Glaucoma management requires long-term personalized approach

Guidelines for glaucoma treatment have been issued by international societies, but specialists agree that treatment should be tailored to the individual needs of each patient.

“We treat people and not eyes or IOPs,” Alain Bron, MD, professor of ophthalmology at Dijon University Hospital, France, said.

Dr. Bron said he believes that strategies should be differentiated according to the patient’s age, lifestyle, activities and capability of using drops correctly.

“I don’t prescribe pilocarpine to a patient who is working because it requires a three-times-a-day instillation and gives side effects like reading impairment,” he said.

Alain Bron, MD, examines a patient. He said that physicians should treat the overall glaucoma patient and not just the disease. Image: Bron A

Tetsuya Yamamoto, MD, professor at Gifu University School of Medicine, Japan, said that the effects of drugs are different in each patient. The majority of patients are satisfied with ordinary treatment approaches, but there are exceptions.

“IOP reduction, adverse effects and compliance are the main issues. My extreme case was one in whom no topical medications could be tolerated. The only way I managed to treat this patient was with oral acetazolamide,” he said.

Jason Bacharach, MD, in practice in Petaluma, U.S.A., said that the trend in glaucoma management has departed from standard decision making.

“Tailoring a glaucoma regimen is about how we meet the patient and where we meet the patient on their continuum of disease,” he said.

For instance, he said one of his patients is a female television reporter with pigmentary glaucoma and blue-green irides. The patient was adamantly against the 5% to 10% chance that a prostaglandin could change her eye color, so Dr. Bacharach tailored a regimen specifically for her needs.

Effective medical therapy criteria

As a general rule, medical therapy should start with one drug. Beta-blockers had been first-line therapy but were surpassed by prostaglandin analogues in recent years. Prostaglandins have fewer systemic side effects, are well-tolerated and have once-daily administration.

International guidelines suggest that if target IOP is not reached with one medication, adjunctive therapy might be added.

Dr. Bron said that in clinical practice, the first drug selected depends on the case. Some patients are best started on a prostaglandin, others on beta-blockers and, although a combination is not recommended at the start of medical therapy, a minority of patients might benefit from a combination of medication from the beginning.

“Generally what I do is start with either beta-blockers or prostaglandins. If target pressure is reached, I continue as such. Otherwise, I increase the IOP-lowering effect of the beta-blocker with prostaglandin and that of prostaglandin with a beta-blocker, alpha-2 agonist or carbon anhydrase inhibitor,” he said.

Tetsuya Yamamoto

First-line treatment is typically prostaglandins, Dr. Yamamoto said. Second-line is usually beta-blockers added to a prostaglandin, and third-line is topical carbonic anhydrase inhibitors added to the first two medications.

“My opinion is pretty standard for the majority of Japanese ophthalmologists, though some doctors prefer [carbonic anhydrase inhibitors] as the second line,” he said.

For normal-tension glaucoma, which represents 72% of the total glaucoma cases in Japan, therapy is the same but aimed at lower target pressure.

“We aim at a 30% reduction in [normal-tension glaucoma],” he said.

Dr. Bacharach said he does not find much use in adding a third medication.

Jason Bacharach

“I find it’s a law of diminishing returns when I go to the third bottle. Patients find putting five drops in their eye a day onerous. The return on investment is weakened tremendously by the time you get to the third bottle,” he said.

Fixed combinations hold advantages in this respect. The number of daily instillations is decreased, leading to improved quality of life and better adherence.

Although fixed combinations have become increasingly popular, their introduction raised some controversy. Arguments were mainly theoretical, Dr. Bron said, based on the assumption that beta-blockers are more active in the morning and prostaglandins are more active in the evening. By not taking into account this relation with time, fixed combinations would decrease the efficacy of individual agents, detractors said.

Several studies, however, have shown that the difference is not significant. Since 2003, Dr. Bacharach has been involved in trials investigating the safety and efficacy of fixed combinations vs. single agents.

“Fixed combinations of timolol and either prostaglandins, alpha-agonists or carbon anhydrase inhibitors were shown to provide equivalent or better IOP reduction in most patients who were successfully controlled on concomitant administration of single components,” he said. “Safety and tolerability were also equivalent. Convenience, improved compliance, cost savings and elimination of potential washout effects are significant advantages.”

Monitoring progression, success

Glaucoma is usually a chronic, progressive condition that requires regular monitoring and continuous adaptation of therapy to disease development.

