Angiotensin Receptor-Neprilysin Inhibitor Suppresses Renin-Angiotensin-Aldosterone System Activation After Cardiac Surgery Using Cardiopulmonary Bypass

Abstract

Background: Sacubitril/valsartan, being both a neprilysin inhibitor and angiotensin receptor blocker, exhibits a renin-angiotensin-aldosterone system (RAAS) inhibitory effect. However, no study has investigated the administration of sacubitril/valsartan in patients early after surgery using cardiopulmonary bypass.

Methods and Results: This was a prospective observational study of 63 patients who underwent open heart surgery and were treated with sacubitril/valsartan. No serious adverse events occurred. Among the 63 patients, sacubitril/valsartan was discontinued in 13 due to hypotension (n=10), renal dysfunction (n=2), and dizziness (n=1). Atrial natriuretic peptide concentrations increased significantly from Day 3 of treatment (P=0.0142 vs. Postoperative Day 1) and remained high thereafter. In contrast, plasma renin activity was significantly suppressed from Day 3 onwards (P=0.00206 vs. Postoperative Day 1). A decrease in creatinine concentrations and an increase in the estimated glomerular filtration rate were observed on Day 3; this improvement in renal function was not observed in the historical control group, in which patients did not receive sacubitril/valsartan. New postoperative atrial fibrillation was less frequent in the study group compared with the historical control (12.7% vs. 38.0%; P=0.0034).

Conclusions: Sacubitril/valsartan administration was safe immediately after open heart surgery in patients without postoperative hypotension. It enhanced serum atrial natriuretic peptide concentrations and suppressed RAAS activation.

Continuous-flow extracorporeal circulation during open heart surgery is known to elevate concentrations of certain hormones, notably those within the renin-angiotensin-aldosterone system (RAAS) and catecholamines. These abnormal hormonal fluctuations eventually lead to decreased urine output and fluid retention in the third space postoperatively.¹ Elevated concentrations of RAAS hormones cause renal dysfunction in 2.4–16% of patients with normal preoperative renal function and have been reported to be a poor prognostic factor after heart surgery.^2,3

In contrast, human atrial natriuretic peptide (hANP) is known to protect against renal dysfunction associated with cardiopulmonary bypass.^4–8 hANP has natriuretic, RAAS inhibitory, and coronary artery dilating effects, and is widely used clinically as a treatment for heart failure and acute myocardial infarction in Japan.^9,10 The RAAS inhibitory effect of hANP is also useful in heart surgery using cardiopulmonary bypass. hANP suppresses fluid retention in the third space and reduces the amount of postoperative diuretics required.⁴ It also attenuates ischemia-reperfusion injury in the heart and suppresses arrhythmias and left ventricular remodeling.^5,6 It has been reported that hANP reduced the occurrence of renal dysfunction after heart surgery,⁷ as well as the occurrence of cardiac-related events and the need for dialysis in patients with renal dysfunction.⁸ Nonetheless, the exclusive intravenous administration of hANP and the absence of an oral alternative restrict its use to the acute phase, making it unsuitable for long-term treatment.

Recently, a large-scale randomized controlled trial reported that the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, a combination drug comprising both a neprilysin inhibitor (sacubitril) and an angiotensin II AT₁ receptor antagonist (valsartan), improved prognosis in heart failure patients with impaired left ventricular systolic function.¹¹ Neprilysin inactivates various biological hormones, including natriuretic peptides (i.e., atrial natriuretic peptide [ANP], B-type natriuretic peptide [BNP], and C-type natriuretic peptide [CNP]); thus, its inhibition results in increased blood concentrations of ANP and other related hormones.¹² Angiotensin receptor blockers (ARBs) are potent RAAS inhibitors that possess antihypertensive effects and are widely used for the treatment of heart failure.¹³ Therefore, sacubitril/valsartan, also referred as the “hANP oral drug”, is anticipated to effectively suppress abnormal RAAS activation induced by cardiopulmonary bypass. However, there are currently no reports of the use of sacubitril/valsartan in the early phase after cardiac surgery, and its safety and efficacy remain unclear.

