Baseline-adjusted Mean Difference Research Articles

Clinical Impact of Routine Assessment of Patient-Reported Health Status in Heart Failure Clinic: The PRO-HF Trial.

The impact of routine clinic use of patient-reported outcome (PRO) measures on clinical outcomes in patients with heart failure (HF) has not been well-characterized. We tested if clinic-based use of a disease-specific PRO improves patient-reported quality of life at 1 year. The PRO-HF trial (Patient-Reported Outcome Measurement in Heart Failure Clinic) was an open-label, parallel, patient-level randomized clinical trial of routine PRO assessment or usual care at an academic HF clinic between August 30, 2021, and June 30, 2022, with 1 year of follow-up. In the PRO assessment arm, participants completed the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) at each HF clinic visit, and results were shared with their treating clinician. The usual care arm completed the KCCQ-12 at randomization and 1 year later, which was not shared with the treating clinician. The primary outcome was the KCCQ-12 overall summary score (OSS) between 12 and 15 months after randomization. Secondary outcomes included domains of the KCCQ-12, hospitalization and emergency department visit rates, HF medication therapy, clinic visit frequency, and testing rates. Across 17 clinicians, 1248 participants were enrolled and randomized to PRO assessment (n=624) or usual care (n=624). The median age was 63.9 years (interquartile range [IQR], 51.8-72.8), 38.9% were women, and the median baseline KCCQ-12 OSS was 82.3 (IQR, 58.3-94.8). Final KCCQ-12 (available in 87.9% of the PRO arm and 85.1% in usual care; P=0.16) median OSS were 87.5 (IQR, 68.8-96.9) in the PRO arm and 87.6 (IQR, 69.7-96.9) in the usual care arm with a baseline-adjusted mean difference of 0.2 ([95% CI, -1.7 to 2.0]; P=0.85). The results were consistent across prespecified subgroups. A post hoc analysis demonstrated a significant interaction with greater benefit among participants with a baseline KCCQ-12 OSS of 60 to 80 but not in less or more symptomatic participants. No significant differences were found in 1-year mortality, hospitalizations, emergency department visits, medication therapy, clinic follow-up, or testing rates between arms. Routine PRO assessment in HF clinic visits did not impact patient-reported quality of life or other clinical outcomes. Alternate strategies and settings for embedding PROs into routine clinical care should be tested. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04164004.

Effects of a theory-based advance care planning intervention for nursing homes: A cluster randomized controlled trial

Background: Uptake of advance care planning in routine nursing home care is low. Through extensive literature review, theoretical development, and stakeholder involvement, we developed the ACP+ intervention. Aims: To evaluate the effects of ACP+ on the knowledge and self-efficacy (confidence in own skills) of nursing home care staff concerning advance care planning. Design: Cluster randomized controlled trial, conducted between February 2018 and January 2019 (NCT03521206, clinicaltrials.gov). ACP+ is a multicomponent intervention aimed at training and supporting nursing home staff and management in implementing advance care planning in nursing home practice through a train-the-trainer approach over 8 months. Fourteen nursing homes were randomized using a matched-pairing strategy, seven received ACP+, seven followed usual practice. Analyses (intention-to-treat) involved linear mixed models. Setting/participants: Nursing homes in Flanders (Belgium). Results: 694 of 1017 care staff (68% response rate) at baseline and 491 of 989 care staff (50%) post-intervention (8 months) returned questionnaires. Post-intervention, care staff’s self-efficacy concerning advance care planning was significantly higher in the intervention than in the control group (baseline-adjusted mean difference 0.57; 95% CI 0.20–0.94; p = 0.003; Cohen’s d = 0.30). Advance care planning knowledge (95% CI 0.95–1.15; p = 0.339; ratio: 1.04) did not differ significantly between groups. Conclusions: The ACP+ intervention for nursing homes improved care staff’s self-efficacy but not their knowledge concerning advance care planning. Considering the comprehensive and multi-component approach used, these effects were smaller than expected. Reasons for this may be related to the chosen follow-up period, outcomes and measurements, or to the intervention itself and its implementation.

The interleukin 1 receptor antagonist anakinra to reduce disease severity of palmoplantar pustulosis in adults: APRICOT RCT and PLUM mechanistic study

