Expert Opinion on the Role of Sacubitril/Valsartan in the Management of Hypertension in India.

Hypertension, a key modifiable risk factor for cardiovascular diseases (CVD), significantly contributes to premature death and morbidity worldwide. Despite stabilization in age-adjusted global prevalence, the absolute number of hypertensive individuals doubled from 2000 to 2010, largely due to increases in low- and middle-income countries. In 2021, only 21% of hypertensive individuals globally had effective blood pressure (BP) control. In India, hypertension is the leading risk factor for death and disability, with prevalence rates of 24% in men and 21% in women, as reported by the 2019-2020 National Family Health Survey (NFHS-5). Alarmingly, just 25% of rural and 38% of urban hypertensive Indians are undergoing treatment, with only 10% and 20% achieving BP control, respectively. This highlights the hypertension paradox, where clinical inertia and hesitancy in intensifying BP-lowering therapy persist despite the availability of antihypertensive drugs. This expert opinion paper aims to provide a comprehensive evaluation of sacubitril/valsartan in hypertension management, leveraging insights from its approved use in heart failure and examining its benefits and challenges across diverse hypertensive populations. The formulation of this expert opinion involved employing evidence-based methodologies and utilizing all available data. The document underwent scrutiny by expert cardiologists, whose clinical experiences and examination of the evidence and guidelines informed the formation of the expert opinion. This expert opinion paper provides a thorough and informed evaluation of sacubitril/valsartan, highlighting its potential to address unmet needs in BP control, particularly in challenging cases such as resistant hypertension and chronic kidney disease.

Angiotensin receptor-neprilysin inhibition and improved ventricular-arterial coupling in heart failure with reduced ejection fraction.

Sacubitril/valsartan improves outcome in chronic heart failure (HF) with reduced ejection fraction (EF). The underlying mechanisms on left ventricular (LV) myocardial function are incompletely understood. In this study, 117 patients with symptomatic HF and LV-EF ≤ 40% were enrolled prospectively. Non-invasive pressure-volume analysis was calculated from transthoracic echocardiography with simultaneous arm-cuff blood pressure measurements. Primary outcome parameters were LV end-systolic elastance (Ees; a measure of LV contractility), effective arterial elastance (Ea; a measure of afterload), and the ventricular-arterial coupling ratio (Ea/Ees). Mean age was 65±13 years, 30% were female, and 54.7% had ischemic heart disease. During six months of follow-up, eight patients died, three withdrew their consent, and four were lost to follow-up. 102 patients were included in pressure-volume analyses. After six months of sacubitril/valsartan treatment, Ees increased (0.66mmHg/ml [IQR 0.45-0.94] vs. 0.78mmHg/ml [IQR 0.57-1.10], p=0.001), Ea decreased (1.76mmHg/ml [IQR 1.48-2.13] vs. 1.62mmHg/ml [IQR 1.36-1.96], p=0.014), and the Ea/Ees ratio improved (2.52 [IQR 1.88-4.05] vs. 1.93 [IQR 1.50-2.63], p<0.001). LV end-diastolic pressure and LV volumes were reduced, and LVEF increased from 33% to 43% (both p<0.001). Clinical improvement occurred in NYHA functional class, NT-proBNP level, and 6-minute walking distance. Change in LVEF correlated with change in Ees (r=0.33, p=0.0008), while change in NT-proBNP was associated with change in LVEDP (r=0.42, p<0.0001). In conclusion, sacubitril/valsartan is associated with improved ventricular-arterial coupling by enhancing LV contractility and reducing afterload. Beyond LV reverse remodeling, optimized ventricular-arterial interaction may contribute to the favorable outcome of sacubitril/valsartan treatment in HF with reduced EF.

Meta-analysis of a controlled study of levosimendan combined with Sacubitril/Valsartan for the treatment of heart failure with reduced ejection fraction in China.

