Trial Forge Guidance 4: a guideline for reporting the results of randomised Studies Within A Trial (SWATs).

BACKGROUND: Evidence to support decisions on trial processes is minimal. One way to generate this evidence is to use a Study Within A Trial (SWAT) to test trial processes or explore methodological uncertainties. SWAT evidence relies on replication to ensure sufficient power and broad applicability of findings. Prompt reporting is therefore essential; however, SWAT publications are often the first to be abandoned in the face of other time pressures. Reporting guidance for embedded methodology trials does exist but is not widely used. We sought therefore to build on these guidelines to develop a straightforward, concise reporting standard, which remains adherent to the CONSORT guideline. METHODS: An iterative process was used to develop the guideline. This included initial meetings with key stakeholders, development of an initial guideline, pilot testing of draft guidelines, further iteration and pilot testing, and finalisation of the guideline. RESULTS: We developed a reporting guideline applicable to randomised SWATs, including replications of previous evaluations. The guideline follows the Consolidated Standards for Reporting Trials (CONSORT) statement and provides example text to ensure ease and clarity of reporting across all domains. CONCLUSIONS: The SWAT reporting guideline will aid authors, reviewers, and journal editors to produce and review clear, structured reports of randomised SWATs, whilst also adhering to the CONSORT guideline. TRIAL REGISTRATION: EQUATOR Network - Guidelines Under Development ( https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-clinical-trials/#SWAT ). Registered on 25 March 2021.

A randomised controlled trial of compression therapies for the treatment of venous leg ulcers (VenUS 6): study protocol for a pragmatic, multicentre, parallel-group, three-arm randomised controlled trial.

BACKGROUND: Venous leg ulcer(s) are common, recurring, open wounds on the lower leg, resulting from diseased or damaged leg veins impairing blood flow. Wound healing is the primary treatment aim for venous leg ulceration, alongside the management of pain, wound exudate and infection. Full (high) compression therapy delivering 40 mmHg of pressure at the ankle is the recommended first-line treatment for venous leg ulcers. There are several different forms of compression therapy available including wraps, two-layer hosiery, and two-layer or four-layer bandages. There is good evidence for the clinical and cost-effectiveness of four-layer bandage and two-layer hosiery but more limited evidence for other treatments (two-layer bandage and compression wraps). Robust evidence is required to compare clinical and cost-effectiveness of these and to investigate which is the best compression treatment for reducing time to healing of venous leg ulcers whilst offering value for money. VenUS 6 will therefore investigate the clinical and cost-effectiveness of evidence-based compression, two-layer bandage and compression wraps for time to healing of venous leg ulcers. METHODS: VenUS 6 is a pragmatic, multi-centre, three-arm, parallel-group, randomised controlled trial. Adult patients with a venous leg ulcer will be randomised to receive (1) compression wraps, (2) two-layer bandage or (3) evidence-based compression (two-layer hosiery or four-layer bandage). Participants will be followed up for between 4 and 12 months. The primary outcome will be time to healing (full epithelial cover in the absence of a scab) in days since randomisation. Secondary outcomes will include key clinical events (e.g. healing of the reference leg, ulcer recurrence, ulcer/skin deterioration, amputation, admission/discharge, surgery to close/remove incompetent superficial veins, infection or death), treatment changes, adherence and ease of use, ulcer related pain, health-related quality of life and resource use. DISCUSSION: VenUS 6 will provide robust evidence on the clinical and cost-effectiveness of the different forms of compression therapies for venous leg ulceration. VenUS 6 opened to recruitment in January 2021 and is currently recruiting across 30 participating centres. TRIAL REGISTRATION: ISRCTN67321719 . Prospectively registered on 14 September 2020.

Correction to Effect of vitamin K on bone mineral density and fractures in adults: an updated systematic review and meta-analysis of randomised controlled trials.

Following the work of Avenell et al. that has raised concerns about the integrity of the Yamaguchi Osteoporosis Prevention Study (YOPS) conducted by Ishida and Kawai we issue here an adjustment to all meta-analysis estimates that contained this work within our systematic review.

Effect of vitamin K on bone mineral density and fractures in adults: an updated systematic review and meta-analysis of randomised controlled trials.

