Ocular hypertension and the risk of blindness.

PURPOSE: To estimate the risk of blindness in patients with ocular hypertension (OHT) using an appropriate model and current empirical data. DESIGN: A Markov model with data from a systematic literature review. METHODS: A Markov model with 3 health states was built: OHT, primary open-angle glaucoma (POAG), and unilateral blindness. Literature was searched for reports on conversion from OHT to POAG and progression from POAG to blindness, to estimate a range of annual conversion and progression probabilities. The model had a cycle length of 1 year. RESULTS: The 15-year risk estimates ranged from 3.1% to 9.4% in untreated, and from 0.9% to 8.6% in treated patients with OHT. The ranges were the result of differences in patient populations, treatments, and outcome definitions in currently available empirical data. CONCLUSIONS: The best estimates of the 15-year risk of unilateral blindness in patients with OHT, based on the currently available empirical data and an appropriate model, show that the risk is <10%.

The long term effectiveness and cost-effectiveness of initiating treatment for ocular hypertension.

PURPOSE: To investigate the long-term health and economic consequences of direct treatment initiation in ocular hypertension patients. METHODS: A cost-effectiveness analysis with a societal perspective and a lifelong horizon was performed. The primary outcomes were the incremental quality-adjusted life years (QALYs) and costs of direct pressure-lowering treatment for ocular hypertension, compared to a strategy where treatment is postponed until conversion to glaucoma has been observed. We used a decision analytic model based on individual patient simulation to forecast disease progression and treatment decisions in both strategies in a representative heterogeneous patient population and in 18 patient subgroups stratified by initial intraocular pressure and additional risk factors for conversion. RESULTS: The incremental discounted health gain of direct treatment was 0.27 QALYs, whereas the incremental discounted costs were -€ 649 during an average lifetime of 26 years. In the simulations of patient subgroups, the model outcomes moved towards higher health gains and lower incremental costs with increasing risk of conversion in the patient population. The incremental cost-effectiveness ratio of direct treatment ranged from € 15,425 per QALY gained in the lowest-risk subgroup to dominance in the highest-risk subgroup. Probabilistic sensitivity analysis indicated that uncertainty surrounding the model input parameters did not affect the conclusions. CONCLUSION: Direct, early, pressure-lowering treatment is a dominant cost-effective treatment strategy over a strategy to start the same treatment approach later, after glaucoma has occurred for patients with ocular hypertension. Its implementation and consequences should be discussed with ophthalmologists and individual patients.

The long-term outcomes of four alternative treatment strategies for primary open-angle glaucoma.

PURPOSE: To evaluate the long-term effects and costs of four treatment strategies for primary open-angle glaucoma compared to usual care. METHODS: Cost-effectiveness analyses with a lifelong horizon were made from a societal perspective. Data were generated with a patient-level model based on discrete event simulation. The model structure and parameter estimates were based on literature, particularly clinical studies on the natural course of glaucoma and the effect of treatment. We simulated heterogeneous cohorts of 3000 patients and explored the impact of uncertainty with sensitivity analyses. RESULTS: The incremental cost-effectiveness ratio (ICER) of initial treatment with a prostaglandin analogue compared with a ß-blocker was €12.931 per quality-adjusted life year (QALY) gained. A low initial target pressure (15 mmHg) resulted in 0.115 QALYs gained and €1550 saved compared to a gradual decrease from 21 to 15 mmHg upon progression. Visual field (VF) measurements every 6 rather than 12 months lead to health gains at increased costs (ICER €173,486 per QALY gained), whereas measurements every 24 months lead to health losses at reduced costs (ICER €21,516 per QALY lost). All treatment strategies were dominant over 'withholding treatment'. CONCLUSIONS: From a cost-effectiveness point of view, it seems advantageous to aim for a low intraocular pressure in all glaucoma patients. The feasibility of this strategy should therefore be investigated. Additionally, the cost-effectiveness outcomes of initiating monotherapy with a prostaglandin analogue and reducing the frequency of VF testing may be acceptable.

The role of the expected value of individualized care in cost-effectiveness analyses and decision making.

OBJECTIVE: To explore the feasibility and potential role of the expected value of individualized care (EVIC) framework. METHODS: The EVIC quantifies how much benefits are forgone when a treatment decision is based on the best-expected outcomes in the population rather than in the individual patient. We have reviewed which types of patient-level attributes contribute to the EVIC and how they affect the interpretation of the outcomes. In addition, we have applied the EVIC framework to the outcomes of a microsimulation-based cost-effectiveness analysis for glaucoma treatment. RESULTS: For EVIC outcomes to inform decisions about clinical practice, we need to calculate the parameter-specific EVIC of known or knowable patient-level attributes and compare it with the real costs of implementing individualized care. In the case study, the total EVIC was €580 per patient, but patient-level attributes known at treatment decision had minimal impact. A subgroup policy based on individual disease progression could be worthwhile if a predictive test for glaucoma progression could be developed and implemented for less than €130 per patient. CONCLUSIONS: The EVIC framework is feasible in cost-effectiveness analyses and can be informative for decision making. The EVIC outcomes are particularly informative when they are (close to) zero. When the EVIC has a high value, implications depend on the type of patient-level attribute. EVIC can be a useful tool to identify opportunities to improve efficiency in health care by individualization of care and to quantify the maximal investment opportunities for implementing subgroup policy.

Modeling complex treatment strategies: construction and validation of a discrete event simulation model for glaucoma.

