ARNI reduces adverse renal events and slows kidney function decline in HFpEF patients
Angiotensin-Neprilysin Inhibition and Renal Outcomes in Heart Failure with Preserved Ejection Fraction
Introduction and methods
Patients with heart failure (HF) have a higher prevalence of comorbidity of chronic kidney disease (CKD) and an increased risk of an adverse CV event compared to HF patients without CKD [1-3]. Inhibiting the renin-angiotensin system (RAS) in HF patients with reduced ejection fraction (HFrEF) reduces mortality and in diabetes slows down the course of proteinuric CKD [4-6]. However, blocking RAS in HF patients with preserved ejection fraction (HFpEF) has not led to a reduction in mortality or adverse renal events [7-10].
The angiotensin neprilysin inhibitor (ARNI) sacubitril/valsartan in HFrEF patients reduced CV mortality and HF hospitalization, and also slowed the rate of decrease in estimated glomerulus filtration rate (eGFR) [11,12]. In a subanalysis of the phase 2 PARAMOUNT trial the results suggest less decline in renal function with sacubitril/valsartan compared with valsartan only in a small group of HFpEF patients .
This study reports the pre-specified secondary renal outcome of the PARAGON-HF trial. The PARAGON-HF was a multicenter, double blind clinical trial of HFpEF patients with high prevalence of comorbidities , who were randomized to sacubitril/valsartan (n=2407) or valsartan alone (n=2389). The renal outcome in this substudy was a composite of ≥50% decline in eGFR relative to baseline, development of end-stage renal disease (ESRD), or renal death and an exploratory outcome was the overall effect of the treatment on eGFR decline in time. To assess the effect of drug administration on individual renal outcome, the cohort was divided into subgroups based on eGFR baseline kidney function (≥30 - <60 ml/min/1.73m2 and ≥60 ml/min/1.73m2). At baseline, the mean eGFR (±SD) was 63 (±19) ml/min/1.73m2. Total follow-up time was 129 weeks.
- There were less adverse renal events in the sacubitril/valsartan group (1.4%) compared to the valsartan only group (2.7%) (HR 0.50, 95% CI: 0.33-0.77, P<0.001).
- The sacubitril/valsartan group had a lower incidence of ≥50% decline in eGFR relative to baseline compared to valsartan, namely, 1.1% treated with sacubitril/valsartan compared to 2.5% with valsartan treatment (HR 0.44, 95% CI: 0.28-0.69). ESRD occurred in 0.3% of patients treated with sacubitril/valsartan compared to 0.5% of patients treated with valsartan (HR 0.58, 95% CI: 0.23-1.47). Renal death occurred in 2 patients; one in the sacubitril/valsartan group and one in the valsartan alone group.
- The decline in eGFR was attenuated for patients treated with sacubitril/valsartan (-2.0 ml/min/1.73 m2 per year [95%CI: 2.2 to -1.9]) compared with patients treated with valsartan (-2.7 ml/min/1.73 m2 per year [95%CI: -2.8 to -2.5]). The adjusted mean difference between sacubitril/valsartan and valsartan treatment was 0.6 ml/min/1.73 m2 per year (95% CI: 0.4-0.9, P<0.001). When additionally adjusted for blood pressure, the eGFR change difference was still 0.6 ml/min/1.73 m2 per year (95% CI: 0.3-0.8, P<0.001).
- No differences in treatment effects on renal outcome were observed between the two baseline eGFR groups (Pinteraction=0.92).
- Patients with baseline eGFR <60 ml/min/1.73 m2 treated with sacubitril/valsartan had, compared with the valsartan group, more episodes of hypotension, fewer episodes of elevated serum creatinine ≥2 mg/dL. Patients with baseline eGFR ≥60 ml/min/1.73 m2 in the sacubitril/valsartan group experienced fewer episode of elevated creatinine ≥2 mg/dL or hyperkalemic (≥6 mmol/L) events.
In this prespecified analysis of the PARAGON-HF trial, patients with HFpEF who were on sacubitril/valsartan had fewer renal outcomes and a slower decline of eGFR compared to those on valsartan. These effects were independent of baseline eGFR, indicating that sacubitril/valsartan may slow down renal function decline in patients with HFpEF.