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Background and Aims The efficacy and safety of early sacubitril/valsartan (Sac/Val) initiation after acute heart failure (AHF) has not been demonstrated outside North America. The present study aimed to evaluate the effect of in-hospital Sac/Val therapy initiation after an AHF episode on N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in Japanese patients. Methods This was an investigator-initiated, multicentre, prospective, randomized, open-label, blinded-endpoint pragmatic trial. After haemodynamic stabilization within 7 days after hospitalization, eligible inpatients were allocated to switch from angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to Sac/Val (Sac/Val group) or to continue angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (control group). The primary efficacy endpoint was the 8-week proportional change in geometric means of NT-proBNP levels. Results A total of 400 patients were equally randomized, and 376 (median age 75 years, 31.9% women, de novo heart failure rate 55.6%, and median left ventricular ejection fraction 37%) were analysed. The per cent changes in NT-proBNP level geometric means at Weeks 4/8 were −35%/−45% (Sac/Val group) and −18%/−32% (control group), and their group ratio (Sac/Val vs. control) was 0.80 (95% confidence interval 0.68–0.94; P =.008) at Week 4 and 0.81 (95% confidence interval 0.68–0.95; P =.012) at Week 8, respectively. In the pre-specified subgroup analyses, the effects of Sac/Val were confined to patients with a left ventricular ejection fraction < 40% and were more evident in those in sinus rhythm and taking mineralocorticoid receptor antagonists. No adverse safety signal was evident. Conclusions In-hospital Sac/Val therapy initiation in addition to contemporary recommended therapy triggered a greater NT-proBNP level reduction in Japanese patients hospitalized for AHF. These findings may expand the evidence on Sac/Val therapy in this clinical situation outside North America. Clinical Trial Registration ClinicalTrial.gov (NCT05164653) and Japan Registry of Clinical Trials (jRCTs021210046). [ABSTRACT FROM AUTHOR]

Heart failure (HF) and renal dysfunction often coexist and interact in many complex and bidirectional pathways, leading to detrimental effects on patient outcomes. The treatment of HF patients with renal dysfunction presents a significant clinical challenge. Interestingly, sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor (ARNI), may have beneficial effects on cardiac and renal outcomes in patients with HF with reduced ejection fraction, particularly by slowing the rate of decrease in the estimated glomerular filtration rate compared to a single angiotensin–converting enzyme inhibitor. Recently, more reports have emphasized the renal protection of sacubitril/valsartan in patients with HF. In HF patients with renal dysfunction, however, there is no strong evidence supporting the use of sacubitril/valsartan to reduce the absolute risk of hyperkalemia and worsening renal function; therefore, the administration of ARNI requires a careful balance between the benefits and risks. Furthermore, the lack of evidence‐based management highlights the importance of an individualized approach based on published experience and multidisciplinary collaborations, as well as underlines the need for in‐depth studies investigating the underlying mechanisms in cardiorenal interactions with a focus on treatments. [ABSTRACT FROM AUTHOR]

Ventricular remodeling (VR) after acute ST-elevation myocardial infarction (STEMI) is an important predictor for medium- and long-term prognosis. This study focuses on the relevant indexes of VR in patients with AMI, in which, the intervention effects of sacubitril/valsartan and enalapril were compared, guiding the clinical treatment. 58 patients with acute STEMI treated with PCI were divided into research group and control group. UCG was performed at 1 week, 1 month and 3 months after MI, and the patients' indexes were collected to compare VR and adverse reactions in the two groups. The test results showed that there was no statistical difference in the baseline data of patients in the two groups, which were comparable. In the blood biochemical index examination, no statistical difference was found in cTnI and NT-proBNP between the two groups. At 1 week after operation, the levels of cTnI and NT-proBNP in research group were lower than those in the control group. In ECG examination, there was no statistical significance in the levels of LVEF, LVEDD and LVESD at admission between the two groups. After 1 week, the results of LVEF, LVEDD, LVESD in the research group were higher than those in the control group. The results of this study show that sacubitril/valsartan can be used in patients with AMI instead of enalapril. Sacubitril/valsartan improves cardiac function in patients with emergency percutaneous coronary intervention (PCI) for AMI, inhibits ventricular remodeling, and has a low incidence of adverse cardiac events and adverse drug reactions. [ABSTRACT FROM AUTHOR]

Aims: We explored timing, settings and predictors of angiotensin receptor–neprilysin inhibitor (ARNI) initiation in a large, nationwide cohort of patients with heart failure (HF) with reduced ejection fraction (HFrEF). Methods and results: Patients with HFrEF (ejection fraction <40%) registered in the Swedish HF Registry in 2017–2021 and naïve to ARNI were evaluated for timing and location of, and their characteristics at ARNI initiation. ARNI use increased from 8.3% in 2017 to 26.7% in 2021. Among 3892 hospitalized patients, 8% initiated ARNI in‐hospital or ≤14 days after discharge, 4% between 15 and 90 days, and 88% >90 days after discharge or never initiated. Factors associated with earlier initiation included follow‐up in specialized HF care, more severe HF, previous HF treatment use and higher income, whereas older age, higher comorbidity burden and living alone were associated with later/no initiation. Of 16 486 HFrEF patients, 8.1% inpatients and 5.9% outpatients initiated an ARNI at the index date. Factors associated with initiation in outpatients were overall consistent with those linked with an in‐hospital/earlier ARNI initiation; 4.9% of 10 209 with HF duration <6 months and 9.1% of 5877 with HF duration ≥6 months initiated ARNI. Predictors of ARNI initiation in HF duration <6 months were inpatient status, lower ejection fraction, hypertension, whereas previous angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker use was associated with less likely initiation. Discontinuation at 1 year ranged between 13% and 20% across the above‐reported analyses. Conclusions: In‐hospital and early initiation of ARNI are limited in real‐world care but still slightly more likely than in outpatients. ARNI were more likely initiated in patients with more severe HF, which might suggest its use as a second‐line treatment and only following worsening of clinical status. One‐year discontinuation rates were consistent regardless of the timing/setting of ARNI initiation. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions 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.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.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. [ABSTRACT FROM AUTHOR]

Introduction and purpose Heart failure has become a civilization disease, affecting 1-2% of the world's population. It is a condition with various etiologies and phenotypes. The annual mortality rate due to heart failure is approximately 10%, with organ dysfunction caused by hypoperfusion and sudden cardiac death being the leading causes of death. The aim of this study is to present current knowledge of heart failure, focusing on its pathophysiology, and the mechanism of action and applications of sacubitril/valsartan. Material and methods The following review was based on articles from the PubMed and Google Scholar databases. Key search terms included pathophysiology of heart failure; natriuretic peptide pathways; treatment of heart failure; sacubitril/valsartan. Conclusions Heart failure is a syndrome marked by the activation of various neurohormonal systems such as the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system (SNS) and natriuretic peptides (NP). Historically, the therapeutic approach has focused on reducing RAAS activity and SNS activity. In recent years, increasing attention has been given to potential benefits associated with the NP system. Following disappointing outcomes from studies involving neprilysin (NEP) inhibitors, administered alone or in conjunction with an ACE inhibitor and vasopeptidase inhibitors, there have been findings with the pharmacological class termed ARNI (angiotensin receptor and NEP inhibitors). Sacubitril/valsartan has proven to be an effective and safe treatment that reduces the need for hospitalization, enhances the quality of life and longevity of patients with chronic HFrEF. [ABSTRACT FROM AUTHOR]

