Hormone replacement therapy and prevention of vertebral fractures: a meta-analysis of randomised trials

BACKGROUND: Hormone replacement therapy (HRT) is often seen as the treatment of choice for preventing fractures in women. We undertook a recent meta-analysis of randomised trials which suggested that HRT reduced non-vertebral fractures by 30%. In this analysis we extend that analysis to vertebral fractures. METHODS: We searched the main electronic databases until the end of August 2001. We sought all randomised controlled trials (RCTs) of HRT where women had been randomised to at least 12 months of HRT or to no HRT. RESULTS: We found 13 RCTs. Overall there was a 33% reduction in vertebral factures (95% confidence interval (CI) 45% to 98%). CONCLUSIONS: This review and meta-analysis showed a significant reduction in vertebral fractures associated with HRT use

Missing data in randomized controlled trials testing palliative interventions pose a significant risk of bias and loss of power: a systematic review and meta-analyses

Objectives To assess the risk posed by missing data (MD) to the power and validity of trials evaluating palliative interventions. Study Design and Setting A systematic review of MD in published randomized controlled trials (RCTs) of palliative interventions in participants with life-limiting illnesses was conducted, and random-effects meta-analyses and metaregression were performed. CENTRAL, MEDLINE, and EMBASE (2009-2014) were searched with no language restrictions. Results One hundred and eight RCTs representing 15,560 patients were included. The weighted estimate for MD at the primary endpoint was 23.1% (95% confidence interval [CI] 19.3, 27.4). Larger MD proportions were associated with increasing numbers of questions/tests requested (odds ratio [OR] , 1.19; 95% CI 1.05, 1.35) and with longer study duration (OR, 1.09; 95% CI 1.02, 1.17). Meta-analysis found evidence of differential rates of MD between trial arms, which varied in direction (OR, 1.04; 95% CI 0.90, 1.20; I 2 35.9, P = 0.001). Despite randomization, MD in the intervention arms (vs. control) were more likely to be attributed to disease progression unrelated to the intervention (OR, 1.31; 95% CI 1.02, 1.69). This was not the case for MD due to death (OR, 0.92; 95% CI 0.78, 1.08). Conclusion The overall proportion and differential rates and reasons for MD reduce the power and potentially introduce bias to palliative care trials

Systematic review of topical treatments for fungal infections of the skin and nails of the feet

OBJECTIVE: To identify and synthesise the evidence for efficacy and cost effectiveness of topical treatments for superficial fungal infections of the skin and nails of the feet. DESIGN: Systematic review. INTERVENTIONS: Topical treatments for superficial fungal infections. MAIN OUTCOME MEASURES: Cure confirmed by culture and microscopy for skin and by culture for nails in patients with clinically diagnosed fungal infections. RESULTS: Of 126 trials identified in 121 papers, 72 (57.1%) met the inclusion criteria. Placebo controlled trials yielded pooled relative risks of failure to cure skin infections: allylamines (0.30, 95% confidence interval 0.24 to 0.38); azoles (0.54, 0.42 to 0.68); undecenoic acid (0.28, 0.11 to 0.74); and tolnaftate (0.46, 0.17 to 1.22). Although meta-analysis of 11 trials comparing allylamines and azoles showed a relative risk of failure to cure of 0.88 (0.78 to 0.99) in favour of allylamines, there was evidence of language bias. Seven reports in English favoured allylamines (0.79, 0.69 to 0.91), but four reports in foreign languages showed no difference between the two drugs (1.01, 0.90 to 1.13). Neither trial of nail infections showed significant differences between alternative topical treatments. CONCLUSIONS: Allylamines, azoles, and undecenoic acid were efficacious in placebo controlled trials. There are sufficient comparative trials to judge relative efficacy only between allylamines and azoles. Allylamines cure slightly more infections than azoles but are much more expensive than azoles. The most cost effective strategy is first to treat with azoles or undecenoic acid and to use allylamines only if that fails

Cost-effectiveness of antibiotics for COPD management : observational analysis using CPRD data

