Benefits and safety of ARNI in elderly HFrEF patients
Age Differences in Effects of Sacubitril/Valsartan on Cardiac Remodeling, Biomarkers, and Health Status
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 . This may be partly related to perceived uncertainty about the clinical benefits and tolerability in this population , 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.
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.
- 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).
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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