ARNI provided no additional benefit on renal function compared with ARB

Effects of Sacubitril/Valsartan Versus Irbesartan in Patients with Chronic Kidney Disease: A Randomised Double-Blind Trial

Literature - Haynes R, Judge PK, Staplin N, et al. - Circulation 2018; published online ahead of print

Introduction and methods

There is evidence showing that renin-angiotensin system (RAS) inhibitors delay the progression of diabetic and non-diabetic chronic kidney disease (CKD), however, there is a considerable residual risk for end-stage renal disease (ESRD) and cardiovascular (CV) events among CKD patients [1,2].

Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), reduces CV mortality in patients with heart failure with reduced ejection fraction. It also slows the renal function decline compared with RAS inhibition alone, but it slightly increases albuminuria, thus, the net benefit on renal function is unclear [3,4].

This study (United Kingdom Heart and Renal Protection, UK HARP-III) [5] assessed the effects of sacubitril/valsartan on renal function, and albuminuria, blood pressure (BP), cardiac biomarkers and adverse effects in patients with CKD, in comparison with irbesartan, an angiotensin receptor blocker (ARB) licensed for diabetic nephropathy. 414 Participants aged ≥18 years with CKD (estimated glomerular filtration rate [eGFR]: 20-60 mL/min/1.73m2) underwent a 4-7 week wash-out period, and were then randomized 1:1 to sacubitril/valsartan 97/103mg twice daily or irbesartan 300 mg once daily. The primary outcome was measured GFR (mGFR) at 12 months.

Main results

  • At 12 months, the mean (SE) mGFR was 29.8 (0.5) mL/min/1.73m² in the sacubitril/valsartan group compared with 29.9 (0.5) mL/min/1.73m² in the irbesartan group (difference: 0.1 (0.7) mL/min/1.73m², P=0.86).
  • Compared to the irbesartan group there was a non-significant 9% (-18 to 1%; P=0.08) reduction in study-average urine albumin:creatinine ratio in the sacubitril/valsartan group.
  • In the sacubitril/valsartan group, the study-average systolic BP was 5.4 mmHg lower (95%CI: -7.4 to -3.4), and diastolic BP was 2.1 mmHg lower (95%CI: -3.3 to -1.0) compared with the irbesartan group.
  • Sacubitril/valsartan was associated with significant reductions in levels of NT-BNP (18%) and troponin I (16%), compared with irbesartan.
  • No significant effects on fatal serious adverse events or any non-fatal serious adverse events were observed with sacubitril/valsartan.


In patients with CKD, sacubitril/valsartan was well-tolerated, had similar effects on renal function and albuminuria compared with irbesartan after 12 months of therapy. ARNI treatment showed additional reductions of BP and cardiac biomarkers.


1. Lewis EJ, Hunsicker LG, Clarke WR, et al and Collaborative Study G. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. New Engl J Med.2001;345:851-860.

2. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med.2001;345:861-869.

3. Packer M, Claggett B, Lefkowitz MP, et al. 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. Lancet Diabetes Endocrinol. 2018;6:547-554.

4. Solomon SD, Claggett B, McMurray JJ, et al. Combined neprilysin and renin-angiotensin system inhibition in heart failure with reduced ejection fraction: a meta-analysis. Eur J Heart Fail. 2016;18:1238-1243.

5. Judge PK, Haynes R, Herrington WG, et al. Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III-rationale, trial design and baseline data. Nephrol Dial Transplant. 2017; 32: 2043-2051.

Find this article online at Circulation

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