Simeprevir with pegylated interferon alfa 2a plus ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a meta-analysis and historical comparison.

BACKGROUND: About one third of patients infected with human immunodeficiency virus (HIV) also have chronic hepatitis due to hepatitis C virus (HCV). HCV therapy with simeprevir, pegylated interferon alfa (PegIFNα) and ribavirin (RBV) have been shown to be superior to PegIFNα + RBV alone in non-HIV patients, but no randomized trials in patients with HCV genotype 1 (HCV-1)/HIV coinfection are available. METHODS: This was a historical comparison of study C212 (simeprevir + PegIFNα-2a + RBV in patients with HCV-1/HIV coinfection) with studies in which HCV-1/HIV coinfected patients were treated with PegIFNα-2a + RBV alone. A systematic literature search was performed to identify eligible studies. Efficacy and safety results of PegIFNα-2a + RBV studies were combined in random- and fixed-effects inverse-variance weighted meta-analyses of proportions using the Freeman-Tukey double arcsin transformation method, and compared with the results of study C212. RESULTS: The literature search revealed a total of 2392 records, with 206 articles selected for full-text review. Finally, 11 relevant articles reporting on 12 relevant study groups were included. Results on sustained virologic response 24 weeks after end of treatment (SVR24) were available from all 12 study groups. Pooled SVR24 for PegIFNα-2a + RBV from the random-effects meta-analysis was 28.2% (95% CI 23.8% to 32.9%). The comparison between study C212 (SVR24 = 72.6%; 95% CI 63.1% to 80.9%) revealed substantial superiority of simeprevir + PegIFNα-2a + RBV compared to PegIFNα-2a + RBV alone, with an absolute risk difference of 45% (95% CI 34 to 55). This finding was robust in a sensitivity analysis that only included historical studies with a planned treatment duration of at least 48 weeks and the same RBV dose as in study C212. No increases in the frequency of important adverse event categories including anemia were identified, but these analyses were limited by the low number of studies. CONCLUSION: This historical comparison provides first systematic evidence for the superiority of simeprevir + PegIFNα-2a + RBV compared to PegIFNα-2a + RBV in patients with HCV-1/HIV coinfection. Given the limitations of the historical comparison for safety endpoints, additional data on the comparative safety of simeprevir in patients with HCV-1/HIV coinfection would be desirable. TRIAL REGISTRATION: Identifier for study TMC435-TiDP16-C212 (ClinicalTrials.gov): NCT01479868.

Cost-effectiveness of outpatient treatment in depressive patients with escitalopram in Germany.

We investigated the cost-effectiveness of escitalopram (10 mg daily dose) vs. venlafaxine XR (75 mg daily dose) in a German outpatient setting for the treatment of unipolar depression (MADRS score 20-34) over a period of 70 days. To assess the cost effectiveness of the two substances we combined data from physician's surveys and clinical response data; cost-effectiveness was calculated using a Markov model. In a second step we considered the therapeutic decisions of the attending physicians. Cost-effectiveness was indicated as costs per successfully treated patient. Escitalopram demonstrated a more favorable cost-effectiveness ratio than venlafaxine XR. The analysis of treatment patterns showed that attending physicians intervene fairly early if the chosen therapy is ineffective. Additional costs for the use of venlafaxine XR over those of escitalopram were estimated from Euro 7,446 to Euro 9.836 per successfully treated per patient. Hence escitalopram may be a cost-effective alternative to venlafaxine XR in outpatient care setting in Germany.

Health Technology Assessment of laparoscopic compared to conventional surgery with and without mesh for incisional hernia repair regarding safety, efficacy and cost-effectiveness.

