Achievements and Limits of Current Medical Therapy of Glaucoma

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Bettin P, Khaw PT (eds): Glaucoma Surgery. 2nd, revised and extended edition. Dev Ophthalmol. Basel, Karger, 2017, vol 59, pp 1–14 ( DOI: 10.1159/000458482 )

Pelagia Kalouda · Christina Keskini · Eleftherios Anastasopoulos · Fotis Topouzis Laboratory of Research and Clinical Applications in Ophthalmology, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki , Greece

Abstract ery systems are being investigated to open new horizons Prescribing medical therapy for the treatment of glauco- in glaucoma management. Although the general rule is ma can be a complex process since many parameters to initiate glaucoma management with medical treat- should be taken into consideration regarding its achieve- ment, the limits of medical therapy should be considered ments and limits. Today, a variety of options, including to identify those patients in need of surgical manage- multiple drug classes and multiple agents within classes, ment. © 2017 S. Karger AG, Basel are available to the clinician, but caution should be given to their side effects and contraindications. Glaucoma patients with preexisting ocular surface disease should be State of the Art treated with caution, and preferably with preservative- free formulations, as there is an increased risk for symp- Glaucoma is a medical term describing a group of tom deterioration. The development and use of progressive optic neuropathies characterized by fixed-combination therapies has reduced the preserva- the degeneration of retinal ganglion cells and of tive-related side effects that threaten patient adherence the retinal nerve fiber layer, resulting in changes and has minimized the washout effect of multiple instil- in the optic nerve head. Glaucoma is one of the lations. Adherence to medical treatment is not only cru- leading causes of blindness worldwide and pres- cial to its efficacy but also to its cost-effectiveness. Further ents with a significant prevalence in the popula- factors to consider are that there are patients who are tion. nonresponders to treatment, and also that the target in- It is therefore essential to accurately define and traocular pressure (IOP) cannot be reached in all patients, detect the population that should be treated for regardless of the response to treatment. The progression glaucoma and to precisely define the goal of our of damage can occur even under maximum medical intervention. In order to decide who should be treatment or maximally tolerated medical treatment, and treated for glaucoma, it has to be considered that regardless of whether low IOP levels are reached. Further- the rate of ganglion cell loss and resulting func- more, there is some conflict between medical treatment tional decay is very different among different and quality of life due to long-term everyday use and to glaucoma eyes. An older patient, diagnosed late side effects of treatment. New molecules and new deliv- in life, with a moderate rate of progression has a Downloaded by: Massachusetts Eye & Ear 205.166.145.254 - 2/20/2018 5:26:46 PM much lower risk of developing severe functional 5]. Moreover, OHTS [2] revealed the following impairment than a younger patient with the same data for the progression of OH to primary open- amount of field loss at diagnosis and rate of pro- angle glaucoma: (a) a 22% increased risk per de- gression. Moreover, a very slow rate of progres- cade of age, (b) a 10% increased risk per 1-mmHg sion may be tolerated by a patient, while a rapid increase in IOP, and (c) a 71% increased risk per rate of progression requires a considerably lower 40-μm decrease in central corneal thickness. target pressure. The goal of glaucoma treatment is to maintain Target Intraocular Pressure the patient’s visual function and related quality of Target IOP is a useful concept in glaucoma man- life, at a sustainable cost. Regarding the cost of agement. It can be described as the upper limit of treatment, factors like inconvenience, side effects, IOP that is estimated to prevent further glauco- and financial implications for the individual and matous damage or that can slow disease progres- society require careful evaluation [1] . According sion to a minimum [1] . Target IOP will vary for to the EGS guidelines, patients for whom treat- each patient depending on the IOP level before ment for glaucoma should be considered are treatment, stage of glaucoma, rate of progression those with diagnosed or suspected glaucoma who during follow-up, age and life expectancy, and the are: (a) at risk of developing functional impair- presence of other risk factors, such as exfoliation ment that will lead to a deterioration in visual syndrome. The target pressure should be reas- function-related quality of life, (b) patients with a sessed and modified regularly depending on the definitive glaucomatous visual field (VF), partic- patient’s course of the disease. ularly those with progressive disease, and (c) patients with significant changes in the optic nerve Progression of Visual Field Damage head and retinal nerve fiber layer characteristic of The functional impact of glaucoma is mainly as- glaucoma. In the decision to treat glaucoma or sessed by evaluation of the VF damage. The de- not there are additional factors to consider, which tection of VF damage progression directly affects are mentioned below. the therapeutic decisions and the patients’ quality of life. Different analytical tools have been devel- Risk Assessment in Glaucoma oped in order to identify VF progression. Com- Risk factors for the progression from ocular hy- puter-assisted progression can be divided into pertension (OH) to glaucoma are: intraocular event- and trend-based analyses. pressure (IOP), age, central corneal thickness, Event-based analyses answer the question of vertical cup/disk ratio, and standard deviation whether there is disease progression or not by pattern in the VF [2, 3] . Current risk calculators comparing each follow-up examination with the that estimate an ocular hypertensive patient’s risk baseline. Using Glaucoma Change Probability of developing glaucoma over a 5-year period of (GCP) software, all VF tests are compared to time include the aforementioned parameters and baseline consisting of an average of 2 baseline should be used for populations that resemble the tests. However, this analysis is based on the total population studied in the Ocular Hypertension deviation plot, which means that it may be affect- Treatment Study (OHTS) [2] and the European ed by diffuse media opacities. On the other hand, Glaucoma Prevention Study (EGPS) [3] . Guided Progression Analysis (GPA) software is Additional risk factors that may increase the based on the pattern deviation plot, meaning it risk of glaucoma and should be considered in the evaluates progression adjusted for diffuse defects. risk assessment are exfoliation, cardiovascular Trend-based analyses are primarily designed disease, a positive family history, and myopia [4, to determine the rate of progression and show the

