Unearthing the subtle lessons of OHTS: an ongoing process

With results initially released 2 years ago, the Ocular Hypertensive Treatment Study (OHTS) continues to yield new information on the prevention and treatment of glaucoma. Most recently, results have shown that topical ocular hypotensive therapy is effective in preventing the onset of primary open-angle glaucoma (POAG) in African-American patients with ocular hypertension.

Armed with this new information, practitioners continue to clarify and re-interpret the data gleaned from OHTS.

“It’s a study prone to misinterpretation,” said G. Richard Bennett, MS, OD, FAAO, a principal investigator of OHTS at the Pennsylvania College of Optometry. “And the study continues. We’re continuing to try to extrapolate and apply the lessons of OHTS.”

Preventing POAG in African-Americans

The most recent findings of the OHTS study were reported in the June 2004 issue of the Archives of Ophthalmology. The study found that daily pressure-lowering drops diminished the development of POAG by almost 50% in African-Americans.

“The gist of it is that, for the first time, we have shown that prophylactic treatment of ocular hypertension is effective in delaying or preventing the onset of glaucoma in African-Americans,” Dr. Bennett told Primary Care Optometry News. “It’s the first time we have ever had a significant African-American component to a glaucoma study.”

Although the initial results from 2002 found that treating patients with elevated intraocular pressure could prevent the onset of glaucoma, results for the subgroup of African-Americans were not conclusive.

The recent results found that of the African-American study participants who received the eye drops, 8.4% developed glaucoma. By comparison, 16.1% of the African-American study participants who did not receive the eye drops developed glaucoma.

“The prognosis for them not developing damage to their optic nerve is much rosier on treatment,” Dr. Bennett said. “That is the case for everybody, but even more so for black patients.”

Dr. Bennett said these findings will definitely affect the treatment approach to African-American patients. “There will be a lot more treatment of patients at risk,” he said. “But an important caveat is that this does not mean we need to treat everyone. That would be totally inappropriate.”

According to Eve J. Higginbotham, MD, a clinical investigator of OHTS, chair of the department of ophthalmology at the University of Maryland Medical Center and first author of the journal article, the findings from this study will help define specific risk factors for all patients.

“Now we can go beyond skin color, because we can outline specific risk factors that can be measured and determine who can be treated,” Dr. Higginbotham said in an interview with Primary Care Optometry News. “This helps us better delineate who should be treated.”

Dr. Higginbotham cited an example. “A patient who has thin corneas in addition to having a higher cup-to-disc ratio would be a person who, in the presence of a slightly higher pressure, would warrant treatment,” she said. “But if a person has thick corneas, even if he or she is African-American, and he or she has a small cup, then we can say that this person should be watched.”

Dr. Higginbotham cautioned against unnecessary glaucoma treatment. “We don’t want to burden patients in the prime of their lives with the idea that they have a chronic disease, when in fact they don’t,” she said. “Every practitioner should put himself or herself in the place of the patient when making these decisions.”

Dr. Higginbotham said this study was unlike any that has been done previously and will not be repeated. “There will never be a paper like this again, where we have so many African-Americans in whom there was no treatment but they were being followed,” she said. “Because this study does show that medication prevents or delays the onset of glaucoma, it would be unethical to do this study again in the future.”

Importance of central corneal thickness

According to Dr. Bennett, one of the most significant findings to come out of the original OHTS results was the significance of central corneal thickness.

“One of the biggest values of this study is that we have really identified, for the first time, that central corneal thickness is a significant risk factor – in fact, the most significant risk factor – for glaucoma,” he said. “In fact, the highest pressure levels we allowed in the study were 32 in both eyes, which is very high. And that was less significant in those with thicker corneas than in those who had very thin corneas, with respect to identifying individuals who would convert at the 60-month level to open-angle glaucoma.”

Dr. Bennett did point out, however, that the OHTS study worked with a relatively limited pressure range. “It’s important to know that we can’t extrapolate these lessons from patients who have normal pressures,” he said. “Their average corneal thicknesses would be considered thin in a population of ocular hypertensives.”

Louis Phillips, OD, FAAO, a practitioner in Sewickley, Pa., said patients with high measured IOP and thick central corneal thickness (CCT) have very little risk of progressing to POAG in a 5-year period.

“Patients with high IOP and thin CCT have a significant risk of progressing to POAG in a 5-year period,” Dr. Phillips said. “But OHTS does not prove that thick corneas are protective independent of IOP, or that thin corneas cause glaucoma risk independent of IOP.”

Is diabetes protective?

Dr. Bennett said practitioners should be careful when interpreting the data presented in the original June 2002 publication of OHTS.

“We found that when you looked at a single factorial analysis, instead of a multi-factorial analysis, something odd happens with all of these risk factors that showed up,” he said. “Diabetes looked as though it was protective. That is not a fact in my opinion.”

Dr. Bennett said one factor that could account for this discrepancy was that the researchers relied on the patients’ verbal confirmation that they were diabetic. He added that patients with any signs of diabetic retinopathy were excluded from the study.

