Medical Treatment of Glaucoma

edited by Robert N. Weinreb, Makoto Araie, remo Susanna, Ivan Goldberg, Clive Migdal and Jeffrey Liebmann
2010. 9 tables, 4 figures and 57 photos of with 1 in full color. Hardbound.
ISBN-10: 90 62992 226 9. ISBN-13: 978-90-6299-226-3
Kugler Publications. Click here for more information on all publications in the Consensus series.

• Who should be treated?
• Treatment goals
• Drugs
• Selection of drugs
• Medical treatments of other types of open-angle glaucomas
• Drug delivery
• Health economics
• Non-pharmaceutical medications and approaches
• Neuroprotective therapies
• Medical management of glaucoma in infants and children
• Treatment of glaucoma in pregnancy
• Unmet needs

Summary Consensus Points

Section 1 – Who should be treated?

• In general, treatment is indicated for patients with glaucoma or glaucoma suspects who are at risk for developing functional impairment or decrease in vision-related quality of life from the disease.
  Comment: Treatment is generally indicated when the risks of progressive disease outweigh the risks and potential side effects of treatment.
• All treatment decisions should take into account the presence of coexisting ocular conditions, the patient’s life expectancy and general health status, as well as his/her perceptions and expectations about treatment.
• The rate of disease progression is of fundamental importance in considerations of treatment for glaucoma patients. Treatment is indicated for patients whose rates of progression will most likely result in loss in vision-related quality of life over the projected remaining years of life.
• Treatment is generally indicated for patients with definitive glaucomatous visual field loss, particularly in circumstances when such loss has been determined to be progressive at a measurable rate.
• Changes of the optic nerve and/or retinal nerve fiber layer (RNFL) characteristic of glaucoma predict functional vision loss in glaucoma and thus patients with such documented structural evidence of progressive damage should generally be treated with intraocular pressure lowering therapy.
• The decision regarding whether or not to treat glaucoma suspects should involve a consideration of risk factors for disease development, including age, family history of glaucoma, intraocular pressure, central corneal thickness, presence of pseudoexfoliation, disc hemorrhages and measures of structural and functional integrity of the optic nerve head and retinal nerve fiber layer.
  Comment: While it is clear that progress has been made in establishing risk factors for glaucoma progression, much work remains to be done to better refine risk models. Nonetheless, the factors that affect the risk of progression help decide the expected prognosis of the individual’s untreated disease and thereby the frequency of follow-up and aggressiveness of the therapy to be undertaken.
• Imaging of the optic nerve head and retinal nerve fiber layer can provide useful predictive information about the risk of developing functional loss from glaucoma and thus can serve as a surrogate predictor of such vision loss.
• Selective visual function tests may be predictive of functional loss in glaucoma patients and thus may be used as complementary tests to assist in treatment decisions.
• Predictive models or risk calculators may assist clinicians in providing more objective estimates of the risk of glaucoma development for individual patients.
  Comment: Predictive models are based on restricted populations of patients that were selected based on strict inclusion and exclusion criteria and that may not be representative of all patients seen in everyday clinical settings. Use of these models should be restricted to those patients who are similar to the ones included in the studies used to develop and validate such models and calculators.

Section 2 – Treatment goals

• The target IOP is the IOP range at which the clinician judges that the estimated rate of progression is unlikely to affect the patient’s quality of life.
  Comment: Although recommended by most experts, there is insufficient evidence that using target IOP is associated with better clinical outcomes.
• The determination of a target IOP is based upon consideration of the amount of glaucoma damage, the rate of progression, the IOP at which the damage has occurred, the life expectancy of the patient, and other factors including status of the fellow eye and family history of severe glaucoma.
• The use of a target IOP in glaucoma requires ongoing re-evaluation and adjustment.
• The benefits and risks of escalating treatment to reach a target IOP must be balanced.
  Comment: Uncertainties regarding the short- and long-term variations of IOP, accuracy of tonometer readings, patient’s life expectancy, adherence to therapy and estimated progression rates remain unresolved.
• Treatment goals include IOP, visual function and structural (optic disc, RNFL) outcomes and QOL.
  Comment: It is uncertain whether patient reported outcomes of glaucoma can be applied in clinical practice, and whether they capture clinically meaningful progressive changes.