2 Kalouda · Keskini · Anastasopoulos · Topouzis

Bettin P, Khaw PT (eds): Glaucoma Surgery. 2nd, revised and extended edition. Dev Ophthalmol. Basel, Karger, 2017, vol 59, pp 1–14 ( DOI: 10.1159/000458482 ) Downloaded by: Massachusetts Eye & Ear 205.166.145.254 - 2/20/2018 5:26:46 PM overall progression of VF defects. Trend-based considered as the most suitable initial and follow- progression displays the linear regression analysis up treatment for open-angle glaucoma, as well as of the VF index. They help the practitioner to as- for many types of chronic angle-closure glauco- sess the risk of future visual disability associated ma. There are many classes of antiglaucoma drugs with that rate of progression and the current stage that act either on the reduction of aqueous humor of damage. production or on the enhancement of the aqueous humor outflow facility, or on both. Principles of Economic Evaluation/Cost Effectiveness First-Line Drugs Glaucoma is a chronic disease that requires life- Prostaglandin Analogues long management. Extensive and often continu- Antiglaucoma drugs were first introduced in ing therapeutic interventions are required due to glaucoma therapy in 1875, but it was in the 1990s the chronic nature of the disease. The costs (direct that prostaglandin derivatives (latanoprost ini- and indirect) and effects (short and long term) of tially and then travoprost, bimatoprost, and taflu- alternative courses of action, such as medical prost) were available for glaucoma treatment and therapies and surgery, need to be compared in or- gradually replaced β-blockers as first-line thera- der to determine cost-effective treatments for py. Their widespread adoption is due to the fact glaucoma. The direct costs are associated with di- that their IOP-lowering effect is superior to any agnosis, treatment, and monitoring, whereas the other single antiglaucoma drug, their side effects indirect costs are associated with progressive dis- appear to be very mild, and they require just once- ease and visual impairment. Moreover, short- daily administration. term effects are related to diagnosis, adverse ef- Their main mode of action is to enhance the fects, and recovery from therapies, while long- uveoscleral outflow (nonconventional pathway), term effects are related to visual outcome. reducing IOP by 25–35%. They degrade collagen It has been suggested that conventional medi- by activating a cascade which includes tissue-re- cation may be more cost-effective than one-off modeling enzymes and transcription factors. This surgery in the short term, but in the long term a leads to the opening of the intercellular spaces for successful surgery is more cost-effective because fluid drainage, which causes increased uveo- the on-going cost of medications is avoided [6] . scleral flow rates and hence decreases IOP. A re- Reported costs of glaucoma therapy vary, but ran- duction in IOP starts approximately 2–4 hours domized controlled treatment trials rarely include after topical administration. The therapeutic ef- a cost-effectiveness analysis. Furthermore, adher- fect reaches its peak 8–12 hours after application, ence to medication plays a significant role in the with its maximum IOP-lowering effect 3–5 weeks economic evaluation of medical glaucoma thera- after initiation of the treatment [11] . These agents py. It is easily understood that no matter how ef- also minimize IOP fluctuations during a 24-hour ficacious a drug is, if the patient does not adhere period [12, 13]. However, the role of long-term with it then the treatment cannot be cost-effective. 24-hour IOP fluctuation in glaucoma progression is currently still open to debate [14, 15] . From clinical observation, it has been pro- Drug Classes posed that an effect on the trabecular meshwork route (conventional pathway) may also exist since The benefit of decreasing IOP with medical treat- the onset of the drug effect is within hours, and ment has been demonstrated in multicenter ran- the increase in IOP after discontinuing the drugs domized controlled treatment trials [7–10]. It is is quite rapid, which can hardly be explained by

