Tunnel Vision the Economic Impact of Primary Open Angle Glaucoma - a Dynamic Economic Model 105 Main Heading Tocontents Go Here

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The Economic Impact of Primary Open Angle Glaucoma - - Glaucoma Angle Open Primary of Impact Economic The A Dynamic Economic Model A Dynamic Economic Model Economic Dynamic A

Centre for Eye Research Australia Centre for Eye Research Australia Acknowledgments and Disclaimer 11. References

This report was prepared jointly by the Centre Weih L, Van Newkirk M, McCarty C, Taylor H (1998) “Patterns of glaucoma medication use in for Eye Research Australia and Access Economics urban and rural Victoria” Australian and New Zealand Journal of Ophthalmology, 26[Suppl]: Pty Limited. S12 S15. We acknowledge particularly the expert input Weinand F, Althen F (2006) “Long term clinical results of SLT in the treatment of POAG” Eur J and prior research of Ophthalmology, 16: 100-4. Professor Hugh Taylor AC Weinreb RN, Khaw PT (2004) “Primary open-angle glaucoma” The Lancet, 363: 1711-20. Centre for Eye Research Australia and University of Melbourne Weinreb RN, Friedman DS, Fechtner RD, Cioffi GA, Coleman AL, Girkin CA, Liebmann JM, Singh K, Wilson MR, Wilson R, Kannel WB (2004) “Perspective: Risk Assessment in the Management of Professor Jonathan Crowston Patients with Ocular Hypertension” American Journal of Ophthalmology, 138[3]: 458-67. Centre for Eye Research Australia and University of Melbourne Wensor M, McCarty C, Stanislavsky Y, Livingston P, Taylor H (1998) “The prevalence of glaucoma in the Melbourne Visual Impairment Project” Ophthalmology, 105: 733-9. Associate Professor Jill Keeffe OAM Centre for Eye Research Australia and Wilson MR, Coleman AL, Fei Yu, Sasaki IF, Kim MH (2002) “Depression in patients with glaucoma University of Melbourne as measured by self-reported surveys” Ophthalmology, 105[5]: 1018-22. Ms Lynne Pezzullo Wolfs RC, Klauver CC, Ramrattan RS, van Duijin CM, Hofman A, de Jong PT (1998) “Genetic risk Access Economics Pty Ltd of primary open-angle glaucoma. Population based familial aggregation study” Arch Ophthal, Ms Penny Taylor 116: 1640-45. Access Economics Pty Ltd Zahari M, Mukesh B, Rait J, Taylor H, McCarty C (2006) “Progression of visual field loss in open Mr Peter Moore angle glaucoma in the Melbourne Visual Impairment Project” Clinical and Experimental Access Economics Pty Ltd Ophthalmology, 34: 20–6. Zeiter JH, Shin DH (1994) “Diabetes in primary open-angle glaucoma patients with inferior visual field defects”Graefes Archive for Clinical & Experimental Ophthalmology, 232[4]: 205-10. Zghal I, Jeddi A, Hadj Alouane WB, Malouche N, Ayed S, Gaigi S (2000) “Primary open-angle glaucoma and diabetes [French]” Tunisie Medicale, 78[8-9]: 518-21.

Zwerling C, Sprince NL, Davis CS, Whitten PS, Wallace RR, Herringa SG (1998) “Occupational injuries among older workers with disabilities: a prospective cohort study of the Health and Retirement Survey, 1992 to 1994” American Journal of Public Health, 88: 1691-16.

While every effort has been made to ensure the accuracy of this document, the uncertain nature of economic data, forecasting and analysis means that Access Economics Pty Limited is unable to make any warranties in relation to the information contained herein. Access Economics Pty Limited, its employees and agents disclaim liability for any loss or damage which may arise as a consequence of any person relying on the information contained in this document. Publication of this work has been made possible by an unrestricted grant from Allergan who had no part in the direction or findings contained in this report. Centre for Eye Research Australia, University of Melbourne, Australia, February 2008.

Centre for Eye Research Australia Tunnel Vision The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 105 Main heading toContents go here

EXECUTIVE SUMMARY 7 1. Background 10 2. Primary Open Angle Glaucoma 11 3. Risk Factors 13 3.1 Intraocular pressure 13 3.2 Age 15 3.3 Cup-to-disc ratio 16 3.4 Central corneal thickness 16 3.5 Family history and genetics 17 3.6 Ethnicity 17 3.7 Diabetes mellitus 18 3.8 Other potential risk factors 19 4. Epidemiology 20 4.1 Definition of disease stage 20 4.2 Remission 20 4.3 Mortality 20 4.4 Population 21 4.5 Progression 21 4.6 Prevalence and incidence 29 4.7 Disease stages defined 33 5. Treatment 34 5.1 Medication 34 5.2 Laser treatment 39 5.3 Conventional surgery (trabeculectomy) 41 5.4 Prevalence estimates for each treatment group 43 5.5 Treatment efficacy 44 5.6 Side effects 50 6. Disease Costs 55 6.1 Discount rates 55 6.2 The cost to quality of life and wellbeing 56 6.3 Health system costs 60 6.4 Indirect costs 68 6.5 Deadweight losses 69 7. Summary of Model Parameters 70 8. The Model 73 9. Intervention Scenarios 76 9.1 The base case 76 9.2 Improved diagnosis rate 80 9.3 Change in the treatment protocol (Primary laser) 83 9.4 Research and development 87 9.5 Combinations 89

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 1 Contents

10. Appendix 1: Meta-Analysis - Falls and Hip Fractures 92 10.1 Fixed-effects versus random-effects 92 10.2 Heterogeneity 92 10.3 Forest plots 93 10.4 Publication bias 96 10.5 Additional supportive literature 97 11. References 98

Figures Figure 1.1: Peripheral visual field loss in POAG 10 Figure 2.1: The glaucoma continuum 11 Figure 2.2: Healthy optic nerve 12 Figure 2.3 Glaucomorous optic nerve 12 Figure 3.1: Goldmen tonometery 14 Figure 3.2: Demographic distribution of glaucoma, Australians over 40 15 Figure 3.3: Cup-To-Disk ratio 16 Figure 3.4: Corneal thickness 17 Figure 3.5: Pseudoexfoliation pupil margin 19 Figure 4.1: Schematic of the level of impairment for definite glaucoma 29 Figure 4.2: Original prevalence rates 30 Figure 4.3: Smoothed prevalence rates (moving average across three age groups) 31 Figure 5.1: Glaucoma medication dispensed by year and type of script (% of total scripts) 35 Figure 5.2: MBS Trabeculoplasty Procedures, 1994-2005 40 Figure 5.3: Trabeculectomy 41 Figure 5.4: MBS Total of Trabeculectomy Procedures, 1994-2005 42 Figure 8.1: Main Menu 73 Figure 8.2: Options Sheet 74 Figure 8.3: Model Design 75 Figure 9.1: Prevalence OHT and POAG, base case 77 Figure 9.2: Value burden of disease due to POAG ($m), base case 78 Figure 9.3: Impact of increased diagnosis rates on DALYs(a) 82 Figure 9.4: Impacts of increased diagnosis rates on treatment costs 82 Figure 9.5: Cost Effectiveness Plane - Increase Diagnosis Rate(a) 83 Figure 9.6: Cost-savings resulting from a protocol change(a) 85 Figure 9.7: Burden of Disease 85 Figure 9.8: Decline in DALYs from new efficacious treatment 88

2 Centre for Eye Research Australia Tunnel Vision Main heading toContents go here

Figure 9.9: Treatment costs with new treatment costing $1000 per person per year 88 Figure 9.10: Reduction in DALYs, combined interventions 90 Figure 9.11: Treatment costs, combined interventions 91 Figure 9.12: Total costs, combined scenarios 91 Figure 9.13: Cost effectiveness plane, Combined Scenarios(a) 91 Figure 10.1: Annotated Forest Plot (Random Effects Model) for Visual 94 Impairment and Falls Figure 10.2: Annotated Forest Plot (Random Effects Model) Glaucome/VFL and Falls 95 Figure 10.3: Annotated Forest Plot (Random Effects Model) for Visual Impairment and Hip Fractures 95

Tables Table 1.1: Disease stage 7 Table 3.1: Significant risk factors for OHT progression to glaucoma, identified by the OHTS 14 Table 3.2: Hazard ratios for development of POAG from OHT 14 Table 3.3: Risk factors for glaucoma progression, identified by the early manifest glaucoma trial 15 Table 3.4: Association Between Diabetes Mellitus and Glaucoma 19 Table 4.1: Relative risk of mortality by stage of Visual Impairment 21 Table 4.2: Natural progression rates (cumulative probability) 15 year period 25 Table 4.3: Estimates of disease progression in untreated patients 27 Table 4.4: Definitions of level of impairment for definite glaucoma 29 Table 4.5: OHT and Glaucoma prevalence rates 30 Table 4.6: Incidence and prevalence of ocular hypertension (% of age group) 32 Table 4.7: Proportion of people with glaucoma by age and severity (%), smoothed (moving average across three age groups) 32 Table 4.8: Disease Stage 33 Table 5.1: IOP lowering medications 35 Table 5.2: Proportion of each drug class by state, 2005 36 Table 5.3: Number of medications taken in combination 37 Table 5.4: Trabeculectomy - MBS services processed by jurisdiction by year 42 Table 5.5: Incidence and treatment failure rate for each stage of treatment from dismod II 44 Table 5.6: Progression rates (cumulative probability) in treated patients (15 year period) 46 Table 5.7: Studies of the efficacy of laser treatment 47 Table 5.8: Success rates for trabeculectomy 49 Table 5.9: Medication side effects 50 Table 5.10: Risk of COPD (% of Population), 2001 51 Table 5.11: Health System Cost of COPD ($ per Person), 2005 52

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 3 Contents

Table 5.12: Trabeculectomy Side-Effects 53 Table 5.13: Prevalence of Cataract (% of Population) 54 Table 5.14: Health System Cost of Cataract ($ per Person), 2005 54 Table 6.1: AIHW Disability Weightings 59 Table 6.2: Health Costs by Who Bears the Cost, 2004-05 60 Table 6.3: Cost of Medication per Person per Annum 61 Table 6.4: Total Cost of Trabeculoplasty Per Treatment 61 Table 6.5: Total Cost of Trabeculectomy Per Treatment 62 Table 6.6: Probability of Residing in an Aged Care facility, 2004-05 63 Table 6.7: Increased Risk of Falls From Visual impairment 64 Table 6.8: Meta-Analysis, Falls (Random Effects Model) 64 Table 6.9: Relative Risk of an accidental fall by Severity 65 Table 6.10: Risk of Accidental Fall (% of Population), 2001 65 Table 6.11: Health System Cost of an Accidental Fall ($ per Person), 2005 66 Table 6.12: Depression and Vision Loss 67 Table 6.13: Risk of Depression (% of Population), 2001 67 Table 6.14: Health System Cost of Depression ($ per Person), 2005 68 Table 6.15: Indirect Costs ($ per annum), 2005 69 Table 7.1 Prevalence of OHT and POAG 70 Table 7.2 Severity of visual impairment — initial proportional split 71 Table 7.3: Modelled treatment assumptions 71 Table 7.4: Modelled treatment costs $ 2005 (including side-effects and adverse events) 72 Table 7.5: Other modelled variables 72 Table 9.1: Prevalence of OHT and POAG, base case (number of people) 77 Table 9.2: Costs of POAG, 2005 and 2025, base case 78 Table 9.3 Base case (standard treatment) net present value of DALYs and costs 78 Table 9.4 Comparison of prevalence of OHT and POAG with original and smoothed data 79 Table 9.5 Net present value of DALYs and costs, sensitivity analysis on OHT Prevalence and incidence for those aged 80+ years 79 Table 9.6: Model Results – Increased Diagnosis Rate, Net present value 2005 to 2025 81 Table 9.7: Model Results – Protocol Change – Trabeculoplasty as primary treatment 84 Table 9.8: Sensitivity Analysis - A conservative approach to surgery failure rates 86 Table 9.9: Model Results – Research and Development - showing the impact of new treatment to reduce progression by 50% and 75% 89 Table 9.10: Model Results - Combined Scenarios 90 Table 10.1: Fixed Effects and Random Effects, Meta-Analysis Results 92 Table 10.2: Heterogeneity within the Combined Studies 93 Table 10.3: Measures of Publication Bias 96 Table 10.4: Non-quantitative supporting literature 97

4 Centre for Eye Research Australia Tunnel Vision MainGlossary heading and toAcronyms go here

ABS Australian Bureau of Statistics AGIS Advanced Glaucoma Intervention Study AIHW Australian Institute of Health and Welfare ALT Argon Laser Trabeculoplasty AMD Age related macular degeneration AWE Average Weekly Earning BMES Blue Mountains Eye Study CERA Centre for Eye Research Australia CI Confidence interval EDS Early Disease Stage CIGTS Collaborative Initial Glaucoma Treatment Study CNTGS Collaborative Normal Tension Glaucoma Study COPD Chronic Obstructive Pulmonary Disease DALYs Disability adjusted life years DRG Diagnosis Related Group EGPS European Glaucoma Prevention Study EMGT Early Manifest Glaucoma Trial GLT, GLTFU Glaucoma Laser Trial, Glaucoma Laser Trial Follow Up HAP Hodapp-Anderson-Parrish grading system for disease stage IOP Intraocular pressure mm Hg Millimetres of mercury, Measure of intraocular pressure. MBS Medicare Benefits Schedule MMC Mitomycin C - an anti fibrotic drug which inhibits scarring. MVIP Melbourne Visual Impairment Project OHT Ocular hypertension OHTS Ocular Hypertension Treatment Study OR Odds ratio POAG Primary Open Angle Glaucoma PR Prevalence Ratio Pseudoexfoliation Pseudoexfoliation syndrome is a systemic condition characterised by glaucoma/ the production and progressive accumulation of pseudoexfoliative pseudoexfoliation material in many ocular tissues. Glaucoma occurs more commonly in syndrome eyes with this syndrome than in those without it. Exfoliative glaucoma has a more rapid clinical course and worse prognosis than primary open-angle glaucoma. RR Relative risk SD Standard deviation SLT Selective Laser Trabeculoplasty VA Visual acuity VF Visual field - the ability to detect objects to either side, or above or below, the direction of vision. It is measured in terms of degrees from the point of fixation, for example, <10 degree field means that the person can only see in a visual field of less than 10 degrees radius from the point of fixation (CERA 2004). VFL Visual field loss

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 5 6 Centre for Eye Research Australia Tunnel Vision MainExecutive heading toSummary go here

Access Economics was commissioned by the Centre for Eye Research Australia (CERA) to Australian health care construct a dynamic model of primary open angle glaucoma (POAG) in Australia, to inform policy development in relation to this serious source of visual impairment and blindness. cost of glaucoma in 2005 was $342 The model is based on data from a wide variety of sources, and an intensive literature review informed the estimation of parameters, such as risk factors for POAG, natural progression of the million. disease, treatment efficacy, quality of life, and comorbid conditions (falls and depression). The total annual cost • Intraocular pressure (IOP) was identified as the only modifiable risk factor for the development and progression of POAG. Current medical and surgical treatments are centred of glaucoma in 2005 on reducing IOP and maintaining it at lower levels. was $1.9 billion. • Age, cup-to-disc ratio and central corneal thickness are non-modifiable risk factors for glaucoma. The total cost is • Studies of links between POAG and diabetes mellitus have shown mixed results, so diabetes expected to increase was not incorporated in the modelling. As future studies are completed this association will to $4.3 billion by become better understood. 2025. • Studies of family history suggest it is an apparent non-modifiable risk factor, but support for an association is not strong possibly because of ascertainment bias. The incidence, prevalence and mortality associated with POAG and the incidence and prevalence of ocular hypertension (OHT) were based on data from the Melbourne Visual Impairment Project (MVIP) and the Blue Mountains Eye Study (BMES) and use of the DISMOD II model, and based on severity of visual impairment (with severity splits based on MVIP and BMES data). Disease stages are defined in Table 1.1. Demographic groups within the population are projected on the basis of Access Economics Dynamic model population by gender and year of age projections to 2025.

TABLE 1.1: DISEASE STAGE Disease stage Description Visual Visual field acuity loss (VFL) No POAG No visual impairment (OHT or normal tension) Early Disease Stage Definite or Probable Better And No VFL (EDS) Glaucoma. No visual than 6/12 impairment but changes to optic nerve and/or retinal nerve fibre layer Mild Definite Glaucoma with mild <6/12 Or Any loss of visual impairment visual field (VF) Moderate Definite Glaucoma with <6/18 Or <20o field moderate visual impairment Severe Definite Glaucoma with severe <6/60 Or <10o field or profound visual impairment

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 7 Executive Summary

A dynamic model of In studies of glaucoma, disease progression is not always measured in terms of vision loss. Clinical studies often use a combination of changes in VF, IOP and optic disc as indicators of POAG was developed progression. Further, definitions of vision loss vary across researchers, and different researchers to inform policy have developed different grading systems to measure progression. The application of progression development on an rates from the literature therefore proved too problematic. Initially, the approach was to apply the progression rates from the Weinreb et al, (2004) synthesis in the modelling. Unfortunately, ongoing basis. it was not possible to match the Weinreb et al, (2004) rates with the available incidence and prevalence data from the MVIP and BMES to obtain sensible projections. To overcome these problems natural progression rates were derived from prevalence data from the MVIP and BMES to achieve sensible projections and mindful of the approach used to synthesise progression rates in Weinreb et al, (2004). This led to annual progression rates that are for the most part substantially higher than expected so more research and population data — particularly by stage of visual impairment for POAG — are clearly required. Increasing the rate The progression rates for people with treated glaucoma are half of those for untreated of diagnosis to 80% glaucoma, in line with the literature on treatment efficacy (key clinical trials such as the Early Manifest Glaucoma Trial EMGT and the Ocular Hypertension Treatment Study (OHTS)) and the would cost $80,189 methodology from Weinreb et al, (2004). (For treatment efficacy,Weinreb et al, (2004) used per DALY. the results from the OHTS and the EMGT as the only trials which compared treatment with no treatment.) Initial laser Treatment failure rates are around 4% of patients per annum failing medication (consistent trabeculoplasty with Australian data on rates of trabeculoplasty), 50% of patients per annum failing laser therapy (consistent with the literature on the efficacy of laser treatment) and 50% of patients gives significant per annum failing surgery (a conservative estimate which is higher than the literature but cost savings. sensitivity analysis provided in the report shows it makes little difference to the results). Remission was modelled as nil, with relative risks for mortality depending on vision loss (1.67 for mild POAG, 2.34 for moderate POAG and 3.01 for severe POAG decreasing in line The savings from a with older age). new treatment will The costs of POAG include: depend on the annual • health system costs — derived from data from the Australian Institute for Health and treatment cost. Welfare, Medicare fees and the Department of Health and Ageing National Hospital Costs Data Collection. Health cost data are also included in the model in relation to the costs of falls and depression that are associated with vision loss from POAG. • Indirect costs — including productivity losses (lower than average employment rates of people with visual impairment). Productivity losses are low since POAG generally affects older people. Carer costs and the costs of aids and equipment and deadweight losses based on CERA’s research and previous Access Economics calculations are also included. • Loss of wellbeing (measured as the burden of disease — Disability Adjusted Life Years (DALYs). The model itself is constructed on a user-friendly Excel platform to enable ease of policy simulations. Three scenarios were analysed in relation to the base case. The results reported here are calculated for smoothed prevalence rates and reflect the net present value of costs and benefits over the period 2005 to 2025.

8 Centre for Eye Research Australia Tunnel Vision Executive Summary

• The first scenario reflects an improvement in diagnostic methods. More than 50% of individuals with glaucoma in the developed world are unaware they have the disease (Quigley, 1996). In a population based study (the MVIP), Wensor et al, (1998) found that 50% of those with definite POAG had not been diagnosed previously, and Wong et al, (2004) examined MVIP data and found that 59% of definite cases of OAG were undiagnosed in people who had visited an eye care provider in the previous year. Even at zero additional costs (ie. no additional costs of educating clinicians) and improved diagnosis rates of 70%, 80% and 90%, the modelling suggests that these scenarios are cost effective but relatively expensive, at between $153,000 to $167,000 per DALY avoided. Improved diagnosis rates are associated with a rise in health system costs as more people are treated. However, the burden of disease (DALYs) falls. • The second scenario is a change in the treatment protocol, with laser replacing medication as first line therapy. The Glaucoma Laser Trial (GLT) showed that Argon Laser Therapy was as efficacious as timolol (prostaglandins and Selective Laser Therapy were not in use at that time). However, Argon Laser Trabeculoplasty (ALT) was not commonly adopted as a primary treatment because of concern about side effects and the reduced efficacy of repeat ALT treatments. More recent evidence for the effectiveness of laser treatments as a primary therapy include the EMGT, Nagar et al, (2005), and McIlraith et al, (2006). The modelling shows that changing the treatment protocol (based on the assumption that current laser treatments are as efficacious as medication) is cost saving, reflecting the assumption that primary laser would be provided alone whereas as a second line treatment (as per current approaches), laser and medication are provided together. Even tripling the cost of laser trabeculoplasty or increasing it five fold (from $724 to $3,622) to account for the possibility of side effects (and assuming these don’t affect quality of life), a change in the treatment protocol remains cost saving. • The final scenario modelled a new potential therapy to delay progression (for example availability of a neuroprotectant drug that protects by means other than IOP lowering ). The model allows for a new therapy that reduces the progression of glaucoma by a further 50% or 75% over and above the reduction in progression from current treatments to be analysed. Cost effectiveness depends on the cost per person per annum of the new treatment. At treatment costs of $1,000 per person per annum, new treatments are cost saving. New treatments remain cost effective and relatively cheap at $5,000 per diagnosed patient per annum ($44,700/DALY avoided if progression is delayed by 50% over the base case and $23,400/DALY avoided if progression is delayed by 75% over the base case). At $10,000 per diagnosed patient per annum, new treatments are still cost effective but become relatively expensive ($114,400/DALY avoided and $71,914/DALY avoided respectively).

The POAG dynamic model enables rapid comparison of the cost-effectiveness of various interventions for the disease and is a valuable tool for ongoing policy formulation and best practice treatment to address visual impairment and blindness from POAG.

1 Memantine is used for Alzheimers disease and in phase III trials for glaucoma at the time of writing.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 9 1. Background

Glaucoma causes Access Economics Pty Limited was commissioned by the Centre for Eye Research characteristic loss of Australia (CERA) to: peripheral vision and 1. Construct a dynamic model of primary open angle glaucoma (POAG) in Australia, that encompassed prevalence, incidence, risk factors, health and indirect financial costs, optic nerve changes. treatment options and measures of wellbeing; and 2. Document the model and report on the impacts over the period 2005-2025 of: < better detection of POAG; < a change in treatment protocol; and < a potential new therapy to delay disease progression. A similar model was previously developed to examine the impact of a number of new treatments modes on age-related macular degeneration: a quit smoking program; new research that delays progression; and a new therapy that enhances treatment efficacy (CERA 2006). The model has the capacity to be adapted to incorporate other sources of visual impairment in the future, such as diabetic retinopathy, cataract, and refractive error. This project follows on from earlier reports2: • Clear Insight: The Economic Impact and Cost of Vision Loss in Australia (CERA 2004); Figure 1.1: Peripheral visual • Investing in Sight: Strategic Interventions to Prevent Vision Loss in Australia field loss in POAG. (CERA 2005); and • Centrally Focused: The Impact of Age-related Macular Degeneration, A Dynamic Economic Model (CERA 2006). Due to the technical nature of the modelling, this report assumes familiarity with the terminology used in these previous reports. This report is structured as follows: • Description of POAG; • Epidemiology of the disease (including remission, mortality, progression of the disease when untreated and incidence and prevalence); • Treatment of the disease (including a description of the conventional treatment steps, their side effects and efficacy); • The costs of the disease (including its impact on quality of life, the health system costs, productivity costs and other indirect costs); • Description of the Model, its structure and user interface; and • Discussion of the scenarios that the model can be used to analyse.

2 Available online at www.cera.org.au.

10 Centre for Eye Research Australia Tunnel Vision 2. PrimaryMain Open heading Angle toGlaucoma go here

Glaucoma is a progressive, neurodegenerative disease that causes accelerated loss of optic Moderate nerve neurons. Initial changes to the optic nerve and retina are asymptomatic and often undetectable with current diagnostics (Weinreb et al, 2004). Glaucoma can be described as a glaucoma is continuum (Figure 2.1) where undetectable disease progresses to asymptomatic disease with characterised optic nerve and visual ﬁeld (VF) change, and ﬁnally to symptomatic visual impairment and by loss of blindness. peripheral vision

FIGURE 2.1: THE GLAUCOMA CONTINUUM and sparing of central vision.

Source: reproduced from Weinreb et al, (2004).

Box 1: Vision loss from POAG In advanced glaucoma central Central vision is the detailed vision people use to read and recognize faces, while peripheral vision is the side vision that is used for navigating obstacles in the environment vision may be lost. (like doorways and coffee tables) and for detecting oncoming vehicles from a side street. The diagnosis of glaucoma is often made late in the disease course, because early stages of 1 in 10 Australians glaucoma are usually asymptomatic. Moderate glaucoma is characterised by loss of peripheral vision and sparing of central vision. Patients often fail to notice peripheral vision over 80 will loss until it has progressed towards the centre of vision. develop glaucoma. Source: Reproduced from Kwon et al (2007), A patient’s guide to glaucoma, http://www.medrounds.org/glaucoma-guide/2006/02/table-of-contents-patients-guide- to.html, accessed 4 May 2007

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 11 2. Primary Open Angle Glaucoma

Elevated intraocular There are several different types of glaucoma: primary open angle, angle closure, congenital and secondary glaucoma. Primary open angle glaucoma (POAG) is the most common worldwide pressure is a risk and the topic of this report (Box 2). POAG is characterised by3: factor for glaucoma • open anterior-chamber angles; although not • loss of neuroretinal rim and nerve ﬁbre layer defects; necessarily an • VF abnormality; integral part of the • adult onset; and • absence of other known mechanisms. disease. While many POAG patients present with elevated intraocular pressure (IOP), a signiﬁcant number of patients with POAG do not have detectable IOP elevation. Elevated IOP is a risk factor for glaucoma and not necessarily an integral part of the disease.

Box 2: Primary Open Angle Glaucoma

Glaucoma is a degenerative disease of the optic nerve that can lead to vision loss and blindness. The optic nerve comprises over a million nerve fibres (axons) that connect the retina with the brain. In the front of the eye is a space called the anterior chamber - clear fluid (aqueous humour) flows in to this space and leaves the chamber at the angle where the cornea and iris meet. When the aqueous humour reaches the angle, it flows through a meshwork and leaves the eye. Increased IOP occurs when there is increased resistance to outflow.

Figure 2.2: Healthy optic nerve Figure 2.3: Glaucomorous optic nerve

3 American Academy of Ophthalmology (2005).

12 Centre for Eye Research Australia Tunnel Vision 3. Risk Factors

Not all cases of glaucoma have an endpoint of unilateral or bilateral blindness. There is Intraocular pressure considerable variation in the risk of progression across patients (Weinreb et al, 2004). This section discusses the current theory on the risk factors associated with glaucoma. More is a measurement research is needed to fully establish the role and impact of these. of the fluid pressure within the eye. 3.1: INTRAOCULAR PRESSURE IOP is a measurement of the fluid pressure within the eye. IOP is determined by aqueous Intraocular pressure humour flow into and out of the anterior chamber (the space between the lens and cornea. is a risk factor for This fluid is produced in the ciliary body and flows through the pupil and the trabecular meshwork or through non-trabecular pathways, commonly called uveoscleral pathways. glaucoma. The balance between the production and outflow of aqueous humour controls the IOP. The normal range for IOP is between 10 and 21 millimetres of mercury (mm Hg) with an A significant average of 16 mm Hg, but average IOP varies across populations. High IOP for populations is proportion of usually defined as being greater than two standard deviations (SDs) from the population mean. IOPs that are within the normal population range may still be too high for individual patients. glaucoma patients Increased IOP is a risk factor for the development and progression of POAG. However, the have IOPs in the level of IOP that causes nerve damage varies between individuals. A certain proportion of those normal range. with elevated IOP (ocular hypertension or OHT) will develop glaucoma. However, a significant proportion of those with POAG do not appear to have increased IOP. A univariate and multivariate analysis completed by the Ocular Hypertension Treatment Study (OHTS) showed that for the OHTS population, every 1mm Hg increase in mean IOP level was associated with a 10% increased risk of progression from OHT to glaucoma (Table 3.1) (Gordon, Beiser and Brandt et al, 2002). The OHTS Group and the European Glaucoma Prevention Study Group et al, (2007) confirmed that IOP is a risk factor for the development of POAG in untreated individuals with OHT (Table 3.2).

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 13 3. Risk Factors

IOP is currently In a literature review of progression rates, Friedman et al, (2004) also found that IOP was a risk factor for progression of glaucoma (Table 3.3). In particular, the EMGT found that the risk of the only treatable deterioration of the optic nerve in a population of patients with POAG decreased by 10% for risk factor that has each 1mm Hg reduction in IOP (for example, Leske et al, 2003). Jay and Murdoch (1993) also been identified to found progression was faster with higher IOP. delay progression of IOP is currently the only treatable risk factor that has been identified to delay progression glaucoma. of glaucoma. Current medical and surgical treatments are centred on reducing IOP and maintaining it at lower levels.

