Efficacy of sacubitril/valsartan on improving clinical symptoms in patients with acute myocardial infarction complicated with heart failure: a retrospective study

Introduction

Acute myocardial infarction (AMI) is a serious coronary heart disease caused by diminished blood supply to the myocardium and leads to significant morbidity and mortality worldwide (Bauersachs et al., 2019; Mechanic, Gavin & Grossman, 2023). Not only does AMI accelerate the progression toward heart failure (HF), but it also heightens the risk of developing persistent complications (Roger, 2013; Vernon et al., 2019). Approximately 25% of patients with ST-segment elevation AMI are likely to develop HF (Kelly et al., 2011; Danchin et al., 2020), with up to 13% of these patients experiencing HF within 3 years post-event (Sulo et al., 2016).

Pharmacological interventions for HF, primarily angiotensin-converting enzyme inhibitors (ACEIs), target the renin-angiotensin-aldosterone system (RAAS), which plays a crucial role in left ventricular remodeling post-AMI (Heart Failure Group of Chinese Society of Cardiology of Chinese Medical Association, Chinese Heart Failure Association of Chinese Medical Doctor Association, Editorial Board of Chinese Journal of Cardiology, 2018). This mechanism blocks the conversion of angiotensin I to angiotensin II, reducing vascular resistance, lowering blood pressure, and alleviating cardiac workload (Ferrari, 2013). Recent advancements in the understanding of AMI and HF pathophysiology have led to the development of innovative therapeutic agents such as sacubitril/valsartan (S/V), a leading drug in the class of angiotensin receptor-neprilysin inhibitors (ARNIs). Sacubitril prolongs the natriuretic peptides by inhibiting neprilysin, an enzyme that degrades vasoactive peptides, while valsartan blocks the angiotensin II type 1 receptor, together offering a synergistic effect that inhibits RAAS further and promotes natriuresis and vasodilation (Mangiafico et al., 2013; Wang et al., 2015; Sauer et al., 2019).

Several large-scale trials have shown the efficacy of sacubitril/valsartan (S/V) in heart failure management. The Prospective Comparison of ARNI with ACEIs to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial involving over 8,000 patients with reduced ejection fraction (HFrEF) demonstrated that S/V reduced all-cause mortality by 16% and cardiovascular death by 20% compared to enalapril, making it the first therapy to outperform ACE inhibitors (McMurray et al., 2014). The PIONEER-HF trial (Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure) confirmed the early use of S/V in hospitalized patients with acute HF, evidencing a greater reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels compared to enalapril (Velazquez et al., 2019). Similarly, the PARAMOUNT-HF trail reaffirmed S/V’s benefits in improving ventricular remodeling and reducing HF symptoms. However, the PARADISE-MI trial revealed no significant differences between S/V and ramipril in post-AMI patients (Pfeffer et al., 2021). Additionally, various systematic reviews and meta-analyses have consistently demonstrated that S/V significantly decreases NT-proBNP levels and reduces the incidence of major adverse cardiovascular events across diverse patient populations, including those with AMI, HF, or heart failure following to AMI (HF-AMI) (Zhao, Zeng & Shen, 2021; Liu et al., 2022; Gao et al., 2023).

Despite the established efficacy of S/V, clinical evidence remains limited regarding its use among Chinese patients with AMI complicated by HF. While advancements in treatment have been recognized, the mortality risk continues to be substantial for HF patients with a history of AMI (Gerber et al., 2016), as current strategies predominantly focus on AMI management, potentially neglecting the progression of HF. Additionally, demographic shifts toward an aging population have exacerbated the prevalence of HF following AMI (Roger, 2013; Salari et al., 2023). As the incidence of HF post-AMI increases, identifying the most effective treatment approaches becomes imperative for enhancing patient outcomes and alleviating the burden on healthcare systems. We hypothesized that S/V is more effective than ACEIs in improving clinical outcomes in Chinese patients with AMI complicated by HF, as measured by reductions in NT-proBNP levels and improvements in dyspnea symptoms. Thus, this study aims to investigate the early application of S/V in AMI patients with concurrent HF, offering insights into optimizing clinical care and reducing the healthcare burden.

