Considerations about the effectiveness and cost effectiveness of therapies in the treatment of hyperphosphataemia

Because of an elevated serum phosphate level, patients who suffer from chronic kidney failure frequently tend to have cardiovascular calcification and are therefore exposed to a higher probability of a fatal event. Phosphate binders are able to reduce these negative effects. Currently, there are primarily two groups of phosphate binders (calcium-containing and calcium-free phosphate binders) which are considered to be almost equally effective in terms of binding of free phosphate. There are, however, a few disadvantages of the two groups. While the calcium-containing binders are associated with an increased risk of hypercalcaemia, which is dose dependent, calcium-free binders have been criticized as being too expensive. As the expenditure for patients suffering from chronic kidney failure increases from year to year, as a result of increasing prevalence, there is a growing need for an alternative to existing phosphate binders. The study presented here therefore summarizes available information for the novel combination preparation OsvaRen® (calcium acetate/magnesium carbonate) as an alternative therapy to the calcium-free phosphate binder Renagel® (sevelamer-hydrochloride) and to calcium-containing preparations. The results of this systematic review showed that OsvaRen® is at least equally effective in the regulation of serum phosphate level as Renagel®. In particular, OsvaRen® shows no clinically relevant difference in terms of the control of the serum calcium levels compared to Renagel® and thereby does not increase the risk of a hypercalcaemia, in contrast to pure calcium-based phosphate binders. On the other hand, Renagel® therapy is much more frequently associated with gastrointestinal side-effects, a tendency to result in higher tablet burden for patients and high medication costs. The CALMAG study showed that OsvaRen® was at least as effective and safe in terms of controlling serum phosphate and serum calcium levels as Renagel® while, at the same time, resulting in about 80% lower costs. In addition, OsvaRen® offers a lower risk of hypercalcaemia and associated subsequent costs and is thereby also superior to pure calcium-containing phosphate binders. Because of the effectiveness and tolerability of calcium acetate/magnesium carbonate, OsvaRen® offers a clinically suitable and, at the same time, cost-effective therapeutic option in the therapy of hyperphosphataemia.Fresenius Medical Care Deutschland Gmb

Biologic TNF inhibiting agents for treatment of inflammatory rheumatic diseases: Dosing patterns and related costs in Switzerland from a payers perspective

Background: To obtain detailed real-life data on costs and dosing patterns in the utilisation of the TNF inhibitors adalimumab, etanercept, and infliximab in patients treated in Switzerland. Methods: Administrative claims processed by a major Swiss health insurer between 2005 and 2008 were analysed. Patients with inflammatory rheumatic diseases (IRDs) with at least one prescription for adalimumab, etanercept, or infliximab were identified. All-cause and disease-specific costs, as well as daily costs of treatment, were calculated. Dosing patterns and discontinuation rates were analysed. Results: A total of 555 IRD patients were identified. All-cause costs during the 12 months after the index event were 20,555CHF in the etanercept group, 24,152CHF in the adalimumab group, and 27,614CHF in the infliximab group. The most important cost driver was mean TNF inhibitor drug cost, which was 15,613CHF in the etanercept group, 19,166CHF in the adalimumab group, and 21,313CHF in the infliximab group. Discontinuation rates during the first year after the index event were 46.8% in etanercept, 41.3% in adalimumab, and 51.2% in the infliximab group. Rates of dosage increase were 13.3% in the etanercept group, 13.0% in the adalimumab group, and 14.1% in the infliximab group. When time on treatment was considered, daily costs of treatment were similar for etanercept and adalimumab, but were higher for infliximab. Conclusions: Marked differences in costs between subcutaneous and intravenous therapies were observed. Among the three groups of patients defined by TNF inhibitor treatment, costs for the infliximab group were highest during the year after the index event.Helsana Versicherungen A

Aspects of outpatient palliative care in Germany - a survey among office-based physicians

