New insights into the epidemiology of ANCA-associated vasculitides in Germany: results from a claims data study.

OBJECTIVE: ANCA-associated vasculitides (AAV) are rare, potentially life-threatening autoimmune diseases characterized by systemic inflammation and organ damage. AAV prevalence rates reported in Europe vary considerably and robust data sources are often lacking. This study aimed to examine the feasibility of claims data analysis as a complementary method to registry-based studies to assess the epidemiology of AAV. METHODS: In this retrospective observational study, anonymized longitudinal claims data from years 2013-2016 from German statutory health insurance companies (data source: InGef, Institute for Applied Health Research) have been analysed on an age- and gender-stratified cohort of ∼3 million persons representative of the German population. In this cohort, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) patients were identified. RESULTS: The study cohort revealed a prevalence for GPA and MPA of 210 and 46 cases per million people, respectively. The annual incidence comprised 34 GPA cases and 13 MPA cases per million people per year. Hence, 17 500 AAV patients (GPA and MPA) are estimated to live in Germany, with an annual increase of 3200 patients. According to their demographic and disease-specific characteristics, AAV patients identified in this claims data approach are representative. CONCLUSION: This is the first study using claims data to assess the epidemiology of AAV. In Germany, AAV was diagnosed more frequently than it was estimated by previous self-reporting registry-based studies. The findings indicate that epidemiological data of AAV may have been underestimated but may also reflect improved diagnostic methods and disease recognition.

Medical Data Management - Approach, Concepts, Strategic and Operative Implications. / Medizinische Datenhaltung ­ Ansatz, Konzepte, strategische und operative Implikationen.

The collection, analysis and management of clinical data with electronic applications has already widely been used. The digitalization of medical records is expected to bear significant potentials for the increase of clinical efficiency and effectiveness. This has led to numerous legal initiatives by policymakers and healthcare systems in many countries to secure the spatially inclusive and comprehensive establishment of electronic health records in preferably all medical entities. The following article describes the principles of electronic medical data management and exemplifies the different approaches which are followed internationally. Furthermore, it discusses how medical data management systems create value in terms of higher clinical quality or lower treatment and administrative costs. And finally, the strategic and operative implications are deducted and concrete opportunities for action are described how the introduction of electronic health records may be optimally structured.

[Health-economic modeling on the use of drug-eluting stents versus coronary artery bypass graft surgery in coronary heart disease]. / Gesundheitsökonomische Modellierung zum Einsatz von Medikamente freisetzenden Stents im Vergleich zu Bypassoperationen bei koronarer Herzkrankheit.

BACKGROUND AND PURPOSE: The therapy of coronary heart disease (CHD) leads to an enormous economic burden on health-care systems. Coronary artery bypass grafting (CABG) and percutaneous revascularizations with implantation of drug-eluting stents (DES) are important treatment methods in CHD. The presented evaluation addresses cost efficacy of the use of DES versus CABG in CHD patients. METHODS: A health-economic model considering linear resource use was performed from a restricted societal perspective for time periods of 1 and 3 years. Because of the short time horizon discounting was not applied. The clinical assumptions for event rates at 1 and 3 years were derived from the ARTS-I study for CABG, and from the ARTS-II study for DES (sirolimus-eluting stents). Cost assumptions for the resources used were based on the German Diagnosis Related Groups 2007 (G-DRG-2007). The base case value was assumed to be 2,800 Euros, the average DES price 1,200 Euros, and the average DES use per patient 3.7. The average per-patient daily clopidogrel costs were assumed to be 2.57 Euros, and the duration of the clopidogrel therapy 12 months. Within the scope of sensitivity analyses, different model parameters were varied and the evaluation was tested for its robustness. RESULTS: The average costs for percutaneous coronary intervention (PCI) without DES were found to be 4,420 Euros, for CABG 12,840 Euros, and for DES intervention 8,860 Euros (Table 4). 1-year clopidogrel intake resulted in 938 Euros, the treatment of patients with myocardial infarction during follow-up in 3,989 Euros. The 1-year per-patient total costs after CABG were calculated to be 13,373 Euros and after DES 10,443 Euros, leading to a difference of 2,930 Euros in favor of DES implantation (Table 6). The 3-year per-patient total costs after CABG were estimated to be 13,630 Euros and after DES 10,905 Euros, showing a Rehabilitationsmasscost difference of 2,725 Euros in favor of DES implantation (Table 6). Changes in cost-weights of G-DRG-2007 for CABG and PCI, DES price and DES use per patient as well as in the duration of the clopidogrel therapy influenced the cost differences considerably; however, they did not reach a break-even point (Figures 2 and 3). Changes in the clinical follow-up assumptions showed a lower effect on the difference in total costs (Figures 2 and 3). CONCLUSION: The presented data, indicating a possible economic middle-term advantage of DES versus CABG, should be proven with clinical assumptions derived from randomized clinical trials.

CT coronary angiography vs. invasive coronary angiography in CHD.

