A model to estimate the lifetime health outcomes of patients with type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS no. 68).

AIMS/HYPOTHESIS: The aim of this study was to develop a simulation model for type 2 diabetes that can be used to estimate the likely occurrence of major diabetes-related complications over a lifetime, in order to calculate health economic outcomes such as quality-adjusted life expectancy. METHODS: Equations for forecasting the occurrence of seven diabetes-related complications and death were estimated using data on 3642 patients from the United Kingdom Prospective Diabetes Study (UKPDS). After examining the internal validity, the UKPDS Outcomes Model was used to simulate the mean difference in expected quality-adjusted life years between the UKPDS regimens of intensive and conventional blood glucose control. RESULTS: The model's forecasts fell within the 95% confidence interval for the occurrence of observed events during the UKPDS follow-up period. When the model was used to simulate event history over patients' lifetimes, those treated with a regimen of conventional glucose control could expect 16.35 undiscounted quality-adjusted life years, and those receiving treatment with intensive glucose control could expect 16.62 quality-adjusted life years, a difference of 0.27 (95% CI: -0.48 to 1.03). CONCLUSIONS/INTERPRETATIONS: The UKPDS Outcomes Model is able to simulate event histories that closely match observed outcomes in the UKPDS and that can be extrapolated over patients' lifetimes. Its validity in estimating outcomes in other groups of patients, however, remains to be evaluated. The model allows simulation of a range of long-term outcomes, which should assist in informing future economic evaluations of interventions in type 2 diabetes.

Cost effectiveness of photodynamic therapy with verteporfin for age related macular degeneration: the UK case.

AIM: To estimate the potential cost effectiveness of photodynamic therapy (PDT) with verteporfin in the UK setting. METHODS: Using data from a variety of sources a Markov model was built to produce estimates of the cost effectiveness (incremental cost per quality adjusted life year (QALY) and incremental cost per vision year gained) of PDT for two cohorts of patients (one with starting visual acuity (VA) of 20/40 and one at 20/100) with predominantly classic choroidal neovascular disease over a 2 year and 5 year time horizon. A government perspective and a treatment cost only perspective were considered. Probabilistic and one way sensitivity analyses were undertaken. RESULTS: From the government perspective, over the 2 year period, the expected incremental cost effectiveness ratios range from 286 000 (starting VA 20/100) to 76 000 UK pounds (starting VA 20/40) per QALY gained and from 14 000 (20/100) to 34 000 UK pounds (20/40) per vision year gained. A 5 year perspective yields incremental ratios less than 5000 UK pounds for vision years gained and from 9000 (20/40) to 30 000 UK pounds (20/100) for QALYs gained. Without societal or NHS cost offsets included, the 2 year incremental cost per vision year gained ranges from 20 000 (20/100) to 40 000 UK pounds (20/40), and the 2 year incremental cost per QALY gained ranges from 412 000 (20/100) to 90 000 UK pounds (20/40). The 5 year time frame shows expected costs of 7000 (20/40) to 10 000 UK pounds (20/100) per vision year gained and from 38 000 (20/40) to 69 000 UK pounds (20/100) per QALY gained. CONCLUSION: This evaluation suggests that early treatment (that is, treating eyes at less severe stages of disease) with PDT leads to increased efficiency. When considering only the cost of therapy, treating people at lower levels of visual acuity would probably not be considered cost effective. However, a broad perspective that incorporates other NHS treatment costs and social care costs suggests that over a long period of time, PDT may yield reasonable value for money.

Estimating the relationship between disease progression and cost of care in dementia.

BACKGROUND: Previous studies have shown a positive relationship between disease severity and cost. AIMS: To explore the factors affecting time to institutionalisation and estimate the relationship between the costs of care and disease progression. METHOD: Retrospective analysis of a longitudinal data-set for a cohort of 100 patients diagnosed with Alzheimer's disease or vascular dementia. RESULTS: Changes in both Mini-Mental State Examination (MMSE) and Barthel scores have independent and significant marginal effects on costs. Each one-point decline in the MMSE score is associated with a pound sterling 56 increase in the four-monthly costs, whereas each one-point fall in the Barthel index is associated with a pound sterling 586 increase in costs. CONCLUSIONS: It may be inappropriate for economic models of disease progression in dementia to be based solely on measures of cognitive change. MMSE and the Barthel index are independent significant predictors of time to institutionalisation and cost of care, but changes in the Barthel index are particularly important in predicting costs outside institutional care.

