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Jens P Klussmann,1 Peter K Schädlich,2 Xiaoyu Chen,2 Vanessa Rémy31Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, Giessen, 2IGES Institut, Berlin, Germany; 3Sanofi Pasteur MSD, Lyon, FranceBackground: Data on the economic burden of head and neck cancers (HNCs) in Germany is scarce. About 16%–28% of these cancers are associated with human papillomavirus (HPV) infection. Therefore, the study reported here aimed to assess the annual costs of HPV-related HNCs incurred by hospitalization, inpatient rehabilitation, and sick leave in Germany in 2008.Methods: A cross-sectional retrospective analysis of five German databases covering hospital treatment, inpatient rehabilitation, and sick leave in 2008 was performed. All hospital, inpatient rehabilitation, and sick leave cases due to HNCs in 2008 were analyzed. Associated numbers of HNC hospitalizations, health care resource use, and costs were identified and extracted using the International Classification of Diseases, tenth revision (ICD-10; World Health Organization, Geneva, 1990) codes C01–C06, C09–C14, and C32 as the main diagnoses. Resources were valued with German official prices in 2008 euros (€). The annual costs of HPV-related HNCs were estimated based on the percentage of HNCs likely to be attributable to HPV infection.Results: In 2008, there were 63,857 hospitalizations, 4898 inpatient rehabilitations, and 17,494 sick leaves due to HNCs, representing costs of €365.78 million. The estimated annual costs associated with HPV-related HNCs were €78.22 million, mainly attributed to males (80%). Direct costs accounted for 84% (80% for hospital treatment, 4% for inpatient rehabilitation) and indirect costs due to sick leave accounted for 16% of HPV-related HNC costs.Conclusion: The economic burden of HPV-related HNCs in Germany in 2008 has been underestimated, since costs incurred by outpatient management, outpatient chemotherapy, long-term care, premature retirement, and premature death were not included. However, as far as we are aware, this study is the first analysis to investigate the economic burden of HNCs in Germany. The estimated annual costs of HPV-related HNCs contribute to a significant economic burden in Germany and should be considered when assessing the health and economic benefits of HPV vaccination in both sexes.Keywords: human papillomavirus, cost of illness, HPV, economic burden, 2008

OBJECTIVE: To estimate, from the perspective of Statutory Health Insurance (SHI, third-party payer) in Germany, the economic consequences of using the subcutaneous low-molecular-weight heparin (LMWH) enoxaparin instead of intravenous unfractionated heparin followed by oral phenprocoumon (UFH/PPC) for anticoagulation in patients undergoing transesophageal echocardiography (TEE)-guided early electrical cardioversion (ECV) of persisting nonvalvular atrial fibrillation (AF) without intracardiac clot. DESIGN AND SETTING: The incremental cost for the enoxaparin-based regimen versus the UFH/PPC-based regimen was chosen as the target variable. A decision-analytic model considering the in- and outpatient sectors was used to quantify the target variable. Resource use during in- and outpatient treatment was taken from the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial and from expert interviews with cardiologists in Germany in order to reflect the day-to-day conditions of clinical practice. Costs were given by SHI expenses for inpatient treatment and for medical services, drugs, disposables, and laboratory tests during outpatient treatment. These costs were determined by multiplying utilized resource items by the price or tariff of each item based on German healthcare regulations for the reference period of 2003/2004. According to the ACE trial, the evaluation encompassed 28 (26-30) treatment days with two consecutive phases. Phase I with 5 (3-12) days comprised diagnostics, start of anticoagulation, and ECV. Phase II with the remaining days consisted of continued anticoagulation and patient monitoring. The dosage of enoxaparin was 1 mg/kg bodyweight twice daily in treatment phase I followed by 40mg twice daily with a bodyweight <65kg or 60mg twice daily with a BW >/=65kg in treatment phase II. The daily dosages of UFH by continuous infusion and overlapping PPC were adjusted to an International Normalized Ratio of 2.0-3.0 in treatment phase I followed by 2.25mg PPC once daily in treatment phase II. Patients with any comorbidity and complication level (CCL) and those with low comorbidity and complications expected to occur in rare cases only (low-risk patients) were analyzed separately. In each base-case analysis, exclusively point estimates of all respective model parameters were applied. MAIN OUTCOME MEASURES AND RESULTS: There were savings of euro339 and euro579 per patient receiving the enoxaparin-based regimen versus the UFH/PPC-based regimen in the case of patients with any CCL and of low-risk patients, respectively (euro1 approximate, equals $US1.25; first quarter 2004 values). In comprehensive sensitivity analyzes, the robustness of the model and its results was shown. First, the impact of the model parameters on the target variable for each patient group was quantified in a deterministic model. Secondly, the dependency of the target variable on random variables was described for each patient group using Monte Carlo simulation. Irrespective of the patient group, the cost weight and the base rate of hospitals for inpatient ECV in phase I turned out to have the greatest impact on the savings obtained by the enoxaparin-based regimen. In the case of patients with any CCL, this impact was about 1.4-fold of that of the probability of enoxaparin patients undergoing outpatient ECV in phase I. In the case of low-risk patients, the impact of the cost weight and the base rate of hospitals for inpatient ECV in phase I was about 4.1-fold of that of the price of enoxaparin 60mg prefilled syringes in the outpatient sector. In 79% and 93% of 10 000 simulated comparisons each versus the UFH/PPC-based regimen, there were savings obtained by the enoxaparin-based regimen in patients with any CCL and in low-risk patients, respectively. CONCLUSIONS: Results of this evaluation showed that an enoxaparin-based regimen for TEE-guided ECV of AF in patients without intracardiac clot offers SHI in Germany a considerable saving potential when used instead of an UFH/PPC-based regimen. [ABSTRACT FROM AUTHOR]