Achievements and Limits of Current Medical Therapy of Glaucoma 3

Bettin P, Khaw PT (eds): Glaucoma Surgery. 2nd, revised and extended edition. Dev Ophthalmol. Basel, Karger, 2017, vol 59, pp 1–14 ( DOI: 10.1159/000458482 ) Downloaded by: Massachusetts Eye & Ear 205.166.145.254 - 2/20/2018 5:26:46 PM tissue remodeling in the uveoscleral pathway macular edema. Eventually, patients with herpes alone. keratits may develop a recurrence and they may The percentage of nonresponders to prosta- also develop anterior uveitis. glandin analogues is lower than 10%. It has been reported that different prostaglandin agents may Beta-Blockers have different receptor profiles, indicating that With over 30 years of clinical use, topical poor responders to one prostaglandin agent might β-blockers (timolol, levobunolol, metipranolol, respond to another agent within the same class carteolol, befunolol, betaxolol) have a proven ef- [16, 17]; however, the general rule is that we do ficacy and a satisfying local tolerability profile. not switch between agents within the same class. Their advantages include their wide use, as they Contraindications include hyperreactivity to- are indicated for the medical treatment of OH wards its compounds or its preservatives (benzal- and of all glaucoma types, as well as their low cost. konium chloride; BAC). Moreover, contact lenses β-Blockers achieve an IOP reduction by de- should be removed before instillation and rein- creasing the aqueous humor production. Apart serted 15 min after the administration of the drug. from betaxolol (β 1 selective), all other β-blockers Caution is advised in all forms of inflammatory have a powerful nonselective β 1 and β2 adreno- (secondary) glaucoma and in cases of elevated ceptor binding. They compete with adrenergics IOP due to uveitis, because of their possible in- for β-adrenoreceptors, thus their mode of action flammatory response. However, recent studies comes from antagonism of endogenous adrener- provided evidence on the effectiveness and safety gic responses. Their IOP-lowering efficacy is 20– of prostaglandin agents in uveitic glaucoma [18, 25% from baseline untreated IOP. Timolol is the 19]. It appears to be a quite common strategy to most effective antiglaucoma drug after the pros- discontinue prostaglandin analogues before cata- taglandin analogues, has its maximum effect ract surgery due to the fact that cases of cystoid achieved within 2 weeks after the initiation of macular edema have been reported. These reports therapy, and its nonresponder rate is about 20%. mainly include cases with intraoperative compli- The standard dosing of β-blockers is twice a day, cations. In this regard, prostaglandin agents are but they can also be used once a day with no sig- avoided in operated cataract eyes with intraop- nificant efficacy difference [20] . They have little erative complications such as posterior capsular nocturnal efficacy. bag rupture. Caution is also advised in pregnancy The local side effects of β-blockers are few, in- since no data on safety during pregnancy are cluding punctuate keratopathy, conjunctival hy- available. Finally, unilateral treatment with pros- peremia, dry eyes, corneal anesthesia, and allergic taglandin agents is not recommended because iris blepharoconjunctivitis. Ocular discomfort also color changes may result in the treated eye, which arises from the use of the preservative agent of BAC. will be noticeable. As β-blockers are systemically absorbed, they Side effects include conjunctival hyperemia, were historically contraindicated in patients with foreign body sensation, as well as itching and cardiac or pulmonary disease. Specifically, pa- stinging, which gradually become less severe. In- tients with asthma or other bronchiospastic dis- creased pigmentation of periocular skin, perior- eases, or with chronic obstructive pulmonary dis- bital fat atrophy, eyelash changes and increased ease, should avoid the use of β-blockers. More- iris pigmentation may also occur. They can lead over, cardiac condition defects such as to the development or worsening of cystoid mac- bradycardia, arrhythmias, and heart failure ap- ular edema in patients after cataract surgery with pear as contraindications to β-blocker therapy. capsule rupture or other known risk factors for However, some evidence suggests that β-blockers

