509

47  Medical Management of Glaucoma: Cost-EffectivenessJENNIFER BURR and LUKE VALE

burden of (already) stretched eye care services. Effective and efficient treatment and monitoring strategies are required. Decisions about treatments, from those available, need to be made at the level of the health service and at the individual patient level. Health economics, and in particu-lar the methods of cost-effectiveness, can inform policy-makers about which treatments are value for money and should be available in a service and influence the choice of treatments at an individual level. Within cost-effectiveness analysis the cost components include the direct costs of diagnosis, treatment and monitoring and the indirect costs associated with progressive disease and visual impairment. The effect side of a cost-effectiveness analysis should cover both short-term effects related to diagnosis, adverse effects and recovery from therapies as well as long-term effects related to visual outcome. To determine cost-effective treat-ments for glaucoma, both the costs and effects of alterna-tive courses of action, e.g. different medical therapies or surgery or no treatment, need to be compared.

Medical Therapy

In the last two decades several new glaucoma medications have become available with different modes of action according to their active ingredients. There are now five main classes of licensed medical treatments for glaucoma. These are prostaglandin analogues, beta-blockers (beta receptor antagonists), carbonic anhydrase inhibitors, sympathomimetics (alpha receptor agonists), and miotics (cholinergic agonists). These drugs act to lowering intraoc-ular pressure (IOP) by either reducing aqueous inflow or increasing aqueous outflow.

The drugs are available in different formulations and, in some cases, strength. They can be used in liquid form alone or in combination. Fixed combination eye drops contain two drugs dispensed in one bottle. Tablets of the oral car-bonic anhydrase inhibitor acetazolamide are also available; their use is usually limited to the control of short-term rises in IOP. All of these drugs can have local and systemic side effects and vary in comparative efficacy (lowering of IOP under ideal conditions) and effectiveness (reducing risk of glaucoma progression and sight impairment). Fixed combi-nation therapy, compared to monotherapies, can offer a simple and convenient dosing regimen. Fixed combinations may result in some cost-saving for patients, depending on what out-of-pocket expenses they might incur such as pre-scription charges. But there is a potential loss of benefit as fixed combinations remove the possibility of titrating the individual components both in terms of concentration and timing of administration and they might not provide the

Introduction

Glaucoma is a chronic disease leading to impaired vision and in some cases blindness. Glaucoma usually presents around the age of 60, although it may affect subgroups, such as those of black ethnicity or those with a genetic predisposition to glaucoma, earlier. Intraocular pressure (IOP) is an important prognostic factor for visual loss attrib-utable to glaucoma and the only factor that can be altered by treatment. Treatment can be either medical, usually as eye drops, laser or surgery all aiming to lower IOP and thus reduce the risk of progressive glaucoma and consequent visual impairment. Extensive and often continuing thera-peutic interventions are required as a result of the chronic nature of the disease.

The incidence of glaucoma and other common eye condi-tions such as cataract and macular degeneration increases with age. With an aging population the number of people requiring eye care and treatment will increase adding to the

Summary

■ Glaucomaisachronicdiseaserequiringlife-longmanagement.Sincethe1990sseveralnewglaucomamedicationsareavailableasarerefinementsinlaserandsurgicaltreatmentsforglaucoma.Inhealthcaresystemswithfinitebudgetsdecisionshavetobemadetodeterminethebestuseofhealthresourcesintermsoftreatmenteffectivenessandcost-effectiveness.Thecost-effectivenessofalternativetreatmentsshouldtakeintoaccountbothshort-andlong-termcostsandbenefits.Therearewidevariationsinreportedcostsofglaucomatherapyacrossnations,butinformationfromeconomicevaluationsalongsiderandomizedcontrolledtreatmenttrialsormodel-basedevaluationslinkingcostsandbenefitsaresparse.Therearefewreportsfromlow-andmiddle-incomecountriesanddataespeciallyeconomicdatafromhigh-incomecountriesmaynotbeapplicable.

■ Cost-effectivenessdecisionsarecountry-specificbecausepatternsofcare(andhenceresourceuse)aswellascostsmayvary.Furthermore,somightthevaluethatpatientsplaceontheoutcomesoftreatment.