Objective: Literature on the economic burden of anal cancer in Germany is scarce. About 84% of these cancers are associated with human papillomavirus infection. This study, therefore, aimed to assess the annual costs of human papillomavirus-related anal cancer incurred by hospitalization, inpatient rehabilitation, and sick leave in 2008 in Germany., Methods: A cross-sectional retrospective analysis of five German databases covering hospital treatment, inpatient rehabilitation, and sick leave in 2008 was performed. All hospital, inpatient rehabilitation, and sick leave cases due to anal cancer in 2008 were analyzed. Associated numbers of anal cancer hospitalizations, healthcare resource use, and costs were identified and extracted using the ICD-10 code C21 as the main diagnosis. The annual cost of human papillomavirus-related anal cancer was estimated based on the percentage of anal cancer likely to be attributable to human papillomavirus., Results: In 2008, there were 5774 hospitalizations (39% males, 61% females), 517 inpatient rehabilitations, and 897 sick leaves due to anal cancer representing costs of €34.11 million. The estimated annual costs associated with human papillomavirus-related anal cancer were €28.72 million, mainly attributed to females (62%). Direct costs accounted for 90% (86% for hospital treatment, 4% for inpatient rehabilitation) and indirect costs due to sick leave accounted for 10% of human papillomavirus-related costs., Conclusions: The economic burden of human papillomavirus-related anal cancer in 2008 in Germany is under-estimated, since costs incurred by outpatient management, outpatient chemotherapy, long-term care, premature retirement, and premature death were not included. However, this study is the first analysis to investigate the economic burden of anal cancer in Germany. The estimated annual costs of human papillomavirus-related anal cancer contribute to a significant economic burden in Germany and should be considered when assessing health and economic benefits of human papillomavirus vaccination in both genders.

Gout affects 1% to 2% of the population, and the prevalence is increasing due to changes in diet and the ageing of the population. Its development and risk factors have been explored frequently, and recommendations for the diagnosis and management of gout implemented. Nevertheless, there is a lack of knowledge regarding the long-term impact on gouty patients. This systematic review therefore evaluates the association between gout and all-cause as well as cardiovascular mortality. A systematic literature search was performed, and seven long-term studies were ultimately analyzed. Six of them used multivariate regressions to assess the adjusted mortality ratio in gouty patients with reference to patients without the disorder. Despite differences in study designs, study populations, and definitions of gout, the results were consistent: There was an independent association between gout and all-cause as well as cardiovascular mortality. Knowing that patients with gout are at risk emphasizes the need for adequate care.

