Highlights
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Assess sacubitril/valsartan’s effectiveness and find the proper dosage for pediatric heart failure patients.
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Patients with no improvement in traditional medicine were studied.
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Echocardiography, NT-proBNP, and the concentration of valsartan, sacubitril, sacubitrilat were measured.
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Low dose sacubitril/valsartan is effective in children with heart failure.
Abstract
Aims
Pediatric heart failure is a significant cause of illness and death in children. We aimed to assess sacubitril/valsartan’s effectiveness and find the proper dosage for pediatric patients.
Methods
Patients unresponsive to traditional medicines for at least 12 months prescribed sacubitril/valsartan from January 2020 to March 2023 were reviewed. The initial dose was 0.2 mg/kg bid, gradually increasing in 0.1 mg/kg increments. The target dose was determined based on blood pressure fluctuations at 70/50 mmHg. Clinical efficacy and quantity-effect relationship were evaluated using echocardiography, NT-proBNP, and the concentration of valsartan, sacubitril, sacubitrilat.
Results
A total of 23 pediatric patients with dilated cardiomyopathy and advanced heart failure were enrolled. Mean sacubitril/valsartan dose was 1.84 mg/kg/day. After 6 months, LVEF increased significantly (38.09% to 45% at 3 months, 52% at 6 months; p < 0.001). LV size reduced to 4.4 cm (IQR, 4.1–5.2) and 4.5 cm (IQR, 4–5.1) at 3 and 6 months, respectively, from 4.6 cm (IQR, 4.2–5.6) at baseline (both P < 0.05). NT-proBNP levels reduced by 5.7 at 3 months ( p < 0.05) and 5.38 at 6 months ( p < 0.001). Sacubitrilat is the active form of Sacubitril. The highest concentration of sacubitrilat was observed at approximately 1.6 mg/kg. The maintenance dose correlated positively with time ( p < 0.001) and valsartan/sacubitril concentration ( p < 0.05).
Conclusion
Low dose sacubitril/valsartan is effective in children with heart failure, with dosage adjustments to avoid hypotension. Adjusted dosing can increase EF and reduce heart size, offering new possibilities for pediatric heart failure treatment.
Introduction
In childhood, heart failure (HF) is a serious and potentially life-threatening condition. It causes significant morbidity and mortality. Cardiomyopathy and congenital heart diseases are often identified as primary etiologies of pediatric heart failure. However, the clinical presentation of heart failure in children can vary significantly. Treating heart failure is crucial for addressing both the root causes and symptoms of the condition, as well as managing its progression. The primary goal of medical treatment for HF in children is to increase cardiac output and improve end-organ perfusion, ultimately delaying disease progression. Historically, diuretics, angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers, aldosterone receptor antagonists, digoxin, anticoagulants, and other medications have been utilized in the treatment of heart failure. Additionally, there is a growing trend in the annual introduction of new pharmacological agents for the management of heart failure in adult patients. However, there remains a need to further explore the efficacy of certain pharmacological agents for treating heart failure in adult populations before considering their application in pediatric patients. It is imperative that thorough surveillance is conducted to identify any potential negative impacts of new medications intended for pediatric use.
Sacubitril/Valsartan (Entresto), also referred to as LCZ696 by Novartis, is an innovative pharmaceutical agent that functions by dual inhibition of neprilysin (neutral endopeptidase 24.11; NEP) and blockade of the renin-angiotensin-aldosterone system (RAAS). Sacubitril/valsartan has received approval for use in multiple countries for the management of heart failure with reduced ejection fraction (HFrEF) in adult patients. Clinical trial data indicates that sacubitril/valsartan offers superior efficacy outcomes when compared to the standard of care, specifically the ACEI enalapril. The medication’s therapeutic efficacy is derived from sacubitrilat, the active metabolite formed by sacubitril’s hydrolysis by esterase. It is an active type and a potent and selective NEP inhibitor. By inhibiting NEP, the circulation may contain more physiologically active natriuretic peptides, which could enhance the natriuretic, diuretic, and cardiovascular functions. Previously, it has been shown that valsartan can be beneficial for treating adult hypertension. Similar to its efficacy in adult patients with heart failure, sacubitril/valsartan may demonstrate superior effectiveness compared to other treatments for pediatric heart failure, especially in patients with a comparable underlying pathophysiology to adult heart failure with reduced ejection fraction. It has been observed that sacubitril/valsartan is effective in pediatric HF in a similar manner to its adult counterpart. In pediatric heart failure, the natriuretic peptide system appears to be heightened in activation, which contributes to disease progression. It is hypothesized that modulating both the renin-angiotensin-aldosterone system (RAAS) and the natriuretic peptide system (NEP) in pediatric patients with systolic heart failure will result in similar benefits to those seen in adult patients with heart failure with reduced ejection fraction (HFrEF). However, the pharmacological impact of valsartan does not align with the physiological traits of pediatric patients. It is a well-documented fact that many children, particularly those below the age of three, are unable to withstand the low pressure that can result from the use of sacubitril/valsartan. In instances of severe heart failure coupled with hypotension, the ensuing shock poses a notable hazard for pediatric patients. Consequently, this study suggests an examination of the effectiveness of sacubitril/valsartan treatment and the appropriate dosage for clinical use in children.
