Physicians' Academy for Cardiovascular Education

Benefits and safety of ARNI in elderly HFrEF patients

Age Differences in Effects of Sacubitril/Valsartan on Cardiac Remodeling, Biomarkers, and Health Status

Literature - Murphy SP, Ward JH, Piña IL, et al. - JACC Heart Fail. 2022 Dec;10(12):976-988. doi: 10.1016/j.jchf.2022.07.001

Introduction and methods


Although the clinical benefits of sacubitril/valsartan (Sac/Val) in HFrEF patients are well established, its utilization is low in older HFrEF patients who are eligible for ARNI therapy [1]. This may be partly related to perceived uncertainty about the clinical benefits and tolerability in this population [2], which in turn is due to the limited number of RCTs in patients >65 years of age and even less in those aged >75 years [3,4].

Previously, the PROVE-HF (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling, and Outcomes) study showed that treatment with Sac/Val was associated with reductions in CV biomarkers linked to cardiac remodeling processes and improvements in measures of cardiac remodeling and health status regardless of sex and race [5,6]. As the investigators of this study had made a conscious effort to enroll elderly patients, 24% of the study participants were ≥75 years of age.

Aim of the study

The authors examined age-related differences in the effects of Sac/Val on CV biomarkers, health status, and echocardiographic measures of reverse cardiac remodeling in the PROVE-HF study.


This was a post-hoc analysis of the PROVE-HF study, a 52-week, multicenter, open-label, single-arm, phase 4 study in which 794 HFrEF patients were initiated on Sac/Val and titrated to a target dose of 97 mg/103 mg twice daily. Levels of NT-proBNP, hs-cTnT, and soluble suppressor of tumorigenicity 2 (sST2) were measured. Health status was assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 overall summary score. With transthoracic echocardiography, LVEF, indexed LV end-systolic volume (LVESVi), indexed LV end-diastolic volume (LVEDVi), and left atrial index volume (LAVi) were measured. In addition, adverse events were assessed.

Main results

Changes in CV biomarkers

Changes in health status

Changes in reverse cardiac remodeling

Adverse events


In a post-hoc analysis of the PROVE-HF study, treatment with Sac/Val was well tolerated and resulted in improvements in prognostic biomarkers, health status, and echocardiographic measures of reverse cardiac remodeling after 12 months in elderly HFrEF patients. However, study participants aged ≥75 years did show a significantly smaller NT-proBNP reduction and significantly less, albeit clinically meaningful, improvement in the KCCQ-23 overall summary score compared with the age groups <65 years and 65–74 years.


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Find this article online at JACC Heart Fail.

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