INTRODUCTION: Incisional hernias are a common complication following abdominal surgery and they represent about 80% of all ventral hernia. In uncomplicated postoperative follow-up they can develop in about eleven percent of cases and up to 23% of cases with wound infections or other forms of wound complications. Localisation and size of the incisional hernia can vary according to the causal abdominal scar. Conservative treatment (e. g. weight reduction) is only available to relieve symptoms while operative treatments are the only therapeutic treatment option for incisional hernia. Traditionally, open suture repair was used for incisional hernia repair but was associated with recurrence rates as high as 46%. To strengthen the abdominal wall and prevent the development of recurrences the additional implantation of an alloplastic mesh is nowadays commonly used. Conventional hernia surgery as well as minimally invasive surgery, introduced in the early 90s, make use of this mesh-technique and thereby showed marked reductions in recurrence rates. However, there are possible side effects associated with mesh-implantation. Therefore recommendations remain uncertain on which technique to apply for incisional hernia repair and which technique might, under specific circumstances, be associated with advantages over others. OBJECTIVES: The goal of this HTA-Report is to compare laparoscopic incisional hernia repair (LIHR) and conventional incisional hernia repair with and without mesh-implantation in terms of their medical efficacy and safety, their cost-effectiveness as well as their ethical, social und legal implications. In addition, this report aims to compare different techniques of mesh-implantation and mesh-fixation as well as to identify factors, in which certain techniques might be associated with advantages over others. METHODS: Relevant publications were identified by means of a structured search of databases accessed through the German Institute of Medical Documentation and Information (DIMDI) as well as by a manual search. The former included the following electronic resources: SOMED (SM78), Cochrane Library - Central (CCTR93), MEDLINE Alert (ME0A), MEDLINE (ME95), CATFILEplus (CATLINE) (CA66), ETHMED (ED93), GeroLit (GE79), HECLINET (HN69), AMED (CB85), CAB Abstracts (CV72), GLOBAL Health (AZ72), IPA (IA70), Elsevier BIOBASE (EB94), BIOSIS Previews (BA93), EMBASE (EM95), EMBASE Alert (EA08), SciSearch (IS90), Cochrane Library - CDSR (CDSR93), NHS-CRD-DARE (CDAR94), NHS-CRD-HTA (INAHTA) as well as NHSEED (NHSEED). The present report includes German and English literature published until 31.08.2005. The search parameters can be found in the appendix. No limits were placed on the target population. The methodological quality of the included clinical studies was assessed using the criteria recommended by the "Scottish Intercollegiate Guidelines Network Grading Review Group". Economic studies were evaluated by the criteria of the German Scientific Working Group Technology Assessment for Health Care. RESULTS: The literature search identified 17 relevant medical publications. One of these studies compared laparoscopic and conventional surgery with and without mesh for incisional hernia repair, while 16 studies compared laparoscopic and conventional surgery with mesh for incisional hernia repair. Among these studies were 14 primary studies (one randomised controlled trial (RCT), two systematic reviews and one HTA-Report. The only study comparing laparoscopic and conventional surgery without mesh found substantial differences in terms of baseline characteristics between treatment groups. The outcome parameters showed decreased recurrence rates for the laparoscopic repair and similar safety of the procedures. Studies comparing laparoscopic and conventional surgery with mesh found similar outcome in terms of medical efficacy and safety. However, there was a trend towards lower recurrence rates, length of hospital stay, and postoperative pain as well as decreased complication rates for laparoscopic repair in the majority of studies. The impact of the technique of mesh-implantation and -fixation as well as the impact of certain factors on the choice of technique has not been systematically assessed in any of the studies. DISCUSSION: All identified studies suffer from significant methodological weaknesses, such as differences between treatment groups, mainly due to the non-randomised study design, small treatment groups causing low case numbers and lack of statistical power as well as the neglect of important risk factors or adjustment for those. Therefore, no conclusive differences could be identified concerning compared operative techniques, mesh-implantation and -fixation techniques or certain risk factors. Only the comparison of laparoscopic and conventional technique with mesh provides some evidence for a trend towards similar or slightly improved outcome in terms of medical efficacy and safety for the laparoscopic technique. However, there is still a great need for further research to investigate these questions. Basically, there is no full economic evaluation focussing on the relevant alternatives. Cost compareisons were available, even though only briefly attached to clinical research results. None of the studies primarily aimed to investigate costs or even cost-effectiveness. CONCLUSION: When deciding on the choice of operative technique for incisional hernia repair, surgeons take various considerations into account, including patient characteristics, hernia characteristics and their own experience. The studies included in this HTA did not provide conclusive evidence to answer the research questions. Nonetheless, laparoscopic surgery demonstrated a trend towards similar or slightly improved outcome following incisional hernia repair. However, for more conclusive recommendations on the choice of operative technique, high quality trials are required From the economic perspective, alternative methods are not yet assessed. Only five of the studies involve a cost analysis, though in an insufficient manner. None of the studies identified were laid out as a health economic evaluation. Hence, further research is strongly recommended.

Hormones for therapy of climacteric afflictions.