It is often difficult to determine the cause of chronic obstructive pulmonary disease (COPD) exacerbations, and antibiotics are frequently prescribed. This study conducted an observational cost-effectiveness analysis of prescribing antibiotics for exacerbations of COPD based on routinely collected data from patient electronic health records. A cohort of 45 375 patients aged 40 years or more who attended their general practice for a COPD exacerbation during 2000-2013 was identified from the Clinical Practice Research Datalink. Two groups were formed ("immediate antibiotics" or "no antibiotics") based on whether antibiotics were prescribed during the index general practice (GP) consultation, with data analysed according to subsequent healthcare resource use. A cost-effectiveness analysis was undertaken from the perspective of the UK National Health Service, using a time horizon of 4 weeks in the base case. The use of antibiotics for COPD exacerbations resulted in cost savings and an improvement in all outcomes analysed; i.e. GP visits, hospitalisations, community respiratory team referrals, all referrals, infections and subsequent antibiotics prescriptions were lower for the antibiotics group. Hence, the use of antibiotics was dominant over no antibiotics. The economic analysis suggests that use of antibiotics for COPD exacerbations is a cost-effective alternative to not prescribing antibiotics for patients who present to their GP, and remains cost-effective when longer time horizons of 3 months and 12 months are considered. It would be useful for a definitive trial to be undertaken in this area to determine the cost-effectiveness of antibiotics for COPD exacerbations

Cost effectiveness analysis of larval therapy for leg ulcers

Objective: To assess the cost effectiveness of larval therapy compared with hydrogel in the management of leg ulcers. Design: Cost effectiveness and cost utility analyses carried out alongside a pragmatic multicentre, randomised, open trial with equal randomisation. Population: Intention to treat population comprising 267 patients with a venous or mixed venous and arterial ulcers with at least 25% coverage of slough or necrotic tissue. Interventions: Patients were randomly allocated to debridement with bagged larvae, loose larvae, or hydrogel. Main outcome measure: The time horizon was 12 months and costs were estimated from the UK National Health Service perspective. Cost effectiveness outcomes are expressed in terms of incremental costs per ulcer-free day (cost effectiveness analysis) and incremental costs per quality adjusted life years (cost utility analysis). Results: The larvae arms were pooled for the main analysis. Treatment with larval therapy cost, on average, 96.70 pound ((sic)109.61; $140.57) more per participant per year (95% confidence interval -491.9 pound to 685.8) pound than treatment with hydrogel. Participants treated with larval therapy healed, on average, 2.42 days before those in the hydrogel arm (95% confidence interval -0.95 to 31. 91 days) and had a slightly better health related quality of life, as the annual difference in QALYs was 0.011 (95% confidence interval -0.067 to 0.071). However, none of these differences was statistically significant. The incremental cost effectiveness ratio for the base case analysis was estimated at 8826 pound per QALY gained and 40 pound per ulcer-free day. Considerable uncertainty surrounds the outcome estimates. Conclusions: Debridement of sloughy or necrotic leg ulcers with larval therapy is likely to produce similar health benefits and have similar costs to treatment with hydrogel. Trial registration: Current Controlled Trials ISRCTN55114812 and National Research Register N0484123692

Randomised, controlled trial of alternating pressure mattresses compared with alternating pressure overlays for the prevention of pressure ulcers : PRESSURE (pressure relieving support surfaces) trial

Objective To compare whether differences exist between alternating pressure overlays and alternating pressure mattresses in the development of new pressure ulcers, healing of existing pressure ulcers, and patient acceptability. Design Pragmatic, open, multicentre, randomised controlled trial. Setting 11 hospitals in six NHS trusts. Participants 1972 people admitted to hospital as acute or elective patients. Interventions Participants were randomised to an alternating pressure mattress (n = 982) of- an alternating pressure overlay (n = 990). Main outcome measures The proportion of participants developing a new pressure ulcer of grade 2 or worse; time to development of new pressure ulcers; proportions of participants developing a new ulcer within 30 days; healing of existing pressure ulcers; and patient acceptability Results Intention to treat analysis found no difference in the proportions of participants developing a new pressure ulcer of grade 2 or worse (10.7% overlay patients, 10.3% mattress patients; difference 0.4%, 95% confidence interval - 23% to 3.1%, P = 0.75). More overlay patients requested change owing to dissatisfaction (23.3%) than mattress patients (18.9%, P = 0.02). Conclusion No difference was found between alternating pressure mattresses and alternating pressure overlays in the proportion of people who develop a pressure ulcer

Subversion of allocation concealment in a randomised controlled trial : a historical case study