Background: Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI) that inhibits the degradation of endogenous natriuretic peptides. Therefore, ARNIs may increase the efficacy of human atrial natriuretic peptide (hANP), a drug for acute heart failure, by mediating its pharmacological mechanism. This study was aimed at evaluating the effects of ARNIs on the pharmacological effects of hANP by using surrogate marker, such as urinary output, in patients with heart failure. Methods: In this multicenter retrospective cohort study, adult patients with heart failure who were taking angiotensin II receptor blockers (ARB) or ARNIs combined with hANP were enrolled. Information on basic characteristics, clinical laboratory data, medical history, and severity of cardiac insufficiency were collected from electronic medical records. The primary outcome was the change in adjusted fluid balance, calculated by IN-volume (mL/day) – OUT-volume (mL/day) / daily hANP dosage (μg). Results: Ninety-two and 62 patients in the ARB + hANP and ARNI + hANP groups, respectively, were eligible for analysis. The adjusted fluid balance in the ARNI + hANP group was significantly lower than that in the ARB + hANP group (p = 0.001). After propensity score matching, 27 patients from each group were included. Similarly, there was a significant reduction in adjusted fluid balance in the ARNI + hANP group after propensity score matching (p = 0.026). Conclusions: These findings suggest that ARNIs may enhance the efficacy of hANP and the combination of the two may be effective in the treatment of heart failure. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion Angiotensin receptor–neprilysin inhibitor (ARNI) has played an increasingly important role in the management of heart failure (HF). However, the evidence on the benefits of ARNI in HF patients with end‐stage kidney disease (ESKD) undergoing dialysis is limited. This study aimed to investigate the efficacy and safety of ARNI in patients with concomitant HF and ESKD on maintenance dialysis.We systematically searched the MEDLINE, Embase, Web of Science, Cochrane, and ClinicalTrials.gov databases for studies reporting outcomes after ARNI treatment in HF patients with ESKD on dialysis. All meta‐analyses were performed using the random effects model. Twenty‐six studies comprising 2494 patients with concomitant HF and ESKD undergoing dialysis were included. Our synthesis showed a significant improvement in left ventricular ejection fraction (LVEF) between before and after ARNI treatment (mean change: 8.05%; 95% confidence interval [CI] 5.57–10.54). Compared to the conventional group, the ARNI group showed a greater improvement in LVEF (mean difference: 4.03%; 95% CI 2.90–5.16). This effect was more pronounced in patients with HF with reduced ejection fraction (pinteraction < 0.0001). Patients treated with ARNI had a lower risk of all‐cause mortality (risk ratio [RR] 0.64; 95% CI 0.45–0.92; p = 0.01) but had a similar rate of HF hospitalization (RR 0.71; 95% CI 0.43–1.18; p = 0.19). ARNI treatment showed benefits in the improvement of left ventricular end‐systolic diameter, left ventricular mass index, left atrial diameter, and E/e′ ratio (p < 0.05), while it did not significantly increase the risk of severe hyperkalaemia (p = 0.33) or symptomatic hypotension (p = 0.53).This meta‐analysis provided insights into the benefits of ARNI in HF patients with ESKD undergoing dialysis by improving left ventricular function, reversing left ventricular remodelling, and reducing the risk of all‐cause mortality, without increasing the risk of HF hospitalizations, severe hyperkalaemia, and symptomatic hypotension. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Pharmacologic blockade of neurohormonal pathways in patients with acute myocardial infarction (MI) can result in acute changes in biomarkers of kidney function. We evaluated the effect of sacubitril/valsartan versus ramipril on initial changes in serum creatinine and the association of these changes with longer‐term outcomes among participants in PARADISE‐MI. Methods and results: In this randomized, double‐blind, active‐controlled, event‐driven trial, 5661 patients with an acute MI were assigned to receive sacubitril/valsartan or ramipril, with no run‐in. The frequency of an initial pre‐specified increase in serum creatinine (≥26.5 or ≥44 μmol/L) from baseline to week 1 was compared between arms. Multivariable Cox regression models were fit to examine the association of acute changes in serum creatinine with the primary cardiovascular composite outcome (cardiovascular death, first heart failure hospitalization, or outpatient heart failure), all‐cause mortality, and longer‐term changes in estimated glomerular filtration rate (eGFR). An initial increase in serum creatinine ≥26.5 μmol/L occurred in 155 of 2604 (6.0%) patients assigned to sacubitril/valsartan and 120 of 2603 (4.6%) patients assigned to ramipril (odds ratio [OR] 1.32; 95% confidence interval [CI] 1.03–1.68). The corresponding numbers for an increase ≥44 μmol/L were 57 (2.2%) and 42 (1.6%), respectively (OR 1.37; 95% CI 0.92–2.05). A higher odds of increased serum creatinine ≥26.5 and ≥44 μmol/L for sacubitril/valsartan versus ramipril appeared to be restricted to patients who had a greater decline in systolic blood pressure over the same period (p‐interaction = 0.05 and 0.001, respectively). In multivariable analyses, neither an acute increase in serum creatinine ≥26.5 or ≥44 μmol/L was associated with a higher risk of cardiovascular outcomes, all‐cause mortality, or differences in longer‐term eGFR slope. Findings were similar across the randomized treatment arms (p‐interaction >0.6 for all). Conclusions: Following acute MI, patients assigned to sacubitril/valsartan had a higher frequency of initial increases in serum creatinine at 1 week, compared with ramipril. In adjusted models, initial increases in serum creatinine with either treatment were not associated with adverse cardiovascular outcomes or changes in longer‐term kidney function. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the clinical effectiveness of the combination of sacubitril and valsartan with conventional therapy in the treatment of patients with heart failure. Methods: This was a retrospective study comprising 100 heart failure patients randomized into study (n = 57) and control groups (n = 43). The study group received sacubitril/valsartan along with conventional drug therapy while control group received only conventional drugs, viz, irbesartan, metoprolol slow release, and furosemide tablets. Echocardiogram showing left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), left anterior descending artery (LAD), Nterminal pro-b-type natriuretic peptide (NT-proBNP), C-reactive protein (CRP), glomerular filtration rate (eGFR), and homocysteine (HCY) of the two groups were compared before and after treatment. Multiple regression was used to analyze the correlation between re-hospitalization and sacubitril/valsartan intervention. Results: The study group showed significantly lower LVEF, LVESD, LVEDD, LAD, NT-proBNP, and homocysteine levels after treatment compared to control group (p < 0.05). Re-hospitalization for abnormal cardiovascular events between the two groups was significantly different in the adjusted Cox proportional hazards regression model. Furthermore, multiple regression analysis showed that sacubitril/valsartan treatment was the independent variable (p < 0.001). Conclusion: Sacubitril/valsartan improves heart function, with reduced incidence of adverse effects without affecting renal function. Further studies are required to validate these findings by expanding sample size, strictly controlling data quality and strengthening follow-up. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions Renin–angiotensin system inhibitors (RASi) have been shown to lower haemoglobin levels, potentially related to reductions in erythropoietin levels and haematopoiesis. We examined whether sacubitril/valsartan might attenuate this effect of RASi alone on incident anaemia in patients with heart failure (HF) with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF).PARAGON‐HF was a global, multicentre randomized clinical trial of sacubitril/valsartan versus the RASi valsartan in patients with HF and left ventricular ejection fraction ≥45%. We evaluated haemoglobin trajectory and risks of incident anaemia and new iron therapy initiation during follow‐up. Among 4795 participants, 1111 (23.2%) had anaemia at randomization and 5.6% were treated with iron at baseline. Over a median follow‐up of 2.9 years, patients with anaemia were at significantly higher risk for total HF hospitalizations and cardiovascular death, compared with those without anaemia (21.6 vs. 11.5 per 100 patient‐years; adjusted rate ratio 1.31; 95% confidence interval [CI] 1.12–1.54; p = 0.001). Sacubitril/valsartan slightly slowed the decline in haemoglobin levels by 0.1 g/dl (95% CI 0.0–0.2 g/dl; p = 0.005). Participants treated with sacubitril/valsartan were at significantly lower risk of developing anaemia (30.3% vs. 37.6%; hazard ratio [HR] 0.76; 95% CI 0.68–0.85; p < 0.001) and starting iron therapy (8.1% vs. 10.0%; HR 0.81; 95% CI 0.67–0.97; p = 0.026). Treatment effects of sacubitril/valsartan versus valsartan on total HF hospitalizations and cardiovascular death were consistent among patients across the haemoglobin spectrum (pinteraction = 0.60).Among patients with HFmrEF/HFpEF, treatment with sacubitril/valsartan resulted in modestly smaller declines in haemoglobin, lower rates of incident anaemia, and fewer new initiations of iron therapy compared with RASi.Clinical Trial Registration: ClinicalTrials.gov ID NCT01920711. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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Abstract Background Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI) that inhibits the degradation of endogenous natriuretic peptides. Therefore, ARNIs may increase the efficacy of human atrial natriuretic peptide (hANP), a drug for acute heart failure, by mediating its pharmacological mechanism. This study was aimed at evaluating the effects of ARNIs on the pharmacological effects of hANP by using surrogate marker, such as urinary output, in patients with heart failure. Methods In this multicenter retrospective cohort study, adult patients with heart failure who were taking angiotensin II receptor blockers (ARB) or ARNIs combined with hANP were enrolled. Information on basic characteristics, clinical laboratory data, medical history, and severity of cardiac insufficiency were collected from electronic medical records. The primary outcome was the change in adjusted fluid balance, calculated by IN-volume (mL/day) – OUT-volume (mL/day) / daily hANP dosage (μg). Results Ninety-two and 62 patients in the ARB + hANP and ARNI + hANP groups, respectively, were eligible for analysis. The adjusted fluid balance in the ARNI + hANP group was significantly lower than that in the ARB + hANP group (p = 0.001). After propensity score matching, 27 patients from each group were included. Similarly, there was a significant reduction in adjusted fluid balance in the ARNI + hANP group after propensity score matching (p = 0.026). Conclusions These findings suggest that ARNIs may enhance the efficacy of hANP and the combination of the two may be effective in the treatment of heart failure.