BACKGROUND: In Western countries hormone replacement therapy (HT) is widely used in the treatment of climacteric women who are affected with hot flashes and night sweats. Besides, long-term HT was frequently used to manage the higher risks for osteoporosis and heart attack in postmenopause. Estrogens alone or combined with progestin feature most frequently in HT. OBJECTIVES: This HTA report addresses the questions on medical efficacy and cost-effectiveness of HT as a treatment of hot flashes and night sweats as well as in the primary prevention of osteoporosis and cardiovascular disease in postmenopause in general healthy women. METHODS: The literature search for articles published after 1998 was conducted in March 2004 in standard medical and economic databases. The analysis included randomised controlled trials, systematic reviews, meta-analysis and economic evaluations considering relevant clinical endpoints in English or German language. The quality of the studies was assessed using checklists corresponding to the study type. RESULTS: HT is highly effective in treating hot flashes in climacteric women. The question of economical efficiency cannot be answered due to the scarce database. As the positive effects (lower risk for fractures and endometrial cancer) do not outweigh the negative effects (higher risk for breast cancer and general cardiovascular risk) estrogen-progestin combination HT cannot be recommended for primary prevention of osteoporosis and cardiovascular disease in postmenopausal women. DISCUSSION: The observation period of most of the studies regarding therapy of hot flashes and night sweats were too short to evaluate possible risks of long-term HT. The economic publications assessing HT for this indication varied vastly in terms of applied methods and were not carried out with respect to the German health care system. CONCLUSIONS: HT can be recommended in the short-term treatment of hot flashes and night sweats in climacteric women. To explore the economic effects of HT for this indication for Germany, studies constructed with respect to the German health care system are desirable.

Therapy of moderate and severe psoriasis.

OBJECTIVE AND METHODS: This health technology assessment (HTA) report synthesises systematically randomized controlled studies (RCT) on the therapy of moderate and severe psoriasis vulgaris which were published between 1999 and 2004; it includes some important clinical studies which have been published after 2004 and thus updates the English HTA report by Griffiths et al. [1]. The major objective is the evaluation of the medical effectiveness of different therapeutical approaches and the cost effectiveness with relevance for Germany. RESULTS: The major conclusions from the results of medical RCT on moderate and severe psoriasis vulgaris are: Oral fumarates are effective in the treatment of moderate to severe psoriasis vulgaris. However, fumarates quiet frequently cause moderate side effects. Cyclosporine and methotrexate are both effective in the treatment of severe psoriasis vulgaris. Both substances have a different spectrum of side effects which may limit the individual applicability. Acetritin is only moderately effective in the treatment of severe psoriasis of the plaque type. Calcipotriol or UV-radiation used at the same time can increase the clinical effectiveness of acetritin. Systemic PUVA, balneo-PUVA and UVB therapy are all effective for the treatment of severe psoriasis. The combination of UV therapy with vitamin D3 analogues or with topical steroids is more effective than the treatment with UV radiation alone. Saltwater baths increase the effectiveness of UVB therapy. No RCT on the therapeutical effects of topical tar or of dithranol in combination with UV therapy have been published so far. A continuous therapy with PUVA should not be applied due to its proven photocarcinogenicity. Three substances from the group of biologicals (Efalizumab, Etanercept, and Infliximab) are now available in Europe and a further substance (Alefacept) is available in the USA for the treatment of moderate to severe psoriasis. All biologicals have been effective in placebo controlled studies. The substances differ in the times until a clinical effect is observable, in the spectrum of side effects and in their efficiency on psoriasis arthritis. From health-economic studies considering both costs and clinical efficiency oral fumarates appear to be superior to acitretin or cyclosporine (although cyclosporine appears to be more effective in severe psoriasis). From the health economic view methotrexate is equivalent with UVB or PUVA and superior to cyclosporine. The therapy options UVB, UVB plus calcipotriol and PUVA are equivalent and superior to balneo-phototherapy. Biologicals are cost intensive and should be used when other approaches are not sufficient or are not applicable due to their side effects. The HTA report summarizes some health-economic studies on dithranol, on calcipotriol and on the combination with tar and UV light. No RCT have been published for the treatment of severe psoriasis with these agents alone but it appears to be certain that these substances are effective in severe psoriasis as well. DISCUSSION: The spectrum of therapeutical options has fortunately increased during the last years. It must be emphasized that a number of therapeutical procedures exist which are not discussed in detail in this HTA. This is due to the search strategy of literature: Only RCT performed with patients with moderate and/or severe psoriasis vulgaris were included into this evaluation. This led to the exclusion of a number of substances which are traditionally used alone or in combination for the treatment of moderate or severe psoriasis vulgaris (e.g. dithranol, salicyc acid, tar, corticosteroids and topical retinoids). Moreover, other approaches which include neither drugs nor UV light are not discussed in this HTA although the authors believe in the importance of psychotherapeutical interventions, educational approaches and combined medical and non-medical approaches in rehabilitational medicine in the management of psoriasis vulgaris. The transferability of the health economic evaluations is strongly limited by the fact that all included health economic evaluations except one were not aligned to a German setting. A future research question will be the evaluation of the duration of remission and relapse ratios in the context of different therapy options of moderate and severe psoriasis. Moreover, the consideration of combined outcomes such as the improvement of psoriatic symptoms and the decrease of symptoms in accompanying psoriasis arthritis represents a future requirement of health assessment. CONCLUSIONS: From the clinical point of view it is positive that the spectrum of therapeutic procedures for a chronic severe skin disease has increased continuously during the last years. In cases of individual contraindications or individual inefficacies it is now possible to try alternative approaches. Moreover the risk of long-term side effects can be reduced by changing the therapeutical procedure after some time (so-called rotation therapy). The therapeutical algorithm for severe psoriasis vulgaris now includes photo(chemo-)therapy in combination with topical substances, oral fumaric acid esters, retinoids (in combination with phototherapy or topical substances), methotrexate, cylosporine and the new biologics. Future studies should address therapeutical approaches which can not easily be studied by RCT, e.g. physical, balneological, climate approaches, educational programs and complex rehabilitation therapy which all may have positive effects on individuals with severe psoriasis. As in medical therapy management of moderate and severe psoriasis the economic evaluation also points out the way of a strategic therapy concept which corresponds to a large extent to the algorithm in medical practice.

