Spotlight on Glaucoma

New thinking on the concepts and controversies at the forefront of care.

By Jack Persico, Executive Editor

For a subspecialty that's sometimes overshadowed by the high-profile research and splashy new product launches of other eyecare niches, glaucoma has lately been coming on strong as a hotbed of activity in its own right. That's why we've decided to shine a spotlight on it this month, highlighting many of the latest advances that are reshaping this 2,400-year-old discipline.

We start things off with a sampling of new ideas and insights presented at last month's annual meeting of the American Glaucoma Society. At the conference, it soon became obvious that surgical innovations have flourished in recent years — so much so, in fact, that the AGS added an entire surgery day to the program this year for the first time. The following article recaps some of the research most pertinent to comprehensive ophthalmologists about glaucoma drainage devices, filtering surgery and laser trabeculoplasty, as well as medical management of IOP — particularly new data from the second phase of the OHTS study, released at AGS for the first time. But it's by no means exhaustive. For expanded coverage, visit http://www.ophthalmologymanagement.com/ags. There you'll find a special blog that includes more detailed discussions plus additional topics not included here. You'll also have the chance to post comments, and perhaps even begin a dialogue with the experts about their research.

The remaining articles in this special section span a wide range of topics in both research and practice: diagnostic pearls on optic nerve examination, new research on the complex interaction between blood pressure and IOP, a preview of how glaucoma drugs may be delivered to the eye in just a few years, a guided tour of the two-surgeon technique for pars plana shunt implantation, and finally a look at the status of efforts to develop a clinically viable 24-hour IOP monitoring device. All in all, it's an exciting time to be a glaucoma specialist, and we think you'll appreciate that several top people in the field have graciously shared their expertise this month.

Drainage Devices

Indications for use of an aqueous tube shunt and selection of the appropriate device figured prominently in the discussions at this year's AGS.

UCLA's Joseph A. Caprioli, MD, discussed the longterm results and clinical implications of aqueous drainage devices, reviewing the three-year data from the Tube Versus Trabeculectomy (TVT) study, which compared the IOPlowering ability of the Baerveldt implant to traditional filtering surgery. Both modalities were equally effective in lowering IOP below 21 mm Hg and achieving mean IOP reductions of at least 20% from baseline, but complications were less likely in tube cases compared to trabeculectomy. However, when the target IOP was ≤14 mm Hg, there was no significant difference between the two modalities.

Though acknowledging the TVT findings, Dr. Caprioli said he felt the complication rates were not consistent with his results, borne out both anecdotally and in a case-control study his group published comparing the Ahmed implant (though TVT used the Baerveldt) to trabeculectomy. The advantages of tube implants, he said, include fewer postop visits, fewer early complications, greater ability for contact lens wear, less dysesthesia and lower rates of endophthalmitis. The disadvantages, he said, include potentially less IOP reduction than trabeculectomy, possible greater need for medication use, and greater risks of tube erosions, strabismus and deleterious impact on corneal health.

Joshua Stein, MD, of the University of Michigan gave a talk on a cost-effectiveness study he performed comparing trabeculectomy with drainage implant surgery. He designed a model based on the frequency of complications found in the one-year TVT results and calculated the likely costs if 100,000 patients had undergone these two procedures, using the 2010 Medicare physician and facility reimbursements as a cost basis. The result: drainage device procedures would cost approximately $84 million more per 100,000 patients than trabeculectomy, his model estimated. He then incorporated the increase in quality-adjusted life years (QALY) generated by each procedure into the results. For every additional QALY gained, glaucoma drainage device surgery cost an additional $93,500.

When assessing medical, laser or incisional procedures for glaucoma, Dr. Stein concluded, after studies have proven their efficacy "we need to next perform cost-effectiveness analyses to ascertain which of these therapies deliver the best bang for the buck." A future report will incorporate the three-year TVT data into the model.

