Focus on 24-hour IOP Control Reveals Differences in Meds

New research is changing the way ophthalmologists approach glaucoma treatment.

It has been known for quite some time that IOP in healthy and glaucomatous eyes is not constant—it varies from one day to the next and throughout the course of each day. New research, however, is challenging old assumptions about the nature of the fluctuation and changing how ophthalmologists approach glaucoma treatment.

Nocturnal IOP has been a major area of interest. In the past, because the production of aqueous humor is lowest at night, it was presumed IOP would be lowest at night as well. Previous studies seemed to confirm this. Investigators were monitoring 24-hour IOP by keeping patients overnight, waking them every few hours and seating them at the slit lamp to take tonometry readings. Later, it was suggested that IOP should be measured while patients are in their “habitual positions,” in other words, sitting during the day and supine at night. When studies were redesigned to take body position into account, the results were quite different. It is now known, based largely on research conducted by Drs. Liu and Weinreb and colleagues at the University of California San Diego Hamilton Glaucoma Center's sleep laboratory, that IOP is higher at night in the majority of people.^1-4

This is significant because IOP is typically measured only during normal office hours. “In geeral, we take about four IOP readings per year in our glaucoma patients and suspects,” says Donald L. Budenz, MD, MPH, professor of ophthalmology at the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine. “Each measurement represents only what the IOP is at that moment. We may measure on different days and at different times of day, but we are not accurately assessing what is going on with IOP in all the rest of the moments of the year. Furthermore, in patients with glaucoma, IOP tends to fluctuate more than in normal eyes, so we really do not know for sure what we are treating.”

An accurate assessment of a patient's IOP is of the utmost importance because lowering pressure is the only evidence-based method to prevent glaucoma from developing or reduce the rate of disease progression. Several landmark clinical trials, including the Ocular Hypertension Study (OHTS), Early Manifest Glaucoma Trial (EMGT), Collaborative Initial Glaucoma Treatment Study (CIGTS) and European Glaucoma Prevention Study (EGPS), have confirmed this. “Large, well-designed studies have consistently shown that reduction of IOP decreases progression across all stages of the disease,” says Ronald L. Gross, MD, professor of ophthalmology at Baylor College of Medicine in Houston. “Treated patients always fare better than untreated patients.”

Dr. Gross also pointed out that post hoc analyses from the major studies showed that the more effectively IOP is lowered, the better patients fared. “In addition, we have some evidence indicating that variability in IOP during treatment may itself be an independent risk factor for progression,” he says.^5-7 “We don't have a definitive answer on this yet, however, because conflicting data also exist.⁸ For example, in the Advanced Glaucoma Intervention Study (AGIS), IOP fluctuation appeared to be an independent risk factor, which was not the case in the EMGT.”

New Treatment Patterns Emerging

The knowledge that lowering IOP reduces the risk of glaucoma development and progression prompted doctors to set lower target pressures and treat patients more aggressively, especially in cases of more severe disease. The new information about IOP levels at night and the potential risks of pressure fluctuation is driving further changes in treatment patterns. “If we think higher IOP at night puts most patients at risk for disease progression, we should be concentrating on lowering nocturnal pressure by prescribing topical medications that have been shown to do that,” Dr. Budenz says. “So far we have no studies confirming the effectiveness of this type of medication tailoring, but it logically follows that if we can lower IOP during the day as well as at night, we can have a more powerful impact on minimizing glaucoma progression.”

