[Methods of health economic evaluation for health services research]. / Methoden der gesundheitsökonomischen Evaluation in der Versorgungsforschung.

On August 30, 2010, the German Network for Health Services Research [Deutsches Netzwerk Versorgungsforschung e. V. (DNVF e. V.)] approved the Memorandum III "Methods for Health Services Research", supported by the member societies mentioned as authors and published in this Journal [Gesundheitswesen 2010; 72: 739-748]. The present paper focuses on methodological issues of economic evaluation of health care technologies. It complements the Memorandum III "Methods for Health Services Research", part 2. First, general methodological principles of the economic evaluations of health care technologies are outlined. In order to adequately reflect costs and outcomes of health care interventions in the routine health care, data from different sources are required (e. g., comparative efficacy or effectiveness studies, registers, administrative data, etc.). Therefore, various data sources, which might be used for economic evaluations, are presented, and their strengths and limitations are stated. Finally, the need for methodological advancement with regard to data collection and analysis and issues pertaining to communication and dissemination of results of health economic evaluations are discussed.

Prescription of insulin glargine in primary care practices in Germany.

BACKGROUND: New classes of antidiabetic medications have been introduced, but details of their use are not well known. The aim was to assess prescription patterns and dosing for insulin glargine (market launch: 6/2000) in primary care patients. METHODS: Computerized data on prescriptions (Disease Analyzer, 6/1999 to 8/2003) from 277 general and internal medicine practices throughout Germany were analysed (67,402 diabetic patients; 340 incident glargine (age: 67+/-12 years) and 378 incident NPH users (66+/-11 years). RESULTS: Diabetes prevalence in the practices increased over the three-year period (5.1% to 6.2%). The highest increase was observed for insulin treated patients (+29%), followed by diet (+21%) and oral antidiabetics (+19%). Premixed insulin (short-acting insulin and NPH) remained constant as largest insulin group. A continuous increase of short-acting insulin analogues was found (+70%). Long-acting insulin analogues (glargine) increased threefold. Glargine was more often prescribed in combination with oral antidiabetics than NPH (76% vs 49%; p<0.05). Only about a quarter received short-acting insulin (NPH: 61%; p<0.05). The cumulative annual dose was higher among NPH users (geometric mean; NPH: 7971 IU; glargine: 5719 IU) (p<0.01), which persisted after adjusting for age, sex, and morbidity (p<0.01). CONCLUSIONS: Diabetes prevalence continuously increased in German primary care practices from 1999 to 2003. The largest increase was found for insulin treatment, in particular, for short and long-acting insulin analogues. Insulin glargine was more often prescribed in combination with oral agents, whereas NPH insulin was more frequently prescribed with short-acting insulin, indicating different prescription patterns in primary care.

Improved glycemic control with decreased hypoglycemia prevents long-term complications in type 2 diabetes patients: long-term simulation analysis using the "diabetes mellitus model".

OBJECTIVE: The purpose of this study was to compare the effect of insulin glargine (glargine) and NPH insulin (NPH) on long-term outcomes in type 2 diabetes patients using the Diabetes Mellitus Model (DMM). METHODS: The DMM predicts short- and long-term complications over ten years using data in studies published previously. The main effect on outcome is the influence of the treatment on the HbA1c level which is simulated over time. The simulation was based on a cohort size of 10,000 type 2 diabetes patients taking either glargine or NPH. The best scenario, baseline scenario and worst case scenario were simulated based on differences of 0.13%, 0.44% and 0.85%, respectively, in HbA1c values and corresponding to potentially attainable improvements with comparable or lower hypoglycemia rates in glargine-treated patients and NPH-treated patients. Assumptions for scenarios 1, 2 and 3 were based on a regression analysis of clinical trial data (pooled data clinical trials comparing glargine and NPH) in which the effect of glargine on the HbA1c/hypoglycemia incidence ratio was superior to that of NPH. RESULTS: The relative risks (RR, glargine/NPH) obtained for scenarios 1, 2 and 3 were 0.97, 0.89 and 0.81, respectively, for long-term microvascular complications and 0.99, 0.95 and 0.91, respectively, for long-term macrovascular complications. RR reductions ranged from 1% in the less optimistic scenario to > 20% in the "best case" scenario. Sensitivity analyses showed that variations in the mean baseline HbA1c values and duration of the diabetes were without effect on these outcomes. CONCLUSIONS: Although there is a need to corroborate the results of these simulations with real, long-term clinical data, they have demonstrated that, assuming comparable or lower rates of hypoglycemia, a better glycemic control (HbA1c reduction) can be expected with glargine when compared to NPH together with a reduction in long-term complications, mortality and associated costs.