TABLE 3.1: SIGNIFICANT RISK FACTORS FOR OHT PROGRESSION TO GLAUCOMA, IDENTIFIED BY THE OHTS

Hazard Ratio (95% Confidence Interval - CI) Putative Predictive Factor Univariate Multivariate Age (per decade) 1.43 (1.19-1.71) 1.22 (1.01-1.49) Black race 1.59 (1.09-2.32) 0.98 (0.65-1.46)* Sex (male) 1.87 (1.31-2.67) 1.42 (0.98-2.05)* Heart disease 2.11 (1.23-3.62) 1.71 (0.95-3.09)* IOP (per mmHg) 1.11 (1.04-1.18) 1.10 (1.04-1.17) Corneal thickness (per 40 mm thinner) (see section 3.4) 1.88 (1.55-2.29) 1.71 (1.40-2.09) Pattern SD (per 0.2 dB greater) (see Box 3) 1.36 (1.16-1.60) 1.27 (1.06-1.52) Horizontal cup-to-disc ratio (per 0.1 larger) (see section 3.3) 1.25 (1.14-1.38) 1.27 (1.14-1.40) Figure 3.1: Goldmen tonometery Vertical cup-to-disc ratio (per 0.1 larger) (see section 3.3) 1.32 (1.19-1.46) 1.32 (1.19-1.47)

*Not significant at p<=0.05. mm = micrometer. dB = decibels. Source: reproduced from Gordon, Beiser and Brandt et al, (2002). ARTICLE IN PRESS TABLE 3.2: HAZARDOHTS RATIOS Group and FOR EGPS DEVELOPMENT Group � Validated OF POAG Prediction FROM Model OH forT POAG

Table 5. Univariate and Multivariate Hazard Ratios (HRs) and 95% Conﬁdence Intervals (CIs) for the Development of POAG in the Pooled OHTS and EGPS Control Groups

Model Univariate Final Multivariate No. of 95% Lower 95% Upper No. of 95% Lower 95% Upper Baseline Variables n Events HR CI CI P Value n Events HR CI CI P Value Age (decade) 1312 165 1.41 1.20 1.65 �0.0001 1123 154 1.26 1.06 1.50 0.0072 Male gender 1312 165 1.23 0.91 1.67 0.1772 Mean IOP per mmHg* 1312 165 1.10 1.03 1.17 0.0052 1123 154 1.09 1.03 1.17 0.0067 Mean CCT per 40 �m thinner 1128 156 2.16 1.81 2.59 �0.0001 1123 154 2.04 1.70 2.45 �0.0001 Mean vertical C/D ratio per 1311 165 1.21 1.12 1.32 �0.0001 1123 154 1.19 1.09 1.31 0.0001 0.1 larger Mean PSD per 0.2 dB greater 1308 163 1.12 1.04 1.21 0.0019 1123 154 1.13 1.04 1.24 0.0065 History of heart disease 1312 165 1.62 1.00 2.61 0.0488 Mean deviation defect per 0.1 1308 163 0.93 0.81 1.06 0.2799 dB greater History of high blood pressure 1312 165 1.14 0.83 1.56 0.4300 History of migraine 1312 165 0.90 0.51 1.58 0.7073 Current use systemic 1309 165 0.99 0.49 2.01 0.9736 �-blockers Current use systemic 1309 165 1.00 0.61 1.66 0.9876 calcium-channel blockers Myopia ��1 D spherical 1312 165 0.89 0.64 1.25 0.5108 equivalent

CCT � central corneal thickness; CID � cup-to-disc; D � diopters; dB � decibels; IOP � intraocular pressure; PSD � pattern standard deviation. *Eye-speciﬁc variables are the mean of right and left eyes for each participant.

Source: Ocular Hypertension Treatment Study Group and the European Glaucoma Prevention Study Group et al, (2007). In the following example, we estimate the 5-year risk of de- age, higher IOP, larger vertical C/D ratio, thinner central veloping POAG for a 55-year-old male whose baseline IOPs for corneal measurement, and greater PSD as predictive fac- Centre for Eye Researchright and Australia left eyes are 22 and 26 mmHg; vertical C/D ratios, 0.4 tors for the development of POAG in ocular hypertensive 14 and 0.4; CCT measurements, 532 and 548 �m; and PSDs, 2.2 and individuals. When the generalizabilityTunnel of theVision OHTS 2.2 dB. Means of the values for the right and left eyes are averaged for each eye-specific predictor and the points are summed (Table model was tested by applying it to data from the placebo 6) to estimate the 5-year risk of developing POAG. The sum of group of the EGPS, the same predictive factors were points for this theoretical patient is 11, which yields an estimated identified. The hazard ratios for the predictive factors 5-year risk of developing POAG of 20% (Table 6). The estimated were very similar in the separate models, the pooled risk for this same patient from the Cox proportional hazards model model, as well as recently published models by Medeiros is 16.9%. et al22 and the EGPS Group.23 Thus, the OHTS predictive model, including CCT, has been replicated in a European sample and a separate U.S. sample. The pooled OHTS– Discussion EGPS sample has a large number of participants and large number of POAG end points, which yield greater Using data from the OHTS observation group, we devel- stability of the hazard ratios and narrower CIs for oped a multivariate model that identified baseline older predictions.

Table 6. A Point System for Estimating an Ocular Hypertensive Patient’s 5-Year Risk of Developing Primary Open-Angle Glaucoma (POAG)

Points for Baseline Predictor Baseline Predictor 0 1 2 3 4 Age (yrs) �45 45 to �55 55 to �65 65 to �75 �75 Mean IOP (mmHg)* �22 22 to �24 24 to �26 26 to �28 �28 Mean CCT (�m)* �600 576–600 551–575 526–550 �525 Mean vertical cup-to-disc ratio by contour* �0.3 0.3 to �0.4 0.4 to �0.5 0.5 to �0.6 �0.6 Mean PSD (dB)* �1.8 1.8 to �2.0 2.0 to �2.4 2.4 to �2.8 �2.8

Sum of points 0–6 7–8 9–10 11–12 �12 Estimated 5-yr risk of POAG �4.0% 10% 15% 20% �33%

CCT � central corneal thickness; dB � decibels; IOP � intraocular pressure; PSD � pattern standard deviation. *Eye-speciﬁc variables are the mean of right and left eyes.

7 3. Risk Factors

TABLE 3.3: RISK FACTORS FOR GLAUCOMA PROGRESSION, IDENTIFIED BY THE EARLY The prevalence of MANIFEST GLAUCOMA TRIAL glaucoma increases H hazard Ratio (95% CI) markedly with age. Baseline Factors Univariate Multivariate Age (≥68, <68 years*) 1.42 (1.01-1.98)† 1.47 (1.04-2.09)† IOP (≥21, <21mm Hg*) 1.67 (1.19-2.35)‡ 1.70 (1.18-2.43)‡ Pattern SD (≤-4, >-4*) 1.46 (1.04-2.05)† 1.58 (1.10-2.28)† Pseudoexfoliation (yes, no*) 3.15 (1.93-5.15)§ 2.22 (1.31-3.74)‡ Both eyes eligible (yes, no*) 1.92 (1.34-2.75)§ 1.96 (1.36-2.82)§ Post Baseline Factors || Initial change in IOP at 3 months (per mmHg ) 0.90 (0.86-0.94)§ IOP at first follow-up visit (per mmHg ) 1.11 (1.06-1.17)§ Mean IOP at all follow-up visits (per mmHg ) 1.13 (1.07-1.19)§ Percent of visits with disc haemorrhage (per % )(a) 1.02 (1.01-1.03)§

*Reference category for multivariate analysis; † P≤0.05; ‡ P<0.005; § P<0.001; || Adjusted for baseline IOP, pseudoexfoliation, number of eligible eye, mean deviation and age. (a) Haemorrhages or bleeding around the optic nerve can indicate ongoing damage to the optic nerve and inadequate control of glaucoma. Source: reproduced from Leske et al, (2003)

3.2: AGE The prevalence of glaucoma increases markedly with age (Figure 3.2). In their literature The cost of eye review of progression rates, Friedman et al, (2004) found that there was strong evidence of a link between older age and the risk of progression from OHT to glaucoma (Table 3.1) and for care will continue progression of glaucoma (Table 3.3). The OHTS Group and the European Glaucoma prevention to increase as the Study Group et al, (2007) confirmed that age (by decade) is a significant risk factor for population ages. progression from OHT to glaucoma (Table 3.2).

FIGURE 3.2: DEMOGRAPHIC DISTRIBUTION OF GLAUCOMA, AUSTRALIANS OVER 40

10% Undiagnosed 8% Diagnosed

Percent 4%

0% 40-49 50-59 60-69 70-79 80-89 90+ Age

Source: Taylor (2001)

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 15 3. Risk Factors

A thin central cornea 3.3: CUP-TO-DISC RATIO has been shown to The optic disc is the region of the eye where the nerve fibres converge to form the optic nerve have an independent and exit the back of the eye into the orbit. The optic cup is the centre portion of the optic disc and is smaller by comparison. The loss of optic nerve cells causes the cup to become larger association with the relative to the optic disc, increasing the cup-to-disc ratio.4 The cup to disc ratio compares progression from the diameter of the cup to the entire diameter of the optic disc. The cup-to-disc ratio is often ocular hypertension measured both in the vertical and horizontal position to estimate the amount of cupping and amount of optic nerve damage. The cup to disc ratio also increases in non-glaucomatous nerves to POAG with increasing disc diameter (Crowston et al, 2004). Large cup-to-disc ratios have been identified as a baseline risk factor for disease progression with values of >0.4 and ≥0.5 associated with an increased risk of progression. The univariate analysis completed in the OHTS shows that the risk of glaucoma is significantly increased with increases in cup-to-disc ratios (Table 3.1) as did the OHTS Group and the European Glaucoma prevention Study Group et al, (2007) (Table 3.2). However, larger cup-to-disc ratios in ocular hypertensive patients may be an indication of early structural damage and therefore serve as a disease marker rather than a risk factor.

FIGURE 3.3: CUP-TO-DISK RATIO

Cup-to-disk ratio refers to the ratio of the cup diameter to the vertical disc diameter.

Source: http://hubnet.buffalo.edu/ophthalmology/site/Home/ Physical_Exam/Cup-to-Disc_ratio_normal_.jpg accessed September 2006

3.4: CENTRAL CORNEAL THICKNESS A thin central cornea has been shown to have a strong association with the progression from ocular hypertension to POAG (Table 3.1 and Table 3.2). This relationship has been explained by the possibility that low corneal thickness may be associated with structural differences in the optic nerve architecture that predispose to the development of glaucoma. Another explanation is that measurement of IOP is affected by the thickness of the cornea. In thicker corneas, the true IOP is lower than the measured IOP. On the other hand, in thinner corneas, the true IOP is higher than the measured IOP. In the OHTS, thinner corneas were associated with a higher risk of disease progression (Gordon et al, 2002).

4 Axons from the optic nerve form the optic rim. Central excavation (the cup) is free from optic nerve axons. The neuroretinal rim thins focally or diffusely due to axon loss in glaucoma. This leads to enlargement of the cup in relation to the optic nerve (increasing the cup to disc ratio).

16 Centre for Eye Research Australia Tunnel Vision 3. Risk Factors

FIGURE 3.4: CORNEAL THICKNESS POAG has a complex, Corneal thickness multifactorial aetiology.

Source: University of Illinois Eye and Ear Infirmary Positions, The Eye Digest, http://www.agingeye.net/mainnews/ glaucomapachymetry.php

3.5: FAMILY HISTORY AND GENETICS First-degree relatives of individuals with primary open-angle glaucoma have up to an eight- First degree relatives fold increase in the risk of developing the disease compared to the general population (Wolfs of OAG patients have et al, 1998; Tielsch et al, 1994). Weih et al, (2001) found that, in multivariate logistic regression models and adjusted for age, the strongest risk factor for glaucoma was a family history of an 8-fold increased glaucoma (Odds Ratio - OR 3.5, 95% CI: 1.9 to 6.7). Friedman et al, (2004) on the other hand risk of developing concluded that strong support for an association between family history and progression from glaucoma. OHT to POAG is lacking, reflecting that many studies of the link between family history and POAG may be affected by ascertainment bias due to poor recall or lack of knowledge of family history. For example, McNaught et al, (2000) found that 27% of previously diagnosed POAG patients were unaware of their positive family history, suggesting that a higher percentage of adult POAG may be inherited than hitherto reported. POAG has an apparent complex or multifactorial aetiology (Weinreb and Khaw, 2004). The chromosomal locations of several genes that can independently cause the disease have been mapped. More than 43 different glaucoma gene mutations have been reported in open-angle glaucoma patients, and several large studies have suggested that as a group these mutations are associated with 3-4% of patients with the condition in populations worldwide (Fingert et al, 2002). The glaucoma gene at GLC1A locus (myocilin) has been shown to be associated with both juvenile and adult-onset primary open-angle glaucoma (Sheffield et al, 1993; Stone et al, 1997; Alward et al, 1998; Fingert et al, 1999; Polansky et al, 2000; Clark et al, 2001). The low attributable risk portion of genetic factors indicates that non-genetic factors play an influential role in the development and progression of glaucoma.

3.6: ETHNICITY Ethnicity has been proposed as a risk factor in many studies. In particular, American based studies have noted a higher prevalence and rate of progression in African-American populations. Results from the OHTS suggest that the African-American race itself does not increase the risk of glaucoma progression but reflects a higher prevalence of other risk factors within that population. African Americans tend to have thinner corneas, higher IOP and larger cup to disc ratios on average than Caucasians (Friedman et al, 2004).

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 17 3. Risk Factors

The association 3.7: DIABETES MELLITUS between POAG and The OHTS showed that diabetes mellitus may protect against progression from OHT to POAG Diabetes is not clear. - (hazard ratio 0.37 in multivariate analysis, p<0.05) - however, the people with diabetes enrolled in the study were carefully selected (those with diabetic retinopathy were excluded) and may represent an unusually healthy diabetic population (OHTS Group; European Glaucoma Prevention Study Group et al, 2006). Over 40 gene Two glaucoma management trials showed a link between the likelihood of glaucoma progression mutations have been and the presence of diabetes mellitus (the Advanced Glaucoma Intervention Study (AGIS, 2002) and the Collaborative Initial Glaucoma Treatment Study - CIGTS (Lichter et al, 2001)), while reported in POAG. many others have either excluded individuals with diabetes or not examined any relationships (Friedman et al, 2004). Population based studies as well as retrospective and prospective cohort studies also provide mixed results (see Table 3.4) - including population based studies in Australia. While Mitchell et al (1997) found an increased prevalence of glaucoma for those with diabetes (OR=2.12) and OHT (OR=1.86), a study by Weih et al, (2001) found that with adjustment for age, there was no significant difference in the prevalence of glaucoma among those with diabetes and those without (results for diabetes not presented in the article). Variations in the definition of POAG may explain some of the different findings (de Voogd et al, 2006). For example, de Voogd et al, (2006) note that a revision in their definition of POAG led to a revision in the results from the Rotterdam Eye Study - from an initially significant relative risk (RR) of the prevalence of POAG in participants with diabetes mellitus of 3.11 (95% CI 1.12 to 8.66) to a non-significant RR of 1.40 (95% CI 0.96 to 2.03) (De Voogd et al, 2006:1830). De Voogd et al, (2006) also noted that the results from the meta analysis by Bonovas et al (2004) (see Table 3.4) were based on previous work from the Rotterdam Eye Study which has been revised based on a new definition of POAG5.

5 The results changed from an initially significant RR of the prevalence of POAG in participants with diabetes mellitus of 3.11 (95% CI 1.12 to 8.66) to a non-significant RR of 1.40 (95% CI 0.96 to2.03). (De Voogd et al, 2006:1830).

18 Centre for Eye Research Australia Tunnel Vision 3. Risk Factors

TABLE 3.4: ASSOCIATION BETWEEN DIABETES MELLITUS AND GLAUCOMA Source Details Assoc. Bonovas et al, 2004* Statistically significant association assuming a random effects 3 model (OR=1.50, 95% CI 1.16 to 1.93) or fixed effects model (OR=1.27, 95% CI 1.10 to 1.45) de Voogd et al, 2006† RR of incident open-angle glaucoma with diabetes was 0.82 x (95% CI 0.33 to 2.05) Dielemans et al, 1996† Association between newly diagnosed diabetes mellitus and high levels of 3 blood glucose with high-tension glaucoma, OR=3.11 (95% CI, 1.12 to 8.66) Klein et al, 1994§ Open-angle glaucoma increased with age-related diabetes ?^ (4.2% versus 2.0%, in people with diabetes versus people without) Figure 3.5: Pseudoexfoliation Weih et al, 2001 With adjustment for age, more people with self reported diabetes x pupil margin. had possible, probably or definite glaucoma (12/230, 5.2%) than those without diabetes (175/4392, 2.5%) but the difference was not statistically significant (chi sq test, 1 df = 0.86, p=0.36) Mitchell et al, 1997‡ Prevalence of glaucoma and OHT increased in people with diabetes 3 OR=2.12, 95% CI 1.18 to 3.79) (OHT: OR=1.86, 95% CI 1.09 to 3.20) Tielsch et al, 1995# Diabetes was not associated with POAG (OR=1.03, 95% CI 0.85 to 1.25) Pasquale et al, 2006 Type 2 diabetes was associated to POAG in women with a 3 RR=1.82 (95% CI, 1.23 to 2.70) Zghal et al, 2000 volution of open-angle glaucoma in diabetes did not x significantly different to people without diabetes Budde et al, 1998 Patients with or without diabetes did not significantly x differ in the morphology of the optic disc Zeiter et al, 1994 People with primary open-angle glaucoma and predominantly 3 inferior VF defects in one or both eyes are more likely to have diabetes

* - Meta-analysis; † - Rotterdam Study; § - Beaver Dam Eye Study; ‡ - BMES; # - Baltimore Eye Survey ^ These results were obtained from the study abstract. It was unclear whether age was controlled in this comparison, therefore the result cannot be determined to be either supportive on non-supportive of an association. With such mixed results, the association between diabetes mellitus and glaucoma has not been modelled here. As future studies are completed this association will become better understood and can thus be included in modelling some indirect intervention scenarios such as improved diagnosis of diabetes and better glycemic control. 3.8: OTHER POTENTIAL RISK FACTORS A number of other potential risk factors have been highlighted including: • migraine: the OHTS showed a positive association although not statistically significant; • myopia (nearsightedness); • hyperopia (farsightedness); • pseudoexfoliation: found to be a major risk factor for progression in the EMGT which included a small number of patients with this condition; • outflow facility: conflicting results from progression studies; • male gender; • optic disc haemorrhage; • sleep apnoea; and • peripheral vasospasm6. In general, the limited number of studies in which these additional suspected risk factors were evaluated does not support firm conclusions concerning their relative importance.

6 A peripheral vasospasm is a contraction of a blood vessel — reducing its internal diameter and blood flow — in the outer part of the visual field. The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 19 4. Epidemiology

The effect of the In this section, the characteristics of the disease are discussed - remission, mortality, progression and ﬁnally, prevalence and incidence. Estimates of prevalence and incidence were modelled disease and its based on Melbourne Visual Impairment Project (MVIP) and BMES data and knowledge of treatment on a remission, and mortality drawn from the literature. Progression rates were modelled based on patient’s health the literature, previous modelling work and taking into account the available data on prevalence and quality of life and incidence by age and visual impairment. is a key outcome The key outcome for measuring the economic impact of disease is the effect of the disease and its treatment on a patient’s health and quality of life. For eye disease, the key outcome is vision for measuring the loss. Deterioration in vision is a fundamental determinant of the costs of glaucoma (particularly economic impact indirect costs such as participation in the workforce, need for care and vision aids, as well as quality of life). In the case of glaucoma, however, non-vision, physiological changes (changes in of disease. IOP or optic disc for example) may also determine treatment, and therefore health system costs. While the costs of the disease are measured and incurred by individuals, diagnosis and quality of life depend on the interrelationship between vision in each eye. In some patients, glaucoma may affect only one eye. If it affects both eyes, disease severity and progression in each eye can differ, so there is often a better eye and a worse eye. Further, eyes that were originally “better” may become the “worse” eye over time. While a diagnosis of glaucoma is based on the worst eye, quality of life - on the other hand - is determined by the best eye (Brown, 1999, Kobelt et al, 2006:369).

4.1: DEFINITION OF DISEASE STAGE There are ﬁve disease stages in the model which are discussed and deﬁned throughout the text below. For ease of reference, a summary of the disease stages is provided in Table 4.8.

4.2: REMISSION Currently there is no natural remission in open angle glaucoma (to either no disease or an earlier stage of the disease), nor any current treatments that improve VF or acuity. Consequently the remission rate for every stage of the disease is nil.

4.3: MORTALITY General population mortality rate forecasts are from the Access Economics Demographic Model (AE-DEM) of the Australian population (see Section 4.4 for more information). The rate of mortality from glaucoma is assumed to be determined by the person’s level of visual impairment — people do not die from glaucoma itself but from associated complications such as higher rates of accidental falls, isolation and depression (which are implicit in the calculation of the RR of mortality). McCarty et al, (2001) estimated that visual impairment (best corrected visual acuity of <6/12) was associated with a signiﬁcantly increased risk of mortality (OR adjusted for age, sex, country of birth, smoking, hypertension and arthritis of 2.34), which converted to a RR is 2.15. The RRs of mortality from vision loss by disease stage used in the model are loosely based on McCarty et al (2001)7 and fall with age as per Table 4.1.

7 2.34 plus 0.67 (the difference between 1 and 1.67 or between 1.67 and 2.34).

20 Centre for Eye Research Australia Tunnel Vision Main heading4. Epidemiology to go here

TABLE 4.1: RELATIVE RISK OF MORTALITY BY STAGE OF VISUAL IMPAIRMENT The impact of disease Age OHT/EDS Mild Moderate Severe on vision determines 40-44 1.00 1.67 2.33 3.00 the impact on health 45-49 1.00 1.67 2.33 3.00 and quality of life. 50-54 1.00 1.67 2.33 2.99 55-59 1.00 1.66 2.32 2.98 60-64 1.00 1.66 2.31 2.95 65-69 1.00 1.65 2.29 2.91 70-74 1.00 1.64 2.26 2.85 75-79 1.00 1.62 2.20 2.75 80-84 1.00 1.59 2.11 2.59 85-89 1.00 1.53 1.98 2.37 90+ 1.00 1.45 1.79 2.06 Source: Loosely based on McCarty et al, (2001). The aetiological fraction for mortality due to glaucoma (as opposed to the number of people who died) is 1.27% based on the same techniques used in CERA (2004: 37) but using updated data.

4.4: POPULATION Forecasts of the Australian population are from AE-DEM which uses a combination of fertility, mortality and migration rates to project the future Australian population. Base fertility and mortality proﬁles for each age and gender (for mortality) are sourced from Productivity Commission (2005), and adjust over time to match the projection for the total value. Migration rates are projected in line with the assumptions in the Australian Bureau of Statistics (ABS) publications: Australian Demographic Statistics (catalogue number 3101.0) and Overseas Arrivals and Departures (catalogue number 3401.0), with adjustments for changes to Australia’s migration program and to reﬂect the latest actual migration (international and interstate) results.

4.5: PROGRESSION For this dynamic study, a key parameter is the rate at which POAG causes vision to deteriorate (the rate of disease progression). The impact of disease on vision determines the impact on health and quality of life. Unfortunately, in studies of glaucoma, disease progression is not always measured in terms of vision loss. Clinical studies often use a combination of changes in VF, IOP and optic disc as indicators of progression. As IOP is the focus of treatment, treatment efﬁcacy is generally measured according to its impact on IOP. Further, deﬁnitions of vision loss vary across researchers.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 21 4. Epidemiology

Patients enrolled in Measuring and grading glaucomatous vision loss Measuring the progression of VFL in glaucoma is complex (see Box 3 for an explanation of the clinical trials do not method of testing VF). necessarily represent • Glaucomatous change needs to be isolated from other factors such as changes in lens the community norm. opacity due to cataract, or physiological change due to ageing. • There can be substantial measurement variability (caused for example by loss of fixation), and there is a learning effect, both of which need to be accommodated when examining patients. Where possible • Glaucomatous vision deterioration is very slow. Even when a change in field is detected via population-based perimetry, the patient may not notice any vision loss. Clinical studies have found that only a data has been used. subset of patients with OHT develop glaucoma, and of these, a small proportion lose functional vision during the course of their lifetime. Further, different researchers have developed different grading systems to measure progression. For example, the AGIS, EMGT and CIGTS all used different grading systems to measure progression. Other grading systems include those developed by Anderson, Blumenthal, and Hodapp-Anderson-Parrish (HAP). Different grading systems show different rates of progression in the same population (Zahari et al, 2006, Wilson et al, 2002). There is no gold standard, so it is difficult to compare progression rates derived from studies using different methodologies (Katz et al, 1999). Comparisons of progression rates suggest that rates produced using the AGIS method might represent a lower bound in judging progression, and the CIGTS and EMGT methods produce relatively similar results (Katz et al, 1999, Wilson et al, 2002, Zahari et al, 2006). Weinreb et al, (2004) developed a methodology for overcoming this problem (section 4.5.1.).

Box 3: Measuring change in VF

VF is tested by examining a patient’s ability to detect light at various intensities at various test locations in the VF. The dimmer the light detected, the better the vision at that point in the field. The results of tests are generally expressed in a decibel scale derived from the reciprocal of the log intensity of the light projected. Thus detection of dimmer light (representing better vision) is indicated by higher numbers. These numbers can be used to create a grading system for VFL. Parameters from VF tests used to measure field loss are: a) Mean deviation or defect - the measurement of how the mean of the patient’s responses varies from the mean of the responses of a series of normal patients of similar age under similar testing conditions. Mean deviation is affected by media opacity, refractive error and glaucoma. b) Pattern SD, also known as corrected loss variance, represents non-uniform loss of field thus providing an indication of focal defects as occur in glaucoma.

22 Centre for Eye Research Australia Tunnel Vision 4. Epidemiology

The importance of study population characteristics in selecting progression rates for modelling Ideally, in selecting progression rates for modelling, data need to be drawn from studies that are based on populations with similar characteristics to that being modelled. As noted in section 3, a number of factors can affect progression rates including age, IOP, central corneal thickness and cup to disc ratio, or African American origin (for example). In addition, patients with pseudoexfoliation syndrome and pigmentary glaucoma are often included together with POAG patients in studies of treatment efficacy and disease progression. While the ideal would involve recalculation of the results where the inclusion of these patients has a material impact on the progression estimates, the reported results often preclude re-calculation excluding these participants. Further, the parameters selected for the modelling need to reflect the likely outcomes of administering therapy in the community, rather than simply replicating the trials. Progression rates based on estimates from clinical trials do not necessarily reflect the experience in the community. Those enrolled in clinical trials often do not have disease risk profiles or health service utilisation habits that represent the average or community ‘norm’. As an example, Henson et al, (2006) suggested that glaucoma progression rates found in retrospective studies tend to be higher than rates derived from prospective studies because patients willing to enrol in prospective studies may be more concerned about their condition and are likely to be more attentive, demanding and compliant with their therapy than average. Constant or variable linear progression Some studies have found that progression rates speed up as damage worsens (for example, Martus et al, 2005), while others have found the opposite (eg. Rasker et al 2000). There is also some evidence that progression is episodic rather than constant, for example, Kwon et al, (2001) found that around 25% patients showed non-linear disease progression.

4.5.1: NATURAL (UNTREATED) PROGRESSION Data on disease progression in untreated patients is available from the placebo or observation arms of clinical trials (with the proviso above that the experience of participants in clinical trials may not match that of the community at large). In addition, Jay and Murdoch (1993) estimated untreated progression and Wilson et al, (2002) examined untreated progression in black patients. These studies are summarised in Table 4.3. Despite examining progression rates in treated patients, Hattenhauer et al, (1998) is included in the table for the reasons outlined below. The data in the table suggest the following natural population progression rates for OHT to POAG (noting that the distinction between OHT and glaucoma is based on clinician observation of clinical signs as well as in most cases detection of VFL): • Data from the OHTS suggest progression rates for white patients of 2% per year. For all participants, the rate was just under 2% per year. • Data from the EGPS suggest annual progression rates for OHT to POAG of around 3.4%.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 23 4. Epidemiology

Data from Table 4.3 suggest the following progression rates for POAG (noting that progression is defined in different ways as per the discussion above): • For the EMGT, the most recent data (Leske et al, 2007) suggest annual progression rates of between 9 and10%, whereas Leske et al, (2003) found annual progression rates of just over 10%. • From Wilson et al (2002), progression to at least unilateral blindness in black patients was 1.6% per year according to the AGIS criteria, and 3.5% according to the CIGTS criteria. • Data from the CNTGS suggest an annual progression rate of 6.6%. Weinreb et al, (2004) synthesised these results by modelling the risk of blindness in patients with OHT using the OHTS, Hattenhauer at al, (1998), and Wilson et al, (2002). The selected end point was unilateral blindness as an indicator of the severity of VF deterioration that can be compared across different studies. Weinreb et al, (2004) assumed that progression rates from OHT to blindness can be estimated by adding the time reported for progression of OHT to glaucoma from one study with the time reported for progression from glaucoma to blindness in another study (Weinreb et al, 2004:462). In addition, progression was assumed to be linear (Weinreb et al, 2004:462). Progression rates from Hattenhauer et al, (1998) were also used despite ostensibly being based on treated patients. Weinreb et al, (2004) argued that the treatment regimens in the Hattenhauer population — based on patients newly diagnosed with POAG between 1965 and 1980 — may not reflect current or even recent therapy and thus these patients could be considered only partially treated — or untreated. The Hattenhauer et al (1998) progression rates might also be erroneously high because of lack of data on other causes of vision loss, thus Weinreb et al, (2004:465) used these as an upper bound. The estimates of the probability of a patient with OHT developing glaucoma and finally becoming blind in one eye over 15 years calculated by Weinreb et al, (2004) were: • 1.5% — OHTS and Wilson et al, (2002) AGIS; • 2.6% — OHTS and Hattenhauer et al, (1998); • 3.3% — OHTS and Wilson et al, (2002) CIGTS; and • 10.5% — Hattenhauer et al, (1998).

Results from the EGPS (2005) were not available for the Weinreb analysis. If these are substituted for the OHTS, the calculated probabilities are: 2.7%, 4.5%, 5.9% and 10.5% respectively. It is worth noting that the relative value of Hattenhauer et al, (1998) is that the data were drawn from a database of medical records for all sources of medical care used by the local population of Olmsted County (USA). As a population based study, the results are probably more reflective of experience in the community. By comparison, longitudinal studies of medical records from specific medical centres may be biased because of the types of patients presenting to the clinic, or because of the treatment approach at the clinic (for example, treatment may be more aggressive).

24 Centre for Eye Research Australia Tunnel Vision 4. Epidemiology

Two examples of rates markedly lower than those of Hattenhauer et al, (1998) are below: • Chen (2003) examined records for 186 patients, (82% white), diagnosed with POAG in 1975 or later and who presented to a tertiary referral clinic (University of Washington Medical Centre). He estimated that the probability of progression from glaucoma to unilateral blindness at 15 years was 14.6% (95% CI 7.6-21.6) and to bilateral blindness was 6.4% (95% CI 0-14.4). • Similarly, Kwon et al, (2001) studied 40 eyes of 40 patients followed at a University clinic since 1972 with POAG and found that around 13% of eyes were legally blind after 15 years, noting, however, that the selection of patients may have been biased towards those with worse glaucoma. Table 4.2 provides a summary of the findings of the studies of natural progression. Notably, progression from OHT to unilateral blindness is lower than from POAG to unilateral blindness since some of those with detected OHT do not progress to glaucoma.

