Micro-stents progressively defining their role in glaucoma management

Through an evolution that has seen several prototypes enter and leave the scene, ultra-small drainage devices have developed good standards of safety and efficacy and are gaining a place in glaucoma management. They are part of a new frontier aimed at making surgery, in all branches of medicine and all subspecialties of ophthalmology, minimally invasive. In glaucoma surgery, in which only traumatic surgical procedures seemed to produce acceptable results, the search for new microsurgical methods has been particularly intense.

To understand where to place micro-stents and how to differentiate between them, a classification of microsurgical methods according to their anatomical approach is necessary, according to Tarek M. Shaarawy, MD, MSc.

There are the more classical ab externo approaches that aim at subconjunctival filtration, he said.

“One of them is the Ex-Press (Alcon Laboratories), which relies on the same mechanisms of function as trabeculectomy but in a more controlled fashion,” Shaarawy said. “In the same direction but without penetration, we have CO₂ laser-assisted sclerectomy surgery, similar to deep sclerectomy but using a laser system rather than manual dissection.”

Alternatively, ab interno procedures targeting Schlemm’s canal are the Trabectome (NeoMedix) and high-frequency deep sclerectomy (Oertli). Ultrasound circular cyclocoagulation (EyeTechCare) is a new method for targeted cyclodestruction of the ciliary body.

Micro-stents also offer a variety of approaches.

“Aiming at the subconjunctival space, but ab interno, is the Xen implant (AqueSys). Other implants, namely the Hydrus Microstent (Ivantis) and the first- and second-generation iStent trabecular micro-bypass (Glaukos) target the Schlemm’s canal, while the third-generation iStent and the CyPass Micro-Stent (Transcend Medical) aim ab interno at the suprachoroidal space. The InnFocus MicroShunt (previously Midi-Arrow, InnFocus) renews the concept of subconjunctival filtration with ab externo drainage devices but with a simple tube and in a minimally invasive fashion,” Shaarawy said.

Indications

IOP-lowering medications are first-line treatment in glaucoma management; however, in 5% to 10% of patients, they are not tolerated or not sufficient to halt progression.

“In these cases we go on to surgery, but traditional surgical methods are rather invasive, especially trabeculectomy,” Norbert Pfeiffer, MD, said.

Micro-stents provide an opportunity to treat glaucoma in a less-invasive manner and earlier in the process.

“They are safer than other tube shunt devices or trabeculectomy. They are procedurally very efficient, less invasive and tissue-sparing, and recovery is faster and with fewer complications,” Ike K. Ahmed, MD, FRCSC, OSN U.S. Edition Glaucoma Board Member, said.

Combining safety and minimal trauma with high efficacy in terms of IOP lowering is a challenge most micro-stents have not met, but researchers and companies are working hard to achieve this. So far, micro-stents have usually been tested in the early stages of glaucoma, often in combination with cataract surgery.

“At the early stages of the disease, they have proven effective in reducing IOP to a level that allows patients to do without medications or with reduced medications for a number of years,” Shaarawy said. “Though they don’t lower IOP to the level of trabeculectomy, deep sclerectomy or older tube shunts, they should be looked at with a lot of attention, particularly in combined procedures. Cataract patients can have in 10 minutes an additional procedure that controls pressure in an acceptable fashion.”

“With stents that reactivate the internal outflow pathways, we can aim at a pressure not lower than 15 mm Hg. Besides, at advanced stages they might not work because the drainage system, downstream to the trabecular meshwork, is too badly affected by disease progression and by the prolonged use of medications,” Stefano Gandolfi, MD, said.

However, the stents that direct aqueous outflow externally to the sub-Tenon or subconjunctival space also might prove effective in more advanced glaucoma. If studies provide evidence of these extended capabilities, stents might obtain a more significant space in glaucoma management.

iStent

The first-generation iStent is the only commercially available micro-stent that has obtained U.S. Food and Drug Administration approval as well as the CE mark. It is an L-shaped titanium implant that connects the anterior chamber with the Schlemm’s canal and allows aqueous outflow to bypass the trabecular meshwork.

“It is implanted with an inserter, which drives the tip of the stent through a corneal incision of 1.5 mm to 1.8 mm and then through the trabecular meshwork. You need a gonioscopic lens to visualize the maneuvers, which are quite cumbersome to perform with one hand while you hold the lens with the other hand,” Julian García-Feijoo, MD, PhD, said.

The second-generation iStent inject is currently used in clinical studies. It is cone-shaped and needs only a 1-mm corneal incision.

