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.

As surgical procedures become standardized, stents will play an expanding role, according to Thomas W. Samuelson, MD, OSN Glaucoma Section Editor.

“Currently, I use a device for most of my incisional glaucoma procedures. While some believe this adds unnecessary expense, I respectfully disagree. Our traditional procedures are primitive and desperately wanting for technological modernization,” he said.

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. For example, the more classical ab externo approaches 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. 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,” he said.

Alternatively, ab interno procedures targeting the 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.

“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.

“Undoubtedly, the availability of safer glaucoma procedures allows the possibility of earlier surgical intervention in cases of poor compliance with medication, ocular surface disease, medication intolerability, or simply as an alternative to complex medical regimens,” Samuelson said.

Noncompliance can be a hindrance in the use of medical therapy in treating glaucoma patients.

“Even if we’re willing to accept the redness and irritation and the complaint of patients on medical therapy, compliance is an unsolvable problem,” Reay H. Brown, MD, said at Kiawah Eye 2013. “Patients don’t fill their prescriptions, they don’t take their drops, they don’t refill their prescriptions, and they don’t come back.”

Because of these medication compliance issues, glaucoma should be a “surgical disease,” Brown said.

“A safe and effective surgery avoids eye drops, their side effects, compliance issues and recurring expense,” he said. “We’re kidding ourselves if we think that medical therapy is effective.”

Earlier treatment

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

“These types of interventions will certainly be used earlier in the treatment algorithm than traditional glaucoma surgery,” Brian Flowers, MD, said. “I also foresee a time when patients have multiple micro-stent procedures before undergoing filtration-type procedures.”

OSN Glaucoma Board Member Ike K. Ahmed, MD, FRCSC, said he considers micro-stent procedures to be 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,” he said.

The challenge is for researchers and companies to combine safety and minimal trauma with high efficacy in terms of IOP lowering. 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.”

In addition, the stents that direct aqueous outflow externally to the sub-Tenon’s 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.

Samuelson said that the most appealing feature of the iStent is its impeccable safety profile.

He said patients who received the 
iStent in the premarket approval process in the U.S. were on fewer postoperative medications. The safety profile of cataract surgery alone compared with cataract surgery in conjunction with iStent implantation did not statistically differ.

“It helps to fill a safety gap that has long existed between medications and lasers on one hand and more traditional surgery, such as filtration surgery and aqueous drainage devices, on the other hand,” Samuelson 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.

Brown said he recommends the iStent to be used in patients with mild to moderate glaucoma who undergo cataract surgery, with the goal of alleviating any medical therapy.

“Fifteen percent to 20% of our patients undergoing cataract surgery have some degree of glaucoma, so there’s a big group of patients out there,” he said.

“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 in these cases,” 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 the 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 approximately 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.

“One of the most exciting aspects of the FDA approval of iStent is the fact that it allows for continued innovation and momentum in this expanding space,” Samuelson said.

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

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

This novel 8-mm device stents and dilates the canal, providing a greater possibility that multiple collector channels are within the surgical watershed zone, Samuelson said.

The distal end of the Hydrus is advanced through the trabecular meshwork and then into Schlemm’s canal, allowing the aqueous humor to enter the eye at its end and leave the implant through oval-shaped holes into the canal. Studies are testing the effects of the Hydrus in patients with mild-to-moderate glaucoma, relatively high pressure and visual field defects.

“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.

The Hydrus has the CE mark in Europe, and Ivantis is active in providing scientific evidence of the safety and efficacy of the device.

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 keep 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

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.

In a clinical trial, Juan Batlle, MD, successfully implanted the InnFocus MicroShunt in more than 20 mixed-race patients 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.

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, Xen and InnFocus all seem promising for stability, according to researchers.

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.

“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.

“The iStent really gives us, for the first time, the option to treat glaucoma as a surgical disease,” Brown 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.

“There may come a time when patients undergo serial micro-stent procedures for a decade or more before transitioning to more aggressive therapy,” Flowers said.

For many patients, micro-stents will provide adequate control of their IOP for a lifetime, he said.

“If polled, I believe most glaucoma surgeons would choose a micro-stent procedure over trabeculectomy surgery,” Flowers said.

“Glaucoma has long awaited the microsurgical innovation that has transformed other fields within ophthalmology. The time appears right to improve glaucoma surgery for patients with all levels of disease severity,” Samuelson said. – by Michela Cimberle and Christi Fox