TABLE 4.2: NATURAL PROGRESSION RATES (CUMULATIVE PROBABILITY) 15 YEAR PERIOD Start point Unilateral blindness Bilateral Blindness OHT 1.5% to 10.5% (Weinreb et al, 2004) 3% (Hattenhauer et al, 1998) Glaucoma 40.5% (Hattenhauer et al, 1998) 16.5% (Hattenhauer et al, 1998)

Initially, the approach was to apply the progression rates from the Weinreb et al, (2004) synthesis in the modelling. Unfortunately, it was not possible to match the Weinreb et al, (2004) rates with the available incidence and prevalence data from the MVIP and BMES to obtain sensible projections (see Section 4.6). In addition, for the model it was necessary to measure progress of mild or moderate vision loss, but the Weinreb et al, (2004) rates were only for blindness as defined in the USA. The estimates of the proportion of people with POAG in each visual impairment severity group (early stage, mild, moderate and severe) from MVIP/BMES data were based on small sample sizes. Further, MVIP and BMES data are based on a mixed population with both treated and untreated disease. Final progression rates were therefore derived using the available MVIP and BMES incidence and prevalence data and the splits of disease severity (the methodology is outlined in more detail in Section 4.6 below). Smoothed prevalence rates were used, and the diagnosis rate was set at 50% (consistent with research findings). This led to annual progression rates that are for the most part substantially higher than expected (and higher than Weinreb et al, (2004)) but internally consistent with the other parameters from the literature and population studies used in the model. Clearly more research and population studies investigating incidence, prevalence and progression of based on standard classifications of visual impairment are clearly required.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 25 4. Epidemiology

In summary and for the purposes of modelling, the annual natural progression rates are: • OHT to EDS: 31.2% of the OHT population per annum (markedly higher than studies suggest)8; • Normotensive to EDS: approximate average of 0.22% of the Australian population per annum; • EDS to Mild: 1.5% of those with POAG per annum (in the range of what studies suggest); • Mild to Moderate: 85.0% (markedly higher than studies suggest); and • Moderate to severe: 30.0% (markedly higher than studies suggest).

8 While this number appears high, it is important to note that the prevalence of OHT was only recorded for individuals that were 40 years and over and as discussed earlier in Section 2 the aetiology of POAG resembles that of a continuum. It is therefore very likely that, by only including people aged over 40 years of age, the total prevalence of OHT is being underestimated.

26 Centre for Eye Research Australia Tunnel Vision

American developed POAG met the who

cumulative probability cumulative

OHT: OHT:

of probability cumulative Meier cumulative the Kaplan median time to progression The

0.53) (HR, 16.8% of patients in the placebo group 9.5% of patients. was group was POAG of developing probability 60 months. was in 63 (10.2%) of 614 non-African Progression rate Progression patients and 76% of untreated 59% of treated 47% by progression the HR for reduced progressed. participants. group observation treatment suggested analysis Mulitivariate

syndrome

Sample size Sample size with exfoliation (CI 1-9%). 4% at 20 years

(% white) group) treatment around comprised 10% of the no

glaucoma)

with exfoliation only. optic disc criterion (almost all met the All patients with progression (patients white) with one exception, criteria (75% white) those in the observation glaucoma for developing ollow-up

6 years 255 patients patients progressed. 62% of untreated

(SD 8 years) 9% (around blindness: Bilateral

60 months 1,077 patients 60 months, At

Blindness defined as 15 years (96% white) (95% CI 7-20%). 14% at 20 years probability of 20 VF constriction

20/200, ≤ pattern VF abnormality using corrected 60 months 1,636 patients 60 months, At or vertically horizontally VF (3 or more significant difference least 3 test points showing At

of (VA) Acuity

adjacent points) at 2 or more meridian the nasal horizontal

10dB adjacent points differ or vertically horizontally more normal limits OR optic disc deterioration values. rim) retinal (thinning of neuro

Definition of progression OR optic disc cupping

across of 10dB or more baseline (3) a difference from or more

maps. at the same locations on 3 consecutive in optic disc or change

DISEASE PROGRESSION IN UNTREATED PATIENTS F

examination OHT or OAG. diagnosed and treated in population of or less in widest diameter.

Minnesota USA

Study type Study

Olmsted County,

of case records Visual

Retrospective newly blind from patients going of treated Probability mean 290 patients blindness: Unilateral 2007) clinical trial normal threshold the age-corrected from pattern deviations (Median) 2003) 2002) clinical trial outside were or if the glaucoma hemifield test results SD Progression of O H T to blindness Progression of glaucoma Progression Reference Progression of O H T to glaucoma Progression

EMGT (Leske As above As above

group observation 1998 placebo group clinical trial baseline (2) 2 or from 5dB or more adjacent points differ

No treatment

OHTS (Kass randomised of Development Hattenhauer et al, EMGT (Leske randomised maps based on point wise probability change Glaucoma 8 years

TABLE 4.3: ESTIMATES O

et al,

EGPS (2005) randomised of Worsening group

group et al, No treatment et al,

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 27

AGIS

untreated

the data When Glaucoma Change

AGIS method,

years, at three 60% experienced and 22% of patients and the

31%,

in this mean time to progression The Analysis,

and at 5 years, group 33% of the untreated 2.9 years. (95% CI 42-72%). pointwise linear regression, by CIGTS. 35% by and was criteria vision loss 30 mm over pressures and for 6.5 years Hg was Hg, 1,695 (±143) days. was group Probability blindness: Glaucoma to bilateral arm experienced 40% of patients in the control vision loss, cataract, adjusted for were Progression rate Progression respectively. about 16% by with glaucoma was of 25 to 30 mm pressures for same interval The (CI 8-38%). at 20 years of 21 to 25 mm Hg, pressures For 22% probability cumulative of 14.4 years. in an average to end stage changes 145 5 years, At

patients detected in 35%, Sample size Sample size (100% black) diagnosis from disease in at least one eye

patients field early from to progress disease is likely

(% white) patients progressed.

177

ollow-up 15 years (96% white) 54% at 20 years probability cumulative (SD 8 years)

8 years of 156 156 eyes was at 8 years field progression Visual 10 years 205 patients of reaching end-stage probability Cumulative 5 years 145 eyes, F

Blindness VF constriction

VF defect, or a new VF defects of those VFL with the mean age 20/200, ≤ estimated by POAG VFL in untreated of VA or less in widest diameter. 0 progression AGIS and CIGTS to grade criteria. AGIS progression

of fixation. degrees five

Definition of progression Used

DISEASE PROGRESSION IN UNTREATED PATIENTS continued F

of patients at

points in two POAG

randomised of new appearance time in St Lucia Indies. West diagnosed with absolute field loss within presented who Minnesota USA Case series of Mean rate

Study type Study population of of 20 in case records defined as Olmsted County, with newly relative with early (1998) of examination OHT or OAG. diagnosed and treated Progression of glaucoma to blindness Progression Reference All untreated. examination Progression of glaucoma Progression 2007)

et al, Mahdavi study intervention maps and probability Glaucoma change

al (2002) - clinical study

Murdoch of patients of patients at presentation the mean age comparing No treatment clinical trial visual fixation. to central threat

group AGIS (Nouri- Longitudinal pointwise linear regression, Compared et Wilson retrospective CNTGS group (1998) prospective of an existing Worsening TABLE 4.3: ESTIMATES O

Hattenhauer et Retrospective newly blind from patients going of treated Probability mean 290 patients blindness: Glaucoma to unilateral

and Jay

al,

(1993)

28 Centre for Eye Research Australia Tunnel Vision 4. Epidemiology

4.6: PREVALENCE AND INCIDENCE Loss of visual As foreshadowed previously, the incidence and prevalence estimates used in the model are acuity and visual derived from both MVIP9 and BMES data. field affect quality • Data for persons were used, rather than by gender to ensure the largest sample size possible. of life. No consistent gender differences are reported in glaucoma incidence, prevalence of severity studies. • The EDS group is based on MVIP data for people with probable or definite glaucoma. This stage lacked vision loss by definition and so the diagnosis had been made on optic disc changes or a previous diagnosis of glaucoma. The other stages of POAG are based on combined MVIP and BMES data for people with definite glaucoma. • The data were disaggregated into degree of visual impairment, with VI measured using a combination of VA and VF loss (see definitions and schematic in Table 4 4 and Figure 4.1). The VA categories are created from the best-presented VA data, and VFL (constriction) categories are created from Pattern Deviation data. • For this analysis, severe and profound were combined. • Incidence and prevalence of OHT is based on MVIP data for those with IOP≥21mmHg using tonopen measurements. • The progression rates between the stages of glaucoma have been previously described in Section 4.5.1.

TABLE 4.4: DEFINITIONS OF LEVEL OF IMPAIRMENT FOR DEFINITE GLAUCOMA VA VFL EDS / None Better than 6/12 AND No VFL Mild Impairment <6/12 OR Any loss of VF Moderate Impairment <6/18 OR <20o field loss Severe or profound Impairment <6/60 OR <10o field loss

FIGURE 4.1: SCHEMATIC OF THE LEVEL OF IMPAIRMENT FOR DEFINITE GLAUCOMA

Visual Field Loss Some VF VF <20 - !10 VF <10 - !5 VF <5 Visual Acuity No Loss Loss degrees degrees degrees VA <3/60 or worse VA <6/60 - !3/60 Severe VA <6/18 - !6/60 Moderate VA <6/12 - !6/18 Mild VA <6/6 - !6/12 None VA !6/6

For both OHT and POAG an increase in prevalence is observable with age, although this tails off for OHT, as progression to glaucoma becomes more likely and thereby treatments to reduce IOP (Table 4.5). A small number of individuals were recorded in the oldest age group for people with OHT, which resulted in a prevalence rate estimate of zero. It is possible that once people reach a certain age without contracting OHT or glaucoma, they are unlikely ever to develop it, however, this may also result from the small sample size (Table 4.5).

9 See for example Mukesh et al, (2002), Wensor et al (1998) and Weih et al, (2001).

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 29 4. Epidemiology

TABLE 4.5: OHT AND GLAUCOMA PREVALENCE RATES OHT prevalence - Glaucoma prevalence - Original (%) (%) Age Males Females Original Smoothed 0-39 0.00 0.00 0.00 0.00 40-44 0.13 0.13 0.00 0.07 45-49 0.13 0.13 0.22 0.14 50-54 0.31 0.31 0.21 0.60 55-59 0.31 0.31 1.45 0.94 60-64 0.37 0.37 1.50 2.29 65-69 0.37 0.37 4.22 3.46 70-74 0.49 0.49 5.30 5.51 75-79 0.49 0.49 6.85 5.78 80-84 0.00 0.00 6.19 6.74 85-89 0.00 0.00 9.09 9.66 90+ 0.00 0.00 18.18 20.66

Source: special request from CERA based on MVIP and BMES DISMOD II was used to calculate incidence and prevalence by age for OHT and POAG. A number of steps were taken. First, glaucoma prevalence data from the MVIP and BMES database were smoothed by taking a moving average across three age groups to remove prevalence fluctuations between age- cohorts. While the dynamic model allows the user to switch between the original prevalence rates and the smoothed prevalence rates, the smoothed data is preferred for modelling purposes, as the trends follow a more logical pathway. The differences between the original prevalence rates and the smoothed rates are shown in EconomicFigure impa 4.2ct o andf pr iFiguremary o4.3.pen angle glaucoma Commercial-in-Confidence

FIGURE 4-2: ORIGINAL PREVALENCE RATES FIGURE 4.2: ORIGINAL PREVALENCE RATES 20%

18% EDS

16% Mild Moderate 14% Severe 12%

10%

0% 0-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 90-94 95+

30 Centre for Eye Research Australia Tunnel Vision

FIGURE 4-3: SMOOTHED PREVALENCE RATES (MOVING AVERAGE ACROSS THREE AGE GROUPS)

40%

35% EDS

Mild 30% Moderate Severe 25%

20%

15%

10%

0% 0-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 90-94 95+

Second, raw OHT prevalence estimates (based on a special data request from the MVIP database) were then run through DISMOD II (assuming no remission) and the resulting total prevalence numbers formed the denominator for the progression rate in step three.

A progression rate from OHT to glaucoma was calculated by dividing half the number of incident cases of glaucoma by total prevalence of OHT. This was justified by findings from the Early Manifest Glaucoma Trial where 52% of glaucoma cases identified through population screening had an IOP <21mmHg (Grodum et al, 2002). This resulted in a progression rate of

26 Economic impact of primary open angle glaucoma Commercial-in-Confidence

FIGURE 4-2: ORIGINAL PREVALENCE RATES

20%

18% EDS

16% Mild Moderate 14% Severe

12% 10% 4. Epidemiology 8%

0% 0-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 90-94 95+

FIGURE 4.3: SMOOTHED PREVALENCE RATES (MOVING AVERAGE ACROSS THREE AGE GROUPS) FIGURE 4-3: SMOOTHED PREVALENCE RATES (MOVING AVERAGE ACROSS THREE AGE GROUPS)

40%

35% EDS Mild 30% Moderate Severe 25%

20%

15%

10%

0% 0-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 90-94 95+

Second, raw OHT prevalence estimates (based on a special data request from the MVIP database) were then run through DISMOD II (assuming no remission) and the resulting total Second, rawprevalenceOHT prev numbersalence formedestim atthees denominator(based on fora thespec progressionial data reqrateues in stept fro three.m the MVIP database) were then run through DISMOD II (assuming no remission) and the resulting total prevalence nAu progressionmbers form rateed tfromhe d OHTenom toinat glaucomaor for the waspr calculatedogression byrat dividinge in ste halfp thre thee .number of incident cases of glaucoma by total prevalence of OHT. This was justified by findings from the A progressiEarlyon r atManifeste from GlaucomaOHT to Trialglauc whereoma 52%was ofc alcglaucomaulated casesby div identifiediding half throughthe npopulationumber of incident casscreeninges of glauc hadom ana IOPby t <21mmHgotal preval enc(Grodume of O etH al,T. 2002).This wThisas resultedjustified inby a fprogressionindings fro ratem th ofe Early Manifesapproximatelyt Glaucoma 31.2%Trial perwh ereannum.52% Asof notedglauc earlier,oma thiscas numberes ident appearsified th highroug andh po morepulat researchion screening haandd a datan IOP are< needed.21mmH Itg is(G alsorodu importantm et al, to200 note2). thatThis theres prevalenceulted in a ofpr OHTogres wassio nonlyrat erecordedof for individuals that were 40 years and over and as discussed earlier in Section 2 the aetiology of POAG resembles that of a continuum. It is therefore possible that, by only including people 26 aged over 40 years of age, the total prevalence of OHT may be underestimated. The incidence of early stage POAG from normotensive Australians was then estimated using DISMOD II, with an approximate annual incidence rate of 0.22% of the Australian population. Incidence and prevalence rates for OHT were then re calculated using the rates of progression from OHT to early stage POAG, as well as an OR of mortality of 1. The resulting output is shown in Table 4.6. While OHT amongst those in older age groups was zero in the original data (Table 4.4), this is likely a function of the small sample size and so prevalence rates of those aged 80 or older have been assumed the same as those aged 75-79 years. The results of sensitivity analysis of maintaining the incidence and prevalence of OHT for those aged 80 or over at zero are presented in Chapter 9, Section 9.1.2. Based on the prevalence of glaucoma using the smoothed rates, the proportion of people within each disease stage by age is shown in Table 4.7.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 31 4. Epidemiology

TABLE 4.6: INCIDENCE AND PREVALENCE OF OCULAR HYPERTENSION (% OF AGE GROUP) Prevalence - Original Incidence - DISMOD II Prevalence - DISMOD II Age Males females Males females Males females 0-39 0.00 0.00 0.00 0.00 0.00 0.00 40-44 0.13 0.13 0.02 0.02 0.08 0.08 45-49 0.13 0.13 0.03 0.03 0.15 0.15 50-54 0.31 0.31 0.05 0.05 0.23 0.23 55-59 0.31 0.31 0.08 0.08 0.30 0.30 60-64 0.37 0.37 0.11 0.11 0.35 0.35 65-69 0.37 0.37 0.13 0.13 0.39 0.39 70-74 0.49 0.49 0.14 0.14 0.44 0.44 75-79 0.49 0.49 0.15 0.15 0.49 0.49 80-84 0.49 0.49 0.15 0.15 0.49 0.49 85-89 0.49 0.49 0.15 0.15 0.49 0.49 90+ 0.49 0.49 0.15 0.15 0.49 0.49

Source: Access Economics and MVIP

TABLE 4.7: PROPORTION OF PEOPLE WITH GLAUCOMA BY AGE AND SEVERITY (%), SMOOTHED (MOVING AVERAGE ACROSS THREE AGE GROUPS) EDS Mild Moderate Severe 0-39 0.0 0.0 0.0 0.0 40-44 100.0 0.0 0.0 0.0 45-49 100.0 0.0 0.0 0.0 50-54 100.0 0.0 0.0 0.0 55-59 100.0 0.0 0.0 0.0 60-64 95.1 0.2 1.7 2.9 65-69 94.3 0.4 2.8 2.6 70-74 92.5 0.5 3.7 3.3 75-79 88.6 1.2 8.4 1.8 80-84 84.4 1.7 11.5 2.5 85-89 78.0 2.2 15.1 4.8 90+ 70.6 1.1 7.7 20.6

32 Centre for Eye Research Australia Tunnel Vision

na 1.5%pa 30.0%pa 85.0%pa (normotensive) to POAG Australians ~31.2%pa* OHT to POAG Progression Rate (untreated)# Progression ~ 0.22% of 2.34 3.01 1 1

Mortality (RR) VF 1.67 field field o o VFL V F L loss of Any <20 <10

And Or No Or Or

VA Better <6/12 <6/60

of OHT pOHT = Prevalence Description No visual impairment Definite Glaucoma with mild No visual impairment but changes visual impairment than 6/12 Definite Glaucoma with moderate visual impairment WHO definitions) <6/18 and/or retina to optic nerve DEFINED

STAGES

= Incidence of POAG, iPOAG DISEASE

: 7 Disease stage Mild . of OHT rate the prevalence divided by of POAG of people with OHT to mild glaucoma has been calculated using half the incidence rate progression The 4 TABLE 4.8: DISEASE STAGE No POAG risk, RR = Relative * (POAG) disease stage Early Glaucoma. Definite or Probable Moderate and profound Severe and Blindness (Australian (OHT or normal tension)

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 33 5. Treatment

Current treatment Current treatment regimens centre on the only known treatable risk factor for glaucoma - intraocular pressure (IOP). Management is directed at establishing and maintaining targets regimens centre for reducing IOP. No level of IOP is safe for every patient. In general, the initial target aims to on the only known achieve a 20-50% reduction from the initial pressure at which damage occurred. treatable risk factor Patients with a lower than average risk of glaucoma (<5%) could be observed and monitored for glaucoma - without treatment. For those patients who are at moderate risk of glaucoma (5% to 15%), intraocular pressure a well-informed patient can decide with his or her physician whether to treat or not. (IOP). In patients with a higher than average risk (>15%), treatment for all should be considered (Weinreb et al, 2004).

Clinicians attempt to achieve IOP reductions and control glaucoma by stepping patients through the following course of treatment: 1) Medication; 2) laser therapy (ALT or Selective Laser Trabeculoplasty (SLT) and medication combined; and ﬁnally 3) surgery. The treatment pattern in most cases is the same regardless of the stage at which the disease is diagnosed - that is, patients presenting with both early stage disease and severe disease commence treatment with medication. Occasionally, laser (if compliance is likely to be poor) or surgery (if medical therapy is likely to fail or not be tolerated) are used as ﬁrst line therapy. The side effects of treatment are discussed later in Section 5.6.

5.1: MEDICATION Medication is the first stage of treatment, usually in a topical form (eye drops), but an oral form also exists. A range of medications are available for the reduction of IOP, summarised in Table 5.1. Prostaglandin analogues and beta (β)-adrenergic antagonists are the most frequently used, with topical prostaglandins now the drug of choice in Australia - Lumigan (bimatoprost), Xalatan (latanoprost), Travatan (travoprost). The proportions of medication types used have shifted over time, particularly since the introduction of prostaglandin analogues in 1997 (Figure 5.1). Based on MVIP data, Weih et al (1998) found that the most common glaucoma medications used were (β)-adrenergic antagonists (63%), followed by sympathomimetics (18%) and cholinergic agents (16%). The authors also noted the shift to (β)-adrenergic antagonists and away from the use of pilocarpine over the previous 20 years. Medications reduce the amount of aqueous humour being produced and/or increase the outflow of aqueous humour from the eye. This can be via the conventional outflow pathway through the trabecular meshwork or by the non-conventional outflow pathway (uveo-scleral outflow pathway). Some medications do both. A topical medication can enter the blood supply through the naso-lacrimal drainage system leading to systemic side-effects (ie. side effects in the rest of the body as well as the eye). Systemic side-effects can be reduced substantially with the use of punctal occlusion and gentle eye lid closure for more than two minutes. Side effects are discussed in Section 5.6.

34 Centre for Eye Research Australia Tunnel Vision Main heading5. Treatmentto go here

TABLE 5.1: IOP LOWERING MEDICATIONS Medication Features Prostaglandin analogues (prostamides) Improve the flow of aqueous humour out of the eye through the non-conventional (uveo-scleral) outflow pathway. First-line treatment. Once daily application. Effective IOP reduction (bimatoprost, latanoprost, travoprost) β adrenergic blockers Reduces the production of aqueous humour (betaxolol, carteolol, levobunolol, metipranolol, timolol). Alpha (α) 2 adrenergic agonists Reduce secretion of aqueous humour, and increase aqueous outflow. Less effective in reducing IOP than prostaglandin analogues (apraclonidine, brimonidine). Carbonic anhydrase inhibitors Reduce aqueous secretion, used two to four times a day (dorzolamide and brinzolamide - topical - acetazolamide and methazolamide - oral). Topical forms are not as effective as oral forms. Cholinergic agonists Increase aqueous outflow through the conventional outflow pathway, used up to four times daily (pilocarpine, carbachol).

Source: Weinreb and Khaw (2004:1716).

FIGURE 5.1: GLAUCOMA MEDICATION DISPENSED BY YEAR AND TYPE OF SCRIPT (% OF TOTAL SCRIPTS)

100%

90%

80% Other Anti Glaucoma 70% Preparations Carbonic Anhyrase

s Inhibitors t 60% p i

r Cholinergic Agonists c s

l 50% a t α2 Adrenergic Agonists o t 40% % Beta Blocking Agents 30% Prostaglandin 20% Analogues

10%

0% 1997 1998 1999 2000 2001 2002 2003

Source: Australian Statistics on Medicine 1997, 1998, 1999-2000, 2001-2002, 2003. If a medication fails to reduce IOP, it is generally replaced with an alternative agent or combined with other agents until effective IOP control is established. Some recent studies10 from the literature show the number of medications taken in combination (Table 5.3).

10 Recent studies are preferred because medication efﬁcacy has been improving over time.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 35 5. Treatment

In general, most patients are taking two or more medications by the time they are considered in need of laser treatment or surgery. For modelling, the total costs of medications used were divided by the number of people affected (this is explained in section 6.3.2). The proportion of each medication type dispensed was taken into account in the calculation for total medication costs, with similar proportions of medications reported by state and territory.

TABLE 5.2: PROPORTION OF EACH DRUG CLASS BY STATE, 2005 Prostaglandin b-blocker Carbonic a2 Cholinergic Anhydrase Adrenergic Agonist Inhibitor Agent NSW 51.2 26.2 12.4 7.2 3.0 VIC 53.6 24.2 12.5 7.5 2.3 QLD 55.4 26.4 10.4 4.6 3.3 SA 54.2 28.9 8.5 5.8 2.6 WA 52.9 29.0 10.2 5.9 2.0 TAS 54.2 29.5 9.5 5.2 1.8 ACT 56.2 22.6 14.3 4.4 2.4 NT 61.8 19.6 11.3 5.5 1.7

Source: PBS Item database.

36 Centre for Eye Research Australia Tunnel Vision 5. Treatment

TABLE 5.3: NUMBER OF MEDICATIONS TAKEN IN COMBINATION Source Number medications in combination OHTS (Kass et al, 2002) See Box 4 for a description of the OHTS. At 60 months, in the medication group, 39.7% of participants were receiving two or more medications and 9.3% were receiving three or more. Weinand and Althen (2006) Non randomised prospective non-comparative clinical study of 52 eyes of 52 patients of the effect of SLT as an adjunctive treat ment on eyes with advanced glaucomatous damage. Patients were included if they had uncontrolled IOP (≥20mmHg) on maxi mum tolerable medical therapy, or had failed previous ALT. Patients had a long history of glaucoma treatment and were sent for further treatment to the hospital and so may be considered to have glaucoma that is more difficult to control. The average number of hypotensive medications taken in combination prior to treatment was 2.5. Damji et al, (2006) (a) In Canada, 176 eyes of 152 patients were included in a randomised clinical trial comparing ALT and SLT in terms of their ability to lower IOP in patients with OAG. Patients were given laser if they had uncontrolled IOP (≥16 mmHg), were on maximum medical therapy or had failed previous 180/360 ALT (>6 months previously), were over 18 and had two sighted eyes. Patients were excluded if they had advanced VF defect within 10 degrees of fixation, or had previous glaucoma surgery. The mean number of medications pre treatment was 2.4 for ALT patients and 2.6 for SLT patients. Fontana et al, (2006) (a) 292 eyes and 225 patients were included in a retrospective cohort study of phakic patients with OAG who underwent initial trabeculectomy with adjunctive Mitomycin C (MMC) between August 1997 and December 2003. Eyes that had undergone previous surgery for cataract or glaucoma were excluded. 97% of eyes were receiving medical treatment before surgery with a mean of 2.7 medications (SD±1.0). Ehrnrooth et al, (2002) (a) In Finland, a retrospective evaluation of patients undergoing trabeculectomy without antimetabolites was conducted. Indications for trabeculectomy were uncontrolled IOP despite maximal tolerated medication and disease progression. Prior to surgery, POAG patients had been on glaucoma medication for a mean (±SD) of 7.8 (±5.6) years. Around 2% of patients were on zero medication, 12-15% on one medication, 55-64% on two medications, 20-29% on three medications. Around 55% were on oral medications.

(a) There may be selection bias in these studies and therefore a higher rate of prescribing.

5.1.1: COMPLIANCE AND PERSISTENCE WITH MEDICATIONS The definitions of adherence, compliance and persistence in this section are drawn from the journal articles themselves. Definitions and methods of measurement differ across studies. Adequate treatment of glaucoma and preservation of vision requires adherence to therapy (Schwartz, 2005; Chen, 2003), although the exact relationship between compliance and

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 37 5. Treatment

Ongoing adherence progression of disease has not been quantified (Olthoff et al, 2005). Studies indicate relatively poor adherence to therapy in one-third or more of patients, depending on the medications with daily glaucoma used (AAO, 2005:13). drops is a major • Nordstrom et al, (2005) calculated the duration of continuous treatment with the initially problem. prescribed medication (defined in the article as persistence) and the prevalence of use of the initial medication at various time points (defined in the article as adherence) from health insurance claims data. Claims from 3,623 people with newly diagnosed glaucoma and from 1,677 glaucoma suspects were examined. Four drug classes were included: beta-blockers, alpha-agonists, carbonic anhydrase inhibitors, and prostaglandin analogs. Nearly half of those who had filled a glaucoma prescription discontinued all topical hypotensive therapy within six months, and 37% had refilled their initial medication at 3 years after the first dispensing. Prostaglandins were associated with better persistence and better adherence than other drugs. Patients with diagnosed glaucoma were more likely to adhere to treatment than glaucoma suspects. • Schwartz (2005) conducted a literature review of research published between 1980 and October 2004 on compliance and persistence with treatment by patients with POAG or OHT. Compliance was defined as the extent to which patients’ behaviours corresponded with providers recommendations. Schwartz (2005) found that non-compliance rates of 25% were commonly reported. Using electronic monitoring (the most accurate method of estimating patient compliance), non-compliance rates ranged from 14% to 24%. Persistence over 12 months (the total time on therapy) was around 25% (ranging from 20% to 64%). • Olthoff et al, (2005) conducted a literature review of articles published from 1970 to February 2004 on compliance with glaucoma medications. (POAG as well as other types of glaucoma were included.) Compliance was defined as the degree of correspondence between the prescribed treatment regime and the patient’s actual dosing history. The proportion of patients who deviated from their prescribed medication regimen ranged from 5% to 80% (the figure of 5% came from a study on POAG patients). 30% of patients for whom timolol was prescribed deviated from their treatment regimen. • Tsai (2006) undertook a literature review of articles published on Medline during the 18 months to October 2005 and found that non-adherence (extent of disagreement between the prescribed medical regimen and actual patient practice) to medicinal regimens in patients with glaucoma varied from 24% to 59%. • Reardon et al, (2004) examined patient persistence using records from a managed care data base in the US. Patients had initiated monotherapy between July 1996 and June 2002 with betaxolol, bimatoprost, brimonidine, dorzolamide, latanoprost, timolol, or travoprost. The number of patients included in the analysis was 28,741. Discontinuation was defined as no further index drug (monotherapy drug) refill 90 days (if dispensed one bottle) or 180 days (if dispensed two bottles) after the last prescription fill. Persistence was defined as the number of days from dispense date to discontinuation date or change of medication date (whichever is earlier). Latanoprost was the reference group against which discontinuation dates were compared. At 12 months, 33% of patients were persisting with latanoprost (had not discontinued); and 19% of those treated with other ocular hypotensives had not discontinued. The difference between latanoprost and other agents was significant (p<0.001). In the population (28,741 patients on monotherapy), the three most frequently prescribed drugs were timolol (43%), latanoprost (33%) and brimonidine (18%). Relatively few patients were prescribed either travoprost or bimatoprost (1% of patients for each).

38 Centre for Eye Research Australia Tunnel Vision 5. Treatment

Meta-analysis is not useful in synthesising the results of these studies because of the differences in definitions and methods of measurement. However, compliance rates of 75% seem a reasonable assumption, with persistence rates of 33% for latanoprost and 19% for other medications at 12 months (based on Reardon et al, 2004). The medication cost estimates used in the modelling are calculated based on the costs of dispensed medications for POAG in Australia, and so implicitly include persistence.

