Efficacy and safety of sacubitril/valsartan in heart failure compared to renin-angiotensin-aldosterone system inhibitors: a systematic review and meta-analysis of randomised controlled trials

Heart failure (HF) is a major global cause of morbidity and mortality, with rising prevalence and substantial healthcare costs. In the USA, over 5.7 million people live with chronic HF, with 670,000 new cases yearly. Hospitalizations for HF are common, especially among older adults. Although device therapies have improved survival, optimization of pharmacologic therapy remains central. Current guidelines define HF categories by left ventricular ejection fraction (LVEF): HFrEF, HFmrEF, HFpEF, and improved HF. Sacubitril/valsartan (S/V), an angiotensin receptor–neprilysin inhibitor (ARNI), augments natriuretic peptides via neprilysin inhibition and suppresses the RAAS via AT1 blockade, potentially providing superior neurohormonal modulation compared with RAAS inhibition alone. The PARADIGM-HF trial showed S/V reduced the composite of CV death or HF hospitalization and all-cause mortality versus enalapril. Guidelines recommend ARNI in symptomatic HFrEF and consider its use in HFmrEF and HFpEF under selected circumstances. The benefits and harms of S/V across HF types had not been comprehensively synthesized. The aim of this systematic review was to assess the benefits and harms of S/V versus ACEI or ARB in HF patients.

Previous meta-analyses have examined ARNI versus RAAS inhibition. Wang et al. (2019) reported improvements in functional capacity and reverse remodeling with S/V in HFrEF, with reduced NT-proBNP; effects in HFpEF were limited. Solomon et al. pooled trials of combined neprilysin/RAS inhibition versus RAS inhibition alone and found reduced all-cause mortality or HF hospitalization (HR 0.86) and all-cause mortality (HR 0.88). Li et al. (2017) found S/V decreased serious adverse events and death versus ACEI/ARB or placebo, with increased angioedema risk and less renal dysfunction. Zhang et al. (2020) found higher symptomatic hypotension risk (RR 1.47) and lower risks of worsening renal function and serious hyperkalaemia with S/V versus enalapril/valsartan. Guideline-endorsed biomarkers such as NT-proBNP, not degraded by neprilysin, are preferred for monitoring ARNI effects. These prior findings generally align with this review, which demonstrates mortality and hospitalization benefits and biomarker improvements with S/V, alongside increased hypotension risk.

Design: Systematic review and meta-analysis of randomized controlled trials (RCTs). Search strategy: Comprehensive searches of CENTRAL, MEDLINE (Ovid), Embase (Ovid), Web of Science Core Collection, and Scopus conducted on August 2, 2021. Trial registries searched included ClinicalTrials.gov and WHO ICTRP for ongoing/unpublished trials. Search strategies are in supplementary materials. Eligibility criteria: Included parallel-arm phase 2–4 RCTs comparing sacubitril/valsartan (LCZ696) versus ACEI or ARB in adults (≥18 years) with acute or chronic HF, regardless of LVEF. Exclusions mirrored key ARNI RCTs: history of angioedema; need for both ACEI and ARB; serum K+ > 5.2 mmol/l; eGFR < 15 ml/min/1.73 m²; hypersensitivity to study drugs or contraindications. Study selection: Two reviewers independently screened titles/abstracts and full texts, resolving disagreements with a third reviewer. Duplicates were removed and multiple reports collated per unique trial. Selection was documented per PRISMA 2020. Outcomes: Primary outcomes were HF hospitalizations (time to first event and proportion with ≥1 event) and cardiovascular mortality. Secondary outcomes included all-cause mortality, all-cause hospitalization, kidney function (eGFR and composite renal decline), myocardial dysfunction (NT-proBNP/BNP, LVEF, E/E′), blood pressure (SBP/DBP), quality of life (KCCQ), serious adverse events, and specific AEs (worsening renal function, hyperkalaemia ≥5.5 mmol/l, symptomatic hypotension SBP <100 mmHg, angioedema). Longest follow-up and ITT populations were preferred. Data extraction: Three investigators independently extracted trial characteristics and outcome data; discrepancies were resolved by discussion or adjudication. Risk of bias: Assessed with the Cochrane tool across domains (randomization, allocation concealment, blinding, incomplete outcome data, selective reporting, other biases). Trials were rated high risk if randomization or blinding was high risk; unclear risk if any domain unclear and none high. Statistical analysis: Random-effects meta-analyses using DerSimonian–Laird estimator for between-study variance. Effect measures were HR or RR (with preference for HR for follow-up >6 months) for dichotomous/time-to-event outcomes, and MD or SMD for continuous outcomes. When needed, SDs for change scores were imputed using r=0.75 per standard formula. Heterogeneity assessed by chi-square (p<0.10) and I² (substantial >60%, very substantial >90%). Analyses were performed for S/V vs ACEI or ARB combined (primary) and stratified comparisons vs ACEI alone and vs ARB alone. Skewed continuous data reported narratively. Software: RevMan.