Platelet aggregation inhibitors in primary and secondary prevention of ischemic stroke.

BACKGROUND: The ischaemic stroke (IS) is one of the most frequent cause of death in Germany. Besides of non-drug many drug-based interventions are used in primary or secondary prevention of IS, among them the thrombocyte aggregation inhibitors (TAI). OBJECTIVES: The evaluation addresses the questions on medical efficacy and cost-effectiveness of the TAI administration in the prevention of IS as compared to the management of risk factors alone as well as to the use of anticoagulant drugs. METHODS: The literature search for articles published after 1997 was conducted in December 2003 in the most important medical and economic databases. The medical analysis was performed on the basis of the most up-to date meta-analyses of randomised controlled trials (RCT) as well as of new published RCT. The data from the studies for stroke, bleeding complications as well as for the combined endpoint "severe vascular events" (SVE: death or stroke or myocardial infarction) were summarised in meta-analyses. In order to include grey literature contact has been taken up with the pharmaceutical manufacturers of TAI. Results are presented in a descriptive way. RESULTS: The medical analysis included data from 184 RCT (vs. placebo) and from 22 RCT (vs. anticoagulant drugs). The absolute reduction of IS (4.8% vs. 6.6%; p<0,00001) and SVE (10.0% vs. 12.4%; p<0,00001) were definitely higher than the absolute increase of bleeding complications (1.6% vs. 0.9%; p<0,00001), but relatively similar to this absolute increase in a subpopulation with a low risk for SVE. With regard to the stroke prevention, evidence of efficacy could be yielded for acetylsalicil acid (ASA), dipyridamole, cilostazol, ridogrel and the combination ASA with dipyridamole. ASA is less effective than anticoagulants in the prevention of ischaemic stroke in atrial fibrillation, however, it causes fewer bleeding complications. Low dosed ASA can be considered cost-effective in secondary prevention of ischemic stroke, which is not the case for clopridogrel. Dipyridamole/ASA being more effective compared with ASA alone is connected with higher acquisition costs. DISCUSSION: The exclusive consideration of stroke prevention is limited, as well as physicians by allocation to TAI expect to avoid all thrombotic events. Since no pharmacoeconomic studies exist for the German context, the economic assessment had to be based on international evidence. CONCLUSIONS: From the medical point of view, TAI may be recommended for primary and secondary prevention of IS in patients with a high risk of severe vascular events and with low risk for bleeding complications. ASA may be also administered in patients with atrial fibrillation in case of contraindication to anticoagulation drugs. From the health economic point of view a systematic primary prophylaxis of IS with ASA cannot be recommended, whereas in secondary prophylaxis savings can be made. Neither the use of Dipyridamole/ASS nor Clopidogrel is advisable for a systematic secondary prophylaxis of IS.

Therapy of atopic eczema.

