Selective cardiac myosin activator did not improve dyspnea relief in patients with acute HF
Acute Treatment With Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure
The ATOMIC-AHF Study
Teerlink JR, Felker GM, McMurray JJV, et al.
J Am Coll Cardiol 2016;67:1444–55
BackgroundAcute heart failure (AHF) is associated with high morbidity and mortality, and represents an unmet medical need because only few therapeutic advances were achieved in the past decades . At least 50% of AHF patients have reduced myocardial contractility.
Studies evaluating inotropic agents to improve this underlying pathophysiological mechanism did not show a benefit. It was demonstrated that inotropic activation causes high rates of arrhythmias, hypotension, myocardial ischemia, and increased mortality, due to the increase of myocardial contraction rate and the shortening of the duration of cardiac systole . Therefore, guidelines recommend the use of inotropic agents only for patients with cardiogenic shock or evidence of marked end-organ hypoperfusion [3,4].
Pre-clinical studies and studies in healthy volunteers and in patients with chronic HF and systolic dysfunction, showed that omecamtiv mecarbil (OM), a selective small molecule activator of cardiac myosin that prolongs myocardial systole without changing the velocity of myocardial contraction, increases stroke volume and cardiac output and decreases heart rate [5-8].
This randomised, double-blind, phase II ATOMIC-AHF study evaluated the pharmacokinetics, the pharmacodynamics, as well as the safety, tolerability, and efficacy of a 48-hour intravenous infusion of 3 doses of OM (targeting mean OM plasma concentrations at 48 hours of 115, 230 and 310 ng/mL) or placebo, in 606 patients with AHF (mean age 66).
- OM did not improve the primary endpoint of dyspnea relief (3 OM dose groups and pooled placebo: placebo: 41%; OM cohort 1: 42%; OM cohort 2: 47%; OM cohort 3: 51%; P = 0.33) or any of the secondary outcomes studied.
- An exploratory post hoc logistic regression analysis across all cohorts demonstrated greater dyspnea response rates with higher total OM dose (adjusted response rate ratio per 50 mg increase in OM dose: 1.06, 95%CI: 1.01 - 1.11; P = 0.025) In supplemental, pre-specified analyses, in the high-dose cohort OM resulted in greater dyspnea relief at 48 h (placebo: 37% vs. OM. 51%; P = 0.034) and through 5 days (P = 0.038).
- OM exerted plasma concentration-related increases in left ventricular systolic ejection time (SET)(mean placebo-corrected increase in SET was 23, 34, and 53 ms for OM concentration ranges of 88 to 200 ng/ml, 201 to 300 ng/ml, and >300 ng/ml, respectively (p < 0.005 for all differences from placebo).
- A significant concentration-dependent decrease in heart rate was seen, an increase in blood pressure, and decrease in end-systolic dimension, from baseline with OM relative to placebo.
- The adverse event profile and tolerability of OM were similar to those of placebo, without increases in ventricular or supraventricular tachyarrhythmias.
ConclusionIn patients with AHF, the intravenous administration of OM did not meet the primary endpoint of dyspnea improvement, but it was generally well tolerated, it increased systolic ejection time, and it may have improved dyspnea in the high-dose group.
Editorial comment In his editorial, Starling addresses the question of whether OM warrants further development, after the results of the ATOMIC-AHF trial, a well-designed phase II clinical trial that did not meet its primary endpoint: dyspnea. ‘Dyspnea is a complex endpoint and has been shown to be related to markers of volume overload and pulmonary congestion. It is not surprising in this relatively small study that the primary endpoint was not met. Nesiritide failed to reach the primary efficacy endpoint for dyspnea in a similar patient population in a trial of more than 7000 patients. The investigators gambled, as dyspnea is a very challenging endpoint, but is nonetheless very relevant to congested HF patients and necessary to evaluate.’
It is emphasized that there are signals of potential clinical benefit of OM in systolic HF and that unfortunately, it seems that the basic mechanisms responsible for the progression of HF are still poorly understood. ‘OM is a unique pharmacological agent defined as a myosin activator. OM should not be considered as a positive inotropic agent, which tends to decrease SET; indeed, OM increases SET, which may represent a novel and efficacious physiological target for systolic HF. The findings from ATOMIC-[A]HF provide further proof of concept that OM may provide clinical benefit for HF with reduced ejection fraction. For now, caution is advised; more knowledge from the COSMIC-HF trial may clarify the potential role of OM in the treatment of HF.’
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