SCIENTIFIC BACKGROUND: Various diagnostic tests including conventional invasive coronary angiography and non-invasive computed tomography (CT) coronary angiography are used in the diagnosis of coronary heart disease (CHD). RESEARCH QUESTIONS: The present report aims to evaluate the clinical efficacy, diagnostic accuracy, prognostic value cost-effectiveness as well as the ethical, social and legal implications of CT coronary angiography versus invasive coronary angiography in the diagnosis of CHD. METHODS: A systematic literature search was conducted in electronic data bases (MEDLINE, EMBASE etc.) in October 2010 and was completed with a manual search. The literature search was restricted to articles published from 2006 in German or English. Two independent reviewers were involved in the selection of the relevant publications. The medical evaluation was based on systematic reviews of diagnostic studies with invasive coronary angiography as the reference standard and on diagnostic studies with intracoronary pressure measurement as the reference standard. Study results were combined in a meta-analysis with 95 % confidence intervals (CI). Additionally, data on radiation doses from current non-systematic reviews were taken into account. A health economic evaluation was performed by modelling from the social perspective with clinical assumptions derived from the meta-analysis and economic assumptions derived from contemporary German sources. Data on special indications (bypass or in-stent-restenosis) were not included in the evaluation. Only data obtained using CT scanners with at least 64 slices were considered. RESULTS: No studies were found regarding the clinical efficacy or prognostic value of CT coronary angiography versus conventional invasive coronary angiography in the diagnosis of CHD. Overall, 15 systematic reviews with data from 44 diagnostic studies using invasive coronary angiography as the reference standard (identification of obstructive stenoses) and two diagnostic studies using intracoronary pressure measurement as the reference standard (identification of functionally relevant stenoses) were included in the medical evaluation. Meta-analysis of the nine studies of higher methodological quality showed that, CT coronary angiography with invasive coronary angiography as the reference standard, had a sensitivity of 96 % (95 % CI: 93 % to 98 %), specificity of 86 % (95 % CI: 83 % to 89 %), positive likelihood ratio of 6.38 (95 % CI: 5.18 to 7.87) and negative likelihood ratio of 0.06 (95 % CI: 0.03 to 0.10). However, due to non-diagnostic CT images approximately 3.6 % of the examined patients required a subsequent invasive coronary angiography. Using intracoronary pressure measurement as the reference standard, CT coronary angiography compared to invasive coronary angiography had a sensitivity of 80 % (95 % CI: 61 % to 92 %) versus 67 % (95 % CI: 51 % to 78 %), a specificity of 67 % (95 % CI: 47 % to 83 %) versus 75 % (95 % CI: 60 % to 86 %), an average positive likelihood ratio of 2.3 versus 2.6, and an average negative likelihood ratio 0.3 versus 0.4, respectively. Compared to invasive coronary angiography, the average effective radiation dose of CT coronary angiography was higher with retrospective electrocardiogram (ECG) gating and relatively similar with prospective ECG gating. The health economic model using invasive coronary angiography as the reference standard showed that at a pretest probability of CHD of 50 % or lower, CT coronary angiography resulted in lower cost per patient with true positive diagnosis. At a pretest probability of CHD of 70 % or higher, invasive coronary angiography was associated with lower cost per patient with true positive diagnosis. Using intracoronary pressure measurement as the reference standard, both types of coronary angiographies resulted in substantially higher cost per patient with true positive diagnosis. Two publications dealing explicitly with ethical aspects were identified. The first addressed ethical aspects regarding the principles of beneficence, autonomy and justice, and the second addressed those regarding radiation exposition, especially when used within studies. DISCUSSION: The discriminatory power of CT coronary angiography to identify patients with obstructive (above 50 %) coronary stenoses should be regarded as "high diagnostic evidence", to identify patients without coronary stenoses as "persuasive diagnostic evidence". The discriminatory power of both types of coronary angiography to identify patients with or without functionally relevant coronary stenoses should be regarded as "weak diagnostic evidence". It can be assumed that patients with a high pretest probability of CHD will need invasive coronary angiography and patients with a low pretest probability of CHD will not need subsequent revascularisation. Therefore, CT coronary angiography may be used before performing invasive coronary angiography in patients with an intermediate pretest probability of CHD. For identifying or excluding of obstructive coronary stenosis, CT coronary angiography was shown to be more cost-saving at a pretest probability of CHD of 50 % or lower, and invasive coronary angiography at a pretest probability of CHD of 70 % or higher. The use of both types of coronary angiography to identify or to exclude functionally relevant coronary stenoses should be regarded as highly cost-consuming. WITH REGARD TO ETHICAL, SOCIAL OR LEGAL ASPECTS, THE FOLLOWING POSSIBLE IMPLICATIONS WERE IDENTIFIED: under-provision or over-provision of health care, unnecessary complications, anxiety, social stigmatisation, restriction of self-determination, unequal access to health care, unfair resource distribution and legal disputes. CONCLUSION: From a medical point of view, CT coronary angiography using scanners with at least 64 slices should be recommended as a test to rule out obstructive coronary stenoses in order to avoid inappropriate invasive coronary angiography in patients with an intermediate pretest probability of CHD. From a health economic point of view, this recommendation should be limited to patients with a pretest probability of CHD of 50 % or lower. From a medical and health economic point of view, neither CT coronary angiography using scanners with at least 64 slices nor invasive coronary angiography may be recommended as a single diagnostic test for identifying or ruling out functionally relevant coronary stenoses. To minimise any potential negative ethical, social and legal implications, the general ethical and moral principles of benefit, autonomy and justice should be considered.

Bone graft substitutes for the treatment of traumatic fractures of the extremities.