■ Pricingofglaucomamedicationsisnottransparentandpriceschangeovertimeandbetweencountries.Reductionsinthecostsofocularhypotensiveagentsmayaltercost-effectivenessconclusions.Generictreatmentscanreducethecostsofglaucomatherapyaslongasdeliverymechanismfortheeyedropfacilitateseasydropinstillationbythepatients.

■ Adherencetomedicationisofextremeimportance.Nomatterhowefficaciousadrugisifthepatientdoesnotadherewiththemedicationregimenthenthetreatmentcannotbeeffectiveorcost-effective.

SECTION5 • PrinciplesofManagement510

units (cost-benefit). A composite effect that combines both quality and quantity of life into one unit is believed to be more likely to measure outcomes of importance to individu-als and facilitates comparison across interventions. A com-posite effect can be expressed as Quality Adjusted Life Year (QALY), a year of life adjusted for its quality, or as a Disabil-ity Adjusted Life Year (DALY). DALYs are life years lived adjusted for disease-related disability and time preference. Within high-income countries the QALY is the predomi-nant approach. The challenge is how to ascertain the Q in the QALY. Generic measures of health status capture broad concepts of health and quality of life. One widely used generic measure is the EuroQol, also known as the EQ5D.5 The EQ5D has five questions capturing pain, mood, self-care, usual activities and mobility. QALYs calculated using a generic health status measure allow decision-making across diseases, but may not be sensitive enough to capture all glaucoma-specific health effects that are important to patients such as the impact of smaller variations in visual impairment and less severe adverse events.

Internationally, the DALY is the predominant measure of benefit, particularly in middle- and low-income countries. The DALY combines loss of functioning due to disease and length of life. Although conceptually DALYs and QALYs are similar they differ in terms of how the health states are weighted. The QALY is based on preference of the public or patients for alternative health states whereas DALY calcula-tions are based on valuations from a panel of experts and include evaluations for blindness.6

Principles of Economic Evaluation

Economic evaluation is a method of providing decision-makers with information about the opportunity cost of the decisions that could be made, where opportunity cost is the benefit we would have obtained had the resources used to provide one treatment been used to provide another instead, or more strictly the benefit we would have obtained had we used the resources for their next best alternative use. Eco-nomic evaluation is the comparative analysis of alternative courses of action in terms of both their costs (resource use) and effectiveness (health effects).7 New treatments that improve health but at higher costs relative to a treatment alternative may be considered cost-effective if this addi-tional cost is acceptable to society, i.e. societies’ willingness to pay for an additional unit of health benefit. The applica-tion of economics to medical practice does not necessarily mean that less should be spent, but rather that we can make better uses of the resources we have.

Cost-effectiveness analyses are best described in a matrix format to aid judgment as to whether a new treatment is preferable to usual care as illustrated in Figure 47-1.

For any intervention (e.g. a new ocular hypotensive med-ication) the optimum position in Figure 47-1 is square ‘A1’, where a new treatment would both save costs and have greater effectiveness relative to a comparator (an alterna-tive reference treatment such as standard ocular hypoten-sive medication, surgery or laser or an entirely different health need); such a new intervention would be considered relatively efficient. Likewise in squares A2 and B1, the experimental treatment is more efficient than a comparator

same efficacy as the individual components prescribed sepa-rately. Unnecessary side effects may arise as a result of the higher concentration of beta-blockers in all currently avail-able fixed combinations.1 Tolerance, safety and efficacy/effectiveness have to be balanced to achieve the optimal treatment schedule as intensive follow up incurs greater costs.2,3

ESTIMATING THE COSTS (RESOURCE USE) OF MEDICAL THERAPY FOR GLAUCOMA

Cost-of-illness studies determine the total financial burden of a disease by considering ‘direct’ and ‘indirect’ costs. The direct costs of glaucoma treatment include the costs of the tests and treatment, costs of visits including the costs to patients of attending and the costs of healthcare personnel and facilities. Direct costs also include the expected costs of side effects and adverse events. Direct costs might also include the costs of social support such as use of aids and equipment or adaptation of homes and living spaces to miti-gate the effects of visual impairment for those with severe glaucoma. The direct costs of glaucoma are usually higher during the first year following diagnosis as treatment is sta-bilized and increase for those with more severe glaucoma.4 Thus, minimizing visual impairment by an effective treat-ment schedule and improving adherence and compliance with treatment may all contribute to a reduction in the overall economic burden of glaucoma. The indirect costs of glaucoma include loss of productivity and the need for informal personal care (and the associated impact on the employment of informal carers). Many of these indirect costs are related to the level of visual impairment and are not necessarily specific to glaucoma.

