EUROPEAN GLAUCOMA SOCIETY TERMINOLOGY AND GUIDELINES FOR GLAUCOMA 3rd Edition

Foreword

It gives me great pleasure to introduce thus, the third edition of the European Glaucoma Society ‘Guidelines’. In the 5 years since the last edition the Guidelines have been accepted as one of the standard texts in glaucoma, widely distributed and adopted across Europe. Since the last edition significant changes have taken place in the diagnosis and management of glaucoma: we have a much clearer understanding of the pathogenesis of open angle glaucoma, and have seen a revision of the terminology and mechanisms for angle closure. There have been advances in both diagnosis and method of followup of chronic glaucoma. Treatment both medical and surgical has improved with new drug combinations and new surgical techniques entering the mainstream of practice. More importantly, there have been improvements in measuring the affect that glaucoma has on the patient, how it affects Quality of life. All these changes and more appear in the third edition. The Guidelines owe much to the enthusiasm and effort put in by the writing team, headed by Carlo Traverso with Anders Heijl, and the many co-opted helpers. Without them this edition would not have been possible. The new ‘Guidelines’ build on the reputation established by the earlier versions, and should take forward the understanding of glaucoma in Europe.

Roger Hitchings
EGS President

The Guidelines Task Force Anders Heijl (Editor) Carlo E. Traverso (Editor) Augusto Azuara-Blanco Stefano Gandolfi Franz Grehn Gabor Hollo Anton Hommer Michele Iester Clive Migdal John Thygesen Fotis Topouzis

Contributors and Reviewers Alfonso Anton Alessandro Bagnis Keith Barton Boel Bengtsson Graziano Bricola Howard Cohn Francesca Cordeiro Fabio De Feo Paul Foster David Garway Heath Peng Khaw Yves Lachkar Hans Lemij Selim Orgul Marina Papadia Leopold Schmetterer Riccardo Scotto Ingeborg Stalmans Anja Tuulonen Thierry Zeyen

Production Team Roberta Bertagno Laura Guazzi Maria Musolino Stefania Rela Valentina Scanarotti Executive Committee Roger Hitchings (President) Franz Grehn Anders Heijl Gabor Hollo Yves Lachkar Clive Migdal Norbert Pfeiffer John Thygesen Carlo E. Traverso Anja Tuulonen

The European Glaucoma Society website is: www.eugs.org



III - ECONOMIC EVALUATION OF GLAUCOMA CARE

Glaucoma has received very little attention from health economists for the time being(40). By summer 2008, Pub Med revealed less than 500 hits with keywords glaucoma and cost*, less than 60 hits with glaucoma and resource*, less than 100 hits with glaucoma and cost-effectiveness and less than 20 hits with glaucoma and cost-utility. The number of patients seen with glaucoma related pathologies is predicted to increase significantly over the next few years as a result of an ageing population41. The overburden of glaucoma services demands a reappraisal of current management strategies.(42,43)

The goal of glaucoma treatment is to maintain the patient’s visual function and related quality of life, at a sustainable cost. The cost of treatment in terms of inconvenience and side effects as well as financial implications for the individual and society requires careful evaluation. Quality of life is closely linked with visual function and overall patients with early to moderate glaucoma damage have good visual function and modest reduction in quality of life.

In addition to the need for critical evaluation of clinical research and application of evidence based medicine in every-day practice, it will be even greater challenge for ophthalmologists to be able to critically evaluate economic articles. In 2007, in a sample of 1000 Finnish physicians 80% did not know the basic concept of health economics (cost-utility) and 70% reported that their education for health economics was insufficient at medical school and during the residency program.(44) Also the peer reviewers as well editors need to learn a ‘new’ discipline (health economics was born in 1950’s). The fact that holds true for all scientific publications is true also with health economic papers, i.e. a published article even in a high impact journal is not a synonym for good quality evidence. This was clearly shown in a recent health economic paper which was published in spite of a major flaw of using visual acuity for utility values in glaucoma patients.(45)

In 2000’s it is not enough to read just the abstract of a paper but pay most attention to material and methods before reading the results. To assist critical evaluation and improve the quality and comparability of economic studies, various parties have published Users´ guides for economic analysis for clinical practice(46,47) and compiled methodological guidelines and recommendations for carrying out economic evaluations of pharmaceuticals.(48,49) Source of research funding should be paid special attention in economic papers as well since industry supported reviews of drugs have been reported to show more favourable conclusions than Cochrane reviews.(50)
 

III.1. PRINCIPLES OF ECONOMIC EVALUATION

The fundamental problem facing all health care systems is how to make the system more costeffective. To reach this objective, two approaches are available.(51)The broader one is concerned with chancing the system (e.g. initiate a systematic population screening programme), and the narrower one, making the existing system work better (e.g. improving current care).

