Drug combination may reduce CV mortality in HF patients across the ejection fraction spectrum


Researchers in Late-Breaking Science sessions during Scientific Sessions presented the pooled PARAGON-HF and PARADIGM-HF analysis and the latest results on:

  • Gender differences and response to treatment in heart failure patients with preserved ejection fraction
  • A drug that improves exercise performance with Fontan circulation
  • How older HF patients tolerated dapagliflozin and patients’ reported quality of life

Sacubitril/valsartan associated with better outcomes in HF patients with preserved ejection fraction

In a pooled analysis of 13,195 heart failure patients across the spectrum of ejection fraction, those randomized to sacubitril/valsartan compared with a
renin-angiotensin-aldosterone system inhibitor had:

  • 16% reduction in first cardiovascular death or heart failure hospitalization
  • 12% reduction in all-cause mortality

The PARADIGM-HF group randomized 8,399 heart failure patients with ejection fraction of 40% or lower to sacubitril/valsartan 97/103 mg bid versus enalapril 10 mg bid.

The PARAGON-HF group randomized 4,796 heart failure patients ≥ 50 years, LVEF of 45% or greater to sacubitril/valsartan 97/103 mg bid or valsartan 160 mg bid.

Other than ejection fraction, the inclusion criteria of both trials were similar.

“This is the largest program of heart failure across the full spectrum of ejection fraction,” said Scott Solomon, MD, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital in Boston, and co-chair of PARAGON-HF.

However, among the 13,195 randomized patients, the treatment effect for all outcomes declined with increasing left ventricle ejection fraction, Solomon said.

“The treatment effect began to decline at ejection fractions of around 60%, but it appeared that women derived benefit to higher ejection fractions than men,” Solomon said.

“These data strongly suggest that patients with heart failure and ejection fraction that is lower than normal, but not frankly reduced, might benefit from sacubitril/valsartan,” Solomon said.

Researchers also presented a gender-based analysis of PARAGON-HF. The coprimary endpoint of heart failure hospitalizations and CV death in patients receiving sacubitril/valsartan was reduced by 13%, but the treatment effect didn’t reach statistical significance (P value 0.059).

Still, researchers found a marked heterogeneity in treatment benefits.

“In Paragon-HF, we found that a patient’s sex modified response to treatment, whereby women seemed to benefit substantially with men not nearly as much,” said John JV McMurray, MD, FRCP, FESC, FACC, FAHA, FRSE, professor of cardiology at the Institute of Cardiovascular & Medical Sciences at the University of Glasgow, United Kingdom.

McMurray, co-chair of PARAGON-HF, said women with heart failure, on average, have higher ejection fractions than men.

“There seems to be an interplay between sex hormones and natriuretic peptides,” McMurray said.

Whether sacubitril/valsartan could be effective for women with HFpEF “hinges on whether we believe this phenomenon is a real or chance finding,” McMurray said. “The whole story of women versus men with heart failure preserved ejection fraction needs a lot more research.”

Several potential biological mechanisms may explain it, such as a deficit in cGMP-PKG signaling in post-menopausal women and more systolic dysfunction in women than men in the EF range of 40% to 65%, McMurray said.

Udenafil improved exercise performance in adolescents with Fontan circulation

Udenafil improved submaximal exercise capacity, the secondary outcome, in pediatric patients with single ventricle heart disease after the Fontan operation, according to results from the Pediatric Heart Network’s Fontan Udenafil Exercise Longitudinal Trial (FUEL). The primary endpoint, a change in oxygen consumption at peak exercise, was not statistically improved.

“For the first time since the Fontan procedure was first described in 1971, a medication option has been identified with an identifiable benefit for the single ventricle population,” said David J. Goldberg, MD, a cardiologist in the Cardiac Center and Fetal Heart Program at Children’s Hospital of Philadelphia and the study’s co-principal investigator.

The Fontan procedure creates a cardiopulmonary connection, a circulation that magnifies the importance of pulmonary vascular resistance as a modulator of pulmonary blood flow and cardiac preload. Over time, however, cardiovascular efficiency can deteriorate, marked by a decline in exercise performance that correlates with increased morbidity and early mortality.

The trial randomized 400 adolescents who had the Fontan procedure to either udenafil, 87.5 mg twice daily or to placebo. The primary endpoint was the change in oxygen consumption at peak exercise over six months measured by standardized cardiopulmonary exercise testing.

Goldberg and his research team selected exercise as their primary aim because multiple cardiovascular disease studies demonstrate a strong correlation between exercise capacity and overall morbidity and mortality, heart failure, the need for a transplant, hospitalization and death.

“Because each of those outcomes is relatively rare with Fontan physiology, exercise was an appropriate surrogate,” Goldberg said.

The study found a statistically improvements in submaximal exercise performance measured at the ventilatory anaerobic threshold.

“Improvement in submaximal exercise has real implications for the day-to-day activities of adolescents with Fontan physiology,” Goldberg said.

Glucose-lowering drug may help manage HF, improve quality of life in all ages

In an age-based analysis, dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, effectively reduced cardiovascular death and hospitalization in heart failure patients of all ages.

The 18-month Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure Trial (DAPA-HF) study randomized 4,744 patients with heart failure and reduced ejection fraction to dapagliflozin 10 mg once daily or matching placebo.

Overall, 60% of patients in the study were older than 65; the oldest patient was 94.

“Dapagliflozin was well tolerated, and the rate of treatment discontinuation was low, in all age groups,” said Felipe A. Martinez, MD, professor of medicine at the Cordoba National University in Argentina. “Dapagliflozin offers a new approach to the treatment of HFrEF irrespective of age.”

In a further analysis of DAPA-HF according to symptoms and quality of life, McMurray reported that heart failure patients randomized to dapagliflozin were more likely to report an improvement in symptoms and quality of life compared to the placebo group.

The analysis relied on patient feedback collected with the Kansas City Cardiomyopathy Questionnaire, a standard tool for assessing symptoms and quality of life in clinical trials.