Heart failure (HF) is a clinical syndrome caused by structural or functional cardiac abnormalities and manifests as an increase in internal pressure or a decrease in cardiac output. Due to increases in the size of the aging population and the incidence of risk factors, the prevalence of heart failure has been on the rise as well (1). To date, almost half of the 5 million patients with heart failure in the United States display heart failure with preserved ejection fraction (HFpEF) (2). The pathophysiological mechanism of HFpEF includes left ventricular (LV) structure and remodeling, LV diastolic limitations, and LV systolic limitations. Currently, however, no effective treatment drug exists (3).

Sacubitril/valsartan is the first new angiotensin receptor neprilysin inhibitor for treating hypertension and heart failure (4); such drugs treat HFpEF by blocking a profibrotic/prohypertrophic mechanism and stimulating an antifibrotic/antihypertrophic mechanism. Compared with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), sacubitril/valsartan can increase the levels of many vasoactive peptides, especially natriuretic peptides (NPs), which have powerful effects on sodium, fluid balance, and vascular diastolic function by inhibiting the renin–angiotensin–aldosterone system (RAAS), reducing the sympathetic nervous system activity, and exerting antiproliferative and anti-muscle hypertrophy effects (5).

Kuno et al. (6) demonstrated that treatment with sacubitril/valsartan can reduce the risk of hospitalization for HF, but the results of the PARAGON-HF trial did not reach a similar conclusion (7). The use of sacubitril/valsartan for patients with HFpEF is still controversial. Thus, we conducted a systematic review to evaluate the efficacy and safety of sacubitril/valsartan treatment for patients with HFpEF.

The present meta-analysis, which involved 7,663 patients, is the first to provide composite evidence of the efficacy and safety of sacubitril/valsartan in patients with HFpEF by pooling data from relevant RCTs. All of the studies included in this meta-analysis were randomized, controlled, and double-blind multicenter clinical trials. The results suggest that compared with valsartan or IMT, sacubitril/valsartan showed a significant advantage in reducing the rate of hospitalization for hazard ratio (HR). However, there was no obvious difference in the reduction in all-cause mortality or in the rate of death from cardiovascular diseases. Sacubitril/valsartan increased the risk of hypotension and angioedema, but it could reduce the incidence of worsening renal function. At the same time, the occurrence of hyperkalemia was numerically higher, but not statistically significant, in the sacubitril/valsartan group than in the control group.

The PARAMOUNT study (9) was a prospective study that compared the treatment of patients with HFpEF. The results showed that the level of N-terminal pro-brain natriuretic peptide (NT-proBNP), a key biomarker used in HF diagnosis to reflect the severity of heart failure (10, 11), in patients with HFpEF was significantly lower in the treatment group than in the valsartan group after 12 weeks of treatment (12). After 36 weeks of treatment, the left atrial volume in the treatment group was significantly lower than that in the control group, and the cardiac function in the treatment group was significantly better than that in the control group. Notably, the left atrial volume and dimension were significantly reduced in patients with HFpEF. The PARALLAX trial had similar results at 12 weeks (ratio 0.84, 95% CI: 0.80–0.88, p < 0.0001) (13). Left atrial volume is a biomarker of cardiac diastolic function (14). In addition, the Kansas City Cardiopathy Questionnaire (KCCQ) score was significantly lower than that of the control group. Studies have confirmed that sacubitril/valsartan has a certain therapeutic effect on patients with HFpEF and is beneficial for inhibiting ventricular remodeling.