We hypothesized that sacubitril/valsartan could be safely administered in patients during the acute phase following open heart surgery, and that it would suppress RAAS activation and eventually attenuate renal dysfunction and other cardiac events, such as atrial fibrillation (AF), after open heart surgery using cardiopulmonary bypass. We designed the present study to clarify the safety and usefulness of sacubitril/valsartan in patients undergoing open heart surgery.

Methods

Study Participants

This was a prospective observational study of 63 patients undergoing surgery using cardiopulmonary bypass at Dokkyo Medical University Hospital between October 2021 and August 2022. Patients aged >18 years who were taking an ARB or an angiotensin-converting enzyme inhibitor (ACEi) preoperatively and who underwent valvular, coronary, or vascular surgery using cardiopulmonary bypass were eligible for inclusion in the study. Patients who were unable to take oral medication after surgery and those with systolic blood pressure (SBP) <95 mmHg and/or symptomatic hypotension preoperatively, with hyperkalemia (K >5.4 mmol/L), undergoing dialysis, and who required circulatory arrest with deep hypothermia were excluded from the study.

Ethics Approval

This study was approved by the Institutional Review Board of Dokkyo Medical University, Japan (August 20, 2021; Reference no. R-49-14J) and was conducted in accordance with the Declaration of Helsinki. Before inclusion in the study, patients were given a detailed explanation of the study design and provided written informed consent.

Study Protocol

All patients were administered sacubitril/valsartan postoperatively at a dose of 100 mg daily in 2 divided doses following resumption of oral intake. If tolerated, the dose was increased to 200 mg daily in 2 divided doses after 1 week and to 400 mg daily in 2 divided doses after 2 weeks. If the antihypertensive effect was inadequate, the dose was increased promptly to a maximum dose of 400 mg. If further blood pressure reduction was required, other drugs (e.g., calcium channel blockers) were added at the discretion of the attending physician. The criteria for discontinuation of sacubitril/valsartan included symptomatic hypotension, hyperkalemia, angioedema, or any situation where the attending physician deemed it necessary to halt its administration.

All data were collected in a prospective manner. The clinical data recorded included body weight, blood pressure, dose of diuretics, serum concentrations of creatinine, ANP, aldosterone, N-terminal pro-BNP (NT-proBNP), and BNP, plasma renin activity (PRA), estimated glomerular filtration rate (eGFR), and urine concentrations of albumin and creatinine. All parameters were measured before surgery, the day after surgery, and 3, 7, and 14 days and 1 and 3 months after initiation of treatment with sacubitril/valsartan. We also assessed the incidence of postoperative new AF.

As the historical control group, we analyzed 50 consecutive patients who underwent heart and vascular surgery between February 2021 and September 2021 and who met the same inclusion and exclusion criteria as the study group. Data of the historical control group were extracted from patient charts recorded in the hospital computer database. Serum concentrations of ANP, NT-proBNP, BNP, and aldosterone, urine concentrations of albumin and creatinine, and PRA were not available for the historical control group.

Primary and Secondary Outcomes

The primary outcome was changes in serum ANP concentration and PRA after sacubitril/valsartan initiation. Secondary outcomes were the need for discontinuation of sacubitril/valsartan due to adverse events, changes in serum NT-proBNP and BNP concentrations, changes in renal function, and occurrence of new AF after surgery.

Postoperative Management

Following the resumption of oral intake postoperatively, a regimen of oral diuretics was initiated with 20–40 mg furosemide and 25–50 mg spironolactone. In patients who required more diuresis, tolvaptan was added; adjustment of the diuretic dose was left to the discretion of the attending physician. For all patients, postoperative care adhered to the established standards of care for cardiac surgery patients.

Statistical Analysis

Continuous variables are presented as the mean±SD, and categorical variables are presented as numbers and proportions. All continuous variables were assessed for adherence to normal distribution using the Shapiro-Wilk test and a normal probability plot. For univariate analyses, normally distributed variables were compared using Student’s t-test or Welch’s t-test, as appropriate. Non-normally distributed variables were compared using the Mann-Whitney U test, and categorical variables were compared using Chi-squared analysis or Fisher’s exact test, as appropriate. The optimal cut-off value of SBP on Postoperative Day (POD) 1 for predicting the discontinuation of sacubitril/valsartan due to hypotension was determined using receiver operating characteristic (ROC) curve analysis. The cut-off value was determined as the nearest point of the ROC curve to the left upper corner. Parameters that exhibit changes over time postoperatively were analyzed using repeated-measures analysis of variance (ANOVA) with main effects for group and time and an interaction effect between them. Subsequently, post hoc pairwise comparisons were conducted based on the independent t-test.