OBJECTIVE: Discrete event simulation (DES) modeling has several advantages over simpler modeling techniques in health economics, such as increased flexibility and the ability to model complex systems. Nevertheless, these benefits may come at the cost of reduced transparency, which may compromise the model's face validity and credibility. We aimed to produce a transparent report on the construction and validation of a DES model using a recently developed model of ocular hypertension and glaucoma. METHODS: Current evidence of associations between prognostic factors and disease progression in ocular hypertension and glaucoma was translated into DES model elements. The model was extended to simulate treatment decisions and effects. Utility and costs were linked to disease status and treatment, and clinical and health economic outcomes were defined. The model was validated at several levels. The soundness of design and the plausibility of input estimates were evaluated in interdisciplinary meetings (face validity). Individual patients were traced throughout the simulation under a multitude of model settings to debug the model, and the model was run with a variety of extreme scenarios to compare the outcomes with prior expectations (internal validity). Finally, several intermediate (clinical) outcomes of the model were compared with those observed in experimental or observational studies (external validity) and the feasibility of evaluating hypothetical treatment strategies was tested. RESULTS: The model performed well in all validity tests. Analyses of hypothetical treatment strategies took about 30 minutes per cohort and lead to plausible health-economic outcomes. CONCLUSION: There is added value of DES models in complex treatment strategies such as glaucoma. Achieving transparency in model structure and outcomes may require some effort in reporting and validating the model, but it is feasible.

[Cost-effectiveness of clopidogrel vs. aspirin treatment in high-risk acute coronary syndrome patients in Denmark]. / Omkostningseffektivitet ved clopidogrel- versus acetylsalicylsyrebehandling af højrisikopatienter med akut koronarsyndrom i Danmark.

INTRODUCTION: The aim of this study was to estimate the cost-effectiveness of clopidogrel versus aspirin (ASA) in Denmark in the secondary prevention of cardiovascular events in three high-risk CAPRIE populations: (1) patients with a history of coronary artery bypass grafting, (2) patients with a history of ischemic events and (3) patients with multiple vascular territory involvement. Additionally, the cost-effectiveness of clopidogrel versus no treatment in ASA-intolerant patients was estimated. MATERIALS AND METHODS: Clinical, epidemiological and cost data (Danish estimates) were combined in a Markov model. Estimates of transition probabilities were derived from post hoc analyses of the CAPRIE database. RESULTS: Cost-effectiveness (CE) ratios ranged from 25,445 Danish kroner per LYG (life year gained) in patients with a history of CABG to 55,503 Danish kroner per LYG in patients with multiple vascular territory involvement. The estimated cost-effectiveness ratio of clopidogrel in ASA-intolerant patients was significantly lower (3,093 Danish kroner per LYG). Sensitivity analyses showed that the order of magnitude of these CE ratios is unaffected by changes in model assumptions. CONCLUSION: In a Danish setting, clopidogrel may be considered a cost-effective treatment alternative to ASA for the secondary prevention of cardiovascular events in high-risk populations. Clopidogrel is also an effective and cost-effective treatment for ASA-intolerant patients.

Prevalence and incidence of severe sepsis in Dutch intensive care units.

INTRODUCTION: Severe sepsis is a dreaded consequence of infection and necessitates intensive care treatment. Severe sepsis has a profound impact on mortality and on hospital costs, but recent incidence data from The Netherlands are not available. The purpose of the present study was to determine the prevalence and incidence of severe sepsis occurring during the first 24 hours of admission in Dutch intensive care units (ICUs). METHODS: Forty-seven ICUs in The Netherlands participated in a point prevalence survey and included patients with infection at the time of ICU admission. Clinical symptoms of severe sepsis during the first 24 hours of each patient's ICU stay were recorded and the prevalence of severe sepsis was calculated. Then, the annual incidence of severe sepsis in The Netherlands was estimated, based on the prevalence, the estimated length of stay, and the capacity of the participating ICUs relative to the national intensive care capacity. RESULTS: The participating ICUs had 442 beds available for admissions, which was estimated to be 42% of the national ICU capacity. At the time of the survey, 455 patients were currently admitted and 151 were included in the analysis; 134 (29.5%) patients met criteria for severe sepsis. The most common failing organ system was the respiratory system (90%), and most patients were admitted following surgery (37%) and were admitted because of acute infection (62%). The most prevalent source of infection was the lung (47%). The estimated duration of ICU stay for severe sepsis patients was 13.3 +/- 1.1 days. CONCLUSION: The annual number of admissions for severe sepsis in Dutch ICUs was calculated at 8643 +/- 929 cases/year, which is 0.054% of the population, 0.61% of hospital admissions and 11% of ICU admissions.

Pharmacokinetic-pharmacodynamic modelling of the hypothermic and corticosterone effects of the 5-HT1A receptor agonist flesinoxan.

The current investigation describes the pharmacokinetic-pharmacodynamic correlation of the hypothermic and the corticosterone effect of flesinoxan in the rat simultaneously. A specific objective was to determine the influence of handling the animal. The pharmacokinetic-pharmacodynamic correlation was determined following intravenous administration of 3 and 10 mg/kg flesinoxan in 5 or 15 min. Serial blood samples were obtained for determination of the time course of the flesinoxan and corticosterone concentrations by high performance liquid chromatography. Body temperature was monitored using a telemetric probe. The pharmacokinetics of flesinoxan were described using a three-compartment model. Both the hypothermic and the corticosterone response were successfully described using a physiological indirect response model. It is shown that customizing the animal prior to the experiment has no influence on the pharmacokinetic-pharmacodynamic parameter estimates. Furthermore, the similarity in potency between the hypothermic and corticosterone effects suggests that both are mediated via tissues with a similar receptor-effector coupling efficiency.