Van Elteren Test Research Articles

REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic LMNA-Related Dilated Cardiomyopathy.

LMNA (lamin A/C)-related dilated cardiomyopathy is a rare genetic cause of heart failure. In a phase 2 trial and long-term extension, the selective p38α MAPK (mitogen-activated protein kinase) inhibitor, ARRY-371797 (PF-07265803), was associated with an improved 6-minute walk test at 12 weeks, which was preserved over 144 weeks. REALM-DCM (NCT03439514) was a phase 3, randomized, double-blind, placebo-controlled trial in patients with symptomatic LMNA-related dilated cardiomyopathy. Patients with confirmed LMNA variants, New York Heart Association class II/III symptoms, left ventricular ejection fraction ≤50%, implanted cardioverter-defibrillator, and reduced 6-minute walk test distance were randomized to ARRY-371797 400 mg twice daily or placebo. The primary outcome was a change from baseline at week 24 in the 6-minute walk test distance using stratified Hodges-Lehmann estimation and the van Elteren test. Secondary outcomes using similar methodology included change from baseline at week 24 in the Kansas City Cardiomyopathy Questionnaire-physical limitation and total symptom scores, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration. Time to a composite outcome of worsening heart failure or all-cause mortality and overall survival were evaluated using Kaplan-Meier and Cox proportional hazards analyses. REALM-DCM was terminated after a planned interim analysis suggested futility. Between April 2018 and October 2022, 77 patients (aged 23-72 years) received ARRY-371797 (n=40) or placebo (n=37). No significant differences (P>0.05) between groups were observed in the change from baseline at week 24 for all outcomes: 6-minute walk test distance (median difference, 4.9 m [95% CI, -24.2 to 34.1]; P=0.82); Kansas City Cardiomyopathy Questionnaire-physical limitation score (2.4 [95% CI, -6.4 to 11.2]; P=0.54); Kansas City Cardiomyopathy Questionnaire-total symptom score (5.3 [95% CI, -4.3 to 14.9]; P=0.48); and NT-proBNP concentration (-339.4 pg/mL [95% CI, -1131.6 to 452.7]; P=0.17). The composite outcome of worsening heart failure or all-cause mortality (hazard ratio, 0.43 [95% CI, 0.11-1.74]; P=0.23) and overall survival (hazard ratio, 1.19 [95% CI, 0.23-6.02]; P=0.84) were similar between groups. No new safety findings were observed. Findings from REALM-DCM demonstrated futility without safety concerns. An unmet treatment need remains among patients with LMNA-related dilated cardiomyopathy. URL: https://classic.clinicaltrials.gov; Unique Identifiers: NCT03439514, NCT02057341, and NCT02351856.

Intermittent intravenous paracetamol versus continuous morphine in infants undergoing cardiothoracic surgery: a multi-center randomized controlled trial

BackgroundTo determine whether intermittent intravenous (IV) paracetamol as primary analgesic would significantly reduce morphine consumption in children aged 0–3 years after cardiac surgery with cardiopulmonary bypass.MethodsMulti-center, randomized, double-blinded, controlled trial in four level-3 Pediatric Intensive Care Units (PICU) in the Netherlands and Belgium. Inclusion period; March 2016–July 2020. Children aged 0–3 years, undergoing cardiac surgery with cardiopulmonary bypass were eligible. Patients were randomized to continuous morphine or intermittent IV paracetamol as primary analgesic after a loading dose of 100 mcg/kg morphine was administered at the end of surgery. Rescue morphine was given if numeric rating scale (NRS) pain scores exceeded predetermined cutoff values. Primary outcome was median weight-adjusted cumulative morphine dose in mcg/kg in the first 48 h postoperative. For the comparison of the primary outcome between groups, the nonparametric Van Elteren test with stratification by center was used. For comparison of the proportion of patients with one or more NRS pain scores of 4 and higher between the two groups, a non-inferiority analysis was performed using a non-inferiority margin of 20%.ResultsIn total, 828 were screened and finally 208 patients were included; parents of 315 patients did not give consent and 305 were excluded for various reasons. Fourteen of the enrolled 208 children were withdrawn from the study before start of study medication leaving 194 patients for final analysis. One hundred and two patients received intermittent IV paracetamol, 106 received continuous morphine. The median weight-adjusted cumulative morphine consumption in the first 48 h postoperative in the IV paracetamol group was 5 times lower (79%) than that in the morphine group (median, 145.0 (IQR, 115.0–432.5) mcg/kg vs 692.6 (IQR, 532.7–856.1) mcg/kg; P < 0.001). The rescue morphine consumption was similar between the groups (p = 0.38). Non-inferiority of IV paracetamol administration in terms of NRS pain scores was proven; difference in proportion − 3.1% (95% CI − 16.6–10.3%).ConclusionsIn children aged 0–3 years undergoing cardiac surgery, use of intermittent IV paracetamol reduces the median weight-adjusted cumulative morphine consumption in the first 48 h after surgery by 79% with equal pain relief showing equipoise for IV paracetamol as primary analgesic.Trial Registration Clinicaltrials.gov, Identifier: NCT05853263; EudraCT Number: 2015-001835-20.

