Analysis Makes Stronger Case for Omecamtiv Mecarbil in Severe HF

People with severe heart failure (HF) appeared to be the ones who benefited meaningfully from omecamtiv mecarbil therapy, according to a post-hoc analysis of the GALACTIC-HF trial.

While the overall study population showed only a modest benefit for the direct cardiac myosin activator in HF with reduced ejection fraction, the approximately one-quarter of patients with severe HF saw a substantial drop in risk of HF events and cardiovascular deaths with the investigational drug compared with placebo (HR 0.80, 95% CI 0.71-0.90) over a median 21.8 months of follow-up.

This translated into an absolute risk reduction of 8.3 events per 100 patient-years for the primary endpoint and a number needed to treat of just 12, reported G. Michael Felker, MD, MHS, of Duke Clinical Research Institute in Durham, North Carolina, and collaborators in JAMA Cardiology.

"Omecamtiv mecarbil therapy was well tolerated in patients with severe HF, with no significant changes in blood pressure, kidney function, or potassium level compared with placebo," the authors wrote. "Overall, these data support both the efficacy and tolerability of omecamtiv mecarbil in a patient population that may be difficult to treat effectively with other HF drugs."

Patients with severe HF in the trial were required to meet three criteria distinguishing them from patients with true end-stage HF:

• New York Heart Association (NYHA) classes III and IV
• Left ventricular ejection fraction (LVEF) ≤30%
• HF hospitalization within the previous 6 months

Felker's group reported that patients who did not meet all three requirements had lower absolute risk and lower relative and absolute benefit from omecamtiv mecarbil. Indeed, study participants without severe HF had no benefit from omecamtiv mecarbil in terms of the primary endpoint (HR 0.99, 95% CI 0.91-1.08, P=0.005 for interaction).

The new stage of severe HF described in the post-hoc analysis represents "not a quirk of recruitment within a large clinical trial but a true, common, and actionable clinical dilemma," wrote JAMA Cardiology editors in an accompanying note.

"It is apparent that an emerging and possibly expanding patient population experiences symptomatic HF along a disease continuum that is interspersed between stages C and D, thereby qualifying as a fifth stage that can be reasonably identified as stage C2," wrote Gregg Fonarow, MD, of Ronald Reagan UCLA Medical Center in Los Angeles, and two colleagues.

"If prospectively acquired data are able to validate this candidate phenotype of progressive (more severe) HF, then not only omecamtiv mecarbil but vericiguat [Verquvo] and sotagliflozin may also provide therapeutic opportunities that are already supported by high-quality evidence," the trio suggested.

GALACTIC-HF's main finding was a small reduction of primary endpoint events when omecamtiv mecarbil was given atop usual HF therapies (37.0% vs 39.1% with placebo, HR 0.92, 95% CI 0.86-0.99). There was no observed benefit in cardiovascular death or other secondary outcomes.

The drug was a miss for preventing cardiovascular death in severe HF patients, too (HR 0.88, 95% CI 0.75-1.03), albeit less so than in the non-severe HF group (P=0.03 for interaction).

The double-blind phase III trial had been conducted in 2017-2020 and included 8,232 patients with symptomatic HF (NYHA classes II to IV) and LVEF of 35% or less.

Of this cohort, 2,258 individuals (mean age 64.5 years, 78.9% men) met the criteria for severe HF.

Felker and colleagues acknowledged that their analysis was subject to the usual limitations of a post-hoc analysis and noted that they had excluded patients who had an estimated glomerular filtration rate lower than 20 mL/min/1.73 m² or who had been receiving dialysis.

Comment