Life expectancy difference and life expectancy ratio: two measures of treatment effects in randomised trials with non-proportional hazards

The hazard ratio (HR) is the most common measure of treatment effect in clinical trials that use time-to-event outcomes such as survival. When survival curves cross over or separate only after a considerable time, the proportional hazards assumption of the Cox model is violated, and HR can be misleading. We present two measures of treatment effects for situations where the HR changes over time: the life expectancy difference (LED) and life expectancy ratio (LER). LED is the difference between mean survival times in the intervention and control arms. LER is the ratio of these two times. LED and LER can be calculated for at least two time intervals during the trial, allowing for curves where the treatment effect changes over time. The two measures are readily interpretable as absolute and relative gains or losses in life expectancy

Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis

Objective To investigate whether discrepancies in trials of use of bone marrow stem cells in patients with heart disease account for the variation in reported effect size in improvement of left ventricular function. Design Identification and counting of factual discrepancies in trial reports, and sample size weighted regression against therapeutic effect size. Meta-analysis of trials that provided sufficient information. Data sources PubMed and Embase from inception to April 2013. Eligibility for selecting studies Randomised controlled trials evaluating the effect of autologous bone marrow stem cells for heart disease on mean left ventricular ejection fraction. Results There were over 600 discrepancies in 133 reports from 49 trials. There was a significant association between the number of discrepancies and the reported increment in EF with bone marrow stem cell therapy (Spearman’s r=0.4, P=0.005). Trials with no discrepancies were a small minority (five trials) and showed a mean EF effect size of −0.4%. The 24 trials with 1-10 discrepancies showed a mean effect size of 2.1%. The 12 with 11-20 discrepancies showed a mean effect of size 3.0%. The three with 21-30 discrepancies showed a mean effect size of 5.7%. The high discrepancy group, comprising five trials with over 30 discrepancies each, showed a mean effect size of 7.7%. Conclusions Avoiding discrepancies is difficult but is important because discrepancy count is related to effect size. The mechanism is unknown but should be explored in the design of future trials because in the five trials without discrepancies the effect of bone marrow stem cell therapy on ejection fraction is zero

A protocol for an economic evaluation of a polypill in patients with established or at high risk of cardiovascular disease in a UK NHS setting: RUPEE (NHS) study.

INTRODUCTION: The 'Use of a Multi-drug Pill in Reducing cardiovascular Events' (UMPIRE) trial was a randomised controlled clinical trial evaluating the impact of a polypill strategy on adherence to indicated medication in a population with established cardiovascular disease (CVD) of or at high risk thereof. The aim of Researching the UMPIRE Processes for Economic Evaluation in the National Health Service (RUPEE NHS) is to estimate the potential health economic impact of a polypill strategy for CVD prevention within the NHS using UMPIRE trial and other relevant data. This paper describes the design of a modelled economic evaluation of the impact of increased adherence to the polypill versus usual care among the UK UMPIRE participants. METHODS AND ANALYSIS: As recommended by the International Society for Pharmacoeconomics and Outcomes Research and the Society for Medical Decision Making modelling guidelines, a review of published CVD models was undertaken to identify the most appropriate modelling approach and structure. The review was carried out in the electronic databases, MEDLINE and EMBASE. 40 CVD models were identified from 57 studies, the majority of economic models were health state transition cohort models and individual-level simulation models. The findings were discussed with clinical experts to confirm the approach and structure. An individual simulation approach was identified as the most suitable method to capture the heterogeneity in the population at CVD risk. RUPEE-NHS will use UMPIRE trial data on adherence to estimate the long-term cost-effectiveness of the polypill strategy. DISSEMINATION: The evaluation findings will be presented in open-access scientific and healthcare policy journals and at national and international conferences. We will also present findings to NHS policy makers and pharmaceutical companies

Safety of the Deferral of Coronary Revascularization on the Basis of Instantaneous Wave-Free Ratio and Fractional Flow Reserve Measurements in Stable Coronary Artery Disease and Acute Coronary Syndromes.

OBJECTIVES: The aim of this study was to investigate the clinical outcomes of patients deferred from coronary revascularization on the basis of instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR) measurements in stable angina pectoris (SAP) and acute coronary syndromes (ACS). BACKGROUND: Assessment of coronary stenosis severity with pressure guidewires is recommended to determine the need for myocardial revascularization. METHODS: The safety of deferral of coronary revascularization in the pooled per-protocol population (n = 4,486) of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) and iFR-SWEDEHEART (Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome) randomized clinical trials was investigated. Patients were stratified according to revascularization decision making on the basis of iFR or FFR and to clinical presentation (SAP or ACS). The primary endpoint was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year. RESULTS: Coronary revascularization was deferred in 2,130 patients. Deferral was performed in 1,117 patients (50%) in the iFR group and 1,013 patients (45%) in the FFR group (p < 0.01). At 1 year, the MACE rate in the deferred population was similar between the iFR and FFR groups (4.12% vs. 4.05%; fully adjusted hazard ratio: 1.13; 95% confidence interval: 0.72 to 1.79; p = 0.60). A clinical presentation with ACS was associated with a higher MACE rate compared with SAP in deferred patients (5.91% vs. 3.64% in ACS and SAP, respectively; fully adjusted hazard ratio: 0.61 in favor of SAP; 95% confidence interval: 0.38 to 0.99; p = 0.04). CONCLUSIONS: Overall, deferral of revascularization is equally safe with both iFR and FFR, with a low MACE rate of about 4%. Lesions were more frequently deferred when iFR was used to assess physiological significance. In deferred patients presenting with ACS, the event rate was significantly increased compared with SAP at 1 year.info:eu-repo/semantics/publishedVersio