The PARAGON-HF was a randomized, double-blind, and active-controlled trial (15). The results of the PARAGON trial (7) did not indicate a statistically significant difference but revealed that compared with valsartan, sacubitril/valsartan reduced the risk of experiencing the major endpoints (cardiovascular death and total hospitalization for HF) by 13% (RR: 0.87, 95% CI: 0.75–1.01, p = 0.06). Notably, the subgroup analysis in this trial showed that sacubitril/valsartan had a beneficial effect on patients with an LVEF between 45 and 57% (RR: 0.78, 95% CI: 0.64–0.95). This could be because these patients have systolic dysfunction, and sacubitril/valsartan has the same physiologic effects in these patients as it does in those with heart failure with reduced ejection fraction (HFrEF). For the secondary endpoints, sacubitril/valsartan significantly improved the New York Heart Association (NYHA) grade by 45% compared with valsartan (OR: 1.45, 95% CI: 1.13–1.86). Similarly, compared with the valsartan group, the sacubitril/valsartan group had a higher percentage of patients with a KCCQ clinical summary score of 5 or higher (33.0 vs. 29.6%). In addition, the incidence of the compound renal endpoint in the sacubitril/valsartan group was significantly reduced compared with that in the valsartan group (HR: 0.50, 95% CI: 0.33–0.77). The reasons for the negative results of the PARAGON trial (7) may be as follows: most patients were treated with ACEIs or ARBs before participating in the trial or the main endpoints of observation were different. Another study showed that the occurrence of HFpEF is heterogeneous, and this result was consistent with the PARAGON trial (12). In the PARAGON trial (7), the subgroup analysis showed that the two pre-specified subgroups—those with LVEF ≤ 57% and women—received significant benefits: the risk of the primary endpoints decreased by 27% in women and by 22% in the low LVEF group (16), demonstrating that sacubitril/valsartan may benefit high-risk patients with HFpEF (17). Based on these results, patients with HFpEF with structural heart disease and volume overload may be more sensitive to the sacubitril/valsartan treatment. In the PARALLAX trial (13), hospitalization for HF or the compound endpoint of all-cause mortality or heart failure for hospitalization was lower in the sacubitril–valsartan group than in the IMT group. In the PARALLAX trial (13), sacubitril/valsartan did not show superiority over valsartan in terms of the KCCQ score (13), which may be related to the severity of the patient's condition and insufficient treatment time.

In the PARAGON-HF study (7) and the PARALLAX study (18, 19), there was a higher risk of symptomatic hypotension caused by sacubitril/valsartan. This result is consistent with this meta-analysis; sacubitril/valsartan increased the incidence of hypotension with an RR of 2.66 (p = 0.04) compared with enalapril or valsartan. This finding coincides with previous studies (20–22). In the TITRATION study (23), patients with lower systolic blood pressure were successfully treated by gradual titration, which suggested that patients with lower systolic blood pressure can also use sacubitril/valsartan. Although hypotension can cause insufficient blood perfusion in the kidneys, causing kidney damage, previous studies (24, 25) found that sacubitril/valsartan could protect renal function, which was similar to our outcome that treatment with sacubitril/valsartan could protect renal function to prevent deterioration. Rubattu found that sacubitril/valsartan was more effective in reducing cardiovascular risk in rats with chronic kidney disease than valsartan alone (26). The UK HARP-III experiment showed that sacubitril/valsartan and irbesartan had similar effects on renal function after 12 months of follow-up (27). Damman conducted further studies that had similar results (28). Moreover, the results of the PARAMOUNT (9) and PARAGON-HF (7) studies showed that patients in the sacubitril/valsartan group had more beneficial effects on kidney function than those in the valsartan (ARB) group. The main mechanisms of renal protection by sacubitril/valsartan are as follows: (A) direct action on the kidney, inhibiting water and sodium reabsorption in the proximal and distal nephrons (the inhibition of proximal sodium and potassium exchange, distal sodium chloride exchange, and sodium channels in the collecting tubule) (29); (B) indirectly inhibits the release or action of other vasoconstrictors (renin, vasopressin, aldosterone, and norepinephrine), resulting in natriuretic and diuretic effects (30); and (C) inhibits inflammation and oxidative stress, delays glomerulosclerosis, etc (31, 32). Consequently, sacubitril/valsartan has more beneficial effects on renal function than ACEIs or ARBs in patients with HF. Concerning the incidence of hyperkalemia, there was no difference between the two groups (95% CI: 0.78–1.02, p = 0.11), which was consistent with previous studies (33). Although the risk of angioedema was low in the included studies, the pooled analysis indicated that sacubitril/valsartan led to a higher risk of angioedema (CI: 1.04–6.79, p < 0.04). However, the occurrence of angioedema is known to be related to the inhibition of bradykinin degradation (34), and sacubitril/valsartan does not inhibit ACE or aminopeptidase P, so it does not increase the risk of angioedema (4, 35). The reason for the result needs further research.

