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A nurse-led multicentre randomised controlled trial will compare the clinical effectiveness of weekly ultrasound combined with standard care in the treatment of 'hard-to-heal' venous leg ulcers. Recruitment started last autumn.
OBJECTIVES: To summarise the relevant clinical effectiveness and cost-effectiveness literature, to collect data on survival, transplantation rates, health-related quality of life (HRQoL) and resource use for ventricular assist device (VAD) and non-VAD transplant candidates in the UK, and to construct cost-effectiveness and cost-utility models of VADs in a UK context. Also to investigate the factors that drive costs and survival. DESIGN: A comprehensive systematic review was carried out. Data were collected from April 2002 to December 2004, with follow-up to March 2005. Cost-effectiveness and cost-utility models of VAD devices were developed based on UK activity and outcomes collected from April 2002 to March 2005. SETTING: National Specialist Commissioning Advisory Group funded VAD implantation was carried out at the Freeman, Harefield and Papworth transplant centres in the UK. PARTICIPANTS: Seventy patients were implanted with a VAD as a bridge to transplantation between April 2002 and December 2004. Non-VAD-supported transplant candidates (n = 250), listed at the three centres between April 2002 and December 2004, were divided into an inotrope-dependent group (n = 71) and a non-inotrope-dependent group (n = 179). Although patients in the inotrope-dependent group were closest to the VAD group they were less sick. The last group comprised a hypothetical worst case scenario, which assumed that all VAD patients would die in the intensive care unit (ICU) within 1 month without VAD technology. INTERVENTIONS: Patients were included who were implanted with a VAD designed for circulatory support for more than 30 days, with intention to bridge to transplantation. A multistate model of VAD and transplant activity was constructed; this was populated by data from the UK. MAIN OUTCOME MEASURES: Survival from VAD implant or from transplant listing for non-VAD patients to 31 March 2005. Serious adverse events and quality of life measures were used. Cognitive functioning was also assessed. Utility weights were derived from EuroQoL responses to estimate quality-adjusted life-years (QALYs). Incremental cost-effectiveness ratios (ICERs) were defined as the additional cost of VADs divided by additional QALYs. Time-horizons were 3 years, 10 years and the lifetime of the patients. RESULTS: Of 70 VAD patients, 30 (43%) died pretransplant, 31 (44%) underwent transplantation, and four (6%) recovered and had the VAD removed. Five patients (7%) were still supported for median of 279 days at the end of March 2005. Successful bridge-to-transplantation/recovery rates were consistent with published rates. Survival from VAD implantation was 74% at 30 days and 52% at 12 months. There were 320 non-fatal adverse events in 62 patients during 300 months of VAD support, mostly in the first month after implantation. Commonly observed events were bleeding, infection and respiratory dysfunction. Twenty-nine (41%) patients were discharged from hospital with a VAD. The 1-year survival post-transplantation was 84%. For the inotrope-dependent and non-inotrope-dependent transplant candidates, death rates while listed were 10% and 8% and the median waiting times were 16 and 87 days, respectively. For transplant recipients, 1-year survival was 85% and 84%, respectively. Both VAD and non-VAD patients demonstrated similar significant improvements in their New York Heart Association class after transplantation. All patients had poor EQ-5D pretransplantation; after transplantation the groups had similar EQ-5D of 0.76 irrespective of time after surgery. HRQoL was poor in the first month for VAD patients but better for those who waited longer in all groups. VAD patients reported more problems with sleep and rest and with ambulation in the first month. Symptom scores were similar in all groups pretransplant. After transplantation all groups showed a marked and similar improvement in physical and psychosocial function. Mean VAD implant cost, including device, was pound 63,830, with costs of VAD support for survivors of pound 21,696 in month 1 and pound 11,312 in month 2. Main cost drivers were device itself, staffing, ICU stay, hospital stay and events such as bleeding, stroke and infection. For the base case, extrapolating over the lifetime of the patients the mean cost for a VAD patient was pound 173,841, with mean survival of 5.63 years and mean QALYs of 3.27. Corresponding costs for inotrope-dependent patients were pound 130,905, with mean survival 8.62 years and mean QALYs 4.99. Since inotrope-dependent patients had lower costs and higher QALYs than VAD patients, this group is said to be dominant. Non-inotrope-dependent transplant candidates had similar survival rates to those on inotropes but lower costs, also dominant. Compared with the worst case scenario the mean lifetime ICER for VADs was pound 49,384 per QALY. In a range of sensitivity analyses this ranged from pound 35,121 if the device cost was zero to pound 49,384. Since neither inotrope-dependent transplant candidates nor the worst case scenario were considered fair controls the assumption was investigated that, without VAD technology, there would be a mixture of these situations. For mixtures considered the ICER for VADs ranged from pound 79,212 per QALY to the non-VAD group being both cheaper and more effective. CONCLUSIONS: There are insufficient data from either published studies or the current study to construct a fair comparison group for VADs. Overall survival of 52% is an excellent clinical achievement for those young patients with rapidly failing hearts. However, if the worst case scenario were plausible, and one could reliably extrapolate results to the lifetime of the patients, VADs would not be cost-effective at traditional thresholds. Further randomised controlled trials are required, using current second generation devices or subsequent devices and conducted in the UK.
