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Glaucoma is a common clinical entity that will become more prevalent as the baby boomer population ages. Traditionally, treatment of the most common form of glaucoma—primary open-angle glaucoma (POAG)—starts with topical medications, followed by laser intervention if intraocular pressure (IOP) is not sufficiently controlled, with surgery reserved for recalcitrant or advanced disease. Most patients with glaucoma will never progress to the point at which anything beyond medical therapy or laser is necessary.
However, appropriate medical management of glaucoma is highly nuanced and patient specific. No two clinical presentations are alike, nor will any one approach be efficacious for every patient. Although a general step-wise treatment algorithm can be defined, with preferred first-, second-, and third-line options, the treating specialist should be prepared to alter this typical course if necessary. For example, treatment class efficacy failures, side effects, allergic responses, and managed care coverage of the various medications may result in the clinician needing to abandon a standard protocol quickly. Treatments must be designed to provide ample IOP-lowering efficacy but not to sacrifice safety or quality of life for patients while achieving therapeutic targets.
ENCOUNTER WITH THE PATIENT
My initial evaluation of a patient with known or suspected glaucoma is predicated on identifying damage to the optic nerve and associated retinal nerve fiber layer (RNFL). This is assessed by direct clinical examination and through imaging of the RNFL and ganglion cell layer. There is conclusive evidence that structural change occurs in the ganglion cell layer before the RNFL, and that damage to both typically precedes loss of visual function. There can be incongruence between structure and function—the RNFL and optic nerve on the one hand and the visual field on the other—over the lifetime of a patient with glaucoma; however, at its earliest stages, glaucoma is known to affect the ganglion cells, and this then contributes to axonal damage, and, ultimately, to RNFL loss.1-4
Visual field testing is subject to potentially confounding factors. Structural defects typically precede visual field loss, and so, although field loss is often used to define glaucomatous progression, when it appears, irreversible damage has already been done. As much as 30% to 50% of the RNFL may be lost before visual field defects become apparent. Another confounding factor is the ability of patients to perform the often challenging perimetry test properly. But even when patients are tested properly, early visual field loss can be difficult to detect because early defects are subtle and not always repeatable.
IOP is a critically important value, as it is the only modifiable risk factor for glaucomatous progression. However, glaucoma is also not a singular entity but rather a continuum of optic neuropathies with various mechanistic causes. Although elevated IOP is a feature of POAG and some other types of glaucoma, there is also normal- or low-tension glaucoma. Although IOP is the only target of treatment at this time, we know that approximately 50% of patients with glaucoma will never have an elevated IOP. Furthermore, many people with statistically elevated IOP will never develop glaucoma.
When a patient is evaluated for possible glaucoma but a definitive diagnosis is not reached, careful follow-up is needed to monitor for change over time. We may monitor patients who are glaucoma suspects for years, and many of them will not convert to clinical glaucoma while others will convert 6 to 8 years down the road after the initial workup. For patients who are diagnosed and started on glaucoma medication, quarterly IOP evaluations are needed to monitor for IOP lowering and stability.
Glaucoma is a progressive disease, sometimes despite the best management of IOP. Clinically, we can see progression of RNFL loss on optical coherence tomography imaging and visual function decline on automated visual field testing. This is an indication that the patient’s IOP is not low enough to halt the progression of the disease and further IOP lowering is needed. Sometimes it is not the absolute level of IOP lowering that is important but rather the stabilization of IOP fluctuations over the course of 24 hours. At the end of the day, the only tool we have that is proven to slow the progression of glaucoma is IOP lowering.
The decision about when to initiate treatment is not straightforward, although the weight of evidence supports early intervention. In the Ocular Hypertension Treatment Study, or OHTS, only 10% of untreated patients converted to glaucoma.5,6 In the Early Manifest Glaucoma Trial, after conversion, half of untreated patients progressed to worse disease within 4 years, and almost 70% did so within 6 years.7,8 Untreated patients with elevated IOP are even more likely to progress, demonstrating the need for close follow-up.
In addition to assessing the optic nerve, RNFL, and visual field, corneal hysteresis and pachymetry are helpful in making a diagnosis of glaucoma. Central corneal thickness has been found to be a key part of the algorithm for determining risk of development of glaucoma. In the OHTS, a central corneal thickness of less than 555 µm was a key indicator of risk of conversion from ocular hypertension to glaucoma.5,6 Electrodiagnostics using an electroretinogram can also help the clinician to understand the objective visual function of a patient independent of subjective visual fields.
The criteria for establishing progression in glaucoma are varied depending on the individual patient. Generally speaking, we are looking for progression of RNFL damage on optical coherence tomography or visual field progression as measured by glaucoma progression analysis software. Failure to meet target IOP is another factor to consider in advancing therapy. Finally, other factors such as the occurrence of an optic nerve hemorrhage or identification of an IOP spike during office hours can increase the likelihood of a patient’s needing additional IOP lowering therapy.