The gap between therapeutic possibilities and resources available is broadening all the time. Much more could be done to the patients than we can afford.(52) Therefore, choices have to be made by prioritising (rationing) all interventions, including diagnostics tests, treatments, care processes and practices, i.e. we need to apply evidence-based health care.(53) If resources are used for one purpose, they cannot be simultaneously used for something else, thus creating opportunity costs in terms of health benefits foregone elsewhere.(52) As it is especially the cumulative effect of small changes in clinical practices (e.g. adding new diagnostic tests or therapy) that has a massive impact on the healthcare budgets, clinicians need to weigh not only their benefits and risks but should also consider the costs.(46,53) Nowadays an intervention besides being effective, should also be cost-effective.

Every professional who makes decisions about individual and groups of patients is a decision-maker in health care. Proper decision making requires high-quality, evidence-based data where we should consider 1) who gets the services, 2) who pays for them, and 3) who gets paid for doing what.(54) E.g. fee-for-service has reported to create incentives to over-production of services and rewards unnecessary as well necessary care, the glaucoma medication may be considered ”free” since a third party pays for them in many countries etc.(55)

Main concepts

Efficacy is an outcome of intervention in ideal settings (e.g. randomized controlled trial or selected patient material at a specialist center), while effectiveness describes outcome in every-day practice. Although the best evidence of efficacy can be reached by randomized controlled trials, for economic evaluation they are often ‘small and tight’ due to relatively small sample sizes, tight inclusion and exclusion criteria (i.e. selected patients compared to ‘usual’ patients), protocol driven costs such as frequent tests and visits, as well as short follow-up considering all costs and outcomes in the course of chronic diseases.(52)

Economic evaluation of health care procedures and technologies is about assessing their efficiency, that is the produced health effects are weighed against the sacrifices or costs required attaining them. Efficiency is thus defined as a relationship between health effects and costs. Economic evaluation deals with establishing the efficiency of the whole treatment process compared to another treatment process.(52, 53)

The economic evaluation should be made from the societal perspective. This means that when studying the efficiency all costs, i.e. the value of all resources required by the process are taken into account regardless of who incurs them and pays for them. The principle in economic evaluation is to report the resources used separately from their unit costs. This helps to interpret the results of a study from one setting to another, as unit prices are known to vary by location and by country. Charges should be separated from costs since they may bear little resemblance to economic costs. (56) The charges may also change with time, e.g. the average charge per ALT in 2000 was 40% of the highest average charge per procedure in 1989 although he the technology and techniques were unchanged during the decline of reimbursement for procedure.(57)

Cost-effectiveness analysis

When health effects are measured by simple indicators in ‘natural’ or physical units (such as lives saved, life-years or seeing-years gained, years of blindness avoided, painless/healthy days gained), or numerous disease-specific clinical measures (for example changes in visual acuity, intraocular pressure or visual field indices) and they are related to costs, we are speaking of cost-effectiveness analysis. The cost-effectiveness can only be shown in relation to a defined alternative. A treatment is never cost-effective in itself.(40) The efficiency criterion is the additional cost per additional unit of effectiveness (incremental cost-effectiveness ratio).

The problem with this method often is that the indicators describe health effects inadequately and narrowly. Difficulties arise, if for example the main therapeutic effect of the alternatives to be compared is different (e.g. one may have an effect mainly on length of life, another on its quality) or if the side effects of the alternatives are different in amount or severity. Then the comparability across alternatives is difficult, even impossible.