Methods
Patients information
Patients diagnosed with HF secondary to dilated cardiomyopathy (DCM) who were prescribed sacubitril/valsartan at a medical facility in Wuhan, China, between January 2020 and March 2023, were retrospectively gathered and analyzed. This study protocol had been approved by the Ethics Committee of the Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (2023–0156), and written informed consent was obtained from all patients. These patients failed to improve EF at least 12 months, although they accepted traditional medicine including digoxin, diuretics etc. The inclusion criteria for the current study consisted of (i) age between 1 month and 18 years, (ii) LVEF <55% by echocardiography, and (iii) sacubitril/valsartan treatment for ≥6 months. The exclusion criteria were: (i) age <1 month or ≥18 years, (ii) LVEF ≥55% by echocardiography, or (iii) sacubitril/valsartan treatment for <4 weeks, (iv) loss to follow-up or telephone interview. Date of birth, gender, diagnoses, height, weight, starting time and doses of sacubitril/valsartan medication, and combined medications of all included patients. Laboratory results such as serum NT-proBNP concentrations, echocardiography parameters were collected and analyzed in this study.
Pharmacological intervention protocol for pediatric patients
The starting dose of sacubitril/valsartan was 0.2 mg/kg twice daily, with subsequent incremental increases of 0.1 mg/kg every 3 days. The final maintenance dose, determined by the point at which blood pressure stabilizes at 70/50 mmHg, is to be administered continuously for a period of 3–6 months. The prescribed target doses of 2.3 mg/kg bid or 3.1 mg/kg bid align with the PARANOMA-HF design. The previous medication regimen remained unchanged, with the exception of discontinuation of ACEI. A 10% increase in ejection fraction was deemed to be efficacious. The primary endpoint of the study was the assessment of the effects of sacubitril/valsartan treatment at three months, while the secondary endpoints were evaluated at six months. NT-proBNP levels and echocardiography parameters were used to assess heart failure.
The concentration of valsartan, sacubitril and sacubitrilat detection
The determination of blood concentration was conducted using the LC-MS/MS method previously developed in this investigation. Blood samples were placed in EDTA anticoagulant vessels and plasma samples were taken by centrifugation at 3000 g to determine the concentrations of valsartan, sacubitril and sacubitrilat. A total of 50μL plasma (blank plasma/calibrator /quality control/ clinical sample) was taken, and 5μL formate was added to acidize the sample and vortexed gently, along with 5μL internal standards (500 ng/mL valsartan-d3, sacubitrilin-d4 and sacubitrilat-d4). After a short vortex, 200μL acetonitrile was added to extract the analyte. The supernatant was separated and injected 10μL into LC-MS/MS system for analysis as literature recommendation.
Statistical analysis
Continuous data were presented as mean ± standard deviation if normally distributed or as median (interquartile range) if not normally distributed and categorical variables were presented as percentages. The Student’s t-test or the Mann-Whitney U test was used for comparisons between continuous data, and χ2 test or Wilcoxon test was used for comparisons between categorical data. A two-tailed P value < 0.05 was considered to be statistically significant. All the statistical analyses were performed using the IBM SPSS Statistics 25.0 software. Body weight and height was normalized by age, and echocardiographic data was normalized by body surface area (BSA).
