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March 2004

 
Filtering Surgery Takes New Direction

By Miriam Karmel
 
 

Just when it seems that drugs are eclipsing glaucoma filtering surgery, along comes a new approach. Will it revolutionize the field?

For nearly a century, ophthalmologists have been performing, with some modifications, the same filtering surgery to reduce IOP in glaucomatous eyes. This surgical variation on a theme entails the creation of a conduit for the aqueous humor in the anterior chamber to bypass the eye’s normal filtering channels.

Each refinement of this technique has led to some improvement, as well as a new or modified set of serious complications (see “Doing the Historical Two-Step”). “We’re doing essentially the same thing we did 100 years ago,” said M. Bruce Shields, MD. “We need a better glaucoma operation for the 21st century.”

That better operation could be on the horizon. It is the brainchild of Reay H. Brown, MD, and his wife, Mary Gerard Lynch, MD, and is currently in an FDA-approved Phase 3 clinical trial at 15 centers across the country. While Dr. Brown is quick to acknowledge the many efforts that preceded his, he says that doctors often avoid filtering surgery “because it’s difficult and patients aren’t happy with it.” He added that there’s little room for improving upon the current surgical technique. “I think there’s a better way,” he said. “At some point, you reach a limit.”

Dr. Brown hopes that his procedure will prove to be “safer, more effective, more surgeon friendly, more patient friendly.”

Current Approach
In a healthy eye, aqueous humor flows out primarily through one of two pathways. One, called the conventional pathway, is through the trabecular meshwork, then into Schlemm’s canal. The other is the uveoscleral outflow pathway.

In a glaucomatous eye, the conventional outflow channels are obstructed. While the outflow system isn’t fully understood, said Dr. Brown, it is believed that the obstruction is in the trabecular meshwork or in the inner wall of Schlemm’s canal. “We’re not really sure of all the intricacies of the system,” he said, adding that his research may lead to a better understanding.

Filtering surgery, as practiced for the past century, has sought to relieve IOP by bypassing the presumed obstruction. The bypass is made by creating a new hole in the eye to redirect the fluid so it flows downstream from the obstruction, where, in theory, it reaches a place of less resistance. Aqueous drains directly from the anterior chamber into the subconjunctival space, to either a bleb, or a plastic or silicone reservoir that’s been placed on the outside of the eye.

In each of its iterations, this surgical technique has ignored the eye’s internal plumbing system. “We don’t at all try to use the system that’s still there,” says Dr. Brown. “We give up on it and say, ‘That’s failed, and now we’re going to do something different.’”

New Direction
But Dr. Brown isn’t giving up. Instead, his approach is to control pressure by working with it. “We’re not going to make a hole in the eye,” he said.

Rather than bypass the obstruction, Dr. Brown has chosen to meet it head on. “We’re going to go through it,” he said. That’s done, he explained, by placing a tube directly into Schlemm’s canal. The tube, designed by Drs. Brown and Lynch, directs fluid from inside the eye from the anterior chamber into Schlemm’s canal. It artificially creates a system that directs fluid to where it should be able to leave the eye more easily and gain access to the distal outflow system. It is hoped that this more closely approximates the normal functioning of the eye, he said.

The tube, dubbed the Eyepass Glaucoma Implant, is a kind of shunt, although Dr. Brown hesitates to use that word, because of its negative connotations and implication of “desperate case situations.”

Conceptually, the device is similar to that of a coronary stent, and thus appealed to his research sponsor, GMP Companies, a maker of cardiology devices. It is not easy to find eye companies willing to sponsor research and development of surgical devices for glaucoma, which “has traditionally been an eye drop disease,” Dr. Brown said. “So the glaucoma [pharmaceutical] companies have not invested in surgical approaches to glaucoma.”

To date, Eyepass has been implanted in more than 30 patients, with a goal of testing 100 patients by the end of the Phase 3 enrollment period this spring. A few patients have been followed for two years, and so far, “we have been pleased with the safety and the efficacy,” Dr. Brown said.

This isn’t Dr. Brown’s first attempt at finding a better way to relieve pressure in the eye. Glaucoma surgery has been his area of interest for about 20 years. During that time, he developed two other drainage devices: One made an internal hole in the eye; the other, which lets fluid out through the cornea, “had a modest run,” he said.

But the timing for the Eyepass may be right. Until recently, the technology wasn’t sophisticated enough to create a tube small enough to fit into Schlemm’s canal. To give some idea of its size, Dr. Brown explained that his invention is small enough to fit inside of a Baerveldt or Ahmed tube. “It’s another order of magnitude [smaller],” he said.

Dr. Brown is quick to credit predecessors who have made his work possible, most notably, Robert Stegmann, MD, creator of viscocanalostomy surgery. “But his [Dr. Stegmann’s] technique was demanding technically and hard to get consistent results.”

He also noted that one reason that his technique might succeed, where others failed, is that earlier attempts led to scarring that may have closed the opening in Schlemm’s canal. The Eyepass tube keeps the hole open, he said.

It’s too soon to know whether Dr. Brown’s idea will be the one to revolutionize glaucoma filtering surgery. But after some 20 years of searching for a better way, he believes that he’s on the right path. “Our challenge,” he said, is, “how do we create a mechanism for tapping into the system that God gave us? If we can do that and understand it well enough, I’m sure that we can find a way to access the parts of the system that are still working. And that’s going to have a benefit in terms of lowering pressure.”

Drugs vs. Surgery
A safer, more effective and user-friendly glaucoma filtering surgery will be a welcome addition to the physician’s armamentarium. But even with such a breakthrough, filtering surgery may continue to be a treatment of last resort if current trends continue.

“Most of us will only operate on somebody if they’re at maximal medical therapy,” said Donald L. Budenz, MD. And fewer patients, according to Dr. Budenz, are maxing out on ocular hypotensive medications, according to a study that he and his colleagues reported last November.1

The retrospective, cohort study found that rates of argon laser trabeculoplasty (ALT) and trabeculectomy declined substantially in a managed care population, by an adjusted annual rate of 17.2 percent for ALT and 15.8 percent for trabeculectomy.

These findings were based on numbers obtained from a managed care database, with approximately 3 million members in commercial HMOs and PPOs and in Medicare-risk plans. Of 86,928 eligible patients—all those who received any topical ocular hypotensive agent during the study period—2,041 underwent ALT and 1,357 had trabeculectomy.

The study was conducted because of the perception among ophthalmologists, and particularly glaucoma specialists, that the number of surgeries had dropped significantly in the late 1990s, Dr. Budenz said. The decline was attributed to better medications. “That was the supposition,” he said. Thus, the time period—1996 to 2001—was chosen to reflect the introduction of a new generation of ocular hypotensive drugs (see “A Decade of Drug Advances”).

Overall, the findings did not surprise him. They “pretty much went along with my clinical practice,” he said. “I’ve been doing fewer laser trabeculoplasties and fewer trabeculectomies in the past five to seven years.”

The findings also corroborated those of earlier studies, which reported similar changes in patterns of glaucoma treatment and concluded that new medications might have led to the declining rates of glaucoma surgery.

Researchers at the University of California, Los Angeles, conducted the previous U.S. study, which looked at a random sample of the Medicare population from 1995 to 1998. It found that the volume of both ALTs and trabeculectomies declined during the study period (by 36.7 and 22.0 percent, respectively). The UCLA study concluded that the decline was unrelated to reimbursement rates and “more likely driven by new developments in the clinical management of glaucoma, among other factors.”2

This decline in surgical rates following the introduction of new medications has been seen before. “Those things have been pretty cyclical,” said Dr. Shields. “Every time an important new medicine comes out, there’s a period of decline in the volume of glaucoma surgery. But it seems that, over time, the numbers of surgeries pick up as the medical control starts to diminish.” For example, he noted a dip in surgical rates when timolol (Timoptic and others) was introduced in the late 1970s.

Dr. Budenz acknowledged the decline in surgical rates that accompanied the introduction of timolol. “But I think this is different,” he said. He agrees with those who believe that timolol has a tachyphylaxis effect, in which the drug efficacy wears off over time and pressure begins to creep up. That effect hasn’t been noted with either the carbonic anhydrase inhibitors (CAIs) or the prostaglandin analogs, he said, although it may occur with brimonidine (Alphagan), he added.

As for the cycles of history, “I appreciate historical effect, but I don’t think you can apply that to all new glaucoma medications,” Dr. Budenz said. “Here were are, seven to nine years after the introduction of these new drugs and we haven’t seen, at least in our clinical practice, any rebound effect of people needing trabeculectomy.”

Not only does the effect of the new medications seem to hold, but also the newer maximal medical therapy, which involves only five drops a day, is better tolerated by patients, compared with pre-1994 therapy, Dr. Budenz said. He described that earlier treatment as “a terrible regimen, with terrible ocular side effects from pilocarpine [Pilocar and others], and terrible systemic effects from oral CAIs.” But because this is a well-tolerated regimen, he said that most ophthalmologists don’t proceed to surgery until maximal medical therapy has failed.

Still, eye drops are expensive, Dr. Brown noted. “In most of the world, glaucoma is a blinding disease because people can’t afford eye drops.”

Those who can afford medication may be able to stay on it longer, given the growing pool of evidence that surgical rates, are declining—at least in the short run. It remains to be seen whether the decline holds, or whether it will give way to resistance, as in the past, or to some revolutionary new surgical procedure.

“It’s possible that this trend toward reduced numbers of surgery will last, though my guess is we will see gradual increase of surgery,” Dr. Shields said. “Time will tell.”

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1 Poster 187, presented at the Academy Annual Meeting, Nov. 17, 2003, Anaheim, Calif. To see online, go to www.aao.org/meetings/annual_meeting and click “Past Meetings.”
2 Paikal, D. et al. Ophthalmology 2002;109(7):1372–1376.

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A Decade of Drug Advances

DrugCategoryWhen Approved
Dorzolamide
(Trusopt)
New carbonic anhydrase inhibitor12/94
Latanoprost
(Xalatan)
First prostaglandin analog6/96
Brimonidine
(Alphagan)
First sympathomimetic alpha-2 adrenergic agent9/96
Dorozolamide + timolol
(Cosopt)
First fixed-combination CAI/beta-blocker4/98


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Doing the Historical Two-Step

Here’s a brief history of the ups and downs of filtering surgery:

FIRST STEP. First described approximately 100 years ago.

FORWARD. A key modification was made in the 1960s, when the guarded filtering procedure was introduced. This was intended to overcome problems of the full-thickness filtering procedure, in which fluid ran unimpeded from the anterior chamber to the subconjunctival space. The solution was the creation of a kind of trapdoor over the conduit. Fluid traveled around the trapdoor, which created a little bit of resistance to the flow.

BACK. Long-term pressure control proved to be not as good as with the earlier full-thickness procedure, Dr. Shields said.

FORWARD. The next major advance came in the 1980s, with the introduction of antimetabolites, such as 5-fluorouracil and mitomycin C.

BACK. However, these have been associated with hypotony maculopathy, breakdown of blebs and infection.

FORWARD. Another advance involved the use of drainage devices (plastic tubes placed in the fistula and leading to the subconjunctival space).

BACK. This solution created another set of complications, including pressures in the early preoperative phase that are either too high or too low, depending on the device. Other problems include the potential for erosion of tissue over the device or uncontrolled pressure in the later phases.

NEXT STEP. “For the last 100 years, we have been working with the concept of channeling aqueous humor from the anterior chamber to the subconjunctival space. And despite advances in the techniques, we still have an operation that is really not physiologic and continues to have serious complications,” Dr. Shields said. “In the 21st century, we will hopefully find better operations that are more physiologic.”

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Meet the Experts

Reay H. Brown, MD
In private practice in Atlanta. Financial interests: His filtering surgery research is sponsored by GMP Companies Inc.

Donald L. Budenz, MD Associate professor of ophthalmology at the University of Miami. Financial interests: Is a consultant to Pfizer and is on the speakers’ bureau for Pfizer and Lumenis.

M. Bruce Shields, MD Professor and chairman of ophthalmology and visual science at Yale University. Financial interests: Is a consultant for GMP Companies Inc.