Sultan Al Raddadi,1– 3 Majed Almutairi,1,3 Kholoud AlAamer,1,3 Abdulmahsen Alsalman,3,4 Maram Albalawi,5 Meshary Almeshary,1,3 Hisham A Badreldin,1,2,6 Hind Almodaimegh1– 3 1Department of Pharmaceutical Care, King Abdulaziz Medical City, Ministry of the National Guard-Health Affairs, Riyadh, Saudi Arabia; 2Department of Pharmacy Practice, College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; 3Department of Research Office, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; 4Department of Cardiology Science, King Abdulaziz Medical City, Riyadh, Saudi Arabia; 5Department of Biostatistics and Bioinformatics, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; 6Department of Saudi Biobank, King Abdullah International Medical Research Center, Riyadh, Saudi ArabiaCorrespondence: Sultan Al Raddadi, Department of Pharmaceutical Care, King Abdulaziz Medical City-Riyadh, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia, Email abuibrahim89@yahoo.comBackground: 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.&#x202FResults: 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.Keywords: heart failure with reduced ejection fraction, left ventricular ejection fraction, angiotensin receptor neprilysin inhibitors, sacubitril/valsartan

Abstract 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.

This study aimed to investigate the efficacy and safety of sacubitril/valsartan in abnormal renal function (eGFR < 60 ml/min/1.73m2) patients combined with heart failure based on randomized controlled trials (RCTs) and observational studies. The Embase, PubMed and the Cochrane Library were searched for relevant studies from inception to December 2023. Dichotomous variables were described as event counts with the odds ratio (OR) and 95% confidence interval (CI) values. Continuous variables were expressed as mean standard deviation (SD) with 95% CIs. A total of 6 RCTs and 8 observational studies were included, involving 17335 eGFR below 60 ml/min/1.73m2 patients combined with heart failure. In terms of efficacy, we analyzed the incidence of cardiovascular events and found that sacubitril/valsartan significantly reduced the risk of cardiovascular death or heart failure hospitalization in chronic kidney disease (CKD) stages 3–5 patients with heart failure (OR: 0.65, 95%CI: 0.54–0.78). Moreover, sacubitril/valsartan prevented the serum creatinine elevation (OR: 0.81, 95%CI: 0.68–0.95), the eGFR decline (OR: 0.83, 95% CI: 0.73–0.95) and the development of end-stage renal disease in this population (OR:0.73, 95%CI:0.60–0.89). As for safety outcomes, we did not find that the rate of hyperkalemia (OR:1.31, 95%CI:0.79–2.17) and hypotension (OR:1.57, 95%CI:0.94–2.62) were increased in sacubitril/valsartan group among CKD stages 3–5 patients with heart failure. Our meta-analysis proves that sacubitril/valsartan has a favorable effect on cardiac function without obvious risk of adverse events in abnormal renal function patients combined with heart failure, indicating that sacubitril/valsartan has the potential to become perspective treatment for these patients. [ABSTRACT FROM AUTHOR]

