Heart failure (HF) remains a leading cause of morbidity and mortality globally, despite advancements in prevention and treatment. In the USA alone, millions suffer from chronic HF, incurring substantial healthcare costs and lost productivity. Current guidelines classify HF into four types based on ejection fraction (LVEF): HFrEF, HFmrEF, HFpEF, and HF with improved HF. Sacubitril/valsartan (S/V), a novel therapy, combines neprilysin inhibition with AT1 receptor blockade, offering more effective neurohormonal modulation than RAAS inhibition alone. Neprilysin inhibition increases natriuretic peptides, reducing vasoconstriction, abnormal growth, and remodeling. The PARADIGM-HF trial demonstrated significant improvements in morbidity and mortality with S/V compared to enalapril. However, a systematic review evaluating the benefits and harms of S/V across all HF types was lacking. This study aimed to assess the benefits and harms of S/V compared to ACEI or ARB in HF patients.

Several studies have compared the effects of sacubitril/valsartan to ACE inhibitors or angiotensin receptor blockers. Wang et al. (2019) conducted a meta-analysis that found S/V significantly improved functional capacity and various left ventricle parameters in patients with HFrEF, also showing a reduction in NT-proBNP. Solomon et al. (2016) performed a meta-analysis of three RCTs that showed a reduction in the composite outcome of all-cause mortality or heart failure hospitalization with combined neprilysin/RAS inhibition. Other meta-analyses, such as Li et al. (2017) and Zhang et al. (2020), explored the safety and efficacy of S/V, reporting varying results on specific adverse events like angioedema and hypotension. This study builds upon the existing literature by providing a comprehensive and updated meta-analysis of the efficacy and safety of S/V across a broader range of HF patients.

This systematic review and meta-analysis followed PRISMA 2020 guidelines. Randomized controlled trials (RCTs) comparing S/V to ACEI or ARB in adult patients with acute or chronic HF were identified through a comprehensive search of five bibliographic databases (CENTRAL, MEDLINE Ovid, Embase Ovid, Web of Science Core Collection, and Scopus), ClinicalTrials.gov, and the WHO ICTRP. Inclusion criteria included published and unpublished parallel-arm phase 2, 3, and 4 RCTs. Exclusion criteria were consistent with those used in relevant S/V RCTs and included known angioedema history, concurrent ACEI and ARB use, serum potassium > 5.2 mmol/l, eGFR < 15 ml/min/1.73 m², and hypersensitivity to study drugs. Two review authors independently screened titles and abstracts, with disagreements resolved by a third author. Full-text articles were screened, data extraction was performed by three investigators, and discrepancies were resolved through discussion. The Cochrane risk of bias tool was used to assess the risk of bias in individual RCTs. Random-effects models were used for meta-analyses, with hazard ratios (HR) or risk ratios (RR) for dichotomous outcomes and mean differences (MD) or standardized mean differences (SMD) for continuous outcomes. Heterogeneity was assessed using the I² statistic.

The analysis included 11 RCTs (n=18766) with follow-up times ranging from 2 to 48 months. Compared to ACEI or ARB, S/V significantly reduced the risk of HF hospitalization (HR=0.80, 95% CI: 0.68-0.94; 3 RCTs; I²=65%), CV mortality (HR=0.86, 95% CI: 0.73-1.01; 2 RCTs; I²=57%), and all-cause mortality (HR=0.89, 95% CI: 0.78-1.00; 3 RCTs; I²=36%). S/V also led to reductions in NT-proBNP and hs-TNT levels, indicating improvements in myocardial function. A decline in renal function was observed with S/V (HR=0.67, 95% CI: 0.39-1.14; 2 RCTs; I²=78%), although the clinical significance of this finding needs further investigation. The incidence of hyperkalaemia and angioedema was similar between S/V and control groups. However, S/V was associated with a significant increase in the risk of symptomatic hypotension (RR=1.69, 95% CI: 1.33-2.15; 9 RCTs; I²=65%). Stratified analyses by control type (ACEI vs. ARB) revealed similar trends in the effects of S/V.

This meta-analysis demonstrates the superior efficacy of S/V over ACEI or ARB in reducing major adverse cardiovascular events in patients with HF. The observed reduction in HF hospitalizations, CV mortality, and all-cause mortality, along with favorable changes in biomarkers, strongly supports the clinical benefits of S/V. The slight decline in renal function requires further scrutiny to determine its clinical implications and weigh it against the overall cardiovascular benefits. The increased risk of hypotension associated with S/V needs to be considered in clinical practice, particularly in patients with pre-existing hypotension or those at higher risk for hypotension. The consistent findings across different types of controls support the overall conclusion regarding the superiority of S/V, regardless of whether the comparator was an ACEI or an ARB. Further research is warranted to fully understand the long-term effects and to tailor treatment strategies based on individual patient characteristics and specific HF subtypes.

Sacubitril/valsartan demonstrates significant benefits in reducing HF hospitalizations, cardiovascular mortality, and all-cause mortality in patients with heart failure compared to ACEI or ARB. While an increased risk of hypotension was observed, this needs to be balanced against the substantial improvements in other clinical outcomes. The findings support current guidelines recommending S/V in select HF patients. Future studies should focus on refining treatment selection criteria and exploring the long-term effects in various HF subtypes and patient subgroups.

The study's limitations include the limited number of RCTs for some comparisons, especially those involving ARB controls, and potential publication bias. The heterogeneous nature of the included studies and the limited data on some outcomes might have also influenced the results. The possibility of residual confounding variables not fully accounted for within the RCT designs could affect the interpretation of the findings. Further research with more robust data and larger patient populations is needed to strengthen the conclusions.