Lower vs Higher Oxygenation Target and Days Alive Without Life Support in COVID-19

Supplemental oxygen is ubiquitously used in patients with COVID-19 and severe hypoxemia, but a lower dose may be beneficial. To assess the effects of targeting a Pao2 of 60 mm Hg vs 90 mm Hg in patients with COVID-19 and severe hypoxemia in the intensive care unit (ICU). Multicenter randomized clinical trial including 726 adults with COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 11 ICUs in Europe from August 2020 to March 2023. The trial was prematurely stopped prior to outcome assessment due to slow enrollment. End of 90-day follow-up was June 1, 2023. Patients were randomized 1:1 to a Pao2 of 60 mm Hg (lower oxygenation group; n = 365) or 90 mm Hg (higher oxygenation group; n = 361) for up to 90 days in the ICU. The primary outcome was the number of days alive without life support (mechanical ventilation, circulatory support, or kidney replacement therapy) at 90 days. Secondary outcomes included mortality, proportion of patients with serious adverse events, and number of days alive and out of hospital, all at 90 days. Of 726 randomized patients, primary outcome data were available for 697 (351 in the lower oxygenation group and 346 in the higher oxygenation group). Median age was 66 years, and 495 patients (68%) were male. At 90 days, the median number of days alive without life support was 80.0 days (IQR, 9.0-89.0 days) in the lower oxygenation group and 72.0 days (IQR, 2.0-88.0 days) in the higher oxygenation group (P = .009 by van Elteren test; supplemental bootstrapped adjusted mean difference, 5.8 days [95% CI, 0.2-11.5 days]; P = .04). Mortality at 90 days was 30.2% in the lower oxygenation group and 34.7% in the higher oxygenation group (risk ratio, 0.86 [98.6% CI, 0.66-1.13]; P = .18). There were no statistically significant differences in proportion of patients with serious adverse events or in number of days alive and out of hospital. In adult ICU patients with COVID-19 and severe hypoxemia, targeting a Pao2 of 60 mm Hg resulted in more days alive without life support in 90 days than targeting a Pao2 of 90 mm Hg. ClinicalTrials.gov Identifier: NCT04425031.

#3676 EVALUATION OF HAEMOGLOBIN RESPONSE IN PATIENTS WITH CKD-RELATED ANAEMIA NOT ON DIALYSIS RECEIVING DAPRODUSTAT OR CONTROL IN ASCEND-ND

Abstract Background and Aims Daprodustat (Dapro) is a novel hypoxia-inducible factor prolyl hydroxylase inhibitor being investigated in anaemia of chronic kidney disease (CKD). ASCEND-ND1 achieved non-inferiority (NI) for Dapro vs darbepoetin alfa (Darbe) in both coprimary endpoints, mean change in haemoglobin (Hb) levels from baseline to the evaluation period (EP; Week [Wk] 28–Wk 52) and first occurrence of a composite major adverse cardiovascular event, in patients (pts) with anaemia of CKD not on dialysis. Here, we present key Hb efficacy data and evaluate differences in Hb response within ASCEND-ND subgroups. Method Pts with Stages 3–5 CKD (not on erythropoiesis stimulating agents [ESAs]: Hb 8–10g/dL; on ESAs: Hb 8–11g/dL) were randomised 1:1 to Dapro or Darbe. Statistical analysis methods for the coprimary endpoint have been published.1 Secondary endpoints evaluated during the EP included: 1) the percentage of Hb responders (pts with mean evaluable Hb within the analysis range [10–11.5g/dL]); 2) the percentage of time Hb was within the analysis range; 3) analysis of Hb change from baseline to Wk 52. Secondary endpoints were analysed as follows: 1) Cochran-Mantel-Haenszel test adjusted for ESA use and region; 2) Rosendaal method (evaluable Hb values) and Hodges-Lehmann and stratified Mann-Whitney estimates of treatment effect, analysed with a van Elteren's test stratified by ESA use and region; 3) mixed model repeated measures analysis (on-/off-treatment, observed Hb values from Wks 28–52) with factors for ESA use, region, baseline Hb (by time), treatment by time interactions. Secondary and subgroup analyses were not multiplicity adjusted. Results Of 3872 pts in ASCEND-ND (Dapro n = 1937; Darbe n = 1935), mean baseline Hb levels were similar for both treatment arms and mean change in the EP Hb level for Dapro and Darbe met the prespecified NI margin of ‒0.75 g/dL (difference = 0.08g/dL; 95% confidence interval [CI] = 0.03, 0.13).1 Subgroup analyses were consistent with coprimary analyses (Table), with little or no heterogeneity between most groups: 7/22 subgroups (ethnicity, high-level race, region, ESA use at randomisation, prior ESA dose group, history of stroke, and hospitalisation 6 months prior to screening) had interaction p values &amp;lt;0.1; however, all subgroups met the NI criterion with between-group differences that were not clinically meaningful. Proportions of pts within the Hb analysis range were higher for Dapro than Darbe in the EP overall and regardless of baseline ESA use and similar for region (Table). The median (interquartile range) percentage of time Hb was in the analysis range during the EP was 70.5% (45.3%–93.2%) for Dapro vs 63.2% (33.7%–88.9%) for Darbe. Dapro was associated with a nominally NI (margin of ‒15%) and significant increase in percentage time in analysis range during the EP (estimate of median difference [95% CI] = 4.57% [2.04%, 7.11%]; one-sided p&amp;lt;0.0001). The estimate (95% CI) for the probability that Dapro had a greater percentage of time Hb within the analysis range than Darbe was 0.55 (0.53, 0.57); the lower boundary of the 95% CI exceeded 0.50, representing equal probability between the two treatment arms. Results by region were similar for Dapro vs Darbe (treatment effect): Asia Pacific = 0.56; Eastern Europe/South Africa = 0.51; Western Europe/Canada/Australia/New Zealand/Israel, 0.58; Latin America, 0.58; USA, 0.55). In mixed-model repeated measures analysis, g/dL Hb change (standard error) at Wk 52 was 0.76 (0.029) with Dapro and 0.73 (0.029) with Darbe (difference [95% CI] = 0.03 [−0.05, 0.11]). Hb efficacy was similar regardless of ESA use (Figure). Conclusion Dapro was effective and NI to Darbe for maintaining Hb in non-dialysis pts with anaemia of CKD, and results of subgroup analyses were consistent with the coprimary analyses. Additionally, Dapro raised and maintained Hb within the analysis range regardless of baseline ESA use or region. These preliminary analyses indicated a nominal NI showcasing greater Hb time in range with Dapro vs Darbe; further analyses will be presented to fully characterise this interaction.