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OBJECTIVES: 1. To identify all published randomised controlled trials of allergen specific immunotherapy in asthma. 2. To estimate the overall efficacy of allergen specific immunotherapy upon asthmatic symptoms, medication requirements, lung function, nonspecific bronchial hyperreactivity (BHR) and allergen specific BHR. SEARCH STRATEGY: A search of the asthma database by the Cochrane Airways Group at St. Georges Hospital Medical School, London identified 660 nonunique citations with the keywords Immunotherapy* or Hyposensitive or Desensiti*. This database included all studies published up to 1997 with the keywords Asthma or Wheez* from the Medline, Embase and Cinahl databases, together with other studies identified by handsearching. SELECTION CRITERIA: The review was restricted to randomised controlled trials (RCT). Only studies which focussed upon asthma were included. Allergen specific immunotherapy was defined as the subcutaneous administration of extracts of house dust mites, pollens, animal danders or moulds, chemically modified allergoids or antigen-antibody complexes. Although placebo controlled trials were methodologically stronger, studies which administered house dust or other relatively antigenically inactive preparations to the control group were also considered. Double blinded trials were preferred, but single blind and open studies were also reviewed for possible inclusion. At least one of the following clinical outcomes had to be reported: asthmatic symptoms, asthma medication requirements, lung function, nonspecific BHR or allergen specific BHR. Inclusion of studies in the review was decided by a simple majority of all three reviewers, who independently read the methods sections of papers identified by the search strategy and applied the stated criteria. Quality assessment was performed by 2 reviewers, who independently assessed the concealment of allocation. DATA COLLECTION AND ANALYSIS: The comparisons were: Allergen immunotherapy v placebo, Allergen immunotherapy v antigenically inactive control, House dust v placebo and Allergen immunotherapy v untreated control. These comparisons were performed separately for each outcome, whenever these results were reported. Outcome data were extracted and entered into RevMan 3.0.1 for statistical analysis. Categorical outcomes were analysed as odds ratios (OR) and 95% confidence intervals (95% CI) calculated by Peto's method. Continuous outcomes were analysed as standardised mean differences (SMD). Fixed effects models were used to obtain summary statistics for the overall efficacy of allergen immunotherapy and x2 tests were performed to assess heterogeneity between studies. MAIN RESULTS: Fifty four randomised controlled trials published between 1954 and 1997 satisfied the inclusion criteria. There were 25 studies reporting immunotherapy for mite allergy, 13 studies of pollen allergy, eight studies of animal dander allergy, two studies of allergy to the mould Cladosporium and six studies which attempted simultaneous immunotherapy for multiple aeroallergens. Concealment of allocation was assessed as clearly adequate in only 11 studies. The adequacy or otherwise of 40 studies could not be determined from the details published in the papers. Only three studies used a clearly inadequate method for concealment of allocation. There was a significant overall improvement in asthma symptom scores following immunotherapy (combined SMD -0.52; 95% -0.70 to -0.35). Patients randomised to immunotherapy were also significantly less likely to report a deterioration in asthma symptoms than those randomised to placebo (OR 0.27; 95% CI 0.21 to 0.35). Asthma medication requirements were significantly reduced (SMD -0.51; 95% CI -0.74 to -0.28). Patients randomized to immunotherapy were also significantly less likely to require medication than those randomised to placebo (OR 0.28; 95% CI 0.19 to 0.42). There was no overall improvement in lung function following immunotherapy and marked hete
BACKGROUND: Twin-twin transfusion syndrome, a condition affecting monochorionic twin pregnancies, is associated with a high risk of perinatal mortality and morbidity. A number of treatments have been introduced to treat the condition but it is unclear which intervention improves maternal and fetal outcome. OBJECTIVES: The objective of this review was to evaluate the impact of treatment modalities in twin-twin transfusion syndrome. SEARCH STRATEGY: We searched The Cochrane Pregnancy and Childbirth Trials Register and Cochrane Controlled Trials Register. We also searched conference proceedings and made personal contact with experts active in the area of the review. Date of last search: August 2000. SELECTION CRITERIA: Randomised and quasi-randomised studies of amnioreduction versus laser coagulation, septostomy versus laser coagulation or septostomy versus amnioreduction. DATA COLLECTION AND ANALYSIS: Eligibility was assessed by one reviewer. Study authors were contacted for additional information. MAIN RESULTS: No studies were included. REVIEWER'S CONCLUSIONS: There is no current evidence from randomised trials to influence practice. Three ongoing randomised studies have been identified.
