The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial

Cleland, John G.F.; Teerlink, John R.; Senior, Roxy; Nifontov, E. M.; Murray, John; Lang, Chim C.; Цырлин, В. А.; Greenberg, Barry; Mayet, Jamil; Francis, Dárrel P.; Shaburishvili, Tamaz; Monaghan, Mark; Saltzberg, Mitchell T.; Neyses, Ludwig; Wasserman, Scott M.; Lee, Jacqueline H.; Saikali, Khalil G.; Clarke, Cyril P.; Goldman, Jonathan H.; Wolff, Andrew; Malik, Fady I.

doi:10.1016/s0140-6736(11)61126-4

Cited by 300 publications

(249 citation statements)

References 16 publications

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“…Atrial contraction was also prolonged. A subsequent Phase II trial observed similar cardiovascular effects in patients with systolic heart failure 85 . Serum drug levels were monitored and correlated well with haemodynamic changes, with stroke volume reaching a plateau at ~400 ng per ml.…”

Section: Myosin Modulators In Clinical Trialsmentioning

confidence: 88%

“…Thus, omecamtiv mecarbil has a favourable effect on systolic function both in healthy volunteers and in patients with HFrEF. Although omecamtiv mecarbil was generally well tolerated, there were some concerning trends observed at higher drug concentrations 85 . Diastolic filling was progressively slowed with increasing doses, which could be problematic in patients with underlying diastolic dysfunction.…”

Section: Myosin Modulators In Clinical Trialsmentioning

confidence: 91%

See 1 more Smart Citation

Targeting the sarcomere to correct muscle function

Hwang

Sykes

2015

Nat Rev Drug Discov

109

122

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Section: Myosin Modulators In Clinical Trialsmentioning

confidence: 88%

Section: Myosin Modulators In Clinical Trialsmentioning

confidence: 91%

Targeting the sarcomere to correct muscle function

Hwang

Sykes

2015

Nat Rev Drug Discov

109

122

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“…Importantly, improvements in cardiac contractility were not associated with increased intracellular calcium transients nor with increased myocardial oxygen consumption [125]. First clinical studies demonstrated a dose-related increase in cardiac contractile function without clinically relevant changes in diastolic function [135,136]. However, as omecamtiv mecarbil increases contractility by prolonging systolic ejection time, cardiac filling might be impaired at higher heart rates (as usually observed in septic patients).…”

Section: Novel Therapies For the Septic Heartmentioning

confidence: 99%

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Rudiger¹,

Singer²

2013

Current Vascular Pharmacology

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Septic shock is characterized by circulatory compromise, microcirculatory alterations and mitochondrial damage, which all reduce cellular energy production. In order to reduce the risk of major cell death and a diminished likelihood of recovery, adaptive changes appear to be activated. As a result, cells and organs may survive in a non-functioning hibernation-like condition. Sepsis-induced cardiac dysfunction may represent an example of such functional shutdown. Sepsis-induced myocardial dysfunction is common, corresponds to the severity of sepsis, and is reversible in survivors. Its mechanisms include the attenuation of the adrenergic response at the cardiomyocyte level, alterations of intracellular calcium trafficking and blunted calcium sensitivity of contractile proteins. All these changes are mediated by cytokines. Treatment includes preload optimization with sufficient fluids. However, excessive volume loading is harmful. The first line vasopressor recommended at present is norepinephrine, while vasopressin can be started as a salvage therapy for those not responding to catecholamines. During early sepsis, cardiac output can be increased by dobutamine. While early administration of catecholamines might be necessary to restore adequate organ perfusion, prolonged administration might be harmful. Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine reduces myocardial oxygen expenditure and ameliorates diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. All these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice. While early administration of catecholamines might be necessary to restore adequate organ perfusion and pressure, prolonged administration might be harmful.Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine will reduce myocardial oxygen expenditure and ameliorate diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. However, all these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice.-3 -Alain Rudiger & Mervyn Singer: The heart in sepsis

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“…They first mention LCZ 696 which is a combined angiotensin receptor II blocker(valsartan) and neprilysin inhibitor (sacubitril) recently approved by the Food and Drug Administration (FDA) based on the overwhelmingly positive PARADIGM-HF trial [9] and the heart rate lowering drug ivabradine that was also approved by the FDA based on data from the SHIFT trial [10]. The rational for introducing omecamtiv mecarbil which increases the force of contraction without increasing calcium store is discussed along with the results of the phase II COSMIC-HF [11] study that showed favorable effect on remodeling and NT-proBNP. The initial concern for precipitating ischemia was alleviated by an exercise study [12], phase III is being launched at the present time.…”

Section: Potential New Drugsmentioning

confidence: 99%

Newer drugs for heart failure: hype or hope?

Ghali

2016

Expert Opinion on Investigational Drugs

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The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial

Cited by 300 publications

References 16 publications

Targeting the sarcomere to correct muscle function

Targeting the sarcomere to correct muscle function

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Newer drugs for heart failure: hype or hope?

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