Section 3 – Drugs

• All eye drops have the potential for systemic effects, which may be decreased with a lower concentration, reduced frequency of administration and using nasolacrimal occlusion or gentle eyelid closure.
  Comment: During pregnancy and lactation, the risks and benefits of these medications should be evaluated for each patient.
• Topical cholinergic agents can effectively reduce intraocular pressure.
  Comment: In open-angle glaucoma, cholinergics enhance aqueous outflow through the trabecular meshwork by means of ciliary muscle contraction.
  Comment: Cholinergics may open the drainage angle in certain instances of angle closure by stimulating the iris sphincter muscle.
  Comment: The effects of pilocarpine are representative of this class. Pilocarpine has an additive hypotensive effect to β-blockers, alpha-2 adrenergic agonists, and carbonic anhydrase inhibitors. It can be additive to prostaglandin analogues in some patients.
  Comment: Common ocular side effects of pilocarpine, which limit its use, include brow-ache, induced myopia, and dimness of vision. Comment: TID or QID dosing is associated with poor adherence.
• Indirect cholinergic agents are reserved for open-angle glaucomas in aphakic or pseudophakic eyes.
  Comment: Indirect cholinergic agents are cataractogenic and also may cause adverse systemic effects.
• Topical β-blockers are effective IOP-lowering agents.
  Comment: Topical β-blockers decrease IOP by reducing aqueous humor formation. All non-selective β-blockers have comparable IOP-lowering efficacy.
  Comment: Topical and systemic β-blockers are poorly additive with respect to lowering IOP.
  Comment: Although some β-blockers have intrinsic sympathomimetic activity (ISA) or α-blocking properties, their clinical properties are similar to those of other non-selective β-antagonists. However, ISA may reduce respiratory and cardiovascular side-effects related to β-blockade.
• Timolol, and possibly all other β-blockers, have minimal IOP-lowering efficacy during sleep.
  Comment: Non-selective topical β-blockers are contraindicated in patients with asthma, chronic obstructive pulmonary disease (emphysema and bronchitis) some cases of congestive heart failure, bradycardia, and heart block.
• The IOP-lowering efficacy of betaxolol, a relatively selective β-1-blocker, is less than that of non-selective β-blockers.
  Comment: Betaxolol is relatively safer than a non-selective β-blocker in patients with known reactive airway disease.
• Carbonic anhydrase inhibitors (CAIs) are effective IOP-lowering agents.
  Comment: CAIs reduce IOP by suppressing aqueous humor production through inhibition of the isoenzyme carbonic anhydrase II.
  Comment: CAIs are the only category of drugs available commercially in both topical and systemic formulations to lower IOP.
  Comment: For systemic CAIs, major side effects include paresthesia, malaise, gastrointestinal disturbances, renal disorder, blood dyscrasia, and metabolic acidosis.
  Comment: For topical CAIs, side effects include ocular burning, stinging, bitter taste, superficial punctuate keratopathy, blurred vision, tearing, headache, and transient myopia.
  Comment: CAIs may increase ocular blood velocity; however, there is insufficient evidence for any clinical benefit of this effect for glaucoma patients.
  Comment: Topical CAIs and systemic CAIs are poorly additive with respect to lowering IOP.
• Systemic CAIs are contraindicated with sulfonamide allergy, with depressed sodium and/or potassium blood levels, and in metabolic acidosis.
• The non-selective adrenergic agonists, epinephrine and its pro-drug (dipivefrin) are effective IOP-lowering agents.
  Comment: Adrenergic agonists reduce IOP by decreasing aqueous formation and increasing outflow.
  Comment: Adrenergic agonists are contraindicated in infants and children because of systemic side effects.
  Comment: IOP-lowering efficacy of adrenergic agonists is less than that with timolol. This class is often additive to prostaglandin analogues but not to non-selective β-blockers.
  Comment: Local side effects include hyperemia and blepharoconjunctivitis. Systemic circulatory effects include hypertension and tachyarrhythmias.
• Selective alpha-2 adrenergic agonists reduce IOP by suppressing aqueous inflow and increasing outflow. They also may affect episcleral venous pressure.
  Comment: Systemic side effects with selective alpha-2 adrenergic agonists include dry mouth, drowsiness and hypotension.
• There is insufficient evidence for neuroprotection by selective alpha-2 adrenergic agonists in humans.
• Bunazosin, a selective α1A antagonist, increases uveoscleral outflow.
  Comment: Although it is well-tolerated, the hypotensive effect of topical bunazosin is weaker than that of topical timolol.
• Prostaglandin analogues (PGAs) are the most effective IOP-lowering agents of all topical glaucoma medications, and generally are first line therapy.
  Comment: PGAs lower IOP by increasing uveoscleral aqueous humor outflow, and may also have an effect on outflow facility.
  Comment: Common side effects of prostaglandin analogue drops include conjunctival hyperemia, reversible increase of eyelash length, thickness and pigmentation, irreversible increase of iris pigmentation, and increase of eyelid skin pigmentation. Rare side effects include uveitis, reactivation of herpetic keratitis and cystoid macula edema.
  Comment: PGAs are systemically safe, but are relatively contraindicated in pregnancy, as are all glaucoma medications.
• Preservatives used for multi-dose topical ophthalmic medications can cause ocular surface changes.
  Comment: Benzalkonium chloride (BAK), in particular, has been associated with ocular surface changes in chronic use. Alternative preservative systems are increasingly used in multi-dose bottles in an effort to decrease the potential for deleterious effects on ocular surface. However, direct comparisons between these agents are lacking.
  Comment: Preservative free systems, in the form of unit dose packages, are a viable alternative to traditional multi-dose bottles. In theory, they may have fewer ocular surface effects, however, direct comparisons with preserved agents are lacking.