Cost-effectiveness analysis of ramipril in heart failure after myocardial infarction. Economic evaluation of the Acute Infarction Ramipril Efficacy (AIRE) study for Germany from the perspective of Statutory Health Insurance.

OBJECTIVE: Data from the Acute Infarction Ramipril Efficacy (AIRE) study were used in a cost-effectiveness analysis to determine the incremental cost per life-year gained (LYG) when the ACE inhibitor ramipril was added to conventional treatment in patients with heart failure after acute myocardial infarction. In the AIRE trial, the addition of ramipril significantly lowered rates of total mortality and rehospitalisation due to heart failure. DESIGN AND SETTING: The cost-effectiveness analysis was conducted from the perspective of the Statutory Health Insurance (SHI) provider in Germany. A modelling approach was used which was based on secondary analysis of existing data, and costs were those incurred by SHI (i.e. expenses of SHI). In the base-case analysis, average case-related expenses of SHI were applied and LYG were quantified by the method of Kaplan and Meier. MAIN OUTCOME MEASURES AND RESULTS: The incremental cost-effectiveness ratios of ramipril varied between 2500 and 8300 deutschmarks (DM) per LYG (1993 values for inpatient and 1995 values for outpatient treatment; DM1 approximately $US0.70), according to the treatment periods of 3.8 years and 1 year, respectively. In the sensitivity analysis, the robustness of the model and its results was shown when the extent of influence of different model variables on the base-case results was investigated. First, survival probability and LYG were estimated according to the Weibull method. Second, the dependency of the target variable (i.e. incremental cost per LYG) on random variables was described in a simulation. Third, the influence of the model variables on the target variable was quantified using a deterministic model. The variance of the target variable was broad and the hospitalisation impact of adding ramipril to conventional treatment was an independent variable with much greater influence on the target variable than the parameter of clinical effectiveness, i.e. the number of LYG. CONCLUSION: Results of this evaluation showed that ramipril has a favourable incremental cost-effectiveness ratio for the treatment of heart failure in post myocardial infarction patients and can be considered an economical therapeutic agent from the perspective of SHI (third-party payer) in Germany.

Cost effectiveness of ramipril in patients with non-diabetic nephropathy and hypertension: economic evaluation of Ramipril Efficacy in Nephropathy (REIN) Study for Germany from the perspective of statutory health insurance.

BACKGROUND: In the Ramipril Efficacy In Nephropathy (REIN) trial, ramipril significantly lowered the rate of reaching the combined end-point of doubling of baseline serum creatinine levels or end-stage renal failure (ESRF). OBJECTIVE: To determine the additional cost per patient-year of chronic (long term) dialysis avoided (PYCDA) when the ACE inhibitor, ramipril, was added to conventional treatment of patients with non-diabetic nephropathy and hypertension. STUDY PERSPECTIVE: Statutory Health Insurance (SHI) provider in Germany. DESIGN AND SETTING: Data from the REIN Study were used in a cost-effectiveness analysis (CEA). A modelling approach was used, which was based on secondary analysis of published data, and costs were those incurred by the SHI provider (i.e. SHI expenses). In the base-case analysis, average case-related SHI expenses were applied and PYCDA were quantified using the cumulative incidence of ESRF as observed in the REIN trial. MAIN OUTCOME MEASURES AND RESULTS: The incremental cost-effectiveness ratios (ICERs) of ramipril varied between about -76,700 deutschmarks (DM) and -DM81,900 per PYCDA (DM 1 approximately equals 0.55 US dollars; 1999 values), according to the treatment periods of 1 year and 3 years, respectively. In the sensitivity,analysis, the robustness of the model and its results were shown when the extent of influence of different model variables on the base-case results was investigated. First, probabilities of ESRF and PYCDA were estimated according to the Weibull method. Second, the influence of the model variables on the target variable was quantified using a deterministic model. Third, the dependency of the target variable (ICER) on random variables was described in a simulation. The cost for chronic dialysis had by far the greatest impact on the target variable, which was 28 times greater than the impact of clinical effectiveness of ramipril, i.e. the number of PYCDA. There were net savings per PYCDA with ramipril treatment after 1, 2 and 3 years: 95% of the 10,000 simulation steps resulted in savings of between DM69 500 and D94,600 per PYCDA after 3 years. CONCLUSIONS: Results from this evaluation show that ramipril offers enormous savings from the perspective of the SHI provider (third-party payer) in Germany when added to the conventional treatment of patients with non-diabetic nephropathy and hypertension.

