Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial

PURPOSE: To explore potential differences in efficacy, treatment completion, and adverse events (AEs) in elderly women receiving adjuvant tamoxifen or letrozole for five years in the Breast International Group (BIG) 1-98 trial. METHODS: This report includes the 4,922 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial. The median follow-up was 40.4 months. Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was used to examine the patterns of differences in disease-free survival and incidences of AEs according to age. In addition, three categoric age groups were defined: "younger postmenopausal" patients were younger than 65 years (n = 3,127), "older" patients were 65 to 74 years old (n = 1,500), and "elderly" patients were 75 years of age or older (n = 295). RESULTS: Efficacy results for subpopulations defined by age were similar to the overall trial results: Letrozole significantly improved disease-free survival (DFS), the primary end point, compared with tamoxifen. Elderly patients were less likely to complete trial treatment, but at rates that were similar in the two treatment groups. The incidence of bone fractures, observed more often in the letrozole group, did not differ by age. In elderly patients, letrozole had a significantly higher incidence of any grade 3 to 5 protocol-specified non-fracture AE compared with tamoxifen (P = .002), but differences were not significant for thromboembolic or cardiac AEs. CONCLUSION: Adjuvant treatment with letrozole had superior efficacy (DFS) compared with tamoxifen in all age groups. On the basis of a small number of patients older than 75 years (6%), age per se should not unduly affect the choice of adjuvant endocrine therapy.

Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study

OBJECTIVE: To examine whether the association of inadequate or unclear allocation concealment and lack of blinding with biased estimates of intervention effects varies with the nature of the intervention or outcome. DESIGN: Combined analysis of data from three meta-epidemiological studies based on collections of meta-analyses. DATA SOURCES: 146 meta-analyses including 1346 trials examining a wide range of interventions and outcomes. MAIN OUTCOME MEASURES: Ratios of odds ratios quantifying the degree of bias associated with inadequate or unclear allocation concealment, and lack of blinding, for trials with different types of intervention and outcome. A ratio of odds ratios <1 implies that inadequately concealed or non-blinded trials exaggerate intervention effect estimates. RESULTS: In trials with subjective outcomes effect estimates were exaggerated when there was inadequate or unclear allocation concealment (ratio of odds ratios 0.69 (95% CI 0.59 to 0.82)) or lack of blinding (0.75 (0.61 to 0.93)). In contrast, there was little evidence of bias in trials with objective outcomes: ratios of odds ratios 0.91 (0.80 to 1.03) for inadequate or unclear allocation concealment and 1.01 (0.92 to 1.10) for lack of blinding. There was little evidence for a difference between trials of drug and non-drug interventions. Except for trials with all cause mortality as the outcome, the magnitude of bias varied between meta-analyses. CONCLUSIONS: The average bias associated with defects in the conduct of randomised trials varies with the type of outcome. Systematic reviewers should routinely assess the risk of bias in the results of trials, and should report meta-analyses restricted to trials at low risk of bias either as the primary analysis or in conjunction with less restrictive analyses.

Subjective wellbeing under quetiapine treatment: effect of diagnosis, mood state, and anxiety

To examine the effect of diagnosis, mood state, and anxiety on subjective wellbeing in patients with affective and non-affective psychotic disorders treated with quetiapine IR.

Is the sedimentation sign associated with spinal stenosis surgical treatment effect in SPORT?

STUDY DESIGN Subgroup analysis of the lumbar spinal stenosis (LSS) without degenerative spondylolisthesis diagnostic cohort of the Spine Patient Outcomes Research Trial multicenter randomized clinical trial with a concurrent observational cohort. OBJECTIVE To determine if sedimentation sign on magnetic resonance image can help with LSS treatment decisions. SUMMARY OF BACKGROUND DATA LSS is one of the most common reasons for surgery in the US elderly, but there is a dearth of reliable diagnostic tools that give a clear indication for surgery. Recent studies have suggested that positive sedimentation sign on magnetic resonance image may be a possible prognostic indicator. METHODS All patients with LSS in both the randomized and observational cohorts had imaging-confirmed stenosis, were surgical candidates, and had neurogenic claudication for at least 12 weeks prior to enrollment. Patients were categorized as "mild," "moderate," or "severe" according to stenosis severity. Of the 654 patients with LSS enrolled in Spine Patient Outcomes Research Trial, complete T2-weighted axial and sagittal digitized images of 115 patients were available for retrospective review. An independent orthopedic spine surgeon evaluated these deidentified Digital Imaging and Communications in Medicine files for the sedimentation sign. RESULTS Sixty-six percent (76/115) of patients were found to have a positive sedimentation sign. Those with a positive sedimentation sign were more likely to have stenosis at L2-L3 (33% vs. 10% P=0.016) or L3-L4 76% vs. 51%, P=0.012), and to have severe (72% vs. 33%, P<0.0001) central stenosis (93% vs. 67% P<0.001) at 2 or more concurrent levels (57% vs. 18%, P=0.01). In multivariate models, the surgical treatment effect was significantly larger in the positive sedimentation sign group for Oswestry Disability Index (-16 vs. -7; P=0.02). CONCLUSION A positive sedimentation sign was associated with a small but significantly greater surgical treatment effect for Oswestry Disability Index in patients with symptomatic LSS, after adjusting for other demographic and imaging features. These findings suggest that positive sedimentation sign may potentially be a useful adjunct to help guide an informed treatment choice regarding surgery for LSS. LEVEL OF EVIDENCE 2.

