Stool DNA testing for early detection of colorectal cancer: systematic review using the HTA Core Model® for Rapid Relative Effectiveness Assessment.

Background: Stool DNA testing for early detection of colorectal cancer (CRC) is a non-invasive technology with the potential to supplement established CRC screening tests. The aim of this health technology assessment was to evaluate effectiveness and safety of currently CE-marked stool DNA tests, compared to other CRC tests in CRC screening strategies in an asymptomatic screening population. Methods: The assessment was carried out following the guidelines of the European Network for Health Technology Assessment (EUnetHTA). This included a systematic literature search in MED-LINE, Cochrane and EMBASE in 2018. Manufacturers were asked to provide additional data. Five patient interviews helped assessing potential ethical or social aspects and patients' experiences and preferences. We assessed the risk of bias using QUADAS-2, and the quality of the body of evidence using GRADE. Results: We identified three test accuracy studies, two of which investigated a multitarget stool DNA test (Cologuard®, compared fecal immunochemical test (FIT)) and one a combined DNA stool assay (ColoAlert®, compared to guaiac-based fecal occult blood test (gFOBT), Pyruvate Kinase Isoenzyme Type M2 (M2-PK) and combined gFOBT/M2-PK). We found five published surveys on patient satisfaction. No primary study investigating screening effects on CRC incidence or on overall mortality was found. Both stool DNA tests showed in direct comparison higher sensitivity for the detection of CRC and (advanced) adenoma compared to FIT, or gFOBT, respectively, but had lower specificity. However, these comparative results may depend on the exact type of FIT used. The reported test failure rates were higher for stool DNA testing than for FIT. The certainty of evidence was moderate to high for Cologuard® studies, and low to very low for the ColoAlert® study which refers to a former version of the product and yielded no direct evidence on the test accuracy for ad-vanced versus non-advanced adenoma. Conclusions: ColoAlert® is the only stool DNA test currently sold in Europe and is available at a lower price than Cologuard®, but reliable evidence is lacking. A screening study including the current product version of ColoAlert® and suitable comparators would, therefore, help evaluate the effectiveness of this screening option in a European context.

Estimation of Input Costs for a Markov Model in a German Health Economic Evaluation of Newer Antidepressants.

Background: Estimating input costs for Markov models in health economic evaluations requires health state-specific costing. This is a challenge in mental illnesses such as depression, as interventions are not clearly related to health states. We present a hybrid approach to health state-specific cost estimation for a German health economic evaluation of antidepressants. Methods: Costs were determined from the perspective of the community of persons insured by statutory health insurance ("SHI insuree perspective") and included costs for outpatient care, inpatient care, drugs, and psychotherapy. In an additional step, costs for rehabilitation and productivity losses were calculated from the societal perspective. We collected resource use data in a stepwise hierarchical approach using SHI claims data, where available, followed by data from clinical guidelines and expert surveys. Bottom-up and top-down costing approaches were combined. Results: Depending on the drug strategy and health state, the average input costs varied per patient per 8-week Markov cycle. The highest costs occurred for agomelatine in the health state first-line treatment (FT) ("FT relapse") with €506 from the SHI insuree perspective and €724 from the societal perspective. From both perspectives, the lowest costs (excluding placebo) were €55 for selective serotonin reuptake inhibitors in the health state "FT remission." Conclusion: To estimate costs in health economic evaluations of treatments for depression, it can be necessary to link different data sources and costing approaches systematically to meet the requirements of the decision-analytic model. As this can increase complexity, the corresponding calculations should be presented transparently. The approach presented could provide useful input for future models.

Effectiveness and efficiency of CT-colonography compared to conventional colonoscopy for the early detection and diagnosis of colorectal cancer.