Vitamin K may affect bone mineral density and fracture incidence. Since publication of a previous systematic review the integrity of some of the previous evidence has been questioned and further trials have been published. Therefore an update to the systematic review was required. INTRODUCTION: This systematic review was designed to assess the effectiveness of oral vitamin K supplementation for increasing bone mineral density and reducing fractures in adults. METHODS: MEDLINE, EMBASE, CENTRAL, CINAHL, clinicaltrials.gov, and WHO-ICTRP were searched for eligible trials. Randomised controlled trials assessing oral vitamin K supplementation that assessed bone mineral density or fractures in adult populations were included. A total of 36 studies were identified. Two independent reviewers extracted data using a piloted extraction form. RESULTS: For post-menopausal or osteoporotic patients, meta-analysis showed that the odds of any clinical fracture were lower for vitamin K compared to controls (OR, 0.72, 95%CI 0.55 to 0.95). Restricting the analysis to low risk of bias trials reduced the OR to 0.76 (95%CI, 0.58 to 1.01). There was no difference in vertebral fractures between the groups (OR 0.96, 95%CI 0.83 to 1.11). In the bone mineral density meta-analysis, percentage change from baseline at the lumbar spine was higher at 1 year (MD 0.93, 95%, CI - 0.02 to 1.89) and 2 years (MD 1.63%, 95%CI 0.10 to 3.16) for vitamin K compared to controls; however, removing trials at high risk of bias tended to result in smaller differences that were not statistically significant. At 6 months, it was higher in the hip (MD 0.42%, 95%CI 0.01 to 0.83) and femur (MD 0.29%, 95%CI 0.17 to 0.42). There was no significant difference at other anatomical sites. CONCLUSIONS: For post-menopausal or osteoporotic patients, there is no evidence that vitamin K affects bone mineral density or vertebral fractures; it may reduce clinical fractures; however, the evidence is insufficient to confirm this. There are too few trials to draw conclusions for other patient groups.

Compliance effects in a randomised controlled trial of yoga for chronic low back pain: a methodological study.

STUDY DESIGN: Methodological study nested within a multicentre randomised controlled trial (RCT) of yoga plus usual general practitioner (GP) care vs usual GP care for chronic low back pain. OBJECTIVE: To explore the treatment effects of non-compliance using three approaches in an RCT evaluating yoga for low back pain. SUMMARY OF BACKGROUND DATA: A large multicentre RCT using intention-to-treat (ITT) analysis found that participants with chronic low back pain who were offered a 12-week progressive programme of yoga plus usual GP care had better back function than those offered usual GP care alone. However, ITT analysis can underestimate the effect of treatment in those who comply with treatment. As such, the data were analysed using other approaches to assess the problem of non-compliance. The main outcome measure was the self-reported Roland Morris Disability Questionnaire (RMDQ). METHODS: Complier average causal effect (CACE) analysis, per-protocol analysis and on-treatment analysis were conducted on the data of participants who were fully compliant, predefined as attendance of at least three of the first six sessions and at least three other sessions. The analysis was repeated for participants who had attended at least one yoga session (i.e. any compliance), which included participants who were fully compliant. Each approach was described, including strengths and weaknesses, and the results of the different approaches were compared with those of the ITT analysis. RESULTS: For the participants who were fully compliant (n=93, 60%), a larger beneficial treatment effect was seen using CACE analysis compared with per-protocol, on-treatment and ITT analyses at 3 and 12 months. The difference in mean change in RMDQ score between randomised groups was -3.30 [95% confidence interval (CI) -4.90 to -1.70, P<0.001] at 3 months and -2.23 (95% CI -3.93 to -0.53, P=0.010) at 12 months for CACE analysis, -3.12 (95% CI -4.26 to -1.98, P<0.001) at 3 months and -2.11 (95% CI -3.33 to -0.89, P=0.001) at 12 months for per-protocol analysis, and -2.91 (95% CI -4.06 to -1.76, P<0.001) at 3 months and -2.10 (95% CI -3.31 to -0.89, P=0.001) at 12 months for on-treatment analysis. For the participants who demonstrated any compliance (n=133, 85%), the results were generally consistent with the fully compliant group at 3 months, but the treatment effect was smaller. The difference in mean change in RMDQ score between randomised groups was -2.45 (95% CI -3.67 to -1.24) for CACE analysis, -2.30 (95% CI -3.43 to 1.17) for per-protocol analysis and -2.15 (95% CI -3.25 to -1.06) for on-treatment analysis, which was slightly less than that for ITT analysis. In contrast, at 12 months, per-protocol and on-treatment analyses showed a larger treatment effect compared with CACE and ITT analyses: per protocol analysis -1.86 (95% CI -3.02 to -0.71), on-treatment analysis -1.99 (95% CI -3.13 to -0.86) and CACE analysis -1.67 (95% CI -2.95 to -0.40). CONCLUSION: ITT analysis estimated a slightly smaller treatment effect in participants who complied with treatment. When examining compliance, CACE analysis is more rigorous than per-protocol and on-treatment analyses. Using CACE analysis, the treatment effect was larger in participants who complied with treatment compared with participants who were allocated to treatment, and the difference between ITT and CACE analyses for the fully compliant group at 3 months was small but clinically important. Per-protocol and on-treatment analyses may produce unreliable estimates when the effect of treatment is small. INTERNATIONAL STANDARD RANDOMISED TRIAL NUMBER REGISTER: ISRCTN 81079604.