BACKGROUND: There has been a recent trend to encourage routine outcome measurement and needs assessment as an aid to decision making in clinical practice and patient care. Standardised instruments have been developed which measure clinical symptoms of disorders such as schizophrenia, wider health related quality of life and patients' needs. Such measures might usefully be applied to aid the recognition of psychosocial problems and to monitor the course of patients' progress over time in terms of disease severity and associated deficits in health related quality of life. They might also be used to help clinicians to make decisions about treatment and to assess subsequent therapeutic impact. Such an approach is not, however, without cost and the actual benefit of the adoption of routine outcome and needs assessment in the day-to-day care of those with schizophrenia remains unclear. OBJECTIVES: To establish the value of the routine administration of outcome measures and needs assessment tools and the feedback they provide in improving the management and outcome of patients with schizophrenia and related disorders. SEARCH STRATEGY: The reviewers undertook electronic searches of the British Nursing Index (1994 to Sept 1999), the Cochrane Library (Issue 2, 2002), the Cochrane Schizophrenia Group Trials Register (2002), EMBASE (1980-2002), MEDLINE (1966-2002), and PsycLIT (1887-2002), together with hand searches of key journals. References of all identified studies were searched for further trials, and the reviewers contacted authors of trials. SELECTION CRITERIA: Randomised controlled trials comparing the feedback of routine standardised outcome measurement and needs assessment, to routine care for those with schizophrenia. DATA COLLECTION AND ANALYSIS: Reviewers evaluated data independently. Studies which randomised clinicians or clinical teams (rather than individual patients) were considered to be the most robust. However only those which took account of potential clustering effects were considered further. Where possible and appropriate, risk ratios (RR) and their 95% confidence intervals (CI) were calculated. For continuous data Weighted Mean Differences (WMD) were calculated. Data were inspected for heterogeneity. MAIN RESULTS: No randomised data were found which addressed the specified objectives. One unpublished and one ongoing trial was identified. REVIEWER'S CONCLUSIONS: The routine use of outcomes measures and needs assessment tools is, as yet, unsupported by high quality evidence of clinical and cost effectiveness. Clinicians, patients and policy makers alike may wish to see randomised evidence before this strategy is routinely adopted.
BACKGROUND: Although there have been considerable gains in understanding the cascade of events that lead to secondary injury after traumatic brain injury (TBI), efforts to translate this understanding into new therapeutic, so-called neuroprotective, approaches have so far proven disappointing. Animal models suggest an alternative strategy: agents enhancing monoaminergic transmission, particularly amphetamines, have been shown to promote motor recovery from focal brain injury and it has been suggested that this might represent a complementary means of therapeutic intervention in the later post-injury phase. OBJECTIVES: To evaluate the evidence that amphetamines improve final outcome after traumatic brain injury. SEARCH STRATEGY: We searched MEDLINE, EMBASE, Science Citation Index, Cochrane Controlled Trials Register and the Cochrane Injuries Group's Specialised Register of Controlled Trials. Researchers and authors of published trials were also contacted. SELECTION CRITERIA: Randomised controlled trials comparing the use of a noradrenergic agonist (together with conventional non-pharmacological rehabilitative therapy) versus conventional non-pharmacological rehabilitative therapy alone. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened records, extracted data and assessed trial quality. MAIN RESULTS: Although there is a limited clinical literature addressing this topic, none of the studies identified fully meets inclusion criteria for this review. REVIEWER'S CONCLUSIONS: At present there is insufficient evidence to support the routine use of methylphenidate or other amphetamines to promote recovery from TBI.