Critical to the consideration of cost is the perspective of the analysis. Commonly adopted perspectives are those of healthcare providers (e.g. a hospital); payers (e.g. a publicly funded National Health Service (NHS) or managed care organization); social services; patients or, in the widest form, society. Whose perspective is taken can be very impor-tant as taking a narrower perspective, e.g. the NHS alone, could lead to a different conclusion being drawn than when a wider perspective, e.g. the NHS and the patient, is taken.

ESTIMATING THE EFFECTS OF GLAUCOMA

Preservation of visual function is best achieved by lowering IOP but medical treatments are associated with side effects and difficulties in treatment administration. Glaucoma can thus impact on patients’ self-reported health and quality of life in multiple ways even in the early stages. The need to adhere to treatment and side effects of treatment all need to be considered when comparing alternative treatment regimens for those with or at risk of developing glaucoma. Progressive visual field loss can impair patients’ abilities to perform common daily activities and also may impose an increasing psychological burden on patients and their families.

Effects (units of benefit or dis-benefit) of alternative inter-ventions can be expressed in terms of clinical measures of effectiveness, e.g., difference in IOP in mmHg (cost-effectiveness) or consequences, e.g. number of cases of glaucoma progression (cost-consequence) or monetary

47  • MedicalManagementofGlaucoma:Cost-Effectiveness 511

in two randomized controlled trials (Ocular Hypertensive Treatment Study [OHTS]9 and the European Glaucoma Pre-vention Study [EGPS]).10 Combining these data and data from eight smaller trials a policy of treating ocular hyper-tension compared to no treatment appears to be effective with a 40% reduction in the incidence of glaucomatous visual field defects with treatment at five years (odds ratio 0.62; 95% confidence interval 0.5 to 0.8).11

The cost-effectiveness of treating ocular hypertension depends on the risk of developing glaucoma and life expect-ancy. For example, based on OHTS,12 subjects with a 2% or greater annual risk of developing glaucoma aged >45 treat-ment is likely to be cost-effective if life expectancy is at least 23 remaining years but for someone aged 65 years life expectancy must be at least 18 years.13 The findings suggest that under ideal conditions treating ocular hypertension is likely to be cost-effective for higher-risk groups. To apply these findings to clinical practice important issues need to be considered. These are: reliable predictors of an individu-al’s risk of glaucoma, adherence to treatment and treat-ment side effects. A model-based economic evaluation in a Dutch context with a societal perspective and lifetime horizon supports an approach of direct pressure-lowering treatment for ocular hypertension compared to a strategy where treatment is postponed until glaucoma has been observed.14 A similar evaluation in the UK with different assumptions found that of the care pathways modeled direct treatment was the most likely cost-effective strategy.15 The cost-effectiveness was influenced by the baseline risk of developing glaucoma and the frequency of monitoring visits, monitoring more frequently than biennially is unlikely to be cost-effective.15 One key difference between the Dutch and UK studies was the exclusion of productivity effects (an element of indirect costs) in the UK study. The inclusion of such costs in evaluations is contentious and as a consequence different countries adopt different guidelines about whether these costs should be included or not. The critical issue for a reader is that the UK study would tend to provide a more conservative estimate of cost-effectiveness than the Dutch study. However, in both of these models there are uncertainties particularly around the risk of developing glaucoma, adherence to treatment and the cost of adverse effects from medical therapy.