Background: Currently, palliative care is widely discussed. The aim of this study is to explore different aspects of the ambulatory treatment environment of palliative care patients and its structure in Germany from the viewpoint of caring physicians. Methods: A structured questionnaire was developed and sent to 1,003 office-based physicians in Germany. Topics were the delivery and effort of care, cooperation among health care providers, the subjective assessment of existing health care structures, the reimbursement system, as well as an assessment of future developments. Sub-group analyses were conducted. Results: Three hundred fourteen questionnaires were included in the statistical analyses. Fifty percent of physicians estimate the additional time and effort for palliative care patients compared to non-palliative care patients to be 50% and more. The best cooperation is seen with caregivers; however, cooperation with psycho-social care providers should be improved. Fifty percent describe the outpatient health care situation as (very) insufficient, but improvements are expected in the future. Ninety percent assess German reimbursement structures as (very) insufficient. Conclusions: This study gives an insight into the German outpatient health care setting for palliative care patients. Palliative care patients have higher and more complex needs with respect to health care than other patients. Further studies should focus on the collection of longitudinal patient data for more comprehensive insight

Why Is It So Difficult to Evaluate Nursing Interventions in Dementia?

Two recent health technology assessment (HTA) reports published in Germany focused on non-pharmacological interventions for patients with dementia. One of the major results was the poor methodological quality of the studies in this field. This paper concisely presents the main quantitative and qualitative findings of the HTA report published by the German Agency for HTA at the Institute of Medical Information and Documentation (dahta@DIMDI), followed by a detailed discussion of the major methodological problems observed for the inclusion criteria, interventions, the setting, number of patients included, duration of observation, comparators, clinical endpoints, health economics, and, most obvious, the impossibility of blinding and eliminating placebo effects for future clinical studies. We conclude with several suggestions addressing these challenges for future research in this field

Biologic TNF inhibiting agents for treatment of rheumatoid arthritis: persistence and dosing patterns in Germany

Objective: To obtain detailed real-world data on persistence and dosing patterns in the utilisation of the TNF inhibitors adalimumab, etanercept, and infliximab in rheumatoid arthritis (RA) patients treated in Germany. Methods: In this retrospective observational study claims data of a major German health insurance fund between 2005 and 2008 were analysed. Patients receiving at least one prescription of adalimumab, etanercept or infliximab were identified and categorised as "TNF inhibitor naive" or "TNF inhibitor continuing". For the calculation of TNF inhibitor persistence a survival analysis with the Kaplan-Meier estimator was used. A Cox regression was used to analyse, if any relevant factors were influencing persistence. Dosage increase rates were analysed for adalimumab, etanercept and infliximab. Sensitivity analyses based on variations in gap length were conducted. Results: A total of 2,201 RA patients were identified. 1,468 of these patients were TNF inhibitor naive patients and 733 were defined as TNF inhibitor continuing patients. There were no significant differences in the treatment persistence rates between adalimumab, etanercept and infliximab for TNF inhibitor naive and continuing patients. The persistence rate after three years was 22.47% for adalimumab, 24.27% for etanercept and 21.49% for infliximab naive patients. For continuing patients, the persistence rate after three years was 32.88% for adalimumab, 30.95% for etanercept, and 33.90% for infliximab, respectively. Gender, medication and Charlson Comorbidities Index did not influence the persistence significantly. Dosage increase occurred in 7.3% adalimumab, 1.4% etanercept, and 17.2% infliximab naive patients and 5.8%, 1.1% and 11.9% respectively in the continuing patients. Conclusions: In this study, there were no significant differences in persistence among adalimumab, etanercept and infliximab treated patients. Consistent with previous research, there was a higher dose escalation for infliximab than for the two subcutaneous treatments, adalimumab or etanercept

Review on the medical and health economic evidence for an inclusion of colposcopy in primary screening programs for cervical cancer

Introduction: With 3.2% of all cancer cases in 2002, cervical carcinoma is the tenth most common cancer in Germany and causes 1.8% of all cancer deaths in women in Germany. To date diagnosis in Germany solely has been based on cervical cytology which has been criticised due to its low sensitivity and consequently high rate of false negative results. Objectives: How does colposcopy compare to cytological tests in terms of sensitivity and specificity, and what may be the effects of changes in screening for cervical carcinoma in Germany? Is there health economic evidence that may foster an inclusion of colposcopy into national screening programms? Methods: A systematic literature review was performed, including studies that compared colposcopy to cervical cytology in terms of sensitivity and specificity. In addition, a systematic review of the relevant health economic literature was performed to analyse cost-effectiveness issues relevant to the German setting. Results: A total of four studies fulfilled the inclusion criteria, of which only two were of high methodologic quality. In all studies, the sensitivity of colposcopy was lower than that of cytology. In three studies the specificity of colposcopy was lower than that of cytology, in one study specificity of colposcopy and cytology was similar. No health economic data suggesting positive effects of adding colposcopy in primary screening could be identified. Discussion: Only few studies have compared the test criteria of colposcopy with those of cytology for screening in cervical cancer. In all studies, sensitivity of colposcopy was even lower than the sensitivity of cytology, which has been critisized because of its low sensitivity. Conclusion: Based on the present data, an inclusion of colposcopy in primary cervical cancer screening programmes can not be recommended

Archaeal Nucleosome Positioning In Vivo and In Vitro is Directed by Primary Sequence Motifs

Background: Histone wrapping of DNA into nucleosomes almost certainly evolved in the Archaea, and predates Eukaryotes. In Eukaryotes, nucleosome positioning plays a central role in regulating gene expression and is directed by primary sequence motifs that together form a nucleosome positioning code. The experiments reported were undertaken to determine if archaeal histone assembly conforms to the nucleosome positioning code. Results: Eukaryotic nucleosome positioning is favored and directed by phased helical repeats of AA/TT/AT/TA and CC/GG/CG/GC dinucleotides, and disfavored by longer AT-rich oligonucleotides. Deep sequencing of genomic DNA protected from micrococcal nuclease digestion by assembly into archaeal nucleosomes has established that archaeal nucleosome assembly is also directed and positioned by these sequence motifs, both in vivo in Methanothermobacter thermautotrophicus and Thermococcus kodakarensis and in vitro in reaction mixtures containing only one purified archaeal histone and genomic DNA. Archaeal nucleosomes assembled at the same locations in vivo and in vitro, with much reduced assembly immediately upstream of open reading frames and throughout the ribosomal rDNA operons. Providing further support for a common positioning code, archaeal histones assembled into nucleosomes on eukaryotic DNA and eukaryotic histones into nucleosomes on archaeal DNA at the same locations. T. kodakarensis has two histones, designated HTkA and HTkB, and strains with either but not both histones deleted grow normally but do exhibit transcriptome differences. Comparisons of the archaeal nucleosome profiles in the intergenic regions immediately upstream of genes that exhibited increased or decreased transcription in the absence of HTkA or HTkB revealed substantial differences but no consistent pattern of changes that would correlate directly with archaeal nucleosome positioning inhibiting or stimulating transcription. Conclusions: The results obtained establish that an archaeal histone and a genome sequence together are sufficient to determine where archaeal nucleosomes preferentially assemble and where they avoid assembly. We confirm that the same nucleosome positioning code operates in Archaea as in Eukaryotes and presumably therefore evolved with the histone-fold mechanism of DNA binding and compaction early in the archaeal lineage, before the divergence of Eukaryotes

Sudemycin E Influences Alternative Splicing and Changes Chromatin Modifications

Sudemycin E is an analog of the pre-messenger RNA splicing modulator FR901464 and its derivative spliceostatin A. Sudemycin E causes the death of cancer cells through an unknown mechanism. We found that similar to spliceostatin A, sudemycin E binds to the U2 small nuclear ribonucleoprotein (snRNP) component SF3B1. Native chromatin immunoprecipitations showed that U2 snRNPs physically interact with nucleosomes. Sudemycin E induces a dissociation of the U2 snRNPs and decreases their interaction with nucleosomes. To determine the effect on gene expression, we performed genome-wide array analysis. Sudemycin E first causes a rapid change in alternative pre-messenger RNA splicing, which is later followed by changes in overall gene expression and arrest in the G2 phase of the cell cycle. The changes in alternative exon usage correlate with a loss of the H3K36me3 modification in chromatin encoding these exons. We propose that sudemycin E interferes with the ability of U2 snRNP to maintain an H3K36me3 modification in actively transcribed genes. Thus, in addition to the reversible changes in alternative splicing, sudemycin E causes changes in chromatin modifications that result in chromatin condensation, which is a likely contributing factor to cancer cell death

Decision-analytic modeling to evaluate the long-term effectiveness and cost-effectiveness of HPV-DNA testing in primary cervical cancer screening in Germany

Sroczynski G, Schnell-Inderst P, Muhlberger N, et al. Decision-analytic modeling to evaluate the long-term effectiveness and cost-effectiveness of HPV-DNA testing in primary cervical cancer screening in Germany. GMS health technology assessment. 2010;6:Doc05.Persistent infections with high-risk types of human papillomavirus (HPV) are associated with the development of cervical neoplasia. Compared to cytology HPV testing is more sensitive in detecting high-grade cervical cancer precursors, but with lower specificity. HPV based primary screening for cervical cancer is currently discussed in Germany. Decisions should be based on a systematic evaluation of the long-term effectiveness and cost-effectiveness of HPV based primary screening. What is the long-term clinical effectiveness (reduction in lifetime risk of cervical cancer and death due to cervical cancer, life years gained) of HPV testing and what is the cost-effectiveness in Euro per life year gained (LYG) of including HPV testing in primary cervical cancer screening in the German health care context? How can the screening program be improved with respect to test combination, age at start and end of screening and screening interval and which recommendations should be made for the German health care context? A previously published and validated decision-analytic model for the German health care context was extended and adapted to the natural history of HPV infection and cervical cancer in order to evaluate different screening strategies that differ by screening interval, and tests, including cytology alone, HPV testing alone or in combination with cytology, and HPV testing with cytology triage for HPV-positive women. German clinical, epidemiological and economic data were used. In the absence of individual data, screening adherence was modelled independently from screening history. Test accuracy data were retrieved from international meta-analyses. Predicted outcomes included reduction in lifetime-risk for cervical cancer cases and deaths, life expectancy, lifetime costs, and discounted incremental cost-effectiveness ratios (ICER). The perspective of the third party payer and 3% annual discount rate were adopted. Extensive sensitivity analyses were performed in order to evaluate the robustness of results and identify areas of future research. In the base case analysis screening resulted in a 53% to 97% risk reduction for cervical cancer with a discounted ICER between 2,600 Euro/LYG (cytology alone every five years) and 155,500 Euro/LYG (Annual cytology age 20 to 29 years, and annual HPV age 30 years and older). Annual cytology, the current recommended screening strategy in Germany, was dominated. In sensitivity analyses variation in the relative increase in the sensitivity of HPV testing as compared to cytology, HPV test costs, screening adherence, HPV incidence, and annual discount rate influenced the ICER results. Variation in the screening start age also influenced the ICER. All cytology strategies were dominated by HPV screening strategies, when relative sensitivity increase by HPV testing compared to cytology was higher (scenario analysis with data for test accuracy from German studies). HPV testing every one, two or three years was more effective than annual cytology. With increased screening adherence a longer screening interval and with low screening adherence a shorter interval would be more cost-effective. With a reduction in HPV incidence of more than 70% triennial HPV screening in women aged 30 years and older (and biennial Pap screening in women aged 20 to 29 years) is cost-effective. The discounted ICER increases with increasing annual discount rate. Increasing screening start age to 25 years had no relevant loss in effectiveness but resulted in lower costs. An optimal strategy may be biennial HPV testing age 30 years and older with biennial cytology at age 25 to 29 years (ICER of 23,400 Euro/LYG). Based on these results, HPV-based cervical cancer screening is more effective than cytology and could be cost-effective if performed at intervals of two years or greater. Increasing the age at screening start to 25 years causes no relevant loss in effectiveness but saves resources. In the German context an optimal screening strategy could be biennial HPV testing at age 30 years and older with biennial cytology at the age of 25 to 29 years. An extension to a three-yearly screening interval requires substantially improved screening adherence or a higher relative increase in the sensitivity of HPV testing as compared to cytology. The implementation of an organised screening program for quality-controlled introduction of HPV-screening and -vaccination with continued systematic outcome evaluation is recommended

Assessment of effectiveness and cost-effectiveness of HPV testing in primary screening for cervical

Introduction: The introduction of a screening programme for cervical carcinoma in Germany has led to a significant reduction in incidence of the disease. To date, however, diagnosis in Germany has been based solely on cervical cytology, which has been criticised because of a low sensitivity and consequently high rate of false negative results. Because an infection with the human papillomavirus (HPV) previously was found to be a necessary aetiological factor in the development of cervical cancer, there has been some discussion that HPV testing should be included in cervical cancer screening. Objectives: How do HPV tests compare to cytological tests in terms of sensitivity and specificity, and what are the effects of screening for cervical carcinoma in Germany? Is there health economic evidence that may foster an inclusion of HPV testing into national screening programms? Methods: A systematic literature review was performed, including studies that compared the HPV test to cervical cytology in terms of sensitivity and specificity in the diagnosis of CIN 2+ (CIN=Cervical Intraepithelial Neoplasia). In addition, a systematic review of the relevant health economic literature was performed to analyze cost-effectiveness in the German setting. Results: A total of 24 studies fulfilled the inclusion criteria. One study consisted of three substudies. Hence, results of 26 comparisons of HPV and cytology are reported. In 25 of these, the HPV test was more sensitive than cytology, whereas cytology had better specificity in 21 studies. The combination of HPV test and cytology increased sensitivity. Variability in results was considerably larger for cytology than for HPV testing. Results of the economic meta-analysis suggest that in health care settings with already established PAP screening programms, cost-effectiveness strongly depends on screening intervals. In analyses comparing HPV screening to conventional PAP screening with two-yearly intervals, only 25% of the HPV strategies were found to be cost-effective, whereas in comparison with one-, three-, and five-yearly PAP screening, the percentage of overall cost-effective HPV strategies was 83%, 55%, and 92%, respectively. Results for annual screening intervals are based on the assumption of complete screening compliance, which has to be further evaluated in decision analyses in the future adapting to the German health care setting. Discussion: Including HPV testing in screening procedures for cervical carcinoma could lead to a reduction in false positive results. Doing so would involve one of the following approaches: a) combining the HPV test with cytology, or b) using cytology as triage in HPV-positive women. The most appropriate interval between screening tests and the best age to start or stop screening remains to be determined. At this point a formal health economic decision analyses may help in resolving those questions, additionally incorporating compliance and adherence within different screening scenarios. Conclusion: Considering medical evidence weighing the question whether HPV testing should be implemented into screening routine may not be if but how to do so. Open questions remain in setting the length of optimal screening intervals, the age range in which to screen, and the combination or sequence of existing cytology and HPV testing. Answers to those questions will be gathered in the very near future through large international clinical trials. Cost-effectiveness of implementing HPV testing is likely to exist in the management of borderline or unclear smears in triage treatment as well as in certain scenarios of primary screening within the German health care setting