Associations of cardiometabolic polygenic risk scores with cardiovascular disease in African Americans.

Background: Cardiovascular disease (CVD) is a complex disease, and genetic factors contribute individually or cumulatively to CVD risk. While African American women and men are disproportionately affected by CVD, their lack of representation in genomic investigations may widen disparities in health. We investigated the associations of cardiometabolic polygenic risk scores (PRSs) with CVD risk in African Americans. Methods: We used the Jackson Heart Study, a prospective cohort study of CVD in African American adults and the predicted atherosclerotic cardiovascular disease (ASCVD) 10-year risk. We included 40-79 years old adults without a history of coronary heart disease (CHD) or stroke at baseline. We derived genome-wide PRSs for systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, LDL cholesterol, hemoglobin A1c (HbA1c), triglycerides, and C-reactive protein (CRP) separately for each of the participants, using African-origin UK Biobank participants' genome-wide association summary statistics. We estimated the associations between PRSs and 10-year predicted ASCVD risk adjusting for age, sex, study visit date, and genetic ancestry using linear and logistic regression models. Results: Participants (n=2,077) were 63% female and 66% never-smokers. They had mean (SD) 56 (10) years of age, 127.8 (16.3) mmHg SBP, 76.3 (8.7) mmHg DBP, 200.4 (40.2) mg/dL total cholesterol, 51.7 (14.7) mg/dL HDL cholesterol, 127.2 (36.7) mg/dL LDL cholesterol, 6.0 (1.3) mmol/mol HbA1c, 108.9 (81.7) mg/dL triglycerides and 0.53 (1.1) CRP. Their median (interquartile range) predicted 10-year predicted ASCVD risk was 8.0 (4.0-15.0). Participants in the >75th percentile for HbA1c PRS had 1.42 percentage-point greater predicted 10-year ASCVD risk (1.42 [95% CI: 0.58-2.26]) and higher odds of ≥10% predicted 10-year ASCVD risk (OR: 1.46 [95% CI: 1.03-2.07]) compared with those in the <25th percentile for HbA1c PRS. Participants in the >75th percentile for SBP PRS had higher odds of ≥10% predicted 10-year ASCVD risk (OR: 1.52 [95% CI: 1.07-2.15]) compared with those in the <25th percentile for SBP PRS. Conclusion: Among 40-79 years old African Americans without CHD and stroke, higher PRSs for HbA1c and SBP were associated with CVD risk. PRSs may help stratify individuals based on their clinical risk factors for CVD early prevention and clinical management.

Jordanian perspectives on advanced nursing practice: an ethnography.

AIM: This study aimed to explore how different groups of participants perceived the concept of advanced nursing practice in Jordan. BACKGROUND: In Jordan, there are postgraduate educational programmes offering a Master's degree in clinical nursing for registered nurses. Intended to prepare nurses to practise at an advanced level as potential clinical nurse specialists in critical care, community health nursing and maternal newborn nursing, little was known prior to this study about the development of advanced nursing roles for nurses in Jordan and the drivers behind their establishment. METHODS: Using ethnographic design, narratives from semi-structured interviews and non-participant observation with participants from five Jordanian hospitals and two public universities were collected and analysed according to thematic analysis. FINDINGS AND DISCUSSION: Four themes emerged from the data: core competencies, specific practice area vs. generic practice, beneficiaries of advanced nursing practice and drivers for educational change. The findings are similar to those found in other countries and highlight the need for a consensual understanding between nurse educationalists, professional bodies and employers about what advanced nursing practice in Jordan should be, so that a common framework can be identified. CONCLUSION: Paralleling the lack of consistency in understanding of advanced nursing practice in the broader literature, participants described a number of different elements of advanced practice that are relevant to the specific context of contemporary Jordanian nursing.

Non-invasive diagnostic assessment tools for the detection of liver fibrosis in patients with suspected alcohol-related liver disease: a systematic review and economic evaluation.