The excess cost of acute exacerbations of chronic bronchitis in patients aged 45 and older in England and Wales.

INTRODUCTION: Chronic Bronchitis is a serious and costly health problem. Prevalence is estimated at 45 per 10,000 persons in the United Kingdom. Approximately 120,000 Pounds would be saved for every 100 hospital admissions avoided. A reduction in acute exacerbations of chronic bronchitis (AECB), treatment failures, and subsequent hospital admission could have a significant impact on the burden of AECB borne by secondary care facilities in the UK National Health Service (NHS). OBJECTIVE: The aim of this study is to provide an economic assessment of the direct cost to the health care system associated with the management of chronic bronchitis and its acute exacerbations. DESIGN: A prevalence-based, excess-cost-of-illness analysis is undertaken from the perspective of the UK NHS. Disease prevalence data, primary health care resource utilization, hospital inpatient and outpatient resource utilization, and costs of health care were taken from a variety of data sources, including a large UK national survey of general practice (GP) consultations, the General Practice Research Database, a survey from a single NHS hospital trust, and the national health-care resource and cost statistics. RESULTS: From 1994 to 1995, approximately 233,000 cases of chronic bronchitis were detected in the persons aged 45 and older in the United Kingdom. Prevalence peaked at 204 per 10,000 in the group of subjects aged 75 to 84 years. During that same period, the total excess cost of primary care associated with AECB was calculated at 35.7 million Pounds. The largest component of primary care costs was the excess cost of all prescription medicines, which totaled 27.8 million Pounds. The excess cost attributed to antibacterial and respiratory prescription medications alone was estimated at 9 million Pounds. Excess costs attributed to GP consultations and hospital emergency room visits were 6.5 million Pounds and 1.3 million Pounds, respectively. The excess costs arising from inpatient hospital episodes included 8.3 million Pounds for hospital admissions, 660,000 Pounds for outpatient costs, and 225,000 Pounds for day care. CONCLUSIONS: These results suggest that improving the management of AECB with the objective of reducing the number of AECB treatment failures and the associated hospital admissions could significantly reduce expenditures by the UK NHS.

Apparent galactose appearance rate in human galactosemia based on plasma [(13)C]galactose isotopic enrichment.

Determination of endogenous galactose formation in galactosemic subjects provides important information in understanding the etiology of the long-term complications. To accomplish this task a sensitive method for measurement of isotopic enrichment of plasma galactose was developed. The aldononitrile pentaacetate derivative of galactose was utilized for gas chromatography/mass spectrometry analysis. Using a phenyl-methylsilicone capillary column, adequate separation of galactose from glucose was obtained by temperature programming of the chromatography. The specific fragmentation pattern of m/z 212, 225, 314 from d-[(12)C]galactose and m/z 213, 226, 315 from l-[(13)C]galactose was used for the galactose enrichment measurement by atom percent excess (APE). There was good correlation between expected enrichment and determined APEs at galactose concentrations of 1, 2, and 5 micromol/L with a coefficient of variation ranging from 0.22 to 7.17%. The method provides an accurate estimation of plasma [(13)C]galactose enrichment from which the galactose production rate can be calculated. The steady-state plasma l-[(13)C]galactose isotopic enrichment of three individuals with galactosemia, two males ages 33 and 13, and one female age 9, during constant infusion of l-[(13)C]galactose was 55, 41, and 55%, allowing the estimation of the apparent galactose appearance rate of 0.62, 1.09, and 0.82 mg/kg/h, respectively. The reanalysis of three previous studies by the present method found that APE values determined by the method then employed, butylboronate acetate derivatization, were systemically lower than those determined with aldononitrile pentaacetate derivatization, making for an overestimation of the apparent galactose appearance rate. The small plasma sample volumes needed make it feasible to perform these studies in infants and young children with galactosemia.

Current cost of medical negligence in NHS hospitals: analysis of claims database.