The UK study was underpinned by risks of prediction of developing glaucoma provided by the OHTS-EGPS risk pre-diction model.16 This model is believed to be the best avail-able risk prediction model for glaucoma but because it was developed in selected trial populations it may not be gener-alizable for use in daily practice to improve decision-making and patient outcome for a diverse population with ocular hypertension.15

COST-EFFECTIVENESS OF TREATING GLAUCOMA

Many model-based economic evaluations comparing differ-ent treatment strategies in different country settings, mainly high-income countries, and for different stages of glaucoma have been published with varying findings depending on context and assumptions in the model. Treating glaucoma is worthwhile, if one assumes optimal treatment efficacy and not accounting for the costs of diagnosis.17 There is some evidence from an evaluation in a different context to

and is assigned a ‘✓’ response to the question of whether the experimental treatment is to be preferred to the compa-rator. In squares B3, C2 and C3 the experimental treatment is less efficient than the comparator and this receives an ‘X’ response to the question of whether the experimental treat-ment is to be preferred to the comparator. In the shaded areas (A3 and C1) a judgment would need to be made as to whether the more costly treatment is worthwhile in terms of the extra effectiveness to patients. To aid these judg-ments, information can be provided in terms of an incre-mental cost-effectiveness ratio (ICER). The higher the incremental cost-effectiveness ratio of one intervention is compared with another, the less likely it is that this inter-vention will be considered efficient. Square B2 is neutral as there is no difference in either costs or effectiveness.

Cost-Effectiveness of Medical Therapy for Glaucoma  Compared with Alternative Interventions or No Treatment

The evidence presented below comparing the cost-effectiveness of medical therapy for glaucoma and their alternatives is based on searches of the NHS EED (NHS Eco-nomic Evaluation database), www.crd.york.ac.uk/CRDWeb/AboutNHSEED.asp. Studies reporting costs only are not included (search dates January 2000; date of last search 20 November 2012).

COST-EFFECTIVENESS OF TREATING OCULAR HYPERTENSION

Ocular hypertension is generally defined as an IOP of >21 mmHg (two standard deviations above the population mean – as seen in Caucasian populations) in the absence of clinical signs of glaucoma (optic nerve damage or visual field loss consistent with glaucoma). The effectiveness of medical therapy for ocular hypertension has been evaluated

Figure 47-1 Relationship between difference in costs and effectsbetween a new treatment and a standard (control) treatment. (From Donaldson C, Atkinson A, Bond J, Wright K. Should QALYs be programme-specific? J Health Econ 1988; 7(3):239–257.8)

= recommend experimental treatment = recommend control treatment = neutral = Judgment required as to whether the extra costs are worth the extra benefits

Costincreasing

Effectivenessdecreasing

A

1

B

2

C

3

Compared with control treatment,experimental treatment is: 1. more effective 2. of equal effectiveness 3. less effective

A. less costly B. of equal cost C. more costly

SECTION5 • PrinciplesofManagement512

effectiveness data. For early-stage glaucoma, visual field restriction was not significantly different whether initial treatment is medication or surgery (trabeculectomy) at five years but primary surgery was associated with more eye discomfort and more difficulty with tasks related to visual acuity.45 In more severe open angle glaucoma, initial medi-cation (pilocarpine, now rarely used as first-line medica-tion) was associated with more glaucoma progression than surgery.46,47 None of these trials included a cost-effectiveness analysis. Thus the true balance of costs and benefits of the alternative treatment policy remains unknown.

Decisions on the best treatment from available alterna-tives can be informed by comparative cost-effectiveness. This chapter identifies uncertainties in best treatment options for those with glaucoma. Several high-quality studies are underway with embedded economic evaluations to inform future treatment policy.

References1. UK National Institute of Health and Clinical Excellence. Glaucoma.

Diagnosis and management of chronic open angle glaucoma and ocular hypertension. Available at: http://guidance.nice.org.uk/CG85/Guidance/pdf/English. Accessed November/22, 2012.

2. Nordmann JP, Akesbi J. Improve adherence in glaucoma patients: a doctor’s duty. J Fr Ophthalmol 2011;34(6):403–8.

3. Fiscella RG, Lee J, Davis EJH, et al. Cost of illness of glaucoma: a critical and systematic review. Pharmacoeconomics 2009; 27(3):189–98.