Two-sided P<0.05 was considered statistically significant.

All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria). More precisely, EZR is a modified version of the R commander that includes statistical functions frequently used in biostatistics.¹⁴

Results

Patient Characteristics

In total, 63 patients who met the inclusion criteria were enrolled in the study. The baseline characteristics of the 63 patients in the sacubitril/valsartan group and 50 patients in the historical control group are summarized in Table 1. Patients in the sacubitril/valsartan group were significantly older than those in the control group (70.1±9.3 vs. 65.7±10.9 years, respectively; P=0.025). There were no significant differences between the 2 groups regarding other preoperative parameters. There were also no significant differences regarding operative procedures, cardiopulmonary bypass time, and aortic cross clamp time.

Table 1.

Baseline Patient Characteristics

	SV group (n=63)	HC group (n=50)	P value
Age (years)	70.1±9.3	65.7±10.9	0.025
Female sex	21 (33.3)	18 (36.0)	0.843
Body weight (kg)	61.4±15.0	60.8±12.8	0.802
Body surface area (m2)	1.63±0.22	1.64±0.19	0.814
Etiology			0.243
Valvular disease	36 (57.1)	30 (60.0)
Ischemic heart disease	16 (25.4)	10 (20.0)
Aortic disease	2 (3.2)	4 (8.0)
Valvular+ischemic heart disease	2 (3.2)	5 (10.0)
Aortic+valvular disease	5 (7.9)	1 (2.0)
Others	2 (3.2)	0 (0.0)
Creatinine (mg/dL)	0.969±0.28	0.927±0.27	0.420
eGFR (mL/min/1.73 m2)	57.8±13.9	63.2±21.8	0.117
SBP (mmHg)	119±14.4	117.7±15.3	0.520
DBP (mmHg)	65.3±11.7	63.8±12.5	0.528
LVEF (%)	56.2±10.7	55.0±13.0	0.586
Diuretics
Loop diuretics	29 (46.0)	26 (52.0)	0.567
Loop diureticsA (mg furosemide equivalent)	27.8±28.2	27.7±18.0	0.99
Tolvaptan	10 (15.9)	6 (12.0)	0.780
TolvaptanB (mg)	8.19±4.42	9.29±4.71	0.654
Spironolactone	19 (30.2)	13 (26.0)	0.678
Operative procedure			0.471
Valvular	38 (60.3)	30 (60.0)
Coronary artery	2 (3.2)	5 (10.0)
Valvular+coronary artery	17 (27.0)	10 (20.0)
Vascular/aortic root	6 (9.5)	10 (20.0)
Cardiopulmonary bypass time (min)	195.4±73.4	178.8±59.8	0.198
Aortic cross clamp time (min)	136.0±71.5	118.1±58.7	0.157

Unless indicated otherwise, data are given as the mean±SD or n (%). ^AMean dose of loop diuretic (furosemide equivalent) in patients taking preoperative loop diuretics. ^BMean dose of tolvaptan in patients taking preoperative tolvaptan. DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HC, historical control; LVEF, left ventricular ejection fraction; SBP, systolic blood pressure; SV, sacubitril/valsartan.

Sacubitril/Valsartan Dosage and Adverse Events

The timing of sacubitril/valsartan initiation after the surgery is summarized in Figure 1. Most patients started taking sacubitril/valsartan on POD1 (n=29; 46%) or on POD2 (n=23; 36%). Changes in the dose of sacubitril/valsartan are shown in Figure 2. Sacubitril/valsartan was discontinued in 13 patients due to hypotension (n=10 patients; 15.9%), and renal dysfunction, renal dysfunction and hyperkalemia, and dizziness (n=1 [1.6%] for each). The mean SBP at POD1 (before sacubitril/valsartan initiation) was significantly lower in patients who required sacubitril/valsartan discontinuation than in those who did not (106.9±12.4 vs. 116.7±10.7 mmHg, respectively; P=0.033). Based on ROC curve analysis, an SBP on POD1 of 111 mmHg was identified as the cut-off value to predict sacubitril/valsartan discontinuation due to hypotension, with a sensitivity of 55.6% and specificity of 70.0% (area under the curve 0.62; 95% confidence interval 0.376–0.864; Figure 3).

