Benefits and safety of ARNI in elderly HFrEF patients

Introduction and methods

Background

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.

Methods

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

• Following initiation of Sac/Val treatment, there were significant reductions in NT-proBNP, hs-cTnT, and sST2 levels across all age categories.
• From baseline to 12 months, the extent of reduction in geometric mean NT-proBNP concentration was less in patients aged ≥75 years (–30.5%) compared with the groups 65–74 years (−40.2%) and <65 years (−45.6%) (P for overall comparison=0.02).
• Reductions in hs-cTnT and sST2 levels were similar among the age groups.

Changes in health status

• In all age groups, there was an early and significant increase in the KCCQ-23 overall summary score after initiation of Sac/Val treatment, which was sustained throughout the study period.
• From baseline to 12 months, the magnitude of improvement in mean KCCQ-23 overall summary score was smaller in patients aged ≥75 years (+6.0 points) compared with patients aged 65–74 years (+11.4 points) or <65 years (+11.8 points) (P=0.03 for overall comparison).
• In a responder analysis, similar proportions of each age group achieved increases of ≥10 points or ≥20 points in KCCQ-23 overall summary score from baseline to 12 months (nonsignificant P values for overall comparison).

Changes in reverse cardiac remodeling

• Reverse LV remodeling occurred in all age groups (<65 years vs. 65–74 years vs. ≥75 years). At 12 months, similar changes were observed in LVEF (+9.3% vs. +9.2% vs. +9.8%; P=0.62), LVEDVi (−12.2 vs. −12.0 vs. −12.9 mL/m2; P=0.40), and LVESVi (−15.3 vs. −15.2 vs. −15.7 mL/m2; P=0.70).
• Of note, at 6 months, the magnitude of reverse LV remodeling was slightly but significantly larger among the age groups <65 years and 65–74 years compared with patients ≥75 years of age.
• Similar results were seen for reverse LA remodeling. At 12 months, all age groups showed a comparable improvement in LAVi (−7.6 vs. −7.9 vs. −7.1 mL/m2; P=0.17), but the initial reverse remodeling (from baseline to 6 months) was significantly slower in those ≥75 years compared with the younger age groups.

Adverse events

• In general, the Sac/Val treatment was well tolerated.
• The incidence of adverse events—such as hypotension, hyperkalemia, and worsening renal function—was similar between the age groups, although the target dose was less frequently achieved in patients aged ≥75 years compared with the age groups <65 years and 65–74 years (55% vs. 61% vs. 65%; P=0.003).

Conclusion

References

Find this article online at JACC Heart Fail.