4. Stein JD, Niziol LM, Musch DC, et al. Longitudinal trends in resource use in an incident cohort of open-angle glaucoma patients: resource use in open-angle glaucoma. Am J Ophthalmol 2012;154(3):452,459.e2.

5. Euroqol Group. EuroQol – a new facility for the measurement of health related quality of life. Health Policy 1990;16:199–208.

6. Murray C, Lopez A. Quantifying the burden of disease and injury attributable to ten major risk factors. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. Cambridge, MA, USA: Harvard University Press; 1996.

7. Drummond MF, Sculpher MJ, Torrance GW, et al. Methods for the economic evaluation of health care programmes. 3rd ed. Oxford: Oxford University Press; 2005.

8. Donaldson C, Atkinson A, Bond J, et al. Should QALYs be programme-specific? J Health Econ 1988;09//;7(3):239–57.

9. 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):701–13.

10. Miglior S. Results of the European Glaucoma Prevention Study. Oph-thalmology 2005;112(3):366–75.

11. Vass C, Hirn C, Sycha T, et al. Medical interventions for primary open angle glaucoma and ocular hypertension. Cochrane Database of Sys-tematic Reviews 2007;(4):003167.

12. Kymes SM, Kass MA, Anderson DR, et al. Ocular Hypertension Treat-ment Study Group (OHTS). Management of ocular hypertension: a cost-effectiveness approach from the Ocular Hypertension Treatment Study. Am J Ophthalmol 2006;141(6):997–1008.

13. Kymes SM, Plotzke MR, Kass MA, et al. Effect of patient’s life expect-ancy on the cost-effectiveness of treatment for ocular hypertension. Arch Ophthalmol 2010;128(5):613–18.

14. Van Gestel A, Severens JL, Webers CAB, et al. Modeling complex treat-ment strategies: construction and validation of a discrete event simu-lation model for glaucoma. Value in Health 2010;13(4):358–67.

15. Burr J, Botello-Pinzon P, Takwoingi Y, et al. Surveillance for ocular hypertension: an evidence synthesis and economic evaluation. Health Technol Assess 2012;16(29):1–272.

16. Ocular Hypertension Treatment Study Group, European Glaucoma Prevention Study Group, Gordon MO, Torri V, Miglior S, et al. Validated prediction model for the development of primary open-angle glau-coma in individuals with ocular hypertension. Ophthalmology 2007; 114(1):10–19.

suggest that, from a cost-effectiveness point of view, it seems advantageous to aim for a low IOP in all glaucoma patients and reduce the frequency of visual field testing,18 but no one class of drug is clearly superior in terms of treatment per-sistence, tolerability and cost-effectiveness. The majority of studies have been in high-income countries.19–37 Findings of these economic evaluations tend to be country-specific because the context and in particular drug-pricing arrange-ments vary between countries.38 In a study by Stewart and colleagues, timolol was cost-effective in the UK but latano-prost could be cost-effective compared with timolol in Scan-dinavia.28 This finding was partly driven by differences in methodology and clinical data and partly driven by differ-ence in prices of medications.

Minimizing therapy switches can optimize economic and clinical benefits,39 as can the consideration of interventions to improve adherence to medical therapy. Adherence and long-term persistence with glaucoma medication is poor, reported to be as low as 24% of all those newly prescribed with glaucoma medication accessing repeat prescriptions at five years. These estimates are based on data from a large pharmaceutical database representative of the Australian population.40 Simplifying eye drop regimens, providing ade-quate information and ongoing support according to patient need may have a positive effect on improving adherence.41 The effect on cost-effectiveness is less clear as this will also depend upon the costs of providing information and on-going support. Nevertheless, more research is needed to develop and evaluate interventions to improve patient adherence to glaucoma medication schedules.

Cost-Effectiveness of Primary Medical Therapy Compared with Primary Laser Trabeculoplasty

Primary treatment of open angle glaucoma by laser trabec-uloplasty is an attractive therapeutic option as a single intervention that potentially eliminates the need for life-long adherence to ocular hypotensive eye drops. It may be a more cost-effective alternative to medical therapy particu-larly when adherence to medication is not ideal.42 Several small randomized controlled trials have compared laser trabeculoplasty with either no intervention, with medical treatment, or with surgery, but evidence is lacking on the cost-effectiveness of laser trabeculoplasty compared to con-temporary medication or with contemporary surgical tech-niques.43 A UK National Institute of Health Research-funded randomized controlled trial comparing initial selective laser trabeculoplasty with conventional medical therapy for ocular hypertension and glaucoma in terms of clinical and cost-effectiveness is due to report in 2019. This study prom-ises robust evidence on the role of primary laser therapy for glaucoma. (See www.hta.ac.uk/project/2828.asp.)