Section 4 – Selection of drugs

• Only the IOP lowering effect should be considered to define the comparative efficacy of an ocular hypotensive agent.
• Initiation of therapy: prostaglandin analogues (PGA) are recommended as first choice agents for most eyes with glaucoma.
• IOP reduction with initial monotherapy should be at least 20% from baseline.
  Comment: IOP reduction of less than 10% should be considered as nonresponse.
  Comment: Switching drugs within the PGA class may, upon occasion, provide greater IOP lowering.
• Adjunctive therapy is indicated when existing therapy fails to reach the target IOP.
  Comment: Adjunctive therapy should be limited to one drug from each class.
  Comment: The efficacy of a drug when used as monotherapy is usually less when used as an adjunctive agent.
• Provided the use of the combination product is as efficacious as the two components administered independently, fixed-combinations are preferred when possible over the use of two separate bottles due to convenience, reduced amount of preservative instillation and possible improved adherence.
  Comment: Evidence is lacking that fixed combination products provide better outcomes than the individual components delivered separately.
• Surgery is indicated when medical therapy fails to adequately lower the intraocular pressure or prevent progression, the risk of progression remains too high despite the use of medical therapy, or is not possible due to allergy, intolerance, poor adherence or lack of availability.

Section 5 – Medical treatments of other types of open-angle glaucomas

• PG analogs are first choices for monotherapy in pseudoexfoliative glaucoma and pseudoexfoliation syndrome with ocular hypertension when treatment is required.
  Comment: Pilocarpine can reduce iris movements in eyes with pseudoexfoliation and, therefore, may reduce deposition of exfoliation material or pigment in the trabecular meshwork.
• PGAs are first choices for monotherapy in pigmentary glaucoma.
  Comment: Pilocarpine can be effective in pigmentary glaucoma in reducing reverse pupillary block and diminishing iris movements.
• Medical treatment of inflammation is first line treatment for uveitic glaucoma.