Pain treatment after total hip arthroplasty: Detailed statistical analysis plan for the RECIPE randomised clinical trial.

The RECIPE trial systematically investigates effects of different combinations of paracetamol, ibuprofen and dexamethasone for pain treatment after total hip arthroplasty. To preserve transparency, minimize risk of bias, and to prevent data-driven analysis, we present this detailed statistical analysis plan. The RECIPE trial is a randomized, blinded, parallel four-group multicenter clinical trial for patients undergoing planned primary total hip arthroplasty. Interventions are initiated preoperatively and continued for 24 hours postoperatively. Primary outcome is total opioid consumption 0-24 hours after end of surgery. Primary analysis will be performed in the modified intention to treat population of all patients undergoing total hip arthroplasty, and all analyses will be stratified for site. We will perform pairwise comparisons between each of the four groups. The primary outcome will be analysed using the van Elteren test and we will present Hodges-Lehmann median differences and confidence intervals. Binary outcomes will be analysed using logistic regression. To preserve a family-wise error rate of <0.05, we will use a Bonferroni-adjusted alfa of 0.05/6=0.0083 for all six pairwise comparisons between groups when analysing the primary outcome. We will systematically assess the underlying statistical assumptions for each analysis. Data will be analysed by two blinded independent statisticians, and we will write abstracts covering all possible combinations of conclusions, before breaking the blind. The RECIPE trial will provide important information on benefit and harm of combinations of the most frequently used non-opioid analgesics for pain after primary hip arthroplasty.

Evaluation of the benefit of rivaroxaban on VOYAGER PAD primary composite of limb, heart and brain outcomes using the global rank and win ratio methods

Abstract Background/Introduction The VOYAGER PAD trial demonstrated that rivaroxaban 2.5 mg twice daily added to background antiplatelet therapy reduced a composite of irreversible harm events of the heart limb and brain versus placebo in patients with symptomatic peripheral artery disease (PAD) after lower extremity revascularization. The primary analysis was performed as time to first event with equal weighting of components including fatal and non-fatal events. Purpose Traditional time to event analyses of composites generally assess outcomes with equal weights. Analyses evaluating outcomes using ranked or weighted methods may provide clinicians a mechanism to interpret results including different weighting and enable shared decision making with patients. Methods Exploratory analyses of the primary composite outcome were prespecified prior to trial completion/database lock. Two previously described approaches to evaluate composite outcomes by ranking or weighting were utilized. The first was the global rank method which includes ranking all components of the composite by order of clinical importance (Table 1) with a primary and alternative ranking prespecified. Each patient is assigned a rank with the worse rank for worse outcome and for patients with the same outcome, those occurring earlier assigned the worse rank. Van Elteren test for differences between groups was applied stratified by type of procedure and clopidogrel use consistent with the primary trial analysis. The second was the unmatched win ratio method according to Pocock's rule which ranked CV death higher than non-fatal events and then compared pairs of subjects, one from each treatment group for wins and losses for wins and losses as outlined in Table 1. Finkelstein and Schoenfeld statistics were utilized with confidence intervals provided from bootstrapping. Results A total of 6564 patients were randomized and all outcomes through the common study end date were counted. The global rank method using both the primary and alternative method yielded a statistically significant superior effect of rivaroxaban versus placebo (p-value for primary ranking 0.0158, p-value for alternative ranking 0.0155). When using the win-ratio approach, there were more wins for rivaroxaban (14.8%) than placebo (12.8%) with 72.4% of patients having no primary component events (Figure 1). The overall win ratio was 1.16 95% CI (1.03–1.30) in favor of rivaroxaban with p=0.0167. Conclusion(s) Rivaroxaban significantly reduces acute limb ischemia, amputation, MI, ischemic stroke or CV death in PAD after lower extremity revascularization. Exploratory analyses of this efficacy composite show consistent superiority either when considered as a ranked hierarchy of outcomes with CV death as the worst or whether considering a win-ratio approach ranking CV death as worse followed by non-fatal events. These data support the robustness of the primary trial results when considering ranking of the composite components. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Bayer

Stratified Test Accurately Identifies Differentially Expressed Genes Under Batch Effects in Single-Cell Data.