Objective: Basal insulin analogs are well established in the treatment of type 1 diabetes in Germany. However, little is known about their economic impact. The aim of this study for an adult population was to compare, from the perspective of the Statutory Health Insurance (SHI), the cost effectiveness of the long-acting insulin analog glargine (GLA) with intermediate-acting neutral protamine Hagedorn (NPH) insulin in basal bolus therapy, considering the interaction between glycemic control and the rate of hypoglycemia., Methods: A validated discrete event simulation model was adapted to the German setting to project clinical and cost outcomes over 40 years. Resources were valued with German official prices in 2009/2010 Euros. Health-related disutilities were taken from UK sources. Patient characteristics and risk factors were partially extracted from German sources in a sensitivity analysis., Results: In the base-case analysis, GLA was dominant as it increased life expectancy by 0.196 years and improved quality-adjusted life-years (QALYs) by 0.396 units while at the same time leading to savings of €5246 each per patient after 40 years compared to NPH. These results were robust in the sensitivity analyses. Monte Carlo simulation confirmed dominance of GLA in 70% (life-years gained) and 80% (QALYs gained) of the iterations. The price of GLA had the highest impact on savings. In extreme scenarios, incremental cost-effectiveness ratios increased up to €9576 per QALY gained. Limitations of the evaluation included no myocardial re-infarction(s) and no recurrent stroke(s), patient characteristics, risk factors, and disutilities from the UK due to scarce data in Germany, and that not all diabetes-related direct costs were included, namely insulin pens and blood glucose meters., Conclusion: GLA appears to be cost effective or even cost saving among type 1 diabetics with basal bolus therapy from the perspective of SHI compared to NPH depending on the scenario chosen.

Background: Compared to conventional human basal insulin (neutral protamine Hagedorn; NPH) the long-acting analogue insulin glargine (GLA) is associated with a number of advantages regarding metabolic control, hypoglycaemic events and convenience. However, the unit costs of GLA exceed those of NPH. This study aims to systematically review the economic evidence comparing GLA with NPH in basal-bolus treatment (intensified conventional therapy; ICT) of type 1 diabetes in order to facilitate informed decision making in clinical practice and health policy., Methods: A systematic literature search was performed for the period of January 1st 2000 to December 1st 2009 via Embase, Medline, the Cochrane Library, the databases GMS (German Medical Science) and DAHTA (Deutsche Agentur für Health Technology Assessment), and the abstract books of relevant international scientific congresses. Retrieved studies were reviewed based on predefined inclusion criteria, methodological and quality aspects. In order to allow comparison between studies, currencies were converted using purchasing power parities (PPP)., Results: A total of 7 health economic evaluations from 4 different countries fulfilled the predefined criteria: 6 modelling studies, all of them cost-utility analyses, and one claims data analysis with a cost-minimisation design. One cost-utility analysis showed dominance of GLA over NPH. The other 5 cost-utility analyses resulted in additional costs per quality adjusted life year (QALY) gained for GLA, ranging from € 3,859 to € 57,002 (incremental cost effectiveness ratio; ICER). The cost-minimisation analysis revealed lower annual diabetes-specific costs in favour of NPH from the perspective of the German Statutory Health Insurance (SHI)., Conclusions: The incremental cost-utility-ratios (ICER) show favourable values for GLA with considerable variation. If a willingness-to-pay threshold of £ 30,000 (National Institute of Clinical Excellence, UK) is adopted, GLA is cost-effective in 4 of 6 cost utility analyses (CUA) included. Thus insulin glargine (GLA) seems to offer good value for money. Comparability between studies is limited because of methodological and country specific aspects. The results of this review underline that evaluation of insulin therapy should use evidence on efficacy of therapy from information synthesis. The concept of relating utility decrements to fear of hypoglycaemia is a plausible approach but needs further investigation. Also future evaluations of basal-bolus insulin therapy should include costs of consumables such as needles for insulin injection as well as test strips and lancets for blood glucose self monitoring.