OBJECTIVES: To identify trends in the incidence and cost of clinical negligence claims. To determine the current annual cost to the NHS as a whole in terms of cash paid out to patients and their solicitors and the defence costs incurred. DESIGN: Analysis of records on database. SETTING: A well defined group of hospitals within one health authority which collected information on a consistent basis over many years. MAIN OUTCOME MEASURES: Data on individual claims. Trends in incidence of claims and costs identified independently from organisational reforms and changes in accounting practices. RESULTS: The rate of litigation increased from 0.46 to 0.81 closed claims per 1000 finished consultant episodes between 1990 and 1998. Overall expenditure on clinical negligence by the NHS in England in 1998 was estimated at 84 pound sterling million (95% confidence interval 48 pound sterling million to 130 pound sterling million). CONCLUSIONS: After adjustment for hospital activity, the rate of closed claims increased during the 1990s by about 7% per annum, a substantial rate of growth but not the uncontrolled explosion sometimes alluded to in the wider media. More coordination and openness are needed in data collection.

Cost effectiveness of an intensive blood glucose control policy in patients with type 2 diabetes: economic analysis alongside randomised controlled trial (UKPDS 41). United Kingdom Prospective Diabetes Study Group.

OBJECTIVE: To estimate the cost effectiveness of conventional versus intensive blood glucose control in patients with type 2 diabetes. DESIGN: Incremental cost effectiveness analysis alongside randomised controlled trial. SETTING: 23 UK hospital clinic based study centres. PARTICIPANTS: 3867 patients with newly diagnosed type 2 diabetes (mean age 53 years). INTERVENTIONS: Conventional (primarily diet) glucose control policy versus intensive control policy with a sulphonylurea or insulin. MAIN OUTCOME MEASURES: Incremental cost per event-free year gained within the trial period. RESULTS: Intensive glucose control increased trial treatment costs by pound 695 (95% confidence interval pound 555 to pound 836) per patient but reduced the cost of complications by pound 957 (pound 233 to pound 1681) compared with conventional management. If standard practice visit patterns were assumed rather than trial conditions, the incremental cost of intensive management was pound 478 (-pound 275 to pound 1232) per patient. The within trial event-free time gained in the intensive group was 0.60 (0.12 to 1.10) years and the lifetime gain 1.14 (0.69 to 1.61) years. The incremental cost per event-free year gained was pound 1166 (costs and effects discounted at 6% a year) and pound 563 (costs discounted at 6% a year and effects not discounted). CONCLUSIONS: Intensive blood glucose control in patients with type 2 diabetes significantly increased treatment costs but substantially reduced the cost of complications and increased the time free of complications.

Determination of [(13)C]galactose enrichment in human plasma by gas chromatography/positive chemical ionization tandem mass spectrometry.

Galactosemia is a potentially fatal disease resulting from a deficiency of galactose-1-phosphate uridyl transferase. In order to perform mechanistic studies designed to elucidate further the etiology of the disease, we required a method to monitor (13)C enrichment in plasma galactose following a single oral dose or intravenous infusion of [1-(13)C]galactose. Determinations of plasma [(13)C]galactose enrichment requires methodology with extremely high specificity because of potential interference from other low molecular mass plasma constituents and from glucose, an isomer which is present in much higher concentrations. We have developed a method based on gas chromatography/positive chemical ionization tandem mass spectrometry (GC/PCI-MS/MS) for the precise and accurate determination of plasma [(13)C]galactose enrichment. The method employed a pentaacetylaldononitrile derivative of galactose in order to improve its GC and MS characteristics. Peak areas resulting from the transitions m/z 328 --> 106 and m/z 329 --> 107 were used to quantify the relative abundance of labeled and unlabeled galactose. Validation of the method was performed by determination of the precision and accuracy over a wide range of galactose concentrations and (13)C enrichments. The GC/PCI-MS/MS method was able to determine accurately enrichments at galactose concentrations down to 0.8 microM in the presence of 4 mM glucose, making it both highly selective and the most sensitive method currently available.

Estimating long-term cost savings from treatment of Alzheimer's disease. A modelling approach.