Abstract Since 2014, sacubitril/valsartan (Entresto®) is widely prescribed for heart failure. Despite neprilysin inhibition’s benefits in heart failure, concerns about potential amyloid-beta (Aβ) accumulation and Alzheimer’s disease (AD) risk have persisted. This narrative review, a decade post-approval, evaluates the risk of amyloid pathology and neurocognitive disorders in long-term sacubitril/valsartan use. Clinical trials, real-world studies, and pharmacovigilance data do not indicate an increased risk of cognitive decline. In patients treated with sacubitril/valsartan blood-based amyloid biomarkers show perturbations, while neuroimaging biomarkers reveal no significant increase in amyloid load. Despite a theoretical risk of amyloid accumulation and AD under treatment with sacubitril/valsartan, current clinical data appears reassuring, and there is no signal indicating an increased risk of cognitive decline, but a perturbation of amyloid blood-based biomarkers, which implies great caution when interpreting biomarkers in this context.

Abstract We assessed the real-world effectiveness of sacubitril/valsartan in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF) with an emphasis on those with older age (≥ 75 years) or with New York Heart Association (NYHA) class IV, for whom greater uncertainty existed regarding clinical outcomes. We conducted a retrospective cohort study based on patient-level linkage of electronic healthcare datasets. Data from all adults with HFrEF in Belgium receiving a prescription for sacubitril/valsartan between 01-November-2016 and 31-December-2018 were collected, with a follow-up of > 6 years. The total study population comprised 5446 patients, older than the PARADIGM-HF trial participants, and with higher NYHA class (all P 26% in the overall cohort, and in subgroups of patients ≥ 75 years, with NYHA class III/IV (all P

Purpose: Sacubitril/valsartan is extensively used in heart failure; however, there are few long-term safety studies of it in a wide range of populations. The aim of this study was to evaluate sacubitril/valsartan-induced adverse events (AEs) through data mining of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Reports in the FAERS from the third quarter of 2015 (FDA approval of sacubitril/valsartan) to the fourth quarter of 2023 were collected and analyzed. Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM) algorithms were adopted in data mining to quantify signals of sacubitril/valsartanassociated AEs. Results: A total of 12,001,275 reports of sacubitril/valsartan as the "primary suspected (PS)" and 99,651 AEs induced by sacubitril/valsartan were identified. More males than females reported AEs (59.95% vs. 33.31%), with the highest number of reports in the 60-70 years age group (8.11%), and most AEs occurred < 7 days (14.13%) and = 60 days (10.69%) after dosing. Sacubitril/valsartan-induced AE occurrence targeted 24 system organ classes (SOCs) and 294 preferred terms (PTs). Of these, 4 SOCs were strongly positive for all four algorithms, including cardiac disorders, vascular disorders, ear and labyrinth disorders, and respiratory, thoracic and mediastinal disorders. Among all PTs, consistent with the specification, hypotension (n = 10,078) had the highest number of reports, and dizziness, cough, peripheral swelling, blood potassium increased, and renal impairment were also reported in high numbers. Notably, this study also discovered a high frequency of side effects such as death, dyspnea, weight change, feeling abnormal, hearing loss, memory impairment, throat clearing, and diabetes mellitus. Conclusion: This study identified potential new AE signals and gained a more general understanding of the safety of sacubitril/valsartan, promoting its rational adoption in the cardiovascular system. [ABSTRACT FROM AUTHOR]

Aims: Cardiovascular‐kidney‐metabolic (CKM) multimorbidity is prevalent among individuals with heart failure (HF), but whether cardiac structure and function, clinical outcomes, and treatment response to sacubitril/valsartan vary in relation to CKM status is unknown. Methods and results: In this PARAGON‐HF post‐hoc analysis, we evaluated the impact of CKM multimorbidity (atherosclerotic cardiovascular [CV] disease, chronic kidney disease, and type 2 diabetes) on cardiac structure and function, clinical outcomes, and treatment effects of sacubitril/valsartan versus valsartan. The primary outcome was a composite of total HF hospitalizations and CV death. Secondary outcomes included the individual components of the primary outcome and a composite kidney outcome (sustained estimated glomerular filtration rate reduction of ≥50%, end‐stage kidney disease, or kidney‐related death). At baseline, 35.2% had one CKM condition, 33.3% had two, 15.9% had three, and only 15.6% had HF alone. CKM multimorbidity was associated with higher septal and posterior wall thickness, lower global longitudinal strain, higher E/e', and worse right ventricular function. Total HF hospitalizations or CV death increased with greater CKM multimorbidity, with the highest relative risk observed with three CKM conditions (rate ratio 3.06, 95% confidence interval 2.33–4.03), compared with HF alone. Treatment effects of sacubitril/valsartan were consistent irrespective of the number of CKM conditions for the primary endpoint (pinteraction = 0.75), CV death (pinteraction = 0.82), total HF hospitalizations (pinteraction = 0.67), and the composite kidney endpoint (pinteraction = 0.99). Conclusions: Cardiovascular‐kidney‐metabolic multimorbidity was common in PARAGON‐HF and associated with adverse changes in cardiac structure and function and with a stepwise increase in risk of clinical outcomes. Treatment effects of sacubitril/valsartan were consistent irrespective of CKM burden. Clinical Trial Registration: ClinicalTrials.gov NCT01920711. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this meta-analysis is to determine how sacubitril/valsartan (SV) compares to equivalent and sub-equivalent angiotensin receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACEI) in patients with heart failure with reduced ejection fraction (HFrEF). Methods: The databases of PubMed and EMBASE were used to identify those randomized controlled trials which compared SV to ARB/ACEI in patients with HFrEF. Only those trials that reported outcomes regarding total mortality, cardiovascular mortality, and worsening heart failure were considered. Meta-analysis was performed separately in those patients receiving equivalent doses of ARB/ACEI and those receiving sub-equivalent doses. Equivalent doses were SV 97/103 = valsartan 160 mg twice daily = enalapril 20 mg twice daily = ramipril 5 mg twice daily. Meta-analyses were performed using Review Manager 5.4. Results: Twelve randomized trials were identified involving 17,484 patients: 11,291 in the sub-equivalent group (8 trials) and 6193 in the equivalent group (4 trials). Meta-analyses showed there were no statistical differences regarding the outcomes of total mortality, cardiovascular mortality, and worsening heart failure in the equivalent dosing group. However, SV reduced total mortality (risk ratio (RR) = 0.85, 95% confidence interval (CI) = 0.78–0.93, p < 0.001), cardiovascular mortality (RR = 0.81, 95% CI = 0.73–0.90, p ≤ 0.001) and worsening heart failure (RR = 0.77, 95% CI = 0.64–0.92, p = 0.005) in the sub-equivalent group. Conclusion: When compared to equivalent doses of ARB/ACEI, SV is not superior in reducing mortality and worsening heart failure. SV is superior when compared to sub-equivalent doses of ACEI. [ABSTRACT FROM AUTHOR]

