By Jamie L. W. Kennedy, MD, FACC

Associate Professor, Division of Cardiology, Advanced Heart Failure & Transplant Cardiology, University of California, San Francisco

Dr. Kennedy reports no financial relationships relevant to this field of study.

SYNOPSIS: An analysis of renal outcomes in the PARAGON-HF trial revealed sacubitril/valsartan slows progression of kidney disease in patients with heart failure with preserved ejection fraction compared to valsartan alone.

SOURCE: McCausland FR, Lefkowitz MP, Claggett B, et al. Angiotensin-neprilysin inhibition and renal outcomes in heart failure with preserved ejection fraction. Circulation 2020;142:1236-1245.

Heart failure with preserved ejection fraction (HFpEF) is common, accounting for half of heart failure diagnoses. However, evidence-based treatment options remain elusive — and not for lack of effort. Historically, HFpEF was understood to be the result of left ventricular hypertrophy and fibrosis caused by long-standing hypertension, diabetes, and (often) coronary disease. But, increasingly, the contribution of endovascular dysfunction has been recognized. Furthermore, diseases such as cardiac amyloidosis and variant forms of hypertrophic cardiomyopathy are diagnosed more often. It is likely that unintentional inclusion of these patients in early HFpEF trials blunted the effect of potentially efficacious therapies.

Neprilysin inhibitors increase the concentration of natriuretic peptides, which results in coronary vasodilation and inhibition of cardiomyocyte hypertrophy. Renal effects include higher glomerular filtration rate (eGFR), inhibition of sodium reabsorption, and suppression of renin and aldosterone. Preliminary studies revealed the combination of sacubitril/valsartan lowered NT-proBNP, shrank left atrial size, and improved New York Heart Association (NYHA) functional class compared to valsartan alone, prompting the PARAGON-HF study.

The PARAGON-HF study authors enrolled 4,822 patients with left ventricular ejection fraction (LVEF) 45% or higher. Patients presented with stable NYHA class II-IV symptoms requiring treatment with diuretics, age ≥ 50 years, left atrial enlargement or left ventricular hypertrophy, and elevated NT-proBNP on a sliding scale based on sinus rhythm vs. atrial fibrillation and recent heart failure hospitalization. Patients with hypotension (systolic blood pressure < 110 mmHg), severe chronic kidney disease (eGFR < 30 mL/min/1.73 m2), or hyperkalemia (> 5.2) at baseline were excluded.

Patients with potential alternative explanations for functional limitations, such as severe pulmonary disease, anemia (hemoglobin < 10 g/dL), or morbid obesity, were excluded. Patients with a history of reduced ejection fraction (< 40%), congenital heart disease, constrictive pericarditis, or significant valvular heart disease were excluded, as were patients with known infiltrative, genetic, hypertrophic, peripartum, viral, or chemotherapy-induced cardiomyopathies. Patients were randomized to either valsartan (target dose = 160 mg twice daily) or sacubitril/valsartan (target dose = 97/103 mg twice daily) after a run-in period to ensure tolerance of both agents.

Patients were, on average, age 72.8 years, and 51.7% were women. Most were NYHA class II (77%) or III (19%). Race was predominantly white (81.5%), followed by Asian (12.7%) and Black (2.2%). Most enrolled patients lived in Central or Western Europe, followed by Asia-Pacific, North America, and Latin America. The baseline BMI was 30 kg/m2, the eGFR was measured as 63 mL/min/1.73m2, systolic blood pressure was measured as 130 mmHg, LVEF was 58%, and NT-proBNP was 910 pg/mL. Most patients were hypertensive (95%), half had been hospitalized for heart failure, 43% were diabetic, 37% were living with coronary disease, and one-third exhibited atrial fibrillation or flutter.

The median duration of follow-up was 35 months. The primary outcome was a composite of heart failure hospitalizations and cardiovascular death. Overall, the rate of the primary outcome was 12.8 per 100 patient-years in the sacubitril/valsartan group and 14.6 per 100 patient-years in the valsartan group (rate ratio, 0.87; 95% CI, 0.75-1.01). Interestingly, a subgroup analysis suggested women benefited from sacubitril/valsartan (rate ratio, 0.73; 95% CI, 0.59-0.90) while men did not (rate ratio, 1.03; 95% CI, 0.85-1.25). Other secondary analyses revealed more patients in the sacubitril/valsartan arm demonstrated improved quality of life and NYHA class.

McCausland et al more completely analyzed the effect on renal function. There was a prespecified composite secondary renal endpoint: 50% or greater decline in eGFR from baseline, the development of end-stage renal disease, or death from kidney disease. Additional analyses concerned the rate of decline in renal function over time. At baseline, the average eGFR measurement was 63 ± 19 mL/min/1.73m2. The composite renal outcome occurred in 1.4% of the sacubitril/valsartan group vs. 2.7% of the valsartan group (HR, 0.50; P = 0.001). This outcome was driven primarily by the reduction in eGFR component: 1.1% of sacubitril/valsartan patients vs. 2.5% of valsartan patients (HR, 0.44; 95% CI, 0.28-0.69). There was no statistical difference in the rate of progression to end-stage renal disease or death from renal causes.

In a time-based analysis, the eGFR measurement declined 2 mL/min/1.73m2 annually in the sacubitril/valsartan group compared to 2.7 mL/min/1.73m2 in the valsartan group (P < 0.001). When the outcomes were analyzed by baseline renal function, there was no significant difference. The authors concluded sacubitril/valsartan slows progression of kidney disease in patients with HFpEF.


PARAGON-HF was a negative trial, although several intriguing findings may lead to positive trials in the future. Chronic kidney disease complicates half of heart failure; thus, preventing progressive renal dysfunction is an important goal.

The series of disappointing HFpEF trials continues with the recent publication of VITALITY-HFpEF (vericiguat) and CAPACITY HFpEF (praliciguat).1,2 The results of PARAGON-HF suggests treatment with sacubitril/valsartan slows progression of renal disease in patients with HFpEF compared to valsartan, in addition to the suggestion of benefit in women, improvement in NYHA class, and quality of life.

A wise friend asked me if SGLT2 inhibitors are efficacious in systolic heart failure because we all are prediabetic. He might be on to something. I am disappointed McCausland et al did not break down outcomes by presence or absence of diabetes. I also am disappointed the authors did not assess proteinuria. Trials of SGLT2 inhibitors dapagliflozin and empagliflozin in patients with HFpEF are in progress. I suspect they will demonstrate clear benefit. For now, clinicians should consider substituting sacubitril/valsartan for ACE or ARB in HFpEF patients in whom borderline renal function is present.


  1. Armstrong PW, Lam CSP, Anstrom KJ, et al. Effect of vericiguat vs placebo on quality of life in patients with heart failure and preserved ejection fraction: The VITALITY-HFpEF randomized clinical trial. JAMA 2020;324:1512-1521.
  2. Udelson JE, Lewis GD, Shah SJ, et al. Effect of praliciguat on peak rate of oxygen consumption in patients with heart failure with preserved ejection fraction: The CAPACITY HFpEF randomized clinical trial. JAMA 2020;324:1522-1531.