Background Palmoplantar pustulosis is a rare, debilitating, chronic skin disease involving the hands and feet, and there are limited treatment options. Mechanistic findings suggest that interleukin 1 may be a pathogenic driver. Objective To determine whether or not anakinra [Sobi (Swedish Orphan Biovitrum AB), Stockholm, Sweden], an interleukin 1 receptor antagonist, delivers therapeutic benefit in palmoplantar pustulosis. Design A Phase IV, randomised, double-blind, placebo-controlled study with two stages and an adaptive element (24 participants in stage 1, 64 participants in total) with an open-label extension. Setting Sixteen hospitals across England, Scotland and Wales. Participants Adults (aged ≥ 18 years) with a diagnosis of palmoplantar pustulosis and a disease duration of > 6 months and of sufficient impact and severity to require systemic therapy. Interventions Participants were randomised (1 : 1) to daily self-administered subcutaneous injection of either anakinra or a placebo for 8 weeks. Main outcome measures The primary outcome was the Palmoplantar Pustulosis Area and Severity Index score measured at 0, 1, 4, 8 and 12 weeks, with the primary end point at 8 weeks adjusted for baseline. Secondary outcomes included other investigator-assessed efficacy measures of disease severity, safety measures and participant-reported measures of efficacy and impact. Results A total of 64 participants (mean baseline Palmoplantar Pustulosis Area and Severity Index score of 17.8, standard deviation 10.5) received anakinra (n = 31) or the placebo (n = 33). In the primary intention-to-treat analysis, which estimated the effect of the treatment policy, the mean treatment group difference at 8 weeks after adjustment for baseline Palmoplantar Pustulosis Area and Severity Index score was –1.65 (95% confidence interval –4.77 to 1.47; p = 0.300), in favour of anakinra relative to placebo, but was not statistically significant. Similarly, secondary investigator-assessed outcomes did not show statistical superiority of anakinra: the baseline-adjusted mean difference in fresh pustule count (palms and soles) between the anakinra group and the placebo group was 2.94 (95% confidence interval –26.44 to 32.33), in favour of placebo, and the mean difference in total pustule count was –30.08 (95% confidence interval –83.20 to 23.05), in favour of anakinra. Participant-assessed outcomes were consistent with these objective findings: the baseline-adjusted mean difference in Dermatology Life Quality Index between the anakinra group and the placebo group was 0.52 (95% confidence interval –2.04 to 3.07), in favour of placebo, and the mean difference in Palmoplantar Quality-of-Life Index was 1.27 (95% confidence interval –3.04 to 5.57), in favour of placebo. However, the proportion of participants who strongly agreed that treatment was worthwhile was greater in the anakinra group (12/29, 41%) than in the placebo group (4/28, 14%), a difference in proportion of 27% (95% confidence interval 5% to 49%). In the complier-average causal effect analysis, the baseline-adjusted mean treatment group difference in the week 8 Palmoplantar Pustulosis Area and Severity Index score in individuals who received ≥ 50% of injections was –2.30 (95% confidence interval –6.54 to 1.93; p = 0.287) and in those who received ≥ 90% of injections was –3.80 (95% confidence interval –10.76 to 3.16; p = 0.285), in favour of anakinra. No serious infections, significant neutropenia or other serious adverse events occurred. Injection site reactions were more frequent for those receiving anakinra (19/31, 61%) than for those receiving placebo (1/33, 3%). Conclusions There was no evidence that anakinra was superior to placebo. For the treatment of palmoplantar pustulosis, interleukin 1 blockade is not a useful intervention. Limitations The sample size was calculated to detect a large effect size. Treatment adherence was lower than expected. It cannot be ruled out that there was some selection bias towards less severe or unstable participants entering the trial given that the trial was placebo controlled with a required washout period. Future work Palmoplantar pustulosis remains an area of high unmet need and further research is recommended to (1) identify new drug targets, (2) determine the contributory role of drug exposure (including pharmacokinetics and adherence) and (3) validate outcome measures in palmoplantar pustulosis. Trial registration This trial is registered as ISCRTN13127147 and EudraCT 2015-003600-23. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 2. See the NIHR Journals Library for further project information.

Naloxone Co-Dispensing with Opioids: a Cluster Randomized Pragmatic Trial.

Although naloxone prevents opioid overdose deaths, few patients prescribed opioids receive naloxone, limiting its effectiveness in real-world settings. Barriers to naloxone prescribing include concerns that naloxone could increase risk behavior and limited time to provide necessary patient education. To determine whether pharmacy-based naloxone co-dispensing affected opioid risk behavior. Secondary objectives were to assess if co-dispensing increased naloxone acquisition, increased patient knowledge about naloxone administration, and affected opioid dose and other substance use. Cluster randomized pragmatic trial of naloxone co-dispensing. Safety-net health system in Denver, Colorado, between 2017 and 2020. Seven pharmacies were randomized. Pharmacy patients (N=768) receiving opioids were followed using automated data for 10 months. Pharmacy patients were also invited to complete surveys at baseline, 4 months, and 8 months; 325 survey participants were enrolled from November 15, 2017, to January 8, 2019. Intervention pharmacies implemented workflows to co-dispense naloxone while usual care pharmacies provided usual services. Survey instruments assessed opioid risk behavior; hazardous drinking; tobacco, cannabis, and other drug use; and knowledge. Naloxone dispensings and opioid dose were evaluated using pharmacy data among pharmacy patients and survey participants. Intention-to-treat analyses were conducted using generalized linear mixed models accounting for clustering at the pharmacy level. Opioid risk behavior did not differ by trial group (P=0.52; 8-month vs. baseline adjusted risk ratio [ARR] 1.07; 95% CI 0.78, 1.47). Compared with usual care pharmacies, naloxone dispensings were higher in intervention pharmacies (ARR 3.38; 95% CI 2.21, 5.15) and participant knowledge increased (P=0.02; 8-month vs. baseline adjusted mean difference 1.05; 95% CI 0.06, 2.04). There was no difference in other substance use by the trial group. Co-dispensing naloxone with opioids effectively increased naloxone receipt and knowledge but did not increase self-reported risk behavior. Registered at ClinicalTrials.gov ; Identifier: NCT03337100.

Anakinra for palmoplantar pustulosis: results from a randomized, double-blind, multicentre, two-staged, adaptive placebo-controlled trial (APRICOT).