Analyzing single-cell sequencing data from large cohorts is challenging. Discrepancies across experiments and differences among participants often lead to omissions and false discoveries in differentially expressed genes. We find that the Van Elteren test, a stratified version of the widely used Wilcoxon rank-sum test, elegantly mitigates the problem. We also modified the common language effect size to supplement this test, further improving its utility. On both simulated and real patient data we show the ability of Van Elteren test to control for false positives and false negatives. A comprehensive assessment using receiver operating characteristic (ROC) curve shows that Van Elteren test achieves higher sensitivity and specificity on simulated datasets, compared with nine state-of-the-art differential expression analysis methods. The effect size also estimates the differences between cell types more accurately.

Mann–Whitney test for two‐phase stratified sampling

We consider the Mann–Whitney test for two‐phase stratified sampling. In this design, the independent and identically distributed (i.i.d.) sample is obtained at the first phase and then stratified based on auxiliary variables. At the second phase, stratified subsamples are obtained without replacement to collect variables of interest. The resultant data are biased and dependent sample due to stratification and sampling without replacement. This setting is different from the one considered by the existing method called the van Elteren test that treats multiple i.i.d. samples from nonoverlapping subsets of the infinite population. We propose the inverse probability weighted Mann–Whitney statistic and study its asymptotic properties. The proposed test is shown to have a correct size and power 1 in the limit. Simulation study is presented to illustrate the finite sample performance of our test.

Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia

BackgroundCoronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizumab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials.MethodsIn this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approximately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo.ResultsOf the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval [CI], 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, −1.0; 95% CI, −2.5 to 0; P=0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points; 95% CI, –7.6 to 8.2; nominal P=0.94).ConclusionsIn this randomized trial involving hospitalized patients with severe Covid-19 pneumonia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann–La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov number, NCT04320615.)

An aetiology-based subanalysis of the Telerehabilitation in Heart Failure Patients (TELEREH-HF) trial.

AimsThe aim of our study was to analyse the benefits of a 9 week hybrid comprehensive telerehabilitation (HCTR) programme in heart failure (HF) patients according to aetiology, as a subanalysis of the Telerehabilitation in Heart Failure Patients (TELEREH‐HF) trial.Methods and resultsOverall, 555 (65.3%) patients with ischaemic (IS) and 295 (34.7%) patients with non‐ischaemic (NIS) HF aetiology were randomized. There were no differences between the effect of HCTR and usual care (UC) on the primary outcome of number of days alive and out of the hospital in 26 months from the time of randomization in either aetiology (Wilcoxon–Mann–Whitney test), and no heterogeneity of effect between the aetiologies was noted (van Elteren test, P = 0.746). In Cox proportional hazards regression analysis, treatment was not independently associated with the secondary outcomes. For all‐cause mortality, the adjusted hazard ratio for HCTR vs. UC was 0.90 (95% confidence interval, 0.54–1.51) in IS and 1.42 (95% confidence interval, 0.69–2.94) in NIS (P interaction = 0.316). Differences between HCTR and UC in terms of change in the 6 min walk test distance and cardiopulmonary exercise test time after 9 weeks reached statistical significance in the IS arm (P = 0.015 and P < 0.001, respectively), but not in the NIS arm; however, tests of heterogeneity indicated no statistically significant differences.ConclusionsThe trial showed no difference between HCTR and UC in the primary outcome of percentage of days alive and out of the hospital for either IS or NIS aetiology. Moreover, the magnitude of changes in the clinical and functional statuses of the HF patients did not differ by aetiology. HCTR might have had beneficial effects on the 6 min walk test distance and cardiopulmonary exercise test time after 9 weeks in the IS patients; however, the effect was not statistically significantly different from that observed in the NIS patients.

Low-dose intracoronary alteplase during primary percutaneous coronary intervention in patients with acute myocardial infarction: the T-TIME three-arm RCT