4 Kalouda · Keskini · Anastasopoulos · Topouzis

Bettin P, Khaw PT (eds): Glaucoma Surgery. 2nd, revised and extended edition. Dev Ophthalmol. Basel, Karger, 2017, vol 59, pp 1–14 ( DOI: 10.1159/000458482 ) Downloaded by: Massachusetts Eye & Ear 205.166.145.254 - 2/20/2018 5:26:46 PM may be better tolerated than originally thought in lowering efficacy is about 20%, with their peak patients with these conditions [21] . Other sys- IOP reduction occurring 2 hours after installa- temic side effects like depression, fatigue, and tion. They show modest nocturnal efficacy. sexual dysfunction have been reported, but these Systemic CAI contraindications include cases have not been proven through evidence-based re- of known sulfonamide allergy, cases of renal or search [22]. Additionally, β-blockers may also liver disease, depressed sodium and/or potassium mask the symptoms of hypoglycemia in diabetic blood levels, and hyperchloremic acidosis. Topi- patients. Caution should be applied during preg- cal CAIs should be avoided in patients with a low nancy because topical β-blockers may cause fetal corneal endothelial cell count due to an increased bradycardia and cardiac arrhythmia. risk of corneal edema. Finally, a nonclinically significant reduction in The systemic side effects of CAIs can be blood pressure may be noticed with topical acutely presented due to hypersensitivity, such β-blockers. On the other hand, topically applied as Stevens-Johnson syndrome. For long-term β-blockers to patients that are already receiving medication, systemic CAIs are not preferred be- oral β-blocker therapy seems to be less effective, cause of their systemic side effects, which in- since systemically administered β-blockers result clude blood dyscrasias (agranulocytosis, throm- in the binding of adrenoreceptors and can cause bocytopenia, aplastic anemia or pancytopenia) some reduction of IOP as well [23] . [24] , hearing dysfunction, metabolic acidosis, and electrolyte imbalance. Less severe side ef- Carbonic Anhydrase Inhibitors fects like tiredness, headaches, gastrointestinal Carbonic anhydrase inhibitors (CAIs) are all sul- side effects, renal stone formation, paresthesia, fonamide derivatives that inhibit the active aque- depression, and decreased appetite and libido ous humor secretion by blocking carbonic anhy- are common during long-term systemic CAI drase, a key enzyme in aqueous humor produc- use, and rarely occur under topical CAIs. Cho- tion, in the ciliary processes, thus leading to a roidal detachment and transient myopia are rare reduction of IOP. They are indicated for the treat- side effects that can occur either under systemic ment of various glaucoma types (primary-open or topical CAIs. The chronic use of topical CAI angle, congenital, pediatric, juvenile, normal ten- medication has been associated with an in- sion, aphakic, exfoliative, aniridic, and traumatic). creased frequency of ocular burning, stinging, Acetazolamide, methazolamide, and dichlor- bitter taste, tearing, superficial punctuate kerati- phenamide are systemically administered CAIs tis, periorbital contact dermatitis, allergic con- that are used to break acute angle-closure glau- junctivitis, and blurred vision. coma and in cases of very high IOP spikes, such as those induced by Nd:YAG iridotomy. Systemic Alpha Agonists CAIs provide a 30–40% IOP reduction, their ef- Adrenergic agonists have been used in the treat- fect develops rapidly, about 30 min after oral ad- ment of chronic glaucoma for decades. Selective ministration, reaches its peak at 2 h and lasts ap- α2 -adrenergic agonists reduce IOP by the con- proximately 6–8 h. Topical CAIs, which are dor- striction of the afferent ciliary vasculature, lead- zolamide and brinzolamide, are preferred for ing to decreased aqueous humor production and long-term use. Dorzolamide is used 3 times daily also by increasing uveoscleral outflow. Drugs that as monotherapy, but as part of combined therapy are included in this category are apraclonidine, it can be used either 2 or 3 times a day. Brinzol- brimonidine, and clonidine. amide is used twice a day as monotherapy and Both apraclonidine and brimonidine are very also in combination with other drugs. Their IOP- effective in treating and preventing acute IOP

Achievements and Limits of Current Medical Therapy of Glaucoma 5

Bettin P, Khaw PT (eds): Glaucoma Surgery. 2nd, revised and extended edition. Dev Ophthalmol. Basel, Karger, 2017, vol 59, pp 1–14 ( DOI: 10.1159/000458482 ) Downloaded by: Massachusetts Eye & Ear 205.166.145.254 - 2/20/2018 5:26:46 PM elevation in acute glaucomas and after proce- drugs cause contraction of the ciliary muscle and dures including argon laser trabeculoplasty, scleral spur, leading to mechanical opening of the Nd:YAG or argon laser iridotomy, YAG capsu- trabecular meshwork and/or Schlemm’s canal, lotomy, and after cataract surgery. Apraclonidine and enhancement of conventional aqueous hu- reduces IOP by 25–35%, whereas brimonidine mor outflow. and clonidine show an efficacy of 18–25%. The Initially, pilocarpine was used both in open- dosage regimen of topical brimonidine as mono- angle and primary angle-closure glaucoma, re- therapy is 3 times daily and 2 times daily when ducing IOP by 20–25% within 2 hours and lasting combined with other drugs in fixed combination for at least 8 hours. In recent years, its use has formulations. The drug has little effect on IOP been limited to special conditions, such as iris pla- during nocturnal periods. teau, creeping angle closure, and during episodes There are some contraindications for topical of acute angle-closure glaucoma, once the IOP is α-agonists, such as their use in the pediatric pop- reduced under a certain level. ulation because of their penetration of the blood- Miotics should be avoided in uveitic glauco- brain barrier, an issue possibly more of a concern ma, neovascular glaucoma, phacomorphic glau- with brimonidine. Moreover, they should be coma or other conditions with anterior displace- avoided in oral monoamine oxidase inhibitor us- ment of the iris/lens diaphragm. Other contrain- ers, and in adults with a very low body weight. dications include uncontrolled asthma, breathing They should also be used with caution in patients problems, spastic gastrointestinal disturbances, with severe cardio- and cerebrovascular disease, peptic ulcer, bradycardia, hypotension, recent with hepatic or renal impairment, and with Rayn- myocardial infarction, epilepsy, parkinsonism, aud’s phenomenon or other peripheral circula- and retinal disease. tory insufficiency states. They are also contraindi- Several common side effects such as ocular cated in eyes with severe diabetic disease and an- burning, brow ache, reduced night vision, con- terior segment ischemic syndromes, since they junctival hyperemia, retinal detachment, lens decrease anterior segment circulation. opacities, precipitation of angle closure, iris cysts, The more common local side effects of topical intestinal cramps, bronchospasm, and headache α-agonists are eyelid retraction, conjunctival limit the widespread use of these agents for glau- blanching, limited mydriasis, allergic blepharo- coma therapy [26] . conjunctivitis, and periocular contact dermatitis. Apraclonidine and clonidine are more related to Hyperosmotics allergic reactions than brimonidine. The hyperosmotic agents (glycerol, isosorbide, al- The systemic side effects of topical α-agonists cohol, mannitol, urea) reduce IOP by lowering include dry nose and mouth symptoms, a de- the aqueous fluid volume in the eye and are typi- crease in systolic blood pressure, bradycardia, fa- cally given in emergency and/or preoperative sit- tigue, and sleepiness. Furthermore, brimonidine uations to reduce IOP transiently. Mannitol is ad- has been associated with central nervous system ministered intravenously and its efficacy in IOP depression in children, but larger studies are reduction is 15–30%, whereas that of the other needed in order to investigate this further [25] . oral agents is 15–20%. Contraindications include cardiac or renal failure. The potential side effects Second-Line Drugs of this medication class include nausea, vomiting, Parasympathomimetics (Miotics) dehydration, increased diuresis, fluid and electro- Parasympathomimetics include pilocarpine, car- lyte imbalance, obtundation, metabolic acidosis, bachol, echothiophate, and demecarium. These dry mouth, peripheral edema, headache, blurred

