PIONEER-HF: Sacubitril/valsartan reduced cardiovascular biomarker in patients with reduced ejection fraction hospitalized for acute decompensated heart failure

Compared to enalapril, sacubitril/valsartan was associated with a greater reduction in the biomarker N-terminal pro-brain natriuretic peptide and re-hospitalization for heart failure, according to a study presented at Scientific Sessions 2018 in Chicago.

PIONEER-HF (Angiotensin Receptor-Neprilysin Inhibition in Patients Hospitalized With Acute Decompensated Heart Failure) — a prospective, multicenter, double-blind, randomized, active-controlled trial — compared the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (n = 440) with enalapril (n = 441) in hemodynamically stabilized patients with acute heart failure and reduced ejection fraction.

Presenter Eric Velazquez, MD, professor of medicine in cardiology at Yale University School of Medicine in New Haven, Connecticut, said guideline-directed therapy for acute decompensated heart failure has been limited despite accounting for more than 1 million hospitalizations annually in the United States.

The current standard of care includes decongestion with diuretics and hemodynamic support with vasodilators and inotropes.

Study drug doses were titrated over eight weeks following in-hospital initiation of treatment. The titration algorithm was based on systolic blood pressure and aimed at target doses of sacubitril/valsartan 97/103 mg twice daily or enalapril 10 mg twice daily.

Researchers evaluated a biomarker surrogate of efficacy, safety, tolerability and clinical outcomes.

Key entry criteria included an SBP of at least 100 millimeters of mercury and no symptomatic hypotension, no increase in intravenous diuretics, no IV vasodilators and no IV inotropes within the prior 24 hours.

The primary endpoint was the proportional change in NT-proBNP from baseline to the mean of weeks four and eight. NT-proBNP is a biomarker of neurohormonal activation, hemodynamic stress and subsequent cardiovascular events.

Safety endpoints included worsening renal function, symptomatic hypotension, hyperkalemia and angioedema.

Exploratory clinical outcomes were:

  • Serious clinical composite: death, re-hospitalization for HF, left ventricular assist device or listing for cardiac transplant
  • Expanded composite: serious composite plus addition of HF medication, unplanned outpatient IV diuretics or a greater than 50 percent increase in dose

At baseline, about a third of patients had no prior HF diagnosis; 25-30 percent were women; and 36 percent self-identified as African-American.

  • For the primary endpoint of percent change in NT-proBNP, the reduction was 29 percent greater with sacubitril/valsartan (CI 19 percent, 37 percent; P<0.0001). There were no significant differences in safety events between the sacubitril/valsartan and enalapril treatment groups.
  • For the serious composite clinical endpoint, the event rate for sacubitril/valsartan was 9.3 percent versus 16.8 percent, which was statistically significantly lower (HR 0.54; 95 percent CI 0.37, 0.79; P=0.001).
  • Of the exploratory clinical endpoints, only re-hospitalization for HF was statistically significantly different between treatment groups: 8 percent in the sacubitril/valsartan group versus 13.8 percent in the enalapril group (HR 0.56; P=0.005). There were no statistically significant interactions in subgroup analyses of the primary endpoint or the serious composite endpoint.

Larry Allen, MD, professor of medicine in cardiology at the University of Colorado School of Medicine in Aurora, said sacubitril/valsartan use may be low due to clinical inertia.

He also noted that the median age of 62 years of the study participants was 10 years younger than the typical HF population and that relatively few patients with Stage D HF were included because of the exclusion criteria.

“In a post-PIONEER world, one of the great things about this study is that it keeps it simple,” Allen said. “This simpler algorithm for inpatient and subsequent outpatient HR rRF management is better for both clinicians and patients. It also reinforces the importance and safety of aggressive guideline-determined medical therapy in most patients.”