SummaryBackgroundPalmoplantar pustulosis (PPP) is a rare, debilitating, chronic inflammatory skin disease that affects the hands and feet. Clinical, immunological and genetic findings suggest a pathogenic role for interleukin (IL)‐1.ObjectivesTo determine whether anakinra (an IL‐1 receptor antagonist) delivers therapeutic benefit in PPP.MethodsThis was a randomized (1 : 1), double‐blind, two‐staged, adaptive, UK multicentre, placebo‐controlled trial [ISCRTN13127147 (registered 1 August 2016); EudraCT number: 2015‐003600‐23 (registered 1 April 2016)]. Participants had a diagnosis of PPP (> 6 months) requiring systemic therapy. Treatment was 8 weeks of anakinra or placebo via daily, self‐administered subcutaneous injections. Primary outcome was the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks.ResultsA total of 374 patients were screened; 64 were enrolled (31 in the anakinra arm and 33 in the placebo arm) with a mean (SD) baseline PPPASI of 17·8 (10·5) and a PPP investigator’s global assessment of severe (50%) or moderate (50%). The baseline adjusted mean difference in PPPASI favoured anakinra but did not demonstrate superiority in the intention‐to‐treat analysis [–1·65, 95% confidence interval (CI) –4·77 to 1·47; P = 0·30]. Similarly, secondary objective measures, including fresh pustule count (2·94, 95% CI –26·44 to 32·33; favouring anakinra), total pustule count (–30·08, 95% CI –83·20 to 23·05; favouring placebo) and patient‐reported outcomes, did not show superiority of anakinra. When modelling the impact of adherence, the PPPASI complier average causal effect for an individual who received ≥ 90% of the total treatment (48% in the anakinra group) was –3·80 (95% CI –10·76 to 3·16; P = 0·285). No serious adverse events occurred.ConclusionsNo evidence for the superiority of anakinra was found. IL‐1 blockade is not a useful intervention for the treatment of PPP.

Vericiguat: a QTc interval study in patients with coronary artery disease

Abstract Background Vericiguat is a soluble guanylate cyclase stimulator developed for the treatment of symptomatic chronic heart failure (HF) in adult patients with ejection fraction less than 45% who had a previous decompensation event. Guidelines on QT studies recommend evaluation of investigational drugs at supratherapeutic exposures in healthy volunteers. We anticipated that supratherapeutic doses of vericiguat would decrease blood pressure. We conducted an adjusted QT study using the therapeutic range of vericiguat in patients with coronary artery disease (CAD), who were expected to be more haemodynamically stable with fewer confounders (e.g., on the electrocardiogram) than a HF population. Purpose To assess the effect of vericiguat 10 mg once-daily on placebo-adjusted change from baseline of the Fridericia-corrected QT interval (QTcF) in patients with stable CAD. Methods This was a randomised, Phase Ib, placebo-controlled, double blind, double-dummy, multicentre study (NCT03504982). Test drug was vericiguat once-daily (up-titrated from 2.5 mg to 5 mg and then to 10 mg [treatments A, B, C] at 14-day intervals). The positive control was moxifloxacin 400 mg (single dose on Day 8 or Day 50 with placebo on other days [treatment D]; Figure). Patients were randomised to one of two sequences. We evaluated QTcF interval prolongation potential of vericiguat at increasing doses up to 10 mg, steady state. We investigated the pharmacokinetics, safety and tolerability of vericiguat. A clinically meaningful effect was defined as a QTcF change from baseline >10 ms relative to placebo. Assay sensitivity for moxifloxacin was confirmed by the lower limit of the 90% confidence interval (CI) of the time-matched, baseline-adjusted mean difference to placebo exceeding 5 ms at >1 time point. Results A total of 74 patients (66 males and 8 females) with CAD, mean (standard deviation) age 63.4 (8.0) years, were included. Mean difference between vericiguat and placebo in QTcF change from baseline (≤7 h post-dose) was <6 ms; no upper limit of the 90% CIs crossed the threshold of 10 ms. Lower limits of the two-sided 90% CI of the differences between moxifloxacin and placebo in QTcF change from baseline were >5 ms at 3 of 4 time points (Table). Peak plasma concentration (Cmax) of vericiguat following administration of vericiguat 10 mg was 322 μg/l and median time of maximum concentration (Tmax) was 4.5 h post-dose, in line with concentrations observed following administration of vericiguat 10 mg to patients with HF [1]. For moxifloxacin 400 mg, Cmax was 1960 μg/l and median Tmax was 3 h post-dose, in line with previously reported values [2]. Vericiguat up to 10 mg was generally safe and well tolerated. Conclusion This study supports the assessment that administration of vericiguat 10 mg is not associated with clinically meaningful QTc prolongation. These data contribute to the overall safety profile of vericiguat for the treatment of patients with HF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Funding was provided by Bayer AG, Berlin, Germany, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA QTc study design

Dietary alteration of n-3 and n-6 fatty acids for headache reduction in adults with migraine: randomized controlled trial

ObjectiveTo determine whether dietary interventions that increase n-3 fatty acids with and without reduction in n-6 linoleic acid can alter circulating lipid mediators implicated in headache pathogenesis, and decrease headache...

