Adjunctive Medical Therapy: New Evidence and Treatment Strategies for Glaucoma

Sponsored by The National Retina Institute.
Supported by an unrestricted educational grant from Alcon.

Release Date: November 2008
Expiration Date: November 30, 2009

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Target Audience:

This enduring monograph, a CME planned activity, has been designed to meet the educational needs of ophthalmologists involved in the diagnosis and management of patients with glaucoma.

Statement of Need:

The management of glaucoma requires that a series of decisions be made over time as a patient is followed to ensure that the condition remains stable and further vision is not lost. This course will discuss the risk factors that may lead to glaucoma progression. Several risk factors (e.g., age, race, family history and corneal thickness) are not treatable, whereas others (e.g.,elevated IOP, variation in IOP and ocular perfusion pressure [OPP]), are treatable.

New information has recently become available as to which medications show best additivity for lowering IOP when added to the most commonly used first-line (primary) agent, a prostaglandin. In addition, a series of studies published over the past few years has pointed out the significance of OPP and its relationship to progression. Certain medications may increase OPP, while others may decrease it. This emerging information will help clinicians make better management decisions over time for their glaucoma patients.

Learning Objectives:

After completing this educational activity, participants should be better able to:

  1. Identify individuals at greatest risk of progression for glaucoma
  2. Interpret if the addition of a medication to the glaucoma therapeutic regimen is effective
  3. Understand ocular perfusion pressure as a risk factor for glaucoma progression.

Faculty/Editorial Board:

Robert Fechtner, MD, is Professor of Ophthalmology and Director of the Glaucoma Division in the Department of Ophthalmology and Visual Science at the New Jersey Medical School.

Accreditation Statement:

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of The National Retina Institute (NRI) and Jobson Medical Information LLC (Review of Ophthalmology). NRI is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation:

The Bert M. Glaser National Retina Institute (NRI) designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Disclosure of Conflict of Interest:

NRI requires that all continuing medical education (CME) information be based on the application of research findings and the implementation of evidence-based medicine. NRI promotes balance, objectivity and absence of bias in its content. All persons in position to control the content of this activity must disclose any conflict of interest. NRI has mechanisms in place to resolve all conflicts of interest prior to an educational activity being delivered to the learners.

NRI is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in health care and not a specific proprietary business interest of a commercial interest. The faculty has had financial relationships within the last 12 months; however, their apparent conflicts are resolved. They reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Dr. Fechtner is a consultant and receives research support or is on the speaker’s bureau for Allergan, Alcon, Pfizer and Merck.

The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have had with commercial interest related to the content of this CME activity: Bert M. Glaser, MD, The National Retina Institute, has no real or apparent conflicts of interest to report. Ruth A. Zeller, The National Retina Institute, has no real or apparent conflicts of interest to report. Karen Rodemich, Review of Ophthalmology, has no real or apparent conflicts of interest to report. Alicia Cairns, Review of Ophthalmology, has no real or apparent conflicts of interest to report.

Method of Participation:

There are no fees for participating and receiving Continuing Medical Education credit for this activity. During the period of November 2008 through November 30, 2009, participants must:

1) read the learning objectives and faculty disclosures;
2) study the educational activity;
3) complete the post-test by recording the best answer to each question;
4) complete the evaluation form

A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70 percent or better. Your statement of credit will be mailed to you with in 4 weeks. Online test takers will be issued a printer-friendly, real-time certificate.

Media:

Website.

Disclosure of UnLabeled Use:

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. NRI, Review of Ophthalmology and Alcon do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of NRI, Review of Ophthalmology and Alcon. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings.

Disclaimer:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of the patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer's product information and comparison with recommendations of other authorities.


In September, a continuing medical education teleconference was held on the topic of adjunctive medical therapy for glaucoma. Presenter Robert D. Fechtner, MD, explored new evidence and treatment strategies, and in the following pages, we share with you this information.

For the majority of our glaucoma patients, our first choice for treatment is usually prostaglandin monotherapy. This may be one of the few things upon which glaucoma specialists agree. But it is possible to reach a consensus on others. Several leading glaucoma specialists participated in a panel consensus assessment of glaucoma diagnosis and therapy using a modified RAND-like appropriateness methodology.1 This study was supported by Pfizer, Inc.