Health-economic comparison of three recommended drugs for the treatment of osteoporosis.

Osteoporosis is a large and growing disease with significant health consequences. Based on an evaluation of clinical evidence, the German osteology umbrella organization DVO (Dachverband Osteologie deutschsprachiger wissenschaftlicher Fachgesellschaften) published guidelines in March 2003 for the diagnosis and treatment of osteoporosis. For prevention of fractures in women with postmenopausal and senile osteoporosis, these guidelines recommend three treatment options as first-line therapy: risedronate, alendronate and raloxifene. No evidence is currently available for the reduction of hip fractures by raloxifene. Only risedronate and alendronate, therefore, are recommended for prevention of hip fractures. Information on the cost-effectiveness of preventing and treating osteoporosis may support decision makers in more efficient allocation of resources. Accordingly, the objective of this study is the comparative assessment of the cost-effectiveness of risedronate, alendronate and raloxifene for patient populations in Germany at high risk of osteoporotic fracture due to low bone mineral density (BMD) (i.e., T-score < -2.5) and resulting from a history of at least one previous vertebral fracture, as compared to osteoporotic patients with no treatment. Target variables for the economic comparison are costs per hip fracture avoided and costs per quality-adjusted life year (QALY) gained. Hip fractures are the most costly and best-documented complication of osteoporosis. A cost-effectiveness analysis was therefore conducted, using as criteria for evaluating intervention the incremental cost per hip fracture avoided and the cost per QALY gained. We used a fracture-incidence-based Markov model of osteoporosis, with analysis of patients' transition across outcome states over time (e.g., fracture, healthy, dead). Base-case analysis was conducted on a cohort of 1,000 women aged 70 with low spine BMD and prevalent vertebral fracture, over 3 years of treatment with risedronate, alendronate or raloxifene, and with application of a 10-year analytic time horizon. Model inputs included hip and vertebral fracture incidence rates; relative risk of fracture given low BMD and prevalent vertebral fracture, fracture cost, treatment prices/day (risedronate: 35 mg, 1.76 euro; alendronate: 70 mg, 1.82 euro; raloxifene: 60 mg, 1.82 euro); health utility; and efficacy in terms of relative-risk reduction of fracture of the hip (60% risedronate; 51% alendronate; not significant raloxifene) and vertebrae (49% risedronate; 47% alendronate; 30% raloxifene). A 5% discount rate was applied to cost and outcomes. In the base case, treatment with risedronate reduces costs from the social insurance perspective with respect to both endpoints: i.e., costs per averted hip fracture and QALY. Over the 3-year treatment period and 10-year observation, furthermore, risedronate proved superior to alendronate and raloxifene (i.e., risedronate was less expensive and more effective). From the perspective of statutory health insurance, the cost per averted hip fracture is 37,348 euro for risedronate and 48,349 euro for alendronate (costs for raloxifene were not calculated due to a nonsignificant effect on prevention of hip fractures); and cost per QALY gained is 32,092 euro for risedronate, in comparison to patients in Germany with no therapy (alendronate 41,302 euro; raloxifene 1,247,119 euro). This cost-effectiveness analysis gives evidence that bisphosphonates are cost effective. Under consideration of current prices and the published clinical evidence, risedronate dominates the comparison of DVO-recommended drugs.

Pharmacoeconomic analysis of osteoporosis treatment with risedronate.

