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

COMPARACIÓN DE DOS MÉTODOS PARA EVALUAR LA TRANSPORTACIÓN APICAL

The purpose of the present study was to compare a radiographic versus anatomic method for apical transportation measurement in curved root canal. Sixty recently removed human mandibular molars with buccolingual curved root canals ranging from 15º to 45º, were selected. The distal roots were removed to avoid radiographs interferences with mesiodistal incidence. Before been sectioned mesial roots were inclosed in transparent resin using a grilon key-like muffle with modificated Bramante´s procedure. The inclosed teeth were radiographed buccolingually and mesiodistally using a plastic dispositive to allow for standart pre and postinstrumentation radiographs. The roots canals were horizontally sectioned. Cuts made at 3 mm from the apex and photographed. The sections were reassembled in the muffle and the canals were instrumented with manual and mechanized techniques. After instrumentation was finished, radiographs of the teeth and photographs of the segment were taken. Transportation radiographic measurement was made with a micrometer on radiographic projection tracing magnified 8 times, in two planes. Transportation anatomic measurement was made analyzing photographs pre and posinstrumentation using and Image 1.45 Sofware Macintosh computer. Radiographic and anatomic methods showed different data due to the different levels and criteria of measurement. Statistical analysis (ANOVA) showed significant difference (p<0.0001) between radiographic and anatomic methods. Media comparison between radiographic and anatomic transportation, in each group, showed no significant difference (p=0.21).ResumenEl objetivo del presente trabajo fue comparar un método radiográfico con un método anatómico para medir la transportación apical en conductos curvos. Se seleccionaron 60 molares inferiores humanos, con angulaciones en sus conductos mesio-vestibularees de 15º a 45º. La raíz distal de cada pieza fue eliminada, para evitar la interferencia en las radiografías con incidencia mesio-distal. Aplicando el procedimiento propuesto por Bramante modificado, la raíz mesial antes de ser seccionada fue incluida en resina transparente usando una mufla de grilon como llave para la reposición de los fragmentos. Las piezas incluidas fueron radiografiadas con incidencia vestíbulo-lingual y mesio-distal utilizando un dispositivo plástico para sistematizar las tomas radiográficas pre y pos operatorias. Luego, las raíces fueron seccionadas horizontalmente a 3 mm del ápice y fotografiadas. Los segmentos fueron reposicionados en la mufla y los conductos instrumentados con técnicas manual y mecanizada. Completada la instrumentación se tomaron radiografías de las raíces y fotografías de los segmentos. La medición radiográfica de la transportación apical se realizó con calibre micrométrico sobre trazados de las proyecciones ampliadas 8 veces de ambas tomas radiográficas. La medición anatómica se realizó analizando las fotografías pre y pos instrumentación con un equipo de digitalización de imágenes Macintosh (Image 1.45). Los métodos radiográfico y anatómico presentan datos diferentes debido a los distintos niveles y criterios de medición. El análisis estadístico (ANOVA) mostró diferencias significativas entre el método radiográfico y el método anatómico (p<0.0001). La comparación entre las medidas de transportación obtenidas radiográficamente y anatómicamente en cada uno de los grupos no mostró diferencias (p=0.21)

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.)

Alirocumab and cardiovascular outcomes after acute coronary syndrome

BACKGROUN