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Article Open Access

Cardiorenal safety and efficacy of angiotensin receptor‑neprilysin inhibitors in heart failure across the ejection fraction spectrum: A meta‑analysis and meta‑regression of RCTs with 28,001 patients

  • Authors:
    • Derren D.C.H. Rampengan
    • Stevanus C. Surya
    • Kevin C. Tjandra
    • Juan A.J.M.N. Lele
    • Starry H. Rampengan
    • Ika N. Kadariswantiningsih
    • Bulat Idrisov
    • Alina Idrisova
    • Maulana A. Empitu
  • View Affiliations / Copyright

    Affiliations: Medical Doctor Program, Faculty of Medicine, Universitas Sam Ratulangi, Manado 95115, Indonesia, Medical Doctor Program, Faculty of Medicine, Universitas Udayana, Denpasar 80232, Indonesia, Medical Doctor Program, Faculty of Medicine, Universitas Diponegoro, Semarang 50275, Indonesia, Medical Doctor Program, Faculty of Medicine, Universitas Kristen Indonesia, Jakarta 10430, Indonesia, Department of Cardiology and Vascular Medicine R.D. Kandou Central General Hospital, Faculty of Medicine, Universitas Sam Ratulangi, Manado 95115, Indonesia, Faculty of Medicine, Airlangga University, Surabaya, East Java 60131, Indonesia, Health Services Research Department of Health Systems and Population Health, University of Washington, Seattle, Washington 98195, USA
    Copyright: © Rampengan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 23
    |
    Published online on: December 3, 2025
       https://doi.org/10.3892/br.2025.2096
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Abstract

Angiotensin receptor‑neprilysin inhibitors (ARNIs), including sacubitril/valsartan, exert blood pressure‑lowering and organ‑protective effects in patients with heart failure (HF). However, differences of these effects across HF phenotypes and their impact on renal outcomes remain unclear. The present systematic review aimed to evaluate the antihypertensive efficacy, safety and cardiorenal benefits of ARNIs vs. angiotensin‑converting enzyme inhibitors (ACE‑Is) or angiotensin receptor blockers (ARBs) in patients with HF with reduced, mildly reduced, and preserved ejection fractions. Data were extracted from PubMed, Scopus, Cochrane, ProQuest and Google Scholar up to July 2025. Risk of bias was evaluated using the Cochrane Risk of Bias 2 tool. Meta‑analyses were performed using risk ratios (RRs) with 95% confidence intervals (CIs). Data analyses were conducted using RevMan version 5.4 and STATA version 16.0. Outcomes encompassed all‑cause mortality, cardiovascular mortality, HF‑related hospitalization, major adverse cardiovascular events (MACEs) and adverse events. A total of 18 randomized control trials involving 28,001 patients were included. Compared with ACE‑I/ARB, ARNI decreased all‑cause (RR=0.67; 95% CI=0.83‑0.97) and cardiovascular mortality (RR=0.84; 95% CI=0.77‑0.92), HF hospitalization (RR=0.87; 95% CI=0.81‑0.93) and MACE (RR=0.89; 95% CI=0.85‑0.94), but increased symptomatic hypotension (RR=1.54; 95% CI=1.43‑1.65). Subgroup analysis by left ventricular ejection fraction category did not reveal any significant effect modification across outcomes. Meta‑regression identified N‑terminal prohormone of brain natriuretic peptide (P=0.02) and body mass index (P<0.0001) as predictors of cardiovascular mortality. Estimated glomerular filtration rate was associated with all‑cause mortality (P=0.001) and hypotension (P=0.03), while sex (P=0.001) predicted hospitalization. Systolic blood pressure (P=0.001) was linked to renal outcomes. Overall, ARNIs confer consistent cardiorenal benefits across the HF spectrum, particularly in patients with elevated systolic blood pressure and decreased renal function, though hypotension requires careful monitoring. The present study was registered in PROSPERO (registration no. CRD42024569374).
View Figures

Figure 1

Preferred Reporting Items for
Systematic Reviews and Meta-Analyses flowchart. RCT, randomized
control trial.

Figure 2

Quality assessment using the Cochrane
Risk of Bias 2.0 tool. (A) Domain-specific quality assessment. (B)
Quality assessment summary.

Figure 3

Effect of angiotensin
receptor-neprilysin inhibitor vs. control on all-cause mortality.
Square represents the study weights; diamond shape represents the
overall effect. MH, Mantel-Haenszel; df, degrees of freedom.

Figure 4

Effect of ARNI vs. control on (A)
cardiovascular-related mortality, (B) heart failure hospitalization
and (C) major adverse cardiovascular event. The blue square
represents the study weights; the black diamond, overall effect.
ARNI, angiotensin receptor-neprilysin inhibitor; MH,
Mantel-Haenszel; df, degrees of freedom.