Background Microvascular obstruction commonly affects patients with acute ST-segment elevation myocardial infarction and is independently associated with adverse outcomes. Objective To determine whether or not a strategy involving low-dose intracoronary fibrinolytic therapy infused early after coronary reperfusion will reduce microvascular obstruction. Design This was a multicentre, randomised, double-blind, parallel-group, placebo-controlled, dose-ranging trial. Setting The trial took place at 11 hospitals in the UK between 17 March 2016 and 21 December 2017. Participants Patients with acute ST-segment elevation myocardial infarction and a symptom onset to reperfusion time of ≤ 6 hours were eligible for randomisation. Radial artery access was a requirement, and further angiographic criteria included a proximal-to-middle coronary artery occlusion or impaired coronary flow in the presence of a definite thrombus in the culprit coronary artery. Exclusion criteria included a functional coronary collateral supply to the infarct-related artery, any contraindication to fibrinolysis and lack of informed consent. Additional exclusion criteria for safety were (1) requirement for immunosuppressive drug therapy for ≤ 3 months and (2) treatment with an antimicrobial agent. Intervention A total of 440 participants were randomly assigned 1 : 1 : 1 to treatment with placebo (n = 151), 10 mg of alteplase (n = 144) or 20 mg of alteplase (n = 145) administered by manual infusion directly into the infarct-related coronary artery over 5–10 minutes. The intervention was scheduled to happen after reperfusion and before stent implantation. Outcomes The primary outcome was the amount of microvascular obstruction (percentage of left ventricular mass) demonstrated by contrast-enhanced cardiac magnetic resonance imaging at 2–7 days after enrolment. The primary analysis was the comparison between the 20 mg of alteplase group and the placebo group; if this comparison was not significant, the comparison of the 10 mg of alteplase group with the placebo group was considered as a secondary analysis. Sample size A total of 618 patients (minimum of 558 patients). Recruitment was halted on 21 December 2017 given that conditional power for the primary outcome based on a prespecified analysis of the first 267 randomised participants was &lt; 30% in both treatment groups (futility criterion). Methods The primary outcome was compared between groups using a stratified Wilcoxon rank-sum test (van Elteren test), stratified by the location of the myocardial infarction. Results Among the 440 patients (mean age of 60.5 years; 15% women), the primary end point was measured in 396 (90%) patients, 17 (3.9%) withdrew, seven died and all other patients were followed up to 3 months. The amount (mean percentage of left ventricular mass) of microvascular obstruction was 2.3% versus 2.6% versus 3.5% in the placebo, 10 mg of alteplase and 20 mg of alteplase groups, respectively. In the primary analysis, microvascular obstruction did not differ between the 20 mg of alteplase group and the placebo group: 3.5% versus 2.3%, estimated difference 1.16% (95% confidence interval –0.08% to 2.41%; p = 0.32). In the secondary analysis, microvascular obstruction did not differ between the 10 mg of alteplase group and the placebo group: 2.6% versus 2.3%, estimated difference 0.29% (95% confidence interval –0.76% to 1.35%; p = 0.74). By 3 months, major adverse cardiac events (cardiac death, non-fatal myocardial infarction and unplanned hospitalisation for heart failure) had occurred in 15 (10.1%) patients in the placebo group, 18 (12.9%) in the 10 mg of alteplase group and 12 (8.2%) in the 20 mg of alteplase group. Conclusions Adjunctive low-dose intracoronary alteplase given during the primary percutaneous intervention did not reduce microvascular obstruction compared with placebo. Limitations Premature discontinuation of enrolment limited the power of the secondary and safety analyses. Future work Low-dose intracoronary alteplase or tenecteplase could be compared with placebo at the end of primary percutaneous coronary intervention in patients with an ischaemic time of &lt; 4 hours. Trial registration This trial is registered as ClinicalTrials.gov NCT02257294. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 5. See the NIHR Journals Library website for further project information.

Adjusted win ratio with stratification: Calculation methods and interpretation.

The win ratio is a general method of comparing locations of distributions of two independent, ordinal random variables, and it can be estimated without distributional assumptions. In this paper we provide a unified theory of win ratio estimation in the presence of stratification and adjustment by a numeric variable. Building step by step on the estimate of the crude win ratio we compare corresponding tests with well known non-parametric tests of group difference (Wilcoxon rank-sum test, Fligner-Policello test, van Elteren test, test based on the regression on ranks, and the rank analysis of covariance test). We show that the win ratio gives an interpretable treatment effect measure with corresponding test to detect treatment effect difference under minimal assumptions.

Identification of Genotype-Specific Therapeutic Vulnerabilities By Comparative Dynamic BH3 Profiling Analysis of Human and Murine CLL

Identification of Genotype-Specific Therapeutic Vulnerabilities By Comparative Dynamic BH3 Profiling Analysis of Human and Murine CLL

Do cystic fibrosis centres with the lowest FEV1 still use the least amount of intravenous antibiotics? A registry-based comparison of intravenous antibiotic use among adult CF centres in the UK

BackgroundThe Epidemiologic Study of Cystic Fibrosis using 1995–1996 and 2003–2005 data found that CF centres with lowest FEV1 tended to use fewer intravenous antibiotics. We repeated the analyses using 2013–2014 UK CF registry data to determine if this was still the case. MethodsAnalysing data for 2013 and 2014 separately, 28 adult CF centres were ranked according to median % age-adjusted FEV1. The top 7 centres were placed in the ‘upper quarter’ (best FEV1), the bottom 7 centres in ‘lower quarter’ (lowest FEV1), and the rest in ‘middle half’. IV use was stratified according to %FEV1, then compared between the three groups. ResultsCentres in the ‘upper quarter’ and ‘middle half’ used significantly more IV antibiotics compared to centres in the ‘lower quarter’ (van Elteren test P-value<0.001). Regression analyses showed that people with CF attending centres in the ‘upper quarter’ or ‘middle half’ are 30–50% more likely to receive at least one IV course per year compared to people attending centres in the ‘lower quarter’. ConclusionsCF centres with lowest FEV1 are still distinguished by lower use of intravenous antibiotics.