Cost-effectiveness analysis of general anaesthesia versus local anaesthesia for carotid surgery (GALA Trial).

BACKGROUND: Health outcomes and costs are both important when deciding whether general (GA) or local (LA) anaesthesia should be used during carotid endarterectomy. The aim of this study was to assess the cost-effectiveness of carotid endarterectomy under LA or GA in patients with symptomatic or asymptomatic carotid stenosis for whom surgery was advised. METHODS: Using patient-level data from a large, multinational, randomized controlled trial (GALA Trial) time free from stroke, myocardial infarction or death, and costs incurred were evaluated. The cost-effectiveness outcome was incremental cost per day free from an event, within a time horizon of 30 days. RESULTS: A patient undergoing carotid endarterectomy under LA incurred fewer costs (mean difference pound178) and had a slightly longer event-free survival (difference 0.16 days, but the 95 per cent confidence limits around this estimate were wide) compared with a patient who had GA. Existing uncertainty did not have a significant impact on the decision to adopt LA, over a wide range of willingness-to-pay values. CONCLUSION: If cost-effectiveness was considered in the decision to adopt GA or LA for carotid endarterectomy, given the evidence provided by this study, LA is likely to be the favoured treatment for patients for whom either anaesthetic approach is clinically appropriate.

Population screening for osteoporosis risk: a randomised control trial of medication use and fracture risk.

UNLABELLED: Randomised control trial of osteoporosis screening in 4,800 women aged 45-54 years was carried out. Screened group observed an increase of 7.9% in hormone replacement therapy (HRT) use (p < 0.001), 15% in other osteoporosis treatments (p < 0.001) and a 25.9% reduction in fracture risk compared with control. Screening for osteoporosis significantly increases treatment use and reduces fracture incidence. INTRODUCTION: Population screening programmes can identify menopausal women with low bone mineral density (BMD) and elevated risk of future fracture but require to be proven effective by a randomised control trial. METHODS: A total of 4,800 women, 45-54 years, were randomised in equal numbers to screening or no screening (control) groups. Following screening, those in the lowest quartile of BMD were advised to consider HRT. Nine years later, the effect of screening on the uptake of treatment and the incidence of fractures were assessed by postal questionnaire. Categorical differences were assessed using chi(2) test. Cox regression was used to assess hazard ratio (HR). RESULTS: Of the screened and the control groups, 52.4% vs 44.5%, respectively, reported taking HRT (p < 0.001). In addition, 36.6% of the screened vs 21.6% of the control groups reported the use of vitamin D, calcium, alendronate, etidronate or raloxifene (p < 0.001). In a per protocol analysis of verified incident fractures, a 25.9% reduction in risk of fractures (of any site) in the screened group was observed (HR = 0.741, 95% CI = 0.551-0.998 adjusted age, weight and height). CONCLUSIONS: Screening for osteoporosis as assessed by low bone density significantly increases the use of HRT and other treatments for osteoporosis and reduces fracture incidence.

VenUS II: a randomised controlled trial of larval therapy in the management of leg ulcers.

OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of larval therapy with a standard debridement technique (hydrogel). DESIGN: A pragmatic, three-arm, randomised controlled trial with an economic evaluation. SETTING: Community nursing services, community leg ulcer clinics and hospital outpatient leg ulcer clinics. A range of urban and rural settings. PARTICIPANTS: Patients with venous or mixed venous/arterial ulcers (minimum ankle brachial pressure index of 0.6) where a minimum of 25% of ulcer area was covered by slough and/or necrotic material. INTERVENTIONS: Loose larval therapy and bagged larval therapy compared with hydrogel. MAIN OUTCOME MEASURES: The primary end point was complete healing of the largest eligible ulcer. The primary outcome was time to complete healing of the reference ulcer. Secondary outcomes were: time to debridement, cost of treatments, health-related quality of life (including ulcer-related pain), bacterial load, presence of methicillin-resistant Staphylococcus aureus and staff and patient attitudes to and beliefs about larval therapy. RESULTS: Between July 2004 and May 2007 the trial recruited 267 people aged 20-94 years at trial entry. There were more female (n = 158) than male (n = 109) participants and most ulcers were classified by the nurse as having an area greater than 5 cm(2). The time to healing for the three treatment arms was compared using the log rank test. The difference in time to healing in the three treatments was not statistically significant at the 5% level. Adjustment was then made for stratification and prespecified prognostic factors (centre, baseline ulcer area, ulcer duration and type of ulcer) using a Cox proportional hazards model. No difference was found in healing rates between the loose and bagged larvae groups. Results for larvae (loose and bagged pooled) compared with hydrogel showed no evidence of a difference in time to healing. When the same analytical steps were used to investigate time to debridement, larvae-treated ulcers debrided significantly more rapidly than hydrogel-treated ulcers; however, the difference in time to debridement between loose and bagged larvae was not significant. The adjusted analysis reported the hazard of debriding at any time for those in loose and bagged larvae groups as approximately twice that of the hydrogel group. No differences in health-related quality of life or bacteriology were observed between trial arms. Larval therapy was associated with significantly more ulcer-related pain than hydrogel. Our base-case economic evaluation showed large decision uncertainty associated with the cost-effectiveness of larval therapy compared with hydrogel, suggesting that larval therapy and hydrogel therapy have similar costs and effects in the treatment of sloughy and/or necrotic leg ulcers. CONCLUSIONS: Larval therapy significantly reduced the time to debridement of sloughy and/or necrotic, chronic venous and mixed venous/arterial leg ulcers, compared with hydrogel; however, larval therapy did not significantly increase the rate of healing of the ulcers. It was impossible to distinguish between larval therapy and hydrogel in terms of cost-effectiveness. Future research should investigate the association of debridement and healing and the value of debridement as a clinical outcome for patients and clinicians. To inform decision-makers' selection of debriding agents where debridement is the treatment goal, decision analytic modelling of all alternative debridement treatments is required. TRIAL REGISTRATION: Current Controlled Trials ISRCTN55114812.

The health-related quality of life and cost implications of falls in elderly women.

SUMMARY: Fractures and falls are serious cause of morbidity and cost to society. Our results suggest that the main burden to morbidity, measured as impact on health-related quality of life, is due to fear of falling rather than falls or their sequelae, such as fractures. INTRODUCTION: Fractures and falls are serious cause of morbidity and cost to society. We investigated the impact on health-related quality of life (HRQoL) associated with falls, fractures and fear of falling and falls and fractures cost. METHODS: Three datasets providing longitudinal data on fear of falling, HRQoL and a common set of baseline risk factors for fracture (smoking status, weight and age) were analysed. Multilevel random effects models were used to estimate the long-term impact on HRQoL associated with falls, fractures and fear of falling. Healthcare resource use primary data were collected to estimate falls and fractures cost. RESULTS: Older, low weight and smoking women reported lower HRQoL. The impact on HRQoL of a fracture was at least twice as large as that associated with falls. The largest negative effect on HRQoL was associated with self-reported fear of falling. The cost of falls was 1088 pounds. Similarly, the cost of falls leading to a fracture was 15,133 pounds, 2,753 pounds, 1,863 pounds, 1,331 pounds and 3,498 pounds for hip, wrist, arm, vertebral and other fractures, respectively. DISCUSSION: The main burden to morbidity is due to fear of falling. Interventions aimed at reducing fear of falling may produce larger gains in HRQoL.

Clinical effectiveness of a brief educational intervention in Type 1 diabetes: results from the BITES (Brief Intervention in Type 1 diabetes, Education for Self-efficacy) trial.

