samuelson said.

“For the most part, it’s an untapped reservoir, the suprachoroidal space. We really haven’t utilized that space in the past, at least very effectively, so we have a whole new opportunity to divert aqueous and lower pressure,” he said. “An important point worth elaborating on is that much of the world has a significant problem with angle-closure glaucoma, especially in Asia. In angle closure, the canal is often compromised such that canal-based procedures may not apply. If an iridotomy or cataract extraction doesn’t adequately open up the angle and the patient is left with chronic angle closure, this technology may be tailor-made for that type of individual.”

Suprachoroidal stents

The CyPass and the iStent Supra, inserted via an ab interno approach through the angle, completely bypass the trabecular meshwork and the ciliary body to connect the anterior chamber with the suprachoroidal space.

“Basically, one uses a specialized lens called a goniolens, a prism type of thing that you put in the eye. You insert it on the direct view into this space. You identify the angle of the eye, and then this two-ply structure, both the CyPass and iStent Supra, is simply pushed out into the periphery when you identify the correct site,” Loewen said.

The CyPass is 6.35 mm long, with a 300 mm lumen and an external diameter of 510 mm.

The iStent Supra is a heparin-coated slightly curved polyethersulfone stent designed to create and maintain a lumen in the suprachoroidal space.

The iStent Supra targets uveoscleral outflow.

“The uveoscleral route is thought to account for up to 50% of flow in healthy eyes anyway, and if you create a cleft or put a device into the cleft, there’s almost no limit. You can achieve very low pressures, down to 5 mm Hg or 10 mm Hg in theory,” Loewen said.

According to Ahmed, the iStent Supra and the CyPass are similar in most respects.

“The iStent Supra and CyPass are very similar in terms of how they are placed in the eye and where they are located in the suprachoroidal space,” Ahmed said. “They have some slight differences with regards to material, and they have some differences with regards to the delivery mechanism. But otherwise, they’re very similar in the sense that they redirect aqueous into the suprachoroidal space through an ab interno approach using corneal incisions.”

Rhee said that the CyPass has shown good biocompatibility.

“There is peripheral anterior synechiae formation, but it’s unclear whether that’s really a biocompatibility issue, a placement issue or both,” Rhee said.

Samuelson said that MIGS with implantation of the iStent Supra or the CyPass shows potential as an alternative to canal surgery.

“I’m greatly anticipating their arrival,” he said. “I think that the canal can only take us so far. I think that things like canal devices or canal surgery will prove to be extremely useful, and they already have, but there are some limitations in terms of the patient type that they might apply to and the efficacy that we can anticipate.”

Samuelson discussed the efficiency of the iStent Supra and the CyPass and their relative ease of use.

“It adds considerable surgical efficiency, and it may be one of the most straightforward devices to implant,” Samuelson said. “I think that surgeons who have found canal surgery difficult to adopt or didn’t get involved in canaloplasty because it was too tedious and laborious, I think that they’ll look favorably on this technology in that it is, I think, more straightforward.”

The Gold Shunt (Solx), the Aquashunt (Opko Health) and the STARflo (iSTAR Medical) also target the suprachoroidal space but are implanted through an ab externo approach, Ahmed said.

“They work on a similar mechanism, but they require additional dissection,” he said. “You keep everything in the eye. You avoid the need to make a scleral dissection, and you potentially avoid causing wounds and tracks for fibroblasts to enter the suprachoroidal space, which sometimes can cause failure.”

Advantages, disadvantages

Rhee said that suprachoroidal MIGS with the CyPass, like any implantation procedure, has upsides and downsides.

“There is no bleb, so there is no long-term risk of blebitis and endophthalmitis from a bleb-related infection,” Rhee said. “With the device, its insertion is ab interno. The pro of that is that there is no bleb. The cons are that it is an insertion of a device, so there is a small learning curve for placement. Whenever there’s a device, there’s a risk of any device-related issues like if you have scar tissue that grows there. But that is not unique. This is endemic with any device, whether it be in the angle or subconjunctiva.”

Loewen also noted that ab interno implantation involves a fairly long learning curve.

“The downside is that doctors who are not yet familiar with doing angle surgery or looking at the eye with a specialized lens will have a hard time learning this, so there is a significant learning curve,” Loewen said. “But once you’re familiar with it, it’s a pretty easy procedure to do.”

An ab interno approach is better than an ab externo approach in terms of better access to the suprachoroidal space, Rhee said.

“The approach is more accessible. It involves less dissection, and in my experience, I believe it’s likely safer,” he said. “It’s certainly less invasive. And the other advantage is that you haven’t exhausted a quadrant of conjunctiva should the procedure not achieve the desired goal. You can still perform any of the subconjunctival-based procedures.”

An ab externo approach significantly lowers IOP but poses a high risk of complications, Brown said.

“External filtration can lower the pressure more effectively and lower than internal approaches like the iStent or the CyPass. But the price you pay is devastating complications like endophthalmitis and hypotony maculopathy,” he said.