“It is smaller and very easy to implant. You just need to press the button on the inserter, and the stent is plunged into the trabecular meshwork,” Feijoo said.

Both stents are indicated in patients with early to mild glaucoma.

“Most of the eligible patients have cataract and use up to three medications. A combined procedure is performed in these cases. Other candidates have very early disease and no cataract and have high pressure in spite of maximal meds. We can offer the iStent as a first step to surgery,” Feijoo said.

The proportion of combined vs. standalone procedures is around 80% vs. 20% both within studies and outside of studies with the marketed device.

The IOP-lowering effect of devices implanted into Schlemm’s canal is limited by the episcleral venous pressure, Feijoo said.

“Without medications, we can aim at a pressure in the mid-teens, around 14 mm Hg to 15 mm Hg. In more advanced glaucoma, where pressure in the low teens is needed, the potential of the first two generations of the iStent is very limited,” Feijoo said.

He performed iStent surgery in about 200 patients. In several cases, he implanted two stents to obtain an IOP decrease of 27% to 36% from baseline and a reduction of 1.3 to 1.5 medications.

“With just one stent, the IOP decrease was no more than 24% with reduction of one medication on average. We had the best results in corticosteroid-induced glaucoma because baseline pressure was higher. The higher the pressure, the better the results in terms of IOP decrease, we found,” he said.

The third-generation iStent supra overcomes the limitations of episcleral venous pressure in the conventional outflow system by using the suprachoroidal drainage pathway.

“The episcleral venous pressure doesn’t play a role, and IOP can be potentially as low as 8 mm Hg to 10 mm Hg. The device is currently evaluated in three clinical trials, in cases of more advanced glaucoma, with or without combined cataract surgery, and after failed trabeculectomy,” Feijoo said.

CyPass Micro-Stent

The CyPass Micro-Stent is a 6.2-mm tube made of polyimide, a material used for three-piece IOL haptics. Fenestrations are present along the tube for aqueous drainage, and three rings on the proximal end retain the device as well as help the surgeon assess the depth of implantation. It is inserted through a 2.2-mm incision in clear cornea, using a delivery system with a blunt end for atraumatic separation of the tissue.

“Before you start the procedure, it is necessary to visualize the anterior chamber and the angle with a gonioscopic lens to find the place where you want to perform your implantation,” Magda Rau, MD, OSN Europe Edition Board Member, said.

In clinical trials, the CyPass device has been shown to effectively reduce IOP either as a standalone procedure or in combination with cataract surgery.

 

“A group of my patients has achieved 3 years of follow-up. On average, an IOP decrease of 8 mm Hg to 9 mm Hg can be expected, as well as a reduction of about half the preoperative medications,” she said.

The device is indicated in patients with high pressure despite maximum drug therapy or in patients who are intolerant to medications.

“Quite a few patients, after years of combined medications, develop severe allergies, pain and red eyes. In some cases, just reducing the number of drugs and being able to treat the patients with the one drug they are more comfortable with is an important achievement,” Rau said.

The best candidates for the CyPass Micro-Stent are patients with pressure lower than 30 mm Hg. However, according to Feijoo, this device, like the third-generation iStent, can be used in patients with more advanced glaucoma.

“The CyPass is implanted in the [supraciliary] space and uses the suprachoroidal drainage pathway. The effect is completely different from that of devices implanted in the Schlemm’s canal, and theoretically we could aim at a lower target pressure, 10 mm Hg to 14 mm Hg,” he said.

While the CE mark for the device was granted in 2008, the CyPass Micro-Stent is currently for investigational use only.

Hydrus

Pfeiffer has used several micro-stents, but currently he is using the Hydrus, mainly in prospective randomized studies but also in patients who have taken part in a study and want to have the Hydrus implanted in the second eye.

The Hydrus is a crescent-shaped device made of nitinol, a highly biocompatible material used for vascular stents. It is implanted into the Schlemm’s canal using an injector through a small incision of less than 2 mm.

“The distal end of the Hydrus penetrates the trabecular meshwork and then is advanced into the Schlemm’s canal for about 3 clock hours, one-fourth of the circumference of the cornea. It is like a scaffold that allows the aqueous humor to enter the eye at its end and then leave the implant and percolate into the canal through oval-shaped holes,” Pfeiffer said.

Studies are testing the effects of the Hydrus in patients with mild to moderate glaucoma, relatively high pressure and visual field defects. The effects on IOP are “quite impressive, in both standalone and combined surgery,” Pfeiffer said. The number of medications used decreases, and most patients can go without medications.