Cost-utility analysis

Cost-utility analysis is presently regarded as the best method of economic evaluation in health care. It is a special form of cost-effectiveness analysis in which health effects are measured in terms of change both in length and quality of life. These changes are aggregated into a single index number by weighting length of life with people’s 'exchange rate' between quality and length of life. This ‘exchange rate’ is elicited from population, or patients with valuation studies. This allows measuring effectiveness in terms of a change in Quality-Adjusted Life Years (QALYs). QALYs are composed in the same principle as the total points in ski jumping points from the length of the jump (length of life) and points from its style (quality of life).(52) The total points (QALYs) can be increased by improving style (quality of life) and/or lengthening the jump (life). The changes in QALYs are related to changes in costs; the efficiency criterion of cost-utility analysis is thus an incremental cost-utility ratio (or as a matter of fact the ratio between change in costs and change in QALYs). (24)

To be able to compare the efficiency of different interventions in terms of cost-utility for the same disease (or even different interventions for different diseases) against each other, it requires the measurement of changes in quality of life with a generic (non-disease-specific) instrument, e.g. the EQ-5D (formerly the EuroQoL), the SF6, Canadian Health Utilities Index (HUI), and 15D.(58-60) This means that one uses the same instrument for measuring quality of life regardless of what disease has brought about the changes in quality of life. In addition, the instrument must produce a single index number for quality of life that reflects a plausible exchange rate between quality and length of life on a 0-1 scale.(52)

Cost minimisation analysis

If treatments lead to the same clinical outcomes, cost minimisation analysis can be used. In this approach one is looking for the treatment alternative that produces identical clinical outcomes at the least cost. Unfortunately, the cases are relatively rare where clinical outcomes across alternatives are virtually the same.

Cost-benefit analysis

If health effects are measured and valued in monetary terms and they are weighed against costs, we are dealing with cost-benefit analysis. The advantage of this form of analysis is that both the costs and benefits are measured in the same units. It is then possible to examine the efficiency of even a single pharmaceutical, that is, whether its monetary benefits are greater than the monetary costs. The biggest problem of this type of analysis is the valuation of health effects in monetary terms: all valuation methods are more or less disputable. The efficiency criterion is cost-benefit ratio or net benefit.

Decision analytical modelling

The use of decision-analytical modelling to estimate the cost effectiveness of healthcare interventions is becoming widespread.(61,62) Ideal study design also for economic evaluation consists of a randomized design with measures of outcome, quality of life and costs, ”usual” patients, ”usual” treatment protocol, non-expert (in addition to expert) clinical experience, long follow-up, follow-up of drop-outs and large sample size. Sometimes the length of follow-up in the clinical trial may be too short for the purposes of economic evaluation. Modelling studies have been undertaken making projections of long-term outcomes from short-term trial data. Modelling can be used to extrapolate cost and effectiveness estimates over a longer time horizon using available epidemiological and natural history data.

Economic modelling is a relatively cheap and effective way of synthesizing existing data and evidence available on the costs and outcomes of alternative interventions. For example, Markov models have a long history of use in healthcare service decision-making and are particularly suited to the modelling of progression of chronic disease over time.(61,62) In Markov modelling disease in question is divided into distinct states and transition probabilities are assigned for movements between these states over a discrete time period (cycle). By attaching estimates of resource use and health outcome consequence to the states and transitions in the model, and then running the model over a large number of cycles, it is possible to estimate the long-term costs and outcomes associated with a disease. Markov models are particularly suited for the calculation of QALYs. Costutility analysis based on Markov models may be sensitive to parametric uncertainty. Probabilistic sensitivity analysis is recommended especially in cases where model parameters are based on limited number of observations.

Modelling studies are often criticized because of assumptions often have to be used due to inadequate evidence.(40) Clinical and epidemiologic studies never give all relevant information but that is no reason for not investigating what such studies can offer to assist decision making process. It appears more useful for decision makers to have some information on potential cost-effectiveness than to have no information at all. A decision is necessary regardless of whether the economic evaluation is performed. A model, even if partly based on assumptions, can provide important information on potential scenarios. It has also been stated that all models are wrong - including our current mental models - since they always remain imperfect and incomplete in their attempt to represent and analyze the real world.(63) We should, thus, not worry about whether or not to use a model, but rather which model to use.