Objective: Levosimendan and Sacubitril/Valsartan are both potent pharmacotherapeutic agents in the clinical management of heart failure characterized by reduced ejection fraction. However, the limited efficacy of monotherapy and the lack of extensive clinical experience with combination therapy necessitate further investigation. This study aimed to evaluate the therapeutic effects of combining levosimendan with sacubitril/valsartan on chronic heart failure with reduced ejection fraction, specifically through a meta-analysis of studies conducted in China. Methods: Cochrane systematic evaluation method was used to complete data retrieval from the following related databases: (1) Wanfang database; (2) CNKI China Academic Journal Network; (3) Wipo Full-text Database of Chinese Sci-tech journals; (4) PubMed; (5) Medline; (6) Chinese Biomedical Literature Database; (7) Web of Science; and (8) Google Scholar database. We searched for studies published up to December 2021. Data were extracted from applicable articles. Meta-analyses were performed to assess the left ventricular ejection fractions (LVEF) level, NT-proBNP level, Clinical efficacy, and the left ventricular end-diastolic dimension (LVEDD) level outcomes, following PRISMA 2020 guidelines. Results: A total of five randomized controlled trials (RCTs) comprising 398 patients were included, half of the patients for levosimendan combined with Sacubitril/Valsartan and half of the patients for control groups. The effective rate in experimental group was significantly higher than that in control group [Peto-OR = 3.08, 95% CI (1.83, 5.19), P < 0.05]. The LVEF level after treatment in the experimental group was significantly higher than that in the control group [MD = 5.51, 95% CI (4.25, 6.76), P < 0.05]. After treatment, the LVEDD level in the experimental group was lower than that in the control group [MD = -3.83, 95% CI (-7.60, -0.05), P < 0.05]. There was a statistically significant difference in the N terminal pro B type natriuretic peptide (NT-proBNP) level between the two groups after treatment, where the value for the experimental group was lower than that for the control group [SMD = -2.68, 95% CI (-3.94, -1.43), P < 0.05]. Conclusion: Meta-analysis results showed that levosimendan combined with Sacubitril/Valsartan has a better therapeutic effect on heart failure with reduced ejection fraction and is beneficial for improving cardiac function. The main mechanism for this may be related to the pharmacological action of levosimendan.

Cardiometabolic effects of sacubitril/valsartan in a rat model of heart failure with preserved ejection fraction.

The promising results obtained in the PARADIGM-HF trial prompted the approval of sacubitril/valsartan (SAC/VAL) as a first-in-class treatment for heart failure with reduced ejection fraction (HFrEF) patients. The effect of SAC/VAL treatment was also studied in patients with heart failure with preserved ejection fraction (HFpEF) and, although improvements in New York Heart Association (NYHA) class, HF hospitalizations, and cardiovascular deaths were observed, these results were not so promising. However, the demand for HFpEF therapies led to the approval of SAC/VAL as an alternative treatment, although further studies are needed. We aimed to elucidate the effects of a 9-week SAC/VAL treatment in cardiac function and metabolism using a preclinical model of HFpEF, the Zucker Fatty and Spontaneously Hypertensive (ZSF1) rats. We found that SAC/VAL significantly improved diastolic function parameters and modulated respiratory quotient during exercise. Ex-vivo studies showed that SAC/VAL treatment significantly decreased heart, liver, spleen, and visceral fat weights; cardiac hypertrophy and percentage of fibrosis; lipid infiltration in liver and circulating levels of cholesterol and sodium. Moreover, SAC/VAL reduced glycerophospholipids, cholesterol, and cholesteryl esters while increasing triglyceride levels in cardiac tissue. In conclusion, SAC/VAL treatment improved diastolic and hepatic function, respiratory metabolism, reduced hypercholesterolemia and cardiac fibrosis and hypertrophy, and was able to modulate cardiac metabolic profile. Our findings might provide further insight into the therapeutic benefits of SAC/VAL treatment in obese patients with HFpEF.

Sacubitril/Valsartan Combination Partially Improves Cardiac Systolic, but Not Diastolic, Function through ß-AR Responsiveness in a Rat Model of Type 2 Diabetes.

Cardiovascular complications are the major cause of diabetes mellitus-related morbidity and mortality. Increased renin-angiotensin-aldosterone system activity and decreased ß-adrenergic receptor (ß-AR) responsiveness contribute to diabetic cardiac dysfunction. We evaluated the effect of sacubitril/valsartan (neprilysin inhibitor plus angiotensin receptor antagonist combination) and valsartan treatments on the diabetic cardiac function through ß-AR responsiveness and on protein expression of diastolic components. Six-week-old male Sprague Dawley rats were divided into control, diabetic, sacubitril/valsartan (68 mg/kg)-, and valsartan-treated (31 mg/kg) diabetic groups. Diabetes was induced by a high-fat diet plus low-dose streptozotocin (30 mg/kg, intraperitoneal). After 10 weeks of diabetes, rats were treated for 4 weeks. Systolic/diastolic function was assessed by in vivo echocardiography and pressure-volume loop analysis. ß-AR-mediated responsiveness was assessed by in vitro papillary muscle and Langendorff heart experiments. Protein expression of sarcoplasmic reticulum calcium ATPase2a, phospholamban, and phosphorylated phospholamban was determined by Western blot. Sacubitril/valsartan improved ejection fraction and fractional shortening to a similar extent as valsartan alone. None of the treatments affected in vivo diastolic parameters or the expression of related proteins. ß1-/ß2-AR-mediated responsiveness was partially restored in treated animals. ß3-AR-mediated cardiac relaxation (an indicator of diastolic function) responses were comparable among groups. The beneficial effect of sacubitril/valsartan on systolic function may be attributed to improved ß1-/ß2-AR responsiveness.

