Renal safety and efficacy of angiotensin receptor‐neprilysin inhibitor: A meta‐analysis of randomized controlled trials

Abstract

What is known and objective Angiotensin receptor‐neprilysin inhibitor (ARNi) therapy has been shown to improve cardiovascular outcomes in the Prospective Comparison of ARNi with angiotensin‐converting enzyme inhibitor to Determine the Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM‐HF) study. However, the renal safety and efficacy of ARNi remains controversial. This meta‐analysis aimed to assess the renal safety and efficacy of angiotensin receptor‐neprilysin inhibitor (ARNi). Methods and Results PubMed, EMBASE, the Cochrane Library, Web of Science and Clinicaltrials.gov were searched for randomized controlled trials. Eleven studies that covered 21,716 patients were included. ARNi was superior to angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers, in terms of risk of renal dysfunction, estimated glomerular filtration rate (eGFR) decline and elevated serum potassium levels, and higher risk of increase in urine albumin‐to‐creatinine ratio. However, there was no difference in the probability of hyperkalemia and elevated serum creatinine levels. The incidence of eGFR decrease in patients with chronic kidney disease (CKD) was lower in patients who received ARNi, although ARNi use was not associated with higher risk of renal dysfunction in patients with CKD. What is new and conclusion. Available evidence supports the effectiveness of ARNi on improving renal outcome. Compared with renin‐angiotensin‐aldosterone system inhibition, ARNi protects against renal impairment, since ARNi users have a lower risk of renal dysfunction and a higher eGFR, without an increased risk of hyperkalemia. However, its benefit for CKD patients still warrants further investigation.

Effectiveness and Safety of Sacubitril/Valsartan in Patients with Chronic Kidney Disease—A Real-World Experience

“…Furthermore, CKD did not show to have a significant impact on S/V uptitration. This is in line with data from the PARADIGM-HF and related clinical trials, which have suggested that S/V offers greater renal protection compared with RAAS inhibition alone, while maintaining the beneficial effects on cardiovascular morbidity/mortality and clinical symptoms [ 7 , 8 , 9 , 10 ]. As opposed to most of these clinical trials, this study did not restrict the included population to patients with eGFR ≥ 30 mL/min/1.73 m 2 , but also included patients with eGFR of 15 to 29 mL/min/1.73 m 2 , in an attempt to add a bit more understanding on the effectiveness and tolerability of S/V in HFrEF patients with severe CKD.…”

“…Some recent publications suggest that S/V in patients with CKD may offer great renal protection while maintaining beneficial effects on cardiovascular events, compared with renin-angiotensin-aldosterone system (RAAS) inhibition alone [ 8 , 9 , 10 ], supporting the beneficial effect of ARNI in HFrEF patients with CKD. As a result of the lack of data on the efficacy and tolerability of S/V in HFrEF patients with severe CKD, the current recommendation is to initiate S/V with caution in patients with eGFR < 30 mL/min/1.73 m 2 , starting at the lowest dose twice daily and not to use the drug in patients with end-stage renal disease (eGFR < 15 mL/min/1.73 m 2 ) [ 11 ].…”

Application of Angiotensin Receptor–Neprilysin Inhibitor in Chronic Kidney Disease Patients: Chinese Expert Consensus

“…Moreover, the incidence of hyperkalemia was significantly lower in the ARNI group than in the valsartan group (13.2 vs. 15.3%, P = 0.048) ( 30 ). A meta-analysis of 11 randomized controlled trials comparing ARNI with RAAS inhibitors showed that, compared with those receiving ACEI/ARB, the ARNI group had a slightly lower risk of hyperkalemia (RR = 0.95; 95% CI = 0.88–1.02) ( 71 ). A meta-analysis published in ASN in 2020 showed similar results ( 72 ); however, patients with heart failure were mainly included in these studies, whereas patients with eGFR <30 mL/min/1.73 m 2 or serum creatinine level > 221 μmol were excluded.…”

Hormonal Regulation of Renal Fibrosis

“…Recently, a new approach for the treatment of CKD has been proposed—the use of a combination of the neprilysin inhibitor (sacubitril), which inhibits the cleavage of natriuretic peptides, and the AT1 antagonist valsartan (ARNI—angiotensin receptor AT1 and neprilysin inhibition). This combination of drugs showed a positive effect on the suppression of the development of TF and glomerulosclerosis in rats [ 149 ] and in clinical studies of acute renal pathologies treatment; however, it is necessary to confirm the positive effects in patients with CKD [ 150 ].…”