UNLABELLED: HEALTH POLITICAL AND SCIENTIFIC BACKGROUND: Bone graft substitutes are increasingly being used as supplements to standard care or as alternative to bone grafts in the treatment of traumatic fractures. RESEARCH QUESTIONS: The efficacy and cost-effectiveness of bone graft substitutes for the treatment of traumatic fractures as well as the ethical, social and legal implications of their use are the main research questions addressed. METHODS: A systematic literature search was conducted in electronic medical databases (MEDLINE, EMBASE etc.) in December 2009. Randomised controlled trials (RCT), where applicable also containing relevant health economic evaluations and publications addressing the ethical, social and legal aspects of using bone graft substitutes for fracture treatment were included in the analysis. After assessment of study quality the information synthesis of the medical data was performed using metaanalysis, the synthesis of the health economic data was performed descriptively. RESULTS: 14 RCT were included in the medical analysis, and two in the heath economic evaluation. No relevant publications on the ethical, social and legal implications of the bone graft substitute use were found. In the RCT on fracture treatment with bone morphogenetic protein-2 (BMP-2) versus standard care without bone grafting (RCT with an elevated high risk of bias) there was a significant difference in favour of BMP-2 for several outcome measures. The RCT of calcium phosphate (CaP) cement and bone marrow-based composite materials versus autogenous bone grafts (RCT with a high risk of bias) revealed significant differences in favour of bone graft substitutes for some outcome measures. Regarding the other bone graft substitutes, almost all comparisons demonstrated no significant difference. The use of BMP-2 in addition to standard care without bone grafting led in the study to increased treatment costs considering all patients with traumatic open fractures. However, cost savings through the additional use of BMP-2 were calculated in a patient subgroup with high-grade open fractures (Gustilo-Anderson grade IIIB). Cost-effectiveness for BMP-2 versus standard care with autologous bone grafts as well as for other bone graft substitutes in fracture treatment has not been determined yet. DISCUSSION: Although there were some significant differences in favour of BMP-2, due to the overall poor quality of the studies the evidence can only be interpreted as suggestive for efficacy. In the case of CaP cements and bone marrow-based bone substitute materials, the evidence is only weakly suggestive for efficacy. From an overall economic perspective, the transferability of the results of the health economic evaluations to the current situation in Germany is limited. CONCLUSIONS: The current evidence is insufficient to evaluate entirely the use of different bone graft substitutes for fracture treatment. From a medical point of view, BMP-2 is a viable alternative for treatment of open fractures of the tibia, especially in cases where bone grafting is not possible. Autologous bone grafting is preferable comparing to the use of OP-1. Possible advantages of CaP cements and composites containing bone marrow over autogenous bone grafting should be taken into account in clinical decision making. The use of the hydroxyapatite material and allograft bone chips compared to autologous bone grafts cannot be recommended. From a health economic perspective, the use of BMP-2 in addition to standard care without bone grafting is recommended as cost-saving in patients with high-grade open fractures (Gustilo-Anderson grade IIIB). Based on the current evidence no further recommendations can be made regarding the use of bone graft substitutes for the treatment of fractures. To avoid legal implications, use of bone graft substitutes outside their approved indications should be avoided.

Percutaneous coronary intervention with optimal medical therapy vs. optimal medical therapy alone for patients with stable angina pectoris.

SCIENTIFIC BACKGROUND: Stable Angina Pectoris (AP) is a main syndrome of chronic coronary artery disease (CAD), a disease with enormous epidemiological and health economic relevance. Medical therapy and percutaneous coronary interventions (PCI) are the most important methods used in the treatment of chronic CAD. RESEARCH QUESTIONS: The evaluation addresses questions on medical efficacy, incremental cost-effectiveness as well as ethic, social and legal aspects in the use of PCI in CAD patients in comparison to optimal medical therapy alone. METHODS: A systematic literature search was conducted in June 2010 in the electronic databases (MEDLINE, EMBASE etc.) and was completed by a hand search. The medical analysis was initially based on systematic reviews of randomized controlled trials (RCT) and was followed by the evaluation of RCT with use of current optimal medical therapy. The results of the RCT were combined using meta-analysis. The strength and the applicability of the determined evidence were appraised. The health economic analysis was initially focused on the published studies. Additionally, a health economic modelling was performed with clinical assumptions derived from the conducted meta-analysis and economic assumptions derived from the German Diagnosis Related Groups 2011. RESULTS: Seven systematic reviews (applicability of the evidence low) and three RCT with use of optimal medical therapy (applicability of the evidence for the endpoints AP and revascularisations moderate, for further endpoints high) were included in the medical analysis. The results from RCT are used as a base of the evaluation. The routine use of the PCI reduces the proportion of patients with AP attacks in the follow-up after one and after three years in comparison with optimal medical therapy alone (evidence strength moderate); however, this effect was not demonstrated in the follow-up after five years (evidence strength low). The difference in effect in the follow-up after four to five years was not found for the further investigated clinical endpoints: death, cardiac death, myocardial infarction and stroke (evidence strength high) as well as for severe heart failure (evidence strength moderate). Two studies were included in the health economic analysis. The costs estimations from these studies are not directly transferable to the corresponding costs in Germany. The average difference in the total costs for PCI in comparison with optimal medical therapy alone, which was calculated in the modelling, was found to be 4,217 Euro per patient. The incremental cost-effectiveness ratio per life-year of a patient with avoided AP attacks was estimated to be 24,805 Euro (evidence strength moderate). No publication was identified concerning ethical, social or legal aspects. DISCUSSION: Important methodical problems of the studies are a lack of blinding of the patients and incomplete data for several endpoints in the follow-up. The determined incremental cost-effectiveness ratio per life-year of a patient with avoided AP attacks was appraised not to be cost-effective. CONCLUSIONS: From a medical point of view the routine use of PCI in addition to the optimal medicinal therapy in patients with stable AP can be recommended for the reduction of the proportion of patients with AP attacks after one year and after three years (recommendation degree weak). Otherwise, PCI is to be performed in patients with refractory or progressing AP despite of optimal medical therapy use; in this case PCI is expected to be applied in 27% to 30% of patients in five years. From the health economic view the routine use of PCI in addition to an optimal medical therapy in patients with stable AP cannot be recommended. No special considerations can be made concerning special ethical, social or legal aspects in the routine use of PCI in addition to optimal medical therapy in patients with stable AP.

Specific immunotherapy (SIT) in the treatment of allergic rhinitis.