The Impact of Sacubitril/Valsartan on Heart Failure Patient with Reduced Left Ventricular Ejection Fraction: Single Center Retrospective Study in Saudi Arabia.

Background: Sacubitril/valsartan (S/V) is used in managing heart failure with reduced ejection fraction (HFrEF), reducing morbidity and mortality while improving symptoms and prognosis. This study aims to evaluate the effectiveness of S/V in patients with reduced left ventricular ejection fraction (LVEF) and its safety. Methods:  This retrospective cohort study included adult patients aged ≥18 years diagnosed with HFrEF, receiving S/V, and followed up at a tertiary hospital in Riyadh. Primary outcomes included improvements in LVEF on echocardiography and the number of hospitalizations due to acute decompensated heart failure (ADHF). Secondary outcomes assessed the safety profile of S/V. Multinomial logistic regression analysis was performed with statistical significance set at P < 0.05. . Results: The study included 107 patients: 80 with LVEF < 30% and 27 with LVEF 30-40%. Six-month follow-up, LVEF improvement was categorized into three groups: no improvement, LVEF increased by 1 to <10 points, and LVEF increased by ≥10 points. The LVEF was similar across groups (P = 0.59). Although hospitalizations due to ADHF were not significantly different between groups, they numerically decreased after initiating S/V (P = 0.1). S/V was generally well tolerated. Conclusion: This study suggests no significant benefit from S/V regarding LVEF improvement. It is recommended that heart failure clinics assess and titrate S/V to the maximum tolerated dose.

A clinical randomized trial: Effects of early application of sacubitril/valsartan on ventricular remodeling and prognosis in acute myocardial infarction patients.

Objectives: To explore the effects of early application of sacubitril/valsartan on ventricular remodeling and prognosis in patients with acute myocardial infarction (AMI). Methods: Total of 295 patients with AMI admitted to the hospital were enrolled between August 2019 and August 2021. According to different treatment methods, they were divided into observation group (sacubitril/valsartan sodium tables combined with standard treatment, 132 patients) and control group (benazepril hydrochloride tablets combined with standard treatment, 163 patients). The levels of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP), creatinine (Cr) and serum K+ before and at 6 months after treatment, standard deviation of all normal-to-normal intervals (SDNN), standard deviation of the average all normal-to-normal intervals (SDANN), root mean square of differences between adjacent normal-to-normal intervals/root mean square differences of successive R-R (RMSSD), left ventricular end-diastolic volume (LVEDV), left ventricular ejection fraction (LVEF) and left ventricular end-systolic volume (LVESV) in the two groups were compared. The adverse reactions during treatment and major adverse cardiac events (MACE) during 6 months of follow-up in both groups were statistically analyzed. Results: The levels of NT-proBNP, Cr and K+, LVEDV and LVESV in observation group were significantly lower than those in control group (P < 0.05), while LVEF, SDNN, SDANN and RMSSD were significantly higher than those in control group (P < 0.05). The incidence of MACE in observation group was lower than that in control group during 6 months of follow-up (7.58 % vs 27.61 %, P < 0.05), but there was no significant difference in the incidence of adverse reactions (9.85 % vs 12.88 %, P > 0.05). Conclusion: Early application of sacubitril/valsartan sodium can effectively delay ventricular remodeling, improve cardiac function and heart rate variability indexes, reduce NT-proBNP level and improve prognosis in AMI patients.

Race in Heart Failure: A Pooled Participant-Level Analysis of the Global PARADIGM-HF and PARAGON-HF Trials.