HEALTH POLITICAL BACKGROUND: Colorectal cancer (CC) is the second most common cancer and cause of cancer death for both men and women in Germany. Various methods for early detection of CC exist, including conventional coloscopy which is reimbursed within the scope of cancer screening, as well as computertomography-coloscopy (CTC) which is currently not reimbursed. SCIENTIFIC BACKGROUND: CTC is a mere diagnostic procedure which has a lower risk of perforation than conventional coloscopy. However, as it is an x-ray procedure, it exposes the patient to radiation. Conventional coloscopy is considered the gold standard due to its high sensitivity and specificity for locating adenomas. Furthermore, it offers the advantage that in addition to extended diagnostic measures therapeutic measures can be undertaken during the procedure. RESEARCH QUESTIONS: This HTA-report aims to evaluate the effectiveness and efficiency of CTC in comparison to conventional coloscopy in the early detection and diagnosis of colorectal cancer and/or its precursors and which ethical and legal aspects have to be considered. METHODS: The systematic literature search (27 international literature data bases) yielded a total of 1,713 abstracts. After a two-step selection process 36 publications remained to be assessed. RESULTS: The results regarding the effectivity of CTC in diagnosis and screening for colorectal cancer and/or its precursors are partly promising, however, they are very heterogeneous. Therefore, regarding its sensitivity and specificity, CTC cannot be considered an equivalent alternative to conventional coloscopy for diagnosis and screening. The heterogeneity of results is due to technical (device type, settings), patient dependent (preparation) and operator dependent (training) factors. No economic results for a comparison of the procedures for diagnosis exist. Regarding the cost-effectiveness of a CTC-screening, international model calculations are available. According to this calculation, the CTC-screening is cost-effective compared to the option 'no screening'; however, conventional coloscopy-screening is generally more cost-effective. DISCUSSION: If modern CTC-devices are used with adequate technical settings, software, appropriate patient preparation and training of the operator, better results regarding sensitivity can be expected. Basically, the fact that no therapeutic measures (polypectomy) can be taken during CTC compared to conventional coloscopy needs to be considered. Unanswered medical questions pertain to the interval of examinations for screening (considering the radiation exposure), the approach to small polyps and the significance of flat and depressed lesions. Regarding its cost-effectiveness, conventional coloscopy-screening results in greater health benefits and lower costs than CTC-screening in most model calculations. These results cannot be applied to Germany directly. An important ethical aspect is the consideration of patient preferences regarding the procedures. Legal aspects concern the stipulation and maintenance of quality standards. CONCLUSIONS: At this time, a clear endorsement of CTC as an alternative procedure for diagnosis and screening to the current gold standard conventional coloscopy cannot be given. On the basis of the available literature this holds true for both the medical as well as the economic assessment. However, despite the numerous studies and analyses on this topic, this assessment is afflicted with uncertainties. Due to the rapid development of CTC, short term revisions of these research questions are needed.

Computerized Physician Order Entry - effectiveness and efficiency of electronic medication ordering with decision support systems.