SCIENTIFIC BACKGROUND: Allergic rhinitis (AR) exhibits a prevalence of approx. 20% in Germany and causes enormous costs in the health care system. Specific immunotherapy (SIT) is considered to be the only potentially causal therapy for AR and mainly administered by two routes, subcutaneous (SCIT) and sublinguale (SLIT). SIT promises a reduction of symptoms and the need for medication in patients with AR. RESEARCH QUESTIONS: The question arises, to what extent is SIT effective and cost effective in the treatment of AR and which ethical-social and legal aspects have to be considered regarding its application. METHODS: The literature search was accomplished in the electronic data bases MEDLINE, EMBASE etc. in February 2008. The medical evaluation was based on systematic reviews of blinded, randomised controlled studies (RCT). The economic evaluation included health-economic studies on the basis of RCT. Additionally, it was also searched for publications explicitly addressing ethical-social and legal aspects of the use of SIT. RESULTS: MEDICAL EVALUATION: Two reviews on SCIT and three on SLIT were included in the medical evaluation. For the evaluation of SIT with grass pollen results for short and medium-term effects are considered from several studies, for SIT with other seasonal allergens (e. g. tree pollen) and with house dust mite allergens from clearly fewer studies and for SIT with other perennial allergens only from a few. The reviews report a significant reduction of the symptom and medication score in favour of SCIT with seasonal allergens and recognise the effectiveness at least for grass pollen allergens. Also for other seasonal allergens SCIT is appraised as effective. The reviews about SLIT determine a significant reduction of the symptom and the medication score in favour of SLIT vs. placebo in short and medium term follow-up in evaluations across all allergens. The subgroup analyses show a significant reduction of the symptom and medication score only in favour of SLIT with seasonal allergens. HEALTH ECONOMIC EVALUATION: Four publications about two health economic studies are identified, one of these publications on Alutard-SQ(®) injections (SCIT) and three on GRAZAX(®) tablets (SLIT). The studies provide more (on Alutard-SQ(®)) or less (on GRAZAX(®)) robust information, but no evidence on cost effectiveness of these SIT administration forms in patients with AR. DISCUSSION: The topic of the report is very broad, so that the evidence is summarised using systematic reviews. In particular the statistic heterogeneity of the studies found in the reviews considerably limits the strength of the findings. The included health economic studies show different methodical flaws, the largest potential bias is the projection of the magnitude of the medium-term clinical effects on the time period of nine years. CONCLUSIONS: The effectiveness of SIT in patients with AR is not equally proven for all SIT administration forms and allergens. For SCIT and SLIT with grass pollen allergens short and medium-term effectiveness can be regarded as proven. These therapy forms should be used if the indication is appropriate and if no contraindications are present. Also SCIT and SLIT with other seasonal allergens such as tree pollen allergens can be an effective treatment option, but used with a certain restraint due to insufficient data especially in the case of SLIT. For SIT with house dust mite allergens and further perennial allergens no consistent proof of effectiveness are to be determined from the available information. Further research addressing non-grass pollen-associated SIT, allergen and manufacturer specific evaluations as well as asthma prevention is needed. Due to the lack of evidence the use of SIT can not be seen proven as cost effective. To provide such evidence further health economic studies with a long term follow-up are needed. The informed consent of the patients is an important ethical requirement within the use of SIT.

Prevention of infection after knee arthroplasty.

SCIENTIFIC BACKGROUND: Man-made joints (joint endoprostheses), including knee endoprostheses, are used in some irreversible diseases of the human joints. The implantation of joint endoprostheses (arthroplasty) is associated with an increased risk for infection. To prevent infections, different interventions without and with the use of antibiotics (hygiene procedures and antibiotic prophylaxis) are used. The benefits of these interventions are not clear yet. RESEARCH QUESTIONS: The presented report addresses the questions regarding the medical effectiveness, the cost-effectiveness as well as the ethical, social and legal aspects related to the use of interventions to prevent infections after knee arthroplasty. METHODS: A systematic literature search is conducted in the medical electronic databases MEDLINE, EMBASE, SciSearch etc. in June 2009 and has been completed by a hand search. The analysis includes publications which describe and/or evaluate clinical data from randomized controlled trials (RCT), systematic reviews of RCT, registers of endoprostheses or databases concerning interventions to prevent infections after knee arthroplasty. The conducted literature search also aims to identify health-economic studies and publications dealing explicitly with ethical, social or legal aspects in the use of interventions to prevent infections after knee arthroplasty. The synthesis of information from different publications has been performed qualitatively. RESULTS: The systematic literature search yields 1,030 hits. Based on the predefined inclusion and exclusion criteria a total of ten publications is included in the analysis. The presented report does not find evidence of the effectiveness of different hygiene interventions with a high evidence level. Most of the unspecific interventions are recommended on the basis of results from non-RCT, from studies for other clinical indications and/or for clinically not relevant endpoints, as well as on the basis of expert opinions. The evidence of the effectiveness of intravenous prophylaxis with antibiotics in knee arthroplasty on a high level of evidence is also missing. The recommendations use evidence on the intravenous antibiotic prophylaxis transferred from RCT in hip arthroplasty to the arthroplasty of all joints including knee replacement. Moreover, no evidence is found for differences in the effectiveness between various antibiotics in knee arthroplasty. The presented report finds strong hints for the effectiveness of antibiotics in cement in addition to the intravenous prophylaxis; however, evidence of the effectiveness may be accepted only for operating rooms without clean-air measures. DISCUSSION: The conclusiveness of the results from non-RCT and from studies for clinically non-relevant endpoints is relatively low. The determined evidence from studies for other clinical indications may be generally transferred to knee replacement operations. CONCLUSIONS: No proposal to change the recommendations of the Robert Koch Institute with respect to hygiene interventions and intravenous antibiotic prophylaxis can be made from the presented analysis. Also, no recommendations on the selection of certain antibiotic can be derived from the analysed data. The use of antibiotics in cement in addition to the intravenous prophylaxis may be generally recommended. The cost-effectiveness of different interventions to prevent infections in knee arthroplasty remains unclear. There are no signs for concern regarding any ethical, social and/or legal consequences in the use of interventions to prevent infections in knee arthroplasty.

Assessments tools for risk prediction of cardiovascular diseases.

