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N-terminal pro-B-type natriuretic peptide (NT-proBNP) is predictive of both outcomes and response to treatment in patients with heart failure with reduced ejection fraction (HFrEF).To examine the effect of the cardiac myosin activator omecamtiv mecarbil according to baseline NT-proBNP level in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure trial (GALACTIC-HF).The primary outcome was the composite of a worsening HF event (urgent clinic visit, emergency department visit, or hospitalization) or cardiovascular death. We prespecified analysis of the effect of treatment according to baseline NT-proBNP (≤median,median), excluding individuals with AF/AFL.Of the 8232 patients analyzed, 8206 had an available baseline NT-proBNP measurement. Among the 5971 patients not in AF/AFL, the median (Q1, Q3) NT-proBNP level was 1675 (812-3579) pg/ml. Hazard ratios (HR) for the effect of omecamtiv mecarbil, compared with placebo, for the primary endpoint in patients without AF/AFL were: ≤median 0.94 (95% CI, 0.80-1.09),median 0.81 (0.73-0.90) [P-interaction = 0.095]; for the overall population (including patients with AF/AFL) the HRs were ≤ median 1.01 (0.90-1.15) and median 0.88 (0.80-0.96) [P-interaction = 0.035]. There was an interaction between treatment and NT-proBNP, examined as a continuous variable, with greater effect of omecamtiv mecarbil on the primary outcome in patients with a higher baseline NT-proBNP (P-interaction = 0.086).In GALACTIC-HF, the benefit of omecamtiv mecarbil appeared to be larger in patients with higher baseline NT-proBNP levels, especially in patients without AF/AFL. This article is protected by copyright. All rights reserved.

BACKGROUND: Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and effects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil. METHODS: In this randomised, double-blind study, done at 87 sites in 13 countries, we recruited patients with stable, symptomatic chronic heart failure and left ventricular ejection fraction 40% or lower. Patients were randomly assigned equally, via an interactive web response system, to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks. We assessed the maximum concentration of omecamtiv mecarbil in plasma (primary endpoint) and changes in cardiac function and ventricular diameters. This trial is registered with ClinicalTrials.gov, number NCT01786512. FINDINGS: From March 17, 2014, to March 5, 2015, we enrolled 150 patients in the fixed-dose omecamtiv mecarbil group and 149 in the pharmacokinetic-titration and placebo groups. Mean maximum concentration of omecamtiv mecarbil at 12 weeks was 200 (SD 71) ng/mL in the fixed-dose group and 318 (129) ng/mL in the pharmacokinetic-titration group. For the pharmacokinetic-titration group versus placebo group at 20 weeks, least square mean differences were as follows: systolic ejection time 25 ms (95% CI 18-32, p