Cardiac-myosin activator yields greatest benefit in severe heart failure

Reuters Health - 20/05/2021 -The novel heart-failure drug omecamtiv mecarbil reduced heart-failure hospitalizations by a greater margin among patients with more severely reduced ejection fraction, according to new data from the GALACTIC-HF trial.

"This is a drug that will potentially help the very group of patients that are most difficult to care for," lead investigator Dr. John R. Teerlink of the University of California, San Francisco, and the San Francisco VA Medical Center said in a news release.

"While the results from GALACTIC-HF show omecamtiv mecarbil brought improvements overall, these new findings point to a group of patients with more severe heart failure in whom there is even greater benefit," he noted.

The findings were published in the Journal of the American College of Cardiology to coincide with presentation at ACC.21, the virtual annual meeting of the American College of Cardiology.

Omecamtiv mecarbil is an experimental, first-in-class, selective cardiac-myosin activator that improves cardiac structure and function in patients with heart failure and reduced ejection fraction (HFrEF).

The GALACTIC-HF trial enrolled 8,256 patients with symptomatic chronic HF and an EF of 35% or less. Patients were randomly allocated to omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo on top of standard therapy. The primary outcome was a composite of a first HF event (hospitalization or urgent visit for HF) or cardiovascular death.

As reported earlier this year in the New England Journal of Medicine (https://bit.ly/3uWxiDA), during a median of 21.8 months, a primary-outcome event occurred in slightly fewer patients taking omecamtiv mecarbil than those taking placebo (37.0% vs. 39.1%; hazard ratio, 0.92; 95% confidence interval: 0.86 to 0.99).

The new analysis shows that the therapeutic effect of omecamtiv mecarbil is modified by baseline EF. Patients receiving omecamtiv mecarbil had a progressively greater relative and absolute benefit in terms of the primary composite outcome as baseline EF decreased, with a 17% reduction in the primary composite endpoint in patients with baseline EF of 22% or less compared to patients with EF at or above 33%.

The absolute risk reduction in patients with baseline EF of 22% or less was 7.4 per 100 patient-years. "Fewer than 12 patients would need to be treated to prevent one heart failure event or cardiovascular death," Dr. Teerlink said in his presentation.

He noted that the drug "appeared to be safe. There were no differences in serious adverse, ischemic or arrhythmic events across the range of ejection fractions between the omecamtiv mecarbil and the placebo groups. And importantly there was no adverse effect on blood pressure, heart rate, potassium homeostasis or renal function, even in the lowest EF quartile."

"We believe that omecamtiv mecarbil represents a novel therapy that holds the promise of improving clinical outcomes in patients with severely reduced ejections fractions, who are the very patients that are often the most challenging to treat," Dr. Teerlink concluded.

Commenting on the study at ACC.21, Dr. Ileana L. Pina of Central Michigan University, in Midlands, said the results are "highly encouraging because how long has it been that we've been waiting for a drug that we can really use in this really sick population where that ejection fraction is getting lower and lower are the people that we recommend for transplant and for mechanical assistance? It fits into that group and where we are very loathe to use an inotrope because we know that ultimately the inotrope is not going to do well. So I see this as an advancement."

In a linked editorial, Dr. Joao Pedro Ferreira of the University of Porto, in Portugal, points out that the primary analysis of the trial suggested a greater benefit of omecamtiv mecarbil among patients in sinus rhythm compared with patients with atrial fibrillation.

"Omecamtiv mecarbil increases systolic stroke power and the atrial contractile function; therefore, it is plausible that the drug only benefits patients with a severely impaired LVEF in sinus rhythm, in whom the increment in ventricular and atrial contraction may produce a meaningful and beneficial impact on outcomes," Dr. Ferreira writes.

"In an era where adding more treatments to the therapeutic armamentarium of patients with HFrEF is increasingly difficult, personalized treatment approaches are necessary to cover unmet needs, benefit patients who need the most, and also to be cost-effective and generate return of investment," he adds.

"Ejection fraction (and atrial rhythm) are probably the best means to stratify and identify patients responsive to omecamtiv mecarbil in a manner that is completely aligned with the biological mechanisms of the drug and using widely available and inexpensive biomarkers (an echo- and electrocardiogram)."

"Based on LVEF as a continuous variable, the 'sweet spot' where the effect of omecamtiv mecarbil begins to occur is below 25%; therefore, based on the large number of patients and events among those with severely impaired ejection fraction in GALACTIC-HF, omecamtiv mecarbil should be recommended to patients with a LVEF <25% to reduce HF hospitalizations. Whether atrial rhythm should be part of the decisional algorithm should be explored in further studies," Dr. Ferreira concludes.

The study was funded by Amgen, Cytokinetics, Inc. and Servier. Several authors have disclosed financial relationships with the companies.

SOURCE: https://bit.ly/3opys82 and https://bit.ly/3474xbD Journal of the American College of Cardiology, online May 17, 2021.

By Megan Brooks



Posted on 20 May 20211 June 2021