Objective To compare 10 year revision rates for frequently used types of primary total hip replacement to inform setting of a new benchmark rate in England and Wales that will be of international ...relevance.Design Retrospective cohort study.Setting National Joint Registry.Participants 239 000 patient records.Main outcome measures Revision rates for five frequently used types of total hip replacement that differed according to bearing surface and fixation mode, encompassing 62% of all primary total hip replacements in the National Joint Registry for England and Wales. Revision rates were compared using Kaplan-Meier and competing risks analyses, and five and 10 year rates were estimated using well fitting parametric models.Results Estimated revision rates at 10 years were 4% or below for four of the five types of total hip replacement investigated. Rates differed little according to Kaplan-Meier or competing risks analysis, but differences between prosthesis types were more substantial. Cemented prostheses with ceramic-on-polyethylene bearing surfaces had the lowest revision rates (1.88-2.11% at 10 years depending on the method used), and cementless prostheses with ceramic-on-ceramic bearing surfaces had the highest revision rates (3.93-4.33%). Men were more likely to receive revision of total hip replacement than were women, and this difference was statistically significant for four of the five prosthesis types.Conclusions Ten year revision rate estimates were all less than 5%, and in some instances considerably less. The results suggest that the current revision rate benchmark should be at least halved from 10% to less than 5% at 10 years. This has implications for benchmarks internationally.
Early trials of garlic preparations on blood lipids mainly supported a lipid-lowering effect, whereas later well-designed garlic tablet trials were mainly entirely null. However, enteric simulation ...tests suggest that this discordance may result from ineffective delivery of bioactive agents from the brands of garlic powder (GP) and cyclodextrin-bound garlic oil (GO) tablets tested in some recent negative trials. In contrast, enteric simulation tests show that the preformed bioactive agents present in “traditional” gelatin capsules of GO are efficiently released, although such capsules have rarely been investigated in lipid-lowering trials. It was hypothesized that gelatin capsules of GO given to normal subjects would improve specified coronary heart disease risk factors. Effects of a GP preparation were also investigated. Subjects (n = 51; men and women, mean age 27 y) were randomly assigned to receive either 8.2 mg/d of GO (allyl sulfides) or placebo for 11 wk. Another 27 subjects received garlic powder (GP) of similar biopotential (7.8 mg allicin/d). Outcome measures were 95% confidence intervals (CI) between GO and placebo groups for differences between baseline and subsequent sample times. Men and women combined showed no significant differences save for an improved total antioxidant capacity at 6 wk (P = 0.01). Hence, no benefit from GO after 11 wk is one plausible conclusion. However, there were significant differences in effect of GO between men and women for HDL cholesterol (HDL-C) (P = 0.004) and total cholesterol (TC)/HDL-C (P = 0.003). Women showed favorable effects in terms of CHD risk factors (i.e., increases in HDL-C and reductions in TC/HDL-C), whereas men had small adverse effects. There was a significant difference in the GO effect for glucose (P = 0.006), with a reduction seen for men and an increase for women. The gender effects were unexpected and such analyses were not planned in advance. Confirmation of these findings with larger numbers of subjects would have importance for the use of garlic against CHD and for the design of future garlic studies. J. Nutr. 131: 1471–1478, 2001.
Crohn's disease (CD) is a severe, lifelong disease characterised by inflammation of the gastrointestinal mucosa. The impact on patients and society is high as ill health can be lifelong and can ...negatively affect patients' quality of life. Costs to the NHS are high, particularly for patients needing hospitalisation. Conventional treatment pathways are complex. More recently, a group of drugs called tumour necrosis factor (TNF) inhibitors (anti-TNF-α agents) have been evaluated for their effectiveness in CD. One of these, infliximab, is currently recommended by the National Institute for Health and Clinical Excellence (NICE; 2002) for patients with severe, active CD where patients are refractory to or intolerant of conventional treatment.
To investigate whether there is evidence for greater clinical effectiveness or cost-effectiveness for either adalimumab or infliximab.
Cochrane Library (Cochrane Central Register of Controlled Trials) 2007 Issue 2; MEDLINE (Ovid) 2000 to May/June 2007; MEDLINE In-Process & Other Non-Indexed Citations (Ovid) 4 June and 26 June 2007; EMBASE (Ovid) 2000 to May/June 2007. The European Medicines Agency, the US Food and Drug Administration and other relevant websites.
Standard systematic review methods were used for study identification and selection, data extraction and quality assessment. Only randomised controlled trials (RCTs) comparing adalimumab or infliximab with standard treatment (placebo), RCTs comparing adalimumab with infliximab, or RCTs comparing different dosing regimens of either adalimumab or infliximab in adults and children with moderate-to-severe active CD intolerant or resistant to conventional treatment were eligible for inclusion. A systematic review of published studies on the cost and cost-effectiveness of adalimumab and infliximab was undertaken. The economic models of cost-effectiveness submitted by the manufacturers of both drugs were critically appraised and, where appropriate, rerun using parameter inputs based on the evidence identified by the authors of the technology asessment report. A de novo Markov state transition model was constructed to calculate the incremental cost-effectiveness ratio for adalimumab and infliximab therapy compared with standard care.
Based on 11 trials, there was evidence from both induction and maintenance trials that both adalimumab and infliximab therapy were beneficial compared with placebo (standard care) for adults with moderate-to-severe CD and, for infliximab, for adults with fistulising CD; results were statistically significant for some time points. Between 6% and 24% (adalimumab), and 21% and 44% (infliximab) more patients achieved remission with anti-TNF-α antibodies than with placebo in the induction trials. Between 24% and 29% (adalimumab), and 14% and 24% (infliximab) more patients achieved remission with anti-TNF-α antibodies in the two large maintenance trials at reported follow-up. In fistulising CD, between 29% and 42% (induction trial) and 23% (maintenance trial) more patients achieved a > 50% reduction in fistulas with infliximab than with placebo at reported follow-up. There was no direct evidence to show that 'responders' were more likely to benefit from treatment than 'non-responders' in the longer term. Few differences were found between treatment and standard care arms for selected adverse events, though high proportions of scheduled crossovers resulted in a lack of a true placebo group in most of the maintenance trials. No published studies on the cost-effectiveness of adalimumab were identified. The four independently funded studies identified for infliximab suggested high cost-effectiveness ratios all above £50,000/quality-adjusted life-year (QALY) for non-fistulising disease and all above £100,000/QALY for fistulising disease. A budget impact assessment suggested that total cost to the NHS in England and Wales for induction in severe disease only could range between £17M and £92M and for maintenance for 1 year between £140M and £200M.
Regarding clinical effectiveness, there were concerns about the trial design and lack of clarity, which may have affected interpretation of results. None of the trials matched exactly the licence indications or NICE guidance, which specify the use of these drugs in patients with 'severe' disease. All trials were multicentre, and applicability to UK populations, particularly in terms of standard care being provided and in terms of patients having failed or having become intolerant to conventional treatment, was uncertain. The published economic models relied heavily on little information and data from small samples.
Anti-TNF therapy with adalimumab or infliximab may have a beneficial effect compared with standard care on outcome measures for induction and maintenance. The findings were that for induction, both adalimumab and infliximab are cost-effective (dominant relative to standard care) in the management of severe CD, and adalimumab (but not infliximab) is cost-effective for moderate CD, according to limits generally accepted by NICE. On the basis of the analysis presented here, neither drug is likely to be cost-effective as maintenance therapy for moderate or severe disease. Perhaps, most importantly, the analysis reflected the fact that a substantial number of patients would achieve remission under standard care and that the incidence of relapse among those in remission was such that maintenance therapy would have to show greater effectiveness than at present and/or be much less costly than it currently is in order to reach the levels of generally accepted cost-effectiveness. Any future trials need to be designed to meet the particular challenges of measuring and quantifying benefit in this patient group.
The research was funded by the HTA programme on behalf of NICE.
To assess the clinical effectiveness and cost-effectiveness of buprenorphine maintenance therapy (BMT) and methadone maintenance therapy (MMT) for the management of opioid-dependent individuals.
...Major electronic databases were searched from inception to August 2005. Industry submissions to the National Institute for Health and Clinical Excellence were accessed.
The assessment of clinical effectiveness was based on a review of existing reviews plus an updated search for randomised controlled trials (RCTs). A decision tree with Monte Carlo simulation model was developed to assess the cost-effectiveness of BMT and MMT. Retention in treatment and opiate abuse parameters were sourced from the meta-analysis of RCTs directly comparing flexible MMT with flexible dose BMT. Utilities were derived from a panel representing a societal perspective.
Most of the included systematic reviews and RCTs were of moderate to good quality, and focused on short-term (up to 1-year follow-up) outcomes of retention in treatment and the level of opiate use (self-report or urinalysis). Most studies employed a trial design that compared a fixed-dose strategy (i.e. all individuals received a standard dose) of MMT or BMT and were conducted in predominantly young men who fulfilled criteria as opiate-dependent or heroin-dependent users, without significant co-morbidities. RCT meta-analyses have shown that a fixed dose of MMT or BMT has superior levels of retention in treatment and opiate use than placebo or no treatment, with higher fixed doses being more effective than lower fixed doses. There was evidence, primarily from non-randomised observational studies, that fixed-dose MMT reduces mortality, HIV risk behaviour and levels of crime compared with no therapy and one small RCT has shown the level of mortality with fixed-dose BMT to be significantly less than with placebo. Flexible dosing (i.e. individualised doses) of MMT and BMT is more reflective of real-world practice. Retention in treatment was superior for flexible MMT than flexible BMT dosing but there was no significant difference in opiate use. Indirect comparison of data from population cross-sectional studies suggests that mortality with BMT may be lower than that with MMT. A pooled RCT analysis showed no significant difference in serious adverse events with MMT compared with BMT. Although treatment modifier evidence was limited, adjunct psychosocial and contingency interventions (e.g. financial incentives for opiate-free urine samples) appeared to enhance the effects of both MMT and BMT. Also, MMT and BMT appear to be similarly effective whether delivered in a primary care or outpatient clinic setting. Although most of the included economic evaluations were considered to be of high quality, none used all of the appropriate parameters, effectiveness data, perspective and comparators required to make their results generalisable to the NHS context. One company (Schering-Plough) submitted cost-effectiveness evidence based on an economic model that had a 1-year time horizon and sourced data from a single RCT of flexible-dose MMT compared with flexible-dose BMT and utility values obtained from the literature; the results showed that for MMT vs no drug therapy, the incremental cost-effectiveness ratio (ICER) was pound 12,584/quality-adjusted life-year (QALY), for BMT versus no drug therapy, the ICER was pound 30,048/QALY and in a direct comparison, MMT was found to be slightly more effective and less costly than BMT. The assessment group model found for MMT versus no drug therapy that the ICER was pound 13,697/QALY, for BMT versus no drug therapy that the ICER was pound 26,429/QALY and, as with the industry model, in direct comparison, MMT was slightly more effective and less costly than BMT. When considering social costs, both MMT and BMT gave more health gain and were less costly than no drug treatment. These findings were robust to deterministic and probabilistic sensitivity analyses.
Both flexible-dose MMT and BMT are more clinically effective and more cost-effective than no drug therapy in dependent opiate users. In direct comparison, a flexible dosing strategy with MMT was found be somewhat more effective in maintaining individuals in treatment than flexible-dose BMT and therefore associated with a slightly higher health gain and lower costs. However, this needs to be balanced by the more recent experience of clinicians in the use of buprenorphine, the possible risk of higher mortality of MMT and individual opiate-dependent users' preferences. Future research should be directed towards the safety and effectiveness of MMT and BMT; potential safety concerns regarding methadone and buprenorphine, specifically mortality and key drug interactions; efficacy of substitution medications (in particular patient subgroups, such as within the criminal justice system, or within young people); and uncertainties in cost-effectiveness identified by current economic models.
Purpose
A first cost-effectiveness analysis has raised a strong concern regarding the cost of tumor treatment fields (TTF) added to maintenance temozolomide for patients with glioblastoma. This ...evaluation was based on effectiveness outcomes from an interim analysis of the pivotal trial, moreover it used a “standard” Markov model. Our objective was to update the cost-effectiveness evaluation using the more flexible potential of the “partitioned survival” model design and using the latest effectiveness data.
Methods
We developed the model with three mutually exclusive health states: stable disease, progressive disease, and dead. Good fit parametric models were developed for overall survival and progression free survival and these generated clinically plausible extrapolations beyond the observed data. We adopted the perspective of the French national health insurance and used a 20-year time horizon. Results were expressed as cost/life-years (LY) gained (LYG).
Results
The base case model generated incremental benefit of 0.604 LY at a cost of €453,848 which, after 4% annual discounting of benefits and costs, yielded an incremental cost effectiveness ratio (ICER) of €510,273/LYG. Using sensitivity analyses and bootstrapping methods results were found to be relatively robust and were only sensitive to TTF device costs and the modelling of overall survival. To achieve an ICER below €100,000/LYG would require a reduction in TTF device cost of approximately 85%.
Conclusions
Using a different type of model and updated survival outcomes, our results show TTF remains an intervention that is not cost-effective, which greatly restrains its diffusion to potentially eligible patients.
A review of therapies for advanced cancers licenced by the EMA between 2009 and 2013 concluded that for more than half of these drugs there was little evidence of overall survival or quality of life ...benefit. Recent years have witnessed a growing number of licensed second-line pharmacotherapies for advanced/metastatic non-small cell lung cancer (NSCLC). With the aim of gauging patient survival benefit, we conducted a systematic review of randomised controlled trials (RCT) and compared survival outcomes from available licensed treatments for patients with advanced/metastatic NSCLC.
RCTs of second/third line treatments in participants with advanced/metastatic NSCLC and negative/low expression of Anaplastic Lymphoma Kinase (ALK) and of Epidermal Growth Factor Receptor (EGFR) were included. We searched electronic databases (MEDLINE; EMBASE; Web of Science) from January, 2000 up to July, 2017. Two or more independent reviewers screened bibliographic records, extracted data, and assessed risk of bias of studies. Published Kaplan Meier plots for OS and PFS along with restricted-mean-survival methods and parametric modelling were used to estimate the survival outcomes as mean number of months of survival. Network meta-analysis was undertaken to rank interventions and to make indirect comparisons.
We included 11 RCTs with data for 7581 participants that compared nine different drugs. In studies of patients regardless of histology groups, targeted drugs (ramucirumab and nintedanib) yielded small overall survival gains of < 2.5 months over docetaxel, erlotinib provided no benefit, while immunotherapies (atezolizumab and pembrolizumab) delivered 5 to 6 months gain. Studies with patients stratified by histology confirmed the apparent superiority of immunotherapy (nivolumab and atezolizumab) over targeted treatments (ramucirumab, nintedanib, afatinib) providing between about 4 to 8 months OS gain over docetaxel. In network analysis immunotherapies consistently ranked higher than alternatives irrespective of population histology and outcome measure.
Our review indicates that nivolumab, pembrolizumab and atezolizumab provide superior survival benefits compared to other licensed drugs for late stage NSCLC. Patient gains from these immunotherapies are substantial compared to the expected average survival with chemotherapy (docetaxel) of < 1 year for people with squamous histology and about 1.25 year for those with non-squamous histology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Most trials of bulb garlic and garlic powder tablets indicate reduced coronary heart disease (CHD) risk in elevated-risk subjects. Most persons taking garlic supplements lack overt risk of CHD. ...However, no trials have tested steam-distilled garlic oil (GO) capsules with healthy subjects. The objectives of the present randomized, double-blind, placebo-controlled study were to determine whether GO capsules reduce CHD risk in trained male runners. Twenty-seven volunteers (mean age, 28.8 years) completed the study. Each took 12.3 mg/day GO (or placebo) capsules for 16 weeks. Main outcome measures were 95% confidence intervals (CIs) between GO and placebo groups for differences in changes of blood pressure (BP), plasma lipids, total antioxidant status (TAS), low-density lipoprotein (LDL) composition and blood clotting factors. Principal results as mean differences (95% CI) between GO and placebo arepulse, 2.9 beats/min (−0.8 to 6.7), P= 0.12; systolic BP, −4.5 mmHg (−10.8 to 1.9), P= 0.16; plasma total cholesterol, 0.01 mmol/l (−0.34 to 0.37), P= 0.95; plasma triglycerides, −0.20 mmol/l (−0.43 to 0.03), P= 0.09; plasma TAS, 45 μmol Trolox equivalent/l (−35 to 124), P= 0.26; LDL density, 0.0019 g/ml (−0.0005 to 0.0043), P= 0.12; LDL triglycerides/protein, −0.078 mg/mg (−0.149 to −0.007), P= 0.03; LDL cholesterol/protein, −0.24 mg/mg (−0.69 to 0.22), P= 0.3; LDL TAS/triglycerides, 29 nmol/mg (11, 68), P= 0.15; prothrombin time, 0.99 s (−0.36 to 2.35), P= 0.14; partial thromboplastin time, 3.0 s (−1.0 to 7.1), P= 0.13. Results were null statistically. Trends with GO were mostly towards lower CHD risk, and a larger study (~150 subjects) is required to test their validity.
A simple spectrophotometric assay was developed for peroxisomal fatty acyl-CoA oxidase activity. The assay, based on the H2O2-dependent oxidation of leuco-dichlorofluorescein catalysed by exogenous ...peroxidase, is more sensitive than methods previously described. By using mouse liver samples, cofactor requirements were assessed and a linear relationship was demonstrated between dye oxidation and enzyme concentration. By using this assay on subcellular fractions, palmitoyl-CoA oxidase activity was localized for the first time in microperoxisomes of rat intestine. The assay was also adapted to measure D-amino acid oxidase activity, demonstrating the versatility of this method for measuring activity of other H2O2-producing oxidases.
Abstract
BACKGROUND
The addition of novel therapy “Tumor-Treating fields” (TTF) to standard radio-chemotherapy with Temozolomide (TMZ) has recently shown superiority over conventional TMZ regimen in ...patients with glioblastoma. Despite the clinical benefit of TTF, there is a strong concern regarding the cost of this new treatment. A first cost-effectiveness analysis, which was published in 2016, was based on effectiveness outcomes from an interim analysis of the pivotal trial and used a “standard” Markov model. Here, we aimed to update the cost-effectiveness evaluation using a partitioned survival model design and using the latest effectiveness data.
MATERIAL AND METHODS
A partitioned survival model was developed with three mutually exclusive health states: stable disease, progressive disease, and dead. Parametric models were fitted to the Kaplan-Meier data for overall and progression-free survival. These generated clinically plausible extrapolations beyond the observed data. The perspective of the French national health insurance was adopted and the time horizon was 20 years. Base case results were expressed as cost/life-years (LY) gained (LYG). Secondary analyses were undertaken, with the results presented as cost/per quality adjusted life years (QALY) gained. Last, we undertook deterministic and probabilistic sensitivity analyses.
RESULTS
After applying 4% annual discounting of benefits and costs, the base case model generated incremental benefit of 0.507 LY at a incremental cost of €258,695 yielding an incremental cost effectiveness ratio (ICER) of €510,273 / LYG. Secondary analyses yielded an ICER of €667,173/QALY. Sensitivity analyses and bootstrapping methods showed the model was relatively robust. The model was sensitive to TTF device costs and the parametric model fitted to the Kaplan-Meier data for overall survival. The cost-effectiveness acceptability curve showed TTF has 0% of being cost-effective under conventional thresholds.
CONCLUSION
Using a partitioned survival model, uprated costs and more mature survival outcomes, TTF when compared to standard radio-chemotherapy with TMZ is not likely to be cost-effective. This has major implications in terms of access of newly eligible patients
Background and aim of the study
Data about the beating heart (BH) technique for isolated tricuspid valve (TV) surgery compared to the arrested heart (AH) technique are sparse. We compared the ...outcomes of isolated TV surgery between BH and AH technique.
Methods
We performed an observational analysis of our database of isolated TV surgery. Patients were divided into two groups according to whether surgery was performed without (BH group) or with (AH group) aortic cross‐clamping and cardioplegic arrest. The primary endpoint was survival to hospital discharge. Risk factors for in‐hospital mortality were searched with multivariate analyses. We undertook further comparisons after propensity‐score matching.
Results
From January 2007 to December 2017, we performed 82 isolated TV surgery (BH group, n = 47, 57.3%; AH group, n = 35, 42.7%). The mean age was 59.1 years, 56.1% were female. BH group patients were older (61.8 vs. 55.4 years; p = .035), had greater impaired renal function (glomerular filtration rate, 61.1 vs. 74.6 ml/min; p = .012), were more frequently operated for secondary TR (61.7 vs. 31.4%; p = .008), underwent more frequently a reoperation (53.2 vs. 28.6%; p = .042) and exhibited a higher surgical risk (EuroSCORE II, 3.92 vs. 2.50%; p = .013). In‐hospital mortality was not different between both groups, either considering unmatched (BH = 10.6 vs. AH = 5.7%; OR = 1.96, 95% confidence interval CI = 0.36–10.77) or matched populations (BH = 10.6 vs. AH = 6.4%; OR = 1.89, 95% CI = 0.36–9.97). Age was the only predictor of in‐hospital mortality.
Conclusions
The BH technique showed comparable outcomes to the AH technique for isolated TV surgery despite a higher risk profile.
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