BACKGROUND: Mechanisms of disease pathobiology, prognosis, and potentially treatment responses might vary by race in patients with heart failure (HF). OBJECTIVES: The authors aimed to examine the safety and efficacy of sacubitril/valsartan among patients with HF by self-reported race. METHODS: PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) were global, randomized clinical trials testing sacubitril/valsartan against a renin-angiotensin system inhibitor ([RASi], enalapril or valsartan, respectively) in patients with HF and left ventricular ejection fraction ≤40% (PARADIGM-HF) or left ventricular ejection fraction ≥45% (PARAGON-HF). Patients with self-reported race were categorized as White, Asian, or Black. We assessed the composite of first HF hospitalization or cardiovascular death, its components, and angioedema across races. RESULTS: Among 12,097 participants, 9,451 (78.1%) were White, 2,116 (17.5%) were Asian, and 530 (4.4%) were Black. Over a median follow-up of 2.5 years, Black (adjusted HR: 1.68; 95% CI: 1.42-1.98) and Asian patients (adjusted HR: 1.32; 95% CI: 1.18-1.47) experienced higher risks of the primary outcome compared with White patients. Treatment effects of sacubitril/valsartan vs RASi on the primary endpoint were consistent among White (HR: 0.84; 95% CI: 0.77-0.91), Asian (HR: 0.92; 95% CI: 0.78-1.10), and Black patients (HR: 0.79; 95% CI: 0.58-1.07; Pinteraction = 0.58). Rates of severe angioedema were higher with sacubitril/valsartan vs RASi (White: 0.2% vs 0.1%; Black: 1.5% vs 0.0%; Asian: 0.1% vs 0.1%). CONCLUSIONS: In a pooled experience of 2 global trials, Black and Asian patients exhibited a higher risk of cardiovascular events than White patients. The benefits of sacubitril/valsartan were consistent across races. Risks of severe angioedema were low but numerically higher with sacubitril/valsartan. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255; Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Cardiac and kidney outcomes after sacubitril-valsartan therapy: recovery of cardiac function relative to kidney function decline.

BACKGROUND: Sacubitril-valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction (HFrEF). However, its long-term protective effects on cardiac function with concurrent acute kidney injury (AKI) remain unclear. This study investigated the recovery of cardiac function relative to kidney function decline. METHODS: A total of 512 patients with HFrEF who started sacubitril-valsartan or valsartan treatment were enrolled in cohort 1. Additionally, patients who experienced AKI and underwent follow-up transthoracic echocardiography were enrolled in cohort 2. In cohort 1, short- and long-term kidney outcomes were analyzed. For cohort 2, changes in cardiac function in relation to changes in kidney function after drug initiation were analyzed. RESULTS: The mean age of the patients was 68.3 ± 15.1 years, and 57.4% of the patients were male. AKI occurred in 15.9% of the sacubitril-valsartan group and 12.5% of the valsartan group. After AKI, 78.4% of patients in the sacubitril-valsartan group and 71.4% of those in the valsartan group underwent recovery. Furthermore, cardiovascular outcomes in patients who developed AKI after drug initiation were analyzed in cohort 2. The sacubitril-valsartan group showed a greater improvement in cardiac function compared with the valsartan group (12.4% ± 15.4% vs. 1.4% ± 5.7%, p = 0.046). The ratio of deltas of cardiac and kidney function in the sacubitril-valsartan and valsartan groups were -1.76 ± 2.58 and -0.20 ± 0.58, respectively (p = 0.03). CONCLUSION: Patients with HFrEF treated with sacubitril-valsartan exhibited significant improvements in cardiovascular outcomes despite AKI.

The in-hospital administration of sacubitril/valsartan in acute myocardial infarction: A meta-analysis.

There is a need to address the evidence gap regarding the in-hospital administration of sacubitril/valsartan in acute myocardial infarction patients. After searching MEDLINE, Google Scholars and Scopus, a random-effects meta-analysis of randomized controlled trials comparing the in-hospital administration of the angiotensin receptor-neprilysin inhibitors (ARNis) versus the standard therapy in patients with reduced heart failure due to myocardial infarction was performed. The primary outcome was major adverse cardiovascular events. All-cause mortality, cardiac death, rehospitalization for heart failure, non-fatal myocardial infarction (MI), changes in left ventricular ejection fraction, left ventricular volumes, N terminal pro brain natriuretic peptide and adverse events were the secondary endpoints. Nine studies (eight randomized controlled trials and one echo-substudy) with a total 6597 individuals (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker: 3300 patients vs. ARNis: 3297 patients) were included for quantitative analysis. Median follow-up was 6 months. Patients receiving an in-hospital coadministration of ARNi had a lower risk of major cardiovascular event [odds ratio (OR) 0.45, 95% confidence interval (CI) 0.32-0.63, P < 0.0001] and lower rate of repeat rehospitalization for heart failure (OR 0.40, 95% CI 0.26-0.62, P < 0.0001), compared with a standard regimen. Additionally, left ventricle volumes were significantly lower in the ARNi group [left ventricular end-diastolic volume, mean difference (MD) 11.48 mL, 95% CI 6.10-16.85, P < 0.0001; left ventricular end-systolic volume, MD 7.09 mL, 95% CI 2.89-11.29, P = 0.0009] with a significant change in left ventricular ejection fraction (MD 3.07, 95% CI 1.61-4.53, P < 0.0001), compared with standard therapy. No significant differences were observed in terms of cardiac death, all cause of mortality, non-fatal myocardial infarction and N terminal pro brain natriuretic peptide. Higher rates of iatrogenic hypotensive events were observed in the ARNi group compared with the standard therapy (OR 1.42, 95% CI 1.26-1.60, P value < 0.00001). In patients with acute myocardial infarction related heart failure, the in-hospital administration of ARNis was associated with a reduced risk of major cardiovascular events and re-hospitalization for heart failure, as well as cardiac remodelling, but higher rates of hypotensive events compared with standard therapy.