Figure 5

Safety outcome analysis related to
renal function and electrolyte imbalance. Analysis of (A) renal
impairment and (B) hyperkalemia incidence in the angiotensin
receptor-neprilysin inhibitor vs. control group. MH,
Mantel-Haenszel; df, degrees of freedom.

Figure 6

Saferty outcome analysis related to
angioedema and hypotension. Analysis of (A) angioedema and (B)
symptomatic hypotension incidence in the angiotensin
receptor-neprilysin inhibitor vs. control group. MH,
Mantel-Haenszel; df, degrees of freedom.

Figure 7

Mechanisms of ARNI in heart failure.
ANP, atrial natriuretic peptide; ARNI, angiotensin
receptor-neprilysin inhibitor; AT, angiotensin; CNP, C-type
natriuretic peptide; NT-proBNP, N-terminal prohormone of brain type
natriuretic peptide; RAAS, renin-angiotensin-aldosterone
system.
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Copy and paste a formatted citation
Spandidos Publications style
Rampengan DD, Surya SC, Tjandra KC, Lele JA, Rampengan SH, Kadariswantiningsih IN, Idrisov B, Idrisova A and Empitu MA: Cardiorenal safety and efficacy of angiotensin receptor‑neprilysin inhibitors in heart failure across the ejection fraction spectrum: A meta‑analysis and meta‑regression of RCTs with 28,001 patients. Biomed Rep 24: 23, 2026.
APA
Rampengan, D.D., Surya, S.C., Tjandra, K.C., Lele, J.A., Rampengan, S.H., Kadariswantiningsih, I.N. ... Empitu, M.A. (2026). Cardiorenal safety and efficacy of angiotensin receptor‑neprilysin inhibitors in heart failure across the ejection fraction spectrum: A meta‑analysis and meta‑regression of RCTs with 28,001 patients. Biomedical Reports, 24, 23. https://doi.org/10.3892/br.2025.2096
MLA
Rampengan, D. D., Surya, S. C., Tjandra, K. C., Lele, J. A., Rampengan, S. H., Kadariswantiningsih, I. N., Idrisov, B., Idrisova, A., Empitu, M. A."Cardiorenal safety and efficacy of angiotensin receptor‑neprilysin inhibitors in heart failure across the ejection fraction spectrum: A meta‑analysis and meta‑regression of RCTs with 28,001 patients". Biomedical Reports 24.2 (2026): 23.
Chicago
Rampengan, D. D., Surya, S. C., Tjandra, K. C., Lele, J. A., Rampengan, S. H., Kadariswantiningsih, I. N., Idrisov, B., Idrisova, A., Empitu, M. A."Cardiorenal safety and efficacy of angiotensin receptor‑neprilysin inhibitors in heart failure across the ejection fraction spectrum: A meta‑analysis and meta‑regression of RCTs with 28,001 patients". Biomedical Reports 24, no. 2 (2026): 23. https://doi.org/10.3892/br.2025.2096
Copy and paste a formatted citation
x
Spandidos Publications style
Rampengan DD, Surya SC, Tjandra KC, Lele JA, Rampengan SH, Kadariswantiningsih IN, Idrisov B, Idrisova A and Empitu MA: Cardiorenal safety and efficacy of angiotensin receptor‑neprilysin inhibitors in heart failure across the ejection fraction spectrum: A meta‑analysis and meta‑regression of RCTs with 28,001 patients. Biomed Rep 24: 23, 2026.
APA
Rampengan, D.D., Surya, S.C., Tjandra, K.C., Lele, J.A., Rampengan, S.H., Kadariswantiningsih, I.N. ... Empitu, M.A. (2026). Cardiorenal safety and efficacy of angiotensin receptor‑neprilysin inhibitors in heart failure across the ejection fraction spectrum: A meta‑analysis and meta‑regression of RCTs with 28,001 patients. Biomedical Reports, 24, 23. https://doi.org/10.3892/br.2025.2096
MLA
Rampengan, D. D., Surya, S. C., Tjandra, K. C., Lele, J. A., Rampengan, S. H., Kadariswantiningsih, I. N., Idrisov, B., Idrisova, A., Empitu, M. A."Cardiorenal safety and efficacy of angiotensin receptor‑neprilysin inhibitors in heart failure across the ejection fraction spectrum: A meta‑analysis and meta‑regression of RCTs with 28,001 patients". Biomedical Reports 24.2 (2026): 23.
Chicago
Rampengan, D. D., Surya, S. C., Tjandra, K. C., Lele, J. A., Rampengan, S. H., Kadariswantiningsih, I. N., Idrisov, B., Idrisova, A., Empitu, M. A."Cardiorenal safety and efficacy of angiotensin receptor‑neprilysin inhibitors in heart failure across the ejection fraction spectrum: A meta‑analysis and meta‑regression of RCTs with 28,001 patients". Biomedical Reports 24, no. 2 (2026): 23. https://doi.org/10.3892/br.2025.2096
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