Studies on micro-stents

“CyPass is a glaucoma implant that is easily combined with cataract surgery. It doesn’t seem to increase the risk of cataract surgery. It has been shown in a large multicenter U.S. FDA trial [the COMPASS] to lower the pressure significantly,” Brown said, noting that the study results have not been published yet. “The company is certainly very optimistic about the results. There are a large number of patients who have participated in studies involving the CyPass.”

The randomized controlled multicenter COMPASS trial is designed to compare the safety and efficacy of CyPass insertion alone vs. insertion with cataract surgery.

The CyPass Clinical Experience (CyCLE) study, a multicenter trial conducted in Europe, was the first large-scale study to evaluate the long-term efficacy of the CyPass. The CyCLE study included 222 patients who underwent CyPass implantation alone and 238 patients who received the CyPass in conjunction with cataract extraction.

As of 2014, 136 of the combined CyPass-cataract patients had reached the 24-month postoperative time point. In a subgroup of 51 patients with uncontrolled IOP of 21 mm Hg or higher, mean IOP decreased 37%, from 25.5 mm Hg at baseline to 15.8 mm Hg (P .0001). Mean medication use dropped from 2.2 to 1. In a cohort of 85 patients with controlled glaucoma and IOP less than 21 mm Hg, mean IOP decreased from 16.4 mm Hg to 15.8 mm Hg and mean medication load decreased from 2 to 1.1.

Adverse events were transient hypotony (15.4%), stent obstruction (8.8%) and postoperative IOP spike (4.4%). There were no reports of endophthalmitis, suprachoroidal hemorrhage or hypotony maculopathy.

A second group of patients in the CyCLE study underwent CyPass insertion alone. In patients with uncontrolled glaucoma, mean IOP decreased 26%, from 27.4 mm Hg to 18.9 mm Hg at 12 months. Medication load was reduced from 2.1 to 1.1 (48%).

IOP remained stable in patients with controlled glaucoma, but medication load was reduced 40%, from 2.3 to 1.4 at 12 months.

The CyCLE study was reported in the Middle East African Journal of Ophthalmology.

In the Journal of Cataract and Refractive Surgery in 2013, Hoeh and colleagues reported that in patients with uncontrolled IOP who received the CyPass, IOP decreased by 36.9% and the total number of medications decreased by one. In patients with controlled IOP, IOP decreased by 71.4%.

Ahmed and colleagues reported results from the CyPass in the Journal of Glaucoma and American Journal of Ophthalmology. Results showed significant IOP reductions with a high safety profile.

“We got a lot of pressure lowering that ends up in the mid-teens. The procedure itself is a fairly straightforward procedure, and it appears to have an effect on IOP lowering with a safety profile which has improved over trabeculectomy,” Ahmed said.

The study published in the American Journal of Ophthalmology showed a mean IOP reduction of 34.7%, from 24.5 mm Hg at baseline to 16.4 mm Hg at 12 months (P < .0001). Mean medication use decreased significantly, from 2.2 at baseline to 1.4 at 12 months (P = .002). No serious intraoperative events or major adverse events were reported.

In the study published in the Journal of Glaucoma, mean IOP decreased from 20.2 mm Hg at baseline to 15.9 mm Hg at 12 months, a 14% reduction. Mean number of medications decreased 49% in patients with IOP of 21 mm Hg or greater and 75% in patients with IOP of 21 mm Hg or less. No major intraoperative or postoperative complications were reported. Two patients had mild hyphema, and there were no cases of prolonged inflammation, persistent hypotony or hypotony maculopathy.

“This is encouraging, but it’s also somewhat discouraging because this is still only early data,” Loewen said. “Glaucoma is a chronic disease that basically requires the surgeon to take into account at least the next 10 years, if not more, so you want procedures that work for decades. Of course, nobody developing a device would expect to be able to present 10-year data, but it would be nice to get at least 1-year data or 2-year data for a start. It is strange that suprachoroidal devices are not able to achieve pressures that are lower than the current surgeries we offer. One-year IOP is higher or similar to outcomes with ab interno procedures that include Trabectome, GATT, iStent and traditional epibulbar surgeries such as trabeculectomy and tube shunt implantation. In contrast, device-free cyclodialysis clefts can achieve IOPs that are much lower. It is clear that this is a very safe procedure. It’s also very quick to do. And for me as a glaucoma surgeon, the current data is good enough to at least offer patients something that’s quite different from trabeculectomy.” – by Matt Hasson

• References:
• Brandao LM, et al. J Ophthalmol. 2013;doi:10.1155/2013/705915.
• Garcia-Feijoo J, et al. Am J Ophthalmol. 2015;doi:10.1016/j.ajo.2015.02.018.
• Hoeh H, et al. J Cataract Refract Surg. 2013;doi:10.1016/j.jcrs.2012.10.040.
• Hoeh H, et al. J Glaucoma. 2014;doi:10.1097/IJG.0000000000000134
• Kammer JA, et al. Middle East Afr J Ophthalmol. 2015;doi:10.4103/0974-9233.148348.
• Multicenter investigation of the Glaukos suprachoroidal stent model G3 in conjunction with cataract surgery. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01461278.
• Unal M, et al. J Glaucoma. 2011;doi:10.1097/IJG.0b013e3181e3d30f.
• Vold S. Suprachoroidal outflow as a surgical target for the treatment of glaucoma. FDA website. http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM390338.pdf.