Dr. Yamamoto said that, except for the early months, his normal visit schedule is every 3 to 4 months. Static perimetry is performed to measure the visual field every 6 to 12 months, and imaging technologies, such as optical coherence tomography or Heidelberg Retina Tomograph, are used once a year.

“This is my basic approach to patient management. Needless to say, in worse conditions, such as severe glaucomatous optic neuropathy or extremely elevated IOP, we need to follow the patient more intensively. On the contrary, some cases, such as ocular hypertension, seldom need consultation, once or twice per year,” he said.

Dr. Bron said he considers visual field the main parameter for monitoring progression. For any new patient, he takes at least three to four visual fields per year in the first 2 years.

“After five visual fields, we have an idea of progression. I use both trend analysis and event analysis. Event analysis is easier because you need only three visual fields. Trend analysis is more reliable because you also have the rate of progression,” he explained.

Evaluation of success in glaucoma therapy is no longer based on only IOP.

“I define success in terms of being able to maintain useful vision during a patient’s lifespan,” Dr. Yamamoto said. “In the practice, no significant mean deviation slope using Humphrey Field Analyzer is the indicator of the success. A 0.2 to 0.3 dB/year progression is acceptable in most of the cases. A higher rate of loss is a big concern.”

With the many cases of normal-tension glaucoma in Japan, IOP values cannot be a primary parameter to evaluate success, he noted.

“Also, we have many patients who achieve pressure levels less than 12 mm Hg with medications, but even then they progress and have to be treated surgically,” he said.

Target pressure remains a useful concept in the practical management of glaucoma patients, but international guidelines emphasize the need to adapt this concept to individual cases. There is no single IOP level that is safe for every patient; in addition, target IOP should be constantly updated in patients, following the development of the disease.

“Even with all of the excellent data that we have accumulated over the years from [National Eye Institute]- and [National Institutes of Health]-sponsored studies, you cannot extrapolate all of that data to a particular patient and assume that your initial target pressure will stay the same for that patient’s life. You have to use your best judgment to set an initial target pressure with the understanding that once you reach that range, you may need to adjust that target pressure again if that disease state continues to progress,” Dr. Bacharach said.

Diurnal pressures should also be considered, he said. IOP fluctuates throughout the day, sometimes from 30 mm Hg in the morning to 18 mm Hg in the afternoon, so an IOP assessment in the office might not reflect what is actually happening in the eye.

“If the glaucoma isn’t so severe that I feel that I need to implement therapy at their first visit, I like to get a diurnal curve of their IOP, at least a reading in the morning and late afternoon, before I initiate therapy so I know what the fluctuation is,” Dr. Bacharach said.

Dr. Yamamoto said he performs repeated IOP measurements during the course of a day in some of his glaucoma patients. His method is an hourly measurement during office hours, from 9 a.m. to 4 p.m. In some cases, he measures IOP for longer periods.

“The subjects are mainly new cases with relatively low IOP, cases with good IOP control on medications but showing visual field progression,” he said.

Several studies have shown that IOP diurnal variation is a marker of the severity and progression of the disease, but there is still some controversy on this issue, Dr. Bron said. He does not perform an IOP curve, as he believes that visits scheduled at different times in the day can give a sufficient idea of fluctuations.

“In very few patients, I take three to five measurements during the day, but it is generally not worth it,” he said.

Medication adherence

Adherence to glaucoma therapy is a well-known issue. Literature reviews report a variable percentage of patients who deviate from their prescribed regimen, anywhere from 25% to 80%. Studies using electronic devices that record the opening and use of a medication dispenser show that between one-quarter and one-half of patients miss between 10% and 25% of their doses. The Glaucoma Adherence and Persistence Study showed that 55% of the 10,260 subjects followed for at least 1 year stopped and restarted medications within that 12-month period. Only 10% of subjects filled prescriptions continuously for 12 months.

Studies have also investigated the reasons for poor adherence and lack of persistence with medications. According to Dr. Bron, there are three main reasons for this.

The first is related to the disease itself: At first, glaucoma is an asymptomatic disease, which raises problems with compliance because patients do not see the need to be treated. Glaucoma patients with better visual acuity have, in fact, been found to be at a greater risk of non-adherence.

The second reason is related to the patient, particularly to the defense mechanism of denial.

“If you don’t accept the disease, you don’t accept the treatment,” Dr. Bron said. “Denial is very common in chronic patients.”