Among the many topics the panel reviewed, they considered statements about adjunctive therapy and agreed that:

  • Adjunctive therapy should be limited to one drug from each class.
  • Adjunctive or switch therapy is indicated if monotherapy fails to achieve target
  • In the absence of mitigating factors, therapy should be advanced whenever there is disease progression, regardless of IOP level.

When we’re adding to a prostaglandin, I first consider efficacy and tolerability (Table 1). Our options for adjunctive medical therapy include beta-adrenergic antagonists (e.g., timolol, betaxolol); alpha2-adrenergic agonists (e.g., brimonidine); topical carbonic anhydrase inhibitors (CAIs) (e.g., brinzolamide, dorzolamide); and fixed combination agents (e.g., timolol/dorzolamide [Cosopt], timolol/brimonidine [Combigan]). It is not surprising that there is a lack of clarity regarding adjunctive therapy. It is the nature of the drug approval process that we usually have access to well-designed prospective monotherapy studies; adjunctive studies are not usually part of this process. We are working with far less rigorously acquired information when trying to sift through what to add to initial prostaglandin monotherapy.

Table 1. Selection Factors for Choosing an Adjunctive Medication to a Prostaglandin Analog

EFFICACY

  • Standard of care/step therapy
  • Maximum additive IOP-lowering efficacy
  • 24-hour control of IOP
  • Minimizing IOP fluctuations

SAFETY

  • Few systemic side effects
  • Enhance or neutral effects on ocular perfusion pressure
  • Low incidence of topical allergic reactions

TOLERABILITY

  • Comfort upon instillation

CONVENIENCE

  • Q.d. or b.i.d. dosing regimen

When latanoprost became available, we commonly prescribed a beta blocker in the morning and latanoprost at night. And while we knew from clinical trials that latanoprost was additive to timolol, there were no studies on whether timolol was additive to latanoprost. It was only when fixed-combination latanoprost/timolol was being developed and studied that we observed that latanoprost alone did nearly as well as the fixed combination of latanoprost and timolol (Figure 1).2 We now appropriately consider beta blockers a less suitable choice as a first adjunct to add to a prostaglandin.


Fig1. Beta Blocker: Minimal IOP lowering in fixed combination
compared with latanoprost monotherapy.2

One of our first signals that the beta blockers may not be our best choice as an adjunct to prostaglandins came from a retrospective chart review by one multi-physician practice and published by O’Connor in 2002.3 They looked at records of patients who had been on a prostaglandin and had a second medication added to it. The authors found that topical CAI was statistically significantly more effective than alpha-agonists or beta blockers (change in IOP: -3.9 mmHg, -2 mmHg, -2.5 mmHg, respectively; p = .006). This study has all the limitations of a retrospective review, but raised a question that has now been examined to some extent prospectively.

In a large, prospective masked study, Feldman and colleagues performed a head-to-head comparison of 163 patients on travoprost 0.004% (Travatan) who were randomized to adjunctive therapy with either brinzolomide 1.0% (Azopt, n=84) or brimonidine 0.15% (Alphagan, n=79) in addition to the prostaglandin.4 Brinzolamide and brimonidine were used twice daily rather than three times daily. This is “off label” use, but is common clinical practice. This three-month, parallel-group, double-masked study compared patients aged 35 years and older with primary open-angle glaucoma, exfoliation glaucoma or ocular hypertension from 18 centers in the United States. Patients also had a history of an insufficient response to travoprost monotherapy (IOP >18 mmHg). Intraocular pressures were measured at 8 a.m., 12 p.m. and 4 p.m. The three-month visit results for the adjunctive use of these drugs twice daily can be seen in Figure 2. Both medications are similarly effective at peak, but by late afternoon, there was some upward drift of IOP in the group using brimonidine. This study was supported by Alcon, Inc.


Fig 2. Additivity of brinzolamide 1.0% vs. brimonidine 0.15%
to travoprost 0.004%. IOP at Month 3 visit.4

In a small crossover study, Konstas and colleagues compared the 24-hour efficacy of twice daily brimonidine 0.15% and twice daily dorzolamide 2% when added to patients using latanoprost. The mean diurnal IOPs show similar modest additivity to the prostaglandin for both drugs. Peak effect was greater with the brimonidine, but nighttime IOP reduction was less than with dorzolamide.5 This study was supported by Merck, Inc.