Background and Objectives: The purpose of this study was to review studies reporting on quality of life and treatment satisfaction of patients with diabetes mellitus being treated with long-acting insulin analogues., Material and Methods: A systematic literature search was made of trials published between January 1, 2000 and June 28, 2007. Retrieved studies were analysed, using predefined inclusion criteria as well as methodological and quality aspects., Results: Twelve studies were included, all of them dealing with insulin glargine as the trial drug or for comparison. With regard to treatment satisfaction, insulin glargine was superior in one head-to-head comparison with NPH (neutral protamine Hagedorn) and one head-to-head comparison with NPH as an add-on to oral glimepiride. There was no difference in comparisons with continuous subcutaneous insulin infusion (CSII), insulin aspart or exenatide. Regarding health related quality of life (HRQoL), insulin glargine was shown to be superior to rosiglitazone as an add-on to metformin and sulfonylurea. Again, there were no differences in comparisons with NPH, CSII or exenatide., Conclusion: There are only a limited number of high quality studies showing that insulin glargine is superior regarding treatment satisfaction and HRQoL of patients with diabetes mellitus. There are fewer publications with good evidence of patient-reported outcomes than those reporting well-established outcomes using HbA1c levels or the incidence of hypoglycaemia.

Objective: To estimate, from the hospital perspective in Germany, the cost effectiveness of the low-molecular-weight heparin (LMWH) subcutaneous enoxaparin sodium 40 mg once daily (ENOX) relative to no pharmacological prophylaxis (NPP) and relative to subcutaneous unfractionated heparin (UFH) 5,000 IU three times daily (low-dose UFH [LDUFH]). Each is used in addition to elastic bandages/compression stockings and physiotherapy in the prevention of venous thromboembolic events (VTE) in immobilised acutely ill medical inpatients without impaired renal function or extremes of body weight., Methods: The incremental cost-effectiveness ratios (ICERs) of the 'additional cost for ENOX per clinical VTE avoided versus NPP' and 'additional cost for ENOX per episode of major bleeding avoided versus LDUFH' were chosen as target variables. The target variables were quantified using a modelling approach based on the decision-tree technique. Resource use during thromboprophylaxis, diagnosis and treatment of VTEs, episode of major bleeding and secondary pneumonia after pulmonary embolism (PE) was collected from a hospital survey. Costs were exclusively those to hospitals incurred by staff expenses, drugs, devices, disposables, laboratory tests and equipment for diagnostic procedures. These costs were determined by multiplying utilised resource items by the price or tariff of each item as of the first quarter of 2003. Safety and efficacy values of the comparators were taken from the MEDENOX (prophylaxis in MEDical patients with ENOXaparin) and the THE-PRINCE (THromboEmbolism-PRevention IN Cardiac or respiratory disease with Enoxaparin) trials and from a meta-analysis. The evaluation encompassed 8 (6-14) days of thromboprophylaxis plus time to treat VTE and episode of major bleeding in hospital. Point estimates of all model parameters were applied exclusively in the base-case analysis., Results: There were incremental costs of euro 1,106 for ENOX per clinical VTE avoided versus NPP (1 euro approximately equals 1.07 US dollars; average of the first quarter of 2003). ENOX dominated LDUFH: cost savings of euro 55,825 were obtained and 7.7 episodes of major bleeding were avoided by ENOX compared with LDUFH, each per 1000 patients. In comprehensive sensitivity analyses, the robustness of the model and its results was shown., Conclusions: Results of this evaluation suggest that, in immobilised acutely ill medical inpatients, ENOX may offer hospitals in Germany a very cost-effective option for thromboprophylaxis compared with NPP and a cost-saving alternative compared with LDUFH.