6 Kalouda · Keskini · Anastasopoulos · Topouzis

Bettin P, Khaw PT (eds): Glaucoma Surgery. 2nd, revised and extended edition. Dev Ophthalmol. Basel, Karger, 2017, vol 59, pp 1–14 ( DOI: 10.1159/000458482 ) Downloaded by: Massachusetts Eye & Ear 205.166.145.254 - 2/20/2018 5:26:46 PM vision, convulsions, hypotension, coma, possible ease (OSD) such as dry eye, meibomian gland increase of blood glucose, acute oliguric renal fail- dysfunction, and chronic allergy [30] due to both ure, hypersensitivity reaction, and tachycardia. active ingredients and preservative agents. The clinical presentation of OSD varies in severity and includes symptoms of dryness, redness, tear- Fixed Combination Antiglaucoma Therapies ing, irritation, burning, foreign body sensation, photophobia, and distorted vision [31] . The most The use of a single topical antiglaucoma medica- widely used preservative is BAC. BAC is usually tion is often inadequate to reach target IOP and associated with signs and symptoms of OSD [32] , prevent glaucoma progression. The OHTS re- the intensity of which is positively correlated ported that 39.7% of patients that were included with the increase in its concentration and with in the treatment arm required more than one the chronicity of its use [33] . Moreover, chronic medication to reach their target IOP [8] . It is, BAC use may decrease the success rate of filtering therefore, mandatory to add a second ocular hy- surgery [34] . For these reasons, in the recent potensive agent. However, administration of years BAC-free or preservative-free formulations more than one medication may result in preser- of antiglaucoma drugs have been developed and vative-related side effects jeopardizing patient ad- are progressively more widely used. According to herence to therapy and in reducing the medica- the EGS guidelines, particular attention should tion efficacy due to washout effects. In order to be paid to glaucoma patients with preexisting overcome these barriers, fixed combinations of OSD or those developing dry eye or ocular irrita- two antiglaucoma drugs have been manufactured tion over time. This can be done by careful as- and are available worldwide. Fixed combinations sessment of the redness of the eyelid margin, pos- have ameliorated clinical practice by reducing the itive corneal and conjunctival fluorescein stain- number of bottles and eye drops needed [27, 28] , ing, or a reduced tear break-up time [1] . Other thus enhancing adherence by simplifying the therapeutic approaches for OSD include the use treatment scheme and exposing patients in less of unpreserved tear substitutes, the use of fixed preservatives, while presenting clinical equiva- combinations of antiglaucoma drugs, and the lence [29] to their unfixed components. There- early performance of laser or surgery for glauco- fore, when available, a fixed combination therapy ma. should be preferable to two separate instillations of agents [1] . Choosing a Medical Therapy

Ocular Surface Disease IOP is a major risk factor for the development of glaucoma and for the progression of glaucoma- In order for the topical multidose medications to tous damage, and it is widely known that it is the be protected against microbial contamination only factor that can be modified. In most cases of and environmental biodegradation, preserva- primary open-angle glaucoma and in many types tives have become widely used in pharmaceutical of chronic-angle closure glaucoma, medications manufacturing. Due to the natural course of the will be initiated as a first step, mostly topically or disease, glaucoma patients are exposed daily to occasionally orally administered. Any drug that topical medical treatment. It has been shown that has been approved by an official controlling body, long-term topical antiglaucoma drugs may cause such as the EMEA, FDA, or national agencies, is and/or exacerbate preexisting ocular surface dis- considered as a first-line treatment [1] .