III.2. COST-EFFECTIVENESS OF SCREENING

The problems of current evidence in relation to economic modelling are highlighted in the two recent Finnish and Scottish cost-effective studies.(64,65) The results of the two studies fully agreed in the major aspect: at this stage we do not have enough proper evidence to decide whether population screening could be cost-effective or not. Both studies, however, encourage further research to study whether – although untargeted population screening may currently not be cost-effective - screening of some subgroups could be. Their results seemingly disagreed whether screening could be cost-effective for 40 year olds compared with 60-75 year olds. The most probable reason for disagreeing result regarding the age was the fact that in the Finnish model also patients with diagnosis of glaucoma were screened in order to better target the treatment to the "right" subjects (=manifest glaucoma). The meaning of this finding emphasizes the great economical burden of false positives and over treatment in our health care systems.(66)

Current evidence of the cost-effectiveness of screening for glaucoma(66)

A. There are major shortcomings of the health care systems.
1. Unequal access to care (both between and within countries).(64)
2. Large variations in the distribution of health care services (both between and within countries).(67)

B. The performance of current glaucoma every-day practice is not optimal.
1. Several epidemiologic studies have shown that at least half of glaucoma patients are undiagnosed.(65)
2. Simultaneously, more than half of the patients currently treated for glaucoma do not have the disease.(64)
3. Considerable proportion of glaucoma patients do not use their drops (range from 5 to 80%).(68)
4. More than half of patients with newly diagnosed glaucoma at screening have seen an ophthalmologist (or optometrist), but their disease was not diagnosed.(69,70)

C. There is a lack of adequate evidence on the values of most of the important parameters needed for the evaluation of cost-effectiveness of screening.
1. The utility data in glaucoma is so far extremely limited and based on cross-sectional pilot studies.(71,72)
2. There is no agreement how cost data should be collected and reported in glaucoma care.(67)
3. In general, the data from randomized controlled trials are too ‘small and tight’ due to small sample sizes for economic evaluation, tight inclusion and exclusion criteria (selected patients), protocol driven costs (frequent tests and visits), short follow-up considering all costs and outcomes and losses of follow-up. The ideal study design for economic evaluation would require randomized design (e.g. screening vs. opportunistic case finding), large sample sizes on both arms (with ”usual” patients and ”usual” care protocol in the opportunistic arm), long follow-up, follow-up of drop-outs and measures of outcome, QoL and costs.

C.1. High quality (= randomized) diagnostic studies are missing(73,74)
1. No single (screening) test is sufficient to discriminate persons with and without glaucoma.(65)
2. Diagnostic studies of glaucoma lack a generally approved definition of the disease.
3. The majority of diagnostic studies have so far been performed on pre-selected patient populations which may lead to over-optimistic results.(74)
4. The estimates of the sensitivity and specificity of diagnostic tests show large variability(65) and are far lower than the thresholds required for screening dominance (= screening being less costly and more effective), i.e. specificity of 98-99% in the age group < 70 years and 94-96% in the age group > 70 years.(64)

C.2. Prevalence of glaucoma, suspected glaucoma and visual disability are variable
1. Due to different definitions of the disease, studies show different estimates for prevalences and incidences of glaucoma in different age groups and races.(64,65)
2. High quality studies using severe visual impairment as an endpoint are lacking.(75)

C.3. Data of staging and progression of glaucoma from one stage to another is minimal.
1. The evidence of early, moderate and advanced stages of glaucoma in the population-based studies is extremely limited and variable regarding how these stages are defined, how long glaucoma patients stay in each state, and what is the proportion of patients in each state.
2. In randomised controlled trials (that is, in ideal settings) the progression rates have been reported for one eye only, that is, not per patients’ two eyes, which determines both the HRQoL and visual disability compared to costs which are driven by the worst eye.

D. Need for future research
1. A randomised screening trial run in several countries would give the most reliable evidence of the cost-effectiveness of screening in preventing glaucoma-induced visual disability.(64,65)
2. Simultaneously, the sensitivity and specificity of diagnostic tests and their combinations could be evaluated in large non-selected populations.(64,65)
3. Establishing a gold standard definition of glaucoma would be essential.(64)
4. The HRQoL scores associated with different glaucoma stages should be measured in a longitudinal study with a generic instrument applicable to cost-utility analysis among an adequate number of individuals.(64,65)