Hip fracture is an important and costly problem. Therapy with the bisphosphonate risedronate effectively prevents hip and other fractures among women with established osteoporosis. Risedronate is a first-choice therapy option in the German Guidelines of the Dachverband Osteologie for Osteoporosis according to evidence-based medicine criteria for the treatment of postmenopausal osteoporosis, osteoporosis of the elderly (women aged > 75 years) and glucocorticoid-induced osteoporosis. There are few published economic evaluations of bisphosphonates in Germany. Therefore, an assessment of the cost-effectiveness of risedronate utilizing a state transition Markov model of established postmenopausal osteoporosis based on randomized clinical trial data was developed. Uncertainty underlying model parameters and outcomes was dealt with using traditional sensitivity analysis and stochastic sensitivity analysis to produce quasi-95% Cls. We focused on patients aged 70 years, since this population most closely matches the randomized controlled trial and is typical of osteoporosis patients in Germany. The baseline model was a cohort of 1,000 70-year-old women, who received risedronate for 3 years and were followed up for an overall observation period of 10 years, modelling transitions through estimated health states and evaluating outcomes. Over the 3-year treatment period and 10-year observation period, risedronate dominated the current average basic treatment in Germany. In the risedronate group 33 hip fractures were averted and 32 quality-adjusted life years (QALYs) were gained (discounted values). Risedronate treatment saves costs for German social insurance: the present net value of the associated costs from the perspective of German social insurance is [symbol: see text]10.66 million if risedronate treatment is used versus [symbol: see text]11 million if basic treatment is used. Thus, net savings of [symbol: see text]340,000 for the treatment group per 1,000 treated women were calculated. Furthermore, risedronate treatment is cost effective from the perspective of the statutory health insurance with costs per averted hip fracture in the analyzed population of [symbol: see text]33,856 and cost per QALY gained of [symbol: see text]35,690. Both results demonstrate cost-effectiveness and are far below the accepted threshold level of [symbol: see text]50,000. Based on this analysis, risedronate is a cost-effective treatment for postmenopausal osteoporosis within the German health care system, offering benefits for osteoporotic patients and for budget decision-makers.

Costs of Diabetes Mellitus (CoDiM) in Germany, direct per-capita costs of managing hyperglycaemia and diabetes complications in 2010 compared to 2001.

INTRODUCTION: To identify direct health care costs of patients with diabetes in Germany in 2010, with focus on costs of treating hyperglycaemia and costs caused by diabetes complications, and to compare findings with results from the CoDiM study 2001. MATERIAL AND METHODS: The cost analysis was based on administrative data (18.75% random sample of 1.5 million insured persons). Medical costs covered by statutory health insurance and costs covered by nursing care insurance were included. Incremental differences in costs of patients with diabetes (n=30 987) and age and sex-matched subjects without a diagnosis of diabetes (controls) were estimated according to the number and type of complications. Costs were standardised to the German population. RESULTS: In 2010, incremental medical costs attributed to diabetes were € 2 391 (95% confidence interval: 2 257-2 524) per patient with diabetes. Of that amount, 26.5% were spent for the management of hyperglycaemia (€ 633 (622-644)) and 73.5% for the treatment of comp-lications (€ 1 758 (1 627-1 889)). Nursing care contributed incremental costs of € 289 (249-330), of which 98.8% was due to complications. From 2001 to 2010 the incremental per-capita costs for medical and nursing care decreased by 4.8% (controls: +3.9%), the per-capita costs for treating hyperglycaemia increased by 2.0% and the per-capita costs for complications decreased by 7.0%. CONCLUSION: Cost for diabetes is largely caused by management of complications. It is important to prevent complications by consequent management of diabetes as well as by primary prevention of its onset.

Direct costs of diabetes mellitus in Germany - CoDiM 2000-2007.