Objective: To quantify direct costs of medication and cost of illness (according to functional capacity) for patients with rheumatoid arthritis (RA) in Germany, allowing further use in a health economic evaluation of sequential therapy with disease-modifying antirheumatic drugs (DMARDs) in specialised, i.e. rheumatological, care in Germany., Design and Setting: The analysis was conducted from the societal perspective in Germany using a modelling approach, which was based on secondary analysis of existing data and on data from a sample of 583 patients from the German rheumatological database of 1998. Functional capacity was defined by the Hannover Functional Ability Questionnaire (HFAQ) scores. Costs were calculated from resources utilised and patients' work capacity. Direct costs consisted of outpatient medical services, inpatient treatment, long-term care and rehabilitation treatment. Indirect costs incurred by sick leave and premature retirement were quantified according to the human-capital approach., Main Outcome Measures and Results: Average total direct costs (year 1998-2001 values) per patient per year for continuous treatment with the selected DMARDs comprising costs for drugs, monitoring and treatment of adverse drug reactions (ADRs) were highest for intramuscular gold (sodium aurothiomalate) [euro 2106 (euro 1 approximately equal to $US 0.91; average of the period from 2000 through 2001)] followed by leflunomide (euro 2010), azathioprine (euro 1878), sulfasalazine (euro 1190), oral methotrexate (euro 708), and lowest for the antimalarials chloroquine/hydroxychloroquine (euro 684). There were additional yearly costs for RA-related non-DMARD medication of euro 554 per patient, including management of ADRs. Mean cost of illness (year 1998 values) excluding medication cost amounted to euro 17,868 per RA patient per year. Annual costs increased with increasing disability, i.e. decreasing functional capacity, of RA patients from euro 6029 per patient with more than 94% of functional capacity to euro 28,509 per patient with <20% of functional capacity. In general, there was a predominance of indirect costs in each of the categories of functional capacity, ranging between 74% and 87% of total (direct and indirect) annual costs per RA patient. Annual direct costs increased from euro 811 to euro 7438 per patient with increasing disability. Inpatient treatment was the predominant component of direct costs. Patients in the worst category (<20%) of function experienced hospital costs that were 6.5 times higher than those of patients in the best category (>94%)., Conclusions: On the basis of the data presented it can be concluded that the results of this investigation are typical for patients in rheumatological care in Germany and can therefore be used in a health economic analysis of different DMARD sequences aimed at changing disease progression over time.

Objective: To estimate the 3-year incremental cost effectiveness and cost utility of introducing leflunomide into sequential therapy, consisting of the most frequently used disease-modifying antirheumatic drugs (DMARDs), for patients with rheumatoid arthritis in specialised, i.e. rheumatological, care in Germany., Design and Setting: The analysis was conducted from the societal perspective in Germany using an existing 3-year simulation model, which was adapted to the German healthcare system after secondary analysis of relevant publications and data. DMARD sequences including leflunomide were compared with those excluding leflunomide. Costs comprised direct costs incurred by treatment and indirect costs incurred by loss of productivity (sick leave and premature retirement) of rheumatoid arthritis patients. Effectiveness parameters were given by response years gained (RYGs) according to the American College of Rheumatology (ACR) criteria for 20%, 50% and 70% improvement (ACR20/50/70RYGs) and by QALYs gained (QALYGs). Costs, effects and QALYs were discounted by 5% per annum. In the base-case analysis, average values of costs, response years and QALYs were applied. Costs were in 1998-2001 values (euro 1 approximately equal to $US 0.91, average of the period from the year 2000 through 2001)., Main Outcome Measures and Results: After 3 years, adding leflunomide was less costly and more effective than the strategy excluding leflunomide when total (direct and indirect) costs were considered. There were savings of euro 271,777 and 8.1, 4.3, 5.1 and 4.9 ACR20RYGs, ACR50RYGs, ACR70RYGs and QALYGs per 100 patients, respectively, obtained through adding leflunomide. Focusing on direct costs, adding leflunomide was more costly and more effective compared with excluding leflunomide, with an incremental cost effectiveness of euro 5004 per ACR20RYG, euro 9535 per ACR50RYG, euro 7996 per ACR70RYG, and an incremental cost utility of euro8301 per QALYG, after 3 years. The robustness of the results was shown in comprehensive sensitivity analyses. In the analysis of extremes, different combinations of the limits of cost, effectiveness and utility parameters were investigated. Adding leflunomide to sequential DMARD therapy remained dominant in 79% of the possible cases, i.e. was less costly and more effective than the strategy excluding leflunomide. Focusing on direct costs, adding leflunomide became dominant in 29% and remained more costly and more effective in 50% of possible cases., Conclusions: Our analysis suggests, with its underlying data and assumptions, that having leflunomide as an additional option in a DMARD treatment sequence extends the time patients benefit from DMARD therapy at reasonable additional direct costs. Adding leflunomide may even be cost saving when total (direct and indirect) costs are considered. As data on DMARD effectiveness were extracted from the results of clinical trials, real-world data from observational studies would be needed to corroborate the findings of the present analysis.