“The limitation in IOP decrease is still the episcleral venous pressure, but you are opening up a wider section of Schlemm’s canal, potentially gaining access to more collection channels. Potentially, the long-term efficacy could be higher,” Feijoo said.

“Surgery is more predictable compared to other devices that go into the Schlemm’s canal,” Gandolfi said, noting that he has implanted several Hydrus devices, mostly within the frame of prospective, randomized trials.

He believes that the mechanism of action of the Hydrus could be comparable to canaloplasty because it opens a significant portion of the canal and also stretches the trabecular meshwork.

“But safety is greater, because it is an ab interno approach,” he said.

Ivantis is active in providing scientific evidence of the safety and efficacy of the device.

“Hydrus has the CE mark, but Ivantis wants to come up with a solid scientific background before launching the device onto the market,” Gandolfi said.

Xen

The Xen implant is a small tube made of soft, collagen-derived gelatin that conforms to the ocular tissue, minimizing tissue reaction. It is inserted ab interno with a 27-gauge needle injector through a sub-2-mm incision in clear cornea to connect the anterior chamber to the sclera and episcleral surface. It has evolved through three generations: Xen, Xen mini and Xen nano. Xen has been granted the CE mark in Europe.

“It is a procedure that is generally more potent than other micro-stents like those going in the canal. There are more requirements for postoperative assessment, but one of the benefits is that it can be titrated and modified after surgery,” Ahmed said.

The creation of a bleb is typically seen and is a good sign of success.

“These blebs are more posterior and diffused than in traditional filtration procedures. Some steps are required to maintain them healthy, including topical medications and wound-healing therapies with mitomycin C in the early postop. If bleb healing is excessive, it can be titrated by a needling procedure to lower the pressure, but this is not required in the majority of cases,” Ahmed said.

The mechanism of action of the Xen allows for a target pressure in the low teens, which makes it suitable for more advanced glaucoma stages. Although it can be used in combination with cataract surgery, its efficacy is equal, if not greater, as a standalone procedure, according to Ahmed.

“It’s the use of MMC that can make the difference. Without MMC, we can aim for IOP in the mid-teens, with little use of medications. With MMC, we lower the pressure more,” he said.

InnFocus

According to Jean-Marie Parel, PhD, the InnFocus MicroShunt can replace “all the surgical techniques, including trabeculectomy.”

“It is more effective and versatile than other methods. Data at 2 years show an average IOP of 11 mm Hg, ranging between 6 mm Hg and 16 mm Hg. More than 90% of the patients are completely off medications,” he said.

Parel, Esdras Arrieta, MD, Ana C. Acosta, MD, and Edgar Espana, MD, PhD, were involved in the development of the device. The first clinical trials of this micro-tube concept began in Bordeaux, France, by Isabelle Riss, MD, PhD.

The InnFocus MicroShunt is a micro-tube made of a biomaterial called SIBS, which is used in coronary stents. It is soft and flexible and conforms to the eye.

“It shunts aqueous fluid from the anterior chamber to a subconjunctival/sub-Tenon flap. The distal fins are wedged into a shallow scleral pocket to keep the device stable into position, preventing irritation and inflammation,” Parel said.

In a clinical trial, Juan Batlle, MD, successfully implanted the InnFocus MicroShunt in more than 20 patients from the Dominican Republic. They were mixed-race patients, mostly of Afro-Caribbean origin, with a genetic predisposition for tissue reaction.

“There was very little postoperative bleeding or inflammation, and the eyes remained quiet throughout the follow-up. The material is very inert, and surgery does not involve dissection of the sclera or iridectomy. The elimination of iridectomy might reduce the risk of inducing cataract,” Paul Palmberg, MD, PhD, who examined several of the patients at their 2-year postoperative visit and graded the bleb photos for an upcoming publication, said.

“Surgery is quite easy,” he said. “One simply opens the conjunctiva, applies MMC and rinses, makes a needle track, inserts the tube and closes. It takes about 15 minutes instead of 30 to 45 minutes for a trabeculectomy with MMC. Virtually no postoperative care is required.”

Fourteen of the 23 study patients had the InnFocus MicroShunt implanted as a standalone procedure.

 “I am not impressed when surgeries combine cataract and glaucoma procedures. If you claim good results, you don’t know how much is due to glaucoma surgery and how much to the removal of the lens,” Parel said.

The InnFocus MicroShunt has the CE mark in Europe, but the company is collecting more scientific data before releasing it for sale.