HEALTH POLITICAL BACKGROUND: Computerized physician order entry (CPOE) systems are software to electronically enter medication orders. They can be equipped with tools for decision support (CDS). In Germany, various vendors offer such systems for hospitals and physicians' offices. These systems have mostly been developed during the last five to ten years. SCIENTIFIC BACKGROUND: CPOE-systems exist since the 1970's. Usually, clinical decision support is integrated into the CPOE to avoid errors. RESEARCH QUESTIONS: This HTA-report aims to evaluate the effectiveness and efficiency of CPOE-/CDS-systems and their ethical, social and legal aspects. METHODS: The systematic literature search (27 international data bases) yielded 791 abstracts. Following a two-part selection process, twelve publications were included in the assessment. RESULTS: All reviews and studies included in the present report show that the use of CPOE-/CDS-systems can lead to a reduction of medication errors. Minor errors can be eliminated almost completely. The effect of CPOE-/CDS-systems on the rate of adverse drug events (ADE) is evaluated in only two primary studies with conflicting results. It is difficult to compare the results of economical studies because they evaluate different settings, interventions and time frames. In addition, the documentation often is not fully transparent. All four studies included measure costs and effects from the perspective of a hospital or hospital affiliation. Concerning social aspects, the literature points at changes regard competing interests of technology and humans that result from the implementation of CPOE-systems. The experience of institutions in which the implementation of CPOE-systems leads to problems showed that the importance of considering the socio-organisational context had partly been underestimated. DISCUSSION: CPOE-/CDS-systems are able to reduce the rate of medication errors when ordering medications. The adherence to guidelines, communication, patient care and personnel satisfaction can also be affected positively. However, the literature also reports negative effects, as through the use of CPOE-/CDS-systems new errors can be generated. This makes continuous revisions of the system, as well as data-updates necessary. Concerning the cost-benefit-ratio from the hospital perspective, the two qualitatively best economic studies show contradictory results. Therefore, a positive cost-benefit-ratio for individual hospitals cannot be assumed, particularly as the study results cannot be generalized. CONCLUSIONS: If the implementation of CPOE-/CDS-systems is well planned and conducted, the system adapted to the needs of the institution and continuously reviewed, and data used are updated on a regular basis, the rate of medication ordering errors can be reduced considerably by using CPOE-/CDS-systems. However, it is not clear how this results in a reduction of ADE. Prospective, systematic multi-centre evaluation-studies with clear methodology are needed, which include an analysis of the user-friendliness and of social and technical aspects of the system. Such studies should evaluate the impact a CPOE-/CDS-system has on ADE-rates and mortality. A detailed description of the system used and of the hospital evaluated is essential. If possible, costs and cost effects should be surveyed and documented transparently.

Evaluation of optical coherence tomography in the diagnosis of age related macula degeneration compared with fluorescence angiography.

BACKGROUND: In industrialised nations age-related macular degeneration (AMD) is the most common cause of blindness and severe visual impairment. AMD is a disease of the retina characterized by the accumulation of metabolic products in the macula. In early stages drusen and pigment disorders occur, in late stages a dry form is distinguished from the exsudative form with choroidal neovascularisation. AMD causes vision disorders such as blurred vision of the central part of the visual field, leading finally to a dark spot. Several therapies are available for the exsudative form, however an exact diagnosis is partially essential. The gold standard for the diagnosis of AMD is fluorescein angiography (FA), an invasive investigation with intravenous application of a dye. Optical coherence tomography (OCT) is a more recent non-invasive procedure. OBJECTIVES: The aim of this HTA report is to investigate the efficacy and efficiency of OCT compared to FA. Ethical, societal and legal aspects are also considered. METHODS: A systematic literature search was performed in 34 international databases which yielded 2324 articles. Eight publications were included for assessment, according to predefined selection criteria. RESULTS: The number of studies investigating OCT compared to FA in patients with AMD is presently very limited and the quality of the studies is generally low. The number of investigated patients is below 35 in four publications and in only one publication it is above 100. Moreover in most of the articles very selected patient groups are studied. Economic studies concerning the efficiency of OCT compared to FA cannot be identified. DISCUSSION: Even though the patient groups investigated and the objectives of the studies are very heterogenous, all publications uniformly show that OCT cannot replace FA. However, OCT yields additional diagnostic findings and may verify unclear findings of FA. Therefore the application of OCT in addition to FA is useful in many cases. With regard to costs German patients on average currently have to pay more for performing OCT than for performing FA. CONCLUSION: Future studies have to show whether OCT may give diagnostic information essential for therapeutic decisions in addition to FA and whether it can replace FA in selected cases. The number of patients included in these studies should be high enough to answer relevant questions with sufficient statistical power. An economic model calculation can be built upon the resulting findings.

The Measels-Mumps-Rubella Vaccination from a health political and economical point of view.