Uptitration of Sacubitril/Valsartan and Outcomes in Patients With Heart Failure　- Insight From the REVIEW-HF Registry.

BACKGROUND: Guideline-directed medical therapy has become an important component of heart failure (HF) therapy, with sacubitril/valsartan as one of the recommended drugs; however, the real-world prognostic implications of sacubitril/valsartan uptitration are unclear. METHODS AND RESULTS: Patients with HF newly initiated on sacubitril/valsartan were registered in a retrospective multicenter study (REVIEW-HF). In all, 995 patients were divided into 3 groups according to the maximum dose achieved: high dose, sacubitril/valsartan 400 mg; intermediate dose, sacubitril/valsartan 200-<400 mg; and low dose, sacubitril/valsartan <200 mg. A total of 397 (39.9%) patients received high-dose sacubitril/valsartan; they had a significantly lower risk of mortality or HF hospitalization than patients in the low-dose (hazard ratio [HR] 0.39; 95% confidence interval [CI] 0.29-0.53; P<0.001) and intermediate-dose (HR 0.64; 95% CI 0.45-0.94; P=0.03) groups. In the multivariable Cox regression model, higher systolic blood pressure and maintained geriatric nutritional risk index were significantly associated with a higher incidence of achieving a high dose of sacubitril/valsartan. Patients who did not receive high-dose sacubitril/valsartan experienced more hypotension during the follow-up period, whereas hyperkalemia, severe renal events, and angioedema did not differ across the achieved dose classifications. CONCLUSIONS: Patients who achieved sacubitril/valsartan uptitration had a better prognosis than those who did not. Before sacubitril/valsartan uptitration, patients need to monitor blood pressure closely to prevent worsening events.

Investigation of H-Bonding and pH on the Fluorescence Spectral Behavior of Valsartan.

The photophysical properties of valsartan (VAL), a potent phenyl tetrazole derivative sartan, were investigated. Valsartan has absorption bands at 230 nm and 255 nm and a fluorescence band at about [Formula: see text] = 346 nm in butanol which is red shifted depending on the H-bonding capability of the solvent. The role of H-bonding in the excited state was approved through the linear correlation of the emission energy of VAL with Camlet-Taft acidity and basicity parameters, α and ß, of polar protic solvents. The position and intensity of fluorescence emission bands of VAL are found to be pH dependent, shifting from 425 nm at pH 2 to 375 nm at pH 4 with enhancement of intermolecular H-bonding and fluorescence intensity depletion beyond pH 5 with formation of tetrazole anion. The results were supported by time-resolved fluorescence measurements which indicated the presence of different species with different lifetimes in the excited state depending on solution pH value. Computational results based on time dependent density functional methods (TDDFT) show that the tetrazole moiety is involved in the [Formula: see text] absorption transitions, while natural bond analysis (NBO) shows that VAL adopts a dimer conformation in water because of effective intermolecular H-bonding.

Sex differences in cardiac structure and function following acute myocardial infarction: Insights from the PARADISE-MI echocardiographic substudy.