BACKGROUND: Excessive alcohol consumption may lead to the development of alcohol-related liver disease (ALD). Liver biopsy may be used in patients with suspected ALD to confirm the diagnosis, exclude other or additional liver pathologies, and provide accurate staging of the degree of liver injury in order to enable the prediction of prognosis and inform treatment decisions. However, as it is an invasive procedure that carries the risk of morbidity and mortality, current UK guidance recommends that biopsy is not required to confirm the diagnosis in patients with a high clinical suspicion of ALD in whom blood tests have excluded other causes of liver disease, unless it is necessary to confirm a diagnosis of acute alcoholic hepatitis in order to inform specific treatment decisions. OBJECTIVES: To evaluate the diagnostic accuracy, cost-effectiveness, and effect on patient outcomes of four non-invasive tests for liver fibrosis [the Enhanced Liver Fibrosis (ELF™) test (Siemens Healthcare Diagnostic Inc., Tarrytown, NY, USA), FibroTest (BioPredictive, Paris, France), FibroMAX (BioPredictive, Paris, France) and transient elastography (FibroScan(®); produced by EchoSens, Paris, France and distributed in the UK by Artemis Medical Ltd, Kent, UK)] in patients suspected of having ALD. DATA SOURCES: A systematic review was undertaken to identify studies reporting the diagnostic and prognostic accuracy of the ELF test, FibroTest, FibroMAX, and FibroScan for the identification of liver fibrosis and associated conditions in patients with suspected ALD. The following databases were searched in January 2010: MEDLINE (from 1950 to January 2010), MEDLINE In-Process & Other Non-Indexed Citations (from 1950 to January 2010), EMBASE (from 1980 to January 2010), Cochrane Database of Systematic Reviews (from 1996 to January 2010), Cochrane Central Register of Controlled Trials (from 1898 to January 2010), Cochrane Methodology Register (from 1904 to January 2010), Database of Abstracts of Reviews of Effects (from 1995 to January 2010), HTA Database (from 1995 to January 2010), NHS Economic Evaluation Database (from 1995 to January 2010), Cumulative Index to Nursing and Allied Health Literature (from 1982 to January 2010), Web of Knowledge and Science Citation Index (from 1969 to January 2010). REVIEW METHODS: Study quality was assessed using the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) checklist. Owing to the heterogeneity of the studies, no formal meta-analysis was undertaken. A de novo mathematical model was constructed to estimate the incremental costs and incremental quality-adjusted life-years (QALYs) associated with alternative strategies compared with a biopsy-all strategy. The tests are assessed first as a replacement for liver biopsy, and secondly as an additional test prior to liver biopsy. Thirty-six scenarios were assessed for each non-invasive test strategy, which varied the sensitivity of biopsy, the anxiety associated with biopsy, sensitivity and specificity values and whether or not the biopsy was percutaneous or transjugular. For each scenario, threshold levels were reported where biopsying all patients was more cost-effective than the strategy for two parameters (the decreased level of abstinence associated with the strategy compared with biopsying all and the level of incidental QALY gain associated with biopsy). RESULTS: No studies were identified that specifically assessed the ELF test, although a study was identified that evaluated the diagnostic accuracy of the European Liver Fibrosis Test (essentially, the ELF test with the addition of age to the algorithm) compared with biopsy. Three studies of FibroTest, no relevant studies of FibroMax, and six studies of FibroScan assessing accuracy compared with biopsy in patients with known or suspected alcohol-related liver disease were identified. In all studies, the number of patients with suspected ALD was small, meaning that the estimated sensitivities and specificities were not robust. No conclusive estimate of the cost per QALY of each non-invasive test could be provided. Scenarios exist in which each of the strategies analysed is more cost-effective than biopsying all patients and, in contrast, scenarios exist in which each strategy is less cost-effective than biopsying all patients. LIMITATIONS: Study selection and data analysis were undertaken by one reviewer. CONCLUSIONS: No conclusive result can be provided on the most cost-effective strategy until further data are available. A large number of parameters require data; however, the following are selected as being of most importance: (1) the sensitivity and specificity of each non-invasive liver test (NILT) against biopsy at validated and pre-selected cut-off thresholds; (2) the influence of potential confounding variables such as current drinking behaviour and the degree of hepatic inflammation on the performance of NILTs; and (3) the likelihood, and magnitude, of decreases in abstinence rates associated with a diagnosis of significant ALD by diagnostic modality and the incidental gains in QALYs that may be associated with biopsy. FUNDING: The National Institute for Health Research Technology Assessment programme.

What is the value of routinely testing full blood count, electrolytes and urea, and pulmonary function tests before elective surgery in patients with no apparent clinical indication and in subgroups of patients with common comorbidities: a systematic review of the clinical and cost-effective literature.

BACKGROUND: The evidence base which supported the National Institute for Health and Clinical Excellence (NICE) published Clinical Guideline 3 was limited and 50% was graded as amber. However, the use of tests as part of pre-operative work-up remains a low-cost but high-volume activity within the NHS, with substantial resource implications. The objective of this study was to identify, evaluate and synthesise the published evidence on the clinical effectiveness and cost-effectiveness of the routine use of three tests, full blood counts (FBCs), urea and electrolytes tests (U&Es) and pulmonary function tests, in the pre-operative work-up of otherwise healthy patients undergoing minor or intermediate surgery in the NHS. OBJECTIVE: The aims of this study were to estimate the clinical effectiveness and cost-effectiveness of routine pre-operative testing of FBC, electrolytes and renal function and pulmonary function in adult patients classified as American Society of Anaesthesiologists (ASA) grades 1 and 2 undergoing elective minor (grade 1) or intermediate (grade 2) surgical procedures; to compare NICE recommendations with current practice; to evaluate the cost-effectiveness of mandating or withdrawing each of these tests in this patient group; and to identify the expected value of information and whether or not it has value to the NHS in commissioning further primary research into the use of these tests in this group of patients. DATA SOURCES: The following electronic bibliographic databases were searched: (1) BIOSIS; (2) Cumulative Index to Nursing and Allied Health Literature; (3) Cochrane Database of Systematic Reviews; (4) Cochrane Central Register of Controlled Trials; (5) EMBASE; (6) MEDLINE; (7) MEDLINE In-Process & Other Non-Indexed Citations; (8) NHS Database of Abstracts of Reviews of Effects; (9) NBS Health Technology Assessment Database; and (10) Science Citation Index. To identify grey and unpublished literature, the Cochrane Register of Controlled Trials, National Research Register Archive, National Institute for Health Research Clinical Research Network Portfolio database and the Copernic Meta-search Engine were searched. A large routine data set which recorded the results of tests was obtained from Leeds Teaching Hospitals Trust. REVIEW METHODS: A systematic review of the literature was carried out. The searches were undertaken in March to April 2008 and June 2009. Searches were designed to retrieve studies that evaluated the clinical effectiveness and cost-effectiveness of routine pre-operative testing of FBC, electrolytes and renal function and pulmonary function in the above group of patients. A postal survey of current practice in testing patients in this group pre-operatively was undertaken in 2008. An exemplar cost-effectiveness model was constructed to demonstrate what form this would have taken had there been sufficient data. A large routine data set that recorded the results of tests was obtained from Leeds Teaching Hospitals Trust. This was linked to individual patient data with surgical outcomes, and regression models were estimated. RESULTS: A comprehensive and systematic search of both the clinical effectiveness and cost-effectiveness literature identified a large number of potentially relevant studies. However, when these studies were subjected to detailed review and quality assessment, it became clear that the literature provides no evidence on the clinical effectiveness and cost-effectiveness of these specific tests in the specific patient groups. The postal survey had a 17% response rate. Results reported that in ASA grade 1, patients aged < 40 years with no comorbidities undergoing minor surgery did not have routine tests for FBC, electrolytes and renal function and pulmonary function. The results from the regression model showed that the frequency of test use was not consistent with the hypothesis of their routine use. FBC tests were performed in only 58% of patients in the data set and U&E testing was carried out in only 57%. LIMITATIONS: Systematic searches of the clinical effectiveness and cost-effectiveness literature found that there is no evidence on the clinical effectiveness or cost-effectiveness of these tests in this specific clinical context for the NHS. A survey of NHS hospitals found that respondent trusts were implementing current NICE guidance in relation to pre-operative testing generally, and a de novo analysis of routine data on test utilisation and post-operative outcome found that the tests were not be used in routine practice; rather, use was related to an expectation of a more complex clinical case. The paucity of published evidence is a limitation of this study. The studies included relied on non-UK health-care systems data, which may not be transferable. The inclusion of non-randomised studies is associated with an increased risk of bias and confounding. Scoping work to establish the likely mechanism of action by which tests would impact upon outcomes and resource utilisation established that the cause of an abnormal test result is likely to be a pivotal determinant of the cost-effectiveness of a pre-operative test and therefore evaluations would need to consider tests in the context of the underlying risk of specific clinical problems (i.e. risk guided rather than routine use). CONCLUSIONS: The time of universal utilisation of pre-operative tests for all surgical patients is likely to have passed. The evidence we have identified, though weak, indicates that tests are increasingly utilised in patients in whom there is a reason to consider an underlying raised risk of a clinical abnormality that should be taken into account in their clinical management. It is likely that this strategy has led to substantial resource savings for the NHS, although there is not a published evidence base to establish that this is the case. The total expenditure on pre-operative tests across the NHS remains significant. Evidence on current practice indicates that clinical practice has changed to such a degree that the original research question is no longer relevant to UK practice. Future research on the value of these tests in pre-operative work-up should be couched in terms of the clinical effectiveness and cost-effectiveness in the identification of specific clinical abnormalities in patients with a known underlying risk. We suggest that undertaking a multicentre study making use of linked, routinely collected data sets would identify the extent and nature of pre-operative testing in this group of patients. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Reasons for the use and non-use of school sexual health services: a systematic review of young people's views.