AIMS: Intensive 5-day educational interventions for people with Type 1 diabetes have shown improved outcomes in a number of European studies. The aim was to assess the effectiveness of a brief (2.5 days) psycho-educational intervention. METHODS: Our randomized trial in a secondary-care setting had 54 and 60 participants allocated to intervention and control groups, respectively. Primary outcomes were HbA1c and severe hypoglycaemia. Secondary outcomes were blood pressure, weight, height, lipids and psychometric profile. RESULTS: HbA1c showed no statistically significant change at 3 months [difference = 0.01, 95% confidence interval (CI) -0.23, 0.26, P = 0.92], 6 months (difference = -0.06, 95% CI -0.32, 0.20, P = 0.67) and 12 months (difference = 0.01, 95% CI -0.30, 0.32, P = 0.94). Incidence of severe hypoglycaemia (per patient per year) in the intervention group (0.41) and control group (0.48) was not statistically different. Treatment satisfaction improved at 3 months (difference = 9.4, 95% CI 5.2, 13.6, P = 0.0005), 6 months (difference = 10.4, 95% CI 6.0, 14.8, P = 0.0005) and 12 months (difference = 7.1, 95% CI 2.1, 12.1, P = 0.006). The 'Managing psychological aspects' and 'Setting and achieving goals' dimensions of the Diabetes Empowerment Scale also showed significant improvement at 3, 6 and 12 months. Diabetes Knowledge Test, Illness Perception Questionnaire, Hypoglycaemia Fear Scale and Short Form 36 showed no significant change. CONCLUSIONS: This brief intervention had no significant impact on HbA(1c) or severe hypoglycaemia, but improved diabetes treatment satisfaction and patient empowerment. Current Controlled Trials ISRCTN75807800.

Contamination in trials of educational interventions.

OBJECTIVES: To consider the effects of contamination on the magnitude and statistical significance (or precision) of the estimated effect of an educational intervention, to investigate the mechanisms of contamination, and to consider how contamination can be avoided. DATA SOURCES: Major electronic databases were searched up to May 2005. METHODS: An exploratory literature search was conducted. The results of trials included in previous relevant systematic reviews were then analysed to see whether studies that avoided contamination resulted in larger effect estimates than those that did not. Experts' opinions were elicited about factors more or less likely to lead to contamination. We simulated contamination processes to compare contamination biases between cluster and individually randomised trials. Statistical adjustment was made for contamination using Complier Average Causal Effect analytic methods, using published and simulated data. The bias and power of cluster and individually randomised trials were compared, as were Complier Average Causal Effect, intention-to-treat and per protocol methods of analysis. RESULTS: Few relevant studies quantified contamination. Experts largely agreed on where contamination was more or less likely. Simulation of contamination processes showed that, with various combinations of timing, intensity and baseline dependence of contamination, cluster randomised trials might produce biases greater than or similar to those of individually randomised trials. Complier Average Causal Effect analyses produced results that were less biased than intention-to-treat or per protocol analyses. They also showed that individually randomised trials would in most situations be more powerful than cluster randomised trials despite contamination. CONCLUSIONS: The probability, nature and process of contamination should be considered when designing and analysing controlled trials of educational interventions in health. Cluster randomisation may or may not be appropriate and should not be uncritically assumed always to be a solution. Complier Average Causal Effect models are an appropriate way to adjust for contamination if it can be measured. When conducting such trials in future, it is a priority to report the extent, nature and effects of contamination.

Randomized trial of two physiotherapy interventions for primary care back and neck pain patients: cost effectiveness analysis.

OBJECTIVES: To assess the cost-effectiveness of a brief physiotherapy pain management approach using cognitive-behavioural principles (Solution-Finding Approach) when compared with a commonly used traditional method of physical therapy (McKenzie Approach). METHODS: Economic evaluation conducted alongside a randomized trial. The study related incremental differences in costs and benefits associated with the Solution Finding and McKenzie approaches over 12 months. Costs were measured in UK pounds sterling. Benefit was measured as health-related quality of life using the EQ-5D, which was used to estimate patient-specific quality adjusted life years (QALYs). RESULTS: The McKenzie treatment required, on average, one extra physiotherapist visit (4.15 vs 3.10). Over a 12-month period, Solution Finding was associated with a lower per patient cost of pound-24.4 (95% CI pound-49.6 to 0.789 pounds). The mean difference in QALYs between the two groups was -0.020 (95% CI -0.057 to 0.017); favouring those receiving McKenzie. Relating incremental mean costs and QALYs gave an incremental cost effectiveness ratio of 1220 pounds (-24.4/-0.020) suggesting the McKenzie treatment is cost effective. CONCLUSIONS: Results suggest that the additional cost associated with the McKenzie treatment when compared with the Solution Finding Approach may be worth paying, given the additional benefit the approach seems more likely to provide. Further research is needed to assess the extent to which the difference in physiotherapy visits between the two strategies is generalizable to other treatment settings.

Randomized trial of two physiotherapy interventions for primary care neck and back pain patients: 'McKenzie' vs brief physiotherapy pain management.