SCIENTIFIC BACKGROUND: Cardiovascular diseases have an enormous epidemiological and economic importance. For the selection of persons with increased total cardiovascular risk for individual-targeted (e. g. drug-based) prevention interventions different risk prognosis instruments (equations, point scores and table charts) were derived from studies or databases. The transferability of these prognostic instruments on the populations not examined in these data sources as well as their comparability are not clear. RESEARCH QUESTIONS: The evaluation addresses the questions on the existence of instruments for risk prediction of cardiovascular diseases, their transferability and comparability. METHODS: A systematic literature search was performed in the medical electronic databases in April 2008 beginning from 2004 and was completed with a hand search. Publications on the prognostic instruments for cardiovascular diseases as well as publications addressing external validity and/or comparing prognostic instruments were included in the evaluation. RESULTS: The systematic lierature search yielded 734 hits. Three systematic reviews, 38 publications with descriptions of prognostic instruments and 29 publications with data on the validity of the prognosis instruments were identified. Most risk prognosis instruments are based on the Framingham cohort of the USA. Only the PROCAM study is completely based on the German reference population. Almost all prognostic instruments use the variables sex, age, smoking, different parameters of the lipid status and of the blood pressure. Different cardiovascular events are considered to be an end parameter in the prognosis instruments. The time span for predicted events in the studies mostly comprises ten years. Data on calibration of the prognosis instruments (a quotient of the predicted by the observed risk) are presented in nearly half of the studies on the validation, however in no study from Germany. Only single studies find the levels of calibration between 0.9 and 1.1. Many studies on the transferability of the prognosis instruments show a value of the discrimination (correct differentiation of persons with different risk levels, best value 1.0) between 0.7 and 0.8, few studies between 0.8 and 0.9 and no study over 0.9. The studies addressing the discrimination of the prognostic instruments on the German population almost always find values between 0.7 and 0.8. The comparison of the validity of different risk prognosis instruments shows a trend for a better calibration and a better discrimination for the prognosis instruments examined on the derivation and/or validation cohorts of one of the compared prognostic instruments. Comparing the prognostic instruments on other cohorts, the newly derived Framingham prognostic instruments show a better discrimination in comparison with previously derived instruments. No studies exists comparing different prognostic instruments on the German population. DISCUSSION: The geographic variance of the cardiovascular morbidity and mortality supposed to be the most important factor limiting the transferability of the prognostic instruments. An appropriate recalibration is considered to be an approach for the improvement of the transferability. CONCLUSIONS: The identified instruments for the risk prediction of cardiovascular diseases are insufficiently validated on the German population. Their use can lead to false risk estimation for a single person. Therefore, the existing prognostic instruments should be used for the informed decision-making and for the therapy selection in Germany only with critical caution.

Arthroplasty register for Germany.

SCIENTIFIC BACKGROUND: The annual number of joint replacement operations in Germany is high. The introduction of an arthroplasty register promises an important contribution to the improvement of the quality of patient's care. RESEARCH QUESTIONS: The presented report addresses the questions on organization and functioning, benefits and cost-benefits as well as on legal, ethical and social aspects of the arthroplasty registers. METHODS: A systematic literature search was conducted in September 2008 in the medical databases MEDLINE, EMBASE etc. and was complemented with a hand search. Documents describing arthroplasty registers and/or their relevance as well as papers on legal, ethical and social aspects of such registers were included in the evaluation. The most important information was extracted and analysed. RESULTS: Data concerning 30 arthroplasty registers in 19 countries as well as one international arthroplasty register were identified. Most of the arthroplasty registers are maintained by national orthopedic societies, others by health authorities or by their cooperation. Mostly, registries are financially supported by governments and rarely by other sources. The participation of the orthopedists in the data collection process of the arthroplasty registry is voluntary in most countries. The consent of the patients is usually required. The unique patient identification is ensured in nearly all registers. Each data set consists of patient and clinic identification numbers, data on diagnosis, the performed intervention, the operation date and implanted prostheses. The use of clinical scores, patient-reported questionnaires and radiological documentation is rare. Methods for data documentation and transfer are paper form, electronic entry as well as scanning of the data using bar codes. The data are mostly being checked for their completeness and validity. Most registers offer results of the data evaluation to the treating orthopedists and/or hospitals, provide annual reports and publish scientific articles and/or presentations. The effects of the arthroplasty registers on clinical practice and on health political decisions in the time after the introduction of these registers are documented in some countries. The influence on cost savings for health services is also reported. DISCUSSION: The most important legal and ethical aspect is the patient's data protection and, therefore, the requirement of patient's consent. The involvement of the physicians in the data collection process is a further organisational and legal challenge. The 100% data collection, which is the aim of the registers due to their definition, should not cause disadvantages for certain groups of patients. CONCLUSION: The arthroplasty registers have a large medical and health-economic potential. Aspects of the patient's data protection and the guaranteed financial support of the registers should be clarified before the introduction of a register.

[Intravascular brachytherapy for peripheral arterial occlusive disease: systematic review of medical efficacy and health economic modelling]. / Intravaskuläre Brachytherapie bei peripherer arterieller Verschlusskrankheit: Systematische Ubersicht zur medizinischen Wirksamkeit und gesundheitsökonomische Modellierung.