Methods to convert continuous outcomes into odds ratios of treatment response and numbers needed to treat: meta-epidemiological study

Clinicians find standardized mean differences (SMDs) calculated from continuous outcomes difficult to interpret. Our objective was to determine the performance of methods in converting SMDs or means to odds ratios of treatment response and numbers needed to treat (NNTs) as more intuitive measures of treatment effect.

A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints

Publication bias and related bias in meta-analysis is often examined by visually checking for asymmetry in funnel plots of treatment effect against its standard error. Formal statistical tests of funnel plot asymmetry have been proposed, but when applied to binary outcome data these can give false-positive rates that are higher than the nominal level in some situations (large treatment effects, or few events per trial, or all trials of similar sizes). We develop a modified linear regression test for funnel plot asymmetry based on the efficient score and its variance, Fisher's information. The performance of this test is compared to the other proposed tests in simulation analyses based on the characteristics of published controlled trials. When there is little or no between-trial heterogeneity, this modified test has a false-positive rate close to the nominal level while maintaining similar power to the original linear regression test ('Egger' test). When the degree of between-trial heterogeneity is large, none of the tests that have been proposed has uniformly good properties.

Native EEG and treatment effects in neuroleptic-naïve schizophrenic patients: time and frequency domain approaches

Time domain analysis of electroencephalography (EEG) can identify subsecond periods of quasi-stable brain states. These so-called microstates assumingly correspond to basic units of cognition and emotion. On the other hand, Global Field Synchronization (GFS) is a frequency domain measure to estimate functional synchronization of brain processes on a global level for each EEG frequency band [Koenig, T., Lehmann, D., Saito, N., Kuginuki, T., Kinoshita, T., Koukkou, M., 2001. Decreased functional connectivity of EEG theta-frequency activity in first-episode, neuroleptic-naive patients with schizophrenia: preliminary results. Schizophr Res. 50, 55-60.]. Using these time and frequency domain analyzes, several previous studies reported shortened microstate duration in specific microstate classes and decreased GFS in theta band in drug naïve schizophrenia compared to controls. The purpose of this study was to investigate changes of these EEG parameters after drug treatment in drug naïve schizophrenia. EEG analysis was performed in 21 drug-naive patients and 21 healthy controls. 14 patients were reevaluated 2-8 weeks (mean 4.3) after the initiation of drug administration. The results extended findings of treatment effect on brain functions in schizophrenia, and imply that shortened duration of specific microstate classes seems a state marker especially in patients with later neuroleptic responsive, while lower theta GFS seems a state-related phenomenon and that higher gamma GFS is a trait like phenomenon.

Randomised controlled trials of homeopathy in hyperactive children: treatment procedure leads to an unconventional study design. Experience with open-label homeopathic treatment preceding the Swiss ADHD placebo controlled, randomised, double-blind, cross-over trial