Section 6 – Drug delivery

• Poor adherence / perseverance / dyscompliance are major problems in glaucoma. Patients taking fewer doses than prescribed are at risk of having worse outcomes than those taking a higher proportion.
  Comment: On average, most studies of glaucoma patients estimate that about 70% of doses are taken. This may vary depending on duration of treatment, number of medications taken and severity of the disease.
• Patient self-report of adherence is often overestimated.
  Comment: Physicians do not accurately predict which patients are poorly compliant.
  Comment: While not readily available, better systems to reliably and easily monitor patient drop taking behavior are desirable since they would provide feedback for physicians to better identify patients with difficulty adhering to drop regimens.
• Risk factors for lower adherence rates have been identified and include younger and older age, race/ethnicity, and depression.
  Comment: While poor adherence can occur in all patients, additional efforts may be required in patients with these risk factors.
• Patients often have difficulty properly administering drops to their eyes.
  Comment: Efforts to improve adherence should address physical barriers.
  Comment: Observation of patient eye drop administration can detect patients that are unable to instill them.
• For at least the next several years, topical IOP-lowering medication will remain the mainstay for glaucoma treatment.
  Comment: Despite limitations (inconvenience, dependence on the compliance of the patients and well-described adverse events in particular on the conjunctiva), topical anti-glaucomatous medication is (relatively) cheap, easily available, and generally safe, and it is reversible, should side effects arise.
• A change in the preservatives of eye drops to a less toxic and more tissuefriendly formulation, and/or the development of preservative free drug delivery systems is needed to reduce the preservative related side-effects and tissue toxicity while delivering enough drug to control the intraocular pressure.
• Non-IOP dependent therapy for glaucoma and also new drug delivery systems remain a high priority unmet medical need in glaucoma management.

Section 7 – Health economics

• There are wide variations in reported costs of glaucoma therapy across nations.
  Comment: There is little information from developing countries.
  Comment: With the exception of the US, the differences in costs of therapy are largely related to the level of economic development in various regions of the world.
• Cost of one time surgery is substantially greater than medication in the short term, but lower in the long term.
  Comment: Changes in medication costs may alter this.
  Comment: Surgical failure may alter this because of the need for additional medication and/or surgery.
• Generic drugs potentially can reduce direct treatment costs.
  Comment: More studies are needed comparing generic and branded drugs.
• Side effects of glaucoma medications have minimal economic impact.
• There do not appear to be significant differences in the cost of fixed combination products compared with individual components.
• Failed medical therapy is defined differently in each country and depends on the cost and availability of medical therapy and surgical alternatives in that country.
  Comment: Pricing of glaucoma medications is not transparent.

Section 8 – Non-pharmaceutical medications and approaches

• There is a paucity of clinical trial information examining neuroprotective effects of non-pharmaceutical compounds (alternative or complementary therapies) for glaucoma.
  Comment: Bio-availability of these natural compounds has not been well studied, and clinical studies of their efficacy and safety are needed.
• Exercise reduces IOP, but the extent, duration and clinical significance are unclear.
  Comment: Exercise also can increase ocular blood flow, but the significance of this is unknown.
• Acupuncture has been reported to lower IOP and increase ocular blood flow.
  Comment: The reported results are inconsistent and additional studies are needed before it is employed in clinical practice.

Section 9 – Neuroprotective therapies

• A neuroprotective strategy for glaucoma is defined as a therapy that prevents the occurrence or progression of optic neuropathy and preserves visual function by mechanisms other than IOP lowering.
• Agents that lower IOP have been shown to protect the optic nerve from glaucoma progression.
  Comment: Some agents that lower IOP might additionally confer protection to the optic nerve through mechanisms that are independent of IOP lowering, but there is insufficient evidence for this dual effect with any agent at the present time.
• Therapeutic approaches for preventing RGC death may aim to prevent primary or secondary degeneration of retinal ganglion cells.
• Evidence from experimental models suggests that neuroprotection could be conferred by:
      a. Inhibiting the pathogenic mechanisms that injure or kill RGCs.
      b. Rendering the optic nerve more resistant to injury.
• Numerous studies have demonstrated neuroprotection in experimental models of glaucoma or optic nerve injury, but good evidence demonstrating neuroprotection in clinical studies is lacking.
• Challenges in translating experimental evidence of neuroprotection into clinical proof may be due to:
      a. The therapy may not be effective in humans.
      b. The lack of sufficiently robust tools to assess clinically the state of optic nerve
          health.
      c. The lack of animal models that are good representatives of human glaucoma.
      d. The lack of well-designed and well-conducted clinical studies.
• Current testing paradigms are insufficiently sensitive and specific to detect change in a logistically feasible time frame. The development of accurate, sensitive, specific and reproducible clinical tests that provide information on the current state of health of the optic nerve are required to increase the feasibility of clinical development of neuroprotective agents.
  Comment: A desired embodiment of such clinical testing would allow detection of progression before the damage is irreversible.

