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Omecamtiv mecarbil (OM) did not improve dyspena in patients with acute heart failure (AHF), but it did increase systolic ejection time and was generally well tolerated, according to results published in the Journal of the American College of Cardiology.
Researchers evaluated OM’s pharmacokinetics, pharmacodynamics, tolerability, safety, and efficacy in patients with AHF. They studied 606 patients (mean age: 66 ± 11 years; 77% male) with left ventricular ejection fraction (LVEF) ≤40% and elevated plasma concentrations of natriuretic peptides (NT-proBNP).
ATOMIC-AHF (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure) was a phase 2 randomized, double-blind, placebo-controlled, dose-escalated, sequential-cohort clinical trial that compared OM with placebo in patients hospitalized for AHF. There were approximately 200 patients per cohort (3 cohorts total) that targeted mean OM plasma concentrations at 48 hours of 115 ng/mL, 230 ng/mL, and 310 ng/mL, using 3 escalating dose regimens.
Prior to index admission, most patients had received guideline-recommended therapy for chronic symptomatic HF (>80% New York Heart Association function calls II to III). Coronary artery disease was determined to be the cause of HF in 62% of patients and the mean LVEF was 26% ± 8%.
The primary end point was dyspnea relief, assuming response rates of 23% in the placebo group and 40% in the OM group. Secondary end points included dyspnea numerical response area under the curve (AUC) through day 5, patient global assessment response, death or worsening HF within 7 days, initial hospital stay length, days alive post-discharge through 30 days, and NT-proBNP change from baseline.
Because the response rates among the placebo groups of the 3 cohorts were not statistically different (P=.316), the pooled placebo group was used as the statistical analysis of the primary end point. The individual OM cohorts also had similar dyspnea relief response rates and did not differ from the pooled placebo group (P=.331). However, the response rate did improve numerically with each increased OM dose.
A pre-specified supplemental analysis of comparisons between placebo and OM groups within each cohort was performed due to delays in data monitoring committee reviews, differences in time to randomization, enrollment region, and baseline characteristics among the cohorts. Relative improvement in dyspnea relief was observed in 41% of cohort 3 at 48 hours (14% absolute difference: placebo 37%; OM 51%; nominal P=.034).
Higher total OM dose appeared to demonstrate greater dyspnea response rates in an exploratory post hoc logistic regression (response rate ratio per 50 mg increase: 1.06; 95% confidence interval: 1.01-1.11; P=.025 adjusted; P=.035 unadjusted).
No statistically significant differences for any of the secondary end points were observed, although the dyspnea numeric rating scale AUC through day 5 demonstrated an increased improvement in cohort 3 OM-treated patients compared with the matching placebo group (nominal P=.038). This supports the notion that the higher total OM dose yields greater dyspnea response rates.
Serious adverse events were similar among all patients, both in placebo and OM groups (23% and 22%, respectively). All-cause rehospitalizations occurred in 47 patients in the placebo group and 39 patients in the OM group. Within 30 days, 10 patients in the OM group died vs 8 in the placebo group.
While the treatment did not meet the primary end point, researchers noted, “…It was generally well tolerated, it increased SET [systolic ejection time], and it may have improved dyspnea in the high-dose group. ATOMIC-AHF provides the basis for additional investigation of IV OM in patients with decompensated HF, as well as the development of oral OM for the treatment of patients with CHF [congestive heart failure], as has been recently explored in the COSMIC-HF study.”
Reference
Teerlink JR, Felker GM, McMurray JJV, et al; on behalf of the ATOMIC-AHF Investigators. Acute treatment with omecamtiv mecarbil to increase contractility in acute heart failure. The ATOMIC-AHF study. J Am Coll Cardiol. 2016;67(12):1444-1455. doi: 10.1016/j.jacc.2016.01.031.