Controlling IOP is the only available strategy for slowing glaucoma progression. In the future, neuroprotective agents may offer a different approach, and neutraceuticals containing antioxidants and blood flow enhancements may be recognized as beneficial in cases in which elevated IOP is not the key feature.
Under the current schema, a target IOP range should be designated for each patient, and efforts should be directed at achieving and maintaining that IOP range. Target IOPs are frequently adjusted based on the patient’s rate of progression or severity of disease. This is done with the caveat that no two patients are alike, and an IOP of 15 mm Hg in one patient may be sufficient, whereas that level may still be too high in a patient with normotensive glaucoma.
Numerous classes of drugs have been used in the effort to control IOP. Over the years these have included beta-blockers, alpha-agonists, carbonic-anhydrase inhibitors, prostaglandin analogues (PGAs), and others. Today, the PGA class is the accepted first-line treatment option for patients with POAG or ocular hypeternsion.9 The various members of this class can be expected to lower IOP by about 28% to 35% depending on peak and trough effect.10-12
Although the drugs in the PGA class are the standard first-line choice, they are contraindicated in patients with aphakia, a history of a broken posterior capsule during cataract surgery, active intraocular inflammation, or cystoid macular edema. I am also hesitant to use them in patients in whom only one eye is being treated, due to their potential side effects, which may include iris color change, pigmentary changes, and deepening of the eyelid sulcus. These effects are obvious cosmetically to patients, and there are sufficient alternatives in most cases that can avoid the cosmetic and adnexal changes seen with PGAs.
The mechanism of action of PGAs is to increase aqueous outflow via the uveoscleral pathway. Although this outflow pathway is used to a very small degree in normal patients, as compared with the trabecular outflow pathway, PGAs tap the uveoscleral pathway as a very efficacious adjunct to overall outflow and IOP lowering. This class of agents is used in virtually all types of glaucoma, although primary surgical intervention is standard for angle-closure glaucoma, neovascular glaucoma, and many of the congenital and juvenile forms of glaucoma.
PGAs are generally well tolerated, with little to no systemic interaction, which is important for patients with coexisting cardiovascular or pulmonary disease. They are also effective with only once-daily dosing, which is advantageous for elderly patients who may be taking multiple medications and perhaps for overall compliance and adherence given the simplicity of dosing.
For patients who do not wish to be exposed to the potential side effects of PGAs and other agents, and for patients unable or unwilling to be compliant with daily drop dosing, we discuss the possibility of selective laser trabeculoplasty (SLT) as a first-line option. Although SLT is gaining acceptance as a first option for treating glaucoma, fewer than 10% of patients in our practice opt for laser trabeculoplasty as initial treatment.
If further IOP lowering is needed in addition to a PGA for medical therapy, I generally prefer the fixed-combination agents. There are three combination agents now available in the US market: dorzolamide HCl 2.0%/timolol maleate 0.5% (Cosopt; Merck and Cosopt PF [preservative free]; Akorn); brimonidine tartrate 0.2%/timolol 0.5% (Combigan; Allergan); and brinzolamide 1%/brimonidine 0.2% (Simbrinza; Alcon). Because adherence to medical therapy decreases as the medication regimen becomes more complex,13-15 combination agents are an advantageous option, especially as they can be expected to deliver efficacy similar to that of a PGA. It is not possible, however, to adjust the concentration, frequency, or timing of the dosage of the individual ingredients, and, if patients experience side effects, the combined nature of the product can sometimes make it difficult to determine which agent might be causing them.
WHEN TO SWITCH, WHEN TO ADD
Primary therapy can fail for a number of reasons. It may not necessarily be related to failure to achieve a target IOP. In some cases, patients become intolerant to a medication or demonstrate poor adherence to their regimens. Adverse events may occur, due either to the active drug or to inactive ingredients, including preservatives. If the patient’s ocular surface appears to be degrading, the preservative benzalkonium chloride (BAK) could be the cause, in which case it may be prudent to switch to an agent with an alternative preservative system. Among available medications, Travatan-Z (Alcon) contains the Sophzia preservative system, which is BAK free, and Zioptan (Akorn) is totally preservative free. Sun Pharmaceuticals also has a PGA agent in late stages of development that is also ultimately preservative free. In the adjunctive market, Cosopt PF is a nonpreserved version of Cosopt.
There is also growing appreciation of the fact that dry eye disease and meibomian gland dysfunction are highly prevalent among patients with glaucoma, and patients may require treatment for these conditions independent of their glaucoma. Certainly, the inflammatory nature of PGAs does not help the ocular surface, but when the BAK preservative in most PGAs is also taken into account, these factors may be a consideration in patients with dry eye disease.
Typically, for a patient taking a PGA who is not responding sufficiently to the therapy, I prefer to switch within the drug class, such as choosing a branded PGA over a generic, or to add a second drop, which now frequently is a fixed-combination agent. SLT may also be an alternative to adding a second-line drop. Finally, when all drug classes have been exhausted, a referral to a glaucoma surgeon for a trabeculectomy or tube shunt procedure may be indicated. If the patient has coexistent cataract, then cataract surgery itself lowers IOP long term, especially when combined with a minimally invasive glaucoma surgery, or MIGS, procedure.