III.3. COST-EFFECTIVENESS OF DIAGNOSTIC AND THERAPEUTIC INTERVENTIONS AND CARE PROTOCOLS

Diagnostic tests

The evidence about the efficiency of diagnostic tests in glaucoma is practically missing. One study analyzed three case-finding strategies (all patients undergo ophthalmoscopy, but tonometry is routinely performed to all initial patients, high-risk patients only, or no one), concluded that routine in all initial ophthalmic patients tonometry is cost-effective.(76) To study effectiveness and cost-effectiveness of glaucoma diagnostics, we would gain best evidence from a randomized trial in which one arm receives the standard test (e.g. white-on-white perimetry) and the other arms additional tests (e.g. imaging of the fundus) and then evaluate whether the additional tests improve patient outcome and quality of life with affordable costs.
In glaucoma care, we do not know what the impact of high resource utilization (e.g. early diagnosis and treatment, frequent visits and testing, several examination methods) have on important outcome, i.e. prevention of glaucoma induced visual disability. As the current legal and cultural environments exert tremendous pressure to do more, it is important to remember that greater expenditure as such does not guarantee better outcomes but might sometimes even be worse.(77-79) Missing a rare – or in case of glaucoma, very early diagnosis - may currently be regarded worse than over-testing. With the shift of spectrum of detected disease, as newly detected cases will in general be milder cases (or in case of glaucoma, have no manifest disease at all), outcomes seem to improve. This in turn creates stimulus to do even more. With more to do, there is also more worry, more unnecessary treatment, more mistakes – and more costs.(77)

In diagnostics and follow-up, it is currently not known the ‘optimum’ number of diagnostic tests, i.e. how many tests are enough and what number represents over-testing with no additional gain incurring unnecessary expenditure. In addition, we do not know how often we should take the tests during the follow-up. With different examination methods we do not know what should be the ‘correct’ and most cost-effective threshold for initiating and intensifying treatment in order to prevent glaucoma induced visual disability.(52)

Several papers have shown that increased costs are associated with increased disease severity.(80) From a priority setting perspective the most important question is whether the lower threshold for treatment – in spite of increase in costs - would be cost-effective in the long run in preventing visual disability. Such studies are not available at present.(67)

Medical, laser and surgical therapy

There are no studies on cost-effectiveness or cost-utility comparing surgical, laser and medication therapies with each other. Further research is needed to establish the efficiency of the alternative treatment modes for glaucoma.

Based on very limited data comparing different treatment modes, it is possible that (initial) laser therapy is less expensive than (initial) medication therapy and that from strictly economic point of view, surgery may not be cost-effective within a 3-4 year perspective. However, with increasing follow-up (up to 8 years) the difference in costs between surgery and medication may even out.(67) The current economic literature regarding glaucoma treatment is predominantly focused on identifying the short-term direct, particularly the precise quantification of glaucoma drug costs and provide only one component of real-world costs for glaucoma.(81,80) Using the European and US treatment guidelines as a benchmark, it is evident that the current body of literature does not satisfy the needs of decision-makers, although certain studies provide some valuable information, which is a step towards reaching this goal. (80) The main methodological issue in the economic models is an absence of a clinically relevant long-term effectiveness measure, or where this measure is produced, there is a lack of transparency and validation of the methods used. Future evaluations of the burden of glaucoma need to consider the issues of comparability between, and generalisability of, study results.(80)
Using cost-utility analysis (Markov modelling), Kymes at al (2006)(82) modeled a hypothetic cohort of people with ocular hypertension and different treatment thresholds from ‘treat no one’ to ‘treat everyone’. ‘Treat everyone’ cost more and was less effective than other options. The treatment of patients with >2% annual risk of the development of glaucoma was likely to be cost-effective. Another study using OHTS data for economic modelling suffers from major methodologic flaw when using visual acuity for utility values.(45)

Care protocols

In spite of large variations in care protocols, studies from different countries show similar overall trends: 1) an increase in the number of prescriptions and costs of glaucoma medications (e.g. in Scotland and Ireland the costs of medical therapy increased 10-16 % per year in 1994-2003), 2) a decrease in the rate of laser trabeculoplasty, except for Canada where the number of selective laser procedures started to increase in the 2000’s, 3) a decrease in the rates of glaucoma surgery, and 4) Increase in the rate of the cataract surgery (despite a decline in trabeculectomy surgery).(67)

Despite the fact that there is now good evidence that many interventions are both clinically effective and cost effective, ignorance about how to translate evidence into practice is considerable.(83) Even if data are available about the costs and benefits on interventions, practitioners and regulators often adopt interventions, which are demonstrably not cost-effective - and while doing this - enhance the perception of under-funding.(83) Typically, physicians practice in the fragmented, isolated tradition and do not have good enough administrative information available by which they could monitor 1) what they produce in terms of activity, case mix and outcome, 2) how they produce, i.e. what criteria they use to abandon and adopt new treatments and technologies, 3) how much they produce relative to their peers, and 4) to whom they deliver care.

 
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