OBJECTIVE: This paper puts forward a proposal for a modelling approach to the estimation of long term cost savings from the treatment of Alzheimer's disease (AD). DESIGN: In the proposed modelling approach, disease progression is defined in terms of intervals in the Mini-Mental State Exam (MMSE) scale. Clinical trial data are then used to determine the time at which a particular patient moved into a more severe stage of the disease. By comparing these durations across treatment groups, survival analysis is used to measure the impact of treatment in delaying the onset of a more costly stage of the disease. SETTING: Patients with varying severity of AD. PATIENTS AND PARTICIPANTS: The model uses clinical trial data on 1333 patients recruited internationally in 2 studies from 67 centres. INTERVENTIONS: The aim of these clinical studies was to evaluate the safety and efficacy of 2 non-overlapping dose ranges of rivastigmine relative to placebo over a 26-week treatment period in patients with probable AD. MAIN OUTCOME MEASURES AND RESULTS: The results indicate that the average cost savings with high-dose rivastigmine at the end of the trial period are quite low (approximately 29 Pounds per patient; 1997 values), but by extrapolating to a projected lifetime of 3 years, they rise to approximately 1100 Pounds per patient. The largest long term cost savings from treatment are obtained from treating those in the mild category (i.e. MMSE > 20). However, if the time horizon over which savings are estimated is short (i.e. if life expectancy is below 2 years), more costs are saved by prioritising patients with moderate AD (i.e. MMSE between 20 and 11). CONCLUSIONS: The model is a possible approach for estimating cost savings with treatment of AD, given the lack of long term data on resource use and drug efficacy. Caution should be used when extrapolating the results beyond the original study parameters.

A validated stable isotope dilution liquid chromatography tandem mass spectrometry assay for the trace analysis of cocaine and its major metabolites in plasma.

A validated method has been developed for the simultaneous quantitation of cocaine and its major metabolites (ecgonine methyl ester, benzoylecgonine, and norcocaine) in rat plasma. The method is based upon the use of stable isotope dilution liquid chromatography/atmospheric pressure chemical ionization/tandem mass spectrometry. Previously reported methods do not have the sensitivity and specificity that can be attained with this method. Plasma samples required no cleanup apart from protein precipitation, and no derivatization was required. Selected reaction monitoring was performed on the transitions of m/z 200 to m/z 182 (ecgonine methyl ester), m/z 290 to m/z 168 (benzoylecgonine), m/z 304 to m/z 182 (cocaine), and m/z 290 to m/z 168 (norcocaine). The standard curves were linear over the range from 2 ng/mL (benzoylecgonine, cocaine, and norcocaine) or 5 ng/mL (ecgonine methyl ester) to 1000 ng/mL in rat plasma. The lower limit of quantitation (LLQ) for benzoylecgonine, cocaine, and norcocaine was 2 ng/mL, and for ecgonine methyl ester, the LLQ was 5 ng/mL for plasma. This simple, rapid, reliable, and sensitive method of quantitation had excellent accuracy and precision for the four analytes. The method was sensitive enough to permit a detailed study of the pharmacokinetics of cocaine and its metabolites after administration of a bolus intravenous dose to rats.

An economic evaluation of vaccination against hepatitis A for frequent travellers.

This paper compares the cost of using inactive Hepatitis A vaccine relative to immunoglobulin as a means of protecting frequent travellers against Hepatitis A. The number of trips to 'at risk' areas is modelled as a Poisson process and results are reported in terms of the discounted gross cost per protected trip over a 10-year period. We find that the expected cost of immunization is lower with immunoglobulin for travellers visiting 'at risk' areas less than five times in 10 years, and lower with Hepatitis A vaccine for those visiting 'at risk' areas more than five times in 10 years.

Confidence intervals or surfaces? Uncertainty on the cost-effectiveness plane.

Although cost-effectiveness analysis is not new, it is only recently that economic analysis has been conducted alongside clinical trials. Whereas in the past economic analysts most often used sensitivity analysis to examine the implications of uncertainty for their results, the existence of patient-level data on costs and effects opens up the possibility of statistical analysis of uncertainty. Unfortunately, ratio statistics can cause problems for standard statistical methods of confidence interval estimation. The recent health economics literature contains a number of suggestions for estimating confidence limits for ratios. In this paper, we begin by reviewing the different methods of confidence interval estimation with a view to providing guidance concerning the most appropriate method. We go on to argue that the focus on confidence interval estimation for cost-effectiveness ratios in the recent literature has been concerned more with problems of estimation than with problems of decision-making. We argue that decision-makers are most likely to be interested in one-sided tests of hypothesis and that confidence surfaces are better suited to such tests than confidence intervals. This approach is consistent with decision-making on the cost-effectiveness plane and with the cost-effectiveness acceptability curve approach to presenting uncertainty due to sampling variation in stochastic cost-effectiveness analyses.