The third reason is related to the treatment because it is “difficult to be regular with so many drops. Compliance studies have clearly shown that a higher dose frequency is significantly associated with greater non-adherence,” he said.

Adverse effects, uncomfortable sensation at the time of instillation and lack of understanding about glaucoma are also major causes of poor compliance, Dr. Yamamoto said.

“Prescribing agents with minimum irritation and adverse effects is important. And instructing the patient carefully and repeatedly because the effect of explanations doesn’t last very long, say 1 to 3 months in most of the cases. My patients are very compliant. They are concerned and know that they have to take their medications,” he said. “With [normal-tension glaucoma], the risk of non-adherence is even greater, but I invest time in talking with patients.”

Dr. Bron said that physicians must be educated about how to best interact with patients.

“Often we speak 80 to 90% of the time and don’t let patients ask questions,” he said. “There are also different ways of asking questions. If you ask, ‘Are you taking your drugs?’ it is likely that patients will say ‘yes’ even if it is not true. But if you ask, ‘Do you have difficulties with instillation where I can help you?’ patients will talk and be motivated to do better.”

Surgery

When medications are not effective or not tolerated, when poor adherence makes the regimen fail and when, according to Dr. Yamamoto, a “severe visual outcome is anticipated within a couple of years,” surgery should be considered.

“Trabeculectomy with mitomycin C is my choice in most of the cases. We obtain very low stable pressure in [normal-tension glaucoma] at the level of 6 mm Hg to 9 mm Hg. At such low pressure, we stabilize the visual field,” he said.

“My choice of surgery depends on the angle,” Dr. Bron said. “If it is open, I perform nonpenetrating surgery like deep sclerectomy, but when the angle is not wide open, I perform trabeculectomy, and when I want to reach very low target IOP between 8 mm Hg and 10 mm Hg, I use antimetabolites like mitomycin C perioperatively.”

Because glaucoma surgery can generate cataracts in a large proportion of patients, concomitant phacoemulsification is often beneficial. Also, the lens plays a key role in glaucoma because it pushes the iris forward, decreasing the opening of the angle, Dr. Bron said.

“I perform [microincision cataract surgery] through a 1.8-mm corneal incision. Trabeculectomy or nonpenetrating surgeries are easier when cataract surgery is performed at the same time because with such small incisions, the tightness of the globe is excellent,” he said.

Dr. Bacharach said an advantage to laser and surgical procedures is the 50% possibility of reducing the number of medications. Monotherapy patients may be able to stop using medication, and polypharmacy patients may reduce the number of medications in some cases.

“The way I describe it to my patient is, if we can get them off of medicine, that’s not the primary reason that we’re doing surgery,” Dr. Bacharach said. “That’s to get them to their target pressure to slow or stop their disease process.”

All three specialists agreed that surgery should not be considered as first-line treatment in the majority of cases. However, there are exceptions, such as post-traumatic and post-inflammatory glaucoma, in which a strong IOP decrease is needed. In angle-closure glaucoma, iridocorneal endothelial syndrome needs rapid surgery, and the same applies to congenital or juvenile glaucoma.

Partnership with patients

Glaucoma is a potentially blinding condition that requires lifelong monitoring and a long-term management plan.

“Good communication and partnership between patient and doctor are critical to prevent progression to blindness. Results to a large extent depend on how much we manage to make patients understand the disease, to involve them in their treatment and to make them aware that they need to invest in their eye health. Achieving this is my best personal success as a physician,” Dr. Bron said.

“Management is a humbling experience, and it’s a rigorous, long grind,” Dr. Bacharach said. “But in hindsight, it’s very fruitful when you see stability because you came up with a good formula, a good cocktail, for people that you’ve tended to bond with over many years.” – by Michela Cimberle and Ryan DuBosar

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• Jason Bacharach, MD, can be reached at North Bay Eye Associates, 104 Lynch Creek Way, Petaluma, CA 94954, U.S.A.; +1-707-762-3573; e-mail: jbacharach@northbayeye.com.
• Alain Bron, MD, can be reached at Hopital Général, 3 Rue de Faubourg Raines, BP 519 21033 Dijon, France; +33-3-80293756/80293277; fax: +33-3-80293589; e-mail: alain.bron@chu-dijon.fr.
• Tetsuya Yamamoto, MD, can be reached at Department of Ophthalmology, Gifu University, Graduate School of Medicine, 1-1 Yanagido, Gifu, Japan 501-1194;+81-58-230-6284; fax: +81-58-230-6285; e-mail: mmc-gif@umin.net.