BACKGROUND: The potential for sexual health services to influence the sexual health and behaviour of school-aged young people is only likely to be realised if these services are accessed. This review and synthesis seeks to explore children and adolescents' views and experiences of school-based and school-linked sexual health services to identify barriers to and facilitators of service use. METHODS: The study design is a systematic review of studies focusing on the views of children and adolescents (11-18 years) about relevant services. Sixteen databases were searched, titles and abstracts were screened against the inclusion criteria, data extraction and quality assessment of included studies were performed and thematic synthesis was undertaken. RESULTS: Nineteen relevant studies were identified, but only studies from the USA and the UK satisfied the inclusion criteria. The principal themes to emerge from the analysis were awareness and need, confidentiality and disclosure, perceptions of staff, service location, physical environment, costs and types of services on offer. These findings were consistent across country and type of service. CONCLUSIONS: In the view of young people, school-linked sexual health services need to guarantee and promote the ideas of privacy, confidentiality and approachability if they are to be accessed and have an impact on behaviour.

Living with wound-associated pain: impact on the patient and what clinicians really think.

OBJECTIVE: To gain an insight into current practice and practitioner opinions on the recognition and management of wound-associated pain as compared with that previously presented in the literature. METHOD: Delegates who attended Wound Expo 2009 and participated in the interactive learning workshops held in the wound pain educational zone were surveyed. This was therefore a convenience sample. All participants signed a consent form prior to the interactive voting session to allow their anonymous responses to be used. The survey consisted of questions that had been devised to generate a clearer insight into current practice and opinion on wound-associated pain. Questions were posed during the workshop (displayed in a PowerPoint presentation) and attendees were given 10 seconds per question to select their preferred responses, each using an individual electronic interactive voting panel. All responses were recorded electronically and the data were subsequently analysed. RESULTS: The survey identified a number of positive approaches used by the delegates in their assessment of wound-associated pain. These include a high level of continuous assessment, an awareness of the wide range of pain assessment tools available and an acknowledgement of the need for a multiprofessional approach to pain management. CONCLUSION: The findings highlight the issues clinicians face in the recognition, assessment and management of wound-associated pain during their everyday practice. Although many of these issues are difficult to resolve entirely, a fundamental element is that the patient's experiences must be assessed and documented in a consistent and informed manner, and then appropriate management actions taken.

School-linked sexual health services for young people (SSHYP): a survey and systematic review concerning current models, effectiveness, cost-effectiveness and research opportunities.