Achievements and Limits of Current Medical Therapy of Glaucoma 7

Bettin P, Khaw PT (eds): Glaucoma Surgery. 2nd, revised and extended edition. Dev Ophthalmol. Basel, Karger, 2017, vol 59, pp 1–14 ( DOI: 10.1159/000458482 ) Downloaded by: Massachusetts Eye & Ear 205.166.145.254 - 2/20/2018 5:26:46 PM When deciding to start a medical therapy, may present a different response to the same treat- there are several parameters that the clinician ment, as well as asymmetric spontaneous fluctua- should take into consideration in order to select tions in IOP. Additionally, monocular topical the proper first-choice treatment, including pa- agents may have a contralateral effect [37, 38] . rameters that refer both to patient’s characteristics and the drug properties. A first treatment Therapeutic Algorithm choice is considered a drug that the treating phy- The latest EGS guidelines recommend initiating sician prefers to use as initial IOP-lowering ther- glaucoma medical treatment with a monotherapy. apy among the first-line drugs [1]. As far as the According to van der Valk et al. [39] , who pub- patient’s characteristics are concerned, the treat- lished a meta-analysis of randomized clinical ing physician should always consider the clinical trials, the highest reduction in IOP is obtained picture of each individual, while evaluating which with prostaglandins, followed by nonselective drug class would guarantee the patient’s ocular β-blockers, α-adrenergic agonists, selective and systematic safety, adherence to medication, β-blockers, and finally topical carbonic anhydrase as well as maintenance of vision-related quality of inhibitors. The superiority of prostaglandins in life. With regards to drug properties, the choice treating primary open-angle glaucoma was also should be based on its mechanism of action and verified by a recent network meta-analysis pub- its efficacy in lowering IOP. Preservative-free for- lished by Li et al. [40] in 2016 that included 4 times mulations are an alternative option but cost-relat- as many clinical trials as those of the previous re- ed considerations and convenience in the use of port. If the selected monotherapy is both well-tol- unidose vials should be taken into account. All erated and effective in terms of IOP reduction by the aforementioned considerations aim to lead to achieving target IOP levels, then it can be left un- the most appropriate drug selection in order to changed while periodically verifying endpoints, achieve an effective and well-tolerated therapy. including VF, optic disc, IOP, and quality of life. On the other hand, if the treated patient does Evaluating the Efficacy of Topical Therapy not respond to the initial therapy by showing an The term “effective” is used to describe a treat- IOP reduction of 10–15%, does not reach the tar- ment that succeeds in producing an IOP reduc- get IOP, or if the treatment is not well tolerated, it tion comparable to the published average range is recommended to switch to another monothera- for that drug in a similar population. However, py or to perform laser therapy. If the initially se- when evaluating treatment effectiveness, baseline lected drug is both tolerated and effective but fails IOP should always be a factor to consider, as high- to achieve target IOP levels, the addition of a sec- er initial rates are expected to present larger re- ond treatment factor that belongs to a different ductions and vice-versa [35] . Moreover, IOP lev- drug class should be considered. For this second els fluctuate during the day and night. Therefore, therapeutic choice, certain aspects with regards to it is important to distinguish whether differences the drug characteristics should be evaluated, such in IOP measurements are due to drug efficacy or as its safety and efficacy, the frequency of dosing whether it is a result of normal IOP fluctuation. and its cost, and the additive effect that it can offer Monocular initiative medical therapy was recom- combined to the medication already used (Ta- mended in the past in order to compare the IOP ble 1). Prescribing a fixed combination is gener- changes in both eyes so as to determine ordinary ally preferred to using two agents separately as the fluctuations [36] . However, studies have shown latter may result in inadequate compliance [41, that such protocols cannot sufficiently predict 42] , increased exposure to preservatives [32, 43] , long-term efficacy as each eye of an individual and reduced efficacy in IOP reduction due to

8 Kalouda · Keskini · Anastasopoulos · Topouzis

Current drug Additional drug

α2-agonists β-blockers topical cholinergic prostaglandin/ CAIs prostamides

α2-Agonists + + + + β-Blockers + + + + Topical CAIs + + + + Cholinergic + + + +/– Prostaglandin/prostamides + + + +/–

