digoxin and omecamtiv-mecarbil

Treatment with inotropic agents is one of the most controversial topics in heart failure. Initial enthusiasm, based on strong pathophysiological rationale and apparent empirical efficacy, has been progressively limited by results of controlled trials and registries showing poorer outcomes of the patients on inotropic therapy. The use of these agents remains, however, potentially indicated in a significant proportion of patients with low cardiac output, peripheral hypoperfusion and end-organ dysfunction caused by heart failure. Limitations of inotropic therapy seem to be mainly related to their mechanisms of action entailing arrhythmogenesis, peripheral vasodilation, myocardial ischemia and damage, and possibly due to their use in patients without a clear indication, rather than to the general principle of inotropic therapy itself. This review will discuss the characteristics of the patients with a potential indication for inotropic therapy, the main data from registries and controlled trials, the mechanism of the untoward effects of these agents on outcomes and, lastly, perspectives with new agents with novel mechanisms of action.

Topics: Acute Disease; Cardiotonic Agents; Digoxin; Dobutamine; Etiocholanolone; Exercise Test; Heart Failure; Hemodynamics; Hospitals, Group Practice; Humans; Hydrazones; Prognosis; Pyrazines; Pyridazines; Quinolines; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Simendan; Treatment Outcome; Urea; Vasodilator Agents

In GALACTIC-HF, the cardiac myosin activator omecamtiv mecarbil compared with placebo reduced the risk of heart failure events or cardiovascular death in patients with heart failure with reduced ejection fraction. We explored the influence of atrial fibrillation or flutter (AFF) on the effectiveness of omecamtiv mecarbil.. GALACTIC-HF enrolled patients with New York Heart Association (NYHA) Class II-IV heart failure, left ventricular ejection fraction ≤35%, and elevated natriuretic peptides. We assessed whether the presence or absence of AFF, a pre-specified subgroup, modified the treatment effect for the primary and secondary outcomes, and additionally explored effect modification in patients who were or were not receiving digoxin. Patients with AFF (n = 2245, 27%) were older, more likely to be randomized as an inpatient, less likely to have a history of ischaemic aetiology or myocardial infarction, had a worse NYHA class, worse quality of life, lower estimated glomerular filtration rate, and higher N-terminal pro-B-type natriuretic peptide. The treatment effect of omecamtiv mecarbil was modified by baseline AFF (interaction P = 0.012), with patients without AFF at baseline deriving greater benefit. The worsening of the treatment effect by baseline AFF was significantly more pronounced in digoxin users than in non-users (interaction P = 0.007); there was minimal evidence of effect modification in those patients not using digoxin (P = 0.47) or in digoxin users not in AFF.. Patients in AFF at baseline were less likely to benefit from omecamtiv mecarbil than patients without AFF, although the attenuation of the treatment effect was disproportionally concentrated in patients with AFF who were also receiving digoxin.Clinical Trial Registration: NCT02929329.

Topics: Atrial Fibrillation; Atrial Flutter; Digoxin; Heart Failure; Humans; Quality of Life; Stroke Volume; Urea; Ventricular Function, Left

Omecamtiv mecarbil (OM), a novel cardiac myosin activator, is being evaluated for the treatment of heart failure with reduced ejection fraction. In vitro studies demonstrate OM as a substrate and inhibitor of P-glycoprotein (P-gp), which can result in drug-drug interactions. Two phase 1, open-label studies assessed the effect of coadministration of OM (50-mg single dose) on the pharmacokinetics of digoxin (0.5-mg single dose; N = 15), a P-gp substrate, and the effect of coadministration of amiodarone (600-mg single dose), a P-gp inhibitor, on the pharmacokinetics of OM (50-mg single dose; N = 14) in healthy subjects. The ratios of the geometric least squares mean (90% confidence interval [CI]) of digoxin coadministered with OM vs digoxin alone for area under the plasma concentration-time curve (AUC) from time 0 to infinity, AUC from time 0 to the time of the last quantifiable concentration, and maximum observed plasma concentration were 1.06 (90%CI, 0.99-1.14), 1.06 (90%CI, 0.98-1.14), and 1.08 (90%CI, 0.92-1.26), respectively. The ratios of the geometric least squares mean of OM coadministered with amiodarone vs OM alone for AUC from time 0 to infinity, AUC from time 0 to the time of the last quantifiable concentration, and maximum observed plasma concentration were 1.21 (90%CI, 1.08-1.36), 1.21 (90%CI, 1.07-1.36), and 1.08 (90%CI, 0.96-1.22), respectively. In conclusion, OM coadministered with digoxin or amiodarone did not result in any clinically relevant pharmacokinetic drug-drug interactions.

Topics: Amiodarone; Clinical Trials, Phase I as Topic; Digoxin; Drug Interactions; Healthy Volunteers; Humans; Urea

Topics: Atrial Fibrillation; Digoxin; Heart Failure; Humans; Urea

Acute heart failure represents an increasingly common cause of hospitalization, and may require the use of inotropic drugs in patients with low cardiac output and evidence of organ hypoperfusion. However, currently available therapies may have deleterious effects and increase mortality. An ideal inotropic drug should restore effective tissue perfusion by enhancing myocardial contractility without causing adverse effects. Such a drug is not available yet. New agents with different biological targets are under clinical development. In particular, istaroxime seems to dissociate the inotropic effect exerted by digitalis (inhibition of the membrane sodium/potassium adenosine triphosphatase) from the arrhythmic effect and to ameliorate diastolic dysfunction (via sarcoendoplasmic reticulum calcium adenosine triphosphatase activation). Additionally, the myosin activator omecamtiv mecarbil appears to have promising characteristics, while genetic therapy has been explored in animal studies only. Further investigations are needed to confirm and expand the effectiveness and safety of these agents in patients with acute heart failure and low cardiac output.

Topics: Acute Disease; Animals; Cardiac Output; Cardiotonic Agents; Clinical Trials as Topic; Digoxin; Dobutamine; Etiocholanolone; Genetic Therapy; Heart Failure; Humans; Hydrazones; Pyridazines; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Simendan; Sodium-Potassium-Exchanging ATPase; Urea