Sacubitril/Valsartan and Frailty in Patients With Heart Failure and Preserved Ejection Fraction

Jawad H Butt, Pooja Dewan, Pardeep S Jhund, Inder S Anand, Dan Atar, Junbo Ge, Akshay S Desai, Luis E Echeverria, Lars Køber, Carolyn S P Lam, Aldo P Maggioni, Felipe Martinez, Milton Packer, Jean L Rouleau, David Sim, Dirk J Van Veldhuisen, Bojan Vrtovec, Faiez Zannad, Michael R Zile, Jianjian GongMartin P Lefkowitz, Adel R Rizkala, Scott D Solomon, John J V McMurray*

*Corresponding author for this work
3 Citations (Scopus)


BACKGROUND: Frailty is an increasingly common problem, and frail patients are less likely to receive new pharmacologic therapies because the risk-benefit profile is perceived to be less favorable than in nonfrail patients.

OBJECTIVES: This study investigated the efficacy of sacubitril/valsartan according to frailty status in 4,796 patients with heart failure with preserved ejection fraction randomized in the PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial.

METHODS: Frailty was measured by using the Rockwood cumulative deficit approach. The primary endpoint was total heart failure hospitalizations or cardiovascular death.

RESULTS: A frailty index (FI) was calculable in 4,795 patients. In total, 45.2% had class 1 frailty (FI ≤0.210, not frail), 43.5% had class 2 frailty (FI 0.211-0.310, more frail), and 11.4% had class 3 frailty (FI ≥0.311, most frail). There was a graded relationship between FI class and the primary endpoint, with a significantly higher risk associated with greater frailty (class 1: reference; class 2 rate ratio: 2.19 [95% CI: 1.85-2.60]; class 3 rate ratio: 3.29 [95% CI: 2.65-4.09]). The effect of sacubitril/valsartan vs valsartan on the primary endpoint from lowest to highest FI class (as a rate ratio) was: 0.98 [95% CI: 0.76-1.27], 0.92 [95% CI: 0.76-1.12], and 0.69 [95% CI: 0.51-0.95]), respectively (Pinteraction = 0.23). When FI was examined as a continuous variable, the interaction with treatment was significant for the primary outcome (Pinteraction = 0.002) and total heart failure hospitalizations (Pinteraction < 0.001), with those most frail deriving greater benefit.

CONCLUSIONS: Frailty was common in heart failure with preserved ejection fraction and associated with worse outcomes. Compared with valsartan, sacubitril/valsartan seemed to show a greater reduction in the primary endpoint with increasing frailty, although this was not significant when FI was examined as a categorical variable. (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Original languageEnglish
JournalJournal of the American College of Cardiology
Issue number12
Pages (from-to)1130-1143
Number of pages14
Publication statusPublished - 20 Sep 2022


  • Aminobutyrates/pharmacology
  • Angiotensin Receptor Antagonists/pharmacology
  • Angiotensin-Converting Enzyme Inhibitors/therapeutic use
  • Biphenyl Compounds/therapeutic use
  • Drug Combinations
  • Frailty
  • Heart Failure/drug therapy
  • Humans
  • Stroke Volume
  • Tetrazoles/pharmacology
  • Valsartan
  • clinical trial
  • heart failure
  • frailty
  • outcomes


Dive into the research topics of 'Sacubitril/Valsartan and Frailty in Patients With Heart Failure and Preserved Ejection Fraction'. Together they form a unique fingerprint.

Cite this