Several antiglaucomatous drug candidates in the pipeline are worth keeping an eye on.
Phase 3 clinical trial data on latanoprostene bunod ophthalmic solution 0.024% (Bausch + Lomb) was recently published,16 and the drug is being reviewed for approval by the US Food and Drug Administration (FDA). This agent is a nitric oxide–donating PGA, and it appears to offer an additional 1 to 2 mm Hg of IOP lowering compared with a standard PGA.17 This would appear to be a good agent to consider for patients who are taking a PGA but need additional IOP-lowering without adding a second agent. The FDA recently gave Bausch + Lomb a complete response letter on its submission for this drug. There was no mention of issues with efficacy or side effects in the letter, but a problem in one of the manufacturing plants was noted, and this must be mitigated before FDA approval of the drug can take place.
Also in development, agents in the rho-kinase inhibitor class will probably reach market within the next 2 years. Two agents are in late stages of development: netarsudil; (Rhopress; Aerie Pharmaceuticals) and ripasudil (Glanatec; Kowa). The rho-kinase inhibitors act on the trabecular meshwork, which is an area in which few available medications have efficacy. In addition, it is expected that rho-kinase inhibitors will be combined with PGAs as combination agents within the next 4 years. This would offer the holy grail of glaucoma treatment: uveoscleral outflow, trabecular outflow, and inhibition of aqueous production.
Neuroprotection is a promising strategy but one that has met with mixed results in clinical trials. Proving a protective effect is difficult, and it may take more fits and starts before viable neuroprotective agents become available.
For now and for the foreseeable future, modifying IOP is the only mechanism known to affect glaucomatous progression. Proper treatment of patients with glaucoma requires the eye care practitioner to consider the need to lower IOP in the context of safety, quality of life, and the efficacy of the various classes of medications. n
1. Howell GR, Libby RT, Jakobs TC, et al. Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J Cell Biol. 2007;179:1523-1537.
2. Schlamp CL, Li Y, Dietz JA, et al. Progressive ganglion cell loss and optic nerve degeneration in DBA/2J mice is variable and asymmetric. BMC Neurosci. 2006;7:66.
3. Quigley HA. Neuronal death in glaucoma. Prog Retin Eye Res. 1999;18:39-57.
4. Hernandez MR. The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Prog Retin Eye Res. 2000;19:297-321.
5. 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;120:701-713.
6. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:714-720.
7. Heijl A, Leske MC, Bengtsson B, et al; Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120:1268-1279.
8. Leske MC, Heijl A, Hyman L, Bengtsson B. Early Manifest Glaucoma Trial: design and baseline data. Ophthalmology. 1999;106:2144-2153.
9. Prum BE Jr, Herndon LW Jr, Moroi SE, et al. Primary Angle Closure Preferred Practice Pattern Guidelines. Ophthalmology. 2016;123(1):P1-P40.
10. van der Valk R, Webers CA, Schouten JS, et al. Intraocular pressure-lowering effects of all commonly used glaucoma drugs: a meta-analysis of randomized clinical trials. Ophthalmology. 2005;112(7):1177-1185.
11. Aptel F, Chiquet C, Romanet JP. Intraocular pressure-lowering combination therapies with prostaglandin analogues. Drugs. 2012;72(10):1355-1371.
12. Tabet R, Stewart WC, Feldman R, Konstas AG. A review of additivity to prostaglandin analogs: fixed and unfixed combinations. Surv Ophthalmol. 2008;53(Suppl1):S85-92.
13. Tsai JC, McClure CA, Ramos SE, et al. Compliance barriers in glaucoma: a systematic classification. J Glaucoma. 2003;12(5):393-398.
14. Sleath B, Robin AL, Covert D, et al. Patient-reported behavior and problems in using glaucoma medications. Ophthalmology. 2006;113(3):431-436.
15. Robin AL, Novack GD, Covert DW, et al. Adherence in glaucoma: objective measurements of once-daily and adjunctive medication use. Am J Ophthalmol. 2007;144(4):533-540.
16. Medeiros FA, Martin KR, Peace J, et al. Comparison of latanoprostene bunod 0.024% and timolol maleate 0.5% in open-angle glaucoma or ocular hypertension: the LUNAR Study. Am J Ophthalmol. 2016;168:250-259.
17. Latanoprostene bunod. Nicox. http://www.nicox.com/rd/vesneo-latanoprostene-bunod-2/. Accessed July 19, 2016
Ben Gaddie, OD, FAAO
• Senior partner and director, Gaddie Eye Centers, Louisville, Kentucky
• President, Optometric Glaucoma Society
• (502) 423-8500; email@example.com
• Financial disclosure: consultant to Aerie Pharmaceuticals, Akorn, Alcon, Allergan, Bausch + Lomb, and Diopsys