• For more information:
• Ike K. Ahmed, MD, FRCSC, can be reached at Credit Valley EyeCare, 3200 Erin Mills Parkway, Unit 1, Mississauga, Ontario L5L 1W8, Canada; email: ike.ahmed@utoronto.ca.
• Reay Brown, MD, can be reached at Atlanta Ophthalmology Associates, 993-D Johnson Ferry Road, NE, Suite 250, Atlanta, GA 30342; email: reaymary@comcast.net.
• Nils A. Loewen, MD, PhD, can be reached at Eye & Ear Institute, 203 Lothrop St., Pittsburgh, PA 15213; email: loewenna@upmc.edu.
• Douglas J. Rhee, MD, can be reached at Department of Ophthalmology and Visual Sciences, Case Western Reserve University School of Medicine Euclid Ave., Mail Stop WRN5068, UHI Institute, Cleveland, OH 44106; email: dougrhee@aol.com.
• Thomas W. Samuelson, MD, can be reached at Minnesota Eye Consultants, 701 E. 24th St., Suite 106, Minneapolis, MN 55404; email: twsamuelson@mneye.com.

Disclosures: Ahmed reports he is a consultant for AqueSys, Glaukos, Ivantis and Transcend Medical. Brown reports a financial relationship with Glaukos and that he served as an investigator in the COMPASS study. Loewen reports no relevant financial disclosures. Rhee reports he is an investigator for Glaukos and Ivantis. Samuelson reports he is a consultant for AqueSys, Glaukos, Ivantis and Transcend Medical.

Which do you prefer: More IOP reduction with external filtration or a reduced risk of bleb infection and hypotony with internal filtration?

Internal filtration reduces risks, complications

In a perfect world, assuming that everything was available, internal filtration. It is theoretical because it is not approved, and we are not doing them. The issue of optimizing internal drainage, working within the existing outflow system, is always more appealing than creating an external bleb-related storage for drainage. The advantages are multiple in that we avoid the irritation, risk of infection, ocular surface disease and contact lens-related problems of having a bleb in favor of creating a system internally. It can be that system working either within the canal or within the suprachoroidal space to achieve pressure reduction. Now, we have to assume that the pressure reduction is of equal magnitude, that both procedures get the pressure to a safe level and that it does not require any additional manipulation or long-term risk.

The suprachoroidal, in the perfect world, could be a better option, but there remains some information that has yet to be divulged, which is the risk of migration of the implant, the risk of erosion and the risk of fibrosis around the implant. So, as those studies release that kind of data and as more clinical experience is gained with this device, I am very optimistic that this could be a nice alternative to trabeculectomy in the future.

Richard A. Lewis, MD, is an OSN Glaucoma Board Member. Disclosure: Lewis reports he is a consultant for AqueSys, Glaukos and Ivantis.

External filtration provides superior IOP reduction

Despite the recent introduction of several new glaucoma operations, trabeculectomy and tube shunt implantation remain the most commonly performed incisional procedures for the management of glaucoma. The current treatment of glaucoma is entirely directed toward providing adequate IOP reduction to prevent progressive optic nerve damage, and external filtration is the most effective method for lowering IOP.

Concern about bleb-related complications associated with trabeculectomy (ie, leaks, infection, dysesthesia) has prompted the search for alternative surgical approaches. However, a trend toward the use of fornix-based conjunctival flaps with diffuse application of mitomycin C at lower concentration appears to have reduced the incidence of bleb-related complications following trabeculectomy. Additionally, tube shunts offer IOP lowering that is comparable to trabeculectomy while avoiding the presence of a perilimbal filtering bleb.

Microinvasive or minimally invasive glaucoma surgery is a group of newer procedures that are performed by an ab interno approach and involve minimal trauma to ocular tissues. MIGS is less effective in providing IOP control than traditional filtration surgery, but it has a more favorable safety profile. Internal filtration to Schlemm’s canal and the suprachoroidal space offer the advantage of blebless surgery. The results achieved with older suprachoroidal implants have been disappointing, as fibrosis around the device appears to limit aqueous outflow. Hopefully, newer designs of suprachoroidal shunts will achieve greater IOP reduction while maintaining a low risk of surgical complications. Long-term data are needed to fully assess their safety and efficacy.

Steven J. Gedde, MD, is an OSN Glaucoma Board Member. Disclosure: Gedde reports no relevant financial disclosures.