washout effect [44, 45] . Selecting an initial thera- eration with the doctor’s recommendations [1] . peutic scheme that consists of more than one drug However, the term “compliance” indicates a more is not generally suggested. However, in cases of passive behavior with respect to the patient and it advanced glaucoma and/or very high IOP levels, a has gradually been replaced by the term “adher- faster administration of an additional drug or ence,” defined as the regular use and correct ad- even an immediate one could be accepted. ministration of medication as prescribed by If, despite using a well-tolerated combination healthcare professionals [47] . Nonadherence to therapy, the IOP reduction fails to reach its target, glaucoma therapy remains at high rates that range the second agent could be replaced with another from 30–80% [41, 48]. Several factors threaten a one indicated for the particular individual or even patient’s adherence to a glaucoma regimen, in- a third drug could be added. However, the clini- cluding falsely applying the correct medication, cian should always consider nonmedical options using therapeutic agents other than those pre- in patients at moderate to high risk of vision loss scribed, or discontinuing the drug application. from glaucoma who are already receiving 2 or 3 According to a recent cross-sectional survey pub- medications. Optimal medical therapy, which lished by Newman-Casey et al. [49], low self-effi- generally includes 2 or 3 medications, has re- cacy, forgetfulness, and difficulty with drop ad- placed the concept of maximal medical therapy ministration and the medication schedule were [46] . However, according to the EGS guidelines, barriers associated significantly with poor adher- the prescription of more than 2 bottles of IOP- ence. “Persistence” is defined as the length of time lowering eyedrops for simultaneous use should during which the patient takes the medication that be avoided as it can lead to noncompliance [1] . is prescribed [50] . Long-term persistence to a therapeutic scheme is necessary for achieving the best drug performance. Using pharmacy claims Adherence and Persistence data, Friedman et al. [51] reported that only 10% of patients had continuously refilled their medica- The ability of a topical medication to prevent glau- tion during the first year of therapy. coma progression is largely dependent on the pa- Poor adherence and persistence are associated tient’s long-term cooperation with the physician’s with deterioration in VF defects and a greater recommendations, which is best described by the fluctuation in IOP, which may contribute to dis- terms “compliance”, “adherence”, and “persis- ease progression. It is therefore crucial to inform tence.” “Compliance” refers to the patient’s coop- the patient in detail about the nature of the disease

Achievements and Limits of Current Medical Therapy of Glaucoma 9

Achievements A variety of options, including multiple classes and multiple agents within classes, are available to the clinician IOP reduction efficacy: prostaglandins 25–35%, β-blockers 20–25%, systemic CAIs 30–40%, topical CAIs 20%, α-agonists 25–35% (apraclonidine) and 18–25% (brimonidine, clonidine), parasympathomimetics 20–25% (pilocarpine), hyperosmotics 15–20% (glycerol) and 15–30% (mannitol) Development and use of fixed combinations aiming to: improve adherence, provide less exposure to preservatives, and lead to a better efficacy in IOP reduction due to elimination of the washout effect Development and use of preservative-free formulations aiming to prevent or minimize ocular surface disease and related cases Limitations Contraindications of each antiglaucoma drug class (systemic or ocular disorders, pregnancy, etc.) Local and systemic side-effects of each antiglaucoma drug class Presence of preservatives (e.g., benzalkonium chloride): ocular surface disease, decrease in the success rate of filtering surgery Many patients present poor adherence to treatment, which is crucial for its efficacy and cost-effectiveness Some patients are nonresponders to medical therapy Target IOP cannot be reached for all patients Progression of damage can occur even under maximum medical treatment or maximally tolerated medical treatment and regardless of whether low IOP levels are reached Interference of medical treatment with quality of life due to long-term everyday use and the side-effects of treatment

and to find a simple and effective therapy that fits new means to augment patient adherence is man- each individual’s lifestyle [52] . The administra- datory in order to reach maximum medication ef- tion of therapy should be clearly explained and ficacy and prevent glaucoma progression (Ta- discussed at each follow-up visit for any potential ble 2 ). side effects that may threaten the patient’s adherence. There is ongoing research for new incen- tives that could possibly improve patients’ long- New Perspectives term adherence. Based on behavioral economic theories which suggest that adherence rates can Given the problems of glaucoma progression de- be improved by offering patients a near-term spite maximal tolerated medical treatment, pa- benefit, the SIGMA study investigated whether tients frequently being nonresponders to differ- adherence-contingent rebates can improve medi- ent drug classes, and their lack of adherence to cation adherence among nonadherent glaucoma topical therapy, researchers are concentrating on patients [53] . Therefore, applying and improving developing new molecules for glaucoma treat- the strategies that have already proven to be effec- ment and designing new sustained-release drug tive in everyday clinical practice and trying to find delivery systems.