OBJECTIVES: Major objective is the evaluation of the medical effectiveness of different therapeutical approaches and the cost effectiveness with relevance for Germany. METHODS: This health technology assessment (HTA) evaluates systemically randomized controlled studies (RCT) on the therapy of atopic dermatitis which were published between 1999 and 2004. Further it includes some important clinical studies which have been published after 2004 and other updates the English HTA report by Hoare et al. [1]. RESULTS: Topical corticosteroids and topical calcineurin-inhibitors are the principal substances which are currently used for anti-inflammatory therapy in atopic dermatitis. These substances have shown a significant therapeutic efficacy in controlled studies. In newer controlled studies no difference was observable when corticosteroids were applied once or more than once daily onto the skin. Moreover, there is now one controlled study available which points to the fact that an interval therapy with a stronger topical corticosteroid over a limited time (some weeks) may lower the risk of recurrent flares of atopic dermatitis. Both topical calcineurin-inhibitors pimecrolimus and tacrolimus have shown a significant therapeutical efficacy in a number of placebo-controlled prospective studies. The wealth of data is high for these substances. Both substances have been shown to be efficient in infants, children and adult patients with atopic dermatitis. The importance of a so-called basic therapy with emollients which have to be adapted to the current status of skin is generally accepted in clinical practice. Controlled studies show the efficacy of "basic therapy" - although the level of evidence is quite low for this approach. The skin of patients with atopic dermatitis is colonized in the majority with Staphylococcus aureus, a gram-positive bacterium. Therefore, a therapeutical approach for the treatment of atopic dermatitis is the anti-bacterial or anti-septic treatment of the skin. Due to the lack of randomized controlled studies there is still not certain proof that antimicrobial or anti-septic treatment of non-infected eczematous skin is efficient for the treatment of atopic dermatitis. A reduction of Staphylococcus aureus is observable during an anti-inflammatory treatment of the skin with topical corticosteroids and/or the topical calcineurin-inhibitor tacrolimus. Antihistaminic drugs which are orally applied in atopic dermatitis may support the therapy of the itching skin disease. One controlled study showed a rapid reduction of itch during the use of a non-sedating antihistaminic drug. There are, however, no controlled studies which show the efficacy of antihistaminic drugs on the skin condition in atopic dermatitis. Dietetic restrictions should be applied only after a specific allergological diagnostic clarification. The "gold standard" is still a (blinded) oral provocation test which has to show an influence of a given food on the skin condition. There is sufficient evidence that there is no general dietetic approach which shows efficacy in atopic dermatitis. The treatment of patients with lactobacillae is still controversially discussed. Available studies which showed an efficacy show methodological weaknesses so that this approach can not be generally recommended for clinical practice at the time now. Approaches reducing house dust mite in the surroundings of patients with atopic dermatitis can have an effect on the skin condition so that at least in mite sensitized patients this approach appears to be reasonable. The specific immunotherapy with house dust mite showed clinical efficacy in a controlled study and in some open studies. The education of patients with atopic dermatitis or their parents is a further efficient approach in the management of this chronic skin disease. Interdisciplinary approaches in patients' education containing also psychological elements appear to be an attractive new approach for the treatment of atopic dermatitis. Phototherapy is a further possibility of intervention in atopic dermatitis in adolescent or adult patients. The available evidence points to the fact that UVB radiation (both small and broad spectrum), UVA-1 radiation and balneo-phototherapy are efficient therapeutical options for atopic dermatitis. The systemic treatment with the immunosuppressive substance cyclosporine A is efficient in the treatment of severe atopic dermatitis. Cyclosoprine A is approved for the treatment of adult patients with this skin disease. The immunosuppressive substance azathioprine showed a high clinical efficacy in two controlled studies for severe atopic dermatitis in adults. There are still controversial results for the application of antagonists to leucotriens in the treatment of atopic dermatitis: in some open studies a therapeutical efficacy was described which was, however, not reproducible in a newer controlled study. The phosphodiesterase-4-inhibitor cipamphyllin was efficient in the treatment of atopic dermatitis in a controlled study but weaker than a topical class II (i. e. moderate strength) corticosteroide. The HTA assessment further describes so-called complementary therapeutical approaches which have either not properly been studied in controlled clinical trials or which have been shown to be of no value for the treatment of atopic dermatitis. Altogether six full health-economic evaluations were found which did not cover the whole therapy spectrum of atopic dermatitis. The choice of the most cost effective treatment option of topic corticosteroids depends less on application frequency, but rather on the drug price and more used or unused quantity of the standard packages, so even smallest improvements justify a more frequent application. The results from health economic evaluations of calcineurin-inhibitors are not reliable. The therapy of severe atopic dermatitis in adults with ciclosporin shows comparable cost effectiveness in comparison to UVA/UVB therapy. DISCUSSION: The spectrum of therapeutical procedures has increased for atopic dermatitis but is still not sufficient. The spectrum of established substances is much smaller compared to psoriasis, another chronic and common inflammatory skin disease. There is need for the development new substances which can be applied topically and which are aimed to treat atopic dermatitis in early childhood. Another need for new developments can be found for the treatment of severe atopic dermatitis in adults. CONCLUSIONS: The spectrum of therapeutical procedures has increased for atopic dermatitis but is still not sufficient. The spectrum of established substances is much smaller compared to psoriasis, another chronic and common inflammatory skin disease. There is need for the development new substances which can be applied topically and which are aimed to treat atopic dermatitis in early childhood. Another need for new developments can be found for the treatment of severe atopic dermatitis in adults. Due to lack of health economic evaluations therapy decisions in the treatment of atopic dermatitis must take place on the basis of clinical decision criteria. The prescription of topic corticosteroids should prefer low priced drugs. Reliable statements about the cost effectiveness of the new calcineurin-inhibitors tacrolimus and pimecrolimus.

