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Acute Treatment With Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure - ATOMIC-AHF
Description:
Omecamtiv mecarbil is a novel cardiac-specific myosin activator. The current study was a phase II study designed to evaluate the effect of 48 hours of intravenous (IV) omecamtiv mecarbil compared with placebo on dyspnea in subjects with left ventricular (LV) systolic dysfunction hospitalized for acute heart failure (HF).
Hypothesis:
At least one dose level of IV omecamtiv mecarbil would be well tolerated and result in improvement of dyspnea in subjects with LV systolic dysfunction hospitalized for acute decompensated HF (ADHF).
Study Design
- Placebo Controlled
- Randomized
- Parallel
Patient Populations:
- Age 18-85 years
- Hospitalized for worsening HF, within 24 hours of initiating IV loop diuretic
- Dyspnea due to HF, at rest or with minimal exertion
- History of LV ejection fraction ≤40%
- Screening BNP ≥400 pg/ml or NT-proBNP ≥1600 pg/ml (BNP ≥600 pg/ml or NT-proBNP ≥2400 pg/ml, if the subject has atrial fibrillation)
Number of enrollees: 606
Duration of follow-up: 7 days
Exclusions:
- Receiving IV vasopressor (excluding low dopamine), inotropic, or mechanical support
- Acute coronary syndrome (ACS)
- Within 30 days prior to enrollment: cardiac resynchronization therapy or implantable cardioverter-defibrillator implantation, ACS, coronary revascularization, transient ischemic attack or stroke, sustained ventricular arrhythmia, or major surgery
- Severe valvular stenosis, hypertrophic obstructive cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically significant congenital heart disease
- Estimated glomerular filtration rate <20 ml/min/1.73 m2
Primary Endpoints:
- Change in dyspnea from baseline to 48 hours (measured on Likert scale)
Secondary Endpoints:
- Death (any cause) and/or worsening HF within 7 days
- Dyspnea area under the curve (baseline to fifth day or discharge), as measured by subject self-assessed Numerical Rating Scale
- Dyspnea by 7-point Likert scale at each scheduled assessment
- Patient Global Assessment response through 48 hours
- Change from baseline in N-terminal pro–B-type natriuretic peptide (NT-proBNP)
- Length of initial hospital stay
- Days alive out of hospital until day 30
Drug/Procedures Used:
Patients with ADHF were randomized in a 1:1 fashion in three sequential, ascending-dose cohorts of omecamtiv mecarbil (115, 230, and 310 ng/ml predicted target plasma concentrations) versus placebo with interim Data Monitoring Committee evaluation.
Concomitant Medications:
Beta-blockers (87%), digoxin (24%), ivabradine (4%), and mineralocorticoid receptor antagonist (56%)
Principal Findings:
A total of 606 patients were randomized, 103 to omecamtiv mecarbil 115 ng/ml, 99 to omecamtiv mecarbil 230 ng/ml, 101 to omecamtiv mecarbil 310 ng/ml, and 303 to placebo. Baseline characteristics were fairly similar between the four arms. Approximately 62% had concomitant ischemic heart disease, and nearly a third had persistent atrial fibrillation or flutter. The mean LV ejection fraction was 26%. Baseline systolic ejection time was 258 msec. The median time from presentation to randomization was 15 hours.
The primary endpoint of change in dyspnea from baseline to 48 hours (% responders) was similar between the omecamtiv mecarbil 115, 230, or 310 ng/ml and placebo arms (42% vs. 47% vs. 51% vs. 41%, p = 0.33). For the omecamtiv mecarbil 310 ng/ml versus its corresponding placebo arm, a significant improvement in dyspnea was noted (51% vs. 37%, p = 0.03). On exploratory analysis, omecamtiv mecarbil demonstrated favorable dose- and concentration-related trends (p = 0.025 and p = 0.007, respectively) on dyspnea response.
Incidence of worsening congestive heart failure (CHF) at 7 days for highest to lowest dose omecamtiv mecarbil versus placebo was 9% vs. 8% vs. 13% vs. 17%. Other clinical endpoints including mortality (3% vs. 4% vs. 1% vs. 3.3%), all rehospitalizations (6.9% vs. 11.1% vs. 10.7% vs. 12.2%), acute myocardial infarction (MI) (0% vs. 0% vs. 1% vs. 0.3%), and CHF hospitalization (5% vs. 11.1% vs. 5.8% vs. 6.3%) were similar between the four arms. All MIs (including troponin elevations) were numerically higher in the highest dose arm (5% vs. 0% vs. 1.9% vs. 1.0%). The increase in troponin I concentration did not appear to be dose related. The incidence of ventricular tachyarrhythmias was similar between the four arms. Heart rate appeared to be reduced in a dose-related fashion compared with placebo (change in LS means from control: -2.3 vs. -2.0 vs. -0.1, p < 0.0001). Similarly, blood pressure appeared to be marginally improved over placebo (2.4 vs. 0.6 vs. 0.3 mm Hg, p = 0.0017).
Change in systolic ejection time increased in a dose-dependent fashion in the omecamtiv mecarbil arms (46.4 vs. 26.9 vs. 16.6 vs. -6.7 msec, p < 0.0001).
Interpretation:
The results of the phase II ATOMIC-AHF trial indicate that omecamtiv mecarbil is not superior to placebo in improving subjective dyspnea in patients with ADHF. Omecamtiv mecarbil is a novel cardiac-specific myosin activator with positive inotropic effects, without additional chronotropic actions.
On secondary analysis, the highest dose omecamtiv mecarbil arm (310 ng/ml) appeared to decrease dyspnea greater than placebo. These findings are hypothesis generating and will need to be tested in phase III trials. The incidence of arrhythmias was similar compared with placebo in this small trial, although troponin elevations were higher. Another trial in patients with chronic CHF (COSMIC-CHF) is ongoing.
References:
Presented by Dr. John R. Teerlink at the European Society of Cardiology Congress, Amsterdam, Holland, September 3, 2013.
Keywords: Myocardial Infarction, Myocardial Ischemia, Follow-Up Studies, Clinical Trials Data Monitoring Committees, Blood Pressure, Dyspnea, Sodium Potassium Chloride Symporter Inhibitors, Heart Rate, Systole, Tachycardia, Heart Failure, Cardiac Myosins, Peptide Fragments, Hospitalization, Urea, Natriuretic Peptide, Brain, Troponin
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