CONTEXT: Percutaneous transluminal angioplasties (PTA) using balloon dilatation with or without stenting are performed to treat peripheral arterial occlusive disease (PAOD). Intravascular brachytherapy (IB) after PTA promises to reduce the restenosis rates. The present article addresses questions concerning medical efficacy and cost-effectiveness of IB in PAOD patients. METHODS: A systematic literature search for randomized controlled studies evaluating IB in PAOD was conducted in August 2007. Information synthesis was conducted using meta-analysis. Health economic modelling was performed on the basis of clinical assumptions derived from the meta-analysis and economical assumptions derived from the German Diagnosis Related Groups (G-DRG) 2007. RESULTS: Twelve publications covering seven studies about IB vs. no IB were included in the evaluation. IB after successful balloon dilatation showed a significant reduction in the rate of restenosis at six and/or twelve months (relative risk 0.62; 95% confidence interval: 0.46 to 0.84) and a significant delay in the time to recurrence of restenosis (17.5 vs. 7.4 months, p < 0.01). IB after stenting did not lead to significant results regarding the restenosis rates, but was more often associated with early and late occlusive thromboses. The incremental cost-effectiveness ratio per restenosis avoided for IB vs. no IB after successful balloon dilatation was--depending on the G-DRG used-Euro 8,484 and Euro 9,058, respectively. In the comparison of IB vs. no IB after stenting IB was demonstrated to be inferior to no IB. CONCLUSIONS: IB after successful balloon dilatation in PAOD can be recommended from a medical point of view. From the health economic perspective the answer is not yet clear. IB after stenting in PAOD cannot be recommended.

Methods for assessment of innovative medical technologies during early stages of development.

Conventional Health Technology Assessment (HTA) is usually conducted at a point in time at which the development of the respective technology may no longer be influenced. By this time developers and/or purchasers may have misinvested resources. Thus the demand for Technology Assessment (TA) which incorporates appropriate methods during early development stages of a technology becomes apparent. Against this health political background, the present report describes methods for a development-accompanying assessment of innovative medical technologies. Furthermore, international research programmes set out to identify or apply such methods will be outlined. A systematic literature search as well as an extensive manual literature search are carried out in order to obtain literature and information. The greatest units of the identified methods consist of assessment concepts, decision support methods, modelling approaches and methods focusing on users and their knowledge. Additionally, several general-purpose concepts have been identified. The identified research programmes INNO-HTA and MATCH (Multidisciplinary-Assessment-of-Technology-Centre-for-Healthcare) are to be seen as pilot projects which so far have not been able to generate final results. MATCH focuses almost entirely on the incorporation of the user-perspective regarding the development of non-pharmaceutical technologies, whereas INNO-HTA is basically concerned with the identification and possible advancement of methods for the early, socially-oriented technology assessment. Most references offer only very vague descriptions of the respective method and the application of greatly differing methods seldom exceeds the character of a pilot implementation. A standardisation much less an institutionalisation of development-accompanying assessment cannot be recognized. It must be noted that there is no singular method with which development-accompanying assessment should be carried out. Instead, a technology and evaluation specific method selection seem to be necessary as medical innovations are diverse and none of the methods are exhaustive. Because of a variety of issues (e. g. ideal time of evaluation, lack of data and uncertainty of data) a development-accompanying assessment should not replace a comprehensive HTA, but rather form a possible preceding step in a multi-staged HTA-process. A final appraisal of the methods for development-accompanying assessment cannot be made based on the available sources. However, the present review may serve as a starting point for further development and application of these methods as well as further examination of the concept of development-accompanying assessment. There is a substantial need for further research concerning the application, validation and comparison of the various methods for development-accompanying assessment.

Interventions for enhancing medication compliance/adherence with benefits in treatment outcomes.

SCIENTIFIC BACKGROUND: Poor compliance or adherence in drug therapy can cause increased morbidity, mortality and enormous costs in the healthcare system (in Germany annually approximately 10 billion euros). Different methods are used for enhancing the compliance or adherence. RESEARCH QUESTIONS: The evaluation addresses the questions about existence, efficacy, cost-benefit relation as well as ethical-social and juridical implications of strategies for enhancing compliance or adherence in drug therapy with concomitant improvements in treatment outcomes. METHODS: A systematic literature search was conducted in the medical, also health economic relevant, literature databases in January 2007, beginning from 2002. Systematic reviews on the basis of (randomised controlled trials (RCT) concerning interventions to enhance compliance or adherence with regard to treatment outcomes as well as systematic reviews of health economic analyses were included in the evaluation. Additionally, it was also searched for publications which primarily considered ethical-social and juridical aspects of these interventions for the German context. RESULTS: One systematic review with data for 57 RCT was included in the medical evaluation and one systematic review with data for six studies into the health economic evaluation. No publication primary concerning ethical-social or juridical implications could be identified. A significant positive effect on the treatment outcome was reported for 22 evaluated interventions. For many interventions the results can be classified as reliable: counseling with providing an information leaflet and compliance diary chart followed by phone consultation for helicobacter pylori positive patients, repeated counseling for patients with acute asthma symptoms, telephone calls to establish the level of compliance and to make recommendations based on that for the therapy of cardiovascular diseases, calls of an automated telephone system with phone counseling in problem cases for diabetics, different family based interventions including repeated family counseling, education and "culturally modified family therapy" in patients with schizophrenia, repeated "compliance therapy" sessions for patients with acute psychosis. For other interventions the results should be viewed with more concern (because of the poor methodical quality of the underlying studies). The effect size of the interventions can not be estimated from the available data. From the available data, no reliable results can be provided concerning the cost-benefit relation of these strategies. DISCUSSION: Many of the reported studies had a poor reporting and methodological quality. The reliability of the conclusions of the studies is restricted because of methodical shortcomings. Efficacy and cost estimates determined in the health economic studies are not transferable to the current situation in Germany. It has been discussed recently that the compliance or adherence enhancing interventions can restrict the autonomy and the privacy of the patients. CONCLUSIONS: In drug therapy some compliance or adherence enhancing interventions with concomitant positive effect on the treatment outcome may be used. The cost-benefit relation of these interventions is to be estimated. Using these interventions the patient's autonomy and privacy are to be restricted as few as possible.

Intravascular brachytherapy for peripheral vascular disease.