INTRODUCTION: The prevalence of treated diabetes in Germany and direct health care costs of individuals with diabetes were analysed for the 8-year period from 2000 to 2007, based on administrative data. Special interest was given to the incremental costs attributed to diabetes. MATERIAL AND METHODS: An 18.75% sample of all members of a large local German statutory health insurance provider, "AOK - Die Gesundheitskasse" in the federal state of Hesse was analysed with regard to cases of treated diabetes. To assess the incremental diabetes-related direct costs, the cost data of individuals with diabetes was compared to that of an age- and sex-matched group of persons without diabetes. Prevalence and costs were standardized according to the gender and age distribution of the German population. RESULTS: Between 2000 and 2007, the administrative prevalence of treated diabetes rose continuously in Germany, from 6.5 to 8.9% (+36.8%). The number of patients treated with 'insulin' or 'insulin & oral antidiabetic agents' increased by +54.7 and +61.7%, respectively. Direct costs per patient with diabetes, calculated using the unit costs reimbursed by statutory health and nursing care insurances, rose from € 5 197 to € 5 726 (+10.2%). Incremental per-capita costs were € 2 400 in 2000 and € 2 605 in 2007 (+8.5%). However, the total direct cost burden of diabetes in Germany grew from € 27.8 billion to € 42.0 billion (+51.1%). The incremental diabetes-related cost burden increased from € 12.9 billion to € 19.1 billion (+48.6%). CONCLUSIONS: There was a continuous increase in the prevalence of diabetes in Germany during the 8-year period. Although there was only a modest increase in annual diabetes-related per-capita costs, total healthcare expenditure rose substantially due to the growing number of patients being treated for diabetes.

Diabetes Mellitus in German Primary Care: quality of glycaemic control and subpopulations not well controlled - results of the DETECT study.

INTRODUCTION: The quality of glycaemic control of patients with T1D and T2D can be assessed with HbA (1c) levels. We aimed to assess the quality of glycaemic control and the prevalence of inadequately controlled diabetes in German primary care, and to determine simple patient and treatment related factors associated with poor control. MATERIAL AND METHODS: Using a nationwide probability sample of 3 188 general practices (response rate 50.6%), a total of 55,518 patients were assessed in DETECT, a cross-sectional and prospective multistage epidemiological study. Diabetes diagnoses were based on physician assessment. HbA (1c) values were taken from the patient charts. RESULTS: The quality of metabolic control was unsatisfactory on the whole in the 277 people with T1D (e.g. mean HbA (1c)=7.4%+/-1.4%). The 8 188 people with T2D had a mean HbA (1c) of 6.89%+/-1.2%. 38.8% of individuals had an HbA (1c)>/=7.0%. The situation was less favourable in subjects with a longer history of diabetes - in many cases in those with diabetes for 5-9 years, but generally in those with a plus-10-year history of diabetes - and also in younger men with a shorter disease history. Patients with a short T2D history, especially older subjects had more favourable values. With regard to age, a higher percentage of patients had an HbA (1c)>/=7.0% (42.0% and 40.6%) in the 45-54 and 55-64 year olds. With respect to the correlation between HbA (1c) and treatment modality, we identified the best metabolic control in T2D patients without drug therapy for diabetes, and the worst in patients on combination regimens (OAD/insulin). The average duration of diabetes in the various treatment groups differs substantially. The average duration was highest (12.1 y) in the insulin group. Oral treatment was the predominant treatment modality in all HbA (1c) categories. CONCLUSION: T1D treatment needs to be improved overall. The situation as regards T2D is less clear-cut. When people with T2D start requiring more intensive and complex treatment in response to disease progression, the treatment efforts of patients and physicians evidently fail to keep up with the actual pace of metabolic deterioration. Early and strict alignment with approximately normal HbA (1c) targets is essential. Close attention should be paid to T2 diabetics with a 5-9-year diabetes history, with the aim of preventing any loss of metabolic control. Likewise, patients aged 45-64 y and younger men require more attention.

[Disease management program (DMP) diabetes mellitus: simulation of therapeutic results of different guidelines. A new diabetes mellitus model (DMM)]. / DMP Diabetes mellitus: Simulation der Behandlungsergebnisse verschiedener Leitlinien. Ein neues Diabetes mellitus Modell (DMM).