Effects of angiotensin receptor/neprilysin inhibitors (ARNI) on ventricular remodeling in patients with heart failure, especially heart failure with reduced ejection fraction (HFrEF), are better than those of angiotensin-converting enzyme inhibitors (ACEI). Acute myocardial infarction (AMI) complicated by mitral regurgitation exacerbates ventricular remodeling and increases the risk of heart failure. There is limited evidence on the effects of early administration of ARNI in patients with AMI complicated by mitral regurgitation. The aim of this trial was to examine the effectiveness and the safety of early administration of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation. This was a randomized, single-blind, parallel-group, controlled trial. From June 2021 to June 2022, we enrolled 142 consecutive patients with AMI complicated by moderate-to-severe mitral regurgitation and followed them for 12 months. The patients received standard treatment for AMI and were randomly assigned to receive ARNI or benazepril. The primary efficacy end points were the differences in mitral regurgitant jet area (MRJA), mitral regurgitant volume (MRV), concentration of n-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), and left ventricular end-diastolic volume and end-systolic volume (LVEDV and LVESV) between groups and within groups at baseline, 1, 3, 6, and 12 months. Secondary end points included the rates of heart failure hospitalization, all-cause mortality, refractory angina, malignant arrhythmias, recurrent myocardial infarction, and stroke. Safety end points included the rates of hyperkalemia, renal dysfunction, hypotension, angioedema, and cough. The ARNI group had significantly lower NT-proBNP levels than the benazepril group at 1 month and later (P < 0.001). MRJA and MRV significantly improved in the ARNI group compared with the benazepril group at 12 months (MRJA: − 3.21 ± 2.18 cm2 vs. − 1.83 ± 2.81 cm2, P < 0.05; MRV: − 27.22 ± 15.22 mL vs. − 13.67 ± 21.02 mL, P < 0.001). The ARNI group also showed significant reductions in LVEDV and LVESV (P < 0.05) and improvement in LVEF (P < 0.05). Secondary end point analysis showed a significantly higher rate of heart failure hospitalization in the benazepril group compared with the ARNI group (HR = 2.03, 95% CI 1.12–3.68, P = 0.021). Safety end point analysis showed a higher rate of hypotension in the ARNI group (P < 0.05). Early use of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation can significantly reduce mitral regurgitation, improve ventricular remodeling, and decrease heart failure hospitalization. Nevertheless, caution is needed to avoid hypotension. Chinese Clinical Trial Registry (ChiCTR2100054255) registered on December 11, 2021. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to investigate the role of sacubitril/valsartan in managing hypertension and cardiac remodeling in patients undergoing hemodialysis. Methods: Hemodialysis patients with stable blood pressure control were enrolled in the study. Sacubitril/valsartan was prescribed to replace previously used angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or other antihypertensive drugs. During a 6-month follow-up period, pre-dialysis blood pressure, routine biochemical markers, and N-terminal pro-brain natriuretic peptide levels were measured. Volume status was assessed using bioelectrical impedance analysis. Endothelial damage was evaluated by measuring asymmetric dimethylarginine expression, while echocardiography and life quality assessed by Short Form-12 Health Survey were conducted at baseline and after treatment. Results: The median daily dose of sacubitril/valsartan in 32 participants was 200 mg, and no obvious adverse reactions were reported. The defined daily dose of other antihypertensive drugs (baseline 2.00 ± 1.18, end point 1.46 ± 1.30, t = 3.216, p = 0.003) reduced significantly. After treatment with sacubitril/valsartan, left ventricular ejection fraction significantly increased from 64.81 ± 8.16% to 67.55 ± 5.85% (t = −4.022, p ≤ 0.001) and the thickness of posterior wall of the left ventricle reduced from 1.05 ± 0.14 cm to 1.00 ± 0.11 cm (t = 2.063, p = 0.048). The interventricular septal thickness (baseline 1.08 ± 0.16 cm, endpoint 1.02 ± 0.12 cm, t = 2.260, p = 0.031) remarkably reduced by the end of follow-up. The tricuspid regurgitation pressure gradient decreased from 28.47 ± 8.26 mm Hg at baseline to 23.79 ± 6.61 mm Hg (t = 2.531, p = 0.020) after treatment. Conclusion: Sacubitril/valsartan effectively manages hypertension in hemodialysis patients and may also independently improve left ventricular hypertrophy and systolic function, regardless of changes in the blood pressure or the volume load. [ABSTRACT FROM AUTHOR]

The characteristics, tolerability, and outcomes in patients with heart failure (HF) who are treated with sacubitril/valsartan remain unclear in Japan. We conducted a nationwide multicenter study to evaluate the features and outcomes of patients newly prescribed sacubitril/valsartan for the management of HF. We analyzed adverse events (AEs) related to sacubitril/valsartan at 3 months, which were defined as hypotension, worsening renal function, hyperkalemia, and angioedema. Additionally, the association between AEs and outcomes was examined. Among 993 patients, the mean age was 70 years and 291 (29.3 %) were female, and 22.8 % had left ventricular ejection fraction ≥50 %. Of them, 20.8 % had systolic blood pressure (sBP) <100 mmHg, and 19.5 % had estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 at baseline, which were the populations excluded from the eligibility in landmark trials. AEs related to sacubitril/valsartan were observed in 22.5 % of the patients at 3 months. Overall, 22.6 % of patients discontinued sacubitril/valsartan, and hypotension was the most common event leading to drug discontinuation. After adjustment, patients who had worse HF symptoms (New York Heart Association III or IV), sBP <100 mmHg, and eGFR <30 ml/min/1.73 m2 were associated with a higher risk of AEs related to sacubitril/valsartan. Additionally, patients experiencing AEs had a higher risk of cardiovascular death or HF hospitalization than those who did not. In Japan, sacubitril/valsartan was also prescribed to patients not eligible for landmark trials, and AEs were observed at a relatively high rate from soon after treatment initiation. Physicians should closely monitor patients for these events, especially in patients anticipated to have a higher risk of AEs. [Display omitted] • In Japan, sacubitril/valsartan was extensively used for HF management across LVEF subtypes. • Elderly patients and others ineligible for landmark trials were also treated with sacubitril/valsartan. • Adverse events potentially related to sacubitril/valsartan were observed in 22.5 %. • Patient who experienced adverse events had worse outcomes than those who did not. [ABSTRACT FROM AUTHOR]