Materials and Methods

Results

Baseline characteristics

During January and December 2021, the hospital treated 376 patients diagnosed with AMI complicated with HF. After exclusions due to incomplete medication data, missing NT-proBNP levels, and concurrent use of both ACEIs and S/V, 88 patients remained eligible for final analysis and were followed up 1-year post-discharge (Fig. 1). As shown in Table 1, the study is comprised of 31 patients in the S/V group with an average age of 62.29 years (SD 13.54), and 57 patients in the ACEIs group with an average age of 62.74 years (SD 11.76). The gender distribution showed 16.13% female in the S/V group vs. 35.09% in the ACEIs group. At baseline, which is also the admission to the hospital, demographic characteristics, lifestyle factors (smoking and drinking), medical history (diabetes and hypertension), and complete blood count parameters (red blood cells, white blood cells, hemoglobin, and platelets) showed no significant differences between the groups. AMI sites were similarly distributed, with anterior myocardial infarction presented in 48.39% of the S/V group and 33.33% of the ACEIs group (P = 0.166) and inferior myocardial infarction in 16.13% of the S/V group and 12.28% of the ACEIs group (P = 0.615).

Table 1:

Baseline characteristics between S/V and ACEIs groups.

Data categories	S/V (n = 31)	ACEIs (n = 57)	Z/t/ ${\mathit{\chi }}^2$	P-value
Demographic
Age (years)	62.29 ± 13.54	62.74 ± 11.76	0.16b	0.872
Female (%)	5 (16.13)	20 (35.09)	3.55c	0.060
Married (%)	30 (96.77)	56 (98.25)	0.20c	0.658
BMI (kg/m2)	26.14 ± 3.32	25.65 ± 3.66	−0.62b	0.537
Lifestyles
Smoking (%)	12 (38.71)	17 (29.82)	0.72c	0.397
Drinking (%)	10 (32.26)	13 (22.81)	0.93c	0.335
Medical history
Diabetes (%)d	11 (35.48)	20 (35.09)	0.02c	0.884
Hypertension (%)	15 (48.39)	39 (68.42)	3.40c	0.065
Complete blood count
Red Blood Cells (mcL)	4.51 ± 0.53	4.48 ± 0.59	−0.27b	0.791
White Blood Cells (mcL)	8.23 (6.98–11.14)	8.67 (7.4–11.19)	0.69a	0.487
Hemoglobin (gm/dL)	139.48 ± 16.41	135.89 ± 18.69	−0.90b	0.372
Platelets (mcL)	233.45 ± 61.19	230.60 ± 54.29	−0.23b	0.822
Myocardial infarction
Anterior myocardial infarction (%)	15 (48.39)	19 (33.33)	2.89c	0.235
Inferior myocardial infarction (%)	5 (16.13)	7 (12.28)
Unclassified (%)	11 (35.48)	31 (54.39)
Biochemical data
Triglycerides (mmol/L)d	1.53 (1.01–2.15)	1.67 (1.23–2.51)	1.08a	0.281
Total cholesterol (mmol/L)d	4.86 ± 1.31	4.77 ± 1.20	−0.31b	0.756
High-Density Lipoprotein (mmol/L)d	0.83 (0.73–1.03)	0.95 (0.80–1.11)	1.89a	0.058
Low-Density Lipoprotein (mmol/L)d	2.92 (2.33–3.56)	2.85 (2.43–3.22)	−0.45a	0.651
Creatinine (mmol/L)	78.05 (68.47–97)	68.02 (56.41–81.19)	−2.69a	0.0072*
Blood glucose (mmol/L)d	6.32 (5.26–7.75)	6.03 (5.03–7.32)	−0.98a	0.328
Cardiac function-associated indexes
Ejection fraction, EF (%)e	51 (43–55)	58 (55–64.5)	4.00a	0.0001*
Left ventricular end-diastolic dimension (mm)e	57 (47–59)	48 (45–50.5)	−2.91a	0.0036*
NT-proBNP (pg/mL)	1,780 (252–5,850)	566 (189–2,590)	−1.86a	0.063
Blood pressure
SBP (mm Hg)	122.77 ± 18.94	134.28 ± 18.08	2.80b	0.0062*
DBP (mm Hg)	76.90 ± 13.04	80.72 ± 11.77	1.40b	0.165
Hospitalization
Hospitalization times (days)d	9 (7–14)	8 (7–9)	−2.54a	0.011

