Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure

Abstract

BACKGROUNDThe 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. METHODSWe 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. RESULTSDuring 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. CONCLUSIONSAmong 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.

Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases

“…However, in one of these trials (ATOMIC-HF) the primary (relief of dyspnoea) and secondary endpoints were not met which has led some to question the value of further trials [ 48 , 49 ]. Recently, results of a large randomised, placebo-controlled phase III Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial were published (see Table 2 ) [ 50 ]. The primary outcome was a composite of a heart-failure event or cardiovascular death (whichever comes first).…”

Classification of Heart Failure: A Farewell to Ejection Fraction?

“…While all these interventions inhibited mainly neurohumoral activation and peripheral vasoconstriction and thereby unloaded the heart and/or reduced renal water and sodium retention, all attempts to stimulate the failing heart, not only with phosphodiesterase inhibitors ( 16 ), but also with other compounds, counterintuitively increased, rather than decreased, mortality despite their beneficial hemodynamic and symptomatic effects. In contrast, in a most recent trial, the novel cardiac myosin activator Omecamtiv Mecarbil improved cardiac performance on top of the standard therapy, but the effect size on MACE was undesirably small ( 17 ). Nevertheless, the management of patients with heart failure with reduced ejection fraction (HFrEF) is a true achievement that led to a marked improvement of the quality of life of such patients and clinical outcomes, with a continuously declining incidence of heart failure hospitalizations, MACE, and mortality, including sudden death ( 18 ).…”

Heart failure in the last year: progress and perspective

“…198 In the GALAC-TIC-HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) trial, the selective cardiac myosin activator omecamtiv mecarbil showed a reduction in the primary composite endpoint of a first HF event or death from CV causes. 199 Neladenoson bialanate, a partial adenosine A1 receptor agonist, failed to demonstrate favourable changes in NT-proBNP, LVEF, high-sensitivity troponin T, or CV mortality and HF hospitalization in PANTHEON trial. On the other hand, a decrease in renal function was observed.…”

“…The median MAGGIC (Meta‐Analysis Global Group in Chronic Heart Failure) risk score was 23 (interquartile range 18–27) in VICTORIA vs. 20 (interquartile range 16–24) in PARADIGM‐HF trial 198 . In the GALACTIC‐HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) trial, the selective cardiac myosin activator omecamtiv mecarbil showed a reduction in the primary composite endpoint of a first HF event or death from CV causes 199 …”