5.2: LASER TREATMENT Those whose IOP is not controlled on medication are considered for laser therapy. Two types of laser therapy are available, for the reduction of IOP, but vary in usage depending on the state in which glaucoma has progressed. • Laser trabeculoplasty is the main form of treatment. • Laser diode cyclophotocoagulation is rarely used in POAG and not therefore included in modelling.

LASER TRABECULOPLASTY Laser trabeculoplasty aims to improve outflow through the trabecular meshwork.It is usually Laser trabeculoplasty performed under topical anesthesia. There are two types of trabeculoplasty. Argon Laser aims to improve Trabeculoplasty (ALT) was developed several decades ago. It was followed more recently by the development of Selective Laser Trabeculoplasty (SLT). While there is some evidence outflow through the that there are fewer side effects with SLT (Latina and de Leon 2005), this remains unproven in trabecular meshwork. a randomised clinical trial setting. For the purposes of this study, the efficacy of ALT and SLT are considered the same. Studies have shown equivalency of SLT to ALT in patients in whom maximal medical therapy has been unsuccessful (McIlraith et al, 2006, Juzych et al, 2004 and Damji et al, 2006). The laser is either applied to all of the trabecular meshwork at once (360 degrees) or to just half (180 degrees). There is no consensus about which approach is preferable, but where 180 degree laser is undertaken first and glaucoma remains uncontrolled, a further 180 degree treatment will be conducted on the previously untreated segment of the trabecular meshwork. The pressure lowering effect of laser diminishes over time (Feldman et al, 1991). Repeat laser (any ALT of the trabecular meshwork after a complete 360 degree ALT (Feldman et al, 1991)) is controversial. Repeat ALT has a markedly reduced effect compared with initial laser11 and is associated with an increase in the risk of an adverse rise in IOP. Data from the Medicare Benefits Schedule (MBS) for laser trabeculoplasty are presented in Figure 5.2. The data are for MBS item number 42782 (defined as each treatment to one eye to a maximum of four treatments to that eye in a two years period)12. The MBS fee for item number 42782 from the 1 November 2006 Schedule is A$398.65.

11 For example, Feldman et al, (1991) concluded that repeat ALT was not generally effective for the long term control of OAG. In their study, repeat ALT was successful in 21% of eyes at one year, and 5% of eyes at 48 months. Richter et al, (1987) found that IOP control was successful in 33% of eyes one year after repeat ALT and in only 14% of eyes after 1.75 years. Both studies defined success as a 3mmHg or greater decrease in IOP to less than 22 mmHg and no further surgical intervention. 12 MBS item number 42783 (Laser trabeculoplasty – each treatment to 1 eye where it can be demonstrated that a 5th or subsequent treatment to that eye (including any treatments to which item 42782 applies) is indicated in a 2 year period) is extremely rarely used — one procedure recorded against this item number in 2002, three procedures recorded in 2003 and negative one procedure in 2005. Otherwise zero procedures for the rest of the period between 1994 and 2006.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 39 5. Treatment

The Medicare data in Figure 5.2 include only procedures covered by Medicare — ie. they exclude procedures undertaken on public patients (both admitted and non-admitted) in public hospitals (funded by the hospital) and procedures on compensable patients (for example, funded by workers compensation organisations).13 However, in general, trabeculoplasties are undertaken at a doctor’s practice and admitted patient hospital procedures represent an exception. Hence, for the modelling, the Medicare data are assumed to adequately represent the number of trabeculoplasty procedures undertaken in Australia. The number of MBS procedures fell from 16,809 in 1996, to 6,201 in 2003, before increasing again to 11,113 in 2006. This probably reflects to some extent greater use of prostaglandin analogues which replaced or delayed trabeculoplasty procedures. It may also reflect the increased use of SLT over ALT. It is estimated that half the people that receive a trabeculoplasty procedure have two 180 degree treatments while the remaining half receive one (personal communication, Professor Jonathan Crowston 15th May 2007). The costs of trabeculoplasty have been adjusted upwards by 1.5 in the model accordingly (see Section 6.3.2).

FIGURE 5.2: MBS TRABECULOPLASTY PROCEDURES, 1994-2005

18,000

16,000

14,000

12,000

10,000

8,000

Number of procedures 6,000

4,000

2,000

0 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Year Source: Medicare Australia statistics, MBS item number 42782 (Laser trabeculoplasty - each treatment to 1 eye, to a maximum of 4 treatments to that eye in a 2 year period).

13 The Australian Health Care Agreements specify that an eligible patient presenting at a public hospital outpatient department will be treated free of charge as a public patient unless: (a) there is a third party payment arrangement with the hospital or Queensland to pay for such services; or (b) the patient has been referred to a named medical specialist who is exercising a right of private practice and the patient chooses to be treated as a private patient. Australian Health Care Agreement between the Commonwealth of Australia and the State of Queensland, 2003-08, http://www.health.qld. gov.au/publications/aust_hlth_care_agreement/Queensland.pdf accessed 7 May 2007.

40 Centre for Eye Research Australia Tunnel Vision 5. Treatment

LASER DIODE CYCLOPHOTOCOAGULATION Cyclodiode laser light is directed to pass through the surface of the eye and behind the iris to affect the ciliary body in order to reduce the production of aqueous humour and therefore decrease the IOP within the eye. This technique is used for refractory cases that don’t respond to conventional treatment. Not many of these procedures are undertaken each year. For the financial years 2004-05 and 2005-06, Medicare Australia data suggest that, respectively, 137 and 145 cyclodestructive procedures for intractable glaucoma were performed (item numbers 42770 and 42771). These procedures are rarely used for POAG and so not included in the model.

5.3: CONVENTIONAL SURGERY (TRABECULECTOMY) If medical and laser therapies fail, surgery is performed. Trabeculectomy is performed under local or general anaesthesia and creates an alternative pathway for the outflow of aqueous humour. A tiny portion of the trabecular meshwork or surrounding tissue is removed, and a small flap inserted to produce a passageway from the anterior chamber of the eye to a “pocket” between the conjunctiva and sclera. A small blister (filtering bleb) is formed under the upper lid, called a trabeculectomy bleb.

FIGURE 5.3: TRABECULECTOMY14 In some cases, scar tissue develops and prevents the operation from working. In cases thought to be at increased risk of scar formation, the surgeon may give the patient antifibrotics - drugs to inhibit scaring such as 5-fluoracil or MMC to reduce scarringand improve the outcomes of surgery. As with trabeculoplasty, it is difficult to estimate the total number of procedures undertaken for POAG each year. Medicare data do not include procedures undertaken on public patients in public hospitals (admitted or non-admitted). Hospital data include both public and private admitted patients are therefore the more reliable in the case of trabeculectomy. The total number of trabeculectomy procedures for people with POAG during the period of 2004 05 has been sourced from the Australian Institute of Health and Welfare (AIHW) as a special data request. • The total number of procedures for ICD-10-codes H401 and H409 (which relate to patients with POAG and Unspecified Glaucoma) have been included in the modelling. For the period 2004 05, 1,683 trabeculectomy procedures were performed. Of these, 583 procedures were performed in a public hospital while 1,060 were performed in a private hospital.

14 International Glaucoma Association website, accessed 10th May 2007 http://www.glaucoma-association.com/nqcontent.cfm?a_id=382&=fromcfc&tt=article&lang=en&site_id=176

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 41 5. Treatment

Decreasing rates of Some patients have more than one trabeculectomy. It is not possible to determine the extent Eofc orepeatnomic surgery impac tfrom of p rtheima AIHWry ope data.n ang Thele g lMBSauco datama suggest that aroundComm 1,435ercia l-trabeculectomyin-Confidence surgery reflect better procedures were undertaken in 2004-05, with 212 repeat operations in the same year (Table trabeculectomy procedures were undertaken in 2004-05, with 212 repeat operations in the medical treatment. 5.4) and while 1302 filtering operations were undertaken in 2005-06, there were also 230 same year (Table 5-4) and while 1302 filtering operations were undertaken in 2005-06, there Economic impact of primary open angle glaucoma Commercial-in-Confidence wrepeatere a lsoperations.o 230 repe Repeatat ope rattrabeculectomiesions. Repeat twererabec alsoulec highertomies costwere (Tablealso 5.4).high er Thecos costst (Tab ofle 5-4). trabeculectomy in the model have been adjusted upwards accordingly based on these figures by trabecTheulcecosttosmofy ptrabrocedecuresulectwomerye inundtherte akmoendelin ha200ve4-b05,eenwitadjh 2us12tedrepupeatwardsoperatacionscordinin tglyhe based on satsummingmhese yeeafrig(urT theables etwoby5-4 )yearssaundmm wtoinhi gfindle t13he that02twfilt orepeatseriyngearso permadetoatiof insndup w16%tehreat unofrepde filteringeatrtaksenm ioperationsnad20e05up-06,16 tandh%ere costof filt 25%erin g wereopemorearatls owhichions230 anre suggestsped atcosopet therat25i%ons costm. oreRofe petrabeculectomieswathictrabh ecsuugglecestotms ineedsesthewerec toosa tbelsofo adjustedhitraghbecer cuos upwardslect (tToabmiesle by5-ne4 around).eds t o20%be Thadj(seee cusos Sectiontteds ofuptrabw 6.3.2).ardseculecbytoaromy unin dth20e m%odel(seehaSveecbteenion 6.adj3.us2)t.ed upwards accordingly based on these figures by summing the two years to find that repeats made up 16% of filtering operatTionsABLanE 5d-4c:osTt R25AB%ECmUoreLECwTOhicMhY —suggMesBStsStEheRVcICosEtS ofPRtOraCbecESSuElecD tBoYmJiesURIneSDedsICTIOtoNbBeY YEAR adjTABLEusted u5.4:pwards TRABECULECTOMYby around 20% (s ee— SMBSectio SERVICESn 6.3.2). PROCESSED BY JURISDICTION BY YEAR

ItemTNAoB. LDEes5cri-pt4ion: TRABECULECTOMY — MFeBe (S$) SERVYIeCarES PNRSWOCESVSICED BQYLDJURISSDAICTIOWNA BY TYaEs AR ACT NT Total Filtering operation for glaucoma (Anaes.) 2004-05 559 337 234 110 118 57 20 0 1,435 42746 (Assist.) 843.85 2005-06 513 311 232 81 117 36 9 3 1,302 Item No. DescFripiltteiorning operation for glaucoma, where Fee ($) Year NSW VIC QLD SA WA Tas ACT NT Total 2004-05 77 62 36 17 10 4 5 1 212 427F4il9terinpgreovpioeurastiofinlteforinr glaoupceormataio(nAhnaessb.)een 2004-05 559 337 234 110 118 57 20 0 1,435 42746 (Assispte.)rformed (Anaes.) (Assist.) 1056.55 2005-06 77 62 49 17 17 6 1 1 230 843.85 2005-06 513 311 232 81 117 36 9 3 1,302 Filtering operation for glaucoma, where (Anaes.) Means the service attracts an an2a00e4-s05thetic.77 (Ass6is2 t.) M3e6dicar1e7 bene10fits are4 paya5ble un1 der 2i1t2em 51300 for (Anaes.)42749 previou Meanss filtering op etheration hserviceas been attracts an anaesthetic. (Assist.) Medicare benefits are payable under item 51300 for assisptearfnormced (Arneaens.d) (Aesrseistd.) at any opera1t0io56n.55 ide2n0t0i5f-i0e6 d by 7t7he w6o2rd "A4s9 sist."17for w1h7ich th6e fee 1does 1not e23x0ceed the fee tassistancehreshold s renderedpecified iatn tanyhe itoperationem descr identifiediptor, or a byt a theser iwordes or “Assist.”combin afortio whichn of o ptheera feetio ndoess ide notntif iexceeded by t hthee w feeord threshold"Assist." (Anspecifiedaes.) Me ainn sthethe itemserv descriptor,ice attracts oran ata naa seriesesthet iorc. combination(Assist.) Med iofca operationsre benefits aidentifiedre payab lebyu nthede rworditem “Assist.”51300 fo forr which the asfsoisrtwanhciechrethnedearegdgraetgantey Sopcehreadtiounleidfeeenttihfieredsbhyoltdhespweocridfie"Adsisnistth."efoiter mwhdicehscthrieptfoerehdaosensontobt eeexnceeexdcetheedfeede. thrSeaggregatesohuorcldes:pMe ecScheduleidfiiecdarinetAh efeeusitte rthresholdmaliadesstcartipis tspecifiedtoicr,so,rFaetea sinsb ethearisees itemdorocno descriptorMmbBinSa1tioNno ohasvfeomp notebrea trbeenio2n0s0i 6dexceeded..entified by the word "Assist." forSource:which th Medicaree aggrega Australiate Sched ustatistics,le fee thre Feesshol dbasedspec ifonied MBSin th e1 iNovembertem descrip 2006.tor has not been exceeded. SoAurcteim: Meedsiceariesre Auwstrasalianotstatisavticsa, ilaFeebles bafsroedmontMheBSAI1 HNoWve,mbbeutr 2M00e6.dicare data suggest that the number of A time series was not available from the AIHW, but Medicare data suggest that the number initial MBS trabeculectomy procedures (item 42746) has fallen from 3,996 in 1996 to 1,246 in A tofim initiale series MBSwas trabeculectomynot available fro mproceduresthe AIHW ,(itembut M 42746)edicare dathasa fallensugges fromt that 3,996the n uinm 1996ber of to init200ial M6 BS(Fitgurrabeecul5-ec4)t.omyTprhisoceprdurobesably(itemres42ult746)s frohasm falltheen fflorowm 3,on996efinfec1t99of6 tothe1,246introinduction of 200pros1,2466 (tFai glgurinand 2006e 5in-4 a)(Figure.nalToghisue 5.4).preyob eThisablydrops probablyresult(diss cf usroresultsmsedthee fromaflorlierw the),onw flowhiceffech onthavof effectetheim provintofro theduced introductiontIiOonP ofcontrol and prosdeloft aayprostaglandingleandd tinheannaleeogd analogueueforeydoewdrns eyeopstrea drops(dism ctreus (discussedatsemdeentarliers. earlier),), which whichhave i mhaveprov improveded IOP co ntIOProl controland and deldelayedayed the thenee needd for dforow downstreamnstream treat mtreatments.ents. FIGURE 5-4: MBS TOTAL OF TRABECULECTOMY PROCEDURES, 1994-2005 FIGURE 5-4: MBS TOTAL OF TRABECULECTOMY PROCEDURES, 1994-2005 FIGURE 5.4: MBS TOTAL OF TRABECULECTOMY PROCEDURES, 1994-2005 4,500 4,500 42746 42749 4,000 42746 42749 4,000

3,500 3,500 s s 3,0030,000 e e r r u u d d e e c c

o 2,500

o 2,500 r r p p f f o o r 2,000 e r 2,000 b e b m u m N 1,u 500 N 1,500

1,000 1,000

500 500 0 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 0 Year 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Source: Medicare Australia statistics, MBS item nos. 42746 (FilteringYoepaerration for glaucoma) and 42749 (Filtering opeSource:ration f oMedicarer glaucom Australiaa, where statistics,previous f iMBSlterin gitemope rnos.atio n42746has be (Filteringen perfor moperationed). for glaucoma) and 42749 S(Filteringource: M operationedicare A forus tglaucoma,ralia statis wheretics, M previousBS item filteringnos. 42 7operation46 (Filter ihasng obeenpera performed).tion for glaucoma) and 42749 (Filtering operation for glaucoma, where previous filtering operation has been performed). 38 42 Centre for Eye Research Australia Tunnel Vision 38 5. Treatment

DRAINAGE IMPLANTS In patients for whom trabeculectomy is likely to fail because of inflammation or scarring, a drainage device is implanted (called a glaucoma drainage device) to create a drainage pathway. Various devices exist (eg. Molteno valves). Drainage implants are rarely used in POAG, but are more commonly used in secondary glaucoma. • Data from the AIHW hospital morbidity data base for 2004-05 suggest that 136 aqueous shunt insertion15 procedures were recorded for glaucoma. • For the financial years 2004-05 and 2005-06, Medicare Australia data suggest that, respectively, 57 and 70 Molteno valve insertions were performed (item number 42752). These procedures are relatively expensive — the MBS fee for the 1 November 2006 was $1,182.75. Since they are relatively rare in primary open angle glaucoma patients, these procedures are not included in the model.

5.4: PREVALENCE ESTIMATES FOR EACH TREATMENT GROUP As noted earlier, once diagnosed with POAG, patients generally follow a standard treatment protocol. The protocol is independent of the severity of the disease stage at diagnosis. Patients usually commence with medications whether they have severe disease or early stage disease. Initially, Dismod II was used to model the progression from one treatment phase to the next, by using the total number of people newly diagnosed with POAG in 2005 as the incidence rate for the medication treatment phase, the total number of trabeculoplasty procedures as the indicator of treatment failure for the medication group, and the total number of trabeculectomy procedures as an indicator of treatment failure for the trabeculoplasty group (the overall RR of mortality of 1.18 – the weighted average RR of mortality from all prevalent severity groups – was applied in the modelling for each treatment phase). In the case of trabeculoplasty, the total number of MBS procedures needed to be scaled down to reflect ‘first-time’ procedures. As noted earlier, it is estimated that half of the people in the trabeculoplasty treatment phase receive two 180 degree treatments while the other half receive one. The total number of trabeculoplasty procedures was scaled down by 1.5 accordingly. Dismod II was also initially used to model the remaining treatment phases (Table 5.5) to ensure that the flow through each phase was internally valid and reflected the number of procedures occurring in practice. However, these modelled rates were not consistent with the literature on failure rates for laser therapy and surgery. In particular, a number of studies outlined in Table 5.7 and Table 5.8 suggested failure rates for laser and surgery were of the order of 50% (with failure defined as the patient requiring further treatment). Failure rates applied in the model are therefore: • 50% per year for laser trabeculoplasty (consistent with Weinand and Althen 2006); and • 50 % for trabeculectomy. While this is a very conservative estimate — higher than the literature — sensitivity analysis shows that it makes little difference to the results. Sensitivity analysis is presented in Section 9.3.3

15 ICD 10 AM code 42752.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 43 5. Treatment

TABLE 5.5: INCIDENCE AND TREATMENT FAILURE RATE FOR EACH STAGE OF TREATMENT FROM DISMOD II. Age Group Incidence of Medication Medication Trabeculoplasty Trabeculectomy (% of population in each failure rates (% of failure rates failure rates age group) those on medication 40-44 0.02 4.3% 3.2% 2.0% 45-49 0.05 4.3% 3.2% 2.0% 50-54 0.07 4.3% 3.2% 2.0% 55-59 0.10 4.3% 3.2% 2.0% 60-64 0.12 4.3% 3.2% 2.0% 65-69 0.14 4.3% 3.2% 2.0% 70-74 0.17 4.3% 3.2% 2.0% 75-79 0.22 4.3% 3.2% 2.0% 80-84 0.26 4.3% 3.2% 2.0% 85-89 0.32 4.3% 3.2% 2.0% 90+ 0.35 4.3% 3.2% 2.0%

5.5: TREATMENT EFFICACY For the reasons outlined earlier in Section 4.5, many of the studies of treatment efficacy (ie. the impact of treatment compared with alternatives including no treatment) are difficult to apply to a cost effectiveness study because progression is not defined consistently and because of the nature of the end points selected. The major clinical trials of treatment efficacy are outlined in Box 4.

Box 4: Major clinical trials of glaucoma treatment efficacy

The Ocular Hypertension Treatment Study (OHTS) in the USA examined patients who, at entry to the trial, had OHT, but no evidence of glaucomatous damage. Enrolment ended in 1996. 1,636 participants were randomised either to observation, or to receive treatment with commercially available topical hypotensive medications used singly or in combination. The aim of treatment was to achieve a target IOP of 24 mm Hg or less and a minimum 20% reduction in IOP. Progression was defined as either the development of a VF defect or deterioration in the optic disc. The European Glaucoma Prevention Study (EGPS) enrolled 1,081 patients between 1997 and 1999 in Belgium, Germany, Italy and Portugal. Participants had OHT, but normal VF and optic disc. Patients were randomised to treatment with dorzolamide (topical carbonic anhydrase inhibitor) or a placebo. Participants and investigators were both masked. The aim was to reduce IOP, but the protocol did not specify a target IOP reduction. End points were changes in VF and/or the optic disc. At entry in the Collaborative Normal Tension Glaucoma Study (CNTGS), 145 patients from specialty centres in the USA had normal IOP, but optic disc abnormalities and VF defects. Participants were randomly assigned to treatment or no treatment. Progression was based on a change in the VF or a change in the optic nerve appearance. In the treatment group, the aim was to reduce eye pressure by 30% in 6 months using eye drops, laser and/ or filtering surgery.

44 Centre for Eye Research Australia Tunnel Vision 5. Treatment

The Early Manifest Glaucoma Trial (EMGT) was conducted in Sweden, and included 255 participants screened between 1992 and 1997. At entry, patients were newly diagnosed with VF defects, but were previously untreated. Patients with advanced VF defects were excluded from entry. Participants were randomised to either 360o laser treatment (ALT) plus betaxolol hydrochloride (topical beta blocker) or no initial treatment. The aim was to evaluate the effect of immediate treatment compared with no initial treatment or later treatment. Progression was based on new VF defect or optic disc deterioration or both. The Collaborative Initial Glaucoma Treatment Study (CIGTS) was conducted in the USA. Enrolment took place between 1993 and 1997. 607 patients with newly diagnosed glaucoma, with limited or no prior treatment, IOP of 20 mm Hg or greater and evidence of optic nerve damage and/or VFL in one or both eyes were enrolled. Participants were randomised to initial trabeculectomy (with or without 5-fluorouacil) or topical medication (topical beta-blocker, followed by an alternate single topical therapeutic agent, dual topical therapy, triple topical therapy, an alternate combination of triple topical therapy and optional additional topical and or oral medications). Further treatment, if considered necessary, followed standard treatment patterns (various combinations of ALT, medications and trabeculectomy). Progression was based on changes in VF. The Glaucoma Laser Trial (GLT) and the Glaucoma Laser Trial Follow Up (GLTFU) Study were conducted in the USA. The GLT (271 participants) ended in 1989, but a proportion of GLT patients (203 participants) were then observed as part of the GLTFU from 1990 to 1993. Participants in the GLT were newly diagnosed with POAG and had an IOP of at least 22 mm Hg in each eye plus one of: a VF defect, or certain OHT and cup to disc ratio characteristics. One eye of each patient was randomised to ALT and the other eye to timolol. End points were VF and IOP. The Advanced Glaucoma Intervention Study (AGIS) conducted in the USA focused on those whose disease was no longer controlled by medication. Between 1988 and 1992, 591 patients were enrolled. At entry, patients had consistently elevated IOP, optic disc rim deterioration and a VF defect score based on the AGIS grading system of between 1 and 1616. Patients were given a different sequence of interventions in each eye — in one eye, the sequence was ALT, trabeculectomy, trabeculectomy; in the other eye, the sequence was trabeculectomy, ALT, trabeculectomy. The goal was to reduce IOP to less than 18 mm Hg. The primary outcome variable in the AGIS was the average per cent of eyes with a decrease of vision (either VF or VA).

Other studies focussing in particular on the efficacy of laser treatment and trabeculectomy administered to patients following failure of maximum tolerable medication to control the disease generally focus on the impact of treatment on IOP and the need for additional intervention. Very few measure the effect of treatment on VF. The studies have different end points and define progression differently. Some are not based on intent to treat. Some examples of studies of the efficacy of trabeculoplasty are outlined in Table 5.7 and examples of studies of the efficacy of trabeculectomy are outlined in Table 5.8.

16 AGIS VF defect scores range from 0 (no defect) to 20 (advanced glaucoma). If the eye has insufficient vision for a patient to count fingers at 30cm, the VF defect score is recorded as 20.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 45 5. Treatment

In order to synthesise the impact of treatment on progression, Weinreb et al, (2004) used the results from the OHTS and the EMGT as the only trials which compared treatment with no treatment. As noted earlier, the EGPS (2005) results were not available at the time Weinreb et al, (2004) was released. In any case, the EGPS (summarised in Box 4) faced certain design problems and so is not used here for the impact of treatment on the risk of developing POAG17. Weinreb et al, (2004:464) combined the impact of treatment on conversion rates from OHT to glaucoma from the OHTS with results from the EMGT on the impact of treatment on the risk of progression of disease. • The OHTS (summarised in Box 4) found that after 60 months, those who were not receiving treatment were more than twice as likely to develop POAG than those on topical medications who had their IOP reduced by 20%, ie. the cumulative probability of developing POAG was 4.4% in the medication group and 9.5% in the observation group (hazard ratio of 0.4, with a 95% CI of 0.27 to 0.59). The difference in progression rates was 46% (4.4/9.5). • The EMGT (summarised in Box 4) showed that early initial treatment with 360o ALT plus beta blocker eye drops delayed progression compared with no treatment. The median time to progression was 48 months in the control group and 66 months in the treatment group (although time to progression varied greatly). At 48 months, 49% of controls had progressed compared with 30% in the treatment group (Heijl et al, 2002). Leske et al, (2003) found that after 6 years, 53% of patients progressed. In multivariate regression analysis, progression risk was halved by treatment (HR=0.5, with a 95% CI of 0.35 to 0.71).

Thus, Weinreb et al, (2004) estimated that treatment reduced the risk of progression from OHT to blindness by 77% (ie. progression rates in treated patients are 46% x 50% = 23% that of progression rates in untreated patients). Progression from glaucoma to blindness in treated patients is assumed to be 50% of that in untreated patients. Rates of progression in treated patients based on Weinreb et al, (2004) are presented in Table 5.6.

TABLE 5.6: PROGRESSION RATES (CUMULATIVE PROBABILITY) IN TREATED PATIENTS (15 YEAR PERIOD)

Start point Unilateral blindness Bilateral Blindness OHT 0.3% to 2.4% (Weinreb et al, 2004) 0.7% (Hattenhauer et al, 1998)

Glaucoma 20.25% (Hattenhauer et al, 1998) 8.25% (Hattenhauer et al, 1998)

17 In the EGPS, there was no statistically significant difference between medical therapy and placebo in reducing the incidence of POAG, although the actively treated arm had a mean IOP reduction ranging between approximately 15% to 22% throughout the 5 years of the trial. The results are mostly explained by a clinically significant placebo effect on IOP of approximately 9% to 19%, which increased during the study.

46 Centre for Eye Research Australia Tunnel Vision

ALT follow- Equivalent each at success SLT IOP 46% and 32% by after one year At

68%, success rate year three decreasing of the GLT the course Over not and medication were ALT in ALT(n=48)). is at least as beneficial ALT synechiae anterior peripheral with initially treated the eyes (1) and criterion 30% and 31% by within one year occurred treatment ALT

(2). criterion 38% and 31% by effective VF and better optic disk status than their group, ALT on the remained 69% of eyes group ALT better similarly were: years and five three proportions were: the equivalent group In the SLT 3.4%(3/89) 6.7%(6/89) and 9%(8/89). In the In the SLT of 53%, success rate year two that suggest the results (2). criterion 23% and 13% by and

Outcome in 1.2% (1/87), formed in 4.6% within one year occurred treatment in 5.7% (5/87) SLT in 8% within one year occurred (4/87) and trabeculectomy (7) patients. 1.1%(1/89), one additional of medications and 29% required same number medication. maintained on were group in the SLT 82% of eyes treatment of medications and 18% had added one the same number medication. of 44%. success rate year of 44% and four at least 20% lowering that achieved proportion of eyes The groups the two similar between was of IOP out to one year (n=43) and 60.3% (59.7% SLT 54%, were success rates ALT 46%, success rate a one year revealed analysis Meier survival Kaplan of 60%, ALT (1) and 58%, criterion between the differences While large, starting with timolol. treatment study, follow-up and the GLT IOP, had lower with topic medication. initially treated eyes fellow IOP. with the pre-treatment up time compared at one, rates

judged Fields assessed VF and optic disc were

VA,

was the treatment laser or surgical) IOP 20% of pre-treatment ≥ or medications or additional glaucoma surgery IOP. treatment of the pre or more post treatment. at one year

Definition of progression assessment). clinicians (subjective by unchanged. considered questionable were in IOP, Mean change further and the patient required after SLT If IOP increased (medical, treatment failed. to have considered criteria: Success defined as meeting all of the following of 1) a reduction Success defined as: without additional of 3 mmHg or more (1) IOP reduction 20% was (1) but the IOP reduction (2) same as criterion baseline. 2) no additional medications needed over needed. treatment 3) no additional glaucoma surgical

ALT

Each and SLT ALT treatments 0

one to each eye. ALT. non-comparative, (2 180 ALT outcome was Primary in patients with SLT ALT prospective, on maximal medical were 180 degree Compared LASERTREATMENT F 3.5 years. was Median followup 7 years was Median follow-up ICACY O Approach 180 degree Compared chart (non randomised) review. Retrospective OAG. with uncontrolled previous or had failed therapy in patients with OAG. in terms of IOP lowering had if they laser treatment received Patients IOP, uncontrolled patients with diagnosed POAG = 271 newly GLT no history of topical or systemic anti-glaucoma 6 months medication use within the previous 1984 1987 and then reassessed enrolled were 1989. GLT = 203 of the original study follow-up GLT The 1990- reassessed and were patients continued 1993. to compare aim was The of 52 patients. of 52 eyes clinical case series treatment as adjunctive SLT Impact of 180 degree glaucomatous damage. with advanced on eyes Randomised clinical trial. with compared of SLT effect the IOP lowering at 12 months. both treatments, patient received Non-randomised, apart) spaced 4 weeks with 0.5% timolol as first diagnosed POAG. newly for line treatment FF E E H T F Trial Althen (2006) (2004) (2006)

Juzych et al, and Weinand Damji et al, Glaucoma Laser (1995) Group Research Source TABLE 5.7: STUDIES O

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 47

Life and 56.7% In subsequent years with POAG, eyes For successful If a patient was (ie. had failed 65% of all eyes of 43.3%). years at five success rate of success was probability Cumulative and 32% after ten years 40% after five years, By five successful at ten years of remaining probability ALT. year in the first was of failure highest probability The

Outcome successful). still considered 35% eyes (80% success) after one year, failed 19.3% of eyes (ie. five year by had failed was successful up to ten years of remaining probability The all 93 eyes. 32% for 77% after one year, years. of 23%. rate failure with a cumulative 5% to 9% per year. approx was of failure the probability disclosed a similar with POAG of the 60 eyes table analysis of 31%. successful up to ten years of remaining probability success rates. affect IOP did not significantly or previous Age 64% after was one year for survival success given Probability and 42% after ten years. years five years, at five 65%. was with became necessary in 32% of all eyes Subsequent surgery of one year no laser retreatment VFL, Definition of progression optic success included no progressive for Clinical criteria or glaucomatous damage nerve and final IOP of less intervention or glaucoma surgical the than or equal to 19mmHg and at least 3mmHg below level pre-treatment surgery no filtration a success when considered was ALT required. was surgery when or a failure required was

ALT. or 360 degree Either 180 degree LASERTREATMENT continued... F as a substitute for employed was ALT

ICACY O Approach of 93 in 118 eyes study Retrospective trabeculectomy. applied. were treatments of 78 of 109 eyes review record Retrospective patients. patients of 360 degree FF E E H T F (1993) Shingleton et al, Spaeth and Baez (1992) Source TABLE 5.7: STUDIES O

48 Centre for Eye Research Australia Tunnel Vision

In terms of 64% at three An IOP <16mmHg

and years 22% at five was 18 B 84%(±2%) and 56%(±4%).

was the unqualified success rate

the showed Meier analysis Kaplan A qualified success (including patients on

visit (mean 20 months) the last follow-up At

in 66.6% of achieved unqualified success was 91% with was the proportion of successful eyes A 85%(±2%) and 62%(±4%),

one year, After cases (823 cases). in 71% of cases (878). achieved medication) was achieving an IOP <21mmHg, 92%. 84% and the qualified success rate in 54.6% of cases. achieved was Meier Kaplan as calculated by of IOP control success rate The post-operation, 80% at one year was analysis post operation. years of blindness probability cumulative seen in 68% after trabeculectomy. complete success was C 79%(±2%) and 45% (±4%) 12 months, At trabeculectomy. of surgery and 54% probability post-operative 46% at ten years after filtration. at 15 years after follow- years and third at first Meier success rates Kaplan up: Success rates (C) 15.