Bypass materials in vascular surgery.

INTRODUCTION: Arteriosclerotic changes can lead to circulatory disturbances in various areas of the human vascular system. In addition to pharmacological therapy and the management of risk factors (e. g. hypertension, diabetes, lipid metabolism disorders, and lifestyle), surgical interventions also play an important role in the treatment of arteriosclerosis. Long-segment arterial occlusions, in particular, can be treated successfully with bypass sur-gery. A number of different materials are available for this type of operation, such as autologous vein or pros-thetic grafts comprised of polytetrafluoroethylene (PTFE) or Dacron(®). Prosthetic materials are used especially in the treatment of peripheral artery disease, such as in aortoiliac or femoropopliteal bypass surgery. The present report will thus focus on this area in order to examine the effectiveness of different bypass materials. Among the efforts being made to refine the newly introduced DRG system in Germany, analysing the different bypass materials used in vascular surgery is particularly important. Indeed, in its current version the German DRG system does not distinguish between bypass materials in terms of reimbursement rates. Differences in cost structures are thus of especial interest to hospitals in their budget calculations, whereas both private and statutory health insurance funds are primarily interested in long-term results and their costs. OBJECTIVES: The goal of this HTA is to compare the different bypass materials used in vascular surgery in terms of their medical efficiency and cost-effectiveness, as well as with regard to their ethical, social and legal implications. In addition, this report aims to point out the areas in which further medical, epidemiological and health economic research is still needed. METHODS: Relevant publications were identified by means of a structured search of databases accessed through the German Institute of Medical Documentation and Information (DIMDI), as well as by a manual search. The for-mer included the following electronic resources: SOMED (SM78), Cochrane Library - Central (CCTR93), MEDLINE Alert (ME0A), MEDLINE (ME95), CATFILEplus (CATLINE) (CA66), ETHMED (ED93), GeroLit (GE79), HECLINET (HN69), AMED (CB85), CAB Abstracts (CV72), GLOBAL Health (AZ72), IPA (IA70), El-sevier BIOBASE (EB94), BIOSIS Previews (BA93), EMBASE (EM95), EMBASE Alert (EA08), SciSearch (IS90), Cochrane Library - CDSR (CDSR93), NHS-CRD-DARE (CDAR94), NHS-CRD-HTA (INAHTA), and NHS-EED (NHSEED). The present report included German and English literature published between the years 1999 and 2004. A list of the search parameters can be found in the appendix. No limits were placed on the target population, and the methodical quality of the included studies was determined using standardised checklists. RESULTS: THE STUDIES INCLUDED IN THIS HEALTH TECHNOLOGY ASSESSMENT COMPARED THE FOLLOWING BYPASS MATERIALS: autologous vein, human umbilical vein (HUV) and synthetic materials such as PTFE or Dacron(®). Both the systematic reviews and the randomised controlled trials comparing autologous vein grafts to other bypass materials come to the conclusion that autologous vein is superior to all other materials. From a medical viewpoint, there are no clear differences between the various synthetic materials. To date, the subject of bypass materials in vascular surgery has not been addressed comprehensively from an economic point of view. Indeed, we were able to identify only one publication that compared the cost of various bypass materials. The remaining health economic studies did not compare costs, cost effectiveness, or quality of life associated with the use of various bypass materials. DISCUSSION: When deciding which bypass material to use, vascular surgeons take a number of medical considerations into account, including the bypass area, the availability of autologous vein, the amount of operation time available, and the health status of the patient. The studies included in this health technology assessment demonstrate that autologous vein is usually the preferred material for bypass grafts. In contrast, comparisons of various synthetic materials did not show any specific differences. It remains to be seen whether studies on newly developed synthetic materials will show these to have any particular advantages. The randomised controlled trials included in the present report were limited by a number of methodological weaknesses, such as different methods for determining patency rates, sample size and power problems, the interpretation of non-significant results, and a lack of consideration of additional factors. From an economic point of view, there is still great need for further research, and we have attempted to describe a number of pressing questions for health economic studies in the present report.