AIMS: The incidence of heart failure hospitalization is higher in women than in men after myocardial infarction (MI). Sex-related differences in left ventricular (LV) remodelling may contribute to the differences in post-MI outcomes. The aim of this study was to assess sex differences in echocardiographic parameters post-MI, and whether the relationship between echocardiographic parameters and clinical outcomes differs by sex. METHODS AND RESULTS: In the PARADISE-MI trial, patients were randomized to sacubitril/valsartan or ramipril within 0.5 to 7 days of high-risk MI. In the pre-specified echocardiographic substudy, 544 patients underwent echocardiography at the time of randomization and after 8 months. We compared key echocardiographic parameters in men and women and their association with primary composite outcome (cardiovascular death or incident heart failure). At baseline, women had higher LV ejection fraction (LVEF), lower LV end-diastolic volume (LVEDV) index, LV end-systolic volume (LVESV) index, and LV mass index. After adjusting for baseline clinical differences, changes in these echocardiographic parameters from baseline to 8 months were not significantly different in women versus men. Lower LVEF, higher LVEDV, LVESV, left atrial volume index, and average E/e' were associated with a higher risk of the primary composite outcome. Sex did not modify the relationship between echocardiographic parameters and clinical outcome. CONCLUSIONS: Despite baseline differences in measures of cardiac function between men and women following acute high-risk MI, there were no significant sex-related changes in chamber size or LV function. Sex did not modify the association between echocardiographic parameters and clinical outcome.

Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial.

BACKGROUND: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established treatment for heart failure (HF) with reduced left ventricular ejection fraction. It has not been rigorously compared with angiotensin-converting enzyme inhibitors in children. PANORAMA-HF (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) is a randomized, double-blind trial that evaluated the pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy of sacubitril/valsartan versus enalapril in children 1 month to <18 years of age with HF attributable to systemic left ventricular systolic dysfunction (LVSD). METHODS: Children with HF attributable to LVSD were randomized to sacubitril/valsartan versus enalapril to assess the efficacy and safety of sacubitril/valsartan at 52 weeks of follow-up. The primary end point of the study was to determine whether sacubitril/valsartan was superior to enalapril for the treatment of pediatric patients with HF attributable to systemic LVSD, assessed using a primary global rank end point consisting of ranking patients from worst to best on the basis of clinical events such as death, listing for urgent heart transplant, mechanical life support requirement, worsening HF, New York Heart Association (NYHA)/Ross class, Patient Global Impression of Severity (PGIS), and Pediatric Quality of Life Inventory physical functioning domain. The change from baseline to 52 weeks in NT-proBNP (N-terminal pro-B-type natriuretic peptide) was an exploratory end point. RESULTS: A total of 375 children (mean age, 8.1±5.6 years; 52% female) were randomized to sacubitril/valsartan (n=187) or enalapril (n=188). At week 52, no significant difference was observed between the 2 treatment arms in the global rank end point (Mann-Whitney probability, 0.52 [95% CI, 0.47-0.58]; Mann-Whitney odds, 0.91 [95% CI, 0.72-1.14]; P=0.42). At week 52, clinically meaningful reductions were observed in both treatment arms in NYHA/Ross, PGIS, Patient Global Impression of Change, and NT-proBNP, without significant differences between groups. Adverse events were similar between treatment arms (incidence: sacubitril/valsartan, 88.8%; enalapril, 87.8%), and the safety profile of sacubitril/valsartan was acceptable in children. CONCLUSIONS: In this study, sacubitril/valsartan did not show superiority over enalapril in the treatment of children with HF attributable to systemic LVSD using the prespecified global rank end point. However, both treatment arms showed clinically meaningful improvements over 52 weeks. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02678312.

Antihypertensive drug-associated adverse events in osteoarthritis: a study of a large real-world sample based on the FAERS database.

Background: Hypertension is a common complication in patients with osteoarthritis (OA). There is increasing interest in the relationship between hypertension and OA. However, hypertension has been reported to negatively affect symptoms and quality of life in patients with OA. Therefore, treating hypertension is crucial for patients with OA. However, there is a lack of real-world studies on the effects of medications for treating hypertension on OA. Methods: Data from the FAERS database from January 2004 to December 2023 were extracted for disproportionality analyses, and proportional reporting ratios (PRRs) were used to assess the association between medications for hypertension and all types of arthritis. Adverse event signals were identified and determined using reporting odds ratios (RORs) Adverse event signals were considered to have occurred if a drug-induced adverse event was recorded more than or equal to 3 and the lower limit of the ROR confidence interval was more than 1. We selected five classes of drugs including, calcium channel blockers (CCBs), angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), thiazide diuretics and ß-blockers and representative drugs were analysed for osteoarthritis-related adverse reactions, and age and gender subgroups were analysed for drugs of significance. We also analysed the occurrence of AEs in relation to time using the Weibull distribution. Results: In terms of overall data, we found significant OA adverse reaction signals only for ARBs among the five drug classes.ARB AEs for spinal osteoarthritis (ROR 4.64, 95% CI 3.62-5.94), osteoarthritis (ROR 3.24 95% CI 2.82-3.72) and gouty arthritis (ROR 3.27 95% CI 1.22-8.75) were the three adverse reactions with the loudest signals. Next, we found that valsartan had strong osteoarthritis adverse reaction signals among the three ARBs, namely, irbesartan, cloxartan, and valsartan. We also analysed age and gender subgroups and found that osteoarthritis signals were strongest in the 18-65 and 65+ population, while females seem to be more prone to valsartan-related OA AEs. Conclusion: ARBs, especially valsartan, have significant positive signals for OA AEs. Therefore, ARB drugs, especially valsartan, should be used with caution when treating patients with OA combined with hypertension.