Figure 1.

Timing of sacubitril/valsartan initiation in patients after the surgery. POD, postoperative day.

Figure 2.

Changes in doses of sacubitril/valsartan over time in the sacubitril/valsartan group.

Figure 3.

Receiver operating characteristic curve analysis to identify the optimal systolic blood pressure cut-off value on Postoperative Day 1 to predict the discontinuation of sacubitril/valsartan due to hypotension. AUC, area under curve; CI, confidence interval.

Postoperative Diuretics and Spironolactone Dose

Figure 4 shows changes in the doses of diuretics and spironolactone, and changes in the rate of patients who were prescribed those drugs. There was no significant difference in the requirement for a diuretic between the sacubitril/valsartan and historical control groups (Figure 4A,B). Preoperatively, spironolactone was prescribed in 30.2% and 26.0% of patients in the sacubitril/valsartan and historical control groups, respectively. On the Day 3 after start of oral intake, 100% and 94% of patients in the sacubitril/valsartan and historical control groups, respectively, were taking spironolactone. This percentage gradually decreased and returned to preoperative levels in 3 months. There was no significant difference in the dose of spironolactone between the 2 groups (Figure 4C).

Figure 4.

Changes in doses of diuretics and spironolactone (solid lines) and the percentage of patients who are taking each drug (dashed lines) in the sacubitril/valsartan (SV) group and the historical control group from preoperatively (preop) to 3, 7, and 14 days and 1 and 3 months after the start of oral medication postoperatively (OM-3d, OM-7d, OM-14d, OM-1m, and OM-3m, respectively). (A) Loop diuretics (furosemide equivalent); (B) tolvaptan; and (C) spironolactone. ANOVA, analysis of variance.

Changes in Natriuretic Peptide Concentrations and RAAS Activity

In the sacubitril/valsartan group, the preoperative mean serum ANP concentration was higher than the normal range (≤40 pg/mL) and did not change on POD1. However, serum ANP concentrations increased significantly on Day 3 after initiation of sacubitril/valsartan treatment (P=0.0142 vs. POD1) and remained high thereafter (Figure 5A). In contrast, PRA (normal range 0.5–2.0 ng/mL/h) peaked on POD1 and dropped significantly on Day 3 after initiation of sacubitril/valsartan treatment (P=0.00206 vs. POD1) and remained low thereafter (Figure 5B). The serum aldosterone concentration also dropped significantly on Day 3 after initiation of sacubitril/valsartan treatment (P=0.0356 vs. POD1); it gradually increased thereafter and returned to preoperative levels on Day 14 after treatment initiation. However, the serum aldosterone concentration remained lower than the normal range (57–150 pg/mL) throughout the study period (Figure 5C). Changes in serum aldosterone concentrations were inversely proportional to the dose of spironolactone. The urinary albumin/creatinine ratio peaked on POD1 and decreased after initiation of sacubitril/valsartan treatment (Figure 5D). The urinary albumin/creatinine ratio reached was lowest on Day 7 after initiation of sacubitril/valsartan treatment, gradually increasing thereafter to return to preoperative levels 3 months after initiation of sacubitril/valsartan. The NT-proBNP concentration peaked on Day 3 after initiation of sacubitril/valsartan and kept decreasing thereafter (Figure 5E). BNP concentrations showed a similar pattern to NT-proBNP concentrations (Figure 5F).

Figure 5.

Changes in (A) serum concentrations of atrial natriuretic peptide (ANP), (B) plasma renin activity (PRA), (C) serum concentrations of aldosterone (Ald), (D), urinary albumin/creatinine ratio (UACR), (E) serum concentrations of N-terminal pro B-type natriuretic peptide (NT-proBNP), and (F) serum concentrations of B-type natriuretic peptide (BNP) from preoperatively (preop) to Postoperative Day 1 (POD1) and 3, 7, and 14 days and 1 and 3 months after the start of oral medication postoperatively (OM-3d, OM-7d, OM-14d, OM-1m, and OM-3m, respectively). *¹P=0.0142, *²P=0.00206, *³P=0.0356 compared with POD1.