Stability and long-term efficacy

A challenge of micro-stents is maintaining the IOP-lowering effect over a reasonably long period of time.

“This is really a challenge of glaucoma surgery in general. With all procedures, failure rate tends to increase with time. Either the IOP goes up or the number of medications goes up,” Feijoo said.

Micro-stent devices have a variable follow-up, ranging between 1 year and 5 years, and for some of them it is too early to draw conclusions. A tendency to lose efficacy after a number of years has been seen with the first-generation iStent, which has the longest follow-up at more than 5 years.

“While after 1 year 83% of the patients are off medications, at 4 years it’s 55% and after 5 years it’s 25%,” Feijoo said. The next generations of the device might show improvement; however, “also with this stent, half of the patients can be off medications for 3 to 4 years. It’s reasonable,” he said.

With the CyPass Micro-Stent, there is good short-term control of pressure, with a decrease of 40% to 50%.

“During the first year postop, IOP is quite stable in the majority of the patients with mild to moderate glaucoma, but additional meds can be required in some of them, especially in more severe cases,” Feijoo said.

The Hydrus seems promising for stability.

“What you see on the first day is what you see at 1 year or more,” Pfeiffer said.

With a follow-up of 3 years, the Xen shows “remarkable stability,” according to Ahmed.

The InnFocus is promising after 2 years of follow-up, with a mean pressure rise of 1 mm Hg compared with the first year, Parel said.

An option for early surgery

Further studies are needed to identify the risk factors and the best candidates for stents, Feijoo said. Researchers also need to determine which patients do better with which stents.

Surgeons are gaining experience on which patients to select for stent implantation, and overall results are improving.

“I do a simple maneuver when I implant the Hydrus. I get a gonioscopic vision, and then I press on the eyeball to create a compression-suction effect and make the blood flow from episcleral veins to the Schlemm’s canal. If this happens, it means that collector channels are open and surgery will be successful. Otherwise, there is no point in implanting the stent,” Gandolfi said.

“We know now that certain options, like the iStent and similar devices, can be used in the early stages, and for more advanced glaucoma, we can concentrate on devices like the Xen,” Ahmed said.

Similar to cardiac surgery, in which coronary stents have become a well-established intermediate option between taking medications and having open-heart surgery, glaucoma micro-stents might become the alternative to invasive surgery when patients are taking too many medications or are intolerant or not responding to medications.

“The jury is still out. It’s too early to place them specifically in our spectrum of options, but there’s a niche that’s well-prepared for those devices if they prove a respectable efficacy,” Shaarawy said.

“I am a stern believer that we operate late, increasing the potential of complications. And once complications occur, surgeons become traumatized and operate even later. It’s a vicious circle. The promise of the new devices is that the safety profile appears to be better than other traditional methods. They might encourage us to operate earlier with potential advantages for both patients and surgeons,” he said. – by Michela Cimberle

• References:
• Arriola-Villalobos P, et al. Br J Ophthalmol. 2012;doi:10.1136/bjophthalmol-2011-300218.
• Arriola-Villalobos P, et al. Br J Ophthalmol. 2013;doi:10.1136/bjophthalmol-2012-302394.
• Morales-Fernandez L, et al. Eur J Ophthalmol. 2012;doi:10.5301/ejo.5000073.
• 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; +1-905-820-3937; fax: +1-905-820-0111; email: ike.ahmed@utoronto.ca.
• Julian García-Feijoo, MD, PhD, can be reached at Departamento de Oftalmologia, Hospital Clinico San Carlos, Martin Lagos sn, 28040 Madrid, Spain; +34-91-3303977; email: jgarciafeijoo@hotmail.com.
• Stefano Gandolfi, MD, can be reached at the Divisione di Oftalmologia dell’Università degli Studi di Parma, Dipartimento di Scienze Biomediche Biotecnologiche e Traslazionali, Via Gramsci 14, Parma, Italy; +39-0521-703138; fax: +39-0521-992137; email: stefano.gandolfi@unipr.it.
• Paul Palmberg, MD, PhD, can be reached at Bascom Palmer Eye Institute, 900 NW 17th St., Miami, FL 33136, U.S.A.; +1-305-326-6310; email: ppalmberg@med.miami.edu.
• Jean-Marie Parel, PhD, can be reached at Biophysics Center, Bascom Palmer Eye Institute, 900 NW 17th St., Miami, FL 33136, U.S.A.; +1-305-326-6369; email: jmparel@med.miami.edu.
• Norbert Pfeiffer, MD, can be reached at Augenklinik Universitätsmedizin Mainz, Langenbeckstr. 1, 55131 Mainz, Germany; +49-6131-177085; fax: +49-6131-176620; email: norbert.pfeiffer@unimedizin-mainz.de.
• Magda Rau, MD, can be reached at Augenklinik Cham, Cham, Bavaria, Germany, 93413; +49-99-7186-1078; email: info@augenklinik-cham.de.
• Tarek M. Shaarawy, MD, MSc, can be reached at Hôpitaux Universitaires de Genève, 22 rue Alcide Jentzer, 1211 Geneva 14, Switzerland; +41-22-3828-400; fax: +41-22-3828-382; email: tarek.shaarawy@hcuge.ch.