INTRODUCTION: Measels, Mumps and Rubella (MMR) are highly contagious infectious diseases which may lead to severe complications. These diseases are vaccine-preventable. The present Health Technology Assessment report (report on technological consequences, HTA report) was commissioned by the German Institute of Medical Documentation and Information (DIMDI) and addresses various aspects of the MMR vaccination, the key question being how the MMR immunisation coverage rate can be increased in Germany. OBJECTIVES: The objectives of this report were to describe the benefits of the MMR vaccination for Germany and to analyse how the desired MMR immunisation coverage of >95% can be achieved. METHODS: A systematic literature search was performed in 29 literature data bases. Particularly for epidemiological data and information on vaccination programs, this systematic search was supplemented by an extensive hand search, written and oral enquiries, as well as interviews with experts. A total of 200 texts were used to prepare this report. RESULTS: At 92.5% (as of 2004) based on the whole of Germany, the current immunisation coverage for measles in children is above the weighted EC-15-average of 90.67%. Statements can only be made regarding the probability of illness for measles, as no data is available for mumps and rubella. With 2.8 infections (per 100,000 residents) in 2006, Germany has not achieved the WHO target. Of cases submitted to the laboratory, only 32% were validated by diagnostic laboratory findings and 45% confirmed clinical-epidemiologically. There are only few economic analyses of vaccination programs in Germany. In international publications, mainly measels are validated economically. An analysis of the cost of measles for Germany shows potential cost savings. Unfortunately, no complete economic evaluation (cost-effectiveness, cost-benefit, or cost-utility analyses) for MMR vaccination has been performed for Germany. Analyses conducted in the US and a model calculation for a hypothetical Western-European country show a considerable cost saving potential for society in general as well as for the health care system. INTERVENTIONS TO INCREASE THE IMMUNISATION RATE WERE CATEGORIZED IN THREE MAIN GROUPS ACCORDING TO THEIR GOALS: interventions increasing the demand for vaccinations, those improving access to vaccination services and those aiming at the providers (e.g. physicians) of vaccinations. DISCUSSION: Various studies concluded that reminders to clients, provided in written, electronic or oral form, are a highly recommendable intervention. Provider based interventions were also strongly advised. DESPITE EFFORTS MADE DURING THE PAST YEARS TO ACHIEVE HERD IMMUNITY IN GERMANY, SOME DEFICITS REMAIN: i. e. there are still ample regional differences between and within German federal states. CONCLUSIONS: In the authors' opinion, a key point in increasing immunisation coverage is the development of a binding vaccination program for Germany with regionally differentiated immunisation targets. During the development of such a program, special emphasis should be placed on determining responsibilities of the federal government, the Laender and health insurance funds (e. g. in the case of a measles outbreak).

Endodontic treatment of molars.

OBJECTIVE: Commissioned by the German Institute of Medical Documentation and Information (DIMDI) the Austrian Health Institute (ÖBIG) prepared a HTA report on the long-term effectiveness of endodontic treatment (root canal treatment, RCT) of molars. The focus is to examine factors influencing the outcome of endodontic treatment and showing their impact on long-term results. Additionally, economic aspects of root canal treatment in Germany are discussed. METHODOLOGY: By performing a systematic literature search in 29 databases (e.g. MEDLINE), the Cochrane Library and by hand searching two peer-reviewed endodontic journals the authors could identify 750 relevant articles, of which finally 18 qualified for assessment. RESULTS: The findings show that the most relevant factor influencing the long-term outcome of endodontic treatment is the preoperative status of a tooth. The lowest success rates are reported for molars with a preoperative devital or necrotic pulp and persisting periapical lesions (so called periapical disease). DISCUSSION: Even if there is no positive selection of patients and the RCT is performed by a normal dentist rather than an endodontist - a fact which is very common - long-term success rates of more then 90% are possible. The overall success rates for endodontic treatment of molars therefore seem to be similar to those of other tooth-types. CONCLUSIONS: Especially primary, conventional (i.e. non-surgical) root canal treatment is an effective and efficient therapy for endodontically ill molars, especially if no large periapical lesion persists. Nonetheless, a long term successful endodontic therapy requires a thorough assessment of the pre-operative status of the molar and treatment according to established guidelines.