Day-care has long been a controversial aspect of social policy in countries such as the U.K. What evidence is there about the effects of out-of-home day-care on educational, health and welfare outcomes for children and their families? This paper applies to day-care studies, the methodology of the systematic review as pioneered in the health care field, in order to establish the evidence-base for day-care provision. Randomised controlled trials of day-care for pre-school children were identified using electronic databases, hand searches of relevant literature and contacts with authors. A total of 8 trials were identified after examining 920 abstracts and 19 books. All the trials were carried out in the U.S.A. European research on this topic is extensive but we did not identify any studies using trial design. Instead observational, case controlled and cohort studies were prominent. The trials were assessed for methodological quality. Results showed that day-care promotes children's intelligence, development and school achievement. Long-term follow up demonstrates increased employment, lower teenage pregnancy rates, higher socio-economic status and decreased criminal behaviour. There are positive effects on mothers' education, employment and interaction with children. Effects on fathers have not been examined. Few studies look at a range of outcomes spanning the health, education and welfare domains. Most of the trials combined non-parental day-care with some element of parent training or education (mostly targeted at mothers); they did not disentangle the possible effects of these two interventions. The trials had other significant methodological weaknesses, pointing to the importance of improving on study design in this field. There is a need for well designed research on day-care to provide an evidence-base for British social policy.
Clinical experience suggests that fasting followed by vegetarian diet may help patients with rheumatoid arthritis (RA). We reviewed the available scientific evidence, because patients frequently ask for dietary advice, and exclusive pharmacological treatment of RA is often not satisfying. Fasting studies in RA were searched in MEDLINE and by checking references in relevant reports. The results of the controlled studies which reported follow-up data for at least three months after fasting were quantitatively pooled. Thirty-one reports of fasting studies in patients with RA were found. Only four controlled studies investigated the effects of fasting and subsequent diets for at least three months. The pooling of these studies showed a statistically and clinically significant beneficial long-term effect. Thus, available evidence suggests that fasting followed by vegetarian diets might be useful in the treatment of RA. More randomised long-term studies are needed to confirm this view by methodologically convincing data.
BACKGROUND: Guidelines to improve standards of care for hypertension and diabetes were disseminated by the National Department of Health in 1996 but have generally not been implemented by health professional in local primary care. A strategy for the adoption and implementation of the Guidelines was developed in collaboration with health professionals in primary care. OBJECTIVES: The development of a structured record, with prompts for the management of diabetes and hypertension according to the Guidelines. SETTING: Three community health centres (CHCs) in the Western Cape. PARTICIPANTS: Doctors and nurses managing patients with diabetes and hypertension. METHODS: A draft of the structured record was developed at a single-pilot CHC in the Western Cape. Focus group discussions established the core requirements for a structured record. Process, result and structural indicators in line with the national Guidelines were considered for inclusion in the draft record. This draft record was then piloted at two other CHCs. Comments from semi-structured interviews and pre- and post-test evaluation questionnaires were used to compile the final instrument. RESULTS: Eleven doctors and 8 nurses participated in the development of the final instrument. Important considerations in the design were a single-page, user-friendly format, tick-boxes to reduce writing, prompts, provision for sequential recording, target setting, and compatibility with the Guidelines. The final instrument was piloted and elicited a favourable overall response. CONCLUSION: The structured record simplifies the application of the Guidelines and the systematic recording of processes of care. The effectiveness of the Guidelines will be evaluated further in a randomised control trial using the structured record.
BACKGROUND: It is considered to be a fundamental ethical premise of human experimentation, that it should be carried out only where the effects of an intervention are unclear. The point at which it is considered that there is insufficient scientific and medical evidence to clearly state the superiority of an intervention has been termed equipoise. This concept has been the subject of much recent impassioned debate but little empirical research about the views of people involved in recruitment to randomized controlled trials (RCTs), and none in the particularly emotive area of neonatal intensive care. METHODS: Thirty neonatologists recruiting into one or both of two neonatal RCTs in five centres in England were interviewed using a semi-structured schedule to explore their involvement in randomised trials. The interviews were tape-recorded and transcribed. Equipoise was one among a range of topics covered. Concepts relating to equipoise were identified by close reading of the entire interviews. Themes emerging from the data were noted in their contexts then discussed between the co-authors. Interviewees also completed a brief questionnaire about their demographic background, and their experience of research and RCTs. RESULTS: Almost all the neonatologists used the concept of equipoise [using words and phrases such as uncertainty, lack of knowledge (or ignorance), strengths of views, and balancing of pros and cons] in their interview and, for most of them, equipoise seemed to be a useful term. They explored ideas about equipoise at the individual and community levels, and some linked equipoise with notions of the responsibility that should be exercised by the scientific and professional communities. They differed in the importance they gave to individual equipoise, and in how they reacted to threats to equipoise. Feelings of doubt about a trial and disturbed equipoise were more often expressed by more junior doctors. CONCLUSIONS: Our findings suggest that the concept of equipoise goes beyond the idea of uncertainty. In part this is because it includes the balancing of benefit and harm; this balancing is part of a professional obligation and requires engagement with 'expert' knowledge. Equipoise could therefore be seen as 'active' or 'responsible' uncertainty. Elucidation of this difficult concept may help to facilitate recruitment for both clinicians and parents in future trials and thereby help to find answers to important clinical questions.