10 Kalouda · Keskini · Anastasopoulos · Topouzis

Bettin P, Khaw PT (eds): Glaucoma Surgery. 2nd, revised and extended edition. Dev Ophthalmol. Basel, Karger, 2017, vol 59, pp 1–14 ( DOI: 10.1159/000458482 ) Downloaded by: Massachusetts Eye & Ear 205.166.145.254 - 2/20/2018 5:26:46 PM New Molecules ducted and the first promising results have been Several new molecules currently being researched published showing a significant IOP reduction in will potentially add new drugs to glaucoma thera- OH and open-angle glaucoma patients during a peutic treatment. Based on the widely known ef- 30-day course [67]. A new phase IIb study com- ficacy of prostaglandins, latanoprostene bunod, a paring this system to timolol drops has been re- new nitric oxide-donating prostaglandin F2α ana- cently completed. Similarly, a phase II clinical tri- log that is able to both increase uveoscleral and al compared a topical bimatoprost ocular insert trabecular meshwork outflow, was tested in phase placed circumferentially in the upper and lower II and III clinical trials both for its efficacy versus fornices to twice-daily timolol eyedrops in pa- timolol and latanoprost [54–56] and for its long- tients with open-angle glaucoma or OH treated term safety [57] . for 6 months. The study has shown a clinically Since the appearance of prostaglandin ana- relevant reduction in mean IOP and a noninferi- logues in 1995, no alternative drug class has been ority of the implant in 2 out of 9 time points. Nov- effective and safe enough to be established as a nov- el injectable delivery systems, releasing glaucoma el glaucoma treatment. Efforts in finding new drug medications into the subconjunctival space, the classes have produced quite promising results. A anterior chamber or the vitreous body, are also new highly selective adenosine mimetic targeting heralding a new shift in glaucoma treatment. A the adenosine A1 receptor (trabodenoson) was clinical trial investigating the ability of a fully bio- tested for its IOP-lowering effect and its safety pro- degradable implant to administer travoprost for file versus placebo in OH and open-angle glauco- more than 6 months from a single dose has com- ma subjects [58–60] . Last but not least, Rho kinase pleted patient recruitment and is ongoing. inhibitors seem to represent a new option in antiglaucoma medications. Multiple clinical trials have recently provided data on their ability in effectively When to Perform Glaucoma Surgery reducing IOP either as a monotherapy or as a combination with other widely known medications, Despite the fact that medical therapy is the first such as timolol and latanoprost [61–65] . step in treating the majority of glaucoma patients in everyday clinical practice, there are certain cir- New Delivery Systems cumstances under which glaucoma surgery As proper topical administration of glaucoma should be considered as the next step in the treat- therapy is a challenge in everyday clinical practice, ment algorithm or even, in some cases, be the best sustained-release drug delivery systems able to initial intervention. Most cases of primary open- overcome factors such as the patients’ adherence- angle glaucoma are initially treated with topically related issues and side effects seem to be an inter- administered medications. However, failure to esting solution. This new perspective is attractive control IOP and glaucoma progression with med- not only to clinicians but also to glaucoma pa- ical treatment should make the physician consid- tients. In a cross-sectional study that aimed to in- er a possible surgical intervention. Furthermore, vestigate the acceptance and preference rates of 3 there are patients for whom the addition of a fur- sustained drug delivery systems in glaucoma pa- ther drug class may be clinically ineffective or tients, the authors concluded that 73.6% of the pa- contraindicated as systemic and topical contrain- tients accepted at least one of the systems [66] . dications, allergies, or pure compliance might be A recent development in this direction is sus- barriers difficult to overcome. Therefore, in such tained drug release by punctual drug delivery sys- cases, surgery seems to be the best choice. More- tems. Early-phase clinical trials have been con- over, if the IOP level at the time of glaucoma

Achievements and Limits of Current Medical Therapy of Glaucoma 11

Bettin P, Khaw PT (eds): Glaucoma Surgery. 2nd, revised and extended edition. Dev Ophthalmol. Basel, Karger, 2017, vol 59, pp 1–14 ( DOI: 10.1159/000458482 ) Downloaded by: Massachusetts Eye & Ear 205.166.145.254 - 2/20/2018 5:26:46 PM diagnosis is exceptionally high and the glaucoma- glaucoma and, consequently, an initial surgery is tous changes are such that imply an immediate an indication in almost all cases [68–70] . The threat to sight, glaucoma surgery is maybe the same treatment profile can be followed for cases best intervention to begin with. with secondary childhood glaucoma and for Although primary open-angle glaucoma usu- young patients with glaucoma established after ally responds well to medical therapy, secondary cataract surgery, as medical therapy is usually in- glaucomas are usually more aggressive clinical sufficient and not practicable in the long term in entities with respect to both their IOP levels and both of the aforementioned categories. their rate of progression. Most cases of pseudoex- In chronic angle-closure cases, failure to con- foliative and pigmentary glaucoma should initial- trol IOP and glaucoma progression indicates the ly be treated using topically administered medica- need for incisional surgery. In cases with acute tions. However, controlling the reduction and angle closure with a pupillary block mechanism, level of IOP is significantly more challenging in a laser iridotomy or a surgical iridectomy when these patients and, therefore, a laser trabeculo- the cornea is transparent or opaque are, respec- plasty or incisional surgery is often performed at tively, the preferred treatments. Laser iridotomy an early stage. may also be indicated as a preventive measure to An early surgical intervention is usually inevi- avoid acute attacks regardless of the effectiveness table in most cases of childhood glaucoma. Medi- of the medical treatment. Recent work on the role cal therapy is highly ineffective when treating pa- of lens extraction in angle closure may result in a tients with primary congenital and early juvenile paradigm shift in the future [71] .

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