DOI: 10.7717/peerj.18873/table-1

Notes:

* indicates a P-value of less than 0.05 between the two groups.

a represents the Z-value.

b represents the t-value.

c represents the chi-squared value.

d represents 1-person missing data for certain variable.

e represents 29 persons missing data for certain variable.

Biochemical data, including triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, and blood glucose levels, were comparable across both groups. Notably, the S/V group exhibited significantly higher creatinine levels (median 78.05, IQR 68.47–97 mmol/L) than the ACEIs group (median 68.02, IQR 56.41–81.19 mmol/L), indicating greater renal impairment in the S/V group at baseline (P < 0.01).

In addition to the creatinine level, cardiac assessments revealed that the S/V group had a lower left ventricular ejection fraction compared to the ACEIs group (median 51 IQR (43–55) vs. median 58 IQR (55–64.5)%; P < 0.001), and a larger left ventricular end-diastolic dimension (median 57 IQR (47–59) vs. median 48 IQR (45–50.5) mm; P < 0.01). Although the difference in NT-proBNP levels between the two groups was insignificant (P = 0.063), the median NT-proBNP in the S/V group reached 1,780 pg/mL. All the cardiac function-associated indexes indicated more severe cardiac dysfunction in the S/V group at baseline.

NT-proBNP levels between two groups at admission, discharge, and follow-up

NT-proBNP, a crucial biomarker for heart failure assessment, was analyzed at various stages of patient care. Initially, at admission, there was no significant difference in NT-proBNP levels between the S/V and ACEIs groups (P = 0.063). However, at discharge, a significant difference emerged, with the S/V group showing higher median NT-proBNP levels at 2,170 pg/mL (IQR 714–3,650) compared to the ACEIs group at 690 pg/mL (IQR 328–1,270) (P = 0.0002).

Within-group comparisons from admission to discharge revealed no significant changes in NT-proBNP levels for either the S/V group (P = 0.624) or the ACEIs group (P = 0.231) despite the observed rise in median levels for both groups (S/V: from 1,780 pg/mL (IQR 252–5,850) to 2,170 pg/mL (IQR 714–3,650); ACEIs: from 566 pg/mL (IQR 189–2,590) to 690 pg/mL (IQR 328–1,270)) (Fig. 2A).

Furthermore, the change in NT-proBNP levels (Δ NT-proBNP) did not differ significantly between the two groups (Fig. 2B). At 1-year follow-up, a trend towards lower NT-proBNP levels was noted in the S/V group, although it did not reach statistical significance (P = 0.052) (Fig. 2C).

Blood pressure response to S/V and ACEIs at admission, discharge, and follow-up

At admission, DBP showed no significant difference between the groups (P = 0.166), while the SBP in the S/V group was significantly lower than in the ACEIs group (122.77 ± 18.94 vs. 134.28 ± 18.08 mm Hg; P < 0.01). By discharge, the S/V group’s mean DBP decreased to 71.97 ± 11.39 mmHg, which was significantly lower than the ACEIs group’s mean of 78.21 ± 10.31 mmHg (P < 0.05). Similarly, the SBP of S/V group was also significantly lower compared to the ACEIs group (116.13 ± 19.97 vs. 128.14 ± 18.07 mmHg; P < 0.01). Both groups demonstrated a significant reduction in SBP from admission to discharge, with the S/V group showing a larger decrease (Fig. 3A). For DBP, the S/V group exhibited a significant reduction by the end of hospitalization (76.90 ± 13.04 vs. 71.97 ± 11.39 mm Hg; P < 0.05), whereas the ACEIs group showed no significant change (Fig. 3B).