Now that studies have been done in all classes of topical glaucoma medications, it is becoming clear that their effects at night are not the same.³ “We've learned that some classes of medications do not affect pressure at all during the night,” Dr. Budenz says. “Interestingly, we had assumed beta blockers, e.g., timolol, were not effective at night because aqueous humor production is already at its lowest level. Therefore, you can't really lower it more. This has now been proven by measuring IOP at night with patients in the supine position.” Richard F. Brubaker, MD, was among the first to study the effects of various agents, including timolol, on aqueous outflow, and subsequent studies have confirmed his findings that beta blockers are not effective at night.⁹

In contrast, prostaglandin analogs (PGAs) and carbonic anhydrase inhibitors (CAIs) have been shown to lower daytime and nocturnal IOP.^3,9-12 “PGAs have the flattest IOP curves,” Dr. Gross said. “They're not quite as effective at night as they are during the day, but they still lower IOP over the full 24-hour period.” It has also been shown that timolol doesn't further decrease nighttime IOP when prescribed as an additive to a PGA, but the topical CAI brinzolamide does. In one study involving patients who were already using latanoprost as monotherapy, the addition of timolol or brinzolamide significantly reduced IOP during the day, but only the brinzolamide add-on treatment lowered IOP at night.¹³ There are now some studies which suggest that monotherapy with alpha² agonists, such as brimonidine, significantly lowers IOP during the day, but not at night.¹⁴

According to Dr. Gross, the new research is affecting treatment decisions among doctors who treat glaucoma. “When we choose a treatment, it is important for us to recognize the possibility that IOP is highest outside of office hours. For example, prescribing an evening dose of a beta blocker is less desirable because it would not lower IOP at night and could have an unwanted effect on perfusion pressure. Once a day in the morning is commonly recommended now,” he says.

Additional Exploration

In addition to the effectiveness of topical medications, other aspects of nocturnal IOP have been studied.^15-18 Conclusions drawn include that eyes with shorter axial lengths in healthy young adults have larger 24-hour IOP variation than longer eyes, concentric rather than nonconcentric optic disc appearance may be associated with higher nocturnal IOP, and changes in corneal biomechanical properties (central corneal thickness, hysteresis) do not appear to be associated with the 24-hour change in IOP. The results of at least one study indicated that laser trabeculoplasty reduced IOP more consistently at night than during the day.

One new study out of Toronto evaluated the effect on nocturnal IOP of sleeping in a 30-degree, head-up position.¹⁹ This sleeping position lowered IOP compared with the flat position. The effect varied among the study patients, who all had glaucoma, but mean IOP was 20% lower in one-third of patients. “The study suggests that mechanical manipulation may decrease the effect of the supine position on nighttime IOP, so this should be further explored,” Dr. Budenz says.

Research is also ongoing into factors other than body position that may cause IOP to rise at night. Possibilities include individual differences in the rate of aqueous production, altered nocturnal outflow facility or changes in episcleral venous pressure that are independent of body position. Another current theory related to high nocturnal IOP is that it may work in conjunction with low nighttime systemic blood pressure to adversely affect circulation in the optic nerve head and thus influence the development or progression of glaucoma.

Looking to the Future

Learning more about fluctuations in IOP, including the role of higher nocturnal pressure, will help the glaucoma community answer several crucial questions about the disease. One of the most important answers will be why glaucoma progresses in some patients even when their measured IOPs are within what is considered a normal range. Ongoing research will also help doctors establish more accurate baseline and target pressures, and enable more accurate assessment of the effects of medications. Researchers also hope to ascertain whether laser or surgical therapy rather than medications might be the best way to stabilize IOP, whether increased IOP is more damaging at certain stages of the disease, and which aspects of IOP, e.g., mean, fluctuating or peak IOP, are most important.

Sleep studies, such as those highlighted in this article, are expensive and difficult to conduct. Therefore, the availability of a 24-hour IOP monitor would be a welcome advance. Work on several such devices has begun. “If we had a monitor inside or on the eye, we would know what is really going on with our patients,” Dr. Budenz says. “Something like a Holter monitor, which is connected to a wireless recording device, would go a long way in helping us to sort out these issues.”

In the meantime, as Dr. Gross explains, “It's not realistic for doctors to routinely monitor IOP day and night, so we have to use the data we have to tailor treatment and give ourselves the best chance possible to control intraocular pressure for all 24 hours in a day.”

References

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