Measures of Heart Rate Variability in 24-h ECGs Depend on Age but Not Gender of Healthy Children.

Many methods computing heart rate variability (HRV) have been applied in studies in children. Not all of these methods have a comprehensive physiological interpretation, and not all of studies are in agreement with the Task Force Standards on HRV from 1996, and the New Joint Position Statement on the advances of HRV from 2015. The study aim was to analyse HRV in the 24-h ECGs of healthy children by the Poincare plots and Lomb-Scargle periodograms, and to follow proper HRV recommendations. Additionally, we investigated the associations between age, children's sex and measured HRV indices. One hundred healthy children, aged 3–18 underwent 24-h ECG Holter monitoring. HRV was analyzed by the Poincaré plots and spectral by Lomb-Scargle periodograms of RR intervals. The Mann-Whitney test was used to compare sex differences in HRV, the van Elteren's test was used to correct for the age-gender interaction, and non-parametric Spearman correlation was applied to analyse the association between age and HRV indices. None of the HRV measures differed significantly between boys and girls. None of the HRV indices was modified by the age-gender interaction. There were statistically significant associations of age with measures of ultra-low (rho = 0.42; p < 0.0001), very low (rho = 0.35; p = 00004) and low (rho = 0.30; p = 0.0028) frequency powers, the ratio of the low to high frequency power (rho = 0.38; p = 0.0001), indices of long-term (SD2; rho = 0.37; p = 0.0002) and total (SDNN; rho = 0.33; p = 0.0008) HRV, and the contribution of the long-term HRV to total HRV (CL; rho = 0.32; p = 0.0012). In general, HRV parameters derived from the analyses of Poincaré plots and Lomb-Scargle periodograms appear not to be affected by gender, however, most of them increase with age in the 24-h ECG recordings in healthy children.

The Pediatric International Knee Documentation Committee (Pedi-IKDC) Subjective Knee Evaluation Form: Normative Data

Background: Children are participating in sports at an increasingly younger age, which has contributed to an increased incidence of knee injuries among this population. Because of increased interest in the application of patient-reported outcome measures in orthopaedic surgery to evaluate treatment results, numerous knee outcome scores, including the International Knee Documentation Committee Subjective Form (IKDC), have been used to evaluate the knee. Although the IKDC has been validated only in adults, it is also being used for children because of a lack of appropriate outcome scores in the pediatric population. To address this concern, a pediatric version of the IKDC (Pedi-IKDC) was developed and evaluated for reliability, validity, and responsiveness. However, normative data for the Pedi-IKDC have not been established. Purpose: We aimed to aid the interpretation of Pedi-IKDC scores by characterizing normative data in children and adolescents and to validate the Pedi-IKDC by examining differences in scores among children who had a history of knee surgery or limited activity compared with those who did not. Study Design: Cross-sectional study; Level of evidence, 3. Methods: We conducted a cross-sectional survey of 2000 children and adolescents aged 10 to 18 years living in the United States, who were recruited by ORC International to obtain equal numbers of participants by sex and by integer age group. Participants were asked to complete the Pedi-IKDC for 1 study-designated “index” knee (right or left) and to provide demographic data and information on their knee surgery history and recent (4-week) activity limitations. Raw Pedi-IKDC total scores were rescaled to a 0 to 100 scale. We used nonparametric Wilcoxon or Kruskal-Wallis tests to compare subgroup scores, and we used the van Elteren test to adjust for age. Unadjusted and adjusted P values were similar, and only unadjusted values are reported. Results: The number of respondents (N = 2000) was uniform with respect to age and sex, with 11% in each age represented (10-18 years). Fifty percent of respondents were female. Forty-nine states plus Washington, DC, were represented. In addition, 68% and 86% of respondents identified themselves as white and non-Hispanic, respectively. Seven percent of respondents (n = 136) respondents reported having prior surgery in 1 or both knees; 4% of these surgeries (n = 79) were in the index knee. The Pedi-IKDC score distribution was skewed left (mean ± SD score, 86.7 ± 16.8; median, 94.6) and 34% of scores reached the ceiling value of 100. Participants who reported prior surgery or limited activity in the index knee had median Pedi-IKDC scores that were approximately 25 points lower than participants without these histories (P < .0001 for both comparisons). In contrast, although it was statistically significant, the variation by age (P = .02), race (P = .02), ethnicity (P = .01), and level of sports/exercise participation (P = .04) was much smaller (all ranges of median scores <4.5). There were no significant differences in scores in terms of respondent sex or geographic region. Conclusion: Normative Pedi-IKDC scores were determined in this study. The strong association between Pedi-IKDC scores and prior knee surgery as well as recent activity limitations in the index knee can be used to evaluate clinical outcomes and supports the construct validity of the Pedi-IKDC. There was a large ceiling effect, with 34% of scores at the maximum value of 100. The lack of a sex-based effect and the minor variation with age both simplify the interpretation and use of the Pedi-IKDC. Therefore, Pedi-IKDC score distributions can provide assumptions for use in sample size or power calculations for research.