Frequency of Postoperative AF

New postoperative AF occurred in 8 (12.7%) patients in the sacubitril/valsartan group, and in 19 (38.0%) patients in the historical control group; this difference was significant (P=0.0034).

Changes in Body Weight and Blood Pressure

Figure 6A shows changes in body weight in the sacubitril/valsartan and historical control groups. Body weight was highest on POD1 and decreased thereafter until 2 weeks after resumption of oral intake, after which patients regained body weight after 1 month (time effect: P<0.001). There was no significant difference in body weight value between the 2 groups (group effect: P=0.946). The amount of change in body weight by time was significantly larger in the sacubitril/valsartan than historical control group (interaction effect: P=0.036).

Figure 6.

Changes in (A) body weight, (B) systolic blood pressure, (C) serum creatinine, and (D) estimated glomerular filtration rate (eGFR) in the sacubitril/valsartan (SV) and historical control groups from preoperatively (preop) to Postoperative Day 1 (POD1) and 3, 7, and 14 days and 1 and 3 months after the start of oral medication postoperatively (OM-3d, OM-7d, OM-14d, OM-1m, and OM-3m, respectively). *P=0.0027, **P=0.0528 compared with the historical control group. ANOVA, analysis of variance.

Figure 6B shows changes in SBP in the sacubitril/valsartan and historical control groups. SBP decreased until 14 days after resumption of oral intake, and then increased thereafter (time effect: P<0.001). SBP was significantly higher in the historical control group than in the sacubitril/valsartan group (group effect: P=0.0046). There was no significant difference in the pattern of changes in SBP between the 2 groups (interaction effect: P=0.209).

Changes in Renal Function

Creatinine levels increased after the operation, and then gradually returned to preoperative levels (time effect: P<0.001, Figure 6C). There was no significant difference in creatinine values between the 2 groups (group effect: P=0.146). Although creatinine levels decreased significantly on Day 3 after initiation of sacubitril/valsartan treatment, this decrease was not observed in the historical control group (interaction effect: P<0.001). Post hoc analysis revealed that the creatinine level on Day 3 after the resumption of oral intake was significantly lower in the sacubitril/valsartan than historical control group (P=0.0027).

eGFR decreased after the operation, and then gradually returned to preoperative levels (time effect: P<0.001, Figure 6D). There was no significant difference in eGFR values between the 2 groups (group effect: P=0.518). Although eGFR improved on Day 3 after initiation of sacubitril/valsartan treatment, this improvement in eGFR was not obvious in the historical control group (interaction effect: P<0.001). Post hoc analysis revealed that eGFR on Day 3 after the resumption of oral intake tended to be higher in the sacubitril/valsartan than historical control group (P=0.0528).

Discussion

In the present study, sacubitril/valsartan was administered to patients who underwent surgery using cardiopulmonary bypass immediately after they resumed oral intake postoperatively. There is strong evidence that sacubitril/valsartan improves the prognosis of patients with heart failure with reduced ejection fraction.^11,12 However, in the present study, sacubitril/valsartan was given not only to patients with a low ejection fraction, but also (and mainly) to those with a normal ejection fraction (Table 1). The main aims of this study were to evaluate: (1) the safety of sacubitril/valsartan in patients immediately after open heart surgery; and 2) the effectiveness of sacubitril/valsartan in suppressing RAAS activation caused by cardiopulmonary bypass. Therefore, heart failure patients with reduced ejection fraction were not the only target of the present study.

The main findings of this study are as follows: (1) sacubitril/valsartan could be administered safely after open heart surgery and the main adverse event was hypotension; (2) following treatment initiation with sacubitril/valsartan, serum ANP concentrations increased and remained high throughout the treatment period; (3) PRA increased after surgery, but was significantly depressed in accordance with the increase in ANP; (4) NT-proBNP concentrations persistently decreased during the period of treatment with sacubitril/valsartan; (5) the incidence of postoperative new AF was significantly lower in the sacubitril/valsartan than historical control group; and 6) creatinine concentrations decreased and eGFR increased on Day 3 after initiation of sacubitril/valsartan treatment, but no such changes were observed at similar time points in the historical control group.