BACKGROUND: Report based on a service-mapping study and a systematic review concerning sexual health services for young people, either based in or closely linked to schools. OBJECTIVES: To identify current forms of school-based sexual health services (SBSHS) and school-linked sexual health services (SLSHS) in the UK, review and synthesise existing evidence from qualitative and quantitative studies concerning the effectiveness, acceptability and cost-effectiveness of these types of service and to identify potential areas for further research. DATA SOURCES: Electronic databases were searched from 1985 onwards. For published material: the Cochrane Library (1991-), MEDLINE, PREMEDLINE (2007-), CINAHL, EMBASE, AMED, ASSIA (1987-), IBSS, ERIC, PsycINFO, Science Citation Index (SCI) and Social Sciences Citation Index. For unpublished material and grey literature: the Social Care Institute of Excellence Research Register; the National Research Register (1997-), ReFeR; Index to Theses, and HMIC. REVIEW METHODS: A service-mapping questionnaire was circulated to school nurses in all parts of the UK, and semistructured telephone interviews with service coordinators in NHS and local authority (LA) roles were conducted. An evidence synthesis was performed based on a systematic review of the quantitative evidence about service effectiveness, qualitative evidence about user and professional views and a mixed-methods synthesis. A proof-of-concept model for assessing cost-effectiveness was drawn up. RESULTS: Three broad types of UK sexual health service provision were identified. Firstly, SBSHS staffed by school nurses, offering 'minimal' or 'basic' levels of service. Secondly, SBSHS and SLSHS staffed by a multiprofessional team, but not medical practitioners, offering 'basic' or 'intermediate' levels of service. Thirdly, SBSHS and SLSHS staffed by a multiprofessional team, including medical practitioners offering 'intermediate' or 'comprehensive' levels of service. The systematic review showed that SBSHS are not associated with higher rates of sexual activity among young people, nor with an earlier age of first intercourse. There was evidence to show positive effects in terms of reductions in births to teenage mothers, and in chlamydial infection rates among young men, although this evidence coming primarily from the USA. Therefore, the findings need to be tested in relation to UK-based services. Also evidence to suggest that broad-based, holistic service models, not restricted to sexual health, offer the strongest basis for protecting young people's privacy and confidentiality, countering perceived stigmatisation, offering the most comprehensive range of products and services, and maximising service uptake. Findings from the mapping study also indicate that broad-based services, which include medical practitioner input within a multiprofessional team, meet the stated preferences of staff and of young people most clearly. Partnership-based developments of this kind also conform to the broad policy principles embodied in the Every Child Matters framework in the UK and allied policy initiatives. However, neither these service models nor narrower ones have been rigorously evaluated in terms of their impact on the key outcomes of conception rates and sexually transmitted infection (STI) rates, in the UK or in other countries. Therefore, appropriate data were not found to support cost-effectiveness modelling. LIMITATIONS: Low response rate to the questionnaire. Scotland, Wales and Northern Ireland were under-represented. Also, the distinction made in the questionnaire between 'general health' and 'sexual health' services did not prove robust. CONCLUSIONS: There is no single, dominant service model in the UK. The systematic review demonstrated that the evidence base for these services remains limited and uneven, and draws largely on US studies. Qualitative research is needed to develop robust process and outcome indicators for the evaluation of SLSHS/SBSHS in the UK. These indicators could then be used both in local evaluations, and in large, longitudinal studies of service effectiveness and cost-effectiveness. Future research should examine the impact of the differing types of services currently evolving in the UK, encompassing school-based and school-linked models, as well as models with and without medical practitioner involvement.

Vitamin K to prevent fractures in older women: systematic review and economic evaluation.

OBJECTIVE: To determine the clinical and cost-effectiveness of vitamin K in preventing osteoporotic fractures in postmenopausal women. DATA SOURCES: Searches were conducted in May 2007 in MEDLINE, MEDLINE In-Process, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, BIOSIS, CINAHL, DARE, NHS EED and HTA databases, AMED, NRR, Science Citation Index and Current Controlled Trials. The MEDLINE search was updated in March 2009. REVIEW METHODS: Selected studies were assessed and subjected to data extraction and quality assessment using standard methods. Where appropriate, meta-analysis was carried out. A mathematical model was constructed to estimate the cost-effectiveness of vitamin K1. RESULTS: The electronic literature searches identified 1078 potentially relevant articles. Of these, 14 articles relating to five trials that compared vitamin K with a relevant comparator in postmenopausal women with osteoporosis or osteopenia met the review inclusion criteria. The double-blind ECKO trial compared 5 mg of phylloquinone (vitamin K1) with placebo in Canadian women with osteopenia but without osteoporosis. Four open-label trials used 45 mg of menatetrenone (vitamin K2) in Japanese women with osteoporosis; the comparators were no treatment, etidronate or calcium. The methodological quality of the ECKO trial was good; however, all four menatetrenone trials were poorly reported and three were very small (n < 100 in each group). Phylloquinone was associated with a statistically significant reduction in the risk of clinical fractures relative to placebo [relative risk 0.46, 95% confidence interval (CI) 0.22 to 0.99]; morphometric vertebral fractures were not reported. The smaller menatetrenone trials found that menatetrenone was associated with a reduced risk of morphometric vertebral fractures relative to no treatment or calcium; however, the larger Osteoporosis Fracture (OF) study found no evidence of a reduction in vertebral fracture risk. The three smaller trials found no significant difference between treatment groups in non-vertebral fracture incidence. In the ECKO trial, phylloquinone was not associated with an increase in adverse events. In the menatetrenone trials, adverse event reporting was generally poor; however, in the OF study, menatetrenone was associated with a significantly higher incidence of skin and skin appendage lesions. No published economic evaluations of vitamin K were found and a mathematical model was thus constructed to estimate the cost-effectiveness of vitamin K1. Comparators were alendronate, risedronate and strontium ranelate. Vitamin K1 and alendronate were markedly more cost-effective than either risedronate or strontium ranelate. The base-case results favoured vitamin K1, but this relied on many assumptions, particularly on the efficacy of preventing hip and vertebral fractures. Calculation of the expected value of sampled information was conducted assuming a randomised controlled trial of 5 years' duration comparing alendronate with vitamin K1. The costs incurred in obtaining updated efficacy data from a trial with 2000 women per arm were estimated to be a cost-effective use of resources. CONCLUSIONS: There is currently large uncertainty over whether vitamin K1 is more cost-effective than alendronate; further research is required. It is unlikely that the present prescribing policy (i.e. alendronate as first-line treatment) would be altered.