≤ (B) Final 21mmHg ≤ 30% reduction 18. ≥ ≤

VF stability at one of IOP 25% reduction ≥ 18mmHg and one of

≤ of success Secondary measures (A) final IOP

of of IOP or a reduction 20% reduction ≥ 12.

≤ 12 and one of the following: ≤ 15 and one of the following: on post op if the patient was Qualified success was ≤ progression and definition of success V F progression Definition of defined as an IOP was Definition of success surgery of less than two trabeculectomy following at one year listing when IOP (as measured the preoperative thirds surgery). the patient for an IOP less than 21mmHg and were year. antiglaucoma medication. scale. Quigley to the 8 stage according VF scored IOP <21mmHg considered of IOP was Successful control with or without antiglaucoma medication a reduction <21mmHg. IOP was of at least 33% if preoperative success: for Criteria defined as an IOP of Successful drainage IOP Final without antiglaucomatous medications the following: to be less than 2 medications with final IOP required or equal to baseline IOP if to of 2 medications with final IOP required or a reduction be less than or equal baseline IOP if IOP of 2 medications with final IOP in IOP or a reduction to be less than or equal baseline IOP if required baseline IOP

reason

or less in its widest diameter. to 20 degrees VF constriction Main

UK. 225 292 eyes (16 eyes 50 eyes reported Results the of intolerance in 45 patients the IOP deemed by VF or optic disc. in 26.5% of cases. VF deterioration

and or of 20/200 or worse VA IOP in of medication to control Failure (Clinical 1454 patients (96% white) 1298 had POAG black), 29 eyes ophthalmologists of corrected trabeculectomy

population based. Retrospective conventional underwent 49 patients who for here procedures. filtration optic disc changes, Progressive also reasons medication and non-compliance were surgery. for the visit closest to one year outcome data for 1240 cases for available were surgery following — 85.3%). patients (73% Caucasian) surgery: for 57.1% cases; cohort of phakic patients study Retrospective initial trabeculectomy underwent who with OAG MMC.with adjunctive to be associated with a high physician treating and glaucomatous of glaucoma progression risk of the worsening comparing Randomised clinical trial with viscocanalostomy. trabeculectomy reported here). only trabeculectomy for (Results practice Antimetabolites used as per standard failure. of drainage patients at high risk for on or secondary OAG primary Uncontrolled medication. tolerated maximally Caucasian, Survey Approach or f rates

2006 2004 2001 uccess 2001 C et al, Parc H et al, Fontana D et al, O’Brart et al, Edmunds Source Definition of blindness used in this study: TABLE 5.8: S 18

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 49 5. Treatment

Prostaglandin 5.6: SIDE EFFECTS analogues are the 5.6.1: MEDICATIONS most frequently Topical anti-glaucoma medications can result in an array of side effects, ranging from used anti glaucoma minor impacts such as eye-lash elongation and darkening of the iris to major impacts such as medications in cardiovascular events (Table 5.9). Australia. TABLE 5.9: MEDICATION SIDE EFFECTS Medication Side effect Prostaglandin analogues (prostamides) Brown discolouring of the iris, lengthening and darkening of eyelashes, ocular irritation and redness, macular oedema or iritis in susceptible patients. b adrenergic blockers Ocular irritation and dry eyes. Contraindicated in patients with bradycardia, heart block, heart failure, asthma or obstructive airway disease. Can have substantial cardiovascular and respiratory side-effects, especially in the elderly. Alpha (a) 2 adrenergic agonists Red eye and ocular irritation, central nervous system effects and respiratory arrest in young children, allergic conjunctivitis, sedation, caution advised in patients with cerebral or coronary insufficiency, Raynaud’s disease, postural hypotension (dizzy spells), hepatic (liver failure) or renal impairment. Carbonic anhydrase inhibitors Topical forms have few side effects, however oral forms may cause transient myopia, nausea, diarrhoea, loss of appetite and taste, parasthesiae, lassitude, renal stones and haematological problems. Cholinergic agonists Substantial ocular side-effects including blurring of vision due to the small pupil and induced myopia, ciliary spasm leading to headaches especially in younger patients. Cataracts and iris-lens adhesions in the long-term.

Prostaglandin and b-blockers are the most frequently used anti glaucoma medications in Australia. • The side effect profile for prostaglandin medications is relatively minor. Topical prostaglandins are rapidly broken down in the blood stream as a result, systemic side effects are rare. Ocular side effects can include conjunctival hyperemia, increased iris pigmentation and pigmentation of the periocular skin as well as lengthening of the eyelashes. Because they are rare, no side effects for prostaglandins are included in the modelling. • More significant side effects are possible for patients taking b-blockers. Two types of topical b-blockers are commercially available, nonselective (timolol, levobunolol, metipranolol and carteolol) and cardioselective (betaxolol), (Brooks and Gillies, 1992). The IOP lowering ability of the nonselective b-blockers is greater than the cardioselective b blockers, providing a greater treatment efficacy, although the side effect profile may be more significant in the nonselective b blocker medication group. These side effects include: stinging, aching or redness in the eyes after using drops; dry eyes and foreign body sensation (the feeling of a foreign body in the eye); bradycardia (slow heartbeat); spasms of the tubes leading to

50 Centre for Eye Research Australia Tunnel Vision 5. Treatment

the lungs (bronchospasm or asthma); heart failure due to the build up of fluid; depression; confusion; fatigue, dizziness and inability to tolerate exercise; and/or reduced libido. Bronchospasm can exacerbate asthma and chronic obstructive pulmonary disease (COPD) while bradycardia can exacerbate congestive heart failure19. Prolonged use of topical b-blockers has also been linked to depression, mood alterations, memory loss, hallucinations, decreased libido as well as impotence. The most significant side effect (which has been included in the dynamic modelling) associated with b blockers is COPD. A population based cohort study conducted in the UK, examining whether topical b blockers are associated with excess respiratory disease in elderly patients not considered to be at excess risk (Kirwan et al, 2002) showed a higher risk of respiratory disease than would normally be expected. A hazard ratio used in the model of 2.29 (95% CI 1.71 to 3.07) was produced for people treated with b blockers to receive a first-time medical treatment for reversible airways obstruction, although this risk ceases to be significant after the first year of treatment with topical b blockers. The risk of COPD for a person not being treated with topical b blockers is assumed to be equal to the prevalence of COPD in the general population.

TABLE 5.10: RISK OF COPD (% OF POPULATION), 2001 Age Males Females Persons 0-4 0.00 0.00 0.00 5-14 0.00 0.00 0.00 15-24 0.05 0.01 0.03 25-34 0.44 0.22 0.33 35-44 1.15 0.57 0.86 45-54 2.61 1.06 1.84 55-64 5.71 2.08 3.92 65-74 10.42 3.61 6.91 75-84 14.22 5.26 9.01 85+ 16.01 6.37 9.35 All Ages 2.51 1.09 1.80

Source: AIHW special request. The cost of COPD per person is based on AIHW data, indexed to 2005 dollars (Table 5.11).

19 www.agingeye.net/glaucoma/glaucomadrugtreatment.php

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 51 5. Treatment

Other more serious TABLE 5.11: HEALTH SYSTEM COST OF COPD ($ PER PERSON), 2005 side effects, such as Age Males Females Persons retinal detachment, 0-4 0 0 0 are also excluded 5-14 255,006 476,620 304,254 from the modelling 15-24 2,893 13,717 5,167 because they occur at 25-34 88 527 233 such a low rate. 35-44 291 978 522 45-54 373 962 543 55-64 858 1,843 1,117 65-74 1,427 2,717 1,775 75-84 1,904 2,524 2,115 85+ 2,010 2,224 2,111 All Ages 1,191 2,085 1,465

Source: AIHW special request.

5.6.2: LASER TREATMENT A number of studies note that the side effects of laser include formation of peripheral anterior synechiae (Latina and de Leon, 2005; GLT and GLTFU), uveitis (Nagar et al, 2005) and transient IOP spikes (Latina and de Leon, 2005). These are excluded from the modelling as for the most part they do not affect quality of life. Other more serious side effects, such as retinal detachment, are also excluded from the modelling because they occur at such a low rate.

5.6.3: SURGERY The complications of trabeculectomy include cataract and an increased risk of eye infection. Cataract is the most severe and costly of these (because of the number involved) and thus has been included in the modelling. Trabeculectomy is an invasive procedure that has a known association with the development of cataracts following surgery. Lichter et al, 2001 (CIGTS) found that initial surgical treatment resulted in the development of more cataracts requiring removal than initial medical treatment. Kaplan-Meier estimates showed that by three years after treatment initiation, the probability of cataract extraction was 11.6% (standard error, 1.9%) in the surgical group versus 2.7% (standard error, 1.0%) in the medical group. The difference was significant (p = 0.0001). Cataracts occurred in approximately 20% to 35% of patients following first time trabeculectomy over 20 months to 10 years (Table 5.12). The occurrence of cataract following trabeculectomy presents as a significant side effect that results directly from glaucoma treatment, with an associated morbidity from VA loss as well as costs from subsequent cataract surgery.

52 Centre for Eye Research Australia Tunnel Vision 5. Treatment

TABLE 5.12: TRABECULECTOMY SIDE-EFFECTS Source Incidence of Cataract Following Trabeculectomy Timeframe Edmunds et al, Cataracts developed in 20.2% of eyes following surgery. *Cross-sectional 1999 survey Parc et al, 2001 Probability of cataract surgery at five years (after surgery) 5, 10 and was 15% and at ten years was 37%. No statistical 20 years difference between patients and the rest of the cohort at 20 years. Fontana et al, Cataract extraction occurred in 35% of eyes following 36 months 2006 trabeculectomy. AGIS The RR of cataract following first trabeculectomy was 10 years 1.78. When complications occurred in surgery the RR = 2.04 and when they did not occur RR = 1.47. Ehrnrooth et al, Cataract surgery was completed in 35% of eyes 3.5 years 2002 following trabeculectomy during the follow up period (mean 3.5 years). Ehrnrooth et al, Cataract surgery was completed in 34.8% of eyes. 3.5 years 2005 O’Brart et al, Cataract formation was similar between the 20 months 2004 trabeculectomy and viscocanalostomy groups.

*Edmunds et al, 1999 is a cross sectional survey of trabeculectomy patients in the National Health Service in the UK. No time frame was provided in this survey between trabeculectomy and cataract occurrence The majority of studies shown in Table 5.12 measure the incidence rate of cataract development or surgery following a first time trabeculectomy. These measures do not take into account the rate of cataract development or surgery in people of an identical demography. If an incident rate of between 20% and 35% from these studies were used the increased morbidity and health system cost would be over estimated. The AGIS study on the other hand measured the RR of cataract following trabeculectomy. People that undergo a first time trabeculectomy procedure have a 78% increased chance of developing a cataract (RR=1.78) according to AGIS. This increased risk is applied in the model to people that have undergone a trabeculectomy procedure, with the risk of cataract for a person that has not undergone this procedure assumed to be equal to the prevalence of cataract in the general population.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 53 5. Treatment

TABLE 5.13: PREVALENCE OF CATARACT (% OF POPULATION) Age Persons 40-44 0.0000 45-49 0.0000 50-54 0.0000 55-59 0.0844 60-64 0.0107 65-69 0.1620 70-74 0.7254 75-79 2.3713 80-84 5.4910 85-89 8.7109 90+ 15.1689

Source: MVIP & BMES special data request. The cost of cataracts per person is based on AIHW data, indexed to 2005 dollars.

TABLE 5.14: HEALTH SYSTEM COST OF CATARACT ($ PER PERSON), 2005 Age Males Females Persons 0-4 0 0 0 5-14 0 0 0 15-24 0 0 0 25-34 0 0 0 35-44 70 71 73 45-54 107 113 110 55-64 118 112 115 65-74 171 178 176 75-84 206 219 215 85+ 210 132 152 All Ages 178 177 178 Source: AIHW special request.

5.6.4: SUMMARY OF SIDE EFFECTS INCLUDED IN THE MODELLING In summary, two side effects have been included in the modelling for glaucoma. These are: • cataract, RR of 1.78 following trabeculectomy; and, • COPD, RR of 2.29 following use of a b-blocker topical eye medication. Health system costs for these side effects have been included into the per person treatment costs of medication and trabeculectomy. The model allocates these costs by increasing the base cost of treatment to incorporate the total expected health system costs of these side effects.

54 Centre for Eye Research Australia Tunnel Vision Main heading6. Disease5. Treatmentto go Costs here

The calculation of disease costs over time is discussed in this section, including: Glaucoma has • the impact of glaucoma on a patient’s quality of life (wellbeing); signiﬁcant social and • the health system costs of glaucoma; and economic costs. • the indirect costs of glaucoma (including the impact on employment, the need for informal and paid formal care, the impact on the paid employment of informal carers, aids and equipment, and the economic costs of welfare payments). However, ﬁrst, discount rates are discussed, as the model is dynamic and calculates the economic impact of glaucoma in net present value terms over time (2005 to 2025).

6.1: DISCOUNT RATES Choosing an appropriate discount rate for present valuations in cost analysis is a subject of some debate, and can vary depending on which future income or cost stream is being considered. There is a substantial body of literature, which often provides conflicting advice, on the appropriate mechanism by which costs should be discounted over time, properly taking into account risks, inflation, positive time preference and expected productivity gains. The absolute minimum option that one can adopt in discounting future income and costs is to set future values in current day dollar terms on the basis of a risk free assessment about the future (that is, assume the future flows are similar to the certain flows attaching to a long term Government bond). Wages should be assumed to grow in dollar terms according to best estimates for inflation and productivity growth. In selecting discount rates for this project, we have thus settled upon the following as the preferred approach. • Positive time preference: We use the long term nominal bond rate of 5.8% pa (from recent history) as the parameter for this aspect of the discount rate. (If there were no positive time preference, people would be indifferent between having something now or a long way off in the future, so this applies to all flows of goods and services.) • General Inflation: The Reserve Bank has a clear mandate to pursue a monetary policy that delivers 2 to 3% inflation over the course of the economic cycle. This is a realistic longer run goal and we therefore endorse the assumption of 2.5% pa for this variable. (It is important to allow for inflation in order to derive a real (rather than nominal) rate.) • Productivity growth: The Commonwealth Government’s Intergenerational report assumed productivity growth of 1.7% in the decade to 2010 and 1.75% thereafter. We suggest 1.75% for the purposes of this analysis. • Health Inflation: Health cost inflation from 2005 onwards is assumed to be 3.2%, based on estimates of increases in health expenditure from the AIHW estimates that health inflation in the eight years to 2004-05 has been around 3.2% per annum (AIHW 2006). This rate is partially general price inflation and partially productivity growth. To be on the conservative side, productivity growth in the health sector is assumed to be equal to general productivity growth.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 55 6. Disease Costs

There are then different discount rates that should be applied: • To discount income streams of future earnings, the discount rate is: 5.8 - 2.5 - 1.75 = 1.55% • To discount health costs, the discount rate is: 5.8 - (3.2 - 1.75) - 1.75 = 2.6% • To discount other future streams (healthy life) the discount rate is: 5.8 – 2.5 = 3.3% While there may be sensible debate about whether health services (or other costs with a high labour component in their costs) should also deduct productivity growth from their discount rate, we argue that these costs grow in real terms over time significantly as a result of other factors such as new technologies and improved quality, and we could reasonably expect this to continue in the future.

6.2: THE COST TO QUALITY OF LIFE AND WELLBEING

6.2.1: DISEASE WEIGHTS As noted above, the impact of treatment on a patient’s health and quality of life is of primary importance in modelling the economic impact of disease. In this study, each stage in the process of vision loss needs to be matched with a utility weight (a patient’s measure of his or her quality of life) reflecting the loss of quality of life experienced at that point in the progression of the disease. This is very difficult for POAG because: • changes in IOP do not easily translate into a health benefit for patients (Kobelt et al, 2006, Hyman et al, 2005, Jampel et al, 2002 and Mills et al, 2001); and • there is no agreed disease staging system based on vision loss (see Section 4.5). The various vision grading systems cannot be easily translated into a quantifiable impact on quality of life. There is a growing literature that attempts to measure the impact of glaucoma on quality of life, although the lack of a consistent disease staging system remains a problem in drawing conclusions from these studies. The literature suggests that during the early stages of disease, glaucoma has little impact, with quality of life deteriorating over time, particularly in the later stages of the disease. Some examples are as follows.20 1) Kobelt et al, (2006) undertook a cross sectional pilot study to test whether utilities for different levels of VF defect could be assessed using a general questionnaire such as the EQ 5D. Utility weights developed using time trade off underlie the EQ 5D. In Sweden, 199 patients with OHT or POAG were grouped according to six stages of vision loss based on VF defects in the worst eye. The disease stages were adapted from the HAP scale — from no defect (OHT) to end stage disease where VF measurement was difficult or no longer possible. The authors found that utility was strongly correlated with overall vision, and patients with severe glaucomatous damage have significantly lower utility. However, while utility decreased with increasing glaucomatous damage, the difference between the stages was not statistically significant when controlling for co-morbidity. When 17 outliers were removed, utility scores for patients with severe glaucomatous damage were significantly worse. Patients in stage 5 had a mean utility of 0.71 (a utility loss of 0.29), compared to

20 For an explanation of the linear rating scale, standard gamble, time trade-off, person trade-off and EQ-5D, see Mathers et al, (1999:10).

56 Centre for Eye Research Australia Tunnel Vision 6. Disease Costs

0.88 in stage 1 and a mean of 0.84 (a utility loss of 0.16) in stages 2.4. The sample size was Vision loss has a very small and the number of patients with moderate to severe bilateral vision loss was limited, however, the results were consistent with other studies (Kobelt et al, 2006). significant impact on the quality of life 2) Jampel et al, (2002) examined how 191 glaucoma patients’ and 46 glaucoma suspects’ rating of their vision correlated with Esterman binocular VF testing and other visual function that is highly valued. tests. They found that utility values that patients assign to their vision do not correlate well with Esterman results and suggested this was because, “there may not be a close relationship between visual function and patient perception of that function, especially when the vision loss is mild ... Perhaps early visual field loss really does not affect patient assessment of their vision and in fact is more of an all or none phenomenon with patients only noticing marked visual field loss.” (On the other hand, appropriate tests may not have been developed.) A linear rating scale and time trade off were used to gauge the preferences of patients with glaucoma for visual states. Based on the linear rating scale, glaucoma patients rated their vision as 0.72 and suspects rated their vision as 0.71 (on a 0 to 1 scale). Blind glaucoma patients (with a VA no better than counting fingers in the better eye and who had been blind for 10 years) rated their visual state as 0.54. Glaucoma patients and suspects assigned a value of 0.38 and 0.34 respectively to total blindness. Time trade off results were less informative as few were willing to give up time for improved vision. 3) A UK study (Brown et al, 2001) used a time trade off and a standard gamble to measure utility associated with blindness from 65 patients with various vision diseases including glaucoma, cataract, age related macular degeneration (AMD) and diabetic retinopathy. A utility value of 1.0 indicates a state of perfect health whereas a utility value of 0 indicates death. Participants were grouped according to various measures of blindness as follows: b) totally blind: 15 patients with no light perception in at least one eye and who were asked to assume a scenario of no light perception in the second eye as well; c) some light perception: 17 patients with light perception to counting fingers in the better seeing eye; d) just over the line for legal blindness: 33 patients with 20/200-20/400 vision in the better seeing eye. The time trade off results suggested utility values for each group of (a) 0.26 QALYs (95% CI 0.19 to 0.33); (b) 0.47 QALYs (95% CI 0.33 to 0.61); and (c) 0.65 QALYs (95% CI 0.58 to 0.72). Thus patients with no light perception in one eye who were presented with the same scenario in the second eye as well were willing to trade almost 3 out of every 4 years of remaining life in return for perfect vision in each eye. Those with light perception to counting fingers would trade approx 1 of 2 remaining years and those with 20/200-20/400 would trade approx 1 of 3 remaining years. The standard gamble utility results were substantially higher: (a) 0.32 (95% CI 0.2 to 0.44); (b) 0.60 (95% CI 0.46 to 0.74); and (c) 0.80 (95% CI 0.73 to 0.87). However, the authors suggested the standard gamble results overestimate risk aversion because participants have difficulty understanding this approach. Notably, in blind patients, utility improved over time suggesting adaptation to blindness (there were significant differences between those blind for less than one year and those blind for more than one year) and the worse the vision in the better eye, the lower the utility. Brown et al, (2001) concluded that:

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 57 6. Disease Costs

Many patients with There is a wide range of utility values associated with legal blindness … the preservation of even small amounts of vision in patients with legal blindness is critically important to their wellbeing OHT or the clinical and functioning in life. (Brown et al, 2001:327) signs of glaucoma do not experience vision AIHW WEIGHTS loss for several years. The choice of disease weights is very important. If the utility (QALY) weights associated with vision loss are too low or the disability weights (Disability Adjusted Life Years - DALYs) are too high, the results will overestimate the cost effectiveness of interventions (and vice versa). Previous models in this series (see the Background — Section 1 of this report) applied the disability weights used by the AIHW in their loss of well being study (Mathers et al, 1999, Table 6.1). These weights are drawn from a Dutch study that used a person trade off method to estimate weights for 53 diseases, including the estimation of weights for 175 disease stages, sequelae and severity levels (cited in Mathers et al, 1999:11). The Dutch weights are based on disease stages defined as follows (Mathers et al, 1999:159): • Mild disease: Some difficulty with newspaper, no difficulty recognising faces at 4m; • Moderate disease: Great difficulty newspaper, some difficulty recognising faces at 4m; and • Severe disease: Unable to read newspaper or recognise faces at 4m.

While it is difficult to relate these definitions to stages of VFL in the studies outlined above, and specifically to a disease such as glaucoma which initially affects mid-peripheral VF, the AIHW weights are not inconsistent with the previous literature review — noting that the AIHW weights reflect disability weights (DALYs) rather than utility weights (QALYs). • Many patients with OHT or the clinical signs of glaucoma do not experience vision loss for several years. Thus there is no loss of utility during early stage disease and the disability weight is 0.0. • The AIHW (Dutch) weight for moderate disease lies below the lowest weight for severe disease found in the literature review (0.17 compared with 0.26). However, if glaucoma really only affects quality of life in the latter stages of disease, then the disability weights for mild and moderate disease might be too high. • Legal blindness in Australia is defined as VA of <6/60 in the better eye with correction (spectacles) or a VF of less than 10 degrees or both (CERA 2004:11). Total blindness refers to people who are unable to see light. These are encompassed in the AIHW weight for severe disease which is 0.43 (compared with the range of estimates of 0.26 to more than 0.6 in the studies outlined above).

The AIHW disease weights will be used here. They are drawn from a study of a number of diseases and comparison with other diseases and interventions is important for budget/resource allocation decisions. In addition, it is also preferable to use weights from the same study so that the same methodology has been used and the set of weights is internally consistent. The AIHW weights are also consistent with the previous models developed by CERA and so allow for easy comparisons across these. Basic AIHW weights are only for the disease and do not take into account co-morbidities. Glaucoma is associated with both accidental falls and depression. Accidental falls and depression are discussed below in Sections 6.3.4 and 6.3.5. The disease weights are not additive — adding the weights for a person with severe glaucoma and severe depression results in a weight greater than 1 which is not intuitively possible.

58 Centre for Eye Research Australia Tunnel Vision 6. Disease Costs

Consequently, the following formulae are used:

WVI ,DEP =WVI + (1"WVI )!WDEP

WVI ,FALL =WVI + (1"WVI )!WFALL

WVI ,DEP ,FALL =WVI ,DEP + (1"WVI ,DEP )!WFALL

where W is the disability weight, VI denotes the severity of visual impairment (EDS, Mild,

Moderate or Severe), DEP denotes depression and FALL denotes a fall. The AIHW weighting for accidental falls is 0.141 and for depression is 0.223 based on 20% of glaucoma suffers experiencing mild depression with a weighting of 0.140 and 5% of glaucoma suffers experiencing moderate to severer depression with a weighting of 0.555 (see Section 6.3.5 for the evidence basis for comorbid depression) (see Mathers et al, 1999, for the derivation of the respective disability weights).

TABLE 6.1: AIHW DISABILITY WEIGHTINGS EDS Mild Moderate Severe Glaucoma only 0.000 0.020 0.170 0.430 Glaucoma and accidental falls 0.141 0.158 0.287 0.510 Glaucoma and depression 0.223 0.239 0.335 0.557 Glaucoma, accidental falls and depression 0.333 0.346 0.446 0.620

CERA WEIGHTS CERA weights are also available for use within the model. These are not correlated with severity of disease based on a finding from research during the development of the VisQoL, the tool to derive vision-related utilities. There was no significant difference between mild, moderate and severe vision loss. The CERA QALY weight for visual impairment of 0.83 (utility loss or DALY of 0.17) applies to all levels of visual impairment and is consistent with results from the VIP suggesting that, with cancer, blindness is the most feared health condition. No additional adjustment for falls and depression are made if CERA weights are used. It should be noted that using the same disability weight for all levels of severity of glaucoma reduces the benefits of slowing progression of glaucoma.

6.2.2: PLACING A DOLLAR VALUE ON THE LOSS OF WELLBEING Loss of wellbeing is estimated using DALYs and applying the lower bound VSL of $3.7 million to yield the estimated value of a life year of $162,561 (CERA, 2004).

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 59 6. Disease Costs

6.3: HEALTH SYSTEM COSTS The health system costs of glaucoma are categorised and discussed in this section as follows: • the cost of monitoring an individual with glaucoma (not including treatment costs); • the costs of treatment for POAG; • the increased likelihood of being admitted to an aged care facility and the associated costs; • the costs associated with an increased likelihood of falls and hip fractures; and • the costs associated with an increased likelihood of depression. Data on the health system costs of POAG are from a special request from the AIHW. The most recent data for expenditure by disease are for the financial year 2000-01 and have been factored up for health inflation. Based on estimates of increases in health expenditure from the AIHW, health inflation in the last eight years to 2004-05 has been around 3.2% per annum (AIHW 2006). Overall, individuals The AIHW include only 87.5% (AIHW 2005) of total recurrent health expenditure in their estimates of expenditure by disease and injury, referred to as ‘allocated’ health expenditure. still pay 19% of The ‘unallocated’ remainder includes capital expenditures, expenditure on community health costs. health (excluding mental health), public health programs (except cancer screening), health administration and health aids and appliances — the coding for these areas of expenditure does not allow allocation by disease category. To ensure comprehensiveness, these aspects of health system costs have been incorporated by multiplying the AIHW ‘allocated’ expenditure estimates by 1.143 (=1/0.875). Factoring up the allocated expenditure in this way means that care needs to be taken to avoid double counting. For example, many aids and appliance costs are provided by community programs (rather than government programs), and are not incorporated in the AIHW expenditure. The proportion of health costs borne by the government (68.2%) and the individual (19.0%) is based on AIHW (2006:30).

TABLE 6.2: HEALTH COSTS BY WHO BEARS THE COST, 2004-05 F federal State/Territory Private Health Individuals Other Total Government Government Insurance % 45.6% 22.6% 6.5% 19.0% 6.3% 100.0%

Source: AIHW (2006:30).

6.3.1: THE COST OF MONITORING AN INDIVIDUAL WITH GLAUCOMA The cost of monitoring an individual with glaucoma in 2005 — not including medical, laser and surgical treatments is $649 per person per year. This was calculated by adjusting the total health costs for glaucoma ($148.3m in 2000-01) in the following ways: • adjust for the change in the population between 2000-01 and 2005; • include unallocated health expenditure (factored up by 1.143); • index spending to $2005 (health inflation of 2.6% pa); and • remove expenditure on treatment (medication, laser and surgery) and aged care; • divide by the number of people receiving treatment in 2005.

60 Centre for Eye Research Australia Tunnel Vision 6. Disease Costs

6.3.2: COST OF TREATMENT Medication costs on average: $960.80 Medication per person per year. The cost estimates were derived using data from the Department of Health and Ageing web publication Australian Statistics on Medicines 2005, and Australian Medicare Benefits Schedule fees. The total cost of anti-glaucoma medications for 2005 is in Table 6.3, and is divided by the total number of people receiving medication in 2005 (ie. the number of people with diagnosed POAG in 2005 estimated in the dynamic model) to derive the cost of medication per person per annum.

TABLE 6.3: COST OF MEDICATION PER PERSON PER ANNUM Total Cost of Anti-glaucoma Medications $99,694,643 Total No. of People on Medication 103,820 Cost of Medication per Person $960

Source: Australian Statistics on Medicines 2005 and Access Economics Economic Model of the Impact of Primary Open Angle Glaucoma. The cost of the side effects of medications were added to the cost of medications per person. The OR of COPD following the use of a topical beta-blocker applied to the average risk of COPD in Table 5 10 is 2.29 and the cost of COPD per person is in Table 5.11. The total cost of medication with side effects included by age and gender is in Table 7.1.