The main adverse event of sacubitril/valsartan was symptomatic hypotension, which resulted in drug discontinuation in 10 (15.9%) patients. Table 2 summarizes the frequencies of the main adverse events in previous large-scale randomized controlled trials of sacubitril/valsartan and in the present study. The frequency of hypotension was 14.0–28.3% in previous studies,^11,15–19 and is equivalent to that in the present study. This study is the first in which sacubitril/valsartan has been administered to patients in the early period after surgery using cardiopulmonary bypass, and we have shown that sacubitril/valsartan administration is safe in post-heart surgery patients, as in other cohorts of patients. The optimal cut-off value of SBP before treatment initiation to predict discontinuation of sacubitril/valsartan due to symptomatic hypotension was 111 mmHg. In daily clinical settings, appropriate timing of sacubitril/valsartan introduction should be carefully chosen in postoperative patients with SBP <111 mmHg.

Table 2.

Frequencies of Main Adverse Events

Study	Inclusion criteria	Follow-up period	Hyperkalemia (%)	Heart failure (%)	Hypotension (%)
PARADIGM-HF13	HFrEF, EF ≤40%	27 months	11.6	17.4	14.0
PARAGON-HF17	HFpEF, EF ≥45%	35 months	13.2	14.1	15.8
PARAMOUNT18	HFpEF, EF ≥45%	36 weeks	8.0	3.0	19.0
PARALLAX19	HFpEF, EF ≥40%	12 weeks	11.6	4.2	14.1
PARADISE-MI20	MI and reduced EF	22 months	10.6	5.8	28.3
PIONEER-HF21	Acute heart failure	8 weeks	11.6	8.0	15.0
Present study	Post-CPB	3 months	1.6	0	15.9

CPB, cardiopulmonary bypass; EF, ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; MI, myocardial infarction; PARADIGM-HF, the Prospective Comparison of ARNI (Angiotensin Receptor-Neprilysin Inhibitor) With ACEI (Angiotensin Converting Enzyme Inhibitor) to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial; PARADISE-MI, the Prospective ARNI Versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction; PARAGON-HF, the Prospective Comparison of ARNI With ARB (Angiotensin Receptor Blocker) Global Outcomes in Heart Failure With Preserved Ejection Fraction; PARALLAX, the Prospective Comparison of ARNI Vs Comorbidity-Associated Conventional Therapy on Quality of Life and Exercise Capacity Trial; PARAMOUNT, the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction Trial; PIONEER-HF, the Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode Trial.

ANP is well-known for its potent inhibitory effects against RAAS activation.^9,10 In the studies of Sezai et al, low-dose hANP was administered intravenously to patients who had undergone coronary artery bypass grafting for 12–24 h from the start of cardiopulmonary bypass.^4–8 PRA and serum angiotensin II and aldosterone concentrations increased significantly after initiation of cardiopulmonary bypass in the placebo group, but this activation of the RAAS was significantly suppressed in patients administered hANP.^4,5,7 The eGFR significantly decreased in the placebo group after the start of cardiopulmonary bypass, but not in the hANP group.^4,7,8 In the present study, we found oral sacubitril/valsartan had a similar effect as hANP infusion. Serum concentrations of ANP increased significantly after treatment initiation with sacubitril/valsartan, and PRA, which was elevated due to the surgery, was significantly suppressed as the ANP concentration increased. Aldosterone remained lower than normal levels throughout the study period. It was further suppressed on Day 3 of treatment. This change in aldosterone concentrations was distinctly influenced by spironolactone (Figures 3C,4C). Serum creatinine concentrations increased slightly and eGFR decreased slightly after surgery in both the sacubitril/valsartan and historical control groups. However, creatinine concentrations dropped and eGFR increased 3 days after initiation of sacubitril/valsartan. This acute improvement in renal function was not observed in the historical control group. These results support the characterization of sacubitril/valsartan as the “oral drug of hANP”.