Discussion

This single-center retrospective clinical study aims to investigate the clinical efficacy of S/V compared to ACEIs in patients with AMI complicated by HF. Pivotal trials such as PARADIGM-HF and PIONEER-HF have underscored the significant role of S/V in heart failure management. However, the results of our study did not demonstrate a statistically significant change in NT-proBNP levels from admission to discharge within both treatment groups and a significant improvement in dyspnea symptoms between the two groups, suggesting that the specific clinical benefit of S/V over ACEIs may not be as pronounced in this particular subset of patients with AMI complicated by HF.

NT-proBNP is a well-established biomarker that reflects the cardiac physiological status, particularly ventricular walls stress (Velazquez et al., 2019). The increased level of NT-proBNP is indicative of both the presence and the prognosis of HF (Januzzi et al., 2006). A study involving 600 patients presenting with dyspnea in the emergency department found that NT-proBNP testing demonstrated high sensitive and specific for diagnosing acute congestive heart failure (CHF) (Januzzi et al., 2005). Previous studies investigating the efficacy of S/V across various heart failure contexts, such as acute decompensated HF, HF with preserved ejection fraction (LVEF > 40%), and chronic HF, consistently reported significant reductions in NT-proBNP. Contrary to prior findings, our study aligned with a recent double-blind, randomized clinical trial involving 335 patients with advanced HF and reduced ejection fraction, which found no significant difference in reducing NT-proBNP levels between the S/V and valsartan treatments over 24 weeks. In this trial, S/V did not significantly improve the clinical outcomes measured by days alive, out of hospital, and free from HF events compared to valsartan (Mann et al., 2022). Similarly, the PARADISE-MI trial also noted no significant benefits of S/V over ramipril in patients post-AMI, with minor differences in cardiovascular outcomes (Pfeffer et al., 2021). The consistent findings across trials suggest a limited role of S/V in certain HF contexts.

One possible explanation for the conflicting result is that patient with AMI complicated by HF, represent a distinct pathophysiological state compared to those with chronic HF. The acute phase of myocardial infarction introduces a complex clinical scenario where the biomarkers and clinical endpoints may not respond to interventions in the same manner as in stable, chronic conditions. Furthermore, the timing of the intervention post-AMI is another factor to consider. The post-AMI pathophysiological state is complex, involving various compensatory mechanisms. The impact of RAAS inhibition via ACEIs or neprilysin inhibition via S/V may vary depending on the timing of the intervention in relation to the AMI event.

Our study’s findings also suggest a regional clinical practice trend where physicians may preferentially prescribe S/V to patients with more severe clinical profiles. This is evidenced by the S/V group’s baseline characteristics, including higher creatinine and NT-proBNP levels, lower left ventricular ejection fraction, and greater left ventricular end-diastolic dimension. This tendency might come from the perceived or demonstrated efficacy of S/V in critically ill patients, especially those with HF with reduced ejection fraction, as seen in prior successful studies. However, a study on the prognostic significance of baseline NT-proBNP found that, although it predicted HF outcomes, it did not affect the treatment efficacy of S/V, which consistently reduced NT-proBNP levels regardless of patient characteristics (Cunningham et al., 2020). Thus, the lack of significant differences in NT-proBNP level reduction between S/V and ACEIs in our study may not be entirely attributable to differences in baseline characteristics. The regional inclination to administer S/V to patients in poorer conditions also highlights the practical complexities and nuanced decision-making in real-world clinical settings, which is an aspect that randomized clinical trials may not fully capture.