Section 10 – Medical management of glaucoma in infants and children

• The primary treatment of glaucoma in infants and young children is surgery.
  Comment: In many situations, however, the clinician must treat elevated IOP medically while awaiting surgery or after a partially-successful procedure.
  Comment: Only rarely should medical therapy be the primary treatment of glaucoma in infants and young children.
  Comment: A young child is not a small adult: systemic adverse reactions rarely seen in adults can occur in young children.
• Outflow medications (pilocarpine and prostaglandin analogues) are variably effective in pediatric glaucomas, whereas aqueous suppressants lower IOP more consistently.
  Comment: Systemic and topical carbonic anhydrase inhibitors can be safe and effective. If possible, systemic use should be monitored by a pediatrician.
  Comment: Topical beta-blockers are effective; systemic safety is the major concern. Betaxolol is safer than timolol.
  Comment: Topical brimonidine is absolutely contraindicated in children under two years, and must be used with great caution in older children. Apraclonidine may be safer, for short-term use, but clinical data is lacking.
  Comment: Prostaglandin agonists are less effective in children than in adults, and are more likely to be effective in older children.
  Comment: Miotics are rarely used in phakic children.

Section 11 – Treatment of glaucoma in pregnancy

• Appropriate management of the pregnant/lactating glaucoma patient requires balancing the risk to the fetus of treatment against the risk to the mother if treatment is reduced or suspended.
  Comment: While a complete lack of prospective human data complicates this decision-making process, publications provide a guide.
• Like all systemically-absorbed medications that are used during pregnancy and lactation, the maternal use of topical anti-glaucoma medications carries risks of teratogenicity, of interference with establishment or maintenance of pregnancy, or of side effects in the neonate.
  Comment: Prostaglandin analogues may be associated with uterine contraction.
  Comment: Beta-blockers and alpha agonists can cause serious toxicity (re spiratory and CNS depression) When possible, these agents should be withdrawn during the last few weeks of pregnancy.
  Comment: Topical CAIs are generally well tolerated.
• Laser trabeculoplasty can be a reasonable initial or adjunctive intervention in pregnant and nursing women.
• Filtering surgery, preferably without anti-fibrosis chemotherapy, can be considered in certain cases.

Section 12 – Unmet needs

• Identification of biomarkers of retinal ganglion cell dysfunction:
  • A more reliable tool for measuring the health of retinal ganglion cells is needed for more effective evaluation of treatment outcome.
  • There is a need to identify new models to test drugs.
• Identification of novel targets for glaucoma treatments that lower IOP and preserve retinal ganglion cell function should be sought.
  Comment: Structural changes in the optic disc or retinal nerve fiber layer often precede functional changes and could be useful for primary endpoints in clinical trials.
• New agents need not necessarily have enhanced pressure-lowering efficacy compared with prostaglandin analogues, particularly if they have an additive effect when used with existing medications.
• Continuous IOP monitoring and home tonometry: There are currently no commercially available devices that allow continuous monitoring of IOP in humans. Comment: There is insufficient evidence at this time to show that home tonometry with any device provides accurate and reliable IOP measurement.
  Comment: Drugs that provide sustained lowering of IOP throughout the 24-hour day may be advantageous.
  Comment: However, it still is uncertain if additional IOP data from continuous IOP monitoring or home tonometry provides additional clinical information to the current measures of IOP peak, mean and fluctuation.
• Objective measurement of patient adherence to glaucoma medication: Nonadherence to treatment regimens is common in glaucoma patients. Addressing the risk factors for poor adherence and developing new methods to improve adherence are pivotal to effective delivery of glaucoma treatment.
• There is insufficient information regarding current treatment practices and the most appropriate glaucoma treatment strategies for developing countries.
• Regulatory agencies should develop uniform standards for preservatives and unpreserved medications that could be applied worldwide.
• A worldwide color-coding scheme for caps of classes and fixed combination of glaucoma medications is recommended.
• Additional studies of the effects of different treatments on ocular blood flow and its relationship to glaucoma are needed.
• Biomarkers for glaucoma diagnosis and progression are needed.
• Improved delivery methods for drug therapies are needed.
• A medical treatment is needed to restore retinal ganglion cell function or regenerate the optic nerve.

See meeting photos