SCIENTIFIC BACKGROUND: Percutaneous transluminal angioplasties (PTA) through balloon dilatation with or without stenting, i.e. vessel expansion through balloons with or without of implantation of small tubes, called stents, are used in the treatment of peripheral artery occlusive disease (PAOD). The intravascular vessel irradiation, called intravascular brachytherapy, promises a reduction in the rate of repeated stenosis (rate of restenosis) after PTA. RESEARCH QUESTIONS: The evaluation addresses questions on medical efficacy, cost-effectiveness as well as ethic, social and legal implications in the use of brachytherapy in PAOD patients. METHODS: A systematic literature search was conducted in August 2007 in the most important medical electronic databases for publications beginning from 2002. The medical evaluation included randomized controlled trials (RCT). The information synthesis was performed using meta-analysis. Health economic modeling was performed with clinical assumptions derived from the meta-analysis and economical assumptions derived from the German Diagnosis Related Groups (G-DRG-2007). RESULTS: MEDICAL EVALUATION : Twelve publications about seven RCT on brachytherapy vs. no brachytherapy were included in the medical evaluation. Two RCT showed a significant reduction in the rate of restenosis at six and/or twelve months for brachytherapy vs. no brachytherapy after successful balloon dilatation, the relative risk in the meta-analysis was 0.62 (95% CI: 0.46 to 0.84). At five years, time to recurrence of restenosis was significantly delayed after brachytherapy. One RCT showed a significant reduction in the rate of restenosis at six months for brachytherapy vs. no brachytherapy after PTA with optional stenting, the relative risk in the meta-analysis was 0.76 (95% CI: 0.61 to 0.95). One RCT observed a significantly higher rate of late thrombotic occlusions after brachytherapy in the subgroup of stented patients. A single RCT for brachytherapy vs. no brachytherapy after stenting did not show significant results for the rate of restenosis at six months. Both, early and late thrombotic occlusions appeared more frequently in the brachytherapy group. HEALTH ECONOMIC EVALUATION : Additional costs of brachytherapy were estimated to be 1,655 or 1,767 Euro according to the used G-DRG. The incremental cost-effectiveness ratio per avoided restenosis was calculated to be 8,484 Euro or 9,058 Euro for brachytherapy use after successful balloon dilatation, 19,027 Euro or 20,314 Euro for brachytherapy after PTA with optional stenting and -39,646 Euro or -48,330 Euro for brachytherapy after stenting. DISCUSSION: Partially poor performing and reporting quality of the RCT exacerbate the interpretation and the transferability of the study results. The used methodical approach enables the highest evidence level for the determined results and presents a good approximation of the current brachytherapy related costs for the German health care system. CONCLUSIONS: Brachytherapy after successful balloon dilatation in PAOD can be recommended from a medical point of view for the reduction of the rate of restenosis at one year. However from a health economic view the answer is not yet clear. Based on the current data the use of brachytherapy after stenting in PAOD cannot be recommended neither from a medical nor from a health economic point of view. The informed consent of the patients is an important ethical aspect in the use of brachytherapy.

Drug-eluting stents vs. coronary artery bypass-grafting in coronary heart disease.

BACKGROUND: Coronary artery bypass graft (CABG) and percutaneous revascularisations with implantation of drug-eluting stents (DES) are important treatment methods in coronary heart disease (CHD). RESEARCH QUESTIONS: The evaluation addresses questions on medical efficacy, health economic parameters as well as ethic, social and legal implications in the use of DES vs. CABG in CHD patients. METHODS: A systematic literature search was conducted in December 2006 in the most important electronic databases beginning from 2004. Register data and controlled clinical studies were included in the evaluation. Additionally, a health economic modelling was conducted. RESULTS: MEDICAL EVALUATION : The literature search yielded 2,312 hits. 14 publications about six controlled clinical studies and five publications about two registers were included into the evaluation. Register data showed low mortality (0.2% to 0.7%) and low rates of myocardial infarction (0.5% to 1.4%) during hospital stay. In patients with stenosis of the left anterior descending coronary artery one study showed in several analyses a significantly higher rate of reinterventions and a significantly higher rate of repeated angina pectoris for DES up to two years after the implantation (16.8% vs. 3.6% and 35% vs. 8%). In patients with left main coronary artery stenosis two studies revealed a significantly higher survival without myocardial infarction and stroke for DES up to one year (96% vs. 79% and 95% vs. 91%) and two studies a significantly higher rate of revascularisations up to two years (20% vs. 4% and 25% vs. 5%) after the primary intervention. In patients with multivessel disease, one study found a significantly higher mortality and myocardial infarction rate for CABG at one year (2.7% vs. 1.0% and 4.2% vs. 1.3%). The rate of revascularisations was significantly higher in two studies up to two years after DES implantation (8.5% vs. 4.2% and 14.2% vs. 5.3%). The rate at repeated angina pectoris was significantly higher in one study in DES patients during two-years follow-up (28% vs. 12%). HEALTH ECONOMIC EVALUATION: The one-year total costs per patient after CABG were calculated to be 13,373 euro and after DES 10,443 euro, leading to a difference of 2,930 euro in favour of DES implantation. The three-year total costs per patient after CABG were estimated to be 13,675 euro and after DES 10,989 euro, showing a cost difference of 2,686 euro in favour of DES implantation. In the performed sensitivity analyses no break even point was reached. DISCUSSION: Existing data should be viewed only as limited evidence for possible medical and health economic effects. CONCLUSIONS: There is limited evidence for the possible advantage of DES vs. CABG with respect to mortality and the rate of myocardial infarction in some indications as well as disadvantages with regard to the rate of revascularisations and the rate of repeated angina pectoris. Moreover there is also a limited evidence for possible economic advantage of DES vs. CABG in multivessel disease. Existing data should be proven in long-term follow-up and in randomised studies.

Benefits and risks of hormonal contraception for women.