Background: Ramipril may prevent cardiovascular death, myocardial infarction and stroke in patients without evidence of left ventricular dysfunction or heart failure who are at high risk for cardiovascular events. In the present study we assessed the cost-effectiveness of ramipril in patients with an increased risk of cardiovascular events from a third party payer's perspective in Switzerland. In addition, the cost-effectiveness of ramipril in the subgroup of diabetic patients was assessed., Methods: We developed a decision analytic cost-effectiveness model to estimate the incremental costs (in 2001 in Swiss Francs [CHF]), incremental effects (in terms of life-years gained [LYG]) and incremental cost-effectiveness (CHF per LYG) of ramipril versus placebo. Clinical input parameters were derived from the Heart Outcomes Prevention Evaluation (HOPE) study. Cost data were extracted from the literature. Deterministic sensitivity analysis was used to assess the impact of varying the input parameters on the cost effectiveness of the intervention. In addition, first order Monte Carlo simulation was used to capture patient-to-patient variability, presented as cost-effectiveness acceptability curves., Results: The incremental cost-effectiveness ratio of ramipril versus placebo was CHF 6,005 per life-year gained in the base case analysis. In diabetic patients the cost-effectiveness ratio was CHF 3,790 per life-year gained. Varying the price of ramipril in a deterministic sensitivity analysis only had a moderate impact on the cost-effectiveness ratio in the overall population (range: CHF 3,652-15,418 per LYG) as well as in diabetic patients (range: CHF 2,370-9,468 per LYG)., Conclusion: Ramipril in patients at high risk for cardiovascular events represents an efficient use of scarce health care resources in Switzerland and is cost-effective under reasonable assumptions. Ramipril is even more cost-effective in the subgroup of diabetic patients.

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.

Background: In the HOPE (Heart Outcomes Prevention Evaluation) trial, ramipril (compared with placebo) significantly reduced cardiovascular death and all-cause mortality as well as the incidence of costly cardiovascular events, such as myocardial infarction, revascularisation, stroke, cardiac arrest, hospitalisation due to heart failure and worsening angina pectoris, new-onset diabetes mellitus and microvascular diabetic complications., Objective: Data from the HOPE study were used in a cost-effectiveness analysis to determine the additional cost per life-year gained (LYG) when the ACE inhibitor ramipril was added to the current medication of patients at high risk for cardiovascular events. The aim was to establish the incremental cost-effectiveness ratio (ICER) of ramipril versus placebo from the perspective of the Statutory Health Insurance (SHI) provider in Germany, for both the study population as a whole and for the subgroup of patients with diabetes., Design: A modelling approach was used, based on secondary analysis of published data and retrospective application of costs. In the base-case analysis, average case-related expenses of the SHI were applied and LYG were quantified using the average of the difference between the survival rates in the ramipril and placebo groups during the HOPE trial. LYG beyond the trial duration were estimated by the method of declining exponential approximation of life expectancy., Results: After a treatment period of 4.5 years, the ICER of ramipril versus placebo was Euros 4074/LYG and Euros 2486/LYG (discounted at 5% per annum and in 1998-2002 values; Euro 1 approximately USD 0.88; first quarter 2002 values) for the HOPE study population as a whole and the subgroup of patients with diabetes, respectively. To test the model's robustness, the influence of the model variables on the results was quantified using a deterministic model, and a best-case/worst-case scenario analysis. The effect of random variables was investigated in a Monte Carlo simulation. The acquisition cost for ramipril had the greatest impact on the ICER of ramipril (2.2-fold greater than the impact of the number of LYG). In 95% of the 10,000 simulation steps, the ICER of ramipril after 4.5 years of treatment was between Euros 1290 and Euros 9005 per LYG for the entire HOPE study population and between Euros 290 and Euros 6115 per LYG in the diabetic subgroup., Conclusions: Results of this evaluation suggest that ramipril is likely to be cost effective in secondary prevention of cardiovascular events from the perspective of the SHI (third-party payer) in Germany. The estimated ICER of ramipril compares well with other ICERs of widely accepted treatments used for the management of cardiovascular diseases, such as HMG-CoA reductase inhibitors.

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.