Experiments performed with bubbly flow in vertical pipes at different flow conditions covering the transition region: Simulation by coupling Eulerian, Lagrangian and 3D random walks models

[EN] Two phase flow experiments with different superficial velocities of gas and water were performed in a vertical upward isothermal cocurrent air-water flow column with conditions ranging from bubbly flow, with very low void fraction, to transition flow with some cap and slug bubbles and void fractions around 25%. The superficial velocities of the liquid and the gas phases were varied from 0.5 to 3 m/s and from 0 to 0.6 m/s, respectively. Also to check the effect of changing the surface tension on the previous experiments small amounts of 1-butanol were added to the water. These amounts range from 9 to 75 ppm and change the surface tension. This study is interesting because in real cases the surface tension of the water diminishes with temperature, and with this kind of experiments we can study indirectly the effect of changing the temperature on the void fraction distribution. The following axial and radial distributions were measured in all these experiments: void fraction, interfacial area concentration, interfacial velocity, Sauter mean diameter and turbulence intensity. The range of values of the gas superficial velocities in these experiments covered the range from bubbly flow to the transition to cap/slug flow. Also with transition flow conditions we distinguish two groups of bubbles in the experiments, the small spherical bubbles and the cap/slug bubbles. Special interest was devoted to the transition region from bubbly to cap/slug flow; the goal was to understand the physical phenomena that take place during this transition A set of numerical simulations of some of these experiments for bubbly flow conditions has been performed by coupling a Lagrangian code, that tracks the three dimensional motion of the individual bubbles in cylindrical coordinates inside the field of the carrier liquid, to an Eulerian model that computes the magnitudes of continuous phase and to a 3D random walk model that takes on account the fluctuation in the velocity field of the carrier fluid that are seen by the bubbles due to turbulence fluctuations. Also we have included in the model the deformation that suffers the bubble when it touches the wall and it is compressed by the forces that pushes it toward the wall, provoking that the bubble rebound like a ball.The authors of this paper are indebted to the National Plan of I+D by the support of the coordinated projects REMOD-ERN ENE2010-21368-C02-01/CON and ENE2010-21368-C02-02/CON to perform the experiments.Muñoz-Cobo, JL.; Chiva, S.; Ali Abdelaziz Essa, M.; Mendez, S. (2012). Experiments performed with bubbly flow in vertical pipes at different flow conditions covering the transition region: Simulation by coupling Eulerian, Lagrangian and 3D random walks models. Archives of Thermodynamics. 33(1):3-39. https://doi.org/10.2478/v10173-012-0001-4S33933

Effects of disease severity distribution on the performance of quantitative diagnostic methods and proposal of a novel ‘V-plot’ methodology to display accuracy values

BACKGROUND: Diagnostic accuracy is widely accepted by researchers and clinicians as an optimal expression of a test’s performance. The aim of this study was to evaluate the effects of disease severity distribution on values of diagnostic accuracy as well as propose a sample-independent methodology to calculate and display accuracy of diagnostic tests. METHODS AND FINDINGS: We evaluated the diagnostic relationship between two hypothetical methods to measure serum cholesterol (Chol_{rapid} and Chol_{gold} by generating samples with statistical software and (1) keeping the numerical relationship between methods unchanged and (2) changing the distribution of cholesterol values. Metrics of categorical agreement were calculated (accuracy, sensitivity and specificity). Finally, a novel methodology to display and calculate accuracy values was presented (the V-plot of accuracies). CONCLUSION: No single value of diagnostic accuracy can be used to describe the relationship between tests, as accuracy is a metric heavily affected by the underlying sample distribution. Our novel proposed methodology, the V-plot of accuracies, can be used as a sample-independent measure of a test performance against a reference gold standard

Post-COVID-19 assessment in a specialist clinical service: a 12-month, single-centre, prospective study in 1325 individuals

INTRODUCTION: Post-COVID-19 complications require simultaneous characterisation and management to plan policy and health system responses. We describe the 12-month experience of the first UK dedicated post-COVID-19 clinical service to include hospitalised and non-hospitalised patients. METHODS: In a single-centre, observational analysis, we report the demographics, symptoms, comorbidities, investigations, treatments, functional recovery, specialist referral and rehabilitation of 1325 individuals assessed at the University College London Hospitals post-COVID-19 service between April 2020 and April 2021, comparing by referral route: posthospitalised (PH), non-hospitalised (NH) and post emergency department (PED). Symptoms associated with poor recovery or inability to return to work full time were assessed using multivariable logistic regression. RESULTS: 1325 individuals were assessed (PH: 547, 41.3%; PED: 212, 16%; NH: 566, 42.7%). Compared with the PH and PED groups, the NH group were younger (median 44.6 (35.6-52.8) years vs 58.3 (47.0-67.7) years and 48.5 (39.4-55.7) years), more likely to be female (68.2%, 43.0% and 59.9%), less likely to be of ethnic minority (30.9%, 52.7% and 41.0%) or seen later after symptom onset (median (IQR): 194 (118-298) days, 69 (51-111) days and 76 (55-128) days; all p<0.0001). All groups had similar rates of onward specialist referral (NH 18.7%, PH 16.1% and PED 18.9%, p=0.452) and were more likely to require support for breathlessness (23.7%, 5.5% and 15.1%, p<0.001) and fatigue (17.8%, 4.8% and 8.0%, p<0.001). Hospitalised patients had higher rates of pulmonary emboli, persistent lung interstitial abnormalities and other organ impairment. 716 (54.0%) individuals reported <75% optimal health (median 70%, IQR 55%-85%). Less than half of employed individuals could return to work full time at first assessment. CONCLUSION: Post-COVID-19 symptoms were significant in PH and NH patients, with significant ongoing healthcare needs and utilisation. Trials of interventions and patient-centred pathways for diagnostic and treatment approaches are urgently required