Omecamtiv mecarbil lowers CV death/HF events in HFrEF: GALACTIC-HF
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Omecamtiv mecarbil, a novel selective cardiac myosin activator, was associated with an 8% reduction in CV death or first HF events in patients with HF with reduced ejection fraction, according to results of the GALACTIC-HF trial.
Researchers randomly assigned 8,256 patients (mean age, 66 years; 21% women) with symptomatic chronic HF with an EF of 35% or less to omecamtiv mecarbil (Amgen/Cytokinetics/Servier) or placebo in addition to standard HF therapies. The primary outcome was a composite of CV death or first HF event (HF hospitalization or urgent HF visit).
A defining feature of HFrEF “is a decrease in systolic function, yet despite extensive investigative efforts for over a century, no therapies for chronic heart failure with reduced ejection fraction that targeted this systolic dysfunction have improved patient outcomes,” John R. Teerlink, MD, FACC, FAHA, FESC, FHFSA, professor of medicine at the University of California, San Francisco, and director of heart failure and the echocardiography laboratory at the San Francisco Veterans Affairs Medical Center, said during a press conference at the virtual American Heart Association Scientific Sessions. “In fact, most have actually increased mortality. Omecamtiv mecarbil is a novel selective cardiac myosin activator, a myotrope, that improves cardiac remodeling and systolic function and decreases heart rate and [N-terminal pro-B-type natriuretic peptide] in patients with HFrEF. The GALACTIC-HF trial tested for the first time the hypothesis that specifically improving cardiac performance can result in improved clinical outcomes in patients with HFrEF.”
The results were simultaneously published in The New England Journal of Medicine.
Improved clinical outcomes
At a median of 21.8 months, the primary endpoint was lower in the omecamtiv mecarbil group compared with the placebo group (HR = 0.92; 95% CI, 0.86-0.99), Teerlink said during the press conference.
“For the first time, these results confirm the hypothesis that selectively increasing cardiac function with a cardiac myosin activator ... can improve clinical outcomes in patients with heart failure and reduced ejection fraction,” he said.
Among the individual components of the primary endpoint, the treatment effect of omecamtiv mecarbil was more prominent for first HF event (HR = 0.93; 95% CI, 0.86-1) than for CV death (HR = 1.01; 95% CI, 0.92-1.11), Teerlink said.
Of note, he said, patients with an EF of 28% (the median of the cohort) or lower benefited more from omecamtiv mecarbil than patients with EF greater than 28%. In the group with EF at or below the median, omecamtiv mecarbil reduced the primary endpoint by 16% (HR = 0.84; 95% CI, 0.77-0.92), but the group with EF above the median, omecamtiv mecarbil had no impact on the primary endpoint (HR = 1.04; 95% CI, 0.94-1.16; P for interaction = .003).
“Given omecamtiv mecarbil’s mechanism of action of increasing cardiac function, there is biological plausibility that there may be greater benefit in patients with more substantially reduced systolic function and suggest there may be patient populations who derive even greater benefit from this therapy,” Teerlink said.
The omecamtiv mecarbil group had more improvement in Kansas City Cardiomyopathy Questionnaire score between baseline and 24 weeks compared with the placebo group, (P for joint test = .028), but the endpoint did not meet the prespecified significance threshold of P = .002, Teerlink said.
Adverse events were similar between the groups, according to the researchers.
Other results were reflective of how omecamtiv mecarbil uses a different mechanism of action from other HF therapies, Teerlink said, noting it did not reduce BP, did not affect renal function or potassium homeostasis, reduced heart rate by 1.6% at 24 weeks, reduced NT-proBNP by 10% at 24 weeks and minimally increased cardiac troponin I at 24 weeks.
This suggests the drug “could be readily incorporated into contemporary heart failure treatment algorithms and would not compete with initiation or dosing of established heart failure therapies,” Teerlink told Healio.
Promising signals, future directions
During a discussant presentation at the press conference, Paul Heidenreich, MD, MS, professor of medicine and epidemiology and public health at Stanford University School of Medicine and chief of medicine at the VA Palo Alto Health Care System, said a treatment’s use is generally considered in terms of survival, health status and cost.
“Clearly, with reduced hospitalizations, we’ve lowered cost,” he said. “There was a signal, although it didn’t meet the prespecified statistical significance level, for an improvement in health status. Those two are encouraging. If we then compare it to what we already have ... three medication groups as well as devices already established, and this is now the third major type of drug tested since [the 2017 American College of Cardiology AHA HF guidelines], the SGLT2 inhibitors did show a survival benefit and will likely become part of quadruple therapy. It remains to be investigated and discussed exactly where omecamtiv mecarbil will fit in.”
He added that it is “encouraging ... that there is no reduction in blood pressure, which is often a major limiting factor for many heart failure patients who can’t tolerate other heart failure therapies. This may be an option [for them].”
Reference:
Perspective
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Lee R. Goldberg, MD, MPH, FACC, FAHA
Omecamtiv mecarbil appears safe in HF with low ejection fraction with at least moderate risk given current or recent hospitalization. This is an important observation, as all other inotropic agents, even digoxin, have been associated with increased mortality, arrhythmias and other adverse effects.
My sense is that this agent would be reserved for use as second or third line after an angiotensin receptor/neprilysin inhibitor, a mineralocorticoid receptor antagonist, biventricular pacing, etc. had been tried. This is because the only impact appeared to be on hospitalization, with no impact on quality of life by KCCQ and no positive impact on mortality. Although hospitalizations are an important patient-centered outcome and could impact global quality of life, I was a little surprised that this agent did not show improved symptoms/quality of life given the mechanism of action. Other inotrope trials typically show improved symptoms but at the cost of increased mortality.
Likely, this agent would be reserved for use as second- or third-line therapy after the treatments mentioned previously had been tried.
I also think that there could be role for those with a more impaired LV function. In the paper, the cut-off of < 28% LVEF was used. This group may get more benefit and may also be at higher risk.
We may need a more focused trial on patients with more advanced symptomatic HF, NYHA class III and IV, to determine if there is an augmented benefit and whether a larger trial in this population would show improved symptoms/quality of life.
Perspective
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Paul J. Mather, MD, FACC, FACP, FAHA, FHFSA, FESC
The one thing that struck me the most about this trial was that all the trials of pro-inotropic agents in the past resulted in higher death rates. This was the first oral inotropic agent that was not associated with increased mortality and arrhythmia. That is a huge barrier that we have overcome with this type of compound.
The results are enough to add the agent to our armamentarium, but not as a first-line therapy. It will still be beta-blockers, which should be the first class of agent tried, followed by ARNIs, MRAs and BiV pacing. Then omecamtiv mecarbil can be used for very sick patients. The agent had no impact on mortality or quality of life. Those with severe HF may derive more benefit from omecamtiv mecarbil.
Usually, inotropic agents improve symptoms at the cost of increased mortality, but with this one, there was no increased mortality but also not a quality-of-life improvement.
We need to have more trials focused on very sick patients with HF. There are more than 64 million patients with HF globally. Even if only 20% have advanced HF, that is still a very large number.
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Teerlink JR, et al. LBS.01: Heart failure and atrial fibrillation: Vitamins, minerals, nutrients and more. Presented at: American Heart Association Scientific Sessions; Nov. 13-17, 2020 (virtual meeting).
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