Effects of a lifestyle modification programme to reduce the number of risk factors for metabolic syndrome: a randomised controlled trial.

To determine the effectiveness of a personal support lifestyle education programme (PSMetS) for reducing risk factors in individuals with metabolic syndrome (MetS). A two-arm randomised controlled trial. Companies in metropolitan Tokyo, Japan. Male workers with diagnosed MetS or a high risk for MetS according to the Counselling Guidance Program, Japan (n 193). The reduction in the number of risk factors for MetS (as defined according to the criteria published by the Japanese Ministry of Health, Labor and Welfare in April 2007 (MHLW-MetS)) in the PSMetS group was not significantly different from that in the usual care group by van Elteren's test (baseline-adjusted P=0·075) for intention-to-treat (ITT), while it was significant (baseline-adjusted P=0·038) for per-protocol set (PPS). The proportion of MHLW-MetS was significantly different between groups by van Elteren's test (baseline-adjusted P=0·031). Two components of MHLW-MetS showed significant reductions in the PSMetS group: waist circumference (baseline-adjusted P=0·001) and BMI (baseline-adjusted P=0·002). PPS and ITT analyses showed similar results. For male workers with MHLW-MetS or a high risk of MHLW-MetS, PSMetS reduced the number of risk factors for MHLW-MetS.

Health-Related Quality of Life Impairment in Patients with Chronic Myeloid Leukemia: Results of a German Cross-Sectional Study of Patients Registered in Prospective, Controlled Clinical Trials

▪Introduction: With many treatment options for chronic myeloid leukemia (CML), endpoints like health-related quality of life (HRQoL) move into focus and might be essential for deciding on treatment strategies. We sought to evaluate HRQoL in CML patients who had been registered in four consecutive studies of the German CML study group.Methods: The EORTC QLQ-C30 questionnaire was used to assess HRQoL of CML patients. Functional scales and global health status were calculated in accordance with Aaronson (1993) and Fayers (2001). With scales ranging from 0 to 100, 8 points are regarded as a minimally important difference (Efficace et al., 2013). Baseline data of responders (R) and non-responders (NR) were compared. Associations between two variables were assessed by the Fisher or Mann-Whitney tests, as appropriate. The global health status and the functioning scores were compared between groups with the van Elteren test, if the groups were stratified for another variable. Furthermore, results of the global health status and the functioning scores in our sample were standardized in accordance with the age (18-29, 30-39, 40-49, 50-59, 60-69, ≥70 years) and sex distribution of the 2448 participants of the German HRQoL outcome study reported by Hinz et al. 2014. The outcome of our sample was then compared with the outcome of these 2448 patients representing QoL of the German population in general. Comparison was performed using a t test.Results: A questionnaire was sent to 1634 patients. During January to April 2011, 858 questionnaires (53%) were sent back. Compared to NR, R were older (median age: 55 vs. 58, p=0.0426); years since diagnosis (median 6.5 vs. 7.4) and the percentage that had been transplanted were lower (24%vs.18%). No differences were observed regarding sex, Euro score, or time after allogeneic hematopoietic stem cell transplantation (HSCT). When answering the questionnaire, 517 (60%) patients received imatinib 400mg (IM400) and 102 (12%) were off therapy after HSCT. Less than 10% of patients received imatinib 800mg, imatinib+AraC or interferon alpha, nilotinib, or dasatinib. Time since diagnosis was ≤3 years in 156 (18%), >3 and ≤7 years in 309 (36%), and >7 years in 393 (46%) of the patients.Women (352, 41%) perceived a significant reduction in global health status (mean: 62.7, p<0.001), role (65.4, p=0.0016), emotional (60.3, p=0.0002), and physical functioning (74.9, p<0.0001) when compared to males (68.9, 71.5, 67.6, and 82.7, respectively). In the latter two cases, this perception met the definition of a clinical relevance. Results on significance did not change with adjustment for age.Compared to the German population, the 858 CML patients had significantly lower scores for global health status (mean: 67.9, p<0.0001), role (70.8, p<0.0001), social (69.2, p<0.0001), emotional (64.6, p<0.0001), physical (81.0, p<0.0001) and cognitive functioning (77.3, p<0.0001). Only for global health status, the difference was below 8.To evaluate HRQoL in patients with long standing disease, 100 patients with diagnosis >7 years off therapy after HSCT and 203 patients receiving IM400 were analyzed.Adjusted for age group and sex, CML patients receiving IM400 for more than 7 years had lower scores for global health status (mean: 63.8, p<0.0001 ), role (66.7, p<0.0001), social (68.8, p<0.0001), emotional (64.0, p<0.0001), physical (75.2, p<0.0001) and cognitive functioning (68.0, p<0.0001) than the German control population.With respect to all six HRQoL scores, significantly lower scores than from the German population were also observed for the CML patients being seven years without treatment after HSCT: global health status (mean: 69.2, p<0.0001 ), role (68.6, p<0.0001), social (67.5, p<0.0001), emotional (68.1, p<0.0001), physical (83.1, p<0.0001) and cognitive functioning (71.2, p=0.0053).Conclusions: In this cross-sectional study, women showed an impaired global health status, role, emotional, and physical functioning compared to males. Considering all 858 CML patients, the HRQoL was significantly impaired in all scales when compared to the German population. The same results were observed for the subgroups of patients either receiving IM400 for at least 7 years or being off therapy 7 years after HSCT.Reduced HRQoL remains an issue for all patients after long-term TKI treatment or after HSCT. These data may serve as a basis to evaluate HRQoL in stopping studies in CML. DisclosuresSaussele:BMS: Honoraria, Other: Travel grant, Research Funding; Novartis Pharma: Honoraria, Other: Travel grant, Research Funding; ARIAD: Honoraria; Pfizer: Honoraria, Other: Travel grant. Kremers:Novartis: Honoraria; Bristol Myers Squibb: Other: Travel costs, supporting educational meeting; Novartis: Other: supporting educational meeting. Hochhaus:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Müller:BMS: Honoraria, Other: Consulting or Advisory Role, Research Funding; Novartis: Honoraria, Other: CONSULTING OR ADVISORY ROLE, Research Funding; ARIAD Pharmaceuticals Inc.: Honoraria, Other: Consulting & Advisory Role, Research Funding. Hehlmann:Novartis Pharma: Research Funding; BMS: Consultancy. Pfirrmann:BMS: Consultancy, Honoraria; Novartis Pharma: Consultancy, Honoraria.