Obesity condition causes morphological and functional alterations involving the cardiovascular system. These can represent the substrates for different cardiovascular diseases, such as atrial fibrillation, coronary artery disease, sudden cardiac death, and heart failure (HF) with both preserved ejection fraction (EF) and reduced EF. Different pathogenetic mechanisms may help to explain the association between obesity and HF including left ventricular remodelling and epicardial fat accumulation, endothelial dysfunction, and coronary microvascular dysfunction. Multi‐imaging modalities are required for appropriate recognition of subclinical systolic dysfunction typically associated with obesity, with echocardiography being the most cost‐effective technique. Therapeutic approach in patients with obesity and HF is challenging, particularly regarding patients with preserved EF in which few strategies with high level of evidence are available. Weight loss is of extreme importance in patients with obesity and HF, being a primary therapeutic intervention. Sodium–glucose co‐transporter‐2 inhibitors have been recently introduced as a novel tool in the management of HF patients. The present review aims at analysing the most recent studies supporting pathogenesis, diagnosis, and management in patients with obesity and HF. [ABSTRACT FROM AUTHOR]

BACKGROUND Optimal antihypertensive medication for chronic type B aortic dissection (AD) remains undecided. This study compared the efficacy and safety of sacubitril/valsartan with valsartan to determine suitable antihypertensive drug combinations. METHODS In this single-center, open-label, randomized, controlled trial, patients with chronic Stanford type B AD and mild hypertension were randomized to receive sacubitril/valsartan 100/200 mg or valsartan 80/160 mg. The primary endpoint was the reduction in mean sitting systolic blood pressure (msSBP) at week 8 in patients with sacubitril/valsartan vs. valsartan. Key secondary endpoints included changes in (i) mean sitting diastolic blood pressure (msDBP); (ii) pulse pressure (PP); and (iii) mean ambulatory blood pressure (BP) for 24-hour, daytime, and nighttime. Safety assessments included adverse events (AEs) and serious AEs. This trial was registered with the Chinese Clinical Trial Registry, identifier: ChiCTR2300073399. RESULTS A total of 315 patients completed the study. Sacubitril/valsartan provided a significantly greater reduction in msSBP than valsartan at week 8 (between‐treatment difference: −5.1 mm Hg [95% confidence interval −5.8 to −4.5], P  < 0.001). Reductions in msSBP, msDBP, and PP as well as the mean ambulatory BP for 24-hour, daytime, and nighttime, were significantly greater in sacubitril/valsartan compared with valsartan (all P  < 0.001). No excessive episodes of AEs occurred in the sacubitril/valsartan group. CONCLUSIONS Sacubitril/valsartan and valsartan reduced BP compared with baseline values. However, sacubitril/valsartan improved BP control to a greater extent than valsartan. It may offer a new treatment option for patients with mild hypertension and chronic type B AD. [ABSTRACT FROM AUTHOR]

Objective: To detect muscular system adverse reaction signals of sacubitril/valsartan treatment combined with statins (atorvastatin, rosuvastatin, simvastatin) to provide a reference for clinical administration. Methods: Multiplicative and additive models were used to mine the FDA's spontaneous reports database to detect signals of drug-drug interactions between sacubitril/valsartan and statins. SAS 9.4 software was used to conduct statistical tests for suspicious signals to determine whether the signals were statistically significant. Results: A total of 8,883,870 adverse reaction reports were analyzed. The combinations "sacubitril/valsartan - simvastatin - musculoskeletal muscle pain" had statistically significant correlation signals in both models (P < 0.05). The combination "sacubitril/valsartan - atorvastatin - myopathy" and "sacubitril/valsartan-simvastatin - myopathy" had statistically significant correlation signal in the multiplicative model (P < 0.05). Conclusion: Compared with a single drug, coadministration of sacubitril/valsartan with atorvastatin may increase safety risks to myopathy, with simvastatin may increase safety risks to the musculoskeletal pain and myopathy, which should be closely monitored in clinical practice. [ABSTRACT FROM AUTHOR]

Purpose Sacubitril/valsartan (SAC/VAL) or angiotensin receptor blockers (ARBs) are recommended therapy for heart failure with preserved ejection fraction (HFpEF), but little is known about their real-world comparative effectiveness among patients with HFpEF. The objective of this study was to determine the comparative effectiveness of SAC/VAL vs ARBs in preventing HF-related hospitalization or all-cause hospitalization among patients with HFpEF. Methods We conducted a cohort study using IBM MarketScan commercial and Medicare supplemental databases to identify patients aged 18 years or older with a diagnosis of HFpEF and initiation of SAC/VAL (2015-2020) or ARB (2009-2014) therapy. The index date was the date of the first SAC/VAL or ARB prescription fill. After propensity score (PS) matching with a ratio of 1 up to 3, Cox proportional hazards regression was used with robust variance estimators to compare the risks of HF-related hospitalization and all-cause hospitalization between the 2 therapies. Several subgroup and sensitivity analyses were conducted to check the robustness of the main analysis. Results After PS matching, 2,520 patients (846 receiving SAC/VAL and 1,674 receiving an ARB) were included in the final analyses. After controlling for covariates, there was no difference in the risk of HF-related hospitalization between SAC/VAL and ARB recipients (adjusted hazard ratio [aHR], 1.33; 95% confidence interval [CI], 0.99-1.77). There was also no difference in the risk of all-cause hospitalization between SAC/VAL and ARB recipients (aHR, 1.06; 95% CI, 0.91-1.24). Conclusion Among individuals with private or Medicare Advantage insurance plans, there was no significant difference in the risk of HF-related hospitalization or all-cause hospitalization between adults with HFpEF who received SAC/VAL and those who received ARB therapy. [ABSTRACT FROM AUTHOR]

Cardiovascular Diseases (CVD) have claimed millions of lives, despite the efforts of medical professionals. There are several treatment methods for blocking a few neurohormonal cascades; however, it is debatable because there are few hypotheses, which claim that in Heart Failure (HF), these systems tend to activate potential counter-regulatory mechanisms. Angiotensin Receptor Neprilysin Inhibitors (ARNI) are developed to modulate both Renin-Angiotensi n-Aldosterone-System and Natriuretic Peptide, regulating neurohormonal cascade in HF. LCZ696 (Sacubitril/Valsartan) is the first-in-class ARNI, approved for managing HF. Initially, ARNI was developed to manage Hypertension, later the FDA regulatory label was expanded for the management of HF. Dapagliflozin belongs to the class of SGLT2 inhibitors that have shown potentially beneficial effects in HF. Would the two medications, which have distinct mechanisms of action but a similar effect-a decrease in the risk of HF-show additive or synergistic effects when taken together? India, known as "The Chronic Heart Disease Capital of the World", is accounting sharp rise in sudden cardiac death with young adults being the worst sufferers. This review inference that, using ARNI and Dapagliflozin together may have a larger positive effect on HF patients' quality of life by lowering their need for hospitalization due to HF deterioration. [ABSTRACT FROM AUTHOR]