The use of statins in primary prevention.

BACKGROUND: The use of statins in secondary prevention of cardiovascular events is well established. However, there is ongoing discussion about the use of statins in the context of primary prevention. Moreover statins - besides cholesterol-lowering effects - are assumed to have pleiotropic effects. Positive impacts on diseases like stroke, Alzheimer's disease or osteoporosis are discussed but still have to be proven. OBJECTIVES: The aim of this report is first to investigate the efficacy and effectiveness of statins in primary prevention of cardiovascular and non-cardiovascular events and second to examine the economic implications for Germany - particularly in comparison to existing prevention programs. Finally ethical questions are considered. METHODS: A systematic literature search was performed for the period between 1998 and 2004 which yielded 3704 abstracts. Overall 43 articles were included for assessment and 167 for background information, according to predefined selection criteria. RESULTS: Most studies within the context of primary prevention describe significant risk reductions with regard to cardiovascular events; yet no significant results according to the reduction of the overall mortality rate can be seen. With respect to stroke, osteoporosis and Alzheimer's disease results are inconsistent. Regarding cost-effectiveness of primary prevention with statins results turn out to be inconsistent as well or even negative for populations with low to moderate risk. For groups with high cardiovascular risk the intervention is mostly assessed to be cost-effective. No cost-effectiveness study for Germany was found. According to a rough estimate of future expenses statin drug expenses of the German legal health insurance might increase at least by 50% in the case of an enlargement of the group of recipients. DISCUSSION: To thoroughly estimate the cost-effectiveness of the use of statins in primary prevention in Germany a model calculation including all relevant parameters has to be done. Moreover - from the economic as well as from the ethic point of view - one of the most important issues in primary prevention therapy is the question of compliance. The amount of risk reduction seen in primary prevention studies can be achieved only if patients as well as doctors follow therapeutic instructions and medical guidelines (as for example the guidelines of the "Adult Treatment Panel III", the "European guidelines on cardiovascular disease prevention in clinical practice" or the guidelines of the German Association of Cardiology and of the "Arzneimittelkommission der deutschen Ärzteschaft für Koronare Herzkrankheit"). CONCLUSION: For (primary) prevention of cardiovascular diseases the use of statins as suggested in guidelines is recommended - provided that these guidelines are scientifically evaluated at regular intervals. Regarding stroke, osteoporosis and Alzheimer's disease definite conclusions cannot be drawn at present. Particular attention has to be paid to the problem of compliance both in statin-therapy as well as in alternative therapies. The cost-effectiveness of primary prevention with statins mainly depends on the development of statin prices.

Computed tomography for the measurement of coronary calcification in asymptomatic risk patients.

BACKGROUND: In 2003 nearly 20% of deaths in Germany were caused by coronary heart disease (CHD). Risk models are used to estimate the ten-year-risk of a coronary event. Coronary calcification may be seen as an additional risk factor. The amount of calcium is correlated with atherosclerotic lesions, but there is no direct correlation with the probability of a plaque rupture. Coronary calcification may be measured either by electron beam computed tomography (EBCT) or multi-detector computed tomography (MDCT). OBJECTIVES: The aim of this HTA report is to investigate the diagnostic validity and cost effectiveness of computed tomography techniques in measuring coronary calcification of asymptomatic risk patients. Ethical aspects are discussed. METHODS: A systematic literature research was performed in 35 international databases which yielded 1080 articles. Overall 43 publications were included for assessment, according to predefined selection criteria. RESULTS: Measuring coronary calcification offers additional information compared with traditional risk factors. Yet at present it cannot be said - according to published literature - which population groups gain most. For determining adequate calcium score thresholds standardisation for age and sex is important. When comparing the reference standard EBCT with MDCT results are inconsistent and depend on the calcium-score value as well as on the scoring method. EBCT as a triage instrument in diagnosing CHD appears to be cost-effective. Yet it is rather not cost-effective as a refinement tool for risk stratification. DISCUSSION: Most of the literature was published in the United States and discusses the use of EBCT as well as (traditional) risk stratification by the Framingham Score. Regarding coronary calcification measured by MDCT (which is more widespread in Germany than EBCT) and a risk model applicable for European populations clear recommendations based on published literature cannot be made at present. CONCLUSION: In conclusion measuring coronary calcification is a promising tool for improving risk stratification with established risk models. Nevertheless many questions remain concerning the targeted use in medical practice, particularly regarding European populations. Therefore also no final conclusions can be drawn with respect to cost-effectiveness. The evaluation of diagnostic procedures measuring other parameters than coronary calcium with regard to CHD risk stratification, compared to EBCT or MDCT, is not part of this report.

