Questioning Glaucoma Therapy

In May, Business Week ran a story¹ alleging that “from heart surgery to prostate care, the health industry knows little about which common treatments really work.” The article chronicles the career of David Eddy, MD, PhD, who is credited with coining the term evidence-based medicine. He has made a career of identifying healthcare practices that he believes are based upon physicians' theories and intuition rather than solid clinical studies.

One example of Dr. Eddy's work cited by the article's author, John Carey, involves a search of the literature in 1987 to evaluate the effectiveness of the medical treatment of glaucoma:² Dr. Eddy “ferreted out decades of research evaluating treatment of high pressure in the eyeball, a condition that can lead to glaucoma and blindness. He found about a dozen studies that looked at outcomes with pressure-lowering medications used on millions of people. The studies actually suggested that the 100-year-old treatment was harmful, causing more cases of blindness, not fewer.” Mr. Carey goes on to state that Dr. Eddy submitted a paper to the Journal of the American Medical Association and that the publication's editors sent it out to specialists for review who “marshaled a counterattack.”

My perspective on what occurred in 1987 and all that has transpired in the field of glaucoma since differs significantly from Mr. Carey's depiction. I believe that glaucoma treatment greatly benefits our patients, and my contention has the support of conclusive research.

WHAT REALLY HAPPENED
Dr. Eddy did indeed write that medical therapy had not been proven effective in preventing progressive visual field loss, but he did not state that treatment caused blindness.² His simple point was that we needed to know whether or not treatment yielded a better outcome than the natural history of glaucoma.

Some ophthalmologists' responses may have been defensive, but Dr. Eddy also received a phone call from me in 1988. I asked him to attend a regional meeting of the AAO in Miami that I had organized. Specifically, I invited him to discuss the existing evidence about the effectiveness of glaucoma treatment, because his review had missed key articles^3-5 that provided evidence of its effectiveness. I also suggested that he participate in discussions with several glaucoma specialists who were launching clinical trials of glaucoma therapy. We did not have the funds to pay Dr. Eddy's appearance fee of several thousand dollars, and he declined my invitation.

Regardless, Dr. Eddy's challenge helped to invigorate an already developing interest in clinical trials within the field of glaucoma. Douglas Gaasterland, MD, and Fred Ederer were ready to launch the NIH-sponsored Advanced Glaucoma Intervention Study (AGIS,1988 to 2003), and Stephen Drance, MD, and Douglas Anderson, MD, had planned the Collaborative Normal Tension Glaucoma Study. In 1989, I organized and moderated the AAO/National Society for the Prevention of Blindness Glaucoma Symposium under the theme The Rationale and Effectiveness of Glaucoma Therapy. A new era in glaucoma had arrived.

WHAT WE KNOW NOW
Overview
Today, we know that adequate glaucoma therapy is extremely effective and that it can markedly reduce or halt glaucomatous damage at any stage of the disease. Several recent clinical trials^6-13 have provided useful information about the relationship between IOP and the risk of future visual field loss in patients with specific types of glaucoma. The guidance obtained from studying the outcomes of similar patients can help us to set a treatment goal—the “target pressure”—that is likely to prevent that portion of damage that is pressure dependent.¹⁴ Because, epidemiologically, elevated IOP alone accounts for a minority of the damage in the glaucomas,^15,16 it was surprisingly good news that a large majority of glaucomatous damage nevertheless depends on pressure. The implication of the studies' findings is that a lower-than-normal IOP can compensate to a large degree for whatever else is harmful in some patients, especially those with normal-tension glaucoma (NTG)¹¹ or advanced primary open-angle glaucoma (POAG).¹²

As a member of the writing team for the AAO's original Preferred Practice Pattern for Primary Open-Angle Glaucoma in 1989, my task was to write a chapter on the rationale for and effectiveness of glaucoma therapy.¹⁷ After reviewing the literature on the long-term outcomes of therapy, it appeared to me that patients with advanced damage did best when their IOP was less than 15 mm Hg, as Paul Chandler, MD, had demonstrated in 1959.³ To focus thinking on the management of advanced glaucoma, I coined the term target pressure. Now, we have much more detailed information about outcomes to guide us, not only in managing advanced POAG, but also mild, initial POAG, NTG, and ocular hypertension.