Incidence and risk factors of hypotension-related adverse events among Japanese patients with heart failure receiving sacubitril/valsartan or enalapril: Results from the PARALLEL-HF study.

BACKGROUND: The PARALLEL-HF trial showed that treatment with sacubitril/valsartan resulted in more symptomatic hypotension versus enalapril in Japanese patients with heart failure (HF) and reduced ejection fraction, similar to PARADIGM-HF. Use of sacubitril/valsartan in these patients may be limited by concerns regarding hypotension. METHODS: This post-hoc analysis characterized hypotension-related adverse events (AEs) and their effects on efficacy using data from PARALLEL-HF, in which patients received sacubitril/valsartan 200 mg twice daily or enalapril 10 mg twice daily. RESULTS: Of 223 patients, 28.2 % experienced hypotension-related AEs and incidence was higher with sacubitril/valsartan versus enalapril (hazard ratio, 2.2; 95 % CI, 1.3-3.8; p = 0.0027). However, reduction in mean systolic blood pressure from baseline to study end did not significantly differ (sacubitril/valsartan: -2.2 mmHg vs enalapril: -1.3 mmHg; p = 0.6895). Patients who experienced hypotension-related AEs had lower mean body mass index, higher median N-terminal pro-brain natriuretic peptide at randomization, and more frequent history of stroke. Hypotension-related AEs leading to treatment discontinuation were not significantly different for sacubitril/valsartan versus enalapril (3.4 % vs 6.9 %, p = 0.5957). Reduction in risk of cardiovascular death or HF hospitalization was similar with sacubitril/valsartan versus enalapril in patients with or without hypotension-related AEs. CONCLUSIONS: Incidence of hypotension-related AEs was higher in the sacubitril/valsartan versus enalapril group but did not affect risk of cardiovascular death or HF hospitalization, which was similar between treatment groups.

Stability-indicating RP-HPLC method development and validation for the quantification of amlodipine besylate and valsartan tablets in solid oral dosage form.

The present study discusses the development of simple, rapid, specific, precision, accuracy, stability indicating the HPLC method for the analysis of amlodipine besylate and valsartan tablet dosage form. The chromatographic separation was achieved using phosphate buffer with 1% triethyl amine (pH 3.0) as mobile phase-A and mixed Methanol and buffer in the ratio of (65:35)(v/v) as mobile phase-B. The detection of components was made at 237 nm for amlodipine besylate and valsartan. Analytical techniques should enrich sensitivity and specificity for the estimation of pharmaceutical drug products. Evaluated stress studies under different types of ICH conditions. The optimized HPLC method was validated as per the current ICH guidelines. The validated HPLC method was obtained highly specific with linearity ranging between 25 and 200 µgmL-1 of amlodipine besylate and 40-320 µgmL-1 of valsartan and both components correlation coefficient was > 0.999. The method showed high accuracy more than 97%. In stress studies, amlodipine besylate and valsartan were found to be sensitive to acid stress conditions and oxidation stress conditions. The method was found to be suitable for the quality control of amlodipine besylate and valsartan in the tablet as well as in stability-indicating studies. The method was applied to the analysis of stability samples.

Sacubitril/valsartan alleviates myocardial infarction-induced inflammation in mice by promoting M2 macrophage polarisation via regulation of PI3K/Akt pathway.

