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Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil.

ABSTRACT: Heart failure continues to be a major global health problem with a pronounced impact on morbidity and mortality and very limited drug treatment options especially with regard to inotropic therapy. Omecamtiv mecarbil is a first-in-class cardiac myosin activator, which increases the proportion of myosin heads that are tightly bound to actin and creates a force-producing state that is not associated with cytosolic calcium accumulation. Phase I and phase II studies have shown that it is safe and well tolerated. It produces dose-dependent increases in systolic ejection time (SET), stroke volume (SV), left ventricular ejection fraction (LVEF), and fractional shortening. In the ATOMIC-AHF trial, intravenous (IV) omecamtiv mecarbil did not improve dyspnoea overall but may have improved it in a high-dose group of acute heart failure patients. It did, however, increase SET, decrease left ventricular end-systolic diameter, and was well tolerated. The COSMIC-HF trial showed that a pharmacokinetic-based dose-titration strategy of oral omecamtiv mecarbil improved cardiac function and reduced ventricular diameters compared to placebo and had a similar safety profile. It also significantly reduced plasma N-terminal-pro B-type natriuretic peptide compared with placebo. The GALACTIC-HF trial is now underway and will compare omecamtiv mecarbil with placebo when added to current heart failure standard treatment in patients with chronic heart failure and reduced LVEF. It is expected to be completed in January 2021. The ongoing range of preclinical and clinical research on omecamtiv mecarbil will further elucidate its full range of pharmacological effects and its clinical usefulness in heart failure.

SUBMITTER: Kaplinsky E

PROVIDER: S-EPMC5916097 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil.

Kaplinsky Edgardo E Mallarkey Gordon G

Drugs in context 20180423

Heart failure continues to be a major global health problem with a pronounced impact on morbidity and mortality and very limited drug treatment options especially with regard to inotropic therapy. Omecamtiv mecarbil is a first-in-class cardiac myosin activator, which increases the proportion of myosin heads that are tightly bound to actin and creates a force-producing state that is not associated with cytosolic calcium accumulation. Phase I and phase II studies have shown that it is safe and wel ...[more]

PMID: 29707029

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Project description:AimsThe aims of this study were to assess prescription patterns, dosages, discontinuation rates, and association with prognosis of conventional heart failure medications in patients with transthyretin cardiac amyloidosis (ATTR-CA).Methods and resultsA retrospective analysis of all consecutive patients diagnosed with ATTR-CA at the National Amyloidosis Centre between 2000 and 2022 identified 2371 patients with ATTR-CA. Prescription of heart failure medications was greater among patients with a more severe cardiac phenotype, comprising beta-blockers in 55.4%, angiotensin-converting enzyme inhibitors (ACEis)/angiotensin II receptor blockers (ARBs) in 57.4%, and mineralocorticoid receptor antagonists (MRAs) in 39.0% of cases. During a median follow-up of 27.8 months (interquartile range 10.6-51.3), 21.7% had beta-blockers discontinued, and 32.9% had ACEi/ARBs discontinued. In contrast, only 7.5% had MRAs discontinued. A propensity score-matched analysis demonstrated that treatment with MRAs was independently associated with a reduced risk of mortality in the overall population [hazard ratio (HR) 0.77 (95% confidence interval (CI) 0.66-0.89), P < .001] and in a pre-specified subgroup of patients with a left ventricular ejection fraction (LVEF) >40% [HR 0.75 (95% CI 0.63-0.90), P = .002]; and treatment with low-dose beta-blockers was independently associated with a reduced risk of mortality in a pre-specified subgroup of patients with a LVEF ≤40% [HR 0.61 (95% CI 0.45-0.83), P = .002]. No convincing differences were found for treatment with ACEi/ARBs.ConclusionConventional heart failure medications are currently not widely prescribed in ATTR-CA, and those that received medication had more severe cardiac disease. Beta-blockers and ACEi/ARBs were often discontinued, but low-dose beta-blockers were associated with reduced risk of mortality in patients with a LVEF ≤40%. In contrast, MRAs were rarely discontinued and were associated with reduced risk of mortality in the overall population; but these findings require confirmation in prospective randomized controlled trials.

Dataset Information

Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil.

Publications

Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil.

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