• Cardiology Clinical Trials
• Heart Failure

• Cardiology Clinical Trials
• Heart Failure
• Cardiology

The Study to Evaluate the Safety and Efficacy of IV Infusion Treatment With Omecamtiv Mecarbil in Subjects With Left Ventricular Systolic Dysfunction Hospitalized for Acute Heart Failure trial [ATOMIC-AHF; NCT01300013], presented by John R. Teerlink, MD, University of California San Francisco, San Francisco, California, USA, was a Phase 2 dose ranging study which aimed to evaluate the safety, pharmacokinetics and pharmacodynamics (PK/ PD), and efficacy of intravenous (IV) omecamtiv mecarbil (OM) in patients with acute heart failure (AHF). The investigators hypothesized that ≥1 dose of IV OM would be well tolerated and improve dyspnea in patients with left ventricular systolic dysfunction hospitalized for AHF.

The study employed a sequential dosing design. Patients presenting with AHF were randomized 1:1 to IV OM versus IV placebo (pooled placebo, n=303) and divided into 3 cohorts, with each cohort receiving increasing OM doses (Table 1).

The primary efficacy endpoint was dyspnea symptom response through 48 hours, evaluated by a 7-point Likert scale. Responders were defined as minimally, moderately, or markedly better at 6 hours and moderately or markedly better at both 24 and 48 hours, without worsening HF or death from any cause by 48 hours. Secondary endpoints included death and/or worsening HF within 7 days, dyspnea area under the curve (AUC), dyspnea by 7-point Likert scale at each assessment, Patient Global Assessment response through 48 hours, change from baseline in NT-proBNP, length of hospital stay, and days alive out of hospital until Day 30. PK/PD were evaluated up to Day 6 after discharge.

Baseline characteristics were well balanced between the OM and placebo groups. Analysis of dyspnea response demonstrated no significant difference between any of the OM cohorts and the pooled placebo group (overall p=0.33).

An exploratory analysis comparing the individual OM groups versus their respective placebo groups found a trend toward a beneficial dyspnea response between OM at the highest dose (Cohort 3) and placebo (51% vs 37%; RRR, 1.41; 95% CI, 1.02 to 1.93; p=0.03).

The risk of worsening HF was similar between groups with OM versus placebo with relative risks of 0.68 (95% CI, 0.38 to 1.21; p=0.179) in Cohort 1; 0.49 (95% CI, 0.24 to 0.98; p=0.034) in Cohort 2; and 0.55 (95% CI, 0.28 to 1.09; p=0.075) in Cohort 3. There were no significant differences between the OM cohorts and the pooled placebo group in the other secondary endpoints.

Adverse event rates were similar between the OM and placebo groups with the exception of myocardial injury which was more frequent with OM (2.3% vs 1.0%); however, these events were characterized by the authors as primarily low level elevations in troponin concentration. Systolic ejection time significantly increased with OM versus placebo (p≤0.005).

In the ATOMIC-AHF trial OM did not significantly improve dyspnea response compared with pooled placebo in patients with left ventricular systolic dysfunction hospitalized for AHF. However, this Phase 2 dose-ranging study found a trend towards reduction of worsening HF with OM (Table 2) with a trend toward improved dyspnea response in the highest dose compared with placebo. OM was associated with increased rates of myocardial injury. Overall these results suggest that further study with this compound in AHF should be considered with a careful evaluation of safety and clinical outcomes to better understand the implications of the associated troponin elevations.

• © 2013 MD Conference Express®