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OBJECTIVE: To assess the association between competing interests and authors' conclusions in randomised clinical trials. DESIGN: Epidemiological study of randomised clinical trials published in the BMJ from January 1997 to June 2001. Financial competing interests were defined as funding by for profit organisations and other competing interests as personal, academic, or political. STUDIES: 159 trials from 12 medical specialties. MAIN OUTCOME MEASURES: Authors' conclusions defined as interpretation of extent to which overall results favoured experimental intervention. Conclusions appraised on 6 point scale; higher scores favour experimental intervention. RESULTS: Authors' conclusions were significantly more positive towards the experimental intervention in trials funded by for profit organisations alone compared with trials without competing interests (mean difference 0.48 (SE 0.13), P=0.014), trials funded by both for profit and non-profit organisations (0.30 (SE 0.10), P=0.003), and trials with other competing interests (0.45 (SE 0.13), P=0.006). Other competing interests and funding from both for profit and non-profit organisations were not significantly associated with authors' conclusions. The association between financial competing interests and authors' conclusions was not explained by methodological quality, statistical power, type of experimental intervention (pharmacological or non-pharmacological), type of control intervention (for example, placebo or active drug), or medical specialty. CONCLUSIONS: Authors' conclusions in randomised clinical trials significantly favoured experimental interventions if financial competing interests were declared. Other competing interests were not significantly associated with authors' conclusions.
BACKGROUND: Combining radiation and hormone therapy (administration of selective estrogen receptor modulators) has become common clinical practice in recent years for receptor positive breast cancer. Little is known about a possible interaction of both treatment modalities if they are given simultaneously. Tamoxifen (antiestrogen molecule, triphenylethylene derivative) may theoretically render cancer cells less responsive to radiotherapy arresting hormone-receptor-positive cells in G0/G1 phase and increase the risk of breast and lung fibrosis stimulating the secretion of transforming growth factor beta in human fibroblasts. PURPOSE: This article reviews the published data to assess the impact of sequencing of hormonal and radiation therapy on outcomes in breast cancer. METHODS: Computerised searches for publications debating the sequencing of hormonal therapy relative to radiation therapy were done using MEDLINE data. RESULTS: Results of tamoxifen experiments with cell culture regarding radioprotection of tumour clonogens are conflicting. In contrast to in vitro results, in animal studies no protective effect of tamoxifen was observed. In one in vitro study, letrozole (non-steroid selective aromatase inhibitor) had a radiosensitizing effect on breast-cancer lines. No randomised clinical trials to date have studied sequencing of tamoxifen or other selective estrogen receptor modulators and radiotherapy. Results from retrospective clinical studies which included treatment arms with and without tamoxifen showed reduction in tumour recurrence with tamoxifen. Some of these studies have noted increased risk of lung and breast fibrosis with tamoxifen with radiotherapy. Results of three articles examined the effect of tamoxifen sequence showed no adverse effect on local control or survival in sequential versus concurrent tamoxifen and radiation patients. One of the three studies also assessed the risk of complications with respect to the timing of tamoxifen with radiotherapy. There was no difference in the rates of complications between the two groups. The association of radiation and selective aromatase inhibitors or aromatase inactivators has not been addressed in clinical studies. CONCLUSIONS: Combined application of tamoxifen and radiotherapy improves survival and local control in breast cancer. Available clinical studies do not indicate that the simultaneous application of tamoxifen and radiotherapy is disadvantageous, as was suggested by some of the in vitro studies. The risk of subcutaneous breast and lung fibrosis might be slightly increased if tamoxifen is given simultaneously with radiotherapy. Both treatment modalities should be started early after surgery. There is no sufficient evidence to withhold tamoxifen administration during irradiation of breast cancer. The issue of optimal sequencing of hormonal and radiotherapy should be addressed in randomised clinical trials.