“If they had a single blot dot hemorrhage, they were excluded,” he said, “So these patients were absolutely clean of diabetic retinopathy.”

Dr. Bennett said he feels certain that the results may have been different if the diabetics in the study had been chosen differently. “I guarantee you that if we could just accept any diabetic who was also ocular hypertensive, we would have seen diabetes as a major correlation,” he said. “So either we had the healthiest diabetics known to man, or we had some people who were really not diabetic. Maybe they had elevated blood sugar during pregnancy, or maybe they were just confused.”

He said the OHTS researchers are now conducting a major questionnaire to determine whether this protective correlation between diabetes and POAG holds true. “But even if it does hold true, the fact that we excluded anybody with diabetic retinopathy excludes everyone with the more severe disease,” he said.

Dr. Phillips maintained that the OHTS findings on diabetes are flawed. “Diabetes is a risk factor for glaucoma. When you get advanced diabetes, it can actually create high pressure in the eye,” he told Primary Care Optometry News. “So late-stage diabetes can cause glaucoma. But the question is, is the typical diabetic in our practice, on medication and with no signs of retinopathy, at higher risk for developing glaucoma? The findings of this study would suggest not.”

Corneal resistance to applanation

Another possible inconsistency in the information culled from the OHTS was the result of incorrect tonometry readings, Dr. Phillips said. “We have a flawed measuring device in the Goldmann tonometer,” he said. “It is giving us variable readings because of the added resistance to applanation offered by thicker corneas and reduced resistance offered by thin corneas.”

Dr. Phillips explained that when the applanation tonometer is used on a wet cornea, surface tension from that water exists. “We have assumed that this attraction always neutralizes the corneal resistance,” he said. “But we have learned that, despite what we believe, variable corneal resistance to indentation or applanation – the rigidity of that cornea – is throwing off the reading.”

The thickness or thinness of the cornea is one of the factors that can add to this rigidity. However, it is not the only factor, Dr. Phillips said. “Corneal thickness is probably not the only variable that affects the cornea’s resistance to applanation,” he said. “Corneal hydration, density of collagen fibrils, attraction of collagen fibrils to each other, etc., could be affecting corneal resistance or rigidity.”

Dr. Phillips said he believes these factors need to be taken into account when taking tonometry readings. “We have to figure out how to take into account the resistance of the cornea,” he said. “Rather than getting a measured pressure that has lots of errors in it, we need to adjust the measurement to get the true pressure inside the eye.”

Undercounted conversions

Dr. Bennett said he now believes that some people who converted were not counted in the initial OHTS study.

“Actually, high standards of conversion to glaucoma were used and some individuals may have not officially converted but were placed in the treatment arm of the study,” he said.

However, the training physician always had the opportunity to “pull the plug” on the study and put the patient into the treatment arm, Dr. Bennett said.

“And I did that with several patients when I thought there was a change in the nerve and the field, even though the reading centers didn’t agree,” he said. “And the pressures went up. I had one patient whose pressures went up into the 40s. It is not ethical to follow a patient like that. But that was not counted as a conversion.”

In the medication group, patients who would likely have converted were treated more aggressively if their IOPs went up and therefore did not convert, Dr. Bennett said. “If the pressure went up, you gave them more drops and you brought it back down,” he said. “So, it would show that a patient who would have converted to glaucoma is not going to convert because I treated him or her.”

Class of drugs and conversion rate

According to Dr. Bennett, the advent of prostaglandin analogs could make for different OHTS findings today than those gathered in 2002.

“We used a criteria of 20% (a 20% lowering of intraocular pressure from pre-treatment levels). Most of the newer studies are using 30%,” he said. “That’s because, with the prostaglandins, you can achieve that.”

Dr. Bennett believes that if OHTS were done today, there would be a lower conversion rate in the treatment group.

“My guess is that if we had used 30%, there would be a much lower conversion rate in the treatment group, even with the low conversion rate there was,” he said. “We started in the days of Timoptic (timolol maleate, Merck) and pilocarpine and Propine (dipivefrin HCl, Allergan), and the bulk of my patients are now on prostaglandins, alpha agonists or topical carbonic anhydrase inhibitors.

“If prostaglandins had been around when we started this study, and people were getting 40% drops in their IOPs, you would see even more dramatic results than what we already saw,” he concluded.

For Your Information:

• G. Richard Bennett, MS, OD, FAAO, can be reached at 1438 Gunpowder Road, Rydal, PA 19046; (215) 276-6145; fax: (215) 885-9424.
• Eve J. Higginbotham, MD, can be reached at 419 West Redwood, Suite 58O, Baltimore, MD 21201; (410) 328-5929; fax: (410) 328-6246.
• Louis Phillips, OD, FAAO, can be reached at 2591 Wexford-Bayne Road, Ste. 104, Sewickley, PA 15143; (724) 933-5588; fax: (724) 933-6051; e-mail: lp@sightlinelaser.com.