BACKGROUND: Treatment of patients with attention deficit hyperactivity disorder (ADHD) with homeopathy is difficult. The Swiss randomised, placebo controlled, cross-over trial in ADHD patients (Swiss ADHD trial) was designed with an open-label screening phase prior to the randomised controlled phase. During the screening phase, the response of each child to successive homeopathic medications was observed until the optimal medication was identified. Only children who reached a predefined level of improvement participated in the randomised, cross-over phase. Although the randomised phase revealed a significant beneficial effect of homeopathy, the cross-over caused a strong carryover effect diminishing the apparent difference between placebo and verum treatment. METHODS: This retrospective analysis explores the screening phase data with respect to the risk of failure to demonstrate a specific effect of a randomised controlled trial (RCT) with randomisation at the start of the treatment. RESULTS: During the screening phase, 84% (70/83) of the children responded to treatment and reached eligibility for the randomised trial after a median time of 5 months (range 1-18), with a median of 3 different medications (range 1-9). Thirteen children (16%) did not reach eligibility. Five months after treatment start, the difference in Conners Global Index (CGI) rating between responders and non-responders became highly significant (p = 0.0006). Improvement in CGI was much greater following the identification of the optimal medication than in the preceding suboptimal treatment period (p < 0.0001). CONCLUSIONS: Because of the necessity of identifying an optimal medication before response to treatment can be expected, randomisation at the start of treatment in an RCT of homeopathy in ADHD children has a high risk of failure to demonstrate a specific treatment effect, if the observation time is shorter than 12 months.

Differences across health care systems in outcome and cost-utility of surgical and conservative treatment of chronic low back pain: a study protocol

BACKGROUND: There is little evidence on differences across health care systems in choice and outcome of the treatment of chronic low back pain (CLBP) with spinal surgery and conservative treatment as the main options. At least six randomised controlled trials comparing these two options have been performed; they show conflicting results without clear-cut evidence for superior effectiveness of any of the evaluated interventions and could not address whether treatment effect varied across patient subgroups. Cost-utility analyses display inconsistent results when comparing surgical and conservative treatment of CLBP. Due to its higher feasibility, we chose to conduct a prospective observational cohort study. METHODS: This study aims to examine if1. Differences across health care systems result in different treatment outcomes of surgical and conservative treatment of CLBP2. Patient characteristics (work-related, psychological factors, etc.) and co-interventions (physiotherapy, cognitive behavioural therapy, return-to-work programs, etc.) modify the outcome of treatment for CLBP3. Cost-utility in terms of quality-adjusted life years differs between surgical and conservative treatment of CLBP.This study will recruit 1000 patients from orthopaedic spine units, rehabilitation centres, and pain clinics in Switzerland and New Zealand. Effectiveness will be measured by the Oswestry Disability Index (ODI) at baseline and after six months. The change in ODI will be the primary endpoint of this study.Multiple linear regression models will be used, with the change in ODI from baseline to six months as the dependent variable and the type of health care system, type of treatment, patient characteristics, and co-interventions as independent variables. Interactions will be incorporated between type of treatment and different co-interventions and patient characteristics. Cost-utility will be measured with an index based on EQol-5D in combination with cost data. CONCLUSION: This study will provide evidence if differences across health care systems in the outcome of treatment of CLBP exist. It will classify patients with CLBP into different clinical subgroups and help to identify specific target groups who might benefit from specific surgical or conservative interventions. Furthermore, cost-utility differences will be identified for different groups of patients with CLBP. Main results of this study should be replicated in future studies on CLBP.

Homeopathic treatment of Arabidopsis thaliana plants infected with Pseudomonas syringae

Homeopathic basic research is still in the screening phase to identify promising model systems that are adapted to the needs and peculiarities of homeopathic medicine and pharmacy. We investigated the potential of a common plant-pathogen system, Arabidopsis thaliana infected with the virulent bacteria Pseudomonas syringae, regarding its response towards a homeopathic treatment. A. thaliana plants were treated with homeopathic preparations before and after infection. Outcome measure was the number of P. syringae bacteria in the leaves of A. thaliana, assessed in randomized and blinded experiments. After a screening of 30 homeopathic preparations, we investigated the effect of Carbo vegetabilis 30x, Magnesium phosphoricum 30x, Nosode 30x, Biplantol (a homeopathic complex remedy), and Biplantol 30x on the infection rate in five or six independent experiments in total. The screening yielded significant effects for four out of 30 tested preparations. In the repeated experimental series, only the homeopathic complex remedy Biplantol induced a significant reduction of the infection rate (p = 0.01; effect size, d = 0.38). None of the other four repeatedly tested preparations (Carbo vegetabilis 30x, Magnesium phosphoricum 30x, Nosode 30x, Biplantol 30x) yielded significant effects in the overall evaluation. This phytopathological model yielded a small to medium effect size and thus might be of interest for homeopathic basic research after further improvement. Compared to Bion (a common SAR inducer used as positive control), the magnitude of the treatment effect of Biplantol was about 50%. Thus, homeopathic formulations might have a potential for the treatment of plant diseases after further optimization. However, the ecological impact should be investigated more closely before widespread application.

Antiplatelets versus Anticoagulants for the Treatment of Cervical Artery Dissection: Bayesian Meta-Analysis

OBJECTIVE To compare the effects of antiplatelets and anticoagulants on stroke and death in patients with acute cervical artery dissection. DESIGN Systematic review with Bayesian meta-analysis. DATA SOURCES The reviewers searched MEDLINE and EMBASE from inception to November 2012, checked reference lists, and contacted authors. STUDY SELECTION Studies were eligible if they were randomised, quasi-randomised or observational comparisons of antiplatelets and anticoagulants in patients with cervical artery dissection. DATA EXTRACTION Data were extracted by one reviewer and checked by another. Bayesian techniques were used to appropriately account for studies with scarce event data and imbalances in the size of comparison groups. DATA SYNTHESIS Thirty-seven studies (1991 patients) were included. We found no randomised trial. The primary analysis revealed a large treatment effect in favour of antiplatelets for preventing the primary composite outcome of ischaemic stroke, intracranial haemorrhage or death within the first 3 months after treatment initiation (relative risk 0.32, 95% credibility interval 0.12 to 0.63), while the degree of between-study heterogeneity was moderate (τ(2) = 0.18). In an analysis restricted to studies of higher methodological quality, the possible advantage of antiplatelets over anticoagulants was less obvious than in the main analysis (relative risk 0.73, 95% credibility interval 0.17 to 2.30). CONCLUSION In view of these results and the safety advantages, easier usage and lower cost of antiplatelets, we conclude that antiplatelets should be given precedence over anticoagulants as a first line treatment in patients with cervical artery dissection unless results of an adequately powered randomised trial suggest the opposite.

Intracoronary injection of bone marrow-derived mononuclear cells early or late after acute myocardial infarction: effects on global left ventricular function

BACKGROUND Intracoronary administration of autologous bone marrow-derived mononuclear cells (BM-MNC) may improve remodeling of the left ventricle (LV) after acute myocardial infarction. The optimal time point of administration of BM-MNC is still uncertain and has rarely been addressed prospectively in randomized clinical trials. METHODS AND RESULTS In a multicenter study, we randomized 200 patients with large, successfully reperfused ST-segment elevation myocardial infarction in a 1:1:1 pattern into an open-labeled control and 2 BM-MNC treatment groups. In the BM-MNC groups, cells were administered either early (i.e., 5 to 7 days) or late (i.e., 3 to 4 weeks) after acute myocardial infarction. Cardiac magnetic resonance imaging was performed at baseline and after 4 months. The primary end point was the change from baseline to 4 months in global LV ejection fraction between the 2 treatment groups and the control group. The absolute change in LV ejection fraction from baseline to 4 months was -0.4±8.8% (mean±SD; P=0.74 versus baseline) in the control group, 1.8±8.4% (P=0.12 versus baseline) in the early group, and 0.8±7.6% (P=0.45 versus baseline) in the late group. The treatment effect of BM-MNC as estimated by ANCOVA was 1.25 (95% confidence interval, -1.83 to 4.32; P=0.42) for the early therapy group and 0.55 (95% confidence interval, -2.61 to 3.71; P=0.73) for the late therapy group. CONCLUSIONS Among patients with ST-segment elevation myocardial infarction and LV dysfunction after successful reperfusion, intracoronary infusion of BM-MNC at either 5 to 7 days or 3 to 4 weeks after acute myocardial infarction did not improve LV function at 4-month follow-up.

Classification and pharmacological treatment of preschool wheezing: changes since 2008.

Since the publication of the European Respiratory Society Task Force report in 2008, significant new evidence has become available on the classification and management of preschool wheezing disorders. In this report, an international consensus group reviews this new evidence and proposes some modifications to the recommendations made in 2008. Specifically, the consensus group acknowledges that wheeze patterns in young children vary over time and with treatment, rendering the distinction between episodic viral wheeze and multiple-trigger wheeze unclear in many patients. Inhaled corticosteroids remain first-line treatment for multiple-trigger wheeze, but may also be considered in patients with episodic viral wheeze with frequent or severe episodes, or when the clinician suspects that interval symptoms are being under reported. Any controller therapy should be viewed as a treatment trial, with scheduled close follow-up to monitor treatment effect. The group recommends discontinuing treatment if there is no benefit and taking favourable natural history into account when making decisions about long-term therapy. Oral corticosteroids are not indicated in mild-to-moderate acute wheeze episodes and should be reserved for severe exacerbations in hospitalised patients. Future research should focus on better clinical and genetic markers, as well as biomarkers, of disease severity.