OBJECTIVES: Interventions that take psychosocial factors into account are recommended for patients with persistent back or neck pain. We compared the effectiveness of a brief physiotherapy pain management approach using cognitive-behavioural principles (Solution-Finding Approach-SFA) with a commonly used method of physical therapy (McKenzie Approach-McK). METHODS: Eligible patients referred by GPs to physiotherapy departments with neck or back pain lasting at least 2 weeks were randomized to McK (n= 161) or to SFA (n= 154). They were further randomized to receive an educational booklet or not. The primary outcome was the Tampa Scale of Kinesiophobia (TSK) (Activity-Avoidance scale used as a proxy for coping) at 6 weeks, and 6 and 12 months. RESULTS: Of 649 patients assessed for eligibility, 315 were recruited (219 with back pain, 96 with neck pain). There were no statistically significant differences in outcomes between the groups, except that at any time point SFA patients supported by a booklet reported less reliance on health professionals (Multidimensional Health Locus of Control Powerful Others Scale), while at 6 months McK patients showed slightly more improvement on activity-avoidance (TSK). At 6 weeks, patient satisfaction was greater for McK (median 90% compared with 70% for SFA). Both interventions resulted in modest but clinically important improvements over time on the Roland Disability Questionnaire Scores and Northwick Park Neck Pain Scores. CONCLUSIONS: The McK approach resulted in higher patient satisfaction overall but the SFA could be more cost-effective, as fewer (three vs four) sessions were needed.

Patient acceptability of larval therapy for leg ulcer treatment: a randomised survey to inform the sample size calculation of a randomised trial.

BACKGROUND: A trial was commissioned to evaluate the effectiveness of larval therapy to debride and heal sloughy and necrotic venous leg ulcers. Larval therapy in the trial was to be delivered in either loose or bagged form. Researchers were concerned that resistance to larval therapy may threaten the feasibility of the trial. Additionally there was concern that the use of larval therapy may require a larger effect size in time to healing than originally proposed by the investigators. METHODS: To formally evaluate patient preferences a survey using two randomly allocated, nurse administered questionnaires was undertaken. Patients were randomised to receive one of the two following questionnaires (i) preferences between loose larvae and standard treatment (hydrogel) or (ii) patient preferences between bagged larvae and standard therapy (hydrogel). The study was undertaken in a Vascular Clinic, in an Outpatients Department of a large teaching hospital in the North of England. The sample consisted of 35 people aged 18 years and above with at least one leg ulcer of venous or mixed (venous and arterial) aetiology. RESULTS: Approximately 25% of participants would not consider the use of larval therapy as an acceptable treatment option for leg ulcers, regardless of the method of containment. For the patients that would consider the use of larval therapy, different preferences in healing times required to use the therapy were observed depending upon the method of containment. The median response of those participants questioned about bagged larvae found that they would be willing to use this therapy even if they were equally able to achieve healing with the use of hydrogel by 20 weeks. For those participants questioned about the use of loose larvae complete healing would have to have taken place over 17 weeks for them to choose larvae as their preferred option rather than hydrogel. This difference was not significant (p = 0.075). CONCLUSION: We found no evidence of widespread resistance to the utilisation of larval therapy from patients regardless of the method of larval therapy containment. These methods have the potential to inform sample size calculations where there are concerns of patient acceptability.

Cost-effectiveness analysis of open colposuspension versus laparoscopic colposuspension in the treatment of urodynamic stress incontinence.

OBJECTIVES: To compare the cost effectiveness of laparoscopic versus open colposuspension for the treatment of female urinary stress incontinence. DESIGN: Cost utility analysis alongside a randomised controlled trial. SETTING: Six gynaecological surgical centres within the UK. POPULATION/SAMPLE: Women with proven stress urinary incontinence requiring surgery. METHODS: Open abdominal retropubic colposuspension or laparoscopic colposuspension carried out by experienced surgeons. MAIN OUTCOME MEASURES: Cost, measured in pounds sterling and generic health-related quality of life, measured using the EQ-5D. The latter was used to estimate patient-specific quality-adjusted life years (QALYs). RESULTS: Healthcare resource use over 6-month follow up translated into costs of pound 1805 for the laparoscopic arm and pound 1433 for the open arm (differential mean cost pound 372; 95% credibility interval [CrI]: 274-471). At 6 months, QALYs were slightly higher in the laparoscopic arm relative to the open arm (0.005; 95% CrI: -0.012 to 0.023). Therefore, the cost of each extra QALY in the laparoscopic group (the incremental cost-effectiveness ratio [ICER]) was pound 74,400 at 6 months. At 24 months, the laparoscopic arm again had a higher mean QALY score compared to the open surgery group. Thus, assuming that beyond 6 months the laparoscopic colposuspension would not lead to any significant additional costs compared with open colposuspension, the ICER was reduced to pound 9300 at 24 months. Extensive sensitivity analyses were carried out to test assumptions made in the base case scenario. CONCLUSIONS: Laparoscopic colposuspension is not cost effective when compared with open colposuspension during the first 6 months following surgery, but it may be cost effective over 24 months.

Pressure relieving support surfaces: a randomised evaluation.

OBJECTIVES: To determine differences between alternating pressure overlays and alternating pressure replacement mattresses with respect to the development of new pressure ulcers, healing of existing pressure ulcers, patient acceptability and cost-effectiveness of the different pressure-relieving surfaces. Also to investigate the specific additional impact of pressure ulcers on patients' well-being. DESIGN: A multicentre, randomised, controlled, open, fixed sample, parallel-group trial with equal randomisation was undertaken. The trial used remote, concealed allocation and intention-to-treat (ITT) analysis. The main trial design was supplemented with a qualitative study involving a purposive sample of 20-30 patients who developed pressure ulcers, to assess the impact of the pressure ulcers on their well-being. In addition, a focus group interview was carried out with clinical research nurses, who participated in the PRESSURE (Pressure RElieving Support SUrfaces: a Randomised Evaluation) Trial, to explore the experiences of their role and observations of pressure area care. SETTING: The study took place in 11 hospital-based research centres within six NHS trusts in England. PARTICIPANTS: Acute and elective patients aged 55 years or older and admitted to vascular, orthopaedic, medical or care of the elderly wards in the previous 24 hours were investigated. INTERVENTIONS: Patients were randomised to either an alternating pressure overlay or an alternating pressure mattress replacement, with mattress specifications clearly defined to enable the inclusion of centres using products from different manufacturers, and to exclude hybrid mattress systems (which either combine foam or constant low pressure with alternating pressure in one mattress, or can be used as either an overlay or a replacement mattress). MAIN OUTCOME MEASURES: Development of a new pressure ulcer (grade < or =2, i.e. partial-thickness wound involving epidermis/dermis only) on any skin site. Also healing of existing pressures ulcers, patient acceptability and cost-effectiveness. RESULTS: In total, 6155 patients were assessed for eligibility to the trial and 1972 were randomised: 990 to the alternating pressure overlay (989 after one postrandomisation exclusion) and 982 to the alternating pressure mattress replacement. ITT analysis found no statistically significant difference in the proportions of patients developing a new pressure ulcer of grade 2 or above [10.7% overlay patients, 10.3% mattress replacement patients, a difference of 0.4%, 95% confidence interval (CI) -2.3 to 3.1%, p = 0.75]. When logistic regression analysis was used to adjust for minimisation factors and prespecified baseline covariates, there was no difference between the mattresses with respect to the odds of ulceration (odds ratio 0.94, 95% CI 0.68 to 1.29). There was no evidence of a difference between the mattress groups with respect to time to healing (p = 0.86). The Kaplan-Meier estimate of the median time to healing was 20 days for each intervention. More patients allocated overlays requested mattress changes due to dissatisfaction (23.3%) than mattress replacement patients (18.9%, p = 0.02) and more than one-third of patients reporting difficulties associated with movement in bed and getting into or out of bed. There is a higher probability (64%) that alternating mattress replacements are cost-saving; they were associated with lower overall costs (74.50 pounds sterling per patient on average, mainly due to reduced length of stay) and greater benefits (a delay in time to ulceration of 10.64 days on average). Patients' accounts highlighted that the development of a pressure ulcer could be pivotal in the trajectory from illness to recovery, by preventing full recovery or causing varied impacts on their quality of life. CONCLUSIONS: There is no difference between alternating pressure mattress replacements and overlays in terms of the proportion of patients developing new pressure ulcers; however, alternating pressure mattress replacements are more likely to be cost-saving. The results suggest that when renewing alternating pressure surfaces or ordering equipment within a rental contract, mattress replacements should be specified; however, overlays are acceptable if no replacement mattress is available. Similarly, patient preferences can be supported, without any great increase in risk, if individual patients request an overlay rather than a replacement mattress. Further research could include a randomised controlled trial comparing alternating pressure mattress replacements and high-specification foam mattresses in patients at moderate to high risk; an accurate costing study to understand better how much pressure ulcers cost health and social services in the UK; and trials in higher risk groups of patients. Also future trials should measure time to ulceration as the primary end-point, since this is more informative economically and possibly also from a patient and clinical perspective.