POAG
For patients with POAG and moderate-to-severe damage (average -10.5 dB mean deviation on Humphrey perimetry [Carl Zeiss Meditec, Inc., Dublin, CA]), the AGIS found that an optimal IOP is approximately 12 mm Hg (no net progression in a group of 105 patients followed for 8 years).⁶ In contrast, glaucomatous damage occurred at an increasing frequency and severity for groups of patients in whom the IOP was above 18 mm Hg at times and averaged 15, 17, and 20 mm Hg, respectively. My colleagues and I conducted a study of 205 patients in Miami with advanced glaucoma who underwent initial glaucoma surgery with 5-fluorouracil or mitomycin C.⁷ No net progression occurred in this group of patients with a baseline mean deviation of -14.6 dB during a mean of 7 years' follow-up. The mean IOP decreased from 26 to 11 mm Hg throughout the 10-year study.

In patients initially diagnosed with POAG who have mild damage (average mean deviation of -4.8 dB on Humphrey visual field testing), the NIH-sponsored Collaborative Initial Treatment of Glaucoma Study (CIGTS) showed that an average 37% reduction in IOP (27 to 17.5 mm Hg) with medication and added laser therapy when needed resulted in no net visual field progression in 5 years.⁸ The study's protocol required an advancement in treatment until an aggressive target pressure was achieved. I have been on the monitoring committees of the AGIS and CIGTS.

In the NIH-sponsored Early Manifest Glaucoma Trial (EMGT) in Sweden,^9,10 newly diagnosed patients with POAG were randomized to treatment or observation without treatment—the randomized trial of therapy versus natural history that Dr. Eddy would have favored. An average 29% reduction in IOP in POAG patients achieved a 50% decrease in their relative risk of progression. The considerably worse outcome in the EMGT (2.2 dB mean deviation progression in the treated subjects vs 3.9 dB in the untreated controls) compared with the CIGTS (0.0 dB net worsening on treatment) may have been due to a difference in protocol. In the EMGT, the treated subjects received a standardized treatment regardless of its effect on IOP. Subjects received Betoptic (Alcon Laboratories, Inc., Fort Worth, TX) b.i.d. and underwent argon laser trabeculoplasty with no advancement of therapy unless their IOP was consistently higher than 25 mm Hg.

The EMGT did show an increased hazard rate of 13% per 1 mm Hg higher average IOP during the study period. An alternative explanation for the difference in outcomes could be the subjects' older age (mean 68 vs 58 years) in the EMGT compared with the CIGTS.

NTG
The Collaborative Normal Tension Glaucoma Study showed that lowering the IOP by 30% (from 16 to 11 mm Hg) reduced the risk of progression in high-risk NTG (previous progression or split fixation documented) from 60% in untreated controls to 20% in treated subjects at 5 years.¹¹

Ocular Hypertension
In the Ocular Hypertension Treatment Study,^12,13 high IOPs (> 25 mm Hg), large cup-to-disc ratios, older age, and normal-to-thin central corneal thickness (< 555 µm on ultrasound pachymetry) were predictive of the development of POAG. The risk was as high as 36% in 5 years. Treatment that decreased the IOP by only approximately 20% reduced the relative risk of white and black subjects' progressing to glaucoma to 36% and 58%, respectively, as much as in controls. A recently presented assessment of the relationship of IOP to the risk of glaucomatous progression in the controls found that the relative risk increased by 24% for each millimeter of mercury.¹⁸ This analysis suggests that lowering the IOP to a greater degree further reduces the risk of glaucomatous progression.

CONCLUSION
Unfortunately, readers of the article in Business Week might be discouraged from using sight-saving therapy for glaucoma as well as life-saving treatments for diabetes.¹⁹ The results of NIH-sponsored clinical trials have established beyond a doubt the remarkable efficacy of the medical and surgical treatment of glaucoma.²⁰ Those who understand this evidence need to publicize the good news. Ensuring that decision makers in the healthcare system and the public appreciate the value of glaucoma therapy will ensure its support and improve patients' adherence to prescribed treatment regimens.

Editor's note: David Eddy, MD, declined to respond to this article.

The author wishes to acknowledge that portions of this piece were adapted from one of his earlier articles.²⁰

Paul Palmberg, MD, PhD, is Professor of Ophthalmology at the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine. He acknowledged no financial interest in the products or companies mentioned herein. Dr. Palmberg may be reached at (305) 326-6386; ppalmberg@med.miami.edu.

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