While our study did not demonstrate a significant difference in NT-proBNP reduction between the S/V and ACEIs groups, ARNI’s role in HF management extends beyond its hemodynamic effects. Studies have shown ARNI can positively influence cardiac remodeling by reducing fibrosis and improving ventricular function in heart failure patients (Sardu et al., 2022). Post-AMI, cardiac remodeling is driven by processes such as myofibroblast phenoconversion, in which fibroblasts transition into myofibroblasts, contributing to fibrosis. Exosomal microRNAs, such as miR-92a, play a critical role in this transition (Wang et al., 2020). Additionally, exosomal epigenetic effectors influence fibroblast activation, potentially contributing to pathological remodeling (Gall & Dupont, 2019). Though our study did not examine these molecular pathways, ARNI’s ability to modulate these processes may explain its broader therapeutic effects in heart failure. Thus, while the immediate clinical benefits of S/V may appear limited, its impact on long-term remodeling through these molecular mechanisms highlights the need for further investigation.

Furthermore, it is important to note that the S/V group exhibited significant reductions in both SBP and DBP, whereas the ACEIs group did not. This finding aligns with broader research indicating S/V’s effectiveness in lowering blood pressure, as evidenced by animal studies and clinical trials, including a phase 2 trial where S/V significantly reduced SBP in heart failure patients with preserved ejection fraction (Solomon et al., 2012) and a retrospective study in China showing positive effects on blood pressure and cardiac function in hypertensive patients with heart failure (Guan et al., 2023). Despite these findings, the clinical significance of blood pressure reduction in the context of ACS remains unclear. Elevated blood pressure increases cardiac workload and promotes pathological myocardial changes, which may contribute to systolic and diastolic dysfunction (Oh & Cho, 2020). By effectively lowering blood pressure, S/V might help mitigate these risks in a broader heart failure population, though its direct impact in acute settings such as post-AMI may not be as pronounced or immediately relevant to clinical outcomes. Therefore, while S/V shows potential in managing hypertension associated with heart failure, its specific role in ACS requires cautious interpretation and further study.

Our research, while providing valuable insights into the treatment of AMI complicated by HF, does contain several limitations. First, the non-randomized design and baseline difference in renal function and cardiac dysfunction between groups introduce selection bias, potentially affecting the outcomes. Second, as a single-center study, our findings may have limited generalizability beyond the specific Chinese patient population and practices observed at our institution. Furthermore, our study was limited by a relatively small sample size, with 88 patients included at baseline and only 19 followed up 1 year later. This small cohort size may reduce the statistical power and the robustness of our findings. Additionally, the infrequent follow-up—only once, 1 year post-discharge—may not sufficiently capture the variability and progression of symptoms over shorter intervals. Another limitation is the disparity in group sizes, with 31 patients in the S/V group and 57 in the ACEI group. However, this is mitigated by the real-time nature of our data collection. A further limitation is the subjective nature of patient-reported clinical symptoms, which may not accurately reflect their true clinical status. Therefore, future research should aim to include larger, multi-center trials with longer follow-up periods to robustly assess the long-term effectiveness of S/V vs ACEIs across varied clinical environments. Moreover, studies designed to stratify patients based on baseline characteristics should be conducted to provide insight into personalized medicine approaches.

Conclusion

This study hypothesized that S/V would be more effective than ACEIs in managing AMI complicated by HF, as measured by changes in NT-proBNP levels and improvements in clinical symptoms. Although no significant differences were observed in NT-proBNP reduction between S/V and ACEIs, S/V was associated with a reduction in blood pressure. Given the constraints of our study, including a small sample size and potential confounding variables, these findings should be regarded as preliminary. To substantiate these initial observations, we advocate for future research in the form of larger, multi-center, randomized controlled trials to confirm these findings and explore the identification of patient subgroups that may benefit more distinctly from one treatment over the other.

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