Of note, although no medical therapy has been shown to reduce all-cause or cardiovascular death in HFpEF trials, according to the latest AHA/ACC/HFSA heart failure guidelines (2022) (36), a number of drugs other than sacubitril/valsartan are recommended for treating HFpEF. Despite a lack of strong evidence, diuretics have been used in HFpEF to reduce symptoms due to volume overload (37). Renin–angiotensin–aldosterone system (RAAS) inhibitors and mineralocorticoid receptor antagonists have a well-established role in HFrEF but have been less effective in HFpEF, possibly because the RAAS plays a less prominent pathophysiological role as LVEF increases (38). Trials of ACEI and ARB use in HFpEF have not shown a significant reduction in all-cause or cardiovascular death, but these drugs may have reduced the risk of HF hospitalization (39–41). The TOPCAT trial (42) found no overall benefit in the primary composite outcome of cardiovascular death or hospitalization for heart failure. However, spironolactone reduced the risk of HF hospitalization in both the TOPCAT and TOPCAT-Americas subgroups, which could be linked to improved diastolic function in patients with HFpEF. In the EMPEROR-Preserved trial (43), a sodium-glucose cotransporter-2 inhibitor (SGLT-2i; empagliflozin) reduced the risk of composite cardiovascular death or total HF hospitalization by 21% in patients with HF with LVEF > 40%, driven primarily by a significant reduction in the HF hospitalization of 29% (no significant reduction in cardiovascular death [hazard ratio (HR), 0.91; 95% CI: 0.76–1.0]), with no benefit for all-cause mortality. In addition, the SOLOIST-WHF trial (44) showed that both patients with HFpEF and HFrEF had a reduced risk of endpoint events (cardiovascular death and HF hospitalizations; LVEF < 50% subgroup: HR = 0.72; LVEF ≥ 50% subgroup: HR = 0.48), which was driven by the reduction in HF hospitalizations. Sacubitril/valsartan and empagliflozin, two new drugs in the field of heart failure, have some similarities and differences in the clinical trials associated with them (Table 3). In the EMPEROR-Preserved subgroup analysis, patients with LVEF > 60% received no benefit. This result was similar to that in the subgroup of patients with LVEF > 57% in the PARAGON trial (RR, 1.00; 95% CI: 0.81–1.23). In terms of safety outcome events, while both drugs resulted in symptomatic hypotension, patients taking empagliflozin were more prone to volume depletion and urinary tract infections (45), while those taking sacubitril/valsartan were more susceptible to hyperkalemia and angioedema. Therefore, when assessing cardiac function and making treatment decisions for patients with heart failure, we should not simply use LVEF as the reference indicator; rather, treatment should be individualized.

There were some limitations to our study. First, because only three RCTs were included in our work, the sample size of this systematic review was too small, and we could not produce a funnel plot. Second, HFpEF was defined as LVEF ≥ 50%, but the studies included in our work defined HFpEF as LVEF ≥ 45%. Third, unpublished data or articles published not in English were excluded. Fourth, we used data that were not published but were available on ClinicalTrials.gov. Fifth, for meaningful conclusions from the meta-analysis of randomized trials, we used secondary outcomes, not primary outcomes. Sixth, there were many mixed factors that may have caused bias. For example, the comparator drug was different among the three trials included in our work. Finally, the majority of the sample in our work was from the PARAGON-HF trial, which may lead to sample imbalance and affect the results of our work. Thus, further studies are needed to assess more potential clinical benefits of sacubitril/valsartan in patients with HFpEF.

In conclusion, the existing evidence shows that sacubitril/valsartan not only is effective in the treatment of heart failure but also has a protective effect on kidney function. Although there was no significant reduction in all-cause mortality or cardiovascular mortality, patients treated with sacubitril/valsartan could obtain the benefits of a reduction in hospitalizations for HF and prevention of renal functional deterioration. Moreover, compared with valsartan or IMT, sacubitril/valsartan could increase the risk of symptomatic hypotension and angioedema but did not differ in the elevation of serum potassium. Compared with ACEIs or ARBs, sacubitril/valsartan is a better choice, but it is best to monitor blood pressure and renal function during treatment.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.

YW and ZH reviewed the articles, performed the meta-analysis and wrote the manuscript. SW, LF, and YS were responsible for the statistical analysis. ZY provided editing assistance. YP and WQ designed and revised the manuscript. All authors have reviewed and agreed on this information before submission.

This work was supported by the Provincial Plans-Social Development Areas—Major Projects of Jiangxi Province (No. 20161ACG70012) and the incubation project of the National Natural Science Foundation of the Second Affiliated Hospital of Nanchang University (No. 2021YNFY2021).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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