From the modified RAND-like appropriateness analysis, the panel agreed on the value of adding a topical CAI to either prostaglandin analogs or beta blockers. However, the group was indeterminate on the value of adding alpha-agonists to these two classes of drugs.1

MULTIPLE MEDICATIONS

How often do our patients require multiple medications to control IOP? In the CIGTS study6, 75 percent of subjects required two or more medications by the end of the first year to reach a calculated target IOP that was fairly aggressively low. But even in the OHTS study,7 where we were aiming for a relatively modest 20-percent reduction, about half (49 percent) of the patients required two or more medications to achieve this. It is worth noting that both studies were initiated before the introduction of prostaglandins and even when first available, the prostaglandins were not indicated for initial monotherapy. The bottom line is that, over the course of years of treatment, many of our patients end up on multiple medications. This is usually done by adding one additional agent at a time.

From the RAND-like methodology, the panel disagreed with the initial use of fixed combination therapy, but did agree that such therapy improves compliance. In my opinion, it is occasionally appropriate to start some patients on three different drugs (a prostaglandin plus a fixed combination) when they first present if IOP is wildly out of control. But, more typically, we will advance through step therapy for the glaucoma patient. I personally would urge you, if you have a patient on three bottles, to think about trying to get them back to two bottles of medication. This can sometimes be accomplished by improving compliance, using fixed combination therapy or performing laser trabeculoplasty. Three bottles of drops is a large therapeutic burden for most patients.

THE IOP-GLAUCOMA CONNECTION: 24-HOUR DATA

We are now beginning to see new information about 24-hour variations in IOP and the diurnal and nocturnal efficacy of IOP-lowering. These have become topics for discussion and debate. We’re now starting to get two somewhat inconsistent sets of data from 24-hour, diurnal and nocturnal studies. Some of these data come from a sleep lab setting with patients in habitual position (upright during the day and lying down at night) while other data come from a more traditional source, where the patient is seated at a slit lamp for all IOP measurements.

Contrary to what I learned during my training—that IOP is usually highest either early morning or late afternoon—a fairly substantial body of literature coming out of a sleep laboratory at the Hamilton Glaucoma Center at the University of California, San Diego, challenges our earlier beliefs. In several studies, these investigators have found that IOP is highest when a patient is lying down at night.8 Further, these investigators have shown that even during the day, IOP is higher with the patient in a supine position than in a seated position.8 The clinical significance of this remains to be more clearly defined. But it is clear that new understandings of diurnal and nocturnal IOP and the effect of medical therapies during the day and night are emerging.

Figure 3 illustrates a group of glaucoma patients who were first measured at baseline with no treatment (orange circles in blue), showing afternoon IOP ranging from 21 mmHg down to just below 20 mmHg; at nighttime an average of about 24 mmHg; and in the morning, lower.9 Patients were treated with timolol 0.5% gel (yellow line), and their pressures were measured in the seated position afternoon and morning and, as we would expect, the IOP measured in the seated position during the day was reduced. At night, however, in the center, the eyes when treated with timolol had the same pressure on average that they did without any treatment when measured with the patients supine.

These results suggest that once-daily timolol in the morning really does not reduce IOP below baseline IOP in patients when they are supine at night. This is an important observation.

Orzalesi et al have studied the diurnal and nocturnal effects of several IOP-lowering drugs. Their experimental design is a little different from the San Diego group; they measured IOP in both the seated (Goldmann applanation) and supine (Tonopen) position at all time points.10 Results were similar regardless of patient position and most results were reported for seated Goldmann applanation tonometry. In one group of patients who were crossed over and tested on several different medications, the researchers found that latanoprost once daily and dorzolamide three times daily lowered IOP below baseline at all time points. Timolol 0.5% dosed twice daily was effective during the day, but did not provide statistically significant IOP reduction at time points during the night.11

In another small study with similar design, these investigators found that latanoprost once daily and a fixed combination of timolol/dorzolamide twice daily lowered IOP at all time points. Brimonidine 0.2% dosed twice was effective during the day, but did not provide significant IOP reduction at midnight, 3 a.m. and 6 a.m.12

These results from different laboratories using different methods do not give an entirely consistent picture, but some patterns emerge. The prostaglandin analogs appear to be effective at lowering IOP during the diurnal and nocturnal periods. Beta blockers and selective alpha-agonists were effective during the diurnal period, but may have less IOP-lowering efficacy during the nocturnal period. Topical carbonic anhydrase inhibitors and timolol/dorzolamide fixed combination appear effective during the diurnal and nocturnal periods.11