Docetaxel for the adjuvant treatment of early node-positive breast cancer: a single technology appraisal.

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of docetaxel for the adjuvant treatment of early node-positive breast cancer based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturer's scope restricts the intervention to docetaxel in combination with doxorubicin and cyclophosphamide (TAC), and the comparator to anthracycline-based chemotherapy. Based on the BCIRG 001 trial, the submitted evidence shows that TAC is associated with superior disease-free and overall survival at 5 years compared with the anthracycline-based regimen FAC. The absolute risk reduction in patients treated with TAC compared with those treated with FAC was 7% for disease-free survival and 6% for overall survival. However, TAC was associated with significantly greater toxicity than FAC. There is also evidence that docetaxel, in an unlicensed sequential regimen FEC100-T, is associated with superior disease-free and overall survival at 5 years compared with FEC100. An economic model was developed by the manufacturer based on the BCIRG 001 trial. This generated central estimates of the cost per life-year gained and cost per quality-adjusted life-year (QALY) gained of TAC compared with FAC of 7900 pounds and 9800 pounds respectively. The manufacturer's submission predicts a cost-effectiveness of 15,000 pounds to 20,000 pounds per QALY gained for TAC compared with E-CMF (epirubicin in sequential therapy with cyclophosphamide, methotrexate, and fluorouracil), and estimates the cost-effectiveness of FEC100-T to be 8200 pounds per QALY compared with FEC100. Taking into account a number of issues identified by the ERG this may generate higher estimates of cost-effectiveness, but these are unlikely to exceed 35,000 pounds per QALY gained. Importantly, FAC is not commonly used in clinical practice in the UK and, therefore, the submitted evidence does not indicate whether TAC is superior to the anthracycline-based regimens that are in common use (FEC or E-CMF). The indirect comparisons presented suggest that the economic case for TAC in comparison to current UK practice may not be proven. The manufacturer's submission failed to record evidence of three serious adverse events in patients receiving docetaxel with doxorubicin or to mention the concern of the European Medicines Agency regarding TAC's long-term adverse events. The guidance issued by NICE in June 2006 as a result of the STA states that docetaxel, when given concurrently with doxorubicin and cyclophosphamide (the TAC regimen), is recommended as an option for the adjuvant treatment of women with early node-positive breast cancer.

Routine antenatal anti-D prophylaxis for RhD-negative women: a systematic review and economic evaluation.

OBJECTIVES: To identify any evidence for advances in the use of routine antenatal anti-D prophylaxis (RAADP) since the 2002 National Institute for Health and Clinical Excellence (NICE) appraisal, and to assess the current clinical effectiveness and cost-effectiveness of RAADP for Rhesus D (RhD)-negative women. DATA SOURCES: Main bibliographic databases were searched from inception to July 2007. REVIEW METHODS: Selected studies were assessed and data extracted using a standard template and quality assessment based on published criteria. Meta-analysis was used where appropriate, otherwise outcomes were tabulated and discussed within a descriptive synthesis. The health economic model developed for the 2002 NICE appraisal of RAADP was modified to assess the cost-effectiveness of different regimens of RAADP. RESULTS: The clinical effectiveness searches identified 670 potentially relevant articles. Of these, 12 papers were included in the review, relating to eight studies of clinical effectiveness. With one exception, no additional studies were identified in comparison with the previous assessment report, and some of the studies of clinical effectiveness included in the 2002 review had to be excluded because they did not use currently licensed doses. Therefore, eight studies comparing RAADP with no prophylaxis were identified in the clinical effectiveness review and nine (including the 2001 assessment report itself) in the cost-effectiveness review. The clinical efficacy studies were generally of poor quality and did not provide a basis for differentiating between regimens of RAADP. The best indication of the likely efficacy of a programme of RAADP comes from two non-randomised community-based studies. The pooled results of these suggest that such a programme may reduce the sensitisation rate from 0.95% (95% CI 0.18-1.71) to 0.35% (95% CI 0.29-0.40). This gives an odds ratio for the risk of sensitisation of 0.37 (95% CI 0.21-0.65) and an absolute reduction in risk of sensitisation in RhD-negative mothers at risk (i.e. carrying a RhD-positive child) of 0.6%. The identified studies suggest that RAADP has minimal adverse effects. Of the nine studies in the cost-effectiveness review, only two described a model that could be applicable to the NHS. The economic model modified from the 2002 appraisal suggests that the cost per quality-adjusted life-year (QALY) gained of RAADP given to RhD-negative primigravidae versus no treatment is between 9000 pounds and 15,000 pounds, and for RAADP given to all RhD-negative women rather than to RhD-negative primigravidae only is between 20,000 pounds and 35,000 pounds depending upon the regimen. The sensitivity analysis suggests that the results are reasonably robust to changes in the assumptions within the model. CONCLUSIONS: RAADP reduces the incidence of sensitisation and hence of haemolytic disease of the newborn. The economic model suggests that RAADP given to all RhD-negative pregnant women is likely to be cost-effective at a threshold of around 30,000 pounds per QALY gained. The total cost of providing RAADP to RhD-negative primigravidae in England and Wales is estimated to be around 1.8-3.1 million pounds per year, depending upon regimen, and to all RhD-negative pregnant women in England and Wales around 2-3.5 million pounds.

A systematic review and economic evaluation of statins for the prevention of coronary events.

OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of statins for the primary and secondary prevention of cardiovascular events in adults with, or at risk of, coronary heart disease (CHD). DATA SOURCES: Electronic databases were searched between November 2003 and April 2004. REVIEW METHODS: A review was undertaken to identify and evaluate all literature relating to the clinical and cost effectiveness of statins in the primary and secondary prevention of CHD and cardiovascular disease (CVD) in the UK. A Markov model was developed to explore the costs and health outcomes associated with a lifetime of statin treatment using a UK NHS perspective. RESULTS: Thirty-one randomised studies were identified that compared a statin with placebo or with another statin, and reported clinical outcomes. Meta-analysis of the available data from the placebo-controlled studies indicates that, in patients with, or at risk of, CVD, statin therapy is associated with a reduced relative risk of all cause mortality, cardiovascular mortality, CHD mortality and fatal myocardial infarction (MI), but not of fatal stroke. It is also associated with a reduced relative risk of morbidity [non-fatal stroke, non-fatal MI, transient ischaemic attack (TIA), unstable angina] and of coronary revascularisation. It is hardly possible, on the evidence available from the placebo-controlled trials, to differentiate between the clinical efficacy of atorvastatin, fluvastatin, pravastatin and simvastatin. However, there is some evidence from direct comparisons between statins to suggest that atorvastatin may be more effective than pravastatin in patients with symptomatic CHD. There is limited evidence for the effectiveness of statins in different subgroups. Statins are generally considered to be well tolerated and to have a good safety profile. This view is generally supported both by the evidence of the trials included in this review and by postmarketing surveillance data. Increases in creatine kinase and myopathy have been reported, but rhabdomyolysis and hepatotoxicity are rare. However, some patients may receive lipid-lowering therapy for as long as 50 years, and long-term safety over such a timespan remains unknown. In secondary prevention of CHD, the incremental cost-effectiveness ratios (ICERs) increase with age varying between pound 10,000 and pound 17,000 per quality adjusted life year (QALY) for ages 45 and 85 respectively. Sensitivity analyses show these results are robust. In primary prevention of CHD there is substantial variation in ICERs by age and risk. The average ICERs weighted by risk range from pound 20,000 to pound 27,500 for men and from pound 21,000 to pound 57,000 for women. The results are sensitive to the cost of statins, discount rates and the modelling time frame. In the CVD analyses, which take into account the benefits of statins on reductions in stroke and TIA events, the average ICER weighted by risk level remains below pound 20,000 at CHD risk levels down to 0.5%. Limitations of the analyses include the requirement to extrapolate well beyond the timeframe of the trial period, and to extrapolate effectiveness results from higher risk primary prevention populations to the treatment of populations at much lower risk. Consequently, the results for the lower age bands and lower risks are subject to greater uncertainty and need to be treated with caution. CONCLUSIONS: There is evidence to suggest that statin therapy is associated with a statistically significant reduction in the risk of primary and secondary cardiovascular events. As the confidence intervals for each outcome in each prevention category overlap, it is not possible to differentiate, in terms of relative risk, between the effectiveness of statins in primary and secondary prevention. However, the absolute risk of CHD death/non-fatal MI is higher, and the number needed to treat to avoid such an event is consequently lower, in secondary than in primary prevention. The generalisability of these results is limited by the exclusion, in some studies, of patients who were hypersensitive to, intolerant of, or known to be unresponsive to, statins, or who were not adequately compliant with study medication during a placebo run-in phase. Consequently, the treatment effect may be reduced when statins are used in an unselected population. The results of the economic modelling show that statin therapy in secondary prevention is likely to be considered cost-effective. In primary prevention, the cost-effectiveness ratios are dependent on the level of CHD risk and age, but the results for the CVD analyses offer support for the more aggressive treatment recommendation issued by recent guidelines in UK. Evidence on clinical endpoints for rosuvastatin is awaited from on-going trials. The potential targeting of statins at low-risk populations is however associated with major uncertainties, particularly the likely uptake and long-term compliance to lifelong medication by asymptomatic younger patients. The targeting, assessment and monitoring of low-risk patients in primary care would be a major resource implication for the NHS. These areas require further research.

Glucocorticoid-induced osteoporosis: a systematic review and cost-utility analysis.