Sacubitril/valsartan (S/V) is the first commercially available angiotensin and eneprilysin receptor blocker worldwide, first approved by the United States Food and Drug Administration in 2015. It presents a clear superiority to renin-angiotensin-aldosterone inhibition alone in terms of reduction in all-cause mortality and cardiovascular mortality in heart failure patients with reduced ejection fraction following the "PARADIGM-HF" study. Therefore, it remains essential to understand its effects on the heart and off target. This approach is crucial not only to minimize potential adverse effects, but also to take full advantage of the benefits that V/S can offer in the management of heart failure. [ABSTRACT FROM AUTHOR]

Introduction: Sacubitril/valsartan is increasingly used in hemodialysis patients due to its cardioprotective benefits. However, its impact on serum potassium levels in anuric patients undergoing hemodialysis remains controversial. Methods: We conducted a retrospective data from patients undergoing hemodialysis at two dialysis centers. A total of 71 out of 332 patients receiving hemodialysis treatment were enrolled. Mean serum potassium (mean value of 6–8 determinations), peak serum potassium (maximum K value observed during follow‐up observations), and other biochemical parameters were recorded at baseline and during the follow‐up period. Findings: After 6 months of follow‐up, mean serum potassium increased from 4.84 ± 0.45 mmol/L at baseline to 5.07 ± 0.46 mmol/L at 3 months and 5.04 ± 0.46 mmol/L at 6 months (p < 0.001). Notably, no significant group differences were found in peak serum potassium concentrations between baseline and 6 months after sacubitril/valsartan therapy (5.69 ± 0.56 vs. 5.75 ± 0.41, p = 0.419). Prior to starting sacubitril/valsartan treatment, none of the patients had severe hyperkalemia; however, after 3 and 6 months of sacubitril/valsartan therapy, two (2.80%) and three (4.20%) patients experienced severe hyperkalemia, respectively; however, this difference was not statistically significant. Additionally, there was a significant reduction in blood pressure; however, serum sodium, bicarbonate, and Kt/V values did not change significantly during either period. Discussion: Sacubitril/valsartan therapy is associated with an increase in serum potassium levels in anuric hemodialysis patients. Nevertheless, the proportion of patients with severe hyperkalemia did not increase significantly. This suggests that the use of sacubitril/valsartan in anuric patients on hemodialysis is relatively safe. [ABSTRACT FROM AUTHOR]

Objectives: Intestinal ischemia reperfusion (IIR) is a critical emergency situation that needs immediate intervention. Small intestine is one of the most sensitive tissues to IR injury and it remains a highly morbid condition, with reported mortality rates ranging from 30% to 90%. Thus, we aimed to evaluate the suspected protective role of sacubitril/valsartan (SAC/VAL) on IIR injury. Methods: Thirty-two adult male Wistar rats were used in our model and divided into four groups: sham group, SAC/VAL treated group without IIR, IIR group, and SAC/VAL treated group with IIR. SAC/VAL in a dose of 30 mg/kg was administered orally just before induction of IIR. Key findings: SAC/VAL significantly ameliorated IIR-induced changes as it decreased malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), angiotensin II (ANG II), interleukin 6 (IL 6), active caspase 3, and signal transducer- and activator-of transcription (STAT1). However, SAC/VAL administration significantly increased antioxidant parameters such as total antioxidant capacity (TAC), superoxide dismutase (SOD), and reduced glutathione (GSH). Moreover, alteration of the histological structure was observed in IIR group that was improved by SAC/VAL. Conclusions: SAC/VAL prevents IIR-induced damage via modulation of renin angiotensin aldosterone system, antioxidant, anti-apoptotic, anti-inflammatory properties, and regulation of IL6/STAT1 pathway. Graphical Abstract [ABSTRACT FROM AUTHOR]

Cardiotoxicity induced by doxorubicin (Dox) is a major complication in cancer patients. Exosomes (Ex) derived from mesenchymal cells could be a promising therapeutic for various heart diseases. This study investigated the role of Ex in Dox‐induced cardiotoxicity and its mechanistic insights, using Sacubitril/valsartan (S/V) as a reference drug widely recommended in heart failure management. The study involved 24 Wistar rats, divided into a control, Dox, Dox + S/V, and Dox + Ex groups. The rats were assessed for cardiac enzymes, inflammatory and oxidative stress markers. Immunohistochemical expression of caspase‐1, nuclear factor erythroid 2‐related factor 2 (NrF2), E‐Cadherin, CD117/c‐kit, and Platelet‐derived growth factor‐α (PDGFα) was evaluated. P53 and Annexin V were assessed by PCR. Histological examination was performed using hematoxylin and eosin and Sirius red stains. Ex ameliorated the adverse cardiac pathological changes and significantly decreased the cardiac enzymes and inflammatory and oxidative stress markers. Ex also exerted antifibrotic and antiapoptotic effect in heart tissue. Ex treatment also improved NrF2 immunohistochemistry, up‐regulated E‐Cadherin immune expression, and restored the telocyte markers CD117/c‐kit and PDGFα. Ex can mitigate Dox‐induced cardiotoxicity by acting as an anti‐inflammatory, antioxidant, antiapoptotic, and antifibrotic agents, restoring telocytes and modulating epithelial mesenchymal transition. Research Highlights: Exosomes exhibit positive expression for CD90 and CD105 whereas showing −ve expression for CD 34 by flow cytometry.Exosomes restore the immunohistochemical expression of the telocytes markers CD117/c‐kit and PDGFα.Exosomes alleviate myocardial apoptosis, oxidative stress and fibrosis. [ABSTRACT FROM AUTHOR]

Sacubitril/valsartan, which is a combined angiotensin receptor–neprilysin inhibitor (ARNI), is used for the treatment of chronic heart failure and hypertension. Substrates of neprilysin are numerous, and the systemic effects of an ARNI remain to be determined. Increased urinary C-peptide (UCPR) and urinary albumin (UAlb) excretion has been reported with the use of an ARNI, but the mechanism is still unknown. We report an 84-year-old man with type 2 diabetes and hypertension. His UAlb and UCPR excretion and (to a lesser degree) the estimated glomerular filtration rate were increased after ARNI administration. They returned to basal levels after discontinuing ARNI administration. There was little or no change in glycemic control. Therefore, increased glomerular permeability and filtration could partially explain how neprilysin inhibition led to an elevation in UCPR excretion, in addition to other mechanisms, such as impairment of the renal ability to degrade C-peptide. Physicians must be cautious when interpreting the insulin secretion capability by UCPR and nephropathy by UAlb in ARNI-treated patients with diabetes. [ABSTRACT FROM AUTHOR]