- Included studies: 11 RCTs (66 reports), n=18,766; follow-up 2–48 months. Controls: 5 ACEI, 5 ARB, 1 ACEI or ARB. Primary outcomes (S/V vs ACEI or ARB): - HF hospitalization: HR 0.80 (95% CI 0.68–0.94); 3 RCTs; n=14,102; I²=65%. - Cardiovascular mortality: HR 0.86 (0.73–1.01); 2 RCTs; n=13,221; I²=57%. Secondary outcomes (S/V vs ACEI or ARB): - All-cause mortality: HR 0.89 (0.78–1.00); 3 RCTs; n=14,102; I²=36%. - Biomarkers: NT-proBNP SMD −0.34 (−0.52 to −0.16); 3 RCTs; n=1,371; I²=62%. hs-TnT ratio of differences 0.84 (0.79–0.88); 2 RCTs; n=1,293; I²=0%. - Echocardiography: E/E′ MD −1.40 (−2.72 to −0.08); 3 RCTs; n=621; I²=61%. LVEF MD −0.13% (−1.24 to 0.99); 3 RCTs; n=703; I²=0%. - Blood pressure: SBP MD −4.4 mmHg (−6.59 to −2.22); 4 RCTs; n=9,225; I²=68%. DBP MD −2.83 mmHg (−4.02 to −1.65); 3 RCTs; n=826; I²=0%. - Quality of life: KCCQ-QoL MD 1.36 (0.49–2.24); 6 RCTs; n=16,404; I²=54%. - Renal outcomes: Composite renal decline HR 0.67 (0.39–1.14); 2 RCTs; n=13,221; I²=78%. Worsening creatinine/eGFR RR 0.93 (0.74–1.17); 8 RCTs; n=18,168; I²=55%. - Adverse events: Symptomatic hypotension RR 1.69 (1.33–2.15); 9 RCTs; n=18,307; I²=65%. Hyperkalaemia RR 1.03 (0.90–1.18); 8 RCTs; n=18,099; I²=47%. Angioedema RR 1.44 (0.62–3.32); 7 RCTs; n=18,050; I²=31%. Stratified comparisons: - Versus ACEI: HF hospitalization HR 0.71 (0.52–0.97); 2 RCTs; n=9,280; I²=60%. CV mortality HR 0.80 (0.71–0.90); 1 RCT; n=8,399. All-cause mortality HR 0.84 (0.76–0.92); 2 RCTs; n=9,280. Worsening renal function RR 0.80 (0.68–0.96); 4 RCTs; n=1,036. Hypotension RR 1.71 (1.25–2.33); 5 RCTs; n=10,502. Hyperkalaemia RR 1.17 (0.88–1.55). Angioedema RR 0.88 (0.21–3.58). - Versus ARB: HF hospitalization HR 0.90 (0.79–1.03); 1 RCT; n=4,822. CV mortality HR 0.95 (0.79–1.14); 1 RCT; n=4,822. All-cause mortality HR 0.97 (0.84–1.12); 1 RCT; n=4,822. Composite renal decline HR 0.50 (0.33–0.76); 1 RCT; n=4,822. eGFR change MD 1.26 ml/min/1.73 m² (−0.92 to 3.44); 2 RCTs; n=4,938; I²=40%. Hypotension RR 1.43 (1.24–1.65); 3 RCTs; n=5,241; I²=0%. Hyperkalaemia RR 1.02 (0.65–1.58); 3 RCTs; n=5,172; I²=44%. Angioedema RR 3.43 (1.20–9.78); 2 RCTs; n=5,123; I²=0%. Overall, S/V improved clinical outcomes (mortality and HF hospitalization), biomarkers, and renal outcomes versus ACEI/ARB, with increased symptomatic hypotension and generally similar hyperkalaemia and angioedema rates (except higher angioedema vs ARB alone).

This review addressed whether sacubitril/valsartan provides superior benefits and acceptable safety compared with ACEI or ARB in HF. Pooled data demonstrate that S/V reduces HF hospitalizations, cardiovascular mortality, and all-cause mortality compared with RAAS inhibitors, with consistent improvements in cardiac biomarkers (NT-proBNP, hs-TnT) and small reductions in E/E′. Blood pressure reductions were observed, accompanied by higher rates of symptomatic hypotension. Renal outcomes favored S/V, with reduced hazards of renal function decline and slight improvements in eGFR in ARB-controlled trials, without increased hyperkalaemia overall. Stratified analyses indicate clearer benefits versus ACEI (predominantly HFrEF populations), while neutral effects versus ARB reflect inclusion of HFpEF populations (e.g., PARAGON-HF), where event reduction is less pronounced. Findings are broadly consistent with prior meta-analyses and support guideline recommendations to use ARNI in HFrEF and consider it in selected HFmrEF/HFpEF patients. Clinically, the results underscore S/V’s role in improving outcomes across diverse HF settings, including acute and chronic care, while emphasizing vigilance for hypotension, particularly in patients with lower baseline SBP.

Sacubitril/valsartan improved HF hospitalization, cardiovascular mortality, and all-cause mortality compared with ACEI and/or ARB, alongside reductions in NT-proBNP and hs-TnT, modest blood pressure lowering, and slight improvements in quality of life. Renal outcomes generally favored S/V without increased hyperkalaemia risk. These benefits appear applicable across HF populations irrespective of LVEF or NYHA class and in both chronic and acute settings, though hypotension risk requires attention and SBP should generally be maintained above 100 mmHg. Further RCTs are warranted in HFmrEF, HFpEF, and key subgroups (e.g., diabetes, hypertension, CKD, elderly) to refine patient selection and optimize outcomes.

The meta-analysis included 11 RCTs, with outcome data available from 10; three large RCTs (PARADIGM-HF, PARAGON-HF, PIONEER-HF) contributed most clinical outcomes. Comparisons versus ARB were largely driven by PARAGON-HF (HFpEF), limiting generalizability across phenotypes. Echocardiographic and diastolic function outcomes were sparse and often derived from subsamples, with low-to-moderate certainty. The composite renal decline outcome was reported in only two large RCTs. All-cause hospitalization data came primarily from one abstract-only trial. Heterogeneity was moderate to high for some outcomes, and certainty varied by endpoint.