OBJECTIVES: To determine whether strategies can be devised for the assessment and treatment of glucocorticoid-induced osteoporosis (GIO). DATA SOURCES: Electronic databases were searched up to October 2002. REVIEW METHODS: A systematic review of interventions was undertaken of all randomised controlled trials in which fracture was measured as an outcome. Effectiveness was compared with effectiveness in postmenopausal osteoporosis. The risk of osteoporotic fractures at any given T-score for bone mineral density (BMD) was determined from published meta-analyses of the relationship between BMD and fracture risk. The risk of an osteoporotic fracture in the presence of a prior osteoporotic fracture was computed from a published meta-analysis of the relationship between the prior occurrence of fracture of each type and the risk of a future fracture of each type. The additional risk due to exposure to glucocorticoids was determined by meta-analysis of prospectively studied population-based cohorts. The consequences of fracture on mortality were assessed for each fracture type. Costs and utilities were determined for osteoporosis in the UK by updating systematic reviews of the literature. A model was prepared that comprised an individual patient-based approach that simulated whether or not events occurred in each subsequent year for each patient. Effectiveness was populated from a systematic review of interventions in GIO and postmenopausal osteoporosis. Treatments were given for 5 years using a 5-year offset time (in this context, offset time is the duration for which an effect on fracture persists after the treatment stops). The analytic framework was set at 10 years. Because of the many uncertainties, extensive sensitivity analysis was undertaken. RESULTS: Evidence of anti-fracture efficacy was confined to a minority of agents used in the management of GIO. Only risedronate (a bisphosphonate) and calcidiol (vitamin D) were shown to have significant effects on vertebral fracture risk, but neither had significant effects on non-vertebral fracture risk. In further meta-analyses, the effects of bisphosphonates in GIO were compared with effects combining all available data for bisphosphonates in GIO and in postmenopausal osteoporosis. Since calcidiol is not licensed for use in the UK, cost-effectiveness analysis was confined to risedronate and to a pooled bisphosphonate effect. Analysis of cost-effectiveness of risedronate using the empirical data in GIO showed better cost-effectiveness with increasing age, but at no age did cost-effectiveness ratios fall below the threshold value of 30,000 pounds per quality-adjusted life-year gained. When account was taken of BMD, cost-effectiveness was confined to less than 10% of patients with very low T-scores for BMD. Assuming that bisphosphonate efficacy on fracture risk was comparable to that observed with bisphosphonates in postmenopausal osteoporosis, cost-effectiveness was shown in patients with a prior fracture. In patients with no prior fracture, cost-effectiveness was observed in individuals aged 75 years or more. In younger patients without a prior fracture, cost-effective scenarios were found contingent upon a T-score for BMD that was 2.0 SD or less. CONCLUSIONS: Cost-effective scenarios for risedronate in the management of GIO were identified, but only at the extremes of age and T-score, such that less than 10% of patients aged 50 years or more would be eligible for treatment. Greater cost-effectiveness was observed assuming that the effects of bisphosphonate in GIO were similar to those observed in postmenopausal osteoporosis, an assumption tested by meta-analysis. An assessment algorithm is proposed based on age, the presence of a prior fragility fracture and BMD tests in individuals aged 50 years or more with no fracture. The conclusions derived are conservative, mainly because of the assumptions that were made in the absence of sufficient data. Thus, conclusions that treatment scenarios are cost-effective are reasonably secure. By contrast, scenarios shown not to be cost-effective are less secure. As information in these areas becomes available, the implications for cost-effectiveness of interventions should be reappraised. Health economic assessment based on probability of fracture is an important area for further research. Other areas for further research arise from gaps in empirical knowledge on utilities and side-effects that are amenable to primary research. Further secondary research is recommended to evaluate more closely the impact of all vertebral fractures (rather than clinically overt vertebral fractures) on cost-effectiveness and methods of monitoring treatment.

The clinical effectiveness and cost-effectiveness of strontium ranelate for the prevention of osteoporotic fragility fractures in postmenopausal women.

OBJECTIVES: To estimate the clinical effectiveness and cost-effectiveness of strontium ranelate for the prevention of osteoporotic fractures in postmenopausal women, at different levels of absolute fracture risk. This considers secondary prevention in women who have sustained a previous fracture and primary prevention in those women without a previous fracture, as women with osteoporosis are asymptomatic until a fracture is sustained. DATA SOURCES: Major electronic bibliographic databases were searched in September 2004 and updated in March 2005. REVIEW METHODS: A systematic review was carried out to determine clinical effectiveness using the major electronic bibliographic databases and handsearching reference lists of relevant articles and sponsor submissions. Data from selected studies were assessed and included in the meta-analyses, if appropriate. The model used to calculate cost-effectiveness ratios was an updated version of Sheffield Health Economic Model for Osteoporosis that was populated with absolute risk of fractures using an algorithm being developed for the World Health Organization and supplied in confidence to the authors. The model calculated the number of fractures that occur and provided as output data the costs associated with osteoporotic fractures, and the quality adjusted life-years (QALYs) accrued by a cohort of 100 osteoporotic women, with each fracture being detrimental to health and incurring a cost. When the costs of the intervention were included, the incremental cost compared with no treatment was calculated and divided by the gain in QALYs to calculate cost-effectiveness measures. Treatment with strontium ranelate was calculated against a no-treatment option to evaluate whether it could be given cost-effectively. An incremental analysis against alendronate was also conducted to estimate the cost-effectiveness of strontium ranelate relative to a current standard treatment. The cost-effectiveness of strategies for identifying and treating women without a prior fracture used the risk of fracture as an input to the cost-effectiveness model. RESULTS: Three trials were identified. Pooled data from two studies indicate that strontium ranelate therapy is associated with a reduction in the risk of vertebral fracture [relative risk (RR) compared with placebo 0.60, 95% confidence interval (CI) 0.53 to 0.69, p < 0.001] and non-vertebral fracture (RR 0.84, 95% CI 0.73 to 0.97, p = 0.01). In general, strontium ranelate therapy did not seem to be associated with an increased risk of adverse events. However, the risk of one rare but serious adverse event, venous thromboembolism (including pulmonary embolism), was found to be significantly higher in patients receiving strontium ranelate compared with placebo (RR 1.42, 95% CI 1.02 to 1.98, p = 0.036). Some nervous system disorders, including mental impairment, disturbed consciousness, memory loss and seizures, were also more common in patients randomised to strontium ranelate. Strontium ranelate provided gains in QALYs compared with no treatment in women with sufficient calcium and vitamin D intakes. The size of the QALY gain for each intervention was strongly related to the absolute risk of fracture. From the algorithm used, it is seen that strontium ranelate can be used cost-effectively in women at relatively high risk of osteoporotic fracture. However, the results of the probabilistic sensitivity analysis, using efficacy data from randomised controlled trials, suggest that it is not as cost-effective as alendronate, a comparator intervention from the bisphosphonate class. The use of strontium ranelate in women without a prior fracture will be dependent on identification algorithms being produced in conjunction with the National Institute for Health and Clinical Excellence Osteoporosis Guidelines Development Group. CONCLUSIONS: Strontium ranelate was shown to be clinically effective in the prevention of osteoporotic fractures. Scenarios have been found where strontium ranelate can be used cost-effectively, however given the probabilistic sensitivity analyses conducted, this intervention appears to be less cost-effective than the bisphosphonate alendronate. The evidence base for the efficacy of fracture prevention for strontium ranelate needs to be strengthened, particularly for hip fractures, where there is currently a non-significant reduction. If it were believed that the efficacy of strontium ranelate is dependent on either age or absolute risk, this would need to be proven. The evidence base on the T-score by age of the general female population needs to be strengthened, particularly in women over the age of 80 years. The prevalence of risk factors associated with fracture rates, over and above that provided by bone mineral density, also needs to be significantly strengthened to ensure that the estimated number of women that could be cost-effectively treated is accurate.