BACKGROUND: Macrophage polarisation-mediated inflammation plays a critical role in ventricular remodelling after myocardial infarction (MI). Sacubitril/Valsartan (Sac/Val) is an angiotensin receptor-neprilysin inhibitor that has shown beneficial effects on MI and heart failure. This study aims to further explore the mechanisms by which Sac/Val exerts its protective effects against MI. METHODS: A mouse MI model was induced by ligating the left anterior descending coronary artery, followed by Sac/Val administration. TTC staining and Masson trichrome staining were employed for estimating myocardial infarct size and fibrosis, respectively. The expression levels of proinflammatory factors were determined by ELISA and RT-qPCR. Flow cytometry and immunofluorescence staining were implemented to detect CD206-positive cell infiltration in mouse hearts. Western blotting was conducted to assess protein levels of Arg1, pro-fibrotic factors, and PI3K/Akt signalling-related markers. RESULTS: Sac/Val treatment reduced myocardial infarct size and fibrosis in mice after MI. Sac/Val administration decreased proinflammatory cytokine production and facilitated M2 macrophage polarisation in MI mouse cardiac tissues. Sac/Val activated PI3K/Akt signalling in MI mouse hearts. Blocking PI3K/Akt signalling counteracted Sac/Val-mediated protective effects in MI mice. CONCLUSION: Sac/Val ameliorates MI-induced inflammation by facilitating M2 macrophage polarisation and activating PI3K/Akt signalling.

Left ventricular reverse remodeling after combined ARNI and SGLT2 therapy in heart failure patients with reduced or mildly reduced ejection fraction.

Background: Cardiac remodeling is an adverse phenomenon linked to heart failure (HF) progression. Cardiac remodeling could represent the real therapeutic goal in the treatment of patients with HF and reduced ejection fraction (HFrEF), being potentially reversed through different pharmacotherapies. Currently, there are well-established drugs such as ACEi/ARBs and ß-blockers with anti-remodeling effects. More recently, ARNI effects on cardiac remodeling were also demonstrated; additional potential benefits of gliflozins remain non clearly demonstrated. Aim of study: To evaluate possible changes in cardiac remodeling in patients with HFrEF/HFmrEF in treatment with ARNI or ARNI plus SGLT2i and the potential benefit on cardiac remodeling of adding SGLT2i to ARNI. Methods: Between June 2021 and August 2023, 100 consecutive patients with HFrEF/HFmrEF underwent conventional and advanced echocardiography (TDI, 2DSTE): patients were therefore divided into three groups according to therapy with neither ARNI nor SGLT2i, just ARNI or both. After 3 months, all patients underwent echocardiographic follow-up. Results: After a 3 months of therapy, significant improvements were observed for LVEF, LVEDD, LVEDV, LVESV, LV mass, E/e', LV GLS, TAPSE (ANOVA p< 0.01 in all cases), RV S' velocity (ANOVA p< 0.001).The trend in favor of additional treatment with SGTL2i over ARNI remained statistically significant even after multivariable analysis (p< 0.001 for LVEF, LVEDD; p< 0.01 for LV GLS, TAPSE, TRVS; p< 0.05 for LV mass). Conclusions: SGLT2i therapy when added to the standard treatment for HFrEF and HFmrEF is associated with an improved biventricular function and ventricular dimensions at follow-up.

Subgroup disproportionality analysis of dementia-related adverse events with sacubitril/valsartan across geographical regions.

This study aimed to evaluate the association between sacubitril/valsartan and dementia-related adverse events (AEs) in geographical subpopulations using subgroup disproportionality analysis. Cases from the FDA adverse event reporting system involving patients aged 60 or older with sacubitril/valsartan or angiotensin receptor blockers (ARBs) were analyzed. The adjusted reporting odds ratios (RORs) for dementia-related AEs were calculated for each continent. A total of 61,518 AEs associated with sacubitril/valsartan or ARBs were identified. Among these, 1441 were dementia-related AEs. In Asia, Europe, and Africa, the reporting risk of dementia-related AEs associated with sacubitril/valsartan was lower compared to ARBs (adjusted ROR, 0.57 [95% CI 0.31-1.01]; adjusted ROR, 0.89 [95% CI 0.69-1.14]; adjusted ROR, 0.40 [95% CI 0.27-0.61], respectively). In Latin America and Oceania, the reporting risk of dementia-related AEs associated with sacubitril/valsartan was similar to that associated with ARBs (adjusted ROR, 1.04 [95% CI 0.75-1.44]; adjusted ROR, 1.02 [95% CI 0.31-3.37], respectively). On the contrary, in North America, the reporting risk associated with sacubitril/valsartan was higher compared to ARBs (adjusted ROR, 1.29 [95% CI 1.10-1.53]). Although the ROR value did not meet the criteria for signal detection, the significantly greater than 1 ROR observed in North America suggests that caution may be warranted regarding potential dementia-related adverse events associated with sacubitril/valsartan.