One of the frontiers in glaucoma treatment today is a group of surgeries referred to as minimally invasive glaucoma surgeries, or MIGS. The primary advantage of these procedures, which currently include the iStent, the Trabectome and endoscopic cylcophotocoagulation, is that they involve far less risk for the patient than options such as trabeculectomy and tube shunts. Furthermore, because they are ab interno procedures, they can be performed through a cataract incision, making them ideal for combining with cataract surgery. The perceived drawback to these procedures is that they tend to produce a smaller pressure reduction than the other surgeries mentioned. As a result, they’re often thought of as intermediate procedures—kind of a bridge to more invasive surgeries that may lower IOP more dramatically.

Today, however, as surgeons become more familiar with these options and more of them make it through the Food and Drug Administration approval process, a new possibility is arising: Increase the pressure-lowering power of these procedures by multiplying them. That can be done in two ways: in the case of a given device, by implanting more than one; and in general, by combining different MIGS approaches—in particular those affecting different mechanisms and pathways.

Using Multiple Pathways

The options we have for maximizing the effectiveness of MIGS procedures in many ways parallel what we can do with pharmaceuticals. For example, we can aim to lower IOP by maximizing a single outflow pathway using multiple drugs that affect that pathway, or by using two aqueous suppressants such as beta-blockers and carbonic anhydrase inhibitors. I think this is much like placing multiple iStents in the trabecular meshwork, which the data suggests lowers pressure more than a single stent.

On the other hand, a lot of what we do with drugs involves lowering pressure by enhancing multiple pathways. We can lower pressure by decreasing aqueous production, but we also have drugs that enhance uveoscleral outflow, such as prostaglandins, and some newer drugs under investigation like rho kinase inhibitors and adenosine agonists that enhance trabecular outflow. (Another new drug, latanoprostene bunod, has a complex molecule that affects both trabecular outflow and uveoscleral outflow.) Experience has confirmed that combining drugs that act on different pathways can increase the amount of pressure reduction, so acting via multiple mechanisms is a reasonable approach.

Putting Glaucoma on ICE
The combination of simultaneous inflow and outflow procedures makes sense for many reasons. One need only look at how we treat glaucoma with eye drops (using both agents that reduce aqueous production and those that enhance its outflow) to see that combined inflow and outflow strategies can be complementary and synergetic. (There is no existing evidence to suggest that one strategy is better than the other for the preservation of visual function.) The potential disadvantage of combining several strategies for traditional glaucoma surgery would be a concern that hypotony might become more of an issue. Fortunately, in the microincisional glaucoma surgery space, hypotony is not a significant concern because we are not typically performing full-thickness filtration procedures.

Shortly after adopting trabecular micro bypass using the iStent (from Glaukos), some colleagues and I began combining cataract extraction, endocyclophotocoagulation and trabecular micro bypass to form the ICE procedure (iStent-cataract-ECP). Mechanistically, the procedure should provide increased trabecular outflow, decreased aqueous production and a likely increase in both trabecular outflow from angle widening and possibly some reduced aqueous production as a result of the cataract surgery.1-3

In a series of 70 moderate glaucoma patients who underwent the procedure, we noted that the procedure was as safe as standard cataract surgery.(Radcliffe N, Noecker R, Sarkisian S, Parikh P. ICE Surgical Technique Outcomes: MIGS Implantation of Trabecular Bypass Stent, Cataract Extraction, and Endoscopic Cyclophotocoagulation. 2014 American Glaucoma Society Annual Meeting, Feb 27-March 2, 2104, Washington, DC.) ECP can create some additional inflammation, but this does not affect the visual outcome if managed appropriately. From a baseline intraocular pressure of 19.4 mmHg, the pressure was reduced to 15.8 mmHg by the three- to six-month visit. While about 60 percent of patients used two or more medications prior to the procedure, only a quarter remained on this many medications after. Note that the procedure did not work for everyone—at least 20 percent of patients experienced minimal or no pressure reduction.

Currently, I offer this procedure to patients with moderate glaucoma damage who are on at least one medication; sometimes I offer it to “tough-to-treat” patients with early glaucoma who are on several medications. I avoid using the procedure on patients with advanced glaucoma, who would likely require more aggressive and riskier interventions.

In summary, the ICE procedure is important not simply because of the combination of these specific procedures, but because it illustrates the potential of combining future inflow and outflow MIGS procedures, as well as combining future dual outflow procedures that take advantage of different outflow pathways.
— Nathan Radcliffe, MD 
The idea of combining treatments is now beginning to show up in the MIGS arena. The early data that’s being reported indicates that combining pathways through multiple MIGS procedures can increase the amount of pressure reduction we can achieve. For now, this data is limited, partly because many potential MIGS devices are still awaiting approval by the FDA. For example, the devices intended to enhance uveoscleral out-flow, including Transcend Medical’s CyPass and Glaukos’s iStent Supra, are not currently FDA-approved, and the Xen Gel Stent (from AqueSys), an ab interno device designed to allow outflow to the subconjunctival space, is also still in the pipeline. However, some surgeons are actively combining the currently approved MIGS procedures with good results. In particular, performing ECP and implanting an iStent during cataract surgery—sometimes referred to as the ICE procedure—has surgeons reporting positive outcomes. (See Putting Glaucoma on ICE, right.) And Glaukos, manufacturer of the iStent, is looking into the possibility of maximizing pressure reduction by combining the trabecular and uveoscleral pathways. This makes sense because they have stents that address each of those pathways; the current iStent and the (not approved) iStent Inject are designed to enhance trabecular outflow, while the (not approved) iStent Supra is intended to enhance uveoscleral outflow.

Which Combination to Use?

One question this raises is whether one particular combination of procedures (and/or outflow pathways) would be more effective at reducing IOP than another. Of course, we have no clinical trial data on which to base such a comparison right now, but even if clinical trials eventually compare different combinations of MIGS procedures, the results might not tell us which combination would work best in a specific patient. This is certainly true for drugs; if a trial compared a fixed combination of a beta blocker and prostaglandin to a beta blocker-brimonidine combination, you might get a bigger average drop in one group than the other, but an individual patient might not mirror that finding. So a trial wouldn’t necessarily tell you which choice is best for the patient seated in front of you.

The nature of the glaucoma, the age of the patient, the stage of the disease, how elevated the pressure is—all of these factors, and possibly others, may determine which combination of procedures will work best for a given individual. You might choose a different combination of MIGS procedures for a patient who has a relatively low IOP but is progressing than for someone with high-tension glaucoma, just because it makes more sense based on the pathophysiology of the disease. With glaucoma drugs (for now, at least) it’s trial and error because of the difficulty of predicting the efficacy of a given treatment. And that will probably also be true when combining MIGS procedures.

Of course, another factor that will affect which combination a given surgeon might end up using is the surgeon’s own preference and comfort level, as well as which techniques he or she happens to learn. If all the options were approved, some surgeons might feel most comfortable combining a Xen Gel implant and a Hydrus. Others might prefer combining ECP and Trabectome, or prefer combining the iStent Inject and the Supra. So which procedures a surgeon ends up using will be partly determined by the patient’s condition and partly by the surgeon’s knowledge and comfort level.
More of a Burden?

What about the burden that performing multiple procedures places on the surgeon and the eye? This really is the infancy of our use of MIGS procedures, but in comparison to other traditional procedures for lowering intraocular pressure these procedures are generally easier on both the surgeon and the eye—even if we do two of them. Most of these procedures can be done through the same single incision; there’s no need to make a second incision (except in some ECP cases). You go in with one instrument and place one type of stent; you come back out and go back in through the same incision and put a different stent in a different part of the anatomy. In the case of ECP, you use the same incision (and possibly a second one) to put the probe into the eye and apply the laser. I believe this compares quite favorably to trabeculectomy and tube shunt procedures in terms of complexity, time spent and trauma to the eye.

The other reality is that the amount of foreign material being implanted in the eye in MIGS procedures is miniscule compared to something like a tube shunt (or for that matter an intraocular lens), even if you implant multiple stents. Of course, they are utilized for different purposes and they’re placed in different parts of the eye, but the comparison is worth noting. (The downside of the small amount of material implanted in MIGS procedures is that the success of most of them requires a great deal of finesse in terms of understanding the anatomy of the eye and the proper placement of these devices.)

Building the Foundation

For now, we’re refining the use of the existing devices to maximize their individual effectiveness. For example, the work done with the iStent by Ike Ahmed, MD, suggests that the success of iStent surgery may be linked to determining the location of the most functional collector channels before placing the iStent.

We’re also learning about conditions that contraindicate specific MIGS approaches. For example, patients who have Sturge-Weber syndrome with a facial hemangioma typically have elevated episcleral venous pressure, countering aqueous outflow. If the episcleral venous pressure is 30 mmHg instead of the normal 10 mmHg, you’re not going to get a pressure reduction by clearing out the resistance in the trabecular meshwork with a stent or Trabectome. Instead, the surgeon might want to favor other pathways, such as using a Xen Gel Stent to generate subconjunctival filtration or reducing aqueous production with ECP.

In the meantime, trabeculectomy and tube shunts remain valuable surgical options. But I believe MIGS procedures will increasingly be considered in certain patients—whether it’s a single MIGS approach, or a combination approach—to eliminate the need for resorting to a trabeculectomy, or at least delay that need. The reality is that when managing glaucoma, we’re always trying to postpone progression with medications, lasers or surgery; we never cure the disease. So the more time and options we can offer to patients with safer procedures, the better.

A Great Opportunity

Of course, we’re just beginning to figure out which MIGS approaches will make the most sense for each patient. Not all of the devices out there will be approved, but hopefully many of them will be, and new modifications and options will be developed. If we have an arsenal of choices, a lot of surgeons will be applying them, perhaps in various combinations. Future development will be guided by people who are very clever who understand the basic science and the pathophysiology of the various diseases that we refer to as glaucoma.

And that’s a reason to be hopeful about the future. The glaucoma microsurgical arena is quite inspiring, and there are a lot of creative people still in their training or in their early years of practice who will make great contributions. We haven’t seen a situation like this in a while, where there are so many different possibilities and avenues an individual can take to make a great idea even better. It’s a wonderful growth opportunity for bright young people to radically change how we approach surgery for this disease, improving techniques and devices and setting more specific guidelines that better individualize care for patients, getting better outcomes and finding ways to minimize the risks. I firmly believe that over the next decade there will be really important contributions from bright young physicians, scientists who are excited about entering this field.  REVIEW

Dr. Katz is the director of the Glaucoma Service at Wills Eye Hospital in Philadelphia. He is a medical monitor and investigator for Glaukos and a medical investigator for InnFocus. Dr. Radcliffe is director of the Glaucoma Service and clinical assistant professor at New York University. He is a consultant for Glaukos, Transcend, Alcon and Allergan.

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