A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children

AbstractMagnesium, a vasodilator, anti-inflammatory, and pain reliever, could alter the pathophysiology of sickle cell pain crises. We hypothesized that intravenous magnesium would shorten length of stay, decrease opioid use, and improve health-related quality of life (HRQL) for pediatric patients hospitalized with sickle cell pain crises. The Magnesium for Children in Crisis (MAGiC) study was a randomized, double-blind, placebo-controlled trial of intravenous magnesium vs normal saline placebo conducted at 8 sites within the Pediatric Emergency Care Applied Research Network (PECARN). Children 4 to 21 years old with hemoglobin SS or Sβ0 thalassemia requiring hospitalization for pain were eligible. Children received 40 mg/kg of magnesium or placebo every 8 hours for up to 6 doses plus standard therapy. The primary outcome was length of stay in hours from the time of first study drug infusion, compared using a Van Elteren test. Secondary outcomes included opioid use and HRQL. Of 208 children enrolled, 204 received the study drug (101 magnesium, 103 placebo). Between-group demographics and prerandomization treatment were similar. The median interquartile range (IQR) length of stay was 56.0 (27.0-109.0) hours for magnesium vs 47.0 (24.0-99.0) hours for placebo (P = .24). Magnesium patients received 1.46 mg/kg morphine equivalents vs 1.28 mg/kg for placebo (P = .12). Changes in HRQL before discharge and 1 week after discharge were similar (P > .05 for all comparisons). The addition of intravenous magnesium did not shorten length of stay, reduce opioid use, or improve quality of life in children hospitalized for sickle cell pain crisis. This trial was registered at www.clinicaltrials.gov as #NCT01197417.

The Pediatric International Knee Documentation Committee (Pedi-IKDC) Subjective Knee Evaluation Form

Objectives:To aid in the interpretation of Pedi-IKDC scores by characterizing normative data in children and adolescents. Also, to validate the Pedi IKDC by examining differences in Pedi IKDC scores between patients with knee ailments compared to patients without a history of knee problems.Methods:Cross sectional survey of 2000 children and adolescents aged 10-18 years living in the United States, recruited by ORC International to obtain equal numbers by sex and by integer age group. In addition to completing the Pedi-IKDC for one study designated “index” knee (right or left), subjects were asked demographic questions and for information on history of knee surgery and recent (four weeks) activity limitations. Raw Pedi-IKDC total scores were re scaled to a 0-100 scale. Non-parametric Wilcoxon or Kruskal-Wallis tests were used to compare subgroup scores and the van Elteren test was used to adjust for age. Unadjusted and adjusted p values were similar and only unadjusted values are reported.Results:Numbers of respondents are uniform with respect to age and sex, with 11% in each age group (10-18) and 50% female. 68% identified themselves as white, and 86% as non-Hispanic. 49 states and DC are represented. 136 (7%) reported prior surgery in one or both knees; 79(4%) in the index knee. The Pedi IKDC score distribution is skewed left with mean score (±SD) of 86.7(±16.8), median 94.6 and 34% reaching the ceiling value of 100. Subjects reporting prior surgery or limited activity in the index knee had median Pedi IKDC scores about 25 points lower than those without these histories (p<0.0001 for both comparisons). In contrast, although statistically significant, the variation by age (p=0.02), race (p=0.02), ethnicity (p=0.01), and level of sports/exercise participation (p=0.04) was much smaller (all ranges of median scores <4.5). There were no significant differences by sex or geographic region.Conclusion:There is only minor variation in Pedi IKDC scores across demographic factors. The strong association between Pedi IKDC score and prior knee surgery and also with recent limitation of activity in the index knee supports the construct validity of the Pedi-IKDC. Using a large, broadly representative sample, this study supports the use of the Pedi-IKDC as a knee specific outcome instrument for pediatric patients aged 10-18 and provides normative values to aid the interpretation of scores in this age range.