SCIENTIFIC BACKGROUND: A large proportion of women of reproductive age in Germany use various methods of pregnancy prevention (contraception), among them various hormone-based methods. Hormonal contraceptives may be divided into combined estrogen-progestogen contraceptives (pills, skin patches, vaginal rings), progestogen-only contraceptives (pills, injections, implants, hormone spirals) and emergency contraceptives. RESEARCH QUESTIONS: The evaluation addressed the question of benefits and risks of hormonal contraceptives, their economic effects as well as their ethical-social and legal implications. METHODS: A systematic literature search was conducted in April 2006 starting from 2000. The evaluation is primarily based on systematic reviews. RESULTS: In perfect use, all hormonal contraceptives excluding emergency contraceptives proved to be the most effective reversible contraceptive methods (rate of unintended pregnancies 0.05% to 0.3%). However, the typical use of oral contraceptives, injections, skin patches, and vaginal rings, which also considers possible application errors, showed a lower contraceptive efficacy (rate of unintended pregnancies 3% to 8%). It was lower than that of copper spirals. The risk of venous thromboembolism increased three to six times in users of hormonal contraceptives, the risks of stroke and myocardial infarction two to three times. The risk declined after discontinuation of use. The effects were estrogen-dose and progestogen-type dependent. The use of hormonal contraceptives showed a relative risk of ovarian and endometrial carcinomas of approximately 0.5 or 0.7, of breast and cervical cancer of approximately 1.2 or 1.6. The effect remained several years after discontinuation of use. The results concerning hepatocellular carcinoma suggested a carcinogenic effect. In women with acne, an improvement due to use of hormonal contraceptives was proven. Cervical chlamydial infections were more frequent in users of hormonal contraception. Headache appeared mostly only at the beginning of the use of combined oral contraceptives. Progestogen-only contraceptives worsened the results of the glucose tolerance test. A review of low evidence reported further risks of hormonal contraceptives (concerning menstrual problems, ovarian cysts, bone density, thyroid diseases and rheumatoid arthritis) as well as further benefits (concerning blood pressure and Crohn's disease). Hormonal spirals were shown to be more effective than spirals which do not release hormones. In emergency contraception, Levonorgestrel was more effective than the Yuzpe method. Most other proven differences between hormonal contraceptives were related to menstrual problems. After spirals with or without hormone release, the other hormonal contraceptives were shown in typical use to be the second most cost-effective reversible methods of contraception. DISCUSSION: The addressed questions could be answered only on relatively low evidence level, partly only for applications with estrogen doses which are not used in Germany any more. The transferability of the results of the analysed primary health-economics studies on the current situation in Germany is limited (clinical assumptions from out-dated information sources of low evidence levels, cost assumptions from the American health system). CONCLUSIONS: In perfect use, hormonal contraceptives have to be classified as the most effective reversible contraceptive methods. For the individual decision concerning the use of hormonal contraception, benefits should be related to the additional risks. Alternative methods such as spirals should be prioritised if perfect use seems to be impossible. In this case, spirals are also preferable from health-economics perspective. No ethical-social or legal conclusions can be derived from the available data.

Laparoscopic vs. open appendectomy: systematic review of medical efficacy and health economic analysis.

SCIENTIFIC BACKGROUND: Appendicitis is an inflammation of the appendix of the blind intestine. Appendicitis remains the most frequent cause for an acute abdomen. Both interventions, the open surgical (through opening of the abdominal cavity) as well as the laparoscopic approach (via insertion of an optic system and instruments into the abdominal cavity through three small incisions), are used for the excision of the inflamed appendix (appendectomy). RESEARCH QUESTIONS: The performed evaluation addresses questions on the medical effectiveness of the use of laparoscopic appendectomy in comparison with the classical open appendix excision as well as on its cost-effectiveness based on the German health system. METHODS: A literature search was conducted in October 2005 in the most important medical electronic databases. The medical analysis was performed on the basis of the most up to date systematic review (basic review) of randomized controlled studies (RCT), newly published RCT and on our own quantitative information synthesis of all studies as well as of selected methodologically high-value RCT. In the health economic analysis, relevant publications were evaluated and cost differences of both interventions were calculated. RESULTS: One systematic review and 56 primary studies were included in the medical evaluation, 24 of these studies were included in the conducted subanalysis on the basis of methodologically high-value studies. In total, a relation of three avoided wound infections per one additional intraabdominal abscess has to be expected by the use of laparoscopic appendectomy in com-parison with the open operation. Diagnostic laparoscopy reduces the rate of unclear diagnoses within the scope of planned appendectomy in fertile women. By routine, leaving the macroscopically bland appendix in situ, the rate of negative appendectomy is reduced significantly and profound. The results speak for a small advantage of the laparoscopic appendec-tomy with regard to pain intensity, the time until reintroduction of liquid and solid diet, time until first stool as well as for a slightly better cosmetic result and slightly better quality of life. In the contemporary practice in Germany, a longer operation time, a reduced length of hospital stay and a similar time to return to work have to be expected by the use of laparoscopic appendectomy in comparison with open appendectomy. In the current health care situation in Germany, the use of laparoscopic appendectomy is associated with additional operation costs of approximately 150 to 200 Euro compared with the open appendectomy. By approximately 200 Euro costs savings due to the shorter length of hospital stay, the total (direct and indirect) costs of in-patient care of both interventions seem to be similar. Due to similar indirect costs, the total costs of both interventions lie also in the same range and the incremental cost-effectiveness ratio of both technologies are driven to zero. DISCUSSION: The use of the results of the performed medical analysis in the cost calculations supports the conclusions of the health-economic evaluation on the same evidence level as in the medical analysis. CONCLUSIONS: Laparoscopic appendectomy shows both small advantages (diagnostics, wound infections, pain intensity, cosmetic result and quality of life) and disadvantages (intraabdominal abscesses) when compared with open appendectomy. From a health-economic view, laparoscopic and open appendectomies are generally similar with respect to the direct in-patient and indirect costs. Therefore, the decision between the two alternatives should be made by the physicians individually.