OPP AND GLAUCOMA PROGRESSION

Ocular perfusion pressure (OPP) has become a topic of interest in understanding glaucoma risk. Low OPP has now been shown to be strongly associated with the prevalence of glaucoma progression in multiple population-based studies such as the EMGT study, the Egna-Neumarkt study and the Barbados eye study.13–17

To explore the effects of IOP-lowering medications on OPP, a study published in 2006 looked at patients treated with each of various topical medications (timolol b.i.d., brimonidine 2% b.i.d., dorzolamide 2% t.i.d. or latanoprost nightly) for six weeks with a four-week washout period.18 The study investigators then monitored IOP with the patients in habitual position (seated during the day, supine at night) as well as systemic blood pressure monitoring for 24 hours. All four medications were effective at lowering IOP but had differing effects on calculated OPP. The study authors concluded that prostaglandins and CAI increased diastolic perfusion pressure at all time points. Beta blockers increased perfusion pressure from 4 a.m. to 4 p.m., but had no effect at other times, and alpha-agonists reduced diastolic perfusion pressure at multiple time points primarily because of an effect on blood pressure. The clinical significance of these observations remains to be elucidated.

NOCTURNAL HYPOTENSION

One might speculate that glaucoma patients are at particular risk at night. Is glaucoma at work while our patients sleep? From laboratory data, we know that IOP is elevated at nighttime, when people are supine. We also know that many people have nocturnal hypotension. A vascular component of glaucoma may be episodic ischemic events occurring at night when OPP is low. We certainly believe anterior ischemic optic neuropathy can be perfusion-related and occurs at night. We should not overlook the glaucoma patients who are being over-treated for systemic hypertension and may be dropping their blood pressure at night.

The Early Manifest Glaucoma Trial randomized patients to no treatment or to a treatment algorithm for newly diagnosed glaucoma. With several of the risk factors, they found the factors stratified to the higher baseline pressure and lower baseline pressure group.17 For the higher baseline IOP group, lower systolic blood pressure increased the risk of progressing with glaucoma and for the people with lower baseline IOP, a higher systolic blood pressure decreased the risk of progressing.

We alter OPP the way we do everything else for glaucoma—by lowering IOP. All things being equal, a lower IOP translates into better OPP. But we can also address OPP by not lowering diastolic blood pressure. It’s going to be very interesting as we start getting some sense of the balance between treating and over-treating systemic hypertension in glaucoma patients. I think there will need to be new strategies to study this emerging risk factor.

When we see normal pressure glaucoma patients who seem to be progressing even with well-controlled pressures, we often get 24-hour blood pressure monitoring and I am impressed at how frequently these people have nocturnal hypotension. Low blood pressure at night, coupled with high IOP in supine position compromises perfusion pressure. Thus, we believe it is better to use systemic blood pressure medications in the morning and avoid the nighttime dose that may cause nocturnal hypotension. Also, the IOP-lowering drugs that lower IOP during both the diurnal and nocturnal periods without lowering diastolic blood pressure are probably a better choice.19–21

To bring this back to clinical practice, we are not routinely measuring blood pressure in our glaucoma patients. I would predict that within the next five years, we are going to be getting blood pressures in these patients. We may be getting supine office pressures to estimate their nighttime IOP and we may be calculating perfusion pressure. And at some time in the not-too-distant future, we may have 24-hour IOP monitoring available outside the laboratory setting to help us answer these questions for individual patients. Until then, we must try to make sense of the available data as we develop our strategies for adjunctive medical therapy.

POINTS TO PONDER

We all have our preferences and our practice habits, so look at what you’ve been selecting as adjunctive IOP-lowering medications. Take a look at the combinations you have patients on and ask yourself if you have considered other options. If a patient appears to be doing okay and is not complaining about the medications, it’s easiest to renew the prescriptions. It takes time, energy and effort to switch treatments, but it may be worth the effort. Look for your patients using prostaglandins and beta-blockers. Is there a better adjunct? Identify those who have advanced to three bottles—are they really getting added efficacy from that third bottle? Can you streamline their therapy or get them a little more compliant? Also, periodically review their systemic medications and think about what might be happening to them at night when their blood pressure is low and their eye pressure is high.