Trabeculoplasty The cost of a trabeculoplasty is applied in the model once at the point when a patient transitions into the ‘laser’ treatment phase. To account for people that have more than one trabeculoplasty procedure, the cost calculated in Table 6.4 is inflated by 1.5 in the modelling calculations (see Section 5.2). The cost of this procedure is based on the treatment fee in the MBS for the treatment as well as the cost of the anaesthesia service (Table 6.5). Based on clinical advice for this report, the cost of an assistant has not been included.

TABLE 6.4: TOTAL COST OF TRABECULOPLASTY PER TREATMENT MBS Code Description Cost Trabeculoplasty costs 42782 Laser Trabeculoplasty – each treatment to 1 eye, to a maximum $398.65 on average $482.90. of 4 treatments to that eye in a 2 year period (Anaes.) (Assist.) 20140 Initiation of management of anaesthesia for procedures on eyes, $84.25 not being a service to which another item in this group applies (5 basic units) Total $482.90

Source: MBS Book, 1 November 2006

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 61 6. Disease Costs

Trabeculectomy Trabeculectomy surgery cost on As with trabeculoplasty, the cost of a trabeculectomy is applied in the model once, when the person moves into the ‘surgery’ treatment phase. To account for people that have a second average $3435. trabeculectomy procedure, the total cost of surgery in Table 6.6 is scaled up by 1.2 to $4,122.50. The cost of this procedure is based on the average diagnosis related group (DRG) cost for trabeculectomy, weighted for public and private hospitals, from the National Hospital Cost Data Collection. The code that relates to trabeculectomy procedures is DRG C15A Glaucoma and Complex Cataract Procedures. The total costs of private hospital trabeculectomy procedures are in Table 6.5.

TABLE 6.5: TOTAL COST OF TRABECULECTOMY PER TREATMENT Total Cost No. of Procedures Weighted Average Private Hospital $3,027 656 0.3993 Private Free Standing Hospital $3,027 404 0.2459 Public Hospital $4,178 583 0.3548 $3,435.42

Source: Personal Communication (Marc Foley, Ear and Eye Hospital); National Hospital Cost Data Collection Round 9 Public Hospital Costs and AIHW special data request

6.3.3: AGED CARE Visual impairment compounds the presence of other disabling conditions, leading to an increased likelihood of utilising institutionalised aged care. Using BMES data, Wang et al, (2003) found a RR of permanent nursing home admission — after adjusting for non-cognitive factors that predicted nursing home placement — for people with best corrected visual impairment (≤6/12) aged over 40 years, of 1.8 (95% CI 1.1–2.9). In this model for people with EDS the RR of being in an aged care facility is assumed to be unity, while for Mild, Moderate and Severe visual impairment the RR of being in an aged care facility is based on a linear adjustment, with moderate visual impairment as the mid point: • 1.4 for mild; • 1.8 for moderate; and • 2.2 for severe visual impairment. The RR is applied to the general population of being in an aged care facility, and the average cost per year of $52,800, from the Access Economics Aged Care Dynamic Cohort Model.

62 Centre for Eye Research Australia Tunnel Vision 6. Disease Costs

TABLE 6.6: PROBABILITY OF RESIDING Older people with IN AN AGED CARE FACILITY, 2004-05 vision impairment Age % of Population are at a higher 0-54 0.0002 risk of falls, 55-59 0.02 approximately 60-64 0.14 half of which result 65-69 0.29 in an injury. 70-74 0.60 75-79 1.40 80-84 3.40 85-89 8.51 90+ 25.40 Source: Access Economics Aged Care Dynamic Cohort Model

6.3.4: FALLS AND HIP FRACTURES It is well established that older people are at a higher risk of falls, approximately half of which result in an injury. Many studies have examined the factors underlying the increased propensity of falls in the elderly and several have found a significant link between falls and vision loss. Elderly individuals progressively rely on visual feedback to maintain balance with increasing age because proprioceptive feedback, musculoskeletal strength and often vestibular function decline with age (Ramrattan et al, 2001). The deterioration of visual function coupled with the loss of other sensory functions result in the higher risk of falls in elderly visually impaired people. The risk of a fall has been linked to many different measures of visual impairment. The majority of studies compare the risk of falls to VA or another measure of visual impairment with very few studies examining the links between glaucoma and falls. Of the small number of studies linking glaucoma and falls some used the consumption of non-miotic topical eye medications as a proxy for VFL, while only one study conducted a diagnostic test to determine the presence of glaucoma and the extent of VFL. A meta-analysis of the available literature that examined the relationship between visual impairment and the risk of an accidental fall was conducted (Table 6.10). Additional supportive articles were found during the literature searches, but could not be included due to a lack of quantitative information. These articles are listed and summarised in Appendix 1, Table 10.4. A random effects model has been applied to the data in Table 6.7 and Table 6.8, with studies that used VFL and glaucoma proxies or measures evaluated separately.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 63 6. Disease Costs

TABLE 6.7: INCREASED RISK OF FALLS FROM VISUAL IMPAIRMENT Source Impairment RR / OR 95% CI Arfken et al, 1994 Impaired VA RR = 0.91 0.45 to 1.83 Coleman et al, 2004 Loss of 0-5 letters OR = 2.08 1.39 to 3.12 Coleman et al, 2004 Loss of 6-10 letters OR = 1.85 1.16 to 2.95 Coleman et al, 2004 Loss of 11-15 letters OR = 2.51 1.39 to 4.52 Coleman et al, 2004 Loss of >15 letters OR = 2.08 1.01 to 4.30 Dolinis J et al, 1997 Medical history of glaucoma RR = 1.63 1.13 to 2.37 Glynn RJ et al, 1991 40% or greater VFL loss RR = 3.00 0.94 to 9.80 Glynn RJ et al, 1991 Miotic eye medication RR = 3.20 1.00 to 10.10 Glynn RJ et al, 1991 Non-miotic eye medication RR = 5.40 1.80 to 16.40 Haymes SA et al, 2007 Glaucoma OR = 3.71 1.14 to 12.05 Ivers RQ et al, 1998 Posterior subcapsular cataract PR = 2.10 1.00 to 4.30 Ivers RQ et al, 1998 Non-miotic eye medication PR = 2.00 1.10 to 3.60 Ivers RQ et al, 1998 Low VA PR = 1.90 1.20 to 3.00 Ivers RQ et al, 1998 Low contrast sensitivity PR = 1.20 1.10 to 1.30 Ivers RQ et al, 1998 Glaucoma PR = 1.50 1.00 to 2.30 Ramrattan et al, 2001 Unilateral VFL RR = 5.31 2.82 to 9.99 Ramrattan et al, 2001 Bilateral VFL RR = 6.32 2.46 to 16.24 Tinetti ME et al, 1988 Visually Impaired RR = 1.70 1.20 to 2.30 Vu et al, 2005 <6/12 better eye OR = 0.98 0.12 to 7.70 Vu et al, 2005 <6/12 worse eye OR = 2.86 1.16 to 7.08 Zwerling C et al, 1998 Visually impaired RR = 1.60 1.10 to 2.40

Highlighted studies provide VF and/or glaucoma related estimates. RR = Relative Risk, OR = Odds Ratio, PR = Prevalence Ratio

TABLE 6.8: META-ANALYSIS, FALLS (RANDOM EFFECTS MODEL) RR 95% CI Risk of Accidental Fall – Visual Impairment 2.05 1.54 to 2.71 Risk of Accidental Fall – VFL or Glaucoma 3.18 1.82 to 5.55 VFL = Visual Field Loss The RR of an accidental fall in people whose visual impairment was caused by VFL or glaucoma was higher than the overall visual impairment group. Although caution is advised with this group as the VFL/glaucoma showed a higher level of estimated publication bias than the visual impairment group. It maybe the case that the small number of published (and included) trials where VFL was included maybe pushing the RR higher than it should be. This can only be resolved with the completion and inclusion of more studies on VFL. The RRs of accidental falls are split by visual impairment severity by applying the RR in Table 6.10 to those with moderate stage disease, allocating a RR of 1.0 to the OHT group and applying a linear extrapolation to determine the RRs for the mild and severe group (Table 6.11).

64 Centre for Eye Research Australia Tunnel Vision 6. Disease Costs

TABLE 6.9: RELATIVE RISK OF AN ACCIDENTAL FALL BY SEVERITY The risk of having Visual Impairment VFL / Glaucoma an accidental fall for OHT 1.00 1.00 a person without Mild 1.52 2.09 glaucoma is assumed Moderate 2.05 3.18 Severe 2.57 4.27 to be equal to Source: Analysis by Access Economics. the prevalence of These results are consistent with Black and Wood (2005) who concluded that the OR of falls and accidental falls in the fractures from reduced vision lay between 1.5 and 2.0. general population. The risk of having an accidental fall for a person without glaucoma is assumed to be equal to the prevalence of accidental falls in the general population.

TABLE 6.10: RISK OF ACCIDENTAL FALL (% OF POPULATION), 2001 Age Males Females Persons 0-4 0.64 0.50 0.57 5-14 0.83 0.551 0.68 15-24 0.74 0.27 0.51 25-34 0.55 0.24 0.40 35-44 0.44 0.28 0.36 45-54 0.42 0.34 0.38 55-64 0.47 0.56 0.51 65-74 0.75 1.16 0.96 75-84 1.78 3.21 2.61 85+ 5.07 7.80 6.95 All Ages 0.68 0.70 0.69 Source: AIHW, special request. The cost of an accidental fall per person is based on AIHW 2000-01 data, indexed to 2005 dollars.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 65 6. Disease Costs

Depression occurs TABLE 6.11: HEALTH SYSTEM COST OF AN ACCIDENTAL FALL ($ PER PERSON), 2005 three times more Age Males Females Persons commonly in those 0-4 8,829 8,071 8,505 with vision loss. 5-14 7,718 12,166 9,363 15-24 8,307 7,967 8,218 25-34 7,324 8,394 7,655 35-44 7,522 9,905 8,455 45-54 8,861 12,613 10,561 55-64 11,291 11,011 11,140 65-74 13,660 14,224 14,012 75-84 14,659 11,464 12,375 85+ 15,246 12,381 13,025 All Ages 9,737 11,500 10,643 Source: AIHW, special request.

6.3.5: DEPRESSION Studies examining the loss of VA and links to the onset of depressive state have shown a higher RR of suffering depression in comparison to the general population. These do not necessarily relate to open angle glaucoma — studies for POAG are required. One study, however, reported that glaucoma does not share the same RR association as other visual impairments. Wilson et al, (2002) reported that there is no association between depression and VA level, VF severity or the use of topical b blockers in people with glaucoma. However this study was conducted on a small number of patients and relied on self reported surveys. Prevalence rates of depression in elderly visually impaired populations are estimated to range between 25% 45% (Burmedi et al, 2002). Within the general elderly population, less than 20% have mild dysphoria with less than 5% suffering from severe depression. Comparing risks from these studies, the RR of depression is likely to be in the order of 35%/10% = 3.5 times higher. Summary results from these studies linking vision impairment are presented in Table 6.12.

66 Centre for Eye Research Australia Tunnel Vision 6. Disease Costs

TABLE 6.12: DEPRESSION AND VISION LOSS Source Finding Brody et al, 2003 33% depressed Karisson, 1998 Less than 10% depressed Kleinschmidt, 1995 22% mildly; 4% moderately to severely depressed Rovner et al, 1997 39%-70% depression depending on measurement scale used Wahl, 1994 43% of blind, 29% of visually impaired depressed Robbins et al, 1988 Mean score of 10.3 (10+ indicates depression) Vu et al, 2005 OR 6.28 for health and emotional problems; OR 4.7 for ‘not full of life’ Wilson et al, 2002 No difference in depressive state Chen and He 2005 Measures for mild anxiety and moderate severe anxiety were all higher for both acute angle closure glaucoma and chronic angle closure glaucoma than the national norm.

For the model base case, people with glaucoma have an OR of depression which is approximately 3.5. The risk of having depression for a person without glaucoma is assumed to be equal to the prevalence of depression in the general population. The cost of depression per person is also based on AIHW 2000-01 data, indexed to 2005 dollars (Table 6.14).

TABLE 6.13: RISK OF DEPRESSION (% OF POPULATION), 2001 Age Males Females Persons 0-4 0.00 0.00 0.00 5-14 0.02 0.01 0.01 15-24 0.95 1.02 0.99 25-34 3.29 4.45 3.87 35-44 4.38 5.95 5.17 45-54 4.35 6.32 5.33 55-64 3.82 5.72 4.76 65-74 2.77 3.97 3.39 75-84 1.93 2.37 2.19 85+ 1.34 1.45 1.41 All Ages 2.53 3.52 3.03 Source: AIHW, special request.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 67 6. Disease Costs

Glaucoma TABLE 6.14: HEALTH SYSTEM COST OF DEPRESSION ($ PER PERSON), 2005 overwhelmingly Age Males Females Persons affects the elderly 0-4 0 0 0 - fewer people 5-14 18,544 75,852 36,831 with severe visual 15-24 2,793 5,659 4,250 impairment are likely 25-34 1,555 2,296 1,983 to be employed. 35-44 1,346 1,831 1,627 45-54 1,634 1,870 1,774 55-64 1,799 2,167 2,017 65-74 2,657 3,610 3,233 75-84 5,872 9,304 8,033 85+ 17,672 12,551 14,052 All Ages 1,915 2,632 2,334

Source: AIHW, special request.

6.4: INDIRECT COSTS The indirect costs of glaucoma can include a reduced likelihood of employment, the need for formal as well as informal personal care (and the associated impact on the employment of informal carers), aids and equipment, and the economic costs of welfare payments. Many of these indirect costs are related to the level of visual impairment rather than glaucoma per se, and are therefore similar to the indirect costs associated with other eye diseases such as AMD.

EMPLOYMENT Glaucoma overwhelmingly affects the elderly so very few people with severe visual impairment are likely to be employed. For the purposes of modelling, people with EDS are assumed to have an OR of being employed of unity, while for Mild, Moderate and Severe visual impairment the OR of being employed is based on a linear adjustment of the OR contained in CERA (2004:66), with moderate visual impairment as the mid point: • 0.75 for mild; • 0.5 for moderate; and • 0.25 for severe visual impairment. The RRs are applied to the general employment rates by age from ABS (2005) and the Average Weekly Earnings (AWE) rates from ABS (2004), indexed to 2005 dollars.

OTHER INDIRECT COSTS Other indirect costs per person (such as the impact on employment of informal carers, formal care costs, aids and modifications, and other indirect costs) were extracted from the MVIP database for those people with VA loss (indirect costs for people without visual impairment are assumed to be nil). Due to high SDs in the data, the mean indirect costs across all levels of visual impairment were used, instead of indirect costs by mild, moderate and severe visual impairment.

68 Centre for Eye Research Australia Tunnel Vision 6. Disease Costs

“Informal care and support” is split between costs and lost productivity of the carer based on Indirect costs of the ratio contained in CERA (2004:75). The proportion of “Medicines, products and equipment” that are aids and modifications is based on the split used in CERA (2004:70-72). Carer vision loss are often productivity costs were indexed to 2005 according to AWE over time, while the remaining overlooked. indirect costs were indexed to health inflation.

TABLE 6.15: INDIRECT COSTS ($ PER ANNUM), 2005 Cost Formal Care 439 Lost Productivity of Carer 1,544 Aids and Modifications 337 Other Expenses 630

Sources: MVIP, CERA (2004).

6.5: DEADWEIGHT LOSSES The following parameters were used to estimate lost taxes and additional welfare payments from glaucoma, which in turn underlie the estimation of deadweight losses to the economy. • Average personal income tax rate of 21.20% and average indirect tax rate of 15.51%, based on Access Economics Macroeconomic model (AEM). • The level of disability support per annum of $10,340.20 ($397.70 x 26 – from www. centrelink.gov.au in 2005), is indexed to the AWE and is received by all individuals with VA worse than 6/60 who are aged 15 to 65 (after this age it is likely they would receive the aged pension regardless of their VA)21 . • The rate of deadweight loss is 0.275 per $1 of tax revenue raised, based on Productivity Commission (2003), plus 0.0125 per $1 of tax revenue raised for Australian Taxation Office (ATO) administration, and is applied to health system costs incurred by the government, lost taxes and welfare payments.

21 If a person on the disability pension is employed, then (depending on the level of income and hours of employment) the amount received may be adjusted slightly downwards. However, given glaucoma mainly affects older people, and those that receive the pension are permanently blind, the number of people employed would be low and any slight adjustments downwards would make negligible impact on the results (especially since we only include the deadweight loss of the government expenditure rather than the expenditure itself).

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 69 7. Summary of Model Parameters

This section summarises the parameters used in the model. • Modelled prevalence rates are in Table 7.1. • Initial severity of visual impairment splits are in Table 7.2. • Modelled treatment assumptions are in Table 7.3. • The costs of treatment including the expected health system costs of side-effects and adverse events are in Table 7.4. There is also a cost of monitoring those who are diagnosed with POAG at $649 per patient per year. • The Sections explaining the other parameters used within the model are listed in Table 7.5.

TABLE 7.1: PREVALENCE OF OHT AND POAG OHT POAG Age Males Females Males Females 0-4 0% 0% 0.0% 0.0% 5-9 0% 0% 0.0% 0.0% 10-14 0% 0% 0.0% 0.0% 15-19 0% 0% 0.0% 0.0% 20-24 0% 0% 0.0% 0.0% 25-29 0% 0% 0.0% 0.0% 30-34 0.00% 0.00% 0.00% 0.0% 35-39 0.02% 0.02% 0.00% 0.00% 40-44 0.08% 0.08% 0.07% 0.07% 45-49 0.15% 0.15% 0.14% 0.14% 50-54 0.23% 0.23% 0.60% 0.60% 55-59 0.30% 0.30% 0.94% 0.94% 60-64 0.35% 0.35% 2.29% 2.29% 65-69 0.39% 0.39% 3.46% 3.46% 70-74 0.44% 0.44% 5.51% 5.51% 75-79 0.49% 0.49% 5.78% 5.78% 80-84 0.49% 0.49% 6.74% 6.74% 85-89 0.49% 0.49% 9.66% 9.66% 90+ 0.49% 0.49% 20.66% 20.66% Source: BMES and MVIP data

70 Centre for Eye Research Australia Tunnel Vision 7. SummaryMain of heading Model Parameters to go here

TABLE 7.2: SEVERITY OF VISUAL IMPAIRMENT — INITIAL PROPORTIONAL SPLIT Age EDS Mild Moderate Severe 0-4 0% 0% 0% 0% 5-9 0% 0% 0% 0% 10-14 0% 0% 0% 0% 15-19 0% 0% 0% 0% 20-24 0% 0% 0% 0% 25-29 0% 0% 0% 0% 30-34 0% 0% 0% 0% 35-39 0% 0% 0% 0% 40-44 100.0% 0.0% 0.0% 0.0% 45-49 100.0% 0.0% 0.0% 0.0% 50-54 100.0% 0.0% 0.0% 0.0% 55-59 100.0% 0.0% 0.0% 0.0% 60-64 95.1% 0.2% 1.7% 2.9% 65-69 94.3% 0.4% 2.8% 2.6% 70-74 92.5% 0.5% 3.7% 3.3% 75-79 88.6% 1.2% 8.4% 1.8% 80-84 84.4% 1.7% 11.5% 2.5% 85-89 78.0% 2.2% 15.1% 4.8% 90+ 70.6% 1.1% 7.7% 20.6% Source: BMES and MVIP data

TABLE 7.3: MODELLED TREATMENT ASSUMPTIONS Treatment efﬁcacy Compliance Treatment Incidence (reduction in and failure rates progression of visual impairment) Medication 50% Inherent in the data See Table 5.5 and calculation (total costs of medications for POAG in 2005 divided by prevalence of diagnosed POAG) Trabeculoplasty 50% 100% 50% of patients fail each year Trabeculectomy 50%# 100% 50% of patients fail each year #Based on equivalence between medication and trabeculectomy demonstrated in CIGTS.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 71 7. Summary of Model Parameters

TABLE 7.4: MODELLED TREATMENT COSTS $ 2005 (INCLUDING SIDE-EFFECTS AND ADVERSE EVENTS) Medication (a) Trabeculoplasty (b) Trabeculectomy (c) Male Female Male Female 40-44 964.58 967.45 724.35 4122.50 4122.50 45-49 972.82 973.42 724.35 4122.50 4122.50 50-54 972.82 973.42 724.35 4122.50 4122.50 55-59 1023.46 1009.71 724.35 4122.58 4122.58 60-64 1023.46 1009.71 724.35 4122.51 4122.51 65-69 1152.08 1086.79 724.35 4122.72 4122.73 70-74 1152.08 1086.79 724.35 4123.47 4123.51 75-79 1309.53 1131.53 724.35 4126.31 4126.55 80-84 1309.53 1131.53 724.35 4131.33 4131.88 85-89 1375.39 1143.02 724.35 4136.77 4131.47 90+ 1375.39 1143.02 724.35 4147.35 4138.12

Calculation of these estimates is explained in Section 6.3.2. a) Cost of anti-glaucoma medications plus the costs of the risk of COPD. b) Cost of trabeculoplasty adjusted upwards by 1.5 to account for people who have a second laser treatment. c) Trabeculectomy adjusted upwards by 1.2 to account for people who have a second trabeculectomy and also adjusted upwards in the older age groups to account for the increasing risk of cataract surgery as a side effect.

TABLE 7.5: OTHER MODELLED VARIABLES Item Reference Disability weights Table 6.1, page 59 Health System Costs Page 60 Aged Care Table 6.6, page 63 Accidental Falls Table 6.9, Table 6.10 and Table 6.11, pages 65 to 66 Depression Table 6.13 and Table 6.14, pages 67 to 68 Employment Page 66 Other Indirect Costs Table 6.15, page 69 Deadweight losses Page 69

Other indirect costs include formal care, lost productivity of carers, aids and modiﬁcations and other expenses.

72 Centre for Eye Research Australia Tunnel Vision 8. The Model

The model was built in Microsoft Ofﬁce Excel 2003 which ensures portability. The model can be navigated by clicking on the relevant button on the Main Menu (see Figure 8.1) or by clicking on the sheet tabs at the bottom of the window. In order to access and view the sheets with the parameters and the model’s workings, click the Show/Hide Parameter Sheets button. Prevalence rates are assumed to be the number of people with the disease at the start of the year. During the year people are treated, progress, or die, with the impacts of these pathways on prevalence rates occurring at the start of the following year (see Figure 8.3 for a diagram of the model’s logical structure). To select scenarios, click on the User Options sheet button (see Figure 8.2). To view output, click the Cost-effectiveness Analysis, PopChart, CostChart or CE-PlaneChart buttons.

FIGURE 8.1: MAIN MENU

Cost effectiveness analysis can be conducted comparing various scenarios with the base case. To set the base case, tick the “No new intervention (Standard treatment)” box on the Options sheet. Three treatment phases are modelled, consistent with the current treatment regimen: medication, laser (trabeculoplasty) and surgery (trabeculectomy). The order in which these treatments is applied can be switched in the “Select intervention” and “Select intervention detail” windows on the options sheet.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 73 8. The Model

Economic impact of primary open angle glaucoma Commercial-in-Confidence Cost effectiveness FIGURE 8.2: OPTIONS SHEET FIGURE 8-2: OPTIONS SHEET analysis can be conducted by running various scenarios of current treatment and comparing with the base case.

72 74 Centre for Eye Research Australia Tunnel Vision 8. The Model

The model incorporates data on CEA costs Disease Burden of Indirect costs Productivity & Health system the costs of OAG and known risk factors, the prevalence costs reatment Rates of T

progression and incidence and and remission associated mortality, progression rates and the response to (No VI) Mild VI (No VI) Severe VI Moderate VI OHT treatment. Early Disease Stage reated Prevalence by severity T (laser) (surgery) ficacy Medication rabeculoplasty rabeculectomy Ef T T reatment options and T (Section 3.7) it has not been is mixed this relationship for since the evidence however Rates of Mortality progression and remission (No VI) Mild VI (No VI) Severe VI Moderate VI OHT Early Disease Stage Untreated Prevalence by severity (OHT) Age Ethnicity Diabetes Genetics Incidence Thickness IOP Family History Central Corneal Cup-to-Disc Ratio reatable T Untreatable Risk factors Research open-angle glaucoma, primary for factor risk as a treatable Diabetes has been represented charts Inputs: tables & Outputs: Summary modifiable parameters IGURE 8.3: MODEL DESIGN

included in the modelling at this stage. F Note:

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 75 9. Intervention Scenarios

The model has been adapted so that users can test the economic impact of changes to current treatment patterns. The scenarios are as follows: • the base case (No new intervention (standard treatment)); • an increase in the rate at which POAG is diagnosed (to 70%, 80% or 90%); • a change in the treatment protocol (using laser trabeculoplasty as the primary treatment instead of medication, with medication becoming the second treatment phase and surgery the third phase); • research to delay progression (by 50% or 75%); and • combination scenarios — an increase in the rate at which POAG is diagnosed from 50% to 80% together with: - A change in the treatment protocol; or - The introduction of a new treatment to delay progression by a further 50%.

9.1: THE BASE CASE The base case scenario can be set to either the current situation (no new intervention/standard treatment) or an other intervention which can be chosen using the “Select intervention” and “Select intervention detail” from the “Options” sheet.

9.1.1: TO RUN A BASE CASE … To select the current situation (No new intervention (Standard treatment)) as the base case for comparison: • tick the “No new intervention (Standard treatment)” box on the “Options” sheet (note: it will take a little while to reset all the parameters to reflect the current situation). • Select frequency every year. • click the “Set as Base Case” button. In brief, the base case parameters are: a POAG diagnosis rate of 50%, treatment regimen of medication first, followed by laser and then finally by surgery, and an impact of treatment (treatment efficacy) of a 50% reduction in the progression of visual impairment. The previous chapters explain the base case in more detail. If you wish to chose another scenario as the base case (for example, increased diagnosis rates), you must first un-tick the “No new intervention (Standard treatment)” box. Then choose an intervention from the “Select Intervention” box and the “Select Intervention Detail” box. Then click the “Set as Base Case” button.

9.1.2: RESULTS If current standard treatments continue for the next 20 years, and no new intervention scenarios are applied: • the prevalence of OHT in Australia will increase from 26,000 people in 2005, to 41,000 people in 2025; • the prevalence of POAG in Australia will increase over the same period from 208,000 people to 379,000; and

76 Centre for Eye Research Australia Tunnel Vision 9.Main Intervention heading to Scenarios go here

• the prevalence of visual impairment from POAG in Australia is expected to grow from The total cost of 24,000 people in 2005 to 52,000 people in 2025 (Table 9.1). glaucoma will The prevalence estimates here vary somewhat from those in Clear Insight, (CERA 2004) that used age and gender speciﬁc prevalence rates from the MVIP and BMES, with visual impairment increase in 2005 to based on loss of VA. This analysis also uses data from the combined MVIP/BMES data set, $1.92 billion, and but for persons rather than by gender, and measuring visual impairment measured using a $4.3 billion in 2025. combination of VA and VF. Figure 9.1 shows a steady increase in the prevalence of POAG from 2005 and 2025, driven by an ageing population.

TABLE 9.1: PREVALENCE OF OHT AND POAG, BASE CASE (NUMBER OF PEOPLE) 2005 2025 OHT 25,986 40,004 POAG Early stage 183,530 326,659 Mild stage 1,872 3,667 Moderate stage 12,914 26,047 Severe stage 9,312 22,613 POAG (all stages) 207,628 378,985 Visual Impairment from POAG 24,098 52,327 Prevalence (Total OHT & POAG) 233,614 419,989

Source: Access Economics/CERA dynamic model

FIGURE 9.1: PREVALENCE OHT AND POAG, BASE CASE Prevalence (diagnosed and undiagnosed)

The health system costs of glaucoma in 2005 were $355 million and the total annual cost of glaucoma in 2005 was $1.9 billion. In real dollar terms, these costs are expected to increase to $784 million and $4.3 billion respectively by 2025 (Table 9.2). The net present value of DALYs and other costs of POAG are depicted in Table 9.3.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 77 9. Intervention Scenarios

Over half the costs TABLE 9.2: COSTS OF POAG, 2005 AND 2025, BASE CASE of glaucoma relate to 2005 2025 loss of well being. DALYs 6,940 15,592 YLD 6,678 15,184 YLL 262 408 Burden of Disease Costs ($) 1,043,713,812 2,325,613,694 Health System Costs ($) 355,121,086 783,978,738 Comorbid Health Costs ($) 166,419,635 423,192,582 Treatment Costs ($) 188,701,450 360,786,156 Productivity Costs ($) 60,406,596 130,614,278 Other Indirect Costs ($) 109,422,685 240,987,552 Total Costs ($) 1,923,785,265 4,265,173,000

TABLE 9.3: BASE CASE (STANDARD TREATMENT) NET PRESENT VALUE OF DALYS AND COSTS Net present value 2005 to 2025 DALYs 155,150 Burden of Disease Costs ($ million) 23,896 Health System Costs ($ million) 8,759 Comorbid Health Costs ($million) 4,505 Treatment Costs ($million) 4,254 Productivity Costs ($ million) 1,665 Other Indirect Costs ($million) 2,695 Total Costs ($million) 37,015

The value of the burden of disease due to POAG over time is depicted in Figure 9.2.

FIGURE 9.2: VALUE OF BURDEN OF DISEASE DUE TO POAG ($M), BASE CASE

2,500 Burden of Disease Costs Millions 2,000

1,500

1,000

500

0 2005 2010 2015 2020 2025 Sensitivity analysis — zero prevalence and incidence of OHT among those aged 80 and over

78 Centre for Eye Research Australia Tunnel Vision 9. Intervention Scenarios

9.1.3: SENSITIVITY ANALYSIS — ZERO PREVALENCE AND INCIDENCE OF OHT AMONG THOSE AGED 80 AND OVER As noted earlier, prevalence data were smoothed in part because of the small sample sizes in the original data set. Unsmoothed original data showed zero prevalence rates for OHT among those aged 80 years or over. The impact of using smoothed rather than original data is presented in Table 9.4 and Table 9.5. The total costs of POAG are slightly lower (Table 9.5).

