Worsening of renal function in heart failure patients slowed down by ARNI, particularly in type 2 diabetic patients

Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure

Literature -

Damman K, Gori M, Claggett B, et al. J Am Coll Cardiol HF 2018; published online ahead of print

Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial.

Packer M, Claggett B, Lefkowitz MP, et al. Lancet Diabetes Endocrinol 2018; published online ahead of print

Introduction and methods

Sacubitril/valsartan has been associated with a reduced risk of death and hospitalization compared with enalapril in patients with heart failure and reduced ejection fraction (HFrEF), and with an increase of the urinary albumin/creatinine ratio (UACR) in patients with heart failure and preserved ejection fraction (HFpEF) [1,2].

In one of these analyses of the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial [3], the effects of sacubitril/valsartan and enalapril on renal function and outcomes were evaluated. The other analysis assessed the effects of the same study medication on renal function in patients with and those without type 2 diabetes (T2DM).

In the PARADIGM-HF study, patients with New York Heart Association II-IV, an EF<40%, and elevated biomarkers, were randomized to receive either enalapril 10 mg or sacubitril/valsartan 97/103 mg twice daily, in a 1:1 ratio, after a run-in phase to test for tolerability. Patients with an estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m2 were excluded from the study. Other major exclusion criteria were symptomatic hypotension and hyperkalemia..

eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation [4]. In a subset of patients, urinary albumin and creatinine concentrations, measured in spot urine samples were used to calculate the urinary albumin and creatinine ratio (UACR). The pre-specified renal endpoint was time to first occurrence of any of:

  • a 50% decline in eGFR relative to baseline
  • >30 ml/min/1.73 m2 decline in eGFR relative to baseline to <60 ml/min/1.73 m2
  • end-stage renal disease, defined as start of permanent dialysis or kidney transplantation

Main results

  • The sacubitril/valsartan group included 4,187 patients and the enalapril group included 4,212 patients. Out of the total of 8,399 patients, 2,745 had chronic kidney disease (CKD), and 3,784 had T2DM.
  • The incidence of the prespecified composite renal outcome did not differ significantly between treatment groups, neither overall, nor by baseline CKD status.
  • The composite outcome of end-stage renal disease or a ≥50% decrease in the eGFR from baseline occurred significantly less frequently in the sacubitril/valsartan group (HR: 0.63; 95%CI: 0.42-0.95; P=0.028), and in both the CKD and no-CKD subgroups (P for interaction=0.97).
  • An increase of ≥25% in the UACR at 1 and 8 months was more common in the sacubitril/valsartan group (46% and 51% of patients, respectively), compared with the enalapril group (39% and 39%; P=0.004 and P <0.001, respectively).
  • The eGFR decreased by 10.2 ml/min/1.73 m2 (95%CI: 12.1-8.3) in patients assigned to enalapril and by 7.8 ml/min/1.73 m2 (95%CI: 9.6-6.0) in those assigned to sacubitril/valsartan.
  • The rate of decrease in the eGFR was less with sacubitril/valsartan compared with enalapril: -1.61 ml/min/1.73 m2/year (95%CI: -1.77 to -1.44) compared with -2.04 ml/min/1.73m2/year (95%CI:-2.21 to -1.88; P <0.001).
  • In patients without T2DM, eGFR decreased by a rate of 1.1 mL/min/1.73 m2/ year (95%CI: 1.0–1.2), and in patients with T2DM, eGFR decreased by a rate of 2.0 mL/min/1.73 m2/ year (95%CI: 1.9–2.1). The difference between patient groups was significant (P <0.0001).
  • Compared with enalapril, the magnitude of the renal function benefit of sacubitril/valsartan in T2DM patients was twice as large as in those without T2DM. The difference in favor of sacubitril/valsartan was 0.6 mL/min/1.73 m2/ year (95%CI: 0.4–0.8) in patients with T2DM compared with 0.3 mL/min/1.73 m2/ year (0.2–0.5) in those without T2DM (treatment-by-diabetes interaction P=0.038).
  • After adjusting eGFR to urinary cyclic guanosine monophosphate, the benefit of sacubitril/valsartain in T2DM patients compared to enalapril was no longer significant (0.1 mL/min/1.73m2/ year; 95%CI: –0.2 to 0.4; P=0.41).


In HFrEF patients, compared with enalapril, sacubitril/valsartan led to a slower rate of decrease in the eGFR, even in patients with CKD, despite causing a modest increase in UACR. Moreover, compared to enalapril, sacubitril/valsartan decelerated the deterioration of renal function in type 2 diabetic patients with HFrEF.


1. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004.

2. Voors AA, Gori M, Liu LC, et al. Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction. Eur J Heart Fail 2015;17:510–7.

3. McMurray JJ, Packer M, Desai AS, et al. Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail 2014;16:817–25.

4. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate.

Ann Intern Med 2009;150:604–12.

Find Damman et al. online at J Am Coll Cardiol HFFind Packer et al. online at J Am Coll Cardiol HF

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