Influence of tumor necrosis factor α in rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is the most prevalent inflammatory rheumatic disorder. It is a chronic and incurable disease that leads to painful inflammation, often irreversible joint damage, and eventually to functional loss. Conventional treatment is based on unspecific immunosuppressive agents, e.g. Methotrexate, Azathioprin or Gold. However, the longterm outcomes of these approaches have been poor with frequently ongoing inflammatory disease activity, functional decline, and temporary or permanent work disability. More recently, antagonists of the human cytokine Tumor Necrosis Factor α (TNF-α) have been introduced that are potent suppressors of inflammatory processes. Infliximab is a chimeric antibody against TNF-α. Etanercept is a soluble human TNF-α receptor. The report assesses the efficacy of TNF-α-antagonists to down-regulate inflammation, improve functional status and prevent joint damage in RA with particular regard to the following indications: Treatment of severe, refractory and ongoing disease activity despite adequate use of conventional antirheumatic agents; and treatment of early RA before conventional treatment failure has been demonstrated. METHODS: A systematic review of the literature is been performed using established electronic databases. The literature search is supplemented by a hand search of journals and publications relevant to RA, reviews of websites of national and international rheumatologic expert societies, as well as contacts to manufacturers. A priori defined inclusion and exclusion criteria are used for literature selection. Analysis and evaluation of included publications are based on standardised criteria sets and checklists of the German Scientific Working Group for Technology Assessment in Health Care. RESULTS: Health Technology Assessment reports and metaanalyses cannot be identified. A total of 12 clinical trials are analysed, as well as national and international expert recommendations and practice guidelines. Numerous non-systematic reviews are found and analysed for additional sources of information that is not identified through the systematic search. Case reports and safety assessements are considered as well. A total of 137 publications is included. The primary outcome measures in clinical trials are suppression of inflammatory disease activity and slowing of structural joint damage. Clinical response is usually measured by standardised response criteria that allow a semi-quantitative classification of improvement from baseline by 20%, 50%, or 70%. In patients with RA refractory to conventional treatment, TNF-α-antagonists are unequivocally superior to Methotrexate with regard to disease activity, functional status and prevention of structural damage. In patients with early RA, TNF-α-antagonists show a more rapid onset of anti-inflammatory effects than Methotrexate. However, differences in clinical response rates and radiologic progression disappear after a few months of treatment and are no longer statistically significant. Serious adverse events are rare in clinical trials and do not occur significantly more often than in the control groups. However, case reports and surveillance registries show an increased risk for serious infectious complications, particularly tuberculosis. Expert panels recommend the use of TNF-α-antagonists in patients with active refractory RA after failure of conventional treatment. Studies that compare Infliximab and Etanercept are lacking. There are no pharmacoeconomic studies although decision analytic models of TNF-α-antagonists for the treatment of RA exist. Based on the results of the models, a combination therapy with Hydroxychloroquin (HCQ), Sulfaslazin (SASP) and Methotrexate as well as Etanercept/Methotrexate can be considered a cost-effective treatment for Methotrexate-resistant RA. CONCLUSIONS: TNF-α-antagonists are clearly effective in RA patients with no or incomplete response to Methotrexate and superior to continuous use of Methotrexate. It refers to both, reduction of inflammatory disease activity including pain relief and improved functional status, and prevention of structural joint damage. Therefore, TNF-α-antagonism is an important new approach in the treatment of RA. There is still insufficient evidence that early use of TNF-α-antagonists in RA prior to standard agents is beneficial and further studies have to be awaited. An analytic model suggests that TNF-α-antagonists are, due to their clinical effectiveness in patients with no or incomplete response to Methotrexate, a cost-effective alternative to common therapies chosen in the subpopulations of patients. Nevertheless, it has to be borne in mind that the acquisition costs of TNF-α-antagonists lead to high incremental costs and C/E ratios, which exceed the common frame of assessing the cost-effectiveness of medical methods and technologies. Hence, society's willingness-to-pay is the critical determinant in the question whether TNF-α-antagonists shall be reimbursed or not, or to define criteria for reimbursement. Changes in the quality of life attributable to the use of TNF-α-antagonists in RA have not yet been assessed which might assist the decision making. With respect of the questions mentioned above and the potential financial effect of a systematic use of TNF-α-antagonists in the treatment of RA, we come to the conclusion that TNF-α-antagonists should not introduced as a standard benefit reimbursed by the statutory health insurers in Germany.