TABLE 9.4: COMPARISON OF PREVALENCE OF OHT AND POAG WITH ORIGINAL AND SMOOTHED DATA Original OHT prevalence Smoothed OHT data (Zero OHT prevalence prevalence data and incidence for those aged 80 years or over) 2005 2025 2005 2025 Prevalence OHT and POAG 227,827 406,840 233,614 419,989 Prev OHT 23,684 36,340 25,986 41,004 Prev early stage POAG 180,149 318,477 183,530 326,659 Prev Mild POAG 1,826 3,550 1,872 3,667 Prev Moderate POAG 12,871 25,918 12,914 26,047 Prev Severe POAG 9,297 22,555 9,312 22,613

TABLE 9.5: NET PRESENT VALUE OF DALYS AND COSTS, SENSITIVITY ANALYSIS ON OHT PREVALENCE AND INCIDENCE FOR THOSE AGED 80+ YEARS Net present value Net present value 2005 to 2025 2005 to 2025 Zero OHT prevalence and Smoothed data incidence for those aged 80 years or over DALYs 154,656 155,150 Burden of Disease Costs ($ million) 23,836 23,896 Health System Costs ($ million) 8,636 8,759 Comorbid Health Costs ($million) 4,474 4,505 Treatment Costs ($million) 4,162 4,254 Productivity Costs ($ million) 1,660 1,665 Other Indirect Costs ($million) 2,666 2,695 Total Costs ($million) 36,798 37,015

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 79 9. Intervention Scenarios

At present, 9.2: IMPROVED DIAGNOSIS RATE 50% of people More than 50% of those in developed countries with glaucoma are unaware they have the with POAG are disease (Quigley, 1996). In a population based study (the MVIP), Wensor et al, (1998) found that 50% of those with definite POAG had not been diagnosed previously, and Wong et al, undiagnosed. (2004) examined the presence of undiagnosed OAG in people who had visited an eye care provider in the previous year using Visual Impairment Project data from Melbourne and rural communities in Victoria. They found that 81% of possible cases, 72% of probable cases and 59% of definite cases of OAG were previously undiagnosed. Of the 115 participants with probable or definite OAG, 72 (63%) were previously undiagnosed. Of these undiagnosed probable and definite cases, 35 (49%) had visited an eye care provider within the previous 12 month period. The 35 undiagnosed patients were compared with 43 diagnosed patients who had visited an optometrist or ophthalmologist or both in the previous 12 months. The type of eye professional seen, and the presence of VF defects were the only statistically significant variables between the diagnosed and undiagnosed glaucoma groups. Diagnosis rates for POAG could be improved by: 1) at the current diagnosis threshold, enhancing the quality of care by ensuring ophthalmologists include the appropriate VF tests when examining patients’ eyes; 2) careful examination of the optic disc in all patients regardless of IOP; and 3) improving the focus on family history since people with a family history of glaucoma have a higher chance of developing POAG. Under the base case scenario, 50% of people with POAG are diagnosed and treated. Under this scenario, the impact of increasing the proportion of people diagnosed with POAG to (i) 70%, (ii) 80% and (iii) 90% can be assessed. No costs have been added to the model to allow for education of clinicians. Under this scenario the only parameter that is varied is the rate at which people are diagnosed. The costs and benefits that result from this analysis reflect more people receiving treatment to slow progression of POAG.

9.2.1: TO RUN THIS INTERVENTION THROUGH THE MODEL … • Tick the “No new Intervention (Standard treatment)” box and click on the “Set as Base Case” button to ensure the current situation is the comparator. • Un-tick the “No new Intervention (Standard treatment)” box and make sure that the “Frequency – Every Year” box is ticked. • On the Options sheet, choose “Improved Diagnosis Rate” in the Select Intervention box and “Diagnosis Rate 70%”, or “Diagnosis Rate 80%”, or “Diagnosis Rate 90%” in the Select Intervention Detail box. • Then click the “Set as Scenario 1” button, to run the new scenario. • A second scenario can be evaluated by reselecting from the “Select Intervention” and “Select Intervention Detail” windows. Then click the “Set as Scenario 2” button, to run the new scenario. • Click Compare Scenarios (CEA).

80 Centre for Eye Research Australia Tunnel Vision 9. Intervention Scenarios

9.2.2: RESULTS In the base case, 50% of people with POAG are diagnosed. The results of increasing the rate of diagnosis are presented in Table 9 6. The estimates in the table reflect the net present value of costs and benefits over the entire period (2005 to 2025). In comparison with the base case, the increased diagnosis rate reduces the total number of DALYs (Table 9 6) as more people receive beneficial treatment, however, this means that treatment costs rise. Productivity costs and comorbid health costs are less than for the base case because a greater proportion of people receive treatment which slow disease progression — allowing them to spend more time in employment, and to avoid comorbid conditions such as depression, falls and fractures associated with the later stages of glaucoma.

TABLE 9.6: MODEL RESULTS – INCREASED DIAGNOSIS RATE, NET PRESENT VALUE 2005 TO 2025 Net Present Values, Base Case 2005 to 2025 (Standard Diagnosis rate Diagnosis rate Diagnosis rate treatment) 70% 80% 90% DALYs 155,150 146,141 142,248 138,702 Burden of Disease Costs ($m) 23,896 22,249 21,529 20,866 Health System Costs ($m) 8,759 10,091 10,747 11,400 Comorbid Health Costs ($m) 4,505 4,403 4,354 4,307 Treatment Costs ($m) 4,254 5,687 6,393 7,093 Productivity Costs ($m) 1,665 1,514 1,443 1,373 Other Indirect Costs ($m) 2,695 2,894 2,993 3,092 Total Costs ($m) 37,015 36,748 36,711 36,731 CE ratio: Return on $1 spent(a) $1.19 $1.14 $1.10 $/DALY avoided(b) $153,144 $159,908 $166,948

(a) CE ratio is the change in total disease costs divided by the change in treatment costs. (b) $/DALY avoided is the change in health system, productivity and other indirect costs divided by the difference in DALYs. Figure 9.3 shows the outcome of a diagnosis rate of 70% and 90%. In the base case, DALYs rise to 15,600 in 2025 (Table 9.2). With improved diagnosis, the burden of disease is lower in 2025 than in the base case — 14,300 DALYs (70% diagnosed) and 13,200 DALYs (90%) diagnosed in 2025 (Figure 9.3). However, with higher diagnosis rates, treatment costs are also higher than in the base case (Figure 9.4).

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 81 9. Intervention Scenarios

Economic impact of primary open angle glaucoma Commercial-in-Confidence Economic impact of primary open angle glaucoma Commercial-in-Confidence diagnosed in 2025 (Figure 9-3). However, with higher diagnosis rates, treatment costs are also higher than in the base case (Figure 9-4). diagnosed in 2025 (Figure 9-3). However, with higher diagnosis rates, treatment costs are also higher than in the base case (Figure 9-4). FIGURE 9-3: IMPACT OF INCREASED DIAGNOSIS RATES ON DALYS(A)

FIGURE 9-3: IMPACT OF INCREASED DIAGNOSIS RATES ON DALYS(A) Increasing the FIGURE 9.3: IMPACT OF INCREASEDD DIAGNOSISALYs RATES ON DALYS(A) DALYs diagnosis rate to 18,000 Base Case (Standard treatment) Diagnosis rate 70% 16,000 Diagnosis rate 90% 80% would cost 18,000 Base Case (Standard treatment) Diagnosis rate 70% 14,000 $160,000/DALY. 16,000 Diagnosis rate 90% 1142,0,00000

1120,0,00000

108,0,000

86,0,00000

64,0,00000

42,0,00000

2,0000 2005 2010 2015 2020 2025 0 2005 2010 2015 2020 2025

FIGURE 9.4:FIG IMPACTSURE 9-4: OIFM INCREASEDPACTS OF IN DIAGNOSISCREASED D RATESIAGNO SONIS R TREATMENTATES ON TR COSTSEATMENT COSTS

FIGURE 9-4: IMPACTTSrOeaFtmINeCnRtECAoSsEtsD DIAGNOSIS RATES ON TREATMENT COSTS

700,000,000 TreatmentBCasoe Csatsse (Standard treatment) Diagnosis rate 70% Diagnosis rate 90% 760000,0,00000,0,00000 Base Case (Standard treatment) Diagnosis rate 70% Diagnosis rate 90% 650000,0,00000,0,00000

540000,0,00000,0,00000

430000,0,00000,0,00000

320000,0,00000,0,00000

210000,0,00000,0,00000

100,000,000 0 2005 2010 2015 2020 2025 0 The relative2005 cost effectiveness2 of010 each scenario is depicted2015 in Figure 9.5. The2020 base case is 2025 The relative cost effectiveness of each scenario is depicted in Figure 9-5. The base case is reprrepresentedesented ata tthethe origin.origi n. EffectivenessEffectiven ises measureds is meas asure thed totalas t henumbertotal ofnu DALYsmber avoidedof DAL Ysandav oided Tandhcostse rcelat osaretsiv totalearecos tcostsottalefc f(excludingecosttivse(exnesc lusthedinof valuegeactheh ofvs athecluene burdenariofotheis ofdepicbur disease).detnedofi ndis Feasiguree).9-5. The base case is represented at the origin. Effectiveness is measured as the total number of DALYs avoided and• c AtosAt zerotszeroare additionaladtotdital iocos nalcoststsc(exos (ie.tcs luno(ie.din additionalngotheadditva ilucostsonealof coftoshe educatingtsburofdeeducn cliniciansofatdisingeasclin ine).ic orderians toin ordimproveer to improve diagnosisdiagnos rates),is rat eimproveds), impr ovdiagnosised diag ratesnosis fromrates 50%fro tom 70%,50% 80%to 7 and0%, 90%,80% arean dcost90%, are cost effectiveAteffezerocti veatad betweenatditiobetnalwec $153,000osents$1(ie.53,n 0ando00a ddita$167,000ndion$1al67c ,peros00t0 sDALYpofereduc Davoided.ALatYinavg colinidicedia.ns in order to improve diagnosis rates), improved diagnosis rates from 50% to 70%, 80% and 90%, are cost • Ifeffe Ieducatingf educctiveatin atcliniciansg bcetlinweicia ewerensn $w1 costly,er53,e 0c00os thesetlyan, dt hesscenarios$1e67s,c0e0 wouldnar0 pioers becomeDwAoLuldY avbec lessooi dcostmeed .leffective.ess cost effective. If educating clinicians were costly, these scenarios would become less cost effective.

80 82 Centre for Eye Research Australia Tunnel Vision 9. Intervention Scenarios

Commercial-in-Confidence Economic impact of primary open angle glaucoma

FIGURE F9.5:IGU RCOSTE 9-5 E:FFCECTIVENESSOST EFFECT PLANEIVENES –S INCREASEPLANE – IDIAGNOSISNCREASE D IRATE(A)AGNOSIS RATE(A) 3,000,000,000

2,500,000,000 Diagnosis rate 90%

2,000,000,000 s t s 1,500,000,000 Diagnosis rate 70% o C

1,000,000,000

500,000,000

0 0 2,000 4,000 6,000 8,000 10,000 12,000 14,000 16,000 18,000 Effectiveness

(a) E(a)ffe Effectivenessctiveness m measuredeasured asas DALYsDALY avoided.s avoid eCostsd. C reflectosts r ehealthflect system,health sproductivityystem, pro andduc othertivity aindirectnd oth costs.er in d irect costs. (Cos(Costt effe effectivenessctiveness is ism measuredeasured asa stheth coste co perst pDALYer D Aavoided.LY av o Theide dvalue. T hofe theval uburdene of t hofe diseaseburde nis oexcludedf disea sfrome is excluded fromthethe costcos estimatet estima tine thein t hnumeratore numera sincetor s ithisnce ist hrepresentedis is repre sbyen DALYsted by avoidedDALY sina thevoi ddenominator).ed in the denominator).

9.39.3: CHANGECHAN ING THEE IN TREATMENTTHE TRE APROTOCOLTMENT P (PRIMARYROTOC OLASER)L (PRIMARY As notedL above,ASE inR brief,) the base case parameters are: a POAG diagnosis rate of 50%, treatment regimen of medication first, followed by laser and then finally by surgery, failure As noted above, in brief, the base case parameters are: a POAG diagnosis rate of 50%, treatratesment forr egimedicationmen of ofm edic4.3%at ofio npatientsfirst, f ollpero annum,wed by 50%laser foran laserd t htrabeculoplastyen finally by andsurg 50%ery, failure ratesforf ortrabeculectomy,medication of and4.3 an% overallof pat ieimpactnts per of atreatmentnnum, 50% on visionfor las (treatmenter trabecu efficacy)loplasty ofand a 50% for trabec50%ul ecreductiontomy, a innd thean progressionoverall im ofpac visualt of impairment.treatment o Undern visi onthis(t scenarioreatme nt— ef“Changeficacy) inof thea 50% reductreatmenttion in tprotocol”he prog res— slaserion replacesof visual topicalimpa medicationirment. U asnde firstr t hisline stherapycenari ofrom— 2005“Chan onwardsge in t he treatsom thatent patientsprotoco l”begin— treatmentlaser replac withes a lasertopic trabeculoplasty,al medication thenas followfirst lin withe t medicationherapy fro andm 2005 onwfinallyards trabeculectomy.so that patient s begin treatment with a laser trabeculoplasty, then follow with medicTreatmentation an cost-savingsd finally trab areec upossiblelectom yfrom. this scenario, as medication is no longer required in combination with laser treatment. Under the base case, on the other hand, where laser is Treatment cost-savings are possible from this scenario, as medication is no longer required in comsecondbination linew therapy,ith laser it tisreat combinedment. withUnd medication.er the base case, on the other hand, where laser is seconThed GLTline (whichthera pycompared, it is com twob in180ed degreewith m ALTedic treatmentsation. with timolol) showed that ALT was at least as efficacious as medication as an initial treatment for glaucoma (Glaucoma Laser Trial Research TheGroup,GLT (1995).which However,compare ALTd t wwaso 18 not0 commonlydegree AL adoptedT treat mase ant primarys with treatmenttimolol) s hobecausewed tofhat concernALT w as at leasaboutt as sideef effectsficaci ousand theas reducedmedicat efficacyion as ofa nrepeatinitial ALTtre treatments.atment for In gaddition,laucom ata the(Gla timeuco ofm atheL aser TrialGLT,R esprostaglandinsearch Grou werep, 1 not99 5)in. useH aso wtopicalever, medicationsALT was fornot glaucomacommonly (as McIlraithadopted et al,as (2006)a pri mary treatment because of concern about side effects and the reduced efficacy of repeat ALT noted). Evidence for the effectiveness of laser treatments as a primary therapy include: treatments. In addition, at the time of the GLT, prostaglandins were not in use as topical medic• at Theions EMGT,for gla a randomiseducoma (as clinicalMcIlrait trialh et comparingal, (2006) ALTnot anded). medicationEvidenc ewithfor nothe treatment,effectiven ess of laser trfoundeatme that,nts as whena pr adjustedimary ther forapy censoringinclude: and other covariates, progression risk was halved by Ttreatment.he EMGT , Aftera ran 6do years,mis edthec HRlinic wasal t rial0.5 (95%comp CIari 0.35ng AL toT 0.71).and medication with no treatment, • foun Nagard tethat al,, 2005,when whoadj usconductedted for ac ensrandomisedoring a ndprospectiveother c ovstudyariat comparinges, progr 360ess iodegreen ris k was halvselectiveed by lasertreat therapyment. Af(SLT)ter with6 yea 0.005%rs, the latanoprostHR was 0. 5at(95 night,% CfoundI 0.3 5noto differences0.71). in mean NVFag defectsar et a betweenl, 2005, groupswho afterconduc 12 tmonths.ed a randomised prospective study comparing 360 • deg McIlraithree s eetlec al,t iv2006,e las iner a non-randomisedtherapy (SLT) pilotwit hstudy0.0 05of 100% l ateyesan opnewlyrost diagnosedat night ,POAGfoun d no difandfere OHTnces ini n61m patients,ean VF anddef eccomparingts betwee 180n gr degreeoups afSLTter with12 mlatanoprost,onths. found that the two treatments were equally efficacious in reducing IOP in over 12 months.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 83 81 9. Intervention Scenarios

• Sanfilippo (1999) cited research suggesting ALT was more efficacious that pilocarpine. Two year success rates when assessing IOP were 63% and 44% for the ALT and pilocarpine groups respectively. It was found that ALT gave a significantly better preservation of the VF than pilocarpine. Through regression analysis the ‘time left to blindness’ for the ALT group was 31 years and for the pilocarpine-treated group, 12 years (assuming a linear decay) (Sanfilippo P, 1999).

9.3.1: TO RUN THIS INTERVENTION THROUGH THE MODEL … • To ensure you start with a “blank page”, on the Options sheet, click the scenario reset buttons. • Tick the “No new intervention (Standard treatment)” box • Select frequency every year • click on the “Set as Base Case” button (so that standard treatment is the comparator). • Un-tick the “No new intervention (Standard treatment)” box. • Make sure that the “Frequency – Every Year” box is ticked. • On the Options sheets, choose “Change Treatment Protocol” in the Select Intervention box and “Primary laser trabeculoplasty” in the Select Intervention Detail box. Then click the “Set as Scenario 1” button, to run the new scenario. • Click Compare Scenarios (CEA).

9.3.2: RESULTS The results are presented in Table 9.7. The change in treatment protocol is cost-saving (consistent with the hypothesis above). There is little impact on the results if the cost of laser is tripled or increases five fold to account for the cost of side effects (assuming these can be fixed relatively quickly so there is no impact on the patient’s quality of life) (Table 9.7). Figure 9.6 shows that the cost-savings associated with the new protocol increase over time as more people are diagnosed and treated for POAG because of population ageing. The burden of disease is depicted in Figure 9.7.

TABLE 9.7: MODEL RESULTS – PROTOCOL CHANGE – TRABECULOPLASTY AS PRIMARY TREATMENT Net Present Standard Primary Standard Primary Standard Primary Values Laser treatment treatment Laser treatment Laser ($724) ($2,173) ($3,622) DALYs 155,150 155,974 155,150 155,974 155,150 155,974 Burden of Disease 23,896 24,095 23,877 24,070 23,858 24,046 Costs ($m) Health System 8,759 8,392 8,865 8,548 8,971 8,703 Costs ($m) Comorbid Health 4,505 4,519 4,505 4,519 4,505 4,519 Costs ($m) Treatment Costs ($m) 4,254 3,873 4,360 4,029 4,465 4,184 Productivity Costs ($m) 1,665 1,671 1,665 1,671 1,665 1,671 Other Indirect Costs ($m) 2,695 2,628 2,715 2,658 2,736 2,689 Total Costs ($m) 37,015 36,787 37,122 36,948 37,230 37,109 CE ratio: Return on $0.40 $0.47 $0.57 $1 spent(a) Cost- Cost- Cost- $/DALY avoided Saving Saving Saving

(a) Defined as the difference in indirect costs between primary laser and the base case for every additional dollar spent on treatment.

84 Centre for Eye Research Australia Tunnel Vision Commercial-in-Confidence Economic impact of primary open angle glaucoma

TABLE 9-7: MODEL RESULTS – PROTOCOL CHANGE — TRABECULOPLASTY AS PRIMARY TREATMENT

Net Present Standard Primary Standard Primary Standard Primary Values treatment Laser treatment Laser treatment Laser ($724) ($2,173) ($3,622) DALYs 155,150 155,974 155,150 155,974 155,150 155,974 Burden of Disease Costs ($m) 23,896 24,095 23,877 24,070 23,858 24,046 Health System Costs ($m) 8,759 8,392 8,865 8,548 8,971 8,703 Comorbid Health Costs ($m) 4,505 4,519 4,505 4,519 4,505 4,519 Treatment Costs ($m) 4,254 3,873 4,360 4,029 4,465 4,184 Productivity Costs ($m) 1,665 1,671 1,665 1,671 1,665 1,671 Other Indirect 9. Intervention Scenarios Costs ($m) 2,695 2,628 2,715 2,658 2,736 2,689 Total Costs ($m) 37,015 36,787 37,122 36,948 37,230 37,109 CE ratio: Return on $1 spent(a) $0.40 $0.47 $0.57 $/DALY Cost- Cost- Cost- avoided Saving Saving Saving (a) Defined as the difference in indirect costs between primary laser and the base case for every additional dollar spent on treatment.

FIGURE 9-6: COST-SAVINGS RESULTING FROM A PROTOCOL CHANGE(A) FIGURE 9.6: COST-SAVINGS RESULTING FROM A PROTOCOL CHANGE(A) Laser trabeculoplasty Treatment Costs actually saves money 400,000,000 Base Case (Standard treatment) Primary laser trabeculoplasty when used as the Scenario 2 350,000,000 initial treatment. 300,000,000

250,000,000

200,000,000

150,000,000

100,000,000

50,000,000

0 2005 2010 2015 2020 2025

E(a(a)c) oL Laseransoemr costingciocs tiimng $724p$a7c2 4tper op eftreatment. rptreimatmareyn to. pen angle glaucoma Commercial-in-Confidence

FIGURE 9-7 BURDEN OF DISEASE FIGURE 9.7: BURDEN OF DISEASE

DALYs 83

18,000 Base Case (Standard treatment) Primary laser trabeculoplasty 16,000 Scenario 2

14,000

12,000

10,000

8,000

6,000

4,000

2,000

0 2005 2010 2015 2020 2025

9.3.3 SENSITIVITY ANALYSIS — THE IMPACT OF THE CONSERVATIVE APPROACH TO SURGERY FAILURE RATES

Taking a conservative approach to the surgery failure rate doesn’t substantively affect the results because treatment efficacy is measured according to whether a patient is treated or not rather than the particular treatment the patient receives. In other words, all treated patients (no matter what order they receive treatments) experience a reduction in progression of visual impairment by 50% compared with people who have undiagnosed POAG. Taking a conservative approach to the surgery failure rate means that more patients progress more quickly to medications — bringing forward the costs of medications for those patients and leading to higher health system cost estimates (Table 9-8) . Repeat surgery may also be performed. Based on MBS data surgery is performed at a rate of 1.2 and costs have been factored accordingly.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 85

84 9. Intervention Scenarios

9.3.3: SENSITIVITY ANALYSIS — THE IMPACT OF THE CONSERVATIVE APPROACH TO SURGERY FAILURE RATES Taking a conservative approach to the surgery failure rate doesn’t substantively affect the results because treatment efficacy is measured according to whether a patient is treated or not rather than the particular treatment the patient receives. In other words, all treated patients (no matter what order they receive treatments) experience a reduction in progression of visual impairment by 50% compared with people who have undiagnosed POAG. Taking a conservative approach to the surgery failure rate means that more patients progress more quickly to medications — bringing forward the costs of medications for those patients and leading to higher health system cost estimates (Table 9.8) . Repeat surgery may also be performed. Based on MBS data surgery is performed at a rate of 1.2 and costs have been factored accordingly.

TABLE 9.8: SENSITIVITY ANALYSIS — A CONSERVATIVE APPROACH TO SURGERY FAILURE RATES Net Present Standard Primary Laser Standard Primary Laser Values treatment ($724) treatment ($724) Laser failure rate 50%, Laser failure rate 50%, surgery failure rate 50% surgery failure rate 10% DALYs 155,150 155,974 155,150 155,974 Burden of Disease Costs ($m) 23,896 24,095 23,950 24,144 Health System Costs ($m) 8,759 8,392 8,468 8,128 Comorbid Health Costs ($m) 4,505 4,519 4,505 4,519 Treatment Costs ($m) 4,254 3,873 3,963 3,609 Productivity Costs ($m) 1,665 1,671 1,665 1,671 Other Indirect Costs ($m) 2,695 2,628 2,638 2,576 Total Costs ($m) 37,015 36,787 36,721 36,520 CE ratio: Return on $1 spent(a) $0.40 $0.43 $/DALY avoided Cost-Saving Cost-Saving

(a) Defined as the difference in indirect costs between primary laser and the base case for every additional dollar spent on treatment.

86 Centre for Eye Research Australia Tunnel Vision 9. Intervention Scenarios

9.4: RESEARCH AND DEVELOPMENT The impact of new This scenario looks at the possible returns from new treatments that might be developed to treatments to reduce further slow the progression of POAG. One possible example currently under investigation progression was might be neuroprotection with the drug Memantine (an NMDA22 -receptor antagonist currently used for Alzheimers disease). Memantine is currently in phase III trials for glaucoma and at the examined. time of writing treatment efficacy results were not available. The model allows for two possible new treatment efficacy options — the new therapy reduces the progression of glaucoma by a further 50% or 75% over and above the reduction in progression from current treatments. It is assumed that the hypothetical treatment is given to each person being treated for POAG, regardless of their treatment stage. The new therapy is taken continuously over the patient’s remaining life. The treatment is added to current treatments rather than substituting for them. In this model, the annual cost per person for this treatment has been set at $1,000 regardless of efficacy.

9.4.1: TO RUN THIS INTERVENTION THROUGH THE MODEL … • To ensure you start with a “blank page”, on the Options sheet, click the reset buttons. • On the Options sheets, choose “Research and Development” in the Select Intervention box and “R&D Reduces Progression (50%)”, or “R&D Reduces Progression (75%)”. • Tick the “No new Intervention (Standard Treatment)” box and click on the “Set as Base Case” button to set the current situation as the base comparator. • Un-tick the “No new Intervention (Standard Treatment)” box and make sure that the “Frequency – Every Year” box is ticked. Then click the “Set as Scenario 1” button, to run the new scenario. • Click Compare Scenarios (CEA).

9.4.2: RESULTS The results of introducing two new therapies that reduce progression by 50% and by 75% over the base case are presented in Table 9.8. Compared with the base case, the net present value of DALYs, productivity costs and comorbid costs are lower. The results reflect the benefits of delaying progression, allowing people to remain in work, and experience fewer comorbid conditions that are associated with the later stages of glaucoma. The decline in DALYs over time associated with delaying progression by 50% and 75% over the base case is depicted in Figure 9.8.

22 N-methyl-D-aspartate

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 87 Economic impact of primary open angle glaucoma Commercial-in-Confidence

Tick the “No new Intervention (Standard Treatment)” box and click on the “Set as Base Case” button to set the current situation as the base comparator. Un-tick the “No new Intervention (Standard Treatment)” box and make sure that the “Frequency – Every Year” box is ticked. Then click the “Set as Scenario 1” button, to run the new scenario. 9. Intervention ScenariosClick Compare Scenarios (CEA).

9.4.2 RESULTS

The results of introducing two new therapies that reduce progression by 50% and by 75% over the base case are presented in Table 9-9. Compared with the base case, the net present value of DALYs, productivity costs and comorbid costs are lower. The results reflect the benefits of delaying progression, allowing people to remain in work, and experience fewer comorbid conditions that are associated with the later stages of glaucoma. The decline in DALYs over time associated with delaying progression by 50% and 75% over the base case is depicted in Figure 9-8.

FIGURE 9-8: DECLINE IN DALYS FROM NEW EFFICACIOUS TREATMENT Treatments with FIGURE 9.8: DECLINE IN DALYS FROM NEW EFFICACIOUS TREATMENT DALYs annual costs over 18,000 Base Case (Standard treatment) $5000 are expensive R&D reduces progression 50% but cost effective. 16,000 R&D reduces progression 75% 14,000

12,000

10,000

8,000

6,000

4,000

2,000

0 2005 2010 2015 2020 2025 Commercial-in-Confidence Economic impact of primary open angle glaucoma Health system costs on the other hand are higher with the new treatment because the Health system costs on the other hand are higher with the new treatment because the treatment is added to currently available therapies (Figure 9.9). treatment is added to currently available therapies (Figure 9-9). FIGURE 9-9 TREATMENT COSTS WITH NEW TREATMENTS COSTING $1000 PER PERSON PER YEAR FIGURE 9.9: TREATMENT COSTS WITH NEW TREATMENTS COSTING $1000 PER PERSON PER YEAR

Treatment Costs

450,000,000 Base Case (Standard treatment) R&D reduces progression 50% 400,000,000 R&D reduces progression 75%

350,000,000

300,000,000

250,000,000

200,000,000

150,000,000

100,000,000

50,000,000

0 2005 2010 2015 2020 2025 86 Overall, cost effectiveness depends on the cost per person per annum of the new treatment Ov(Tableerall, 9.8).cos Att ef treatmentfectivenes costss de ofpe $1,000nds o nperth persone cost perper annum,perso nnewper treatmentsannum of arethe costne wsaving.treat ment (Table 9-9). At treatment costs of $1,000 per person per annum, new treatments are cost However, if the new treatments that delay progression by 50% over the base case cost more saving. However, if the new treatments that delay progression by 50% over the base case than $5,000 per person per annum, they would become relatively expensive (cost effectiveness cost more than $5,000 per person per annum, they would become relatively expensive (cost efratiosfectiv ofen beyondess rat $60,000ios of bey perond DALY$6 0,avoided).000 per DALY avoided).

88 Centre for Eye Research Australia Tunnel Vision

87 9. Intervention Scenarios

TABLE 9.9: MODEL RESULTS – RESEARCH AND DEVELOPMENT – SHOWING THE IMPACT OF NEW TREATMENT TO REDUCE PROGRESSION BY 50% AND 75% Cost of new $1,000 per person $5,000 per person $10,000 per person treatment per annum per annum per annum Net Present Base 50% 75% 50% 75% 50% 75% Values Case DALYs 155,150 134,793 125,718 134,793 25,718 134,793 125,718 Burden of Disease Costs ($m) 23,896 20,660 19,240 20,510 19,091 20,324 18,905 Health System 8,759 8,843 8,773 9,793 9,729 10,980 10,924 Costs ($m) Comorbid 4,505 4,319 4,227 4,319 4,227 4,319 4,227 Health Costs ($m) Treatment 4,254 4,524 4,545 5,474 5,501 6,661 6,697 Costs ($m) Productivity 1,665 1,428 1,317 1,428 1,317 1,428 1,317 Costs ($m) Other Indirect 2,695 2,623 2,575 2,808 2,762 3,040 2,995 Costs ($m) Total Costs ($m) 37,015 33,553 31,905 34,539 32,899 35,772 34,141 CE ratio: Return $13.82 $18.55 $3.03 $4.30 $1.52 $2.18 on $1 spent $/DALY avoided Cost- Cost- $44,670 $23,380 $114,386 $71,914 Saving Saving

9.5: COMBINATIONS The combined effects This section examines the impact of combining the interventions we model. Two scenarios are available here. Both involve an increase in the diagnosis rate for glaucoma from 50% to 80%, of better diagnosis together with either: and laser first, or • the addition of a new therapy that delays progression by a further 50%; or better diagnosis and a • a change in the treatment protocol so that laser becomes the first line therapy instead of new treatment were medication. examined. 9.5.1: TO RUN THIS INTERVENTION THROUGH THE MODEL … • To ensure you start with a “blank page”, on the Options sheet, click the reset buttons. • On the Options sheets, choose “5. Combined scenarios” in the Intervention Focus box and “5.1 Scenario 1.2 and 4.1”, or “5.1 Scenario 1.2 and 3.1” in the Intervention Detail box. • Tick the “No Intervention (Current Situation)” box and click on the “Set as Base Case” button to set the current situation as the base comparator. • Un-tick the “No Intervention (Current Situation)” box and make sure that the “Frequency – Every Year” box is ticked. Then click the “Set as Scenario 1” button, to run the new scenario. • A second scenario can be evaluated by reselecting from the “Interventions Focus” box as well as the “Interventions Detail” box. Then click the “Set as Scenario 2” button, to run the new scenarios. • Click Compare Scenarios (CEA).