Results
Study population
A total of 23 patients with heart failure due to DCM (mean age 7.11±3.76 years) were treated with sacubitril/valsartan from January 2020 to March 2023. The patients were monitored for a median duration of six months. The majority of patients were male (70%), with a mean maintenance dose of sacubitril/valsartan of 1.84 mg/kg/day ( Table 1 ).
| Variables | Total ( n = 23) |
|---|---|
| Age (years) | 7.11 ± 3.76 |
| Male | 16 (70 %) |
| Weight (kg) | 27.32 ± 14.21 |
| Height (cm) | 132.30 ± 28.98 |
| BSA (m2) | 0.87 (0.79,1.38) |
| Sacubitril/Valsartan Time (month) | 6 (6,12) |
| Maintain dose of Sacubitril/Valsartan (mg/kg/d) | 1.84 ± 0.82 |
Baseline of cardiac structure and function
The echocardiographic changes observed from the baseline to the follow-up period following the initiation of sacubitril/valsartan therapy ( Fig. 1 ). Following six months of therapy, the mean LVEF at three and six months was significantly higher than at baseline (38.09% vs. 45% and 52%, respectively; p < 0.001 for both, Fig. 1 a). Additionally, the size of the left ventricle (LV) was significantly reduced to 4.4 cm (interquartile range (IQR), 4.1–5.2) and 4.5 cm (IQR, 4–5.1) at 3 and 6 months, respectively, in comparison to the baseline value of 4.6 cm (IQR, 4.2–5.6) (both P < 0.05, Fig. 1 d). There were no statistically significant differences in the other parameters of echocardiographic changes, including the size of the left atrium (LA), right atrium (RA), right ventricle (RV) and the early (E) to late (A) ventricular filling velocities ( Fig. 1 e-h).Treatment with sacubitril-valsartan was also associated with a significant decrease in log-transformed serum NT-proBNP levels, with a reduction of 5.7 at 3 months ( p < 0.05) and 5.38 at 6 months ( p < 0.001) compared to baseline levels ( Fig. 1 b).
The comparison between two groups
The clinical outcomes of patients with different EF are evaluated. The patients were divided into two groups according to their LVEF. The study included 13 patients with EF < 40 and 10 patients with EF ≥ 40. Table 2 presents the baseline characteristics by LVEF categories. The two groups exhibited comparable age, body mass index (BMI), and male sex distributions. There was no discernible difference in serum NT-proBNP and echocardiography parameters between the various categories. The time-maintained dose and concentration of valsartan, sacubitril, and sacubitrilat were not statistically significant between the two groups ( Table 2 ).
| Variables | EF<40 ( n = 13) | EF≥40 ( n = 10) | P -Value |
|---|---|---|---|
| Age (years) | 6.76 ± 3.82 | 7.57 ± 3.84 | 0.621 |
| Male | 11(85%) | 5(50%) | 0.074 |
| Weight (kg) | 25.04 ± 11.57 | 30.29 ± 17.27 | 0.392 |
| Height (cm) | 128.00 ± 32.70 | 137.90 ± 23.79 | 0.429 |
| BSA (m2) | 1.00(0.7,1.3) | 0.86(0.8,1.8) | 0.456 |
| Sacubitril/Valsartan Time (month) | 6.0(6.0,6.0) | 6.0(4.5,24.0) | 0.66 |
| Maintain dose of Sacubitril/Valsartan (mg/kg/d) | 1.85 ± 0.74 | 1.82 ± 0.96 | 0.942 |
| NT-ProBNP (pg/ml) | 780.00(366.0,1065.0) | 313.00(171.0,418.5) | 0.116 |
| EF (%) | 29.08 ± 7.59 | 49.80 ± 3.16 | 0.027* |
| LA-0M (cm) | 2.7(2.3,4.5) | 2.5(2.4,2.9) | 0.213 |
| LV-0M (cm) | 5.0(4.5,5.9) | 4.3(4.0,4.8) | 0.086 |
| RA-0M (cm) | 2.8(2.2,3.5) | 2.9(2.5,3.2) | 0.298 |
| RV-0M (cm) | 2.7(2.2,3.3) | 2.8(2.4,3.5) | 0.264 |
| E-0 (cm/s) | 1.0(0.8,1.1) | 0.8(0.7,1.1) | 0.996 |
| A-0 (cm/s) | 0.5(0.4,0.6) | 0.7(0.6,0.9) | 0.025* |
| Valsartan (ng/ml) | 326.37 ± 303.21 | 285.93 ± 294.85 | 0.752 |
| Sacubitril (ng/ml) | 35.45 ± 53.13 | 66.22 ± 140.74 | 0.475 |
| Sacubitrilat (ng/ml) | 1057.15 ± 599.10 | 2001.70 ± 1522.56 | 0.053 |
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