The use of unequal randomisation ratios in clinical trials: a review.

OBJECTIVE: To examine reasons given for the use of unequal randomisation in randomised controlled trials (RCTs). MAIN MEASURES: Setting of the trial; intervention being tested; randomisation ratio; sample size calculation; reason given for randomisation. METHODS: Review of trials using unequal randomisation. DATABASES AND SOURCES: Cochrane library, Medline, Pub Med and Science Citation Index. RESULTS: A total of 65 trials were identified; 56 were two-armed trials and nine trials had more than two arms. Of the two-arm trials, 50 trials recruited patients in favour of the experimental group. Various reasons for the use of unequal randomisation were given. Six studies stated that they used unequal randomisation to reduce the cost of the trial, with one screening trial limited by the availability of the intervention. Other reasons for using unequal allocation were: avoiding loss of power from drop-out or cross-over, ethics and the gaining of additional information on the treatment. Thirty seven trials papers (57%) did not state why they had used unequal randomisation and only 14 trials (22%) appeared to have taken the unequal randomisation into account in their sample size calculation. CONCLUSION: Although unequal randomisation offers a number of advantages to trials the method is rarely used and is especially under-utilised to reduce trial costs. Unequal randomisation should be considered more in trial design especially where there are large differences between treatment costs.

Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.

BACKGROUND: Elderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures. METHODS: In a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures. FINDINGS: 698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups. INTERPRETATION: The findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.

Screening elderly women for risk of future fractures--participation rates and impact on incidence of falls and fractures.

We have assessed the acceptability of a method for screening for risk of future hip fracture in elderly women. After receipt of an initial response to a mailed risk-factor questionnaire sent out to 5,306 women, women were randomly assigned to active or control groups. The active group was invited to participate in a screening visit that comprised a life-style questionnaire and a quantitative ultrasound heel scan. General practitioners (GPs) of women who were found to be in the lowest quartile of broadband ultrasound attenuation and/or who had two or more risk factors for hip fracture were advised to prescribe a calcium and vitamin D supplement. A second mailed questionnaire was sent to both groups 1 to 3 years later. Compared with the control group, the active group had a 56% lower risk of fracture (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.24-0.81 adjusted age, weight, and treatment status). At follow-up, the proportion of fallers in the active group (25.3%) was lower than that in the control group (29.6%) (P = 0.064). The control group was found to have a higher rate of falls at follow-up than the active group (95% CI, 0.02-0.22); no difference was found at baseline (95% CI, -0.08 to +0.14). The screening method used was found to be acceptable to the majority of elderly women in this study. Screening the elderly in this way together with simple advice on treatment appears to reduce the age-associated increase in fall rates and the number of subsequent fractures. This form of screening may provide a cost-effective method to reduce falls and fractures in free-living elderly women. However, no such cost-effectiveness analysis has been performed to date.

Axial BMD, change in BMD and bone turnover do not predict breast cancer incidence in early postmenopausal women.

Previous studies have indicated a relationship between bone mineral density and the incidence of breast cancer in middle-aged and elderly women, with women with higher BMD being at significant increased risk. We investigated whether there was such a relationship in younger women who were perimenopausal or in their early postmenopausal years. As part of a population-screening program for osteoporosis, 5,119 women aged between 45 and 54 years were scanned between 1990-1994 at the Osteoporosis Research Unit. In 1997-2001, 3,884 returned for follow-up scans and questionnaires, and 3,144 returned a postal questionnaire in 2002. All cases of incident breast cancer were noted. One hundred sixty-six women indicated that they had suffered from breast cancer, of which 87 were incident cases (59 had prevalent breast cancer at baseline and 20 had benign or unconfirmed diagnosis and were excluded because of the use of agents that may interfere with BMD, e.g., tamoxifen). We compared therefore the incident breast cancer group (BC group; n=87) with a control group (C group; n=3,013). There were no significant differences using a t-test between the BC group and C group for baseline DXA of the spine or femoral neck. Further changes in BMD over a mean period of 6.9 years demonstrated no significant hazard ratio for the lumbar spine or femoral neck. No relationship was seen between the bone turnover markers pyridinoline/creatinine or deoxypyridinoline/creatinine assessed at their second study visit and incidence of breast cancer. In conclusion, in perimenopausal or early postmenopausal women there is no relationship between the incidence of breast cancer and BMD, change in BMD or bone turnover.