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 89 9. Intervention Scenarios

Treatment costs 9.5.2: RESULTS increase over time The results of the combined scenarios are reflected in Table 9.10. Both scenarios reduce the because of an ageing total DALYs compared with the base case (Table 9.10).

population and TABLE 9.10: MODEL RESULTS – COMBINED SCENARIOS an increase in the Net Present Base Case Diagnosis rate Diagnosis rate proportion of people Values standard 80% and 80% and treatment R&D reduces primary laser with POAG who are progression 50% trabeculoplasty diagnosed from 50% DALYs 155,150 121,220 149,999 in the base case to Burden of Disease Costs ($m) 23,896 18,184 21,752 80% in each of the Health System Costs ($m) 8,759 10,921 10,156 combined scenarios. Comorbid Health Costs ($m) 4,505 4,132 4,367 Treatment Costs ($m) 4,254 6,789 5,789 Productivity Costs ($m) 1,665 1,133 1,448 Other Indirect Costs ($m) 2,695 2,918 2,882 Total Costs ($m) 37,015 33,157 36,237 CE ratio: Return on $1 spent $2.52 $1.51 $/DALY avoided $54,607 $112,411

EcTheon oimprovementsmic impact otof ptotalrima DALYsry op eincreasen angle over gla utheco durationma of the modelC o(Figuremme r9.10)cial-i nwith-Co thenfid ence increased benefit from the first Scenario becoming more prominent over time. FIGURE 9-10: REDUCTION IN DALYS, COMBINED INTERVENTIONS FIGURE 9.10: REDUCTION IN DALYS, COMBINED INTERVENTIONS DALYs

18,000 Base Case (Standard treatment)

Diagnosis rate 80% and R&D 16,000 reduces progression 50% Diagnosis rate 80% and primary 14,000 laser trabeculoplasty

12,000

10,000

8,000

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4,000

2,000

0 2005 2010 2015 2020 2025

Treatment costs increase over time (driven by an ageing population and an increase in the Treatment costs increase over time (driven by an ageing population and an increase in the proproportionportion of ofpe peopleople wwithith PPOAGOAG whowho areare diagnoseddiagnos efromd fro 50%m 5 0%in thein basethe bas casee tocas 80%e to in8 0each% in each ofofthe thec combinedombined scenarios)scenarios (Figure) (Figur 9.11).e 9- 1 The1). patternThe p atoft erntotalof coststotal overcos timets ov areer showntime are in shown in FiFiguregure 9 9.12.-12.

FIGURE 9-11: TREATMENT COSTS, COMBINED INTERVENTIONS Centre for Eye Research Australia 90 Treatment Costs Tunnel Vision

700,000,000 Base Case (Standard treatment)

Diagnosis rate 80% and R&D 600,000,000 reduces progression 50% Diagnosis rate 80% and primary laser trabeculoplasty 500,000,000

400,000,000

300,000,000

200,000,000

100,000,000

0 2005 2010 2015 2020 2025

90 Economic impact of primary open angle glaucoma Commercial-in-Confidence

FIGURE 9-10: REDUCTION IN DALYS, COMBINED INTERVENTIONS

DALYs

18,000 Base Case (Standard treatment)

Diagnosis rate 80% and R&D 16,000 reduces progression 50% Diagnosis rate 80% and primary 14,000 laser trabeculoplasty

12,000

10,000 8,000 9. Intervention Scenarios 6,000

4,000

2,000

0 2005 2010 2015 2020 2025

Treatment costs increase over time (driven by an ageing population and an increase in the proportion of people with POAG who are diagnosed from 50% in the base case to 80% in each of the combined scenarios) (Figure 9-11). The pattern of total costs over time are shown in Figure 9-12.

FIGURE 9-11: TREATMENT COSTS, COMBINED INTERVENTIONS FIGURE 9.11: TREATMENT COSTS, COMBINED INTERVENTIONS Combining better Treatment Costs diagnosis rates with 700,000,000 Base Case (Standard treatment)

Diagnosis rate 80% and R&D a hypothetical new 600,000,000 reduces progression 50% Diagnosis rate 80% and primary laser trabeculoplasty therapy to further 500,000,000 reduce progression is 400,000,000 more cost effective 300,000,000 than combining 200,000,000 better diagnosis Commercial-in-Confidence Economic impact of primary open angle glaucoma 100,000,000 Commercial-in-Confidence Economic impact of primary open angle glaucoma rates with primary 0 trabeculoplasty. 2005 FIGURE 92-01120 : TOTAL COSTS, 2C01O5MBINED SCENARIO20S20 2025 FIGURE 9-12: TOTAL COSTS, COMBINED SCENARIOS FIGURE 9.12: TOTAL COSTS, TCOMBINEDotal Costs SCENARIOS Total Costs 4,500,000,000 Base Case (Standard treatment)

Diagnosis rate 80% and R&D Base Case (Standard treatment) 44,0,50000,0,00000,0,00000 reduces progression 50% Diagnosis rate 80% and primary Diagnosis rate 80% and R&D 3,500,000,000 laser trabeculoplasty 4,000,000,000 reduces progression 50% Diagnosis rate 80% and primary 33,0,50000,0,00000,0,00000 laser trabeculoplasty

23,5,00000,0,00000,0,00000

22,0,50000,0,00000,0,00000

12,5,00000,0,00000,0,00000

11,0,50000,0,00000,0,00000 500,000,000 1,000,000,000 0 90500,000,000 2005 2010 2015 2020 2025 0 2005 2010 2015 2020 2025 The cost effectiveness (relative to the base case) of the two scenarios is shown in Figure 9-13. ThThee b ascoste c effectivenessase is repres ent(relativeed at ttohe theorigi basen. case) of the two scenarios is shown in Figure 9.13. TThehe c baseost ef casefectiv isen representedess (relativ ate t othethe origin.base case) of the two scenarios is shown in Figure 9-13. The base casFeIGisURrepE 9res-13ent: CeOdSatT EtFheFEoCrigiTIVEn.NESS PLANE, COMBINED SCENARIOS(A) FIGURE 9.13: COST EFFECTIVENESS PLANE, COMBINED SCENARIOS(A) 2,500,000,000 FIGURE 9-13: COST EFFECTIVENESS PLANE, COMBINED SCENARIOS(A) Diagnosis rate 80% and R&D reduces progression 50% 2,500,000,000 Diagnosis rate 80% and R&D 2,000,000,000 reduces progression 50%

2,000,000,000 1,500,000,000 s t Diagnosis rate 80% and s

o primary laser trabeculoplasty

C 1,500,000,000

s 1,000,000,000 t Diagnosis rate 80% and s

o primary laser trabeculoplasty C 1,000,000,000 500,000,000

500,000,000 0 0 5,000 10,000 15,000 20,000 25,000 30,000 35,000 40,000 Effectiveness 0 (a)(a)E fEffectivenessfectiveness0 m measuredeasured5,0 aas00s DALYsDALY savoided.10a,0v0o0ided .CostsC1o5,s0 reflect0ts0 refle healthct h20e,0a0 0lsystem,th syste productivitym25,,00p0roductiv 3iandt0y,00a0 notherd oth indirecter35i,n00d0ir ecosts.ct co s(Cost4t0s,0.00 (Ceffectivenessost effectiven ise smeasureds is mea sasur ethed a costs th eperco DALYst pe ravoided.DALY a Thevoid Evalueeffde.ctivT eofhne thessva lburdenue of t hofe diseaseburden iso fexcludeddisease fromis ex cthelud costed from the cost estimate in the numerator since this is represented by DALYs avoided in the denominator). (aestimate) Effectiv inen theess numeratormeasured sinceas D thisALY iss representedavoided. C byos tDALYss refle cavoidedt health ins theyste denominator).m, productivity and other indirect costs. (Cost effectiveness is measured as the cost per DALY avoided. The value of the burden of disease is excluded froThem th eEconomiccost estimat eImpactin the nu mofe raPrimarytor since t hOpenis is rep Angleresente dGlaucomaby DALYs av o-id Aed Dynamicin the deno mEconomicinator). Model 91

91 10. Appendix 1: Meta-Analysis - Falls and Hip Fractures

Section 6.3.4 presents the results of a meta analysis of literature that examined the increased likelihood of an accidental fall and hip fracture with a visual impairment as well as speciﬁc VFL or glaucoma impairment. The list of articles used in the meta-analysis is presented in Table 10.4, Table 6.7 and Table 6.8. From those lists, studies that reported the risks of an accidental fall or hip fracture as an OR were excluded, due to their technical incompatibility with RR (as well as a lack of data to accurately convert the ORs into RRs). Meta-analysis refers to the statistical analysis of analyses, where the results of multiple trials are combined to estimate an overall effect size. A number of studies have been published examining the impact that visual impairment has on the risk of an accidental fall and/or hip fracture. The results of these studies have been combined to estimate an overall RR of an accidental fall for people that have a visual impairment.

10.1: FIXED-EFFECTS VERSUS RANDOM-EFFECTS An inverse variance methodology has been used to weight the study trials for both the ﬁxed effects and random effects models23. The results of which are presented in Table 10.1.

TABLE 10.1: FIXED EFFECTS AND RANDOM EFFECTS, META-ANALYSIS RESULTS Accidental Falls Hip Fractures Visual Impairment VFL / Glaucoma No. of Studies 13 6 9 Weighting Method, Inverse variance Inverse variance Inverse variance FE RE Inverse variance + τ Inverse variance + τ Inverse variance + τ Fixed Effects 1.33 (1.24 – 1.43) 2.52 (1.92 – 3.30) 1.43 (1.25 – 1.64) (95% CI) Random Effects 2.05 (1.54 – 2.71) 3.18 (1.82 – 5.55) 1.46 (1.24 – 1.73) (95% CI)

The studies that specifically examined VFL/Glaucoma are a subset of the visual impairment group of studies. Overall the RR of an accidental fall was higher for people with glaucoma (or VFL) than people with any type of visual impairment and the RR of an accidental fall is higher than the RR of a hip fracture. For all three groups, the RR of an accidental fall is greater in the random effects model than the fixed effects model. This indicates that heterogeneity exists between the combined studies. The presence of heterogeneity is not unexpected as the studies incorporated into the meta- analysis include different definitions, measures and severity criteria for visual impairment.

10.2: HETEROGENEITY Heterogeneity between studies can be problematic when using a ﬁxed effects model (which assumes that the studies used to determine the treatment effect have the same criteria). In this instance the studies use a variety of different visual impairment, severity and other criteria and it is not unexpected that (as seen in Table 10.1) heterogeneity exists. Table 10.2 displays a series of statistical tests that estimate the presence of heterogeneity within the meta-analysis.

23 An inverse variance plus tau weighting method has been used for the random effects model.

92 Centre for Eye Research Australia Tunnel Vision 10. AppendixMain heading 1: Meta-Analysis to go here - Falls and Hip Fractures

TABLE 10.2: HETEROGENEITY WITHIN THE COMBINED STUDIES Accidental Falls Hip Fractures Visual Impairment VFL / Glaucoma Fixed Effects Q-statistic 55.11 17.44 9.66 p-value (two-tailed) <0.0001 0.0037 0.2894 H-statistic (95% CI) 2.14 (1.65 – 2.78) 1.87 (1.23 – 2.85) 1.10 (1.00 – 1.57) I2-statistic (95% CI) 78.22% 71.33% 17.22% (63.23% - 87.10%) (33.42% - 87.66%) (0.00% - 59.21%) Random Effects

τ2-statistic 0.1630 0.3191 0.0110

• Q statistic: is the main analysis of heterogeneity and tests whether the assumption that all of the effect sizes are estimating the same population is reasonable. The test statistic has a chi-square distribution with k-1 degrees of freedom. If the test is rejected, the distribution of effect sizes is assumed to be heterogeneous. • H-statistic: describes the relative excess in Q over its degrees of freedom. When considering a regression of a standardised treatment effect on the standard error, the slope of an unweighted least squares regression line corresponds with the ﬁxed effect pooled value. The H statistic is the residual SD from this regression. A low H statistic means high consistency among study results. • I2-statistic: describes the percentage of total variation across studies that cannot be attributed to chance or sampling error and varies between 0% and 100%. In the case of consistent study results, the I2 is 0 or very low. P-values and CI’s can be used to describe the compatibility of the data-based statistic with a null-hypothesis. 2 • τ -statistic: is an estimate of the between study variance. The τ-value is used in the random effects model as an addition to the inverse variance study weight. The statistical tests for heterogeneity presented in Table 10.2 indicate that heterogeneity is present in the results of the accidental falls studies, however heterogeneity for studies examining the relationship between visual impairment and falls is small. The random effects methodology of meta-analysis has been used to control for this inter study heterogeneity, for each interest group. The results are presented in the following section.

10.3: FOREST PLOTS Figure 10.1, Figure 10.2 and Figure 10.3 display the forest plots of each study group using a random effects meta-analysis methodology. The effect size of each trial is represented by the red square with a black line indicating the 95% CI. The size of the red square for each trial indicates the relative weight applied to each study result (using an inverse variance plus tau) weighting methodology. This gives studies with lower standard errors higher weights, as results with more accurate estimations are assumed to provide better estimations of the true effect size. The overall effect size is displayed at the bottom of the ﬁgure as a grey diamond with a horizontal line providing the 95% CI.

The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 93 10. Appendix 1: Meta-Analysis - Falls and Hip Fractures e c n e d i f n ) ) o 2 ) ) ) 4 1 1 8 ) ) ) ) ) 3 8 ) ) e C 1 r 5 9 7 7 2 5 9 4 3 5 4 ) ) - 7 u 3 6 9 4 4 4 4 9 2 3 3 . 6 1 . s 8 1 9 5 0 0 7 9 5 6 2 n . 6 . 8 . 6 i a 2 3 0 3 2 3 3 1 8 0 . . 1 . . . 9 1 . . o - t e l 6 1 6 4 6 3 1 2 2 2 . . o o o 9 t 1 t t a m 9 3 o o o o o o o 4 i t t t t t t t I n 3 o 2 8 4 o t o c t t o C 1 9 7 7 8 1 1 9 9 2 5 r i . t 5 6 9 2 1 3 9 2 5 7 3 1 5 1 % e a 4 0 8 1 0 0 8 8 4 2 8 ( i . 9 5 . . 5 0 7 0 2 1 9 2 0 S c 0 2 . . . 0 . . . 2 2 . . 6 9 ( ( ( m o 9 1 1 1 1 1 1 0 1 1 6 L . . h ( ( ( ( ( ( ( ( s 1 1 2 4 t 0 1 L i s 9 ( 2 4 1 ( 9 2 5 3 3 7 6 0 m ...... A A w 0 3 3 5 2 2 1 1 1 5 6 1 1 2 o F | | | C | | | | D | | | | N | | | | | A | | | | | | T | | | | | | | N | | | | | | | | | | | | | | | | | | | | | | E M t % % % h R % % % % % % % 9 % % % 1 6 g % I i 3 5 3 8 3 9 6 4 9 1 1 8 1 ) . . . 0 e 0 9 0 2 8 0 4 8 7 2 A ...... 2 . . . 0 0 0 % W ( 4 3 4 4 6 8 9 1 9 7 5 1 1 1 P M I L A 0 0 ALLS U 1 F S I V R O F ) L E 0 D 1 ) O t ) + e M l V I a ( c S R s T R g C - o l t ( E o l R F p R F t s E 1 e r o M F ORVISUAL IMPAIRMENTAND O F D N A R ( T 1 . O 0 L P ECTS MODEL) T 9 S 9 7 1 5 8 6 5 7 5 7 FF ] 8 9 3 2 2 3 2 2 2 1 6 E 5 c a 9 8 6 7 0 3 4 1 2 8 6 [ 3 . R 5 5 5 3 3 2 0 2 3 4 1 9 E ...... 0 / 9 m l S 0 0 0 0 0 0 0 0 0 0 0 O / / / / / / / / / / / / 3 1 o ] . 6 2 4 9 1 9 3 5 6 7 6 o r 4 F c 0 t 8 3 6 1 3 1 2 5 9 3 0 / [ 9 c n 9 6 8 4 9 4 8 0 6 4 3 7 0 . D o M 0 1 6 7 6 6 1 4 6 8 5 4 u ...... 0 E C A - 1 1 1 0 0 0 0 0 1 1 0 0 a l T A g 9 T 9 7 1 5 8 6 5 7 5 e 7 l ] 8 9 3 2 2 3 2 2 2 1 6 O 5 e 9 8 6 7 0 3 4 1 2 8 6 g [ 3 N . 5 5 5 3 3 2 0 2 3 4 1 9 E ...... 0 n d / 9 N S 0 0 0 0 0 0 0 0 0 0 0 / / / / / / / / / / / / e 3 1 ] . 6 2 4 9 1 9 3 5 6 7 6 a s 4 A e 0 8 3 6 1 3 1 2 5 9 3 0 / o [ 9 n 9 6 8 4 9 4 8 0 6 4 3 7 p 0 . : M 0 1 6 7 6 6 1 4 6 8 5 4 e x ...... 0 1 E A - 1 1 1 0 0 0 0 0 1 1 0 0 p - OREST PLOT (RANDOM E o 10 F y r E a R m U i r 4 1 1 1 8 8 8 8 8 1 1 8 8 r G a 9 9 9 9 9 9 9 9 9 0 0 8 9 I e 9 9 9 9 9 9 9 9 9 0 0 9 9 p F Y 1 1 1 1 1 1 1 1 1 2 2 1 1 f o t c : a ) ) S I ) ) ) ) ) ) ) ) 1 2 p ( ( l S 1 2 3 1 2 3 4 5 l l ( ( ( ( ( ( ( ( a l Y l l l l l l l l a a t m t t a L a a a a a a a a e l t i t t t t t t t t e e A a e C e e e e e e e e t n n N c i J J J E g e a a D Q Q Q Q Q t t A I R R R t t n M i - n R R R R R l a a i m y n n n t r e r r t A s s s s s d k n n n e r r r r r e T o f m m u y y y r l l l e e e e e n E t a a i w IGURE 10.1: ANNOTATED n v v v v v S A G G G I I I I I R R T Z M F o c 4 E 9 94 Centre for Eye Research Australia Tunnel Vision 10. Appendix 1: Meta-Analysis - Falls and Hip Fractures e a 5 c 9 n m e o d c i f u n a l ) o ) ) ) ) ) ) 3 ) ) 4 ) ) ) 3 7 9 9 4 g e C 2 6 ) ) 3 8 r 8 2 6 9 8 3 1 4 e - 5 5 e r 7 9 4 3 u 9 2 9 4 9 0 5 4 ) ) l ) 5 2 u 9 4 9 2 . s 2 9 8 6 7 6 5 5 n 6 1 . 8 . . . . . i 7 s 9 7 9 5 a 9 5 1 . g 6 8 . 6 . . . 6 2 3 1 2 4 - a 2 2 e 1 l 8 . 1 . 9 1 o 1 1 3 6 n t . e o o o o o 6 6 6 2 t t t t t o a . . m 3 t S o o 6 o o o i 1 t t t t t m 9 3 I a o 4 n 7 6 1 4 9 3 t E o I c t n o 2 8 2 o C 7 4 8 9 9 1 0 1 5 n o t o r i t t R o C 1 1 9 8 t 5 1 1 2 3 6 0 8 3 i . 5 % e e t 9 9 2 5 a 1 6 3 1 2 4 5 0 2 1 5 1 i 0 ...... U % 5 a 8 8 8 4 ( 0 0 1 i 9 5 . . c . . . 9 1 1 0 0 0 1 p 5 9 T 7 9 ( ( ( ( ( ( c 2 . 0 . 2 2 9 m o 1 1 1 0 9 . ( ( h ( ( ( o 9 1 1 0 2 C s 3 7 6 3 1 6 . . t 1 o h ( ( i S s 1 2 8 s 4 3 9 ( 7 1 8 1 6 4 t 0 1 m ...... i A y s ( 4 ( 5 3 3 1 L . . . . . A w 1 1 1 2 1 2 0 1 0 1 r o R A w 3 5 2 1 5 6 3 L a | | | F C | A | | | | | | | | m | F | | i P | | | | I r | | | | | | | D | | | | H | | | | | p | | | N | | | f | | | | | | | | | D | | A | | | | | | | | | | | | | | | | | | o | | | | N | | | | | | | | | | | | | | | | | | | | | | | | t | | | | | | | L | | | | | | | A c F t a T % % t h % % % % % % V % 1 % % 8 % % % % h g % N p / i 3 6 3 3 4 3 9 5 9 1 4 5 9 6 9 g % ) . . 0 i e 6 6 6 1 0 6 E 9 9 8 8 4 9 6 ) ...... 0 A . 3 . . 2 . . . . 0 e % m 9 2 9 2 9 4 0 W ( 8 3 8 6 1 7 6 3 0 1 % M M W ( 1 1 1 2 1 1 1 i R c O I i C A ractures m U P f o A 0 0 M ip 1 0 I n L 1 o L G h c A R E ALLS U F O S I and F

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R s C R g R g - E o M - l o t l ( F t ( o l S o R F l R p R T p R t E t s 1 C . s visual e 1 0 E M e r r o F O o F F F OR OR GLAUCOMA/V D F F E N A M R O ( D T N O 1 A L 0 1 . . R 0 0 P ( T T S ECTS MODEL) ECTS MODEL) O 6 E 7 4 3 5 4 7 6 L 8 4 7 5 5 7 5 ] FF 3 3 4 9 7 5 5 FF ] 1 2 R 8 3 2 2 2 1 c a P 6 0 6 0 1 8 1 c [ 3 0 9 6 0 1 2 8 . . [ 1 1 2 3 2 2 4 O E ...... 5 5 3 2 3 4 0 1 E ...... T / / m l S 0 0 0 0 0 0 0 F / / / / / / / / l S 0 0 0 0 0 0 8 3 / / / / / / / S o ] 5 4 9 1 1 7 2 o ] o r 0 4 6 4 1 5 6 7 c r t 6 2 1 3 8 4 2 c E D [ 5 9 t 8 6 3 5 9 3 c [ n 3 6 4 9 4 7 2 1 4 n 9 8 9 0 6 4 E R . . o M 3 2 6 6 5 7 1 u ...... o M 0 6 6 4 6 8 0 0 ...... T O C A 0 0 0 0 0 0 - 0 - a C A 1 1 0 0 1 1 l A F T g D 6 O 7 4 3 5 4 7 6 e 8 4 7 5 5 7 5 l E ] 3 3 4 9 7 5 5 ] N 1 2 8 3 2 2 2 1 e T 6 0 6 0 1 8 1 e g [ 3 0 9 6 0 1 2 8 N . . [ 1 1 2 3 2 2 4 E ...... 5 5 3 2 3 4 A 0 1 E ...... n d / / S 0 0 0 0 0 0 0 d A S 0 0 0 0 0 0 / / / / / / / / T / / / / / / / e 8 3 e ] ] 5 4 9 1 1 7 2 a 6 4 1 5 6 7 s 0 4 s e O e 6 2 1 3 8 4 2 : 8 6 3 5 9 3 o [ 5 9 o [ n 3 6 4 9 4 7 2 9 8 9 0 6 4 p 1 4 N p 2 . . M 3 2 6 6 5 7 1 e M 0 6 6 4 6 8 x ...... - x ...... 0 0 N E A 0 0 0 0 0 0 - 0 - E A 1 1 0 0 1 1 p A 10 OREST PLOT (RANDOM E o OREST PLOT (RANDOM E : F F E y r 3 R e - a U c m n G 10 i I r 5 5 6 6 9 9 1 1 1 r r 1 1 8 8 1 1 e a 9 9 9 9 8 8 0 0 0 F a 9 9 9 9 0 0 E e 9 9 9 9 9 9 0 0 0 d e 9 9 9 9 0 0 p i R Y 1 1 1 1 1 1 2 2 2 f Y 1 1 1 1 2 2 f ) ) U n 1 2 o ( ( G t o l l I ) ) a a c 1 2 F C t t ( ( : a : - l l e e ) ) ) ) ) ) ) S S a a I I P P 1 2 1 2 3 n p ) ) ) ) 1 2 t t i ( ( ( ( ( S ( ( S 1 3 2 5 e e a a l l l l l l l - ( ( ( ( Y l Y n n a a a a a l l l l a a m R R i i l l t t t t t L t t L a a a a a S S i o o e e e e e i t t t t e e A A s s e e e e M M T T n n n N c n n N c i g g - - J J t t D D a a a r a a D t t t A D Q Q t t A I n n t t t I R R t t i i n n - - n n R R e a a a a a m y e e y n n m m o o r r r A r r A s s d g g d n n s s T o r r T m m r r l l m m m m m m u u y y E l l e e E IGURE 10.3: ANNOTATED t u u a a e e a a a t a a IGURE 10.2: ANNOTATED n v v S C C D D F F R R R M S G G I I R R M F F m o o c 6 E 9 C The Economic Impact of Primary Open Angle Glaucoma - A Dynamic Economic Model 95 10. Appendix 1: Meta-Analysis - Falls and Hip Fractures

To some extent 10.4: PUBLICATION BIAS publication bias will Publication bias presents as a unique problem for meta-analyses. While the inclusion and always be present exclusion of studies can impart some control over publication bias, the potential for its existence is still present with studies showing an effect more likely to be published than studies that show within a meta- no effect at all. To some extent publication bias will always be present within a meta-analysis, analysis, the problem the problem is then to estimate how large and what effect the problem has on the result. is then to estimate how large and what TABLE 10.3: MEASURES OF PUBLICATION BIAS Accidental Falls Hip Fracture effect the bias has on Visual Impairment VFL / Glaucoma the result. Model Random Effects Random Effects Random Effects

Weighting Method IV + τ IV + τ IV + τ Original Outcome 2.05 (1.54 – 2.71) 3.18 (1.82 – 5.55) 1.46 (1.24 – 1.73) (95% CI) Effect Assessment Regression Model Egger Egger Egger Intercepts (95% CI) 2.22 (1.17 – 3.27) 3.44 (-1.11 – 7.99) 0.22 (-1.65 – 2.09) p-value (two-tailed) 0.0007 0.1036 0.7884 Sensitivity Trim-and-fill method L0 L0 L0 Number of imputed 5 0 0 studies Resulting outcome (1.55 (1.18 – 2.02) 3.18 (1.82 – 5.55) 1.46 (1.24 – 1.73) 95% CI)

As with heterogeneity a few statistical tests have been developed to examine the extent of potential publication bias within a meta-analysis (Table 10.3). Two main statistical tests are applied to the results, these are: • Egger’s small study effects: A formal test for publication bias. The test involves regression of the z-scores upon the inverse of the standard error and the intercept of the regression line is used to measure asymmetry (around the standardised pooled value, 0) which is regarded as a sign of publication bias. • Trim-and-fill method: uses funnel plot symmetry as an indicator for publication bias and estimates the number of studies that have no counterpart on the other side of the symmetry axis. These studies are removed (trimmed) and a new symmetry-axis is calculated. The procedure is repeated until there is no asymmetry found. Finally, the trimmed studies are put back in the funnel plot together with hypothetical counterparts and new combined empirical values can be calculated with both original and imputed studies included. The p-value for studies examining accidental falls and visual impairment is less than 5% indicating that publication bias is present within this meta-analyses, while publication bias for the VFL/Glaucoma and hip fracture studies appears too low (p values are greater than 5%). The effect of this publication bias can be seen with the trim-and-fill method, which indicates that the treatment effect should have a RR of approximately 1.55 for people with a visual impairment.

96 Centre for Eye Research Australia Tunnel Vision 10. Appendix 1: Meta-Analysis - Falls and Hip Fractures

10.5: ADDITIONAL SUPPORTIVE LITERATURE A number of additional articles were found during the literature search process, which could not be included within the meta-analysis because of incomplete or the lack of quantitative information required. These additional articles are shown in Table 10.4.

TABLE 10.4: NON-QUANTITATIVE SUPPORTING LITERATURE Visual Impairment Increased Risk Source Visual impairment Risk of first, multiple and injurious falls: Arfken et al, 1994 was not significantly associated with visual impairment Visual impairment Risk of fall was not significantly Campbell et al, 1989 (no specific definition provided) associated with visual impairment ≤ 60/60 (face recognition) OR of hip fracture = 3.1 de Boer et al, 2004* Blindness/poor vision Risk of fall: was significantly associated Gaebler et al, 1993 (no specific definition with blindness and poor vision provided) Poor vision (no specific Risk of wrist fracture was lower in the Haboubi et al, 1991 definition provided) group with poor vision Best (corrected) VA Risk of fall: significant difference between Jack et al, 1995 of < 6/18 low vision of patients attending for falls compared with those attending for other medical problems Patients diagnosed with: Risk of fall: among patients with diabetic Kamel et al, 2000 refractive errors, cataracts, retinopathy and glaucoma the vision glaucoma, diabetic questionnaire had a 100% sensitivity in retinopathy and/or AMD identifying patients with a history of falls Participants of the Beaver Risk of fall and hip fracture: was Klein et al, 1998 Dam Eye Study: significantly associated with VA in the VA based measures over 60s, in the under 60s risk was only associated with some vision measures < 6/12 OR of multiple falls = 1.75 Koski, 1998* Poor distance vision OR of multiple falls = 2.3 Koski, 1998* Low contrast VA and Risk of multiple falls significantly Lord et al, 1994 contrast sensitivity increased in subjects with poor VA and/or a low ability to perceive contrast Blindness (no specific Risk of second hip fracture was Saxena et al, 2000 definition provided) significantly increased in the blind/and those with low vision Visually impaired and blind Risk of fall: the blind demonstrated a Tobis et al, 1990 (no stronger definitions higher risk than the deaf or non- provided) impaired populations

*Not enough information could be obtained from the abstracts to be included in the meta-analysis

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