Sonographic diagnosis of "acute abdomen" in children and adults.

INTRODUCTION: The acute abdomen is the main term for an at first unclear emergency situation of the abdominal cavity. The acute abdomen belongs to the three most important reasons for the admission of patients into the emergency room. Further, this illness ranks 40% of all consultations in the ambulant care sector. The acute abdomen requires an early and direct diagnosis because of its potential of having a life threatening differential diagnosis. This HTA report aimed to assess the ultrasound diagnosis of the acute abdomen considering children and adults. This will be done from a medical and economic perspective. The differential diagnosis respectively the cause of the acute abdomen binds high direct treatment costs, especially in the stationary sector. Ultrasound diagnosis is a procedure that plays a big part in the differential diagnosis process and it is widely used in practise. Other research methods of diagnosing acute abdominal illness are: clinical examinations with inspection and palpation, surgical exploration and laparocopy as well as computer tomography and x-ray examination. OBJECTIVES: The main objective of this HTA report is to assess what significance sonography should have within the examination strategy of the acute abdomen from the medical and economical view. Second, this HTA report will evaluate under which circumstances the ultrasonographic diagnosis of the acute abdomen, considering medical and economical quality classifications, is the alternative of choice to comparable diagnostic measures. METHODS: The target population this HTA report is aimed at are children and adults with acute abdomen or embedded differential diagnosis. A systematic literature search was conducted covering all relevant medical and HTA-databases. Furthermore, handsearch was conducted inside of the known data bases of HTA-institutions as well as from medical and economical journals. The following databases were searched in cooperation with DIMDI to identify relevant literature: Biosis-Previews (BA93), Biotechnobase (ET80), Cab-Health (AZ72), Elsevier Biobase (EB94), EMBASE (EM74), Embase Alert (EA08), Ethmed (ED93), Euroethics (EU93), Gerolit (GE79), Heclinet (HN69), IHTA ( HT83), IPA (IA70), MEDLINE (ME90, Medline Alert (MEOA) and SciSearch (IS74). The search parameters were orientated by the embedded differential diagnosis's as well as diagnostic measures considering the acute abdomen. The bibliographic search covered the period from 1990 to 2003. The relevant languages are English, German in connection to French. The evaluation of the information has been graduated. It must be clear that the abstract follows the topic of the acute abdomen. The as such identified literature will be structured by its methodological quality and relevance. This will be analysed and later valued after it is clear that the minimum requirements are met. RESULTS: The identified and assessed primary studies, reviews and metaanalytic studies demonstrated the medical effectiveness as well as the economical efficiency of the sonographical diagnosis for individual questions or indications. The evaluated papers of the target population 'children' demonstrated that sonography resp. ultrasound as the basic examination is recommended for children with acute abdominal pain. DISCUSSION: The identified studies have not used an extensive setting of the ultrasound diagnosis of the acute abdomen. Instead they focus only on small sections, orientated on certain indications. Blinded medical studies have not been identified. Also, there is no health-economics study that evaluated the diagnostic measures by comparing all available technologies. Altogether, the identified and assessed publications show that sonography is an alternative of choice considering particular questions in comparison to other diagnostic measures of analyzing the acute abdomen. A general deflected dominance from the sonography facing the computer tomography for instance can not be seen as the result of this structured review of the published literature. CONCLUSION: During a structured examination strategy, e.g. guidelines, sonography of children has become the diagnostic method of choice. Taking up sonography as a primary diagnostic evaluation into the guidelines of the analysis of the considered literature is recommended. The usage of already existing ultrasound systems is also recommended. Seeing that existing publications of this subject are scarce, it is not possible to prognose the economical effects of an obligatory primary sonographical diagnostic.