Objective: To use published data to compare the economic consequences of specific immunotherapy (SIT) lasting 3 years with those of continuous symptomatic treatment in patients with either pollen or mite allergy., Design and Setting: The evaluation was conducted from the following 3 perspectives in Germany: (i) society; (ii) healthcare system; and (iii) statutory health insurance (SHI) provider. A modelling approach was used which was based on secondary analysis of existing data. The follow-up period was 10 years. The break-even point of cumulated costs, their difference per patient and the additional cost per additional patient free from asthma symptoms [incremental cost-effectiveness ratio (ICER)] were used as target variables, each from the viewpoint of SIT. The types of costs were direct and indirect (society), direct (healthcare system) and those incurred by SHI (i.e. expenses). In the base-case analysis, the average values of the clinical parameters and average case-related costs/expenses were applied., Main Outcome Measures and Results: The break-even point was reached between year 6 and year 8 after the start of therapy, resulting in net savings of between 650 and 1190 deutschmarks (DM) per patient after 10 years. The ICERs of SIT were between -DM3640 and -DM7410, depending on study perspective and nature of the allergy (1990 values for symptomatic treatment and treatment of asthma, 1995 values for SIT; DM1 approximately $US0.58). The sensitivity analysis demonstrated the robustness of the model and its results. First, all the independent variables of the model were varied. Secondly, the influence of the model variables was quantified using a deterministic model. SIT was more likely to result in net savings than in additional costs. An economic parameter (cost for symptomatic treatment) had the highest influence on the results., Conclusions: This evaluation showed that SIT for 3 years is economically advantageous in patients who are allergic to pollen or mites and whose symptoms are inadequately controlled by continuous symptomatic treatment. After 10 years, the administration of SIT leads to net savings from the perspectives of society, the healthcare system and SHI (third-party payer) in Germany.

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.

Alcoholism places a considerable economic burden on society. The rate of relapse of previously weaned alcoholics has been shown to decrease following treatment with acamprosate. Therefore, this study investigated the cost effectiveness of acamprosate in the treatment of alcoholism in Germany from the perspective of the German healthcare system. In this retrospective analysis of clinical data, the additional direct medical costs per additional abstinent alcoholic incurred by adjuvant acamprosate therapy of previously weaned alcoholics were quantified. In the base-case analysis, average case-related direct costs were applied. The cost-effectiveness ratio was -2600 deutschmarks (DM) per additional abstinent patient. Thus, the administration of acamprosate is cost saving. The cost benefit of acamprosate was also shown in a sensitivity analysis. The variance of the target variable under 'real world' conditions was simulated and the impact of the model variables on the target variable was quantified using a deterministic model. The variance was broad and the rate of abstinence under acamprosate was the independent variable with the greatest impact on the target variable. From the perspective of both the German healthcare system (i.e. direct medical costs) and the Statutory Health Insurance expenses, adjuvant acamprosate therapy led to net savings, while at the same time improved the patient's state of health. Based on the naturalistic design of the underlying clinical trial and on this economic evaluation, it can be concluded that adjuvant acamprosate therapy leads to net savings under 'real world' conditions.

The Cardiac Insufficiency Bisoprolol Study (CIBIS) demonstrates that, for patients with heart failure of different aetiologies, administration of the beta 1-adrenoceptor blocker bisoprolol as an adjuvant to the standard therapy leads to a significant avoidance of hospital admissions. A pharmacoeconomic analysis of the results of the CIBIS was conducted for the Federal Republic of Germany, and was restricted to direct costs only. The costs of bisoprolol medication and inpatient treatment of heart failure were considered, the latter forming the major part of costs incurred. Per 1000 patient-years, adjuvant bisoprolol therapy resulted in overall cost savings of Deutschmarks (DM)157,272. Statutory Health Insurance had a net saving of DM186,719 in 1000 patient-years, while patients experienced additional net expenses of DM17,760 over 1000 patient-years. The economic advantage of adjuvant bisoprolol treatment was also borne out in the sensitivity analysis. Adjuvant therapy with bisoprolol was not only clinically beneficial for the patient with heart failure but was also economically advantageous.

Background: The Cardiac Insufficiency Bisoprolol Study (CIBIS) demonstrates that, for patients with heart failure of different etiologies, the administration of the beta(1)-adrenoceptor blocker bisoprolol adjuvant to the standard therapy leads to a significant avoidance of hospital admissions., Pharmacoeconomic Evaluation: The results of the CIBIS were evaluated pharmacoeconomically for the Federal Republic of Germany, and were restricted to direct costs only. The costs of bisoprolol medication and in-patient treatment of heart failure were considered, the latter forming the major part of costs incurred., Conclusion: Adjunctive therapy with bisoprolol is not only clinically beneficial to the patient with heart failure, but also economically advantageous.