Two presentations at AGS shed new light on the relative performance of two popular tube shunts, based on data from the ongoing Ahmed Baerveldt Comparison (ABC) study, a randomized, unmasked prospective trial with fiveyear follow-up planned. The ambitious project involves 276 patients at 16 investigational sites spread across four continents. Donald Budenz, MD, of the University of Miami presented one-year efficacy data, and his coinvestigator Keith Barton, MD, of Moorefields Eye Hospital, presented data on complications.

Baseline IOP averaged 31.2 mm Hg in the Ahmed group (n=143) and 31.8 mm Hg in the Baerveldt group (n=133). At one day and one week postop, the Ahmed group achieved a statistically significant 7-8 mm greater IOP reduction than the Baerveldt patients. By one month, however, the Baerveldt group's IOP readings were 2-3 mm lower than Ahmed's, and this persisted to the one-year mark. At that visit, average IOP was 15.4 mm for the Ahmed group and 13.2 mm for Baerveldt.

Failure rates were comparable on most measures, with a few small but statistically insignificant differences. But when using a more stringent criterion for failure — IOP greater than 14 mm — 38.6% of Ahmed and 24% Baerveldt cases would be deemed failures, and that difference was statistically significant. Looking at reasons for failure, Dr. Budenz noted that reoperations were more common in the Ahmed group.

Dr. Barton presented one-year data on complication rates in the ABC trial. Mean visual acuity scores were about equal between the groups. At one year, roughly 30% of patients in each group lost about two lines of vision, similar to the VA trends in the TVT study findings. However, "the vast majority were not due to the surgery" but rather glaucoma progression, maculopathy or other disease-based VA loss, Dr. Barton said. Diplopia rates were similar in both groups (10% Ahmed, 8% Baerveldt).

There were relatively few intraoperative complications in either group (mostly hyphema), but more postop interventions were required in the Baerveldt group. However, Dr. Barton said the difference was of borderline significance.

The data do show a statistically significantly higher rate of complications (mainly tube occlusions and corneal edema) during the first three months for the Baerveldt patients. After the three-month mark, there were no significant differences between the groups on complication rates. The number of serious complications — defined as either those requiring reoperation or those that involved two or more lines of VA loss — were also significantly more common in the Baerveldt group than the Ahmed group.

Correlating the outcomes and complications data, Dr. Barton concluded that the Baerveldt implant lowered IOP slightly more than the Ahmed group, but this was achieved at a higher cost in terms of complications and reoperations. Future analyses of their data will look at individual substrata of the sample based on glaucoma type and perhaps other factors at initial presentation.

Trabeculectomy

Jeffrey M. Liebmann, MD, discussed the evolution of filtration surgery since its debut in 1969, noting its impressive ability to lower IOP but also its early complications (e.g., scarring, hypotony) and how development of antifibrotic agents and changes in technique, such as a gradual trend toward fornix-based procedures, have improved outcomes. There are two ways to assess the success of trabeculectomy surgery, he noted: IOP reduction and visual outcome. Dr. Liebman presented data showing the procedure's capabilities in both regards, concluding that surgery offers a better chance of preserving visual function than a medication regimen alone. "Trabeculectomy is likely to retain a central role in glaucoma management, particularly in eyes with moderate to severe disease and a target intraocular pressure less than 16," he said.

Joel S. Schuman, MD, offered suggestions on how to minimize postop hypotony, as it can lead to complications such as choroidal effusion, corneal decompensation and maculopathy. Among the strategies he offered were ensuring that the wound construction is "water-tight" (by testing with fluorescein if possible) and the conjunctival closure is excellent, minimizing exposure to MMC, and using releasable sutures. Opting instead for devices such as the Ex- Press minishunt rather than trabeculectomy in appropriate patients, Dr. Schuman noted, can also significantly reduce early postop hypotony.

Regarding the contentious topic of selecting an antifibrotic agent, Kuldev Singh, MD, reviewed comparative studies of mitomycin C vs. 5-fluorouracil and provided his own insights. The evidence in the literature is inconclusive — some favoring one agent, others finding no difference. A large study his group conducted found a mean IOP reduction of 12.5 mm Hg at three years for both the 5-FU and MMC groups. More patients in the 5-FU group, however, achieved IOP below 12 mm Hg, although that finding was not statistically significant.

Factors that influence success with antifibrotics include agent chosen, dosage used, location of application, delivery vehicle, trabeculectomy technique and amount of rinsing performed, "but there's very little science to guide us in how to use these drugs," he noted.

Dr. Singh summed up his talk by stating that two randomized clinical trials in the US showed similar efficacy and safety for MMC and 5-FU as adjuncts to low-risk primary trabeculectomy, but MMC may be slightly more effective in African-American populations. Substantial variations between surgeons regarding surgical technique and drug application can influence outcomes, positively or negatively.

He advocates underuse rather than overuse of the antifibrotic agent (as you can always supplement later if needed). Be aware that the surgical technique and agent used are not independent, titrating duration of drug exposure influences safety more so than altering concentration, and flexibility at the time of surgery is a must. "Sometimes, Tenon's is thinner or not visible," he said. "You want to be able to modify your technique based on what you see."

Laser Surgery

Jay Katz, MD, of Wills Eye Institute, reminded attendees that the glaucoma management model has always been maximal medical therapy followed by LTP and lastly filtration surgery, but observed that the AGIS trial deviated somewhat from that by including a treatment arm that employed trabeculectomy prior to trabeculoplasty. After seven years follow-up, one conclusion drawn from the AGIS was that there was a lower failure rate among African-American patients in the arm starting with ALT rather than filtering surgery. Visual field loss rate was better in that group as well.

Dr. Katz commented that the first LTP paper in 1981 showed an impressive 12.7 mm drop in IOP after one year, but that subsequent studies (notably those by Brad Shingleton in 1987 and George Spaeth in 1992) found that the first-year failure rate is about 20%, and there's a continued attrition of 8% to 10% per year thereafter.

When comparing medications to LTP, Dr. Katz said the four factors upon which to base your evaluation should be efficacy, compliance, safety and cost.

In the Glaucoma Laser Trial, which compared ALT to timolol as first-line therapy and reported results at two and seven years postop, ALT's success rate was found superior to medical therapy at both time points. Newer trials comparing SLT to prostaglandin analogs have found LTP similar in efficacy to prostaglandin therapy, Dr. Katz said.

On the topic of safety, the major concern in LTP is the potential for an IOP spike. With medical therapy, safety concerns involve hyperemia, ocular surface allergic reaction and systemic effects of beta-blockers.

Adherence to therapy is an ongoing battle in medication use, Dr. Katz said, and pointed to studies estimating compliance rates of 50% to 75% at best with medication regimens. LTP, naturally, obviates this concern. Several cost analyses done in the US, Canada and the UK found LTP to be more cost effective, Dr. Katz mentioned.

He concluded his presentation by stating that LTP (whether primary or adjunctive) achieves IOP reduction comparable to that of medication regimens, with more favorable safety and cost profiles. However, clinicians should be mindful of LTP's long-term gradual attrition rate.

Should LTP be first-line therapy? That was the question posed by Robert L. Stamper, MD, of UC San Francisco. Medical therapy is of course easily modified if the initial result is suboptimal. In LTP's favor: it substantially lowers IOP in the short term and obviates the cost, convenience, compliance and side-effect concerns of medical therapy. Patients also prefer the "gee whiz" aspect of a high-tech laser procedure over the more mundane eye drop.

Dr. Stamper then cited data from the Glaucoma Laser Trial that found mean IOP was slightly lower in patients receiving ALT as initial therapy, at both the two- and seven-year marks. At two years, about half of all ALT patients required a pressure-lowering medication and about 70% of those who had started on timolol required additional therapy. Like Dr. Katz, he pointed out that some newer medications introduced since the GLT began have since shown a general equivalence in efficacy to LTP in the first year.

Offering his own opinion on how to answer the titular question of his talk, Dr. Stamper finished up by saying that medical therapy is probably appropriate in most newly diagnosed patients. Circumstances that would argue in favor of beginning instead with LTP are:

• a known compliance problem (i.e., frequently missed exam appointments)
• the patient is African American
• exfoliative glaucoma
• The patient is very elderly and would stand to benefit more from the immediate impact and convenience of LTP rather than a protracted course of medical therapy.

OHTS Phase 2 Results

Sixteen years after it began, the Ocular Hypertension Treatment Trial is still generating fresh insights into one of the most vexing questions in glaucoma care: does treating ocular hypertension delay or perhaps even prevent glaucoma? Attendees of this year's AGS were given an early look at the OHTS phase 2 data by Michael A. Kass, MD, of St. Louis, principal investigator of the long-running study. In his 40-minute presentation, Dr. Kass reviewed the trial's phase 1 data, published in 2002, and provided highlights of the recently-completed second phase, on which a full report appears in the March 2010 Archives of Ophthalmology.

OHTS enrolled 1,636 subjects with baseline pressures of 24 to 32 mm Hg in one eye and 21 to 32 in the fellow eye, but normal visual fields at initial presentation. Subjects were randomized to either observation or medical therapy sufficient to reduce IOP by at least 20%. At the five-year mark, the incidence of POAG was nearly 60% lower in the medication group than the observation group.

OHTS phase 1, Dr. Kass said, provided proof of concept; namely, that medication reduces the incidence of POAG. It did not, however, indicate when medical therapy should begin or whether all ocular hypertensives should begin treatment. Those were addressed in the second phase, by splitting the study group into early-treatment and latetreatment groups. After 7.5 years of observation, patients in the phase 1 observation group were offered the option to begin therapy; those in the original treatment group simply continued therapy. The early-treatment group continued therapy for 13 years while the late-treatment group has thus far logged 5.5 years of data in phase 2.

Charting the incidence of POAG in the two groups over the 13-year span shows curves that initially diverge (i.e., a higher incidence in the observation group) but then become essentially parallel as the previously untreated patients begin therapy. "The incidence of glaucoma was not different between the observation and medication groups once patients began treatment," Dr. Kass said. "This effect appears to be relatively rapid." The median time to develop glaucoma was 8.7 years in the early-treatment group and six years in the late-treatment group.

Dr. Kass's group has produced a risk calculator based on OHTS data. Using its parameters to stratify subjects into three groups by baseline risk (low, middle and high) reveals some notable findings with implications for care. "If you look at the difference between the medication group and the observation group, there's very little absolute reduction in the occurrence of glaucoma" among low-risk patients, Dr. Kass said. Those at low risk in the observation (i.e., latetreatment) group had a cumulative 13-year incidence of glaucoma of 8%; for the early-treatment group, the incidence was 7%. By contrast, in the high-risk stratum "there is a substantial absolute reduction in the occurrence of glaucoma in this high-risk group," he said. The high-risk, late-treatment group's cumulative incidence was 40% vs. 28% for the high-risk, early-treatment group.

He finished up the 20th AGS lecture with the following observations and conclusions from the OHTS:

• Early medical treatment reduces the cumulative incidence of POAG; delaying treatment increases it.
• Absolute risk of POAG is greatest in high-risk patients.
• Most ocular hypertensives are at low risk for glaucoma, and most low-risk patients can be followed without therapy.
• Delaying treatment for 7.5 years resulted in only a small absolute increase in POAG in low-risk patients.
• Starting treatment of POAG at diagnosis has no major negative effect on prognosis over five years.
• High-risk patients may benefit from more frequent exams and early treatment, after taking into consideration factors such as patient age, health status, life expectancy and personal preference.
• For ocular hypertensives, the risk of developing glaucoma continues over at least a 15-year follow-up period.
• African Americans develop glaucoma at a higher rate despite similar treatment protocols and IOP levels. The higher incidence is related to their baseline risk factors.
• Individualized assessment of risk is useful to both patients and clinicians. OM