COST-EFFECTIVENESS OF PRIMARY MEDICATION COMPARED WITH PRIMARY SURGERY

The cost of one-time surgery is greater than medication in the short term,44 but may be lower in the long term if the surgery is successful because the on-going costs of medica-tions and escalation to surgical interventions amongst those initially treated medically is avoided. Findings from randomized controlled trials comparing an initial treatment policy of medicine or surgery provide some

47  • MedicalManagementofGlaucoma:Cost-Effectiveness 513

visual field deficit progression. Curr Med Res Opin 2006;22(9): 1737–43.

32. Tuil E, Hommer AB, Poulsen PB, et al. The cost-effectiveness of bimatoprost 0.03% in the treatment of glaucoma in adult patients – a European perspective. Int J Clin Pract 2005;59(9):1011–16.

33. Walt JG, Lee JT. A cost-effectiveness comparison of bimatoprost versus latanoprost in patients with glaucoma or ocular hypertension. Surv Ophthalmol 2004;49(Suppl 1):S36–44.

34. Day DG, Schacknow PN, Sharpe ED, et al. A persistency and economic analysis of latanoprost, bimatoprost, or beta-blockers in patients with open-angle glaucoma or ocular hypertension. J Ocul Pharmacol Ther 2004;20(5):383–92.

35. Galindo-Ferreiro A, Sanchez-Tocino H, Fernandez-Munoz M, et al. Cost-effectivity analysis of the most used antiglaucoma drugs. Arch Soc Esp Oftalmol 2004;79(8):379–84.

36. Rouland JF, Le Pen C, Gouveia Pinto C, et al. Cost-minimisation study of dorzolamide versus brinzolamide in the treatment of ocular hyper-tension and primary open-angle glaucoma: in four European coun-tries. Pharmacoeconomics 2003;21(3):201–13.

37. Le Pen C, Ligier M, Berdeaux G. Cost-effectiveness and cost-utility analysis of travoprost versus latanoprost and timolol in the treatment of advanced glaucoma in five European countries: Austria, France, Germany, The Netherlands and the United Kingdom. J Drug Assess 2005;8(3):165–82.

38. De Natale R, Le Pen C, Berdeaux G. Efficiency of glaucoma drug regu-lation in 5 European countries: a 1995–2006 longitudinal prescrip-tion analysis. J Glaucoma 2011;20(4):234–9.

39. Orme M, Collins S, Loftus J. Long-term medical management of primary open-angle glaucoma and ocular hypertension in the UK: optimizing cost-effectiveness and clinic resources by minimizing therapy switches. J Glaucoma 2012;21(7):433–49.

40. Healey P, Goldberg I, Subramaniam K, et al. Persistence and Adher-ence to Glaucoma Therapy in Australia. World Glaucoma Associa-tion; 2011.

41. Gray TA, Orton LC, Henson D, et al. Interventions for improving adherence to ocular hypotensive therapy. Cochrane Database Syst Rev 2009;(2):CD006132. doi(2):CD006132.

42. Stein JD, Kim DD, Peck WW, et al. Cost-effectiveness of medications compared with laser trabeculoplasty in patients with newly diagnosed open-angle glaucoma. Arch Ophthalmol 2012;130(4): 497–505.

43. Rolim de Moura C, Paranhos A Jr, Wormald R. Laser trabeculoplasty for open angle glaucoma. Cochrane Database Syst Rev 2007;(4)(4): CD003919.

44. Ainsworth JR, Jay JL. Cost analysis of early trabeculectomy versus conventional management in primary open angle glaucoma. Eye 1991;5(Pt 3):322–8.

45. Lichter PR, Musch DC, Gillespie BW, et al. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmol-ogy 2001;108(11):1943–53.