In the present study, we also observed a preventative effect of sacubitril/valsartan against AF after open heart surgery. This finding is comparable to that reported by Sezai et al in their hANP studies. Sezai et al infused low-dose hANP in patients who underwent emergency coronary artery bypass grafting using cardiopulmonary bypass. Postoperative AF occurred in 11.1% of patients in the hANP group and in 34.4% of patients in the placebo group (P=0.009).⁶ This observation aligns with existing evidence that suggests a connection between the RAAS and the development of AF.²⁰ RAAS blockers, including ACEi and ARB, have been shown to decrease the occurrence of AF.²¹

In the present study, there was an unexpected significant difference in mean age between the study and historical control groups that occurred by chance. It is well known that greater age is a disadvantage with respect to the occurrence of AF and renal function, and because the study group with an older mean age had “less AF” and “more protected renal function”, we can interpret the results as suggesting that sacubitril/valsartan was protective.

Neprilysin is a neutral endopeptidase responsible for the degradation of several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin.^22–24 The inhibition of neprilysin by sacubitril/valsartan increases the concentrations of these bioactive molecules. Although ANP and CNP are known to be highly susceptible to neprilysin degradation, BNP is a relatively lower-affinity neprilysin substrate.²⁵ Therefore, treatment with sacubitril/valsartan consistently increases serum concentrations of ANP, but results in inconsistent findings regarding BNP concentrations, which have varied across different methods of assessment.^26–28 NT-proBNP is not a direct substrate of the neprilysin enzyme and is not affected by sacubitril/valsartan. Therefore, the decrease in NT-proBNP concentration reflects a reduction in cardiac wall stress, indicating a beneficial effect of sacubitril/valsartan.²⁹ In the present study, both BNP and NT-proBNP concentrations decreased after the start of sacubitril/valsartan and kept decreasing during the treatment period. This change in BNP and NT-proBNP may be attributed, in part, to the effect of sacubitril/valsartan, but may also be due (partly, but significantly) to the effect of the surgery. Because we did not have BNP and NT-proBNP data for the historical control group, the true effect of sacubitril/valsartan on changes in BNP and NT-proBNP concentrations in this cohort is not clear.

The present study has several limitations. The study was conducted in a non-randomized manner, with results from a single institution. The relatively small number of patients included in the study makes it difficult to draw any definitive conclusion regarding the safety and efficacy of sacubitril/valsartan in early phase after cardiac surgery. The patient cohort was restricted to those taking ARB or ACEi preoperatively because the prescription of sacubitril/valsartan is approved only for transition from ARB or ACEi in Japan. This could potentially limit the generalizability of the study’s findings. The area under curve of the ROC analysis to determine the blood pressure cut-off value to predict discontinuation of sacubitril/valsartan was relatively small. The SBP cut-off value of 111 mmHg should be considered as a reference value. Various diuretics were used at different doses postoperatively, and this may have affected postoperative kidney function. In addition, heterogeneous operative procedures could have influenced the outcomes. The study also used a historical control group. Although we could not find any significant differences in the patient backgrounds, except for the younger age of the historical control group, a bias may still have existed. Moreover, important data, such as serum concentrations of ANP, NT-proBNP, BNP, and aldosterone, urine concentrations of albumin and creatinine, and PRA, were not available for the historical control group. Therefore, our conclusions should be interpreted with caution, and a prospective randomized study is needed to clarify the efficacy of sacubitril/valsartan after cardiac surgery. Finally, we did not examine the long-term outcomes, although these should be addressed in a future study.

In conclusion, sacubitril/valsartan was safely administered during the acute phase following open heart surgery to patients without postoperative hypotension. It enhanced serum concentrations of ANP and suppressed RAAS activation caused by cardiopulmonary bypass. There is a possibility that sacubitril/valsartan could protect renal function after open heart surgery and reduce the incidence of AF. These findings should be verified in larger-scale randomized studies.

Acknowledgments

None.

Sources of Funding

This research received no grants from any funding agency in the public, commercial, or non-profit sectors.

Disclosures

The authors declare no conflicts of interest.

IRB Information

This study was approved by the Institutional Review Board of Dokkyo Medical University (August 20, 2021; Reference no. R-49-14J).

Data Availability

The deidentified participant data will be shared on a request basis. Please contact the corresponding author directly to request data sharing. The entire dataset used will be available, including the study protocol. Data will be shared as soon as it is approved by the Institutional Review Board of Dokkyo Medical University, and the data will be available between 9 and 36 months after publication of this paper. The data will be shared with anyone wishing to access it. Any analyses of the data will be approved and the data will be shared as an Excel file via email.

References

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