Disclosures: Ahmed is a consultant and investigator for AqueSys, Glaukos, Transcend and Ivantis. Feijoo is a consultant and investigator for Glaukos, Ivantis and Transcend. Gandolfi is an investigator for Glaukos and Ivantis. Palmberg and Parel are investigators for InnFocus but have no financial interest in the InnFocus MicroShunt. Pfeiffer is a consultant for Ivantis. Rau is an investigator for Transcend but has no direct financial interest in the product. Shaarawy has received research grants from Alcon and EyeTechCare and is investigator for Oertli.

Would you consider implanting micro-stents as an alternative to medications or as a way to cut down on medications in your phakic patients with early-stage glaucoma?

Micro-shunts may allow surgery to be considered as early treatment option

Although shunt surgery is the least frequently performed treatment to lower IOP in glaucoma patients, it currently seems to be the most innovative area with several promising developments. Demographics suggest dramatically increasing numbers of glaucoma patients, and ophthalmologists will have to cope with decreasing patient adherence, increasing intolerance to topical treatments and the limited duration of function of glaucoma surgeries while the individual duration of treatment will increase.

Alternatives and/or additions to topical medication are laser treatments of the trabecular meshwork, ie, argon laser trabeculoplasty and selective laser trabeculoplasty. In the third edition of its guidelines, the European Glaucoma Society suggests using them as possible first-line therapies; however, individual efficacy and lastingness of the IOP-lowering effect are limited, and further measures may be needed to reach target pressure.

The role of recently developed micro-shunts as possible new alternatives to classic penetrating and nonpenetrating glaucoma surgery is currently under investigation. Three new ab interno approaches from the anterior chamber into the Schlemm’s canal (Hydrus, Ivantis), the suprachoroidal space (CyPass, Transcend Medical) or the subconjunctival space (Xen, AqueSys) have reached phase 3 of clinical investigations. Although long-term efficacy data are rare, 36-month data of the AqueSys implant seem promising.

With good safety and efficacy and the possibility of repeated implantation, micro-shunts might overcome some of the major shortcomings of classical penetrating and nonpenetrating glaucoma surgery, and in cases of low adherence to topical regimens, they might be considered as early treatment options rather than a last resort. The results of the ongoing prospective multicenter trials will show if the new micro-shunts measure up to these high expectations.

Herbert A. Reitsamer, MD, is a full professor at the Department of Ophthalmology, Paracelsus Medical University of Salzburg, Austria. Disclosure: Reitsamer holds a patent for the AqueSys shunt implantation technique.

No current evidence supports use of micro-stents as alternative to medications

In the last few years, many different types of glaucoma surgery have become available, but at present there is no evidence to sustain that these types of surgery could be an alternative to medications or a way to cut down on medications. In particular for the micro-stents, there are some interesting studies in the literature, but too few patients have been treated until now.

Most of these new types of surgery are for open-angle glaucoma patients, but currently the European Glaucoma Society guidelines suggest starting glaucoma treatment with any type of topical medication. If drops are not efficient or not sufficient to reach the target IOP, we can think about laser or surgery.

Micro-stent surgery is not a very invasive surgery, and only a small corneal incision is necessary to insert shunt devices into Schlemm’s canal. Theoretically, on the basis of the target IOP, one or more stents could be applied to better modulate IOP reduction and to cut down on medications, but again there is no evidence of this. On the other hand, this surgery has some risks — probably less than the other surgeries but more than topical treatment. Patients must be aware of it.

In the future, there is the possibility of using micro-stents, or any other less invasive surgery, as the first choice in glaucoma treatment, but we still need clinical trials to confirm it.

Michele Iester, MD, PhD, is an associate professor at the University of Genoa, Italy. Disclosure: Iester has no relevant financial disclosures.