Effects of Chewing Gum on Nitric Oxide Metabolism, Markers of Cardiovascular Health and Neurocognitive Performance after a Nitrate-Rich Meal

Objectives Cardiovascular and neurocognitive responses to chewing gum have been reported, but the mechanisms are not well understood. Chewing gum after a nitrate-rich meal may upregulate the reduction of oral nitrate to nitrite and increase nitric oxide (NO), a molecule important to cardiovascular and neurocognitive health. We aimed to explore effects of chewing gum after a nitrate-rich meal on nitrate metabolism (through the enterosalivary nitrate-nitrite-NO pathway), endothelial function, blood pressure (BP), neurocognitive performance, mood and anxiety. Methods Twenty healthy men (n = 6) and women (n = 14) with a mean age of 48 years (range: 23–69) were recruited to a randomized controlled cross-over trial. After consumption of a nitrate-rich meal (180 mg of nitrate), we assessed the acute effects of chewing gum, compared to no gum chewing, on (i) salivary nitrate, nitrite and the nitrate reductase ratio (100 x [nitrite]/([nitrate] + [nitrite]); (ii) plasma nitrite, S-nitrosothiols and other nitroso species (RXNO); (iii) endothelial function (measured by flow mediated dilatation); (iv) BP; (v) neurocognitive performance; (vi) mood; and (vii) anxiety. Results Consumption of the nitrate-rich meal resulted in a significant increase in markers of nitrate metabolism. A significantly higher peak flow mediated dilatation was observed with chewing compared to no chewing (baseline adjusted mean difference: 1.10%, 95% CI: 0.06, 2.14; p = 0.038) after the nitrate-rich meal. A significant small increase in systolic BP, diastolic BP and heart rate were observed with chewing compared to no chewing after the nitrate-rich meal. The study did not observe increased oral reduction of nitrate to nitrite and NO, or improvements in neurocognitive performance, mood or anxiety with chewing compared to no chewing. Conclusion Chewing gum after a nitrate-rich meal resulted in an acute improvement in endothelial function and a small increase in BP but did not result in acute effects on neurocognitive function, mood or anxiety.

Effects and feasibility of hyperthermic baths in comparison to exercise as add-on treatment to usual care in depression: a randomised, controlled pilot study

BackgroundLimitations of current therapy of depression highlight the need for an immediately available, easily implementable add-on treatment option with high acceptance from patients. Hyperthermic baths (HTB) are a form of balneotherapy with head-out-of-water-immersion in a hot pool or tub at 40 °C for 15–20 min. A prior study suggests that HTB added to usual depression care can have antidepressant effects.MethodSingle-site, open-label randomised controlled 8-week parallel-group pilot study at a university outpatient clinic. 45 medically stable outpatients with moderate depression as determined by the 17-item Hamilton Depression Rating Scale (HAM-D) score ≥ 18 and a score ≥ 2 on item 1 (Depressed Mood) were recruited. They were randomised to twice weekly HTB (n = 22) or a physical exercise program (PEP) of moderate intensity (n = 23). Primary outcome measure was the change in HAM-D total score from baseline (T0) to the 2-week time point (T1). Linear regression analyses, adjusted for baseline values, were performed to estimate intervention effects on an intention-to-treat (ITT) and per-protocol (PP) principle.ResultsForty-five patients (HTB n = 22; PEP n = 23) were analyzed according to ITT (mean age = 48.4 years, SD = 11.3, mean HAM-D score = 21.7, SD = 3.2). Baseline-adjusted mean difference after 2 weeks was 4.3 points in the HAM-D score in favor of HTB (p < 0.001). Compliance with the intervention and follow-up was far better in the HTB group (2 vs 13 dropouts). Per protocol analysis only showed superiority of HTB as a trend (p = 0.068). There were no treatment-related serious adverse events. Main limitation: the number of dropouts in the PEP group (13 of 23) was higher than in other trials investigating exercise in depression. Due to the high number of dropouts the effect in the ITT-analysis may be overestimated.ConclusionsHTB added to usual care may be a fast-acting, safe and easy accessible method leading to clinically relevant improvement in depression severity after 2 weeks; it is also suitable for persons who have problems performing exercise training.Trial registrationGerman Clinical Trials Register (DRKS) with the registration number DRKS00011013 (registration date 2016-09-19) before onset of the study.

Effects of a Risk-Stratified Treatment in Patients with Chronic Back Pain in Rehabilitation: Results of a Controlled Clinical Trial

Abstract Background and Aim The management of chronic low back pain is a persisting challenge for multidisciplinary biopsychosocial rehabilitation (MBR). A promising approach to improve the effectiveness is better individual tailoring of the therapeutic minutes to the impairment. We designed a questionnaire-based algorithm to identify individual risk profiles, which allows physicians and patients to decide upon the kind and amount of suitable and adequate therapeutic components of MBR. Our aim was to test whether the algorithm leads to a shift in the therapeutic components depending on the impairment, which should significantly increase the functional capacity of the rehabilitants 6 months after the end of rehabilitation. Methods Between January and November 2016, a controlled clinical trial with a sequential arrangement of study groups and 3 measurement time points (start of rehabilitation, end of rehabilitation and 6-month follow-up) was conducted. The control group (CG) passed through the standard inpatient MBR. In the intervention group (IG)the MBR components were matched to the individual risk-profiles determined via a new algorithm. The shift of therapeutic minutes is displayed via boxplots. The primary outcome was statistically tested by applying an analysis of covariance. All secondary outcomes are presented descriptively. Results Of 169 patients in total, 85 were assigned to the CG and 84 to the IG. Complete data concerning the primary outcome were available for 76 (89.4%) patients in the CG and 75 (89.3%) patients in the IG. Compared to the CG, the boxplots for the IG show a better fit of therapeutic minutes according to the impairments. For example, in the IG, the mean value of psychological therapies was about 120 min if they were impaired and 44.3 min if not. In contrast, impaired tested patients of the CG shown mean values of those therapies of about 96.6 min and 50.6 min if not. The baseline adjusted mean difference in functional capacity was significantly (p=0.047) improved by 4.4 points (95% CI: 0.063–8.465) in favor of the IG. . Main limitation is lack of randomization. In order to avoid inadequate therapy recommendations, the physician had the decision-making authority over the therapies. Conclusion The application of the developed algorithm for individual adaptation of the MBR increases the effectiveness of rehabilitation in terms of functional capacity.

Estudio farmacodinámico del policomprimido cardiovascular: ¿existe algún tipo de interacción entre los monocomponentes?

Introduction and objectivesTo compare the pharmacodynamics of the CNIC polypill (atorvastatin 40mg/ramipril 10mg/aspirin 100mg) in terms of low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP), with the corresponding reference products (atorvastatin and ramipril). MethodsThis was a multicenter, randomized, open-label, and parallel 3-arm study comparing the effect of the CNIC polypill vs ramipril 10mg and atorvastatin 40mg on SBP and LDL-C. The coprimary endpoints were differences in the adjusted mean 24-hour SBP (using ambulatory BP measurement) and LDL-C during the study period estimated using an ANCOVA model. ResultsOf the 241 patients included in the per protocol population, 84 received the CNIC polypill (group A), 84 atorvastatin (group B), and 73 ramipril (group C). SBP decreased from 139.3±12.5 to 133.2±12.9mmHg in group A and from 138.1±11.9 to 134.0±12.8mmHg in group C (baseline adjusted mean difference for the decrease in SBP was 1.77mmHg (90%CI, −0.5 to 4.0) in favor of group A, without reaching statistical significance. LDL-C was reduced by 33.9±21.6 and 29.2±25.8mg/dL in groups A and B, respectively (baseline adjusted mean difference for the decrease in LDL-C was 7.0% (90%CI, 1.5–12.4), a significantly greater decrease with the polypill). The 3 treatments were well tolerated. ConclusionsThe results of this study rule out a negative effect on blood pressure of the interaction between the components of the CNIC polypill. The reduction in LDL-C was greater in the CNIC polypill group, suggesting a synergistic effect of the components.

Yoga-Based Cardiac Rehabilitation After Acute Myocardial Infarction: A Randomized Trial

BackgroundGiven the shortage of cardiac rehabilitation (CR) programs in India and poor uptake worldwide, there is an urgent need to find alternative models of CR that are inexpensive and may offer choice to subgroups with poor uptake (e.g., women and elderly). ObjectivesThis study sought to evaluate the effects of yoga-based CR (Yoga-CaRe) on major cardiovascular events and self-rated health in a multicenter randomized controlled trial. MethodsThe trial was conducted in 24 medical centers across India. This study recruited 3,959 patients with acute myocardial infarction with a median and minimum follow-up of 22 and 6 months. Patients were individually randomized to receive either a Yoga-CaRe program (n = 1,970) or enhanced standard care involving educational advice (n = 1,989). The co-primary outcomes were: 1) first occurrence of major adverse cardiovascular events (MACE) (composite of all-cause mortality, myocardial infarction, stroke, or emergency cardiovascular hospitalization); and 2) self-rated health on the European Quality of Life–5 Dimensions–5 Level visual analogue scale at 12 weeks. ResultsMACE occurred in 131 (6.7%) patients in the Yoga-CaRe group and 146 (7.4%) patients in the enhanced standard care group (hazard ratio with Yoga-CaRe: 0.90; 95% confidence interval [CI]: 0.71 to 1.15; p = 0.41). Self-rated health was 77 in Yoga-CaRe and 75.7 in the enhanced standard care group (baseline-adjusted mean difference in favor of Yoga-CaRe: 1.5; 95% CI: 0.5 to 2.5; p = 0.002). The Yoga-CaRe group had greater return to pre-infarct activities, but there was no difference in tobacco cessation or medication adherence between the treatment groups (secondary outcomes). ConclusionsYoga-CaRe improved self-rated health and return to pre-infarct activities after acute myocardial infarction, but the trial lacked statistical power to show a difference in MACE. Yoga-CaRe may be an option when conventional CR is unavailable or unacceptable to individuals. (A study on effectiveness of YOGA based cardiac rehabilitation programme in India and United Kingdom; CTRI/2012/02/002408).

Pharmacodynamic study of the cardiovascular polypill. Is there any interaction among the monocomponents?

Introduction and objectivesTo compare the pharmacodynamics of the CNIC polypill (atorvastatin 40mg/ramipril 10mg/aspirin 100mg) in terms of low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP), with the corresponding reference products (atorvastatin and ramipril). MethodsThis was a multicenter, randomized, open-label, and parallel 3-arm study comparing the effect of the CNIC polypill vs ramipril 10mg and atorvastatin 40mg on SBP and LDL-C. The coprimary endpoints were differences in the adjusted mean 24-hour SBP (using ambulatory BP measurement) and LDL-C during the study period estimated using an ANCOVA model. ResultsOf the 241 patients included in the per protocol population, 84 received the CNIC polypill (group A), 84 atorvastatin (group B), and 73 ramipril (group C). SBP decreased from 139.3±12.5 to 133.2±12.9mmHg in group A and from 138.1±11.9 to 134.0±12.8mmHg in group C (baseline adjusted mean difference for the decrease in SBP was 1.77mmHg (90%CI, −0.5 to 4.0) in favor of group A, without reaching statistical significance. LDL-C was reduced by 33.9±21.6 and 29.2±25.8mg/dL in groups A and B, respectively (baseline adjusted mean difference for the decrease in LDL-C was 7.0% (90%CI, 1.5–12.4), a significantly greater decrease with the polypill). The 3 treatments were well tolerated. ConclusionsThe results of this study rule out a negative effect on blood pressure of the interaction between the components of the CNIC polypill. The reduction in LDL-C was greater in the CNIC polypill group, suggesting a synergistic effect of the components.

Evaluation of a Palliative Care Program for Nursing Homes in 7 Countries

High-quality evidence on how to improve palliative care in nursing homes is lacking. To investigate the effect of the Palliative Care for Older People (PACE) Steps to Success Program on resident and staff outcomes. A cluster-randomized clinical trial (2015-2017) in 78 nursing homes in 7 countries comparing PACE Steps to Success Program (intervention) with usual care (control). Randomization was stratified by country and median number of beds in each country in a 1:1 ratio. The PACE Steps to Success Program is a multicomponent intervention to integrate basic nonspecialist palliative care in nursing homes. Using a train-the-trainer approach, an external trainer supports staff in nursing homes to introduce a palliative care approach over the course of 1 year following a 6-steps program. The steps are (1) advance care planning with residents and family, (2) assessment, care planning, and review of needs and problems, (3) coordination of care via monthly multidisciplinary review meetings, (4) delivery of high-quality care focusing on pain and depression, (5) care in the last days of life, and (6) care after death. The primary resident outcome was comfort in the last week of life measured after death by staff using the End-of-Life in Dementia Scale Comfort Assessment While Dying (EOLD-CAD; range, 14-42). The primary staff outcome was knowledge of palliative care reported by staff using the Palliative Care Survey (PCS; range, 0-1). Concerning deceased residents, we collected 551 of 610 questionnaires from staff at baseline and 984 of 1178 postintervention in 37 intervention and 36 control homes. Mean (SD) age at time of death ranged between 85.22 (9.13) and 85.91 (8.57) years, and between 60.6% (160/264) and 70.6% (190/269) of residents were women across the different groups. Residents' comfort in the last week of life did not differ between intervention and control groups (baseline-adjusted mean difference, -0.55; 95% CI, -1.71 to 0.61; P = .35). Concerning staff, we collected 2680 of 3638 questionnaires at baseline and 2437 of 3510 postintervention in 37 intervention and 38 control homes. Mean (SD) age of staff ranged between 42.3 (12.1) and 44.1 (11.7) years, and between 87.2% (1092/1253) and 89% (1224/1375) of staff were women across the different groups. Staff in the intervention group had statistically significantly better knowledge of palliative care than staff in the control group, but the clinical difference was minimal (baseline-adjusted mean difference, 0.04; 95% CI, 0.02-0.05; P < .001). Data analyses began on April 20, 2018. Residents' comfort in the last week of life did not improve after introducing the PACE Steps to Success Program. Improvements in staff knowledge of palliative care were clinically not important. ISRCTN Identifier: ISRCTN14741671.

The effect of a programme to improve men's sedentary time and physical activity: The European Fans in Training (EuroFIT) randomised controlled trial.

BackgroundReducing sitting time as well as increasing physical activity in inactive people is beneficial for their health. This paper investigates the effectiveness of the European Fans in Training (EuroFIT) programme to improve physical activity and sedentary time in male football fans, delivered through the professional football setting.Methods and findingsA total of 1,113 men aged 30–65 with self-reported body mass index (BMI) ≥27 kg/m2 took part in a randomised controlled trial in 15 professional football clubs in England, the Netherlands, Norway, and Portugal. Recruitment was between September 19, 2015, and February 2, 2016. Participants consented to study procedures and provided usable activity monitor baseline data. They were randomised, stratified by club, to either the EuroFIT intervention or a 12-month waiting list comparison group. Follow-up measurement was post-programme and 12 months after baseline. EuroFIT is a 12-week, group-based programme delivered by coaches in football club stadia in 12 weekly 90-minute sessions. Weekly sessions aimed to improve physical activity, sedentary time, and diet and maintain changes long term. A pocket-worn device (SitFIT) allowed self-monitoring of sedentary time and daily steps, and a game-based app (MatchFIT) encouraged between-session social support. Primary outcome (objectively measured sedentary time and physical activity) measurements were obtained for 83% and 85% of intervention and comparison participants. Intention-to-treat analyses showed a baseline-adjusted mean difference in sedentary time at 12 months of −1.6 minutes/day (97.5% confidence interval [CI], −14.3–11.0; p = 0.77) and in step counts of 678 steps/day (97.5% CI, 309–1.048; p < 0.001) in favor of the intervention. There were significant improvements in diet, weight, well-being, self-esteem, vitality, and biomarkers of cardiometabolic health in favor of the intervention group, but not in quality of life. There was a 0.95 probability of EuroFIT being cost-effective compared with the comparison group if society is willing to pay £1.50 per extra step/day, a maximum probability of 0.61 if society is willing to pay £1,800 per minute less sedentary time/day, and 0.13 probability if society is willing to pay £30,000 per quality-adjusted life-year (QALY). It was not possible to blind participants to group allocation. Men attracted to the programme already had quite high levels of physical activity at baseline (8,372 steps/day), which may have limited room for improvement. Although participants came from across the socioeconomic spectrum, a majority were well educated and in paid work. There was an increase in recent injuries and in upper and lower joint pain scores post-programme. In addition, although the five-level EuroQoL questionnaire (EQ-5D-5L) is now the preferred measure for cost-effectiveness analyses across Europe, baseline scores were high (0.93), suggesting a ceiling effect for QALYs.ConclusionParticipation in EuroFIT led to improvements in physical activity, diet, body weight, and biomarkers of cardiometabolic health, but not in sedentary time at 12 months. Within-trial analysis suggests it is not cost-effective in the short term for QALYs due to a ceiling effect in quality of life. Nevertheless, decision-makers may consider the incremental cost for increase in steps worth the investment.Trial registrationInternational Standard Randomised Controlled Trials, ISRCTN-81935608.

Promoting school climate and health outcomes with the SEHER multi-component secondary school intervention in Bihar, India: a cluster-randomised controlled trial

School environments affect health and academic outcomes. With increasing secondary school retention in low-income and middle-income countries, promoting quality school social environments could offer a scalable opportunity to improve adolescent health and wellbeing. We did a cluster-randomised trial to assess the effectiveness of a multi-component whole-school health promotion intervention (SEHER) with integrated economic and process evaluations in grade 9 students (aged 13-14 years) at government-run secondary schools in the Nalanda district of Bihar state, India. Schools were randomly assigned (1:1:1) to three groups: the SEHER intervention delivered by a lay counsellor (the SEHER Mitra [SM] group), the SEHER intervention delivered by a teacher (teacher as SEHER Mitra [TSM] group), and a control group in which only the standard government-run classroom-based life-skills Adolescence Education Program was implemented. The primary outcome was school climate measured with the Beyond Blue School Climate Questionnaire (BBSCQ). Students were assessed at the start of the academic year (June, 2015) and again 8 months later at the end of the academic year (March, 2016) via self-completed questionnaires. This study is registered with ClinicalTrials.gov, number NCT02484014. Of the 112 eligible schools in the Nalanda district, 75 were randomly selected to participate in the trial. We randomly assigned 25 schools to each of the three groups. One school subsequently dropped out of the TSM group, leaving 24 schools in this group. The baseline survey included a total of 13 035 participants, and the endpoint survey included 14 414 participants. Participants in the SM-delivered intervention schools had substantially higher school climate scores at endpoint survey than those in the control group (BBSCQ baseline-adjusted mean difference [aMD] 7·57 [95% CI 6·11-9·03]; effect size 1·88 [95% CI 1·44-2·32], p<0·0001) and the TSM-delivered intervention (aMD 7·57 [95% CI 6·06-9·08]; effect size 1·88 [95% CI 1·43-2·34], p<0·0001). There was no effect of the TSM-delivered intervention compared with control (aMD -0·009 [95% CI -1·53 to 1·51], effect size 0·00 [95% CI -0·45 to 0·44], p=0·99). Compared with the control group, participants in the SM-delivered intervention schools had moderate to large improvements in the secondary outcomes of depression (aMD -1·23 [95% CI -1·89 to -0·57]), bullying (aMD -0·91 [95% CI -1·15 to -0·66]), violence victimisation (odds ratio [OR] 0·62 [95% CI 0·46-0·84]), violence perpetration (OR 0·68 [95% CI 0·48-0·96]), attitude towards gender equity (aMD 0·41 [95% CI 0·21-0·61]), and knowledge of reproductive and sexual health (aMD 0·29 [95% CI 0·06-0·53]). Similar results for these secondary outcomes were noted for the comparison between SM-delivered intervention schools and TSM-delivered intervention schools (depression: aMD -1·23 [95% CI -1·91 to -0·55]; bullying: aMD -0·83 [95% CI -1·08 to -0·57]; violence victimisation: OR 0·49 [95% CI 0·35-0·67]; violence perpetration: OR 0·49 [95% CI 0·34-0·71]; attitude towards gender equity: aMD 0·23 [95% CI 0·02-0·44]; and knowledge of reproductive and sexual health: aMD 0·22 [95% CI -0·02 to 0·47]). However, no effects on these secondary outcomes were observed for the TSM-delivered intervention schools compared with the control group (depression: aMD -0·03 [95% CI -0·70 to 0·65]; bullying: aMD -0·08 [95% CI -0·34 to 0·18]; violence victimisation: OR 1·27 [95% CI 0·93-1·73]; violence perpetration: OR 1·37 [95% CI 0·95-1·95]; attitude towards gender equity: aMD 0·17 [95% CI -0·09 to 0·38]; and knowledge of reproductive and sexual health: aMD 0·06 [95% CI -0·18 to 0·32]). The multi-component whole-school SEHER health promotion intervention had substantial beneficial effects on school climate and health-related outcomes when delivered by lay counsellors, but no effects when delivered by teachers. Future research should focus on the evaluation of the scaling up of the SEHER intervention in diverse contexts and delivery agents. John D. and Catherine T. MacArthur Foundation, USA and the United Nations Population Fund India Office.

French lyophilized plasma versus fresh frozen plasma for the initial management of trauma‐induced coagulopathy: a randomized open‐label trial

Background Guidelines recommend beginning hemostatic resuscitation immediately in trauma patients. We aimed to investigate if French lyophilized plasma (FLyP) was more effective than fresh frozen plasma (FFP) for the initial management of trauma-induced coagulopathy. Methods In an open-label, phase 3, randomized trial (NCT02750150), we enrolled adult trauma patients requiring an emergency pack of 4 plasma units within 6h of injury. We randomly assigned patients to receive 4-FLyP units or 4-FFP units. The primary endpoint was fibrinogen concentration at 45min after randomization. Secondary outcomes included time to transfusion, changes in hemostatic parameters at different time-points, blood product requirements and 30-day in-hospital mortality. Results Forty-eight patients were randomized (FLyP, n=24; FFP, n=24). FLyP reduced the time from randomization to transfusion of first plasma unit compared with FFP (median[IQR],14[5-30] vs. 77[64-90]min). FLyP achieved a higher fibrinogen concentration 45min after randomization compared with FFP (baseline-adjusted mean difference, 0.29gL-1 ; 95% confidence interval [CI], 0.08-0.49) and a greater improvement in prothrombin time ratio, factor V and factor II. The between-group differences in coagulation parameters remained significant at 6h. FLyP reduced fibrinogen concentrate requirements. Thirty-day in-hospital mortality rate was 22% with FLyP and 29% with FFP. Conclusion FLyP led to a more rapid, pronounced and extended increase in fibrinogen concentrations and coagulopathy improvement compared with FFP in the initial management of trauma patients. FLyP represents an attractive option for trauma management, especially when facing logistical issues such as combat casualties or mass casualties related to terror attacks or disasters.

Omega-3 decreases IL-6 levels in HIV and human herpesvirus-8 coinfected patients in Uganda.

Kaposi sarcoma is a HIV-associated malignancy caused by human herpesvirus-8 (HHV-8) that occurs at highest incidence in sub-Saharan Africa. Kaposi sarcoma patients often present with inflammatory symptoms associated with higher mortality. We conducted a double-blind, randomized, placebo-controlled study in Uganda to test whether omega-3 supplementation could reduce inflammation in HIV and HHV-8 coinfected adults. Patients with acute illness, AIDS, or advanced Kaposi sarcoma were ineligible, as were pregnant women. Participant IDs were pre-randomized, blocked by Kaposi sarcoma status, to either the omega-3 or placebo arm. Omega-3 participants received a 3-g pill dose daily for 12 weeks (1.8-g eicosapentaenoic acid, 1.2-mg docosapentaenoic acid); placebo participants received 44.8 mg of high oleic safflower oil that appeared indistinguishable from the active supplement. Intervention effects were evaluated as the baseline-adjusted mean difference after 12 weeks between omega-3 and placebo participants in concentrations of fatty acids, inflammatory cytokines, and immune cells. The final study population included 56 Kaposi sarcoma patients and 11 Kaposi sarcoma-negative, HIV and HHV-8-positive participants randomized to receive either omega-3 (N = 33) or placebo (N = 34). Inflammatory cytokine IL-6 concentrations decreased in omega-3 participants (-0.78 pg/ml) but increased in placebo participants (+3.2 pg/ml; P = 0.04). We observed a trend toward decreased IL-6 after omega-3 supplementation specific to Kaposi sarcoma patients (P = 0.08). CD8 T-cell counts tended to increase in the omega-3 arm Kaposi sarcoma patients (+60 cells/μl), in contrast to decreases (-47 cells/μl) among placebo (P = 0.11). Omega-3 supplementation decreased IL-6 concentrations among HIV and HHV-8 coinfected Ugandans, which may have clinical benefit for Kaposi sarcoma patients.

Improving comfort around dying in elderly people: a cluster randomised controlled trial

Over 50% of elderly people die in acute hospital settings, where the quality of end-of-life care is often suboptimum. We aimed to assess the effectiveness of the Care Programme for the Last Days of Life (CAREFuL) at improving comfort and quality of care in the dying phase in elderly people. We did a cluster randomised controlled trial in acute geriatric wards in ten hospitals in Flemish Region, Belgium, between Oct 1, 2012, and March 31, 2015. Hospitals were randomly assigned to implementation of CAREFuL (CAREFuL group) or to standard care (control group) using a random number generator. Patients and families were masked to interventaion allocation; hospital staff were unmasked. CAREFuL comprised a care guide for the last days of life, training, supportive documentation, and an implementation guide. Primary outcomes were comfort around dying, measured with the End-of-Life in Dementia-Comfort Assessment in Dying (CAD-EOLD), and symptom management, measured with the End-of-Life in Dementia-Symptom Management (SM-EOLD), by nurses and family carers. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01890239. 451 (11%) of 4241 beds in ten hospitals were included in the analyses. Five hospitals were randomly assigned to standard health care practice and five to the CAREFuL programme; 118 patients in the control group and 164 in the CAREFuL group were eligible for assessment. Assessments were done for 132 (80%) of 164 patients in the CAREFuL group and 109 (92%) of 118 in the control group by nurses, and 48 (29%) in the CAREFuL group and 23 (19%) in the control group by family carers. Implementation of CAREFuL compared with control significantly improved nurse-assessed comfort (CAD-EOLD baseline-adjusted mean difference 4·30, 95% CI 2·07-6·53; p<0·0001). No significant differences were noted for the CAD-EOLD assessed by family carers (baseline-adjusted mean difference -0·62, 95% CI -6·07 to 4·82; p=0·82) or the SM-EOLD assessed by nurses (-0·41, -1·86 to 1·05; p=0·58) or by family carers (-0·59, -3·75 to 2·57; p=0·71). Although a continuous monitoring of the programme is warranted, these results suggest that implementation of CAREFuL might improve care during the last days of life for patients in acute geriatric hospital wards. The Flemish Government Agency for Innovation by Science and Technology and the Belgian Cancer Society "Kom Op Tegen Kanker".

Optimizing approaches to addressing depression in cardiac patients: a comment on O'Neil et al.

Optimizing approaches to addressing depression in cardiac patients: a comment on O'Neil et al.