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 Gong; Martin P Lefkowitz; Adel R Rizkala; Scott D Solomon; John J V McMurray

doi:10.1016/j.jacc.2022.06.037

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

Department of Cardiology

3 Citations (Scopus)

Abstract

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 language	English
Journal	Journal of the American College of Cardiology
Volume	80
Issue number	12
Pages (from-to)	1130-1143
Number of pages	14
ISSN	0735-1097
DOIs	https://doi.org/10.1016/j.jacc.2022.06.037
Publication status	Published - 20 Sep 2022

Keywords

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

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10.1016/j.jacc.2022.06.037

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Butt, J. H., Dewan, P., Jhund, P. S., Anand, I. S., Atar, D., Ge, J., Desai, A. S., Echeverria, L. E., Køber, L., Lam, C. S. P., Maggioni, A. P., Martinez, F., Packer, M., Rouleau, J. L., Sim, D., Van Veldhuisen, D. J., Vrtovec, B., Zannad, F., Zile, M. R., ... McMurray, J. J. V. (2022). Sacubitril/Valsartan and Frailty in Patients With Heart Failure and Preserved Ejection Fraction. Journal of the American College of Cardiology, 80(12), 1130-1143. https://doi.org/10.1016/j.jacc.2022.06.037

Butt, JH, Dewan, P, Jhund, PS, Anand, IS, Atar, D, Ge, J, Desai, AS, Echeverria, LE, Køber, L, Lam, CSP, Maggioni, AP, Martinez, F, Packer, M, Rouleau, JL, Sim, D, Van Veldhuisen, DJ, Vrtovec, B, Zannad, F, Zile, MR, Gong, J, Lefkowitz, MP, Rizkala, AR, Solomon, SD & McMurray, JJV 2022, 'Sacubitril/Valsartan and Frailty in Patients With Heart Failure and Preserved Ejection Fraction', Journal of the American College of Cardiology, vol. 80, no. 12, pp. 1130-1143. https://doi.org/10.1016/j.jacc.2022.06.037

@article{03c09895072b432398246b9829c60665,

title = "Sacubitril/Valsartan and Frailty in Patients With Heart Failure and Preserved Ejection Fraction",

abstract = "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).",

keywords = "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",

author = "Butt, {Jawad H} and Pooja Dewan and Jhund, {Pardeep S} and Anand, {Inder S} and Dan Atar and Junbo Ge and Desai, {Akshay S} and Echeverria, {Luis E} and Lars K{\o}ber and Lam, {Carolyn S P} and Maggioni, {Aldo P} and Felipe Martinez and Milton Packer and Rouleau, {Jean L} and David Sim and {Van Veldhuisen}, {Dirk J} and Bojan Vrtovec and Faiez Zannad and Zile, {Michael R} and Jianjian Gong and Lefkowitz, {Martin P} and Rizkala, {Adel R} and Solomon, {Scott D} and McMurray, {John J V}",

year = "2022",

month = sep,

day = "20",

doi = "10.1016/j.jacc.2022.06.037",

language = "English",

volume = "80",

pages = "1130--1143",

journal = "American College of Cardiology. Journal",

issn = "0735-1097",

publisher = "Elsevier Inc",

number = "12",

}

TY - JOUR

T1 - Sacubitril/Valsartan and Frailty in Patients With Heart Failure and Preserved Ejection Fraction

AU - Butt, Jawad H

AU - Dewan, Pooja

AU - Jhund, Pardeep S

AU - Anand, Inder S

AU - Atar, Dan

AU - Ge, Junbo

AU - Desai, Akshay S

AU - Echeverria, Luis E

AU - Køber, Lars

AU - Lam, Carolyn S P

AU - Maggioni, Aldo P

AU - Martinez, Felipe

AU - Packer, Milton

AU - Rouleau, Jean L

AU - Sim, David

AU - Van Veldhuisen, Dirk J

AU - Vrtovec, Bojan

AU - Zannad, Faiez

AU - Zile, Michael R

AU - Gong, Jianjian

AU - Lefkowitz, Martin P

AU - Rizkala, Adel R

AU - Solomon, Scott D

AU - McMurray, John J V

PY - 2022/9/20

Y1 - 2022/9/20

N2 - 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).

AB - 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).

KW - Aminobutyrates/pharmacology

KW - Angiotensin Receptor Antagonists/pharmacology

KW - Angiotensin-Converting Enzyme Inhibitors/therapeutic use

KW - Biphenyl Compounds/therapeutic use

KW - Drug Combinations

KW - Frailty

KW - Heart Failure/drug therapy

KW - Humans

KW - Stroke Volume

KW - Tetrazoles/pharmacology

KW - Valsartan

KW - clinical trial

KW - heart failure

KW - frailty

KW - outcomes

UR - http://www.scopus.com/inward/record.url?scp=85137115334&partnerID=8YFLogxK

U2 - 10.1016/j.jacc.2022.06.037

DO - 10.1016/j.jacc.2022.06.037

M3 - Journal article

C2 - 36050227

VL - 80

SP - 1130

EP - 1143

JO - American College of Cardiology. Journal

JF - American College of Cardiology. Journal

SN - 0735-1097

IS - 12

ER -

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

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