Reviwer : Dr. Göksel Çinier

Name of the Study : Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure- GALACTIC-HF

Published Congress : ACC 2021

Link : https://www.jacc.org/doi/pdf/10.1016/j.jacc.2021.04.065

Background :
Myotropes represent a new class of drugs that improve myocardial function by directly augmenting cardiac sarcomere function. The cardiac myosin activator, omecamtiv mecarbil  works by improving the ability for heart muscle cells to contract and operates through a different biological pathway than any of the current heart failure medications. The GALACTIC HF trial was the first trial to demonstrate the cardiac myosin activator, omecamtiv mecarbil, significantly reduced the primary composite endpoint (PCE) of time-to-first heart failure event or cardiovascular death in patients with heart failure and reduced ejection fraction (EF<35).

Objective :
The purpose of this study is to evaluate the therapeutic effect of omecamtiv mecarbil, whose efficacy was investigated by the GALACTIC HF study, according to the baseline ejection fraction.

Methods :
Among the 8,256 patients (mean age 66 years; 21% women) who were enrolled in the GALACTİC-HF trial, mean EF at baseline was 27%. The participants were divided into quartiles in this new trial according to EF: ≤ 22%, 23% to 28%, 29% to 32%, and ≥ 33%
Outcomes in patients treated with omecamtiv mecarbil were compared with placebo according to EF.

Results :
This new analysis confirmed that the relative and absolute benefits from omecamtiv mecarbil improved significantly with progressively lower ejection fraction. [a 17%relative risk reduction for the PCE in patients with baseline EF≤22% (n =2,246; hazard ratio: 0.83; 95% confidence interval: 0.73 to 0.95) compared with patients with EF 33% (n = 1,750; hazard ratio: 0.99; 95% confidence interval: 0.84 to 1.16; interaction as EF by quartiles, p =0.013)]. In an analysis of LVEF quartiles, the drug reduced the risk of PCE only at first two  LVEF quartiles as seen in the bottom :
•          ≤ 22% (HR 0.83; 95% CI 0.73-0.95)
•          23% to 28% (HR 0.85; 95% CI 0.74-0.97)
•          29% to 32% (HR 1.11; 95% CI 0.96-1.28)
•          ≥ 33% (HR 0.99; 95% CI 0.84-1.16)
In the lowest quartile (EF <22%), it was determined that 11.8 patients would need to be treated with omecamtiv mecarbil to prevent one PCE over 3 years. It was also observed that omecamtiv mecarbil was not associated with any negative effects on patients blood pressure, heart rate, potassium levels or renal function in this study. In addition, no increase in cardiac ischemic or ventricular arrhythmic events was detected.

Conclusion :
Treatment with omecamtiv mecarbil was associated with a greater reduction in heart failure related events in patients with low baseline EF. These findings are consistent with the drug’s mechanism of selectively improving systolic function and presents an important opportunity to improve the outcomes in a group of patients most difficult to care.

Interpretations :
Although omecamtiv mecarbil has no significant effect on mortality, it represents a novel therapy that holds the promise of improving outcomes in patients with severely reduced ejection fraction, who are the very patients that are often the most challenging for us to treat.