A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

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. opens in new tab; EudraCT number, 2016-002299-28. opens in new tab.

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

Organization of intensive cardiac care units in Europe: Results of a multinational survey

International audienceBackground:The present survey aims to describe the intensive cardiac care unit organization and admission policies in Europe.Methods: A total of 228 hospitals (61% academic) from 27 countries participated in this survey. In addition to the organizational aspects of the intensive cardiac care units, including classification of the intensive cardiac care unit levels, data on the admission diagnoses were gathered from consecutive patients who were admitted during a two-day period. Admission policies were evaluated by comparing illness severity with the intensive cardiac care unit level. Gross national income was used to differentiate high-income countries ($n$=13) from middle-income countries ($n$=14).Results: A total of 98% of the hospitals had an intensive cardiac care unit: 70% had a level 1 intensive cardiac care unit, 76% had a level 2 intensive cardiac care unit, 51% had a level 3 intensive cardiac care unit, and 60% of the hospitals had more than one intensive cardiac care unit level. High-income countries tended to have more level 3 intensive cardiac care units than middle-income countries (55% versus 41%, $p$=0.07). A total of 5159 admissions were scored on illness severity: 63% were low severity, 24% were intermediate severity, and 12% were high severity. Patients with low illness severity were predominantly admitted to level 1 intensive cardiac care units, whereas patients with high illness severity were predominantly admitted to level 2 and 3 intensive cardiac care units. A policy mismatch was observed in 12% of the patients; some patients with high illness severity were admitted to level 1 intensive cardiac care units, which occurred more often in middle-income countries, whereas some patients with low illness severity were admitted to level 3 intensive cardiac care units, which occurred more frequently in high-income countries.Conclusion: More than one-third of the admitted patients were considered intermediate or high risk. Although patients with higher illness severity were mostly admitted to high-level intensive cardiac care units, an admission policy mismatch was observed in 12% of the patients; this mismatch was partly related to insufficient logistic intensive cardiac care unit capacity

Chronic oral study of myosin activation to increase contractility in heart failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial

Summary: Background: Impaired contractility is a fundamental abnormality in heart failure with reduced ejection fraction (HFrEF). We evaluated the pharmacokinetics of chronic therapy with the cardiac myosin activator omecamtiv mecarbil as well as its effect on cardiac function and structure in such patients. Methods: In this randomised, parallel-group, double-blind study, 448 patients from 87 sites in 13 countries with stable, symptomatic chronic heart failure and left ventricular ejection fraction ≤40% were randomly assigned (1:1:1) using an interactive web response system to oral omecamtiv mecarbil (25 mg twice daily; or 25 mg twice daily with pharmacokinetic-guided uptitration to 50 mg twice daily, PK-titration group) or placebo for 20 weeks. The primary endpoint was the maximal omecamtiv mecarbil plasma concentration (Cmax); secondary endpoints were changes from baseline in cardiac function and dimensions, heart rate and NT-proBNP at week 20. (ClinicalTrials.gov, NCT01786512) Findings: In patients enrolled from March 17, 2014 through March 5, 2015, Cmax (mean ± SD) at 12 weeks was 200±71 and 318±129 ng/mL in the 25 mg (n = 147) and PK-titration (n = 141) groups, respectively. Differences were seen in all secondary endpoints by 20 weeks in the PK titration group (n = 149) compared to placebo (n = 149): systolic ejection time [least square mean difference (95% CI); +25 (18, 32) msec, p<0·0001], stroke volume [+3·6 (0·5, 6·7) mL, p=0·0217], left ventricular end-systolic and end-diastolic dimensions [ 1·8 (-2·9, -0·6) mm, p=0·0027; 1·3 (-2·3, 0·3) mm, p=0·0128, respectively], heart rate [ 3·0 (-5·1, -0·8) bpm, p=0·0070] and NT-proBNP [ 970 (-1672, -268) pg/mL, p=0·0069). The maximum changes from baseline in plasma troponin-I concentrations were greater in patients assigned to omecamtiv mecarbil [PK titration: 0·020 ng/mL, (0·005, 0·038); median (Q1, Q3), p<0·0001] than placebo [0·010 ng/mL (0·000, 0·020)]. No important differences in adverse clinical events were observed. Interpretation: In patients with chronic HFrEF, pharmacokinetic-guided dosing of omecamtiv mecarbil achieved plasma concentrations associated with improvements in cardiac performance and ventricular dimensions