The purpose of this study is to estimate the potential of savings which can be achieved by prophylaxis of myocardial reinfarction with low-dose acetylsalicylic acid (ASA) at 75 mg per day over a treatment period of two years. After secondary analysis of published data, the effectiveness of low-dose ASA is compared to placebo by a model calculation. The difference in the effectiveness between the prophylaxis with ASA and placebo is taken from an international meta-analysis. The economic valuation of this difference is carried out by a cost-effectiveness analysis applying disease costs per case. According to the model calculation, 5535 DM can be saved per patient with a history of myocardial infarction with 75 mg ASA a day over a treatment period of two years. In 1991 there were around 740,000 patients with a history of myocardial infarction in the age group of 25-64 in the Old Bundesländer of the Federal Republic of Germany. The application of the results of the model calculation would lead to considerable savings. Even in the sensitivity analysis with different assumptions regarding costs incurred by hospital treatment and costs incurred by premature retirement, the cost advantage of the ASA-prophylaxis remains. Due to the cautious and conservative assumptions in the model calculation the potential of savings is likely underestimated. Nevertheless, there is a distinct advantage for the prophylaxis with low-dose ASA which already occurs in direct costs thus leading to advantages also for cost carriers.

The purpose of this study was to estimate the direct and indirect costs of alcoholism in the Federal Republic of Germany. Direct costs comprised treatment costs, while indirect costs consisted mainly of costs incurred as a result of work time lost, as well as costs related to premature retirement and premature mortality. The costs of alcoholism were estimated using the aggregated statistics of several social security organisations and official statistics. For the purposes of this study, alcoholism was defined as alcohol dependence syndrome [9th revision of the International Classification of Diseases code (ICD) 303], alcoholic chronic liver disease and cirrhosis (ICD 571.0 to 571.3), and alcoholic psychoses (ICD 291). The reference period consisted of the years 1985 to 1991. All statistics and all analyses were limited to the so-called old states of Germany, within the boundaries as they were before 3rd October 1990. The overall monetary burden (in 1990 Deutschemarks) of alcoholism in the western part of Germany in 1990 was estimated to be DM5975 million. Alcoholism is associated with considerably more indirect costs (DM4422 million) than direct costs (DM1553 million). The predominance of indirect costs is mainly the result of the very high premature mortality of patients with alcoholism. Thus, the cost of premature mortality makes up more than half of the indirect costs of alcoholism (DM2284 million), while about a quarter of the indirect costs (DM1150 million) are associated with inability to work. Early retirement accounts for a similar amount (DM988 million). The majority of direct costs is accounted for by treatment in acute hospitals (DM869 million). Costs incurred as a result of rehabilitation treatment (DM373 million) and ambulatory care (DM331 million) are also considerable.

The opening paper of this symposium discusses the theme [European self-sufficiency and haemophilia prophylaxis: achievable goals or idealistic concepts?' from four aspects: (a) the meaning and interpretation of self-sufficiency in the European Community; (b) a summary of the facts, discussions and developments of the last 20 years; (c) a description of future aims and objectives; and (d) a discussion of what this symposium hopes to achieve. The author suggests that one most important point is to find an adequate definition of the term [self-sufficiency' in this context.

Since 1986, the Federal Health Office (BGA) has supported the model project "Monitoring Adverse Drug Reactions (ADRs) in the Surgeries of Office-Based Physicians". The project itself is being carried out by the Institute for Health Systems Research in Kiel. The aim of the project is to develop a method for the systematic monitoring of the risks involved with selected new drugs. This should also facilitate the determining of the incidence rate of ADRs as well as reveal as yet unknown ADRs. Several conclusions can be drawn when examining the quality of event data when monitoring ADRs through office-based physicians. The documentation quality of the transferred data fluctuates from surgery to surgery. In order to obtain valid outcomes, the data should be thoroughly examined and checked by consulting the participating surgery. When quantifying known events with a suspected ADR, the Sentinel approach leads to reliable results. When monitoring drug therapies through office-based physicians, risk situations can be monitored and assessed more easily under everyday conditions. When assessing the quality of event data with regard to disclosing hitherto unknown, potential ADRs, the character of the individual surgery is of utmost importance. The object of the research project is to examine cause-effect associations which have nothing whatsoever to do with the participating physicians themselves but which reflect interactions between drugs and patients.