46. Migdal C, Gregory W, Hitchings R. Long-term functional outcome after early surgery compared with laser and medicine in open-angle glaucoma. Ophthalmology 1994;101(10):1651–6.

47. Jay JL, Allan D. The benefit of early trabeculectomy versus conven-tional management in primary open angle glaucoma relative to sever-ity of disease. Eye 1989;3(Pt 5):528–35.

17. Rein DB, Wittenborn JS, Lee PP, et al. The cost-effectiveness of routine office-based identification and subsequent medical treatment of primary open-angle glaucoma in the United States. Ophthalmology 2009;116(5):823–32.

18. van Gestel A, Webers CA, Severens JL, et al. The long-term outcomes of four alternative treatment strategies for primary open-angle glau-coma. Acta Ophthalmol 2012;90(1):20–31.

19. Berenson KL, Kymes S, Hollander DA, et al. Cost-offset analysis: bimat-oprost versus other prostaglandin analogues in open-angle glaucoma. Am J Manag Care 2011;17(9):e365–74.

20. Lafuma A, Salmon JF, Robert J, et al. Treatment persistence and cost-effectiveness of latanoprost/latanoprost-timolol, bimatoprost/bimatoprost-timolol, and travoprost/travoprost-timolol in glaucoma: an analysis based on the United Kingdom General Practitioner Research Database. Clin Ophthalmol 2011;5:361–7.

21. Lachaine J, Hodge WG, Steffensen I, et al. Prostaglandin analogues for ophthalmic use: a cost-effectiveness analysis. Can J Ophthalmol 2008;43(1):33–41.

22. Halpern MT, Covert DW, Robin AL. Projected impact of travoprost versus both timolol and latanoprost on visual field deficit progression and costs among black glaucoma subjects. Trans Am Ophthalmol Soc 2002;100:109,17; discussion 117–18.

23. De Natale R, Lafuma A, Berdeaux G. Cost effectiveness of travoprost versus a fixed combination of latanoprost/timolol in patients with ocular hypertension or glaucoma: analysis based on the UK General Practitioner Research Database. Clin Drug Invest 2009;29(2): 111–20.

24. Jothi R, Ismail AM, Senthamarai R, et al. A comparative study on the efficacy, safety, and cost-effectiveness of bimatoprost/timolol and dorzolamide/timolol combinations in glaucoma patients. Indian J Pharmacol 2010;42(6):362–5.

25. Payet S, Denis P, Berdeaux G, et al. Assessment of the cost effectiveness of travoprost versus latanoprost as single agents for treatment of glau-coma in France. Clin Drug Invest 2008;28(3):183–98.

26. Lafuma A, Laurendeau C, Berdeaux G. Costs and persistence of bri-monidine versus brinzolamide in everyday glaucoma care: an analysis conducted on the UK General Practitioner Research Database. J Med Econ 2008;11(3):485–97.

27. Hommer A, Thygesen J, Ferreras A, et al. A European perspective on costs and cost effectiveness of ophthalmic combinations in the treat-ment of open-angle glaucoma. Eur J Ophthalmol 2008;18(5): 778–86.

28. Stewart WC, Stewart JA, Mychaskiw MA. Cost-effectiveness of latano-prost and timolol maleate for the treatment of glaucoma in Scandina-via and the United Kingdom, using a decision-analytic health economic model. Eye (Lond) 2009;23(1):132–40.

29. Lafuma A, Berdeaux G. Costs and persistence of carbonic anhydrase inhibitor versus alpha-2 agonists, associated with beta-blockers, in glaucoma and ocular hypertension: an analysis of the UK-GPRD data-base. Curr Med Res Opin 2008;24(5):1519–27.

30. Lafuma A, Berdeaux G. Costs and effectiveness of travoprost versus a dorzolamide + timolol fixed combination in first-line treatment of glaucoma: analysis conducted on the United Kingdom General Prac-titioner Research Database. Curr Med Res Opin 2007;23(12): 3009–16.

31. Schmier JK, Halpern MT, Covert DW, et al. Travoprost versus latano-prost combinations in glaucoma: economic evaluation based on