Effectiveness and cost-effectiveness of general immunisation of infants and young children with the heptavalent conjugated pneumococcal vaccine.

BACKGROUND: The European Agency for the Evaluation of Medicinal Products (EMEA) granted market authorisation to the heptavalent pneumococcal vaccine Prevenar (Wyeth) in the year 2001. The indication of Prevenar is the active immunisation of infants and young children under the age of two against invasive disease caused by Streptococcus pneumonia serotypes 4, 6B, 9V, 14, 18C, 19F and 23F. At the time of this study the German vaccination scheme advises the immunisation with Prevenar only for children at high risk. OBJECTIVES: The objective of the study is first to determine the efficacy and effectiveness of the immunisation of all children with the heptavalent conjugated pneumococcal vaccine in Germany and second, whether a general recommendation for vaccination of all children would be cost-effective. METHODS: A systematic literature search was performed in 29 relevant databases for the period of January 1999 to June 2004. Thus 1,884 articles were identified which were then assessed according to predefined selection criteria. RESULTS: There is evidence for the medical effectiveness of Prevenar against invasive pneumococcal disease caused by the covered serotypes from a major double-blinded RCT undertaken in California. The vaccine shows lower values of effectiveness against otitis media and pneumonia. The values for effectiveness of the vaccine in Germany are below the data for California because of the different incidence of Serotypes. The cost-effectiveness rates for an immunisation of all children with Prevenar vary across different countries. One reason - besides different Health Systems - can be seen in the uncertainty about the duration of protection, another in the assumption on regional serotype coverage of the vaccine. From the healthcare payers' perspective a general vaccination of all children in Germany is not cost-effective, from a societal perspective the benefits from vaccination could prevail the cost. The actual price of the vaccine (if financed by the Healthcare Payer, 2004) has dropped and is lower than the assumed price in the German cost-effectiveness study. This fact could raise the cost-effectiveness-ratio of a general immunisation. DISCUSSION: The low evidence of information on the herd immunity effect of pneumococcal immunisation, the occurrence on serotype-replacement phenomenon and the effects on the prevalence of antibiotic-resistant strains shall be considered when deciding whether the pneumococcal vaccination for all infants and young children should be added to the German vaccination scheme. There is also little information on the duration of vaccine effectiveness and regional effectiveness because of different serotype incidence. The economic models thus incorporate some uncertainties. CONCLUSION: At present, relatively few pneumococcal strains in Germany show antibiotic resistance. This situation shall further be observed while improving the data evidence for future decisions (epidemiologic data of incidence of pneumococcal diseases and serotyping of pneumococcal bacteria). From the economic perspective no distinct recommendation to add the conjugated vaccination for all children to the German vaccination scheme can be given. This situation may change if the price for the vaccine further decreases. Furthermore a future cost-effectiveness analysis for Germany should incorporate the effects of the replacement phenomenon, the herd immunisation effects and the effects of the vaccination on the antibiotic-resistant pneumococcal strains.