BACKGROUND AND OBJECTIVE: In conjunction with the introduction of disease management programmes in Germany there is an ongoing scientific debate on the desirable goals for HbA1c in the management of patients with type 2 diabetes mellitus. PATIENTS AND METHODS: In this study, a novel computer-based simulation model (diabetes mellitus model = DMM) was used to estimate the consequences of different levels of metabolic control as assessed by HbA1c for the development of short- and long-term complications of this disease. RESULTS: At a mean difference of 1 % the rate of severe hypoglycaemic events over 10 years was by 32-84 % higher in those with a lower HbA1c. In contrast, the incidence of microvascular complications (proliferative retinopathy, end-stage kidney disease, clinical neuropathy) was by 20-33 % lower in the group with the lower as compared to the higher HbA1c level according to the scenario applied. The rates of myocardial infarction and stroke were reduced by 15-20 % under these conditions. CONCLUSIONS: This model calculation suggests that a more strict metabolic control in patients with type 2 diabetes mellitus results in a greater reduction of microvascular complications than of macrovascular complications, but is associated with a higher rate of hypoglycaemic episodes. The diabetes mellitus model is a non-expensive alternative to simulate clinically relevant questions on the management of type 2 diabetes and to provide rapid and realistic answers.

[Contribution of leflunomide to the cost effectiveness of sequential DMARD therapy of rheumatoid arthritis in Germany]. / Wirtschaftlichkeit von Leflunomid bei sequentieller Basistherapie der rheumatoiden Arthritis in Deutschland.

Since November 1999, leflunomide (LEF), an innovative disease-modifying antirheumatic drug (DMARD), is available in Germany for treatment of rheumatoid arthritis (RA). LEF slows radiographic disease progression and improves functional capacity as well as healthrelated quality of life of RA patients. Resources for health care of the patients are limited in Germany as in all other countries. The purpose of the analysis therefore was to compare the cost effectiveness of the following alternatives: LEF in sequential monotherapy with other DMARDs versus sequential monotherapy of other DMARDs. The target variables of this cost-effectiveness comparison were additional direct costs per ACR20-response year (ACR20RY) gained and per quality-adjusted life year (QALY) gained, respectively, each after three years of treatment. The cost-effectiveness comparison was carried out using a modeling study after secondary analysis of relevant data. Oral methotrexate (MTX), sulphasalazine (SSZ), antimalarials (CQ/HCQ), intramuscular gold (IMG), and azathioprine (AZA) were selected as "other" DMARDs representing the current status of sequential monotherapy. Based on health care regulation in Germany-Guidelines on the Prescription of Drugs amended by the Federal Commission of Medical Practitioners and Health Insurance Funds on 10 December 1999-LEF was exclusively considered second within a DMARD sequence. Direct costs were given by outpatient and inpatient treatment, long-term care, and rehabilitation treatment. Prices relate to the period of 1998 to 2001 and were converted to Euro (euro), according to the official exchange rate of 1 euro = 1.95583 DM (1 euro approximately 0.90 US dollars; 2001 values). The comparative cost-effectiveness analysis covered a treatment period of more than one year. To estimate the net present value of future costs and effectiveness, a discount rate of 5% per year was applied. In the case of DMARD-naïve patients with RA, the sequence MTX, LEF, SSZ, IMG, AZA, CQ/HCQ was the most cost effective with direct costs of 7297 euro per ACR20RY and 6499 euro per QALY. In order to estimate the consequences of introducing LEF into the prescribing practice in Germany, the distribution of RA patients by individual DMARD in rheumatological care in 1998 was considered. This distribution was taken from the National Database of the German Collaborative Arthritis Centres. Though the sequences comprising LEF incurred 3% higher direct costs, they led to a higher effectiveness of 6% and 3% in the case of ACR20RYs and QALYs, respectively. Choosing sequences comprising LEF, there were additional direct costs of 5004 euro per ACR20RY gained and 8301 euro per QALY gained, as compared to the corresponding sequences without LEF. In comprehensive sensitivity analyses, the robustness of the model and its results was shown. The contribution of LEF to the cost effectiveness of sequential DMARD therapy is obvious. The modeling study revealed advantages for the patients and the cost carriers. Though there were initially higher medication costs of the sequences comprising LEF, these costs were nearly compensated to remaining excess costs of just 3% after three years. This was caused by cost savings in other sectors of the health care system due to the higher effectiveness of the sequences comprising LEF.