BACKGROUND: If the randomisation process within a trial is subverted, this can lead to selection bias that may invalidate the trial's result. To avoid this problem, it is recommended that some form of concealment should be put into place. Despite ongoing anecdotal concerns about their susceptibility to subversion, a surprising number of trials (over 10%) still use sealed opaque envelopes as the randomisation method of choice. This is likely due in part to the paucity of empirical data quantifying the potential effects of subversion. In this study we report a historical before and after study that compares the use of the sealed envelope method with a more secure centralised telephone allocation approach in order to provide such empirical evidence of the effects of subversion. METHODS: This was an opportunistic before and after study set within a multi-centre surgical trial, which involved 654 patients from 28 clinicians from 23 centres in the UK and Ireland. Two methods of randomly allocating subjects to alternative treatments were adopted: (a) a sealed envelope system administered locally, and (b) a centralised telephone system administered by the trial co-ordination centre. Key prognostic variables were compared between randomisation methods: (a) age at trial entry, a key prognostic factor in the study, and (b) the order in which 'randomisation envelopes' were matched to subjects. RESULTS: The median age of patients allocated to the experimental group with the sealed envelope system, was significantly lower both overall (59 vs 63 years, p < 0.01) and in particular for three clinicians (57 vs 72, p < 0.01; 33 vs 69, p < 0.001; 47 vs 72, p = 0.03). No differences in median age were found between the allocation groups for the centralised system. CONCLUSIONS: Due to inadequate allocation concealment with the sealed envelope system, the randomisation process was corrupted for patients recruited from three clinicians. Centralised randomisation ensures that treatment allocation is not only secure but seen to be secure. Where this proves to be impossible, allocation should at least be performed by an independent third party. Unless it is an absolute requirement, the use of sealed envelopes should be discontinued forthwith

Larval therapy for leg ulcers (VenUS II) : randomised controlled trial

Objective To compare the clinical effectiveness of larval therapy with a standard debridement technique (hydrogel) for sloughy or necrotic leg ulcers. Design Pragmatic, three armed randomised controlled trial. Setting Community nurse led services, hospital wards, and hospital outpatient leg ulcer clinics in urban and rural settings, United Kingdom. Participants 267 patients with at least one venous or mixed venous and arterial ulcer with at least 25% coverage of slough or necrotic tissue, and an ankle brachial pressure index of 0.6 or more. Interventions Loose larvae, bagged larvae, and hydrogel. Main outcome measures The primary outcome was time to healing of the largest eligible ulcer. Secondary outcomes were time to debridement, health related quality of life (SF-12), bacterial load, presence of meticillin resistant Staphylococcus aureus, adverse events, and ulcer related pain (visual analogue scale, from 0 mm for no pain to 150 mm for worst pain imaginable). Results Time to healing was not significantly different between the loose or bagged larvae group and the hydrogel group (hazard ratio for healing using larvae v hydrogel 1.13, 95% confidence interval 0.76 to 1.68; P=0.54). Larval therapy significantly reduced the time to debridement (2.31, 1.65 to 3.2; P<0.001). Health related quality of life and change in bacterial load over time were not significantly different between the groups. 6.7% of participants had MRSA at baseline. No difference was found between larval therapy and hydrogel in their ability to eradicate MRSA by the end of the debridement phase (75% (9/12) v 50% (3/6); P=0.34), although this comparison was underpowered. Mean ulcer related pain scores were higher in either larvae group compared with hydrogel (mean difference in pain score: loose larvae v hydrogel 46.74 (95% confidence interval 32.44 to 61.04), P<0.001; bagged larvae v hydrogel 38.58 (23.46 to 53.70), P<0.001). Conclusions Larval therapy did not improve the rate of healing of sloughy or necrotic leg ulcers or reduce bacterial load compared with hydrogel but did significantly reduce the time to debridement and increase ulcer pain. Trial registration Current Controlled Trials ISRCTN55114812 and National Research Register N0484123692

Methodological bias in cluster randomised trials

Background: Cluster randomised trials can be susceptible to a range of methodological problems. These problems are not commonly recognised by many researchers. In this paper we discuss the issues that can lead to bias in cluster trials. Methods: We used a sample of cluster randomised trials from a recent review and from a systematic review of hip protectors. We compared the mean age of participants between intervention groups in a sample of 'good' cluster trials with a sample of potentially biased trials. We also compared the effect sizes, in a funnel plot, between hip protector trials that used individual randomisation compared with those that used cluster randomisation. Results: There is a tendency for cluster trials, with evidence methodological biases, to also show an age imbalance between treatment groups. In a funnel plot we show that all cluster trials show a large positive effect of hip protectors whilst individually randomised trials show a range of positive and negative effects, suggesting that cluster trials may be producing a biased estimate of effect. Conclusion: Methodological biases in the design and execution of cluster randomised trials is frequent. Some of these biases associated with the use of cluster designs can be avoided through careful attention to the design of cluster trials. Firstly, if possible, individual allocation should be used. Secondly, if cluster allocation is required, then ideally participants should be identified before random allocation of the clusters. Third, if prior identification is not possible, then an independent recruiter should be used to recruit participants