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Angiotensin-Neprilysin Inhibition and Renal Outcomes in HFpEF
Quick Takes
- As compared with valsartan alone, sacubitril/valsartan was associated with a lower risk of adverse renal events in HFpEF patients, driven largely by a lower risk of ≥50% decline in eGFR.
- This study excluded patients with stage 4 and 5 CKD, and more data are needed in this particularly vulnerable population.
Study Questions:
What is the impact of angiotensin-neprilysin inhibition on renal events among patients with heart failure with preserved ejection fraction (HFpEF)?
Methods:
This was a prespecified secondary analysis of renal outcomes within the PARAGON-HF trial. Inclusion criteria were as follows: age ≥50 years, left ventricular ejection fraction (LVEF) ≥45% with LV hypertrophy or left atrial enlargement, elevated natriuretic peptide levels, and need for maintenance diuretic therapy. Notable exclusion criteria were hypotension, evidence of advanced or progressive chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] <30 ml/min/1.73 m2 at screening or <25 ml/min/1.73 m2 at randomization, or a decrease >35% in eGFR between screening and randomization), and hyperkalemia. The composite renal outcome included the following: ≥50% decline in eGFR relative to baseline, development of end-stage renal disease (ESRD), and death due to renal causes. An intention-to-treat approach was used for data analysis. No formal power calculations were performed for renal outcomes.
Results:
A total of 4,796 patients (52% women, 2% Black, 13% Asian, 81% White) were included in the efficacy analysis. The composite renal outcome occurred in 33/2,407 patients (1.4%) in the sacubitril/valsartan group and 64/2,389 patients (2.7%) in the valsartan group (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.33-0.77; p = 0.001). This difference was largely driven by a lower risk of ≥50% decline in eGFR in the sacubitril/valsartan group (27 patients, 1.1% vs. 60 patients, 2.5%; HR, 0.44), as progression to ESRD and death from renal causes were uncommon (ESRD, seven sacubitril/valsartan patients and 12 valsartan patients; renal death, one patient in each group). The 4-year risk of meeting the composite renal endpoint was 2.1% in the sacubitril/valsartan group and 4.1% in the valsartan group (number needed to treat = 51). The treatment effect was not significantly modified by baseline eGFR (<60 vs. ≥60 ml/min/1.73 m2), sex, or EF. Mean decline in eGFR over the approximate 4-year follow-up period was greater in the valsartan group than in the sacubitril/valsartan group (adjusted mean difference, 0.6 ml/min/1.73 m2, 95% CI, 0.4-0.9; p < 0.001) and was similar after additional adjustment for changes in blood pressure. With regard to safety, patients with eGFR <60 ml/min/1.73 m2 had more adverse events and study drug discontinuation than those with eGFR ≥60 ml/min/1.73 m2, and hypotension was more common among those with eGFR <60 ml/min/1.73 m2 assigned to the sacubitril/valsartan group.
Conclusions:
As compared with valsartan alone, sacubitril/valsartan was associated with a lower risk of adverse renal events in HFpEF patients, driven largely by a lower risk of ≥50% decline in eGFR. Patients treated with sacubitril/valsartan had a slightly but significantly slower decline in eGFR than those treated with valsartan.
Perspective:
In PARAGON-HF, sacubitril-valsartan reduced the primary composite endpoint of cardiovascular death and HF hospitalization by 13% as compared with valsartan alone, though this difference was not statistically significant (rate ratio, 0.87; 95% CI, 0.75-1.01; p = 0.06) (Solomon SD, et al., N Engl J Med 2019;381:1609-20). In a prespecified subgroup analysis, patients with eGFR <60 ml/min/1.73 m2 experienced a lower rate of the primary composite endpoint than those with preserved renal function. The secondary renal endpoint analysis presented in the current manuscript is encouraging, and it is plausible that neprilysin inhibition could reduce plasma volume and thereby lead to renal decongestion. While this is likely to be helpful in patients with cardiorenal syndrome, patients with CKD of other etiologies may not experience similar benefits. Limitations of the study include low minority enrollment and lack of data on proteinuria. This study excluded patients with stage 4 and 5 CKD, and more data are needed in this particularly vulnerable population.
Clinical Topics: Diabetes and Cardiometabolic Disease, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Chronic Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: Angiotensins, Blood Pressure, Cardio-Renal Syndrome, Diuretics, Geriatrics, Glomerular Filtration Rate, Heart Failure, Hyperkalemia, Hypertrophy, Left Ventricular, Kidney Diseases, Metabolic Syndrome, Natriuretic Peptides, Neprilysin, Renal Insufficiency, Secondary Prevention, Stroke Volume
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