References

  1. Singh K, Lee BL, Wilson MR; on behalf of the Glaucoma Modified RAND-Like Methodology Group. A panel assessment of glaucoma management: modification of existing RAND-like methodology for consensus in ophthalmology. Part II: results and interpretation. Am J Ophthalmol 2008;145:575–581.
  2. Higginbotham EJ Feldman R, Stiles M, Dubiner H; Fixed Combination Investigative Group. Latanoprost and timolol combination therapy vs monotherapy: one-year randomized trial. Arch Ophthalmol 2002;120(7):915–922.
  3. O’Connor DJ, Martone JF, Mead A. Additive intraocular pressure lowering effect of various medications with latanoprost. Am J Ophthalmol 2002;133(6):836–837.
  4. Feldman RM, Tanna AP, Gross RL, et al. Comparison of the Ocular Hypotensive Efficacy of Adjunctive Briminodine 0.15% of Brinzolamide 1% in Combination with Travoprost 0.004%. Ophthalmology 2007;114(7):1248–1254.
  5. Konstas AGP, Karabatsas CH, Lallos N, et al. 24-hour intraocular pressures with brimonidine purite versus dorzolamide added to latanoprost in primary open-angle glaucoma subjects. Ophthalmology 2005;112:603–608.
  6. Lichter PR, Musch DC, Gillespie BW, et al; CIGTS Study Group. Interim clinical outcomes in the collaborative initial glaucoma treatment study comparing initial treatment randomized to medications or surgery. Ophthalmology 2001;108(11):1943–1953.
  7. Kass MA, Heuer DK, Higginbotham EJ, et al. The ocular hypertension treatment study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120(6):701–713.
  8. Liu JH, Zhang X, Kripke DF, Weinreb RN. Twenty-four-hour intraocular pressure pattern associated with early glaucomatous changes. Invest Ophthalmol Vis Sci 2003;44(5):1586–1590.
  9. Liu JH, Kripke DF, Weinreb RN. Comparison of the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure. Am J Ophthalmol 2004;138(3):389–395.
  10. Orzalesi N, Rossetti L, Bottoli A, et al. The effect of latanoprost, brimonidine, and a fixed combination of timolol and dorzolamide on circadian intraocular pressure in patients with glaucoma or ocular hypertension. Arch Ophthalmol 2003; 121(4):453–457.
  11. Orzalesi N, Rossetti L, Invernizzi T, et al. Effect of timolol, latanoprost, and dorzolamide on circadian IOP in glaucoma or ocular hypertension. Invest Ophthalmol Vis Sci 2000;41:2566–2573.
  12. Orzalesi N, Rossetti L, Bottoli A, et al. The effect of latanoprost, brimonidine, and a fixed combination of timolol and dorzolamide on circadian intraocular pressure in patients with glaucoma or ocular hypertension. Arch Ophthalmol 2003;121:453–457.
  13. Leske MC, Connell AM, Wu SY, et al. Risk factors for open-angle glaucoma. The Barbados Eye Study. Arch Ophthalmol 1995;113(7):918–924.
  14. Leske MC, Wu SY, Menesure B, Hennis A. Incident open-angle glaucoma and blood pressure. Arch Ophthalmol 2002;120(7):954–959.
  15. Quigley HA, West SK, Rodriguez J, et al. The prevalence of glaucoma in a population-based study of Hispanic subjects: proyecto VER. Arch Ophthalmol 2001;119(12):1819–1826.
  16. Bonomi L, Marchini G, Marraffa M, et al. Epidemiology of angle-closure glaucoma: prevalence, clinical types, and association with peripheral anterior chamber depth in the Egna-Neumarkt Glaucoma Study. Ophthalmology 2000;107(5):998–1003.
  17. Leske MC, Heijl A, Hyman L, et al; EMGT Group. Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology 2007;114(11):1965–1972.
  18. Quaranta L, Gandolfo F, Turano R, et al. Effects of topical hypotensive drugs on circadian IOP, blood pressure, and calculated diastolic ocular perfusion pressure in patients with glaucoma. Invest Ophthalmol Vis Sci 2006;47(7):2917–2923.
  19. Graham SL, Drance SM. Nocturnal hypotension: role in glaucoma progression. Surv Ophthalmol 1999;43(suppl 1):S10–16.
  20. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL. Nocturnal aerial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol 1994;117(5):603–624.
  21. Collignon N, Dewe W, Guillaume S, Collignon-Brach J. Ambulatory blood pressure monitoring in glaucoma patients. The nocturnal systolic dip and its relationship with disease progression. Int Ophthalmol 1998;22(1):19–25.