Heart failure (HF) and atrial fibrillation (AF) are prevalent cardiovascular diseases that contribute significantly to morbidity, mortality, hospitalisation, and healthcare costs. It is not uncommon for these conditions to coexist and have mutually reinforcing effects. A critical factor in the aetiology of these conditions is oxidative stress, driven by reactive oxygen species (ROS), which contributes to atrial remodelling and fibrosis. The recent introduction of new drugs for the treatment of heart failure has also had an impact on the management of atrial fibrillation due to their influence on oxidative stress. The objective of this review is to analyse the effects of these therapies, including their role in mitigating ROS, on the prevention and treatment of AF in HF patients. [ABSTRACT FROM AUTHOR]

Objective: To analyze the regulation of sacubitril/valsartan to the RhoA-ROCK signaling pathway in rat with chronic heart failure (CHF), and the effect of ventricular remodeling. Methods: A total of 45 SD rats were divided into 3 groups randomly, which were control group (injected normal saline), model group (made CHF rat model by peritoneal injection with Adriamycin) and therapy group (intragastric administration sacubitril/valsartan with 60 mg/kg 4 weeks to CHF rats). Each group had 15 rats. The cardiac function indexes of left ventricular ejection fraction (LVEF), left ventricular end diastolic diameter (LVEDD), interventricular septal thickness (IVST), left ventricular mass index (LVMI) and the plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), matrix metal-loproteinase-9 (MMP-9), Galectin-3 (Gal-3) were compared among 3 groups. The cardiac histomorphology indexes and degree of myocardial collagen deposition were detected and compared among 3 groups. The expression levels of RhoA and ROCK in myocardial tissue were compared among 3 groups. Results: The LVEF of rats in control group were highest, and the LVEF of rats in therapy group were higher than in model group (P < 0.05) The levels of LVEDD, IVST, LVMI in control group were lowest, and the levels of LVEDD, IVST, LVMI in therapy group were lower than model group (P < 0.05) The plasma levels of NT-proBNP, MMP-9, Gal-3 in control group were highest, and the levels of NT-proBNP, MMP-9, Gal-3 in therapy group were higher than model group (P < 0.05) The enlarged cardiac cell and disorderly arrangement in model group were observed, and the degrees of myocardial collagen deposition in model group were larger than therapy group. The expression levels of RhoA and ROCK of myocardial tissue were different among 3 groups, which the indexes in control group were the lowest, and the therapy group was the second lowest, and the model group was the highest (P < 0.05) The positive relationship of the expression levels of RhoA and ROCK to the levels of LVEDD, IVST, LVMI, NT-proBNP, MMP-9 and Gal-3 were confirmed (P < 0.05), and the negative relationship to LVEF was also confirmed (P < 0.05) Conclusion: Sacubitril/valsartan has significant negative effect on the ventricular remodeling by the RhoA-ROCK signaling pathway in CHE [ABSTRACT FROM AUTHOR]

The Kidney Disease Improving Global Outcomes (KDIGO) classification integrates both estimated glomerular filtration rate and urine-albumin-creatinine ratio to stratify risk more comprehensively in patients with chronic kidney disease. There are limited data assessing whether this classification system is associated with prognosis and treatment response in heart failure populations. The aim of this study was to evaluate the relative treatment effects of sacubitril/valsartan across the KDIGO risk categories in patients with HFrEF. PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) was a global randomized controlled trial evaluating sacubitril/valsartan vs enalapril in patients with heart failure with reduced ejection fraction (HFrEF). Patients were classified according to low, moderate, and high/very high KDIGO risk. Treatment responses were assessed according to baseline KDIGO risk. The primary outcome was a composite of cardiovascular (CV) death or heart failure hospitalization. A renal composite outcome was defined as sustained decline in estimated glomerular filtration rate by ≥40% or end-stage kidney disease. Among 1,910 (23% of total) participants with available data, 42%, 32%, and 26% were classified as low, moderate, and high/very high KDIGO risk, respectively. Patients in the highest KDIGO risk categories experienced the highest rates of the primary composite outcome (7.6 per 100 person-years [95% CI: 6.5-9.0 per 100 person-years], 9.4 per 100 person-years [95% CI: 7.9-11.2 per 100 person-years], and 14.9 per 100 person-years [95% CI: 12.7-17.6 per 100 person-years]; P < 0.001). Sacubitril/valsartan had a similar safety profile and demonstrated consistent effects on the risk of both the primary outcome (P Interaction = 0.31) and the renal composite outcome (P Interaction = 0.50) across the spectrum of KDIGO risk. One in 4 patients with HFrEF were classified as at least high KDIGO kidney risk; these individuals faced concordantly the highest risks of CV events. Sacubitril/valsartan exhibited consistent CV and kidney protective benefits as well as safety across the spectrum of baseline kidney risk. These data further support initiation of sacubitril/valsartan in HFrEF across a broad range of kidney risk. (This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure [PARADIGM-HF]; NCT01035255) [Display omitted] [ABSTRACT FROM AUTHOR]

Aim: Sacubitril/valsartan treatment reduces mortality and hospitalizations in heart failure with reduced ejection fraction but has limited application in hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the effect of sacubitril/valsartan on peak oxygen consumption (VO2) in patients with non‐obstructive HCM. Methods and results: This is a phase II, randomized, open‐label multicentre study that enrolled adult patients with symptomatic non‐obstructive HCM (New York Heart Association class I–III) who were randomly assigned (2:1) to receive sacubitril/valsartan (target dose 97/103 mg) or control for 16 weeks. The primary endpoint was a change in peak VO2. Secondary endpoints included echocardiographic measures of cardiac structure and function, natriuretic peptides and other cardiac biomarkers, and Minnesota Living with Heart Failure quality of life. Between May 2018 and October 2021, 354 patients were screened for eligibility, 115 patients (mean age 58 years, 37% female) met the study inclusion criteria and were randomly assigned to sacubitril/valsartan (n = 79) or control (n = 36). At 16 weeks, there was no significant change in peak VO2 from baseline in the sacubitril/valsartan (15.3 [4.3] vs. 15.9 [4.3] ml/kg/min, p = 0.13) or control group (p = 0.47). No clinically significant changes were found in blood pressure, cardiac structure and function, plasma biomarkers, or quality of life. Conclusion: In patients with HCM, a 16‐week treatment with sacubitril/valsartan was well tolerated but had no effect on exercise capacity, cardiac structure, or function. [ABSTRACT FROM AUTHOR]

Aims: The PARACOR‐19 randomized controlled trial (RCT) was designed to examine the effects of sacubitril/valsartan on markers of cardiac injury, inflammation, structure, and function among patients who have recovered from acute coronavirus disease 2019 (COVID‐19) infection. Methods and results: PARACOR‐19 was a single‐centre, double‐blind RCT of patients with cardiovascular risk factors and a history of COVID‐19 infection 4–16 weeks prