Tests for 2 x 2 Tables in Clinical Trials

Five standard tests are compared: chi-squared, Fisher\u27s exact, Yates’ correction, Fisher’s exact mid-p, and Barnard’s. Yates’ is always inferior to Fisher’s exact. Fisher’s exact is so conservative that one should look for alternatives. For certain sample sizes, Fisher’s mid-p or Barnard’s test maintain the nominal alpha and have superior power

Network meta-analysis on the log-hazard scale, combining count and hazard ratio statistics accounting for multi-arm trials: a tutorial.

BACKGROUND: Data on survival endpoints are usually summarised using either hazard ratio, cumulative number of events, or median survival statistics. Network meta-analysis, an extension of traditional pairwise meta-analysis, is typically based on a single statistic. In this case, studies which do not report the chosen statistic are excluded from the analysis which may introduce bias. METHODS: In this paper we present a tutorial illustrating how network meta-analyses of survival endpoints can combine count and hazard ratio statistics in a single analysis on the hazard ratio scale. We also describe methods for accounting for the correlations in relative treatment effects (such as hazard ratios) that arise in trials with more than two arms. Combination of count and hazard ratio data in a single analysis is achieved by estimating the cumulative hazard for each trial arm reporting count data. Correlation in relative treatment effects in multi-arm trials is preserved by converting the relative treatment effect estimates (the hazard ratios) to arm-specific outcomes (hazards). RESULTS: A worked example of an analysis of mortality data in chronic obstructive pulmonary disease (COPD) is used to illustrate the methods. The data set and WinBUGS code for fixed and random effects models are provided. CONCLUSIONS: By incorporating all data presentations in a single analysis, we avoid the potential selection bias associated with conducting an analysis for a single statistic and the potential difficulties of interpretation, misleading results and loss of available treatment comparisons associated with conducting separate analyses for different summary statistics

The effect of smoking on the plasma concentration of tricyclic antidepressants:A systematic review

Smoking is highly prevalent in the psychiatric population, and hospital admittance usually results in partial or complete smoking cessation. Tobacco use is known to affect the metabolism of certain psychoactive drugs, but whether smoking influences the plasma concentration of tricyclic antidepressants (TCAs) remains unclear. This article investigates the possible effect of smoking on the plasma concentration of TCAs. A systematic review of the literature available on PubMed and EMBASE as of October 2020 was carried out using PRISMA guidelines. Studies reporting plasma concentrations of any TCA in both a smoking and a non-smoking group were included and compared. Ten eligible studies were identified and included. In the eight studies investigating the effect of smoking on amitriptyline and/or nortriptyline, five studies found no significant effect. Two studies investigating the effect of smoking on imipramine found a significant effect, and one study investigating the effect of smoking on doxepin found no significant effect. The majority of studies included in this review were influenced by small study populations and other methodical issues. The effect of smoking on the plasma concentration of TCAs is still not entirely clear. There is a possibility that smoking affects the distribution of TCA metabolites, but this is probably not of clinical importance.</p

The clinical effectiveness and cost-effectiveness of treatments for idiopathic pulmonary fibrosis: a systematic review and economic evaluation

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a life-limiting lung disease that generally affects people over 60 years old. The main symptoms are shortness of breath and cough, and as the disease progresses there is a considerable impact on day-to-day life. Few treatments are currently available. OBJECTIVES: To conduct a systematic review of clinical effectiveness and an analysis of cost-effectiveness of treatments for IPF based on an economic model informed by systematic reviews of cost-effectiveness and quality of life. DATA SOURCES: Eleven electronic bibliographic databases, including MEDLINE, EMBASE, Web of Science, and The Cochrane Library and the Centre for Reviews and Dissemination databases, were searched from database inception to July 2013. Reference lists of relevant publications were also checked and experts consulted. METHODS: Two reviewers independently screened references for the systematic reviews, extracted and checked data from the included studies and appraised their risk of bias. An advisory group was consulted about the choice of interventions until consensus was reached about eligibility. A narrative review with meta-analysis was undertaken, and a network meta-analysis (NMA) was performed. A decision-analytic Markov model was developed to estimate cost-effectiveness of pharmacological treatments for IPF. Parameter values were obtained from NMA and systematic reviews. Univariate and probabilistic sensitivity analyses were undertaken. The model perspective is NHS and Personal Social Services, and discount rate is 3.5% for costs and health benefits. RESULTS: Fourteen studies were included in the review of clinical effectiveness, of which one evaluated azathioprine, three N-acetylcysteine (NAC) (alone or in combination), four pirfenidone, one BIBF 1120, one sildenafil, one thalidomide, two pulmonary rehabilitation, and one a disease management programme. Study quality was generally good, with a low risk of bias. The current evidence suggests that some treatments appear to be clinically effective. The model base-case results show increased survival for five pharmacological treatments, compared with best supportive care, at increased cost. General recommendations cannot be made of their cost-effectiveness owing to limitations in the evidence base. LIMITATIONS: Few direct comparisons of treatments were identified. An indirect comparison through a NMA was performed; however, caution is recommended in the interpretation of these results. In relation to the economic model, there is an assumption that pharmacological treatments have a constant effect on the relative rate of per cent predicted forced vital capacity decline. CONCLUSIONS: Few interventions have any statistically significant effect on IPF and a lack of studies on palliative care approaches was identified. Research is required into the effects of symptom control interventions, in particular pulmonary rehabilitation and thalidomide. Other research priorities include a well-conducted randomised controlled trial on inhaled NAC therapy and an updated evidence synthesis once the results of ongoing studies are reported

Use of implantable cardioverter-defibrillators for primary prevention in older patients: A systematic literature review and meta-analysis

Background: Randomized clinical trials (RCTs) have demonstrated the efficacy of implantable cardioverter-defibrillators (ICDs) in reducing sudden cardiac death (SCD) in specific patient populations. However, patients &#8805; 65 years were under-represented in these trials and the overall benefit of ICDs may be diminished in older patients due to competing risks for death. We evaluate the published data on ICD efficacy at reducing all-cause mortality in patients &#8805; 65 years and in patients &#8805; 75 years. Methods: We searched MEDLINE to identify RCTs and observational studies of ICDs that provided age-based outcome data for primary prevention of SCD. The primary endpoint was mortality evaluated by a meta-analysis of the RCTs using a random-effects model. Secondary endpoints included operative mortality, long-term complications and quality of life. Results: The enrollment of patients &#8805; 65 years in RCTs was limited (range: 33% in DEFINITE to 56% in MUSTT). Combining data from four RCTs (n = 3,562) revealed that primary prevention ICD therapy is efficacious in reducing all-cause mortality in patients &#8805; 65 years (HR 0.66; 95% CI 0.50&#8211;0.87; test of heterogeneity: X2 = 5.26; p = 0.15). For patients &#8805; 75 years, combining data from four RCTs (n = 579) revealed that primary prevention ICD therapy remains efficacious in reducing all-cause mortality (HR 0.73; 95% CI 0.51&#8211;0.974; p = 0.03). There appears to be no difference in ICD-related, operative, in-hospital, or long- -term complications among older patients compared to younger patients, although it remains unclear if older patients have a better quality of life with an ICD than younger patients. Conclusions: Although the overall evidence regarding ICD efficacy in patients &#8805; 65 years is limited and divergent, and the evidence available for patients &#8805; 75 years is even more sparse, our meta-analysis suggests that primary prevention ICDs may be beneficial in older patients. Our findings need to be validated by future studies, particularly ones examining ICD complications and quality of life. (Cardiol J 2011; 18, 5: 503&#8211;514