Recombinant Factor VIIa concentrate versus plasma derived concentrates for the treatment of acute bleeding episodes in people with Haemophilia A and inhibitors.

BACKGROUND: In some people with haemophilia, therapeutic clotting agents are recognised as a foreign protein and anti-FVIII antibodies, known as 'inhibitors', are produced. This review investigates which treatment most effectively arrests acute bleeding in people with haemophilia A and inhibitors. OBJECTIVES: To determine the clinical effectiveness of recombinant FVIIa concentrate in comparison to plasma-derived concentrates for the treatment of acute bleeding episodes in people with haemophilia A and inhibitors. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group trials register which comprises of references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. Date of the most recent search of the Group's trials register: September 2003. SELECTION CRITERIA: Randomised (RCTs) and quasi-randomised controlled clinical trials comparing Recombinant FVIIa concentrate to human plasma-derived concentrates (high-dose human or recombinant FVIII concentrate; prothrombin complex concentrates (PCCs); activated prothrombin complex concentrate (aPCC)) in people with haemophilia A. Comparisons with animal derived products were excluded. DATA COLLECTION AND ANALYSIS: No studies were found that were eligible for inclusion in this review. MAIN RESULTS: A total of four studies were identified by the searches, however, none of these were eligible for inclusion in this review. REVIEWERS' CONCLUSIONS: No RCTs on the relative effectiveness of Recombinant FVIIa concentrate compared to human plasma-derived concentrates in people with haemophilia A and inhibitors were identified for inclusion in this review. The research evidence on which to base clinical decisions is therefore limited to case reports, and other less robust evidence. There is need for a well-designed, adequately-powered randomised controlled trial to assess the relative benefits and risks of using Recombinant FVIIa concentrate compared to human plasma-derived concentrates in people with haemophilia A and inhibitors.

Control of bleeding in patients with haemophilia A with inhibitors: a systematic review.

This paper reports a systematic review of the best available evidence of clinical effectiveness in the treatment of acute bleeding in haemophilia A patients with inhibitors. Because of the lack of randomized controlled trials (RCTs) on this topic, broad inclusion criteria with regard to study design were applied in order to assess the best available evidence for each intervention. Because of the clinical and methodological heterogeneity of the evidence, it was not appropriate to pool data across studies; instead, data were synthesized using tabulation and qualitative narrative assessment. No evidence was found to support the use of high-dose factor VIII (FVIII) in bleeding episodes. However in surgery it was found to be highly successful (100%) for low-titre, low-responding inhibitors although not reliable for high-responding inhibitors. Porcine FVIII (pFVIII) was effective in the control of severe bleeding episodes with high-titre or high-responding inhibitors (100%) and in 60-90% of surgical procedures. Activated prothrombin complex concentrates (APCCs) appear to be more effective than prothrombin complex concentrates (PCCs) in the control of mild to severe bleeding episodes. There was no good evidence for the use of PCCs in surgery. APCCs controlled bleeding in approximately 90% of surgical episodes. Recombinant factor VIIa (rFVIIa) controlled 70-100% of mild to severe bleeding episodes with high-responding inhibitors, and achieved better results when used early. It was effective in 60-100% of surgical episodes. Doses varied from study to study, and side-effects from mild to infrequent but serious adverse events were reported. The quality of the evidence is variable. Limited evidence relating to other treatment options is also included in the review.

The implications of contact with the mentor for preregistration nursing and midwifery students.

AIM OF THE PAPER: To examine the extent to which preregistration nursing and midwifery students have contact with their named mentor, and the implications of this. BACKGROUND/RATIONALE: Mentorship has an important part to play in enabling preregistration nursing and midwifery students to gain the maximum benefit from clinical placements. Previous research has indicated that the benefits of mentorship to learners are related to the number of occasions on which the student and mentor work together. DESIGN/METHODS: A research project commissioned by the Sheffield and North Trent College of Nursing and Midwifery (now the University of Sheffield School of Nursing and Midwifery) provided an opportunity to examine the extent to which their named mentors were available to Project 2000 students, and the implications of this. Students and their named mentors were asked to keep an activity diary for 1 week. The main objective was to collect activity data to inform an analysis of the costs and benefits of clinical placements to service providers. This cost-benefit study has been published elsewhere. However, the data also cast light on the extent to which mentors were available to students, and the implications of this, and it is these findings which are presented here. RESULTS/FINDINGS: Students frequently worked shifts without their named mentors even though unrostered students often worked weekends, evening and night shifts in order to maximize time spent with their mentors. In the mentor's absence, other members of staff covered for some of their activities (in particular, direct and indirect supervision of students). However, students whose named mentors were absent spent significantly less time than other students working with a qualified member of staff as a partner in giving care. CONCLUSIONS: It is suggested that the extent to which named mentors are unavailable to Project 2000 students may be detrimental to the education and professional development of those students.