An economic analysis of varicella vaccination for health care workers.

A simulation model was constructed to assess the relative costs and cost-effectiveness of different screening and vaccination strategies for dealing with hospital incidents of varicella exposure, compared with current policies, using data from published sources and a hospital survey. The mean number of incidents per hospital year was 3.9, and the mean annual cost of managing these incidents was pounds 5170. Vaccination of all staff would reduce annual incidents to 2.2 at a net cost of pounds 48,900 per incident averted. Screening all staff for previous varicella, testing those who are uncertain or report no previous varicella, and vaccinating those who test negative for VZV antibodies, reduces annual incidents to 2.3 and gives net savings of pounds 440 per incident averted. Sensitivity analyses do not greatly alter the ranking of the options. Some form of VZV vaccination strategy for health care workers may well prove a cost-effective use of health care resources.

Trying to do better than average: a commentary on 'statistical inference for cost-effectiveness ratios'.

In a recent paper, Laska, Meisner and Siegel address issues concerning hypothesis testing in cost-effectiveness analysis. They relate the relative magnitude of two average cost-effectiveness ratios to the incremental cost-effectiveness ratio and go on to propose a statistical procedure for testing the equality of two average ratios. In this paper, we show why the use of average cost-effectiveness ratios is misleading and argue that the appropriate focus for cost-effectiveness analysis is the estimation of confidence intervals around incremental cost-effectiveness ratios.

An economic evaluation of universal vaccination against hepatitis B virus.

This report presents the results of an economic evaluation utilizing U.K. data, into a vaccination programme against Hepatitis B using a genetically engineered, yeast-derived vaccine, Engerix B. Cost-effectiveness ratios were calculated for four different programmes: an infant vaccination programme; a child vaccination programme; an adolescent vaccination programme; and a combined child and adolescent programme. For each programme, the number of annual cohorts vaccinated was varied from 1 to 25. The outcome was defined as incremental life years gained, and the results are reported as costs per incremental life-year gained. Benefits were calculated in both undiscounted and discounted forms. All costs were discounted. The discount rate used was 6%. All major epidemiological and cost assumptions were subjected to a sensitivity analysis. Baseline results with benefits discounted range from pounds188015 to pounds301365 per life year gained, depending on the duration of programme and vaccination strategy. With benefits undiscounted, the comparable range is from pounds5234 to pounds13034.

The cost of insulin-dependent diabetes mellitus (IDDM) in England and Wales.

This study estimates the direct health and social care costs of insulin-dependent diabetes mellitus (IDDM) in England and Wales in 1992 to be 96 million pounds, or 1021 pounds per person in a population with IDDM estimated at 94,000 individuals. These costs include insulin maintenance, hospitalization, GP and out-patient consultations, renal replacement therapy, and payments to informal carers. Expenditure is concentrated on younger age groups, with one-third of the total expended on those aged 0-24. Around one-half of the total costs can be directly attributed to IDDM, with the remainder associated with a range of complications of the disease. The single largest area of service expenditure is renal replacement therapy. The cost estimates are most sensitive to incidence rates of IDDM, numbers on dialysis and average duration of dialysis. A further 113 million pounds may be lost each year due to premature deaths resulting in lost productive contributions to the economy. The direct and indirect costs of IDDM are therefore significant. The cost of illness framework presented here should facilitate the economic evaluation of new and existing treatment regimens, which may improve value for money by reducing costs and/or increasing the quality or quantity of life for people with IDDM.

The analysis of censored treatment cost data in economic evaluation.

This article investigates the way in which the presence of censored cost data in clinical trials should dictate the inferential tests adopted when comparing treatment and nontreatment groups for the purpose of economic evaluation. The authors argue that the techniques of survival analysis are appropriate where censoring is present, and that bias will be imparted if cruder methods are used to analyze cost data, even if that data is drawn from a relevant population. The first section of the article discusses the problem of censoring and survival analysis, while the second examines three methods of dealing with censored cost data and possible biases resulting from them. The third section presents results from actual trial data using the three methods described in the preceding section. Conclusions are presented in section four, where it is argued that these methodological issues are likely to become more important as economists are called upon to evaluate the treatment of chronic conditions using data from clinical trials with finite end points.