Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Evaluation of a diode laser based photoacoustic instrument combined with preconcentration sampling for measuring surface-atmosphere exchange of ammonia with the aerodynamic gradient method

We present here a novel instrument for measuring surface-atmosphere exchange fluxes of ammonia. The instrument is the upgraded version of a recently developed near-infrared diode laser based photoacoustic ammonia concentration monitoring instrument, i.e. the original instrument is supplemented with two additional sampling lines, an appropriate gas handling system and an advanced software controlling gradient measurements. As a result of these developments, ammonia concentration can be measured simultaneously at three different heights above the ground and ammonia fluxes can be calculated from these data using the aerodynamic gradient method. The instrument operates fully automatically, requires minimal maintenance and has a temperature controlled, waterproof housing which makes it suitable for measurements even under harsh field conditions. Preliminary tests on stability and accuracy were carried out during two two-week field measurement campaigns, with the three sampling inlets being placed at the same height together with the inlet of a reference instrument. The readings of the three channels agreed well (with correlation coefficients above 0.96). Comparison to reference instruments showed good stability of the photoacoustic instrument, there was no measurable zero-drift or change in sensitivity during the tests. Flux measurements were carried out during a three-week field campaign in southern Scotland over fertilized grassland with reference to a wet-chemical AMANDA instrument in gradient configuration. Ammonia fluxes calculated from the data of the two instruments agreed well. Fluxes up to 2500 ng m^-2 s^-1 were observed after fertilization. The minimum detectable ammonia flux was calculated on the basis of “virtual ammonia fluxes”, from measurements carried out with all inlets at the same height and was found to be 60 ng m^-2 s^-1 which ensures reliable measurements above intensively managed grasslands or agricultural fields

Differences in the use of guideline-recommended therapies among 14 European countries in patients with acute coronary syndromes undergoing PCI.

Despite common European Society of Cardiology recommendations, adherence to guideline therapy varies, both temporally and geographically. We sought to examine current differences in the use of guideline-recommended therapies among 14 European countries in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI).Comparative StudyJournal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Influence of the duration of type 2 diabetes mellitus on colorectal cancer outcomes

Abstract Type 2 diabetes mellitus (T2DM) is a progressive disease, which affects colorectal cancer (CRC) survival. However, data on the relationship between CRC survival and T2DM duration is scarce and controversial. A retrospective observational study was conducted. Sub-cohorts were created based on the duration of T2DM as follows, ≤ or > 5/10/15/20 years. 204 of the 817 (24.95%) included study participants had T2DM at any point of CRC. 160 of the 204 CRC + T2DM patients had detailed T2DM duration data. At the time of CRC diagnosis, 85, 50, 31, and 11 patients had T2DM for > 5/10/15/20 years, respectively, which increased to 110, 71, 45, and 17 during the course of the study. Despite constant glycated hemoglobin values throughout the study, shorter overall and disease-specific survival times were observed for the > 5/10/15 years cohorts and longitudinal survival modeling techniques confirmed the significant effect of T2DM duration in all cohorts. While in the first 3 years after CRC diagnosis, the best survival was found for the ≤ 5 years cohort, all diabetes cohorts had the same survival thereafter. T2DM duration affected CRC survival significantly, therefore, a closer follow-up of this sub-populations is suggested

Deconstructing Immune Cell Infiltration in Human Colorectal Cancer: A Systematic Spatiotemporal Evaluation

Cancer-related immunity has been identified as playing a key role in the outcome of colorectal cancer (CRC); however, the exact mechanisms are only partially understood. In this study, we evaluated a total of 242 surgical specimen of CRC patients using tissue microarrays and immunohistochemistry to evaluate tumor infiltrating immune cells (CD3, CD4, CD8, CD20, CD23, CD45 and CD56) and immune checkpoint markers (CTLA-4, PD-L1, PD-1) in systematically selected tumor regions and their corresponding lymph nodes, as well as in liver metastases. Additionally, an immune panel gene expression assay was performed on 12 primary tumors and 12 consecutive liver metastases. A higher number of natural killer cells and more mature B cells along with PD-1+ expressing cells were observed in the main tumor area as compared to metastases. A higher number of metastatic lymph nodes were associated with significantly lower B cell counts. With more advanced lymph node metastatic status, higher leukocyte—particularly T cell numbers—were observed. Eleven differentially expressed immune-related genes were found between primary tumors and liver metastases. Also, alterations of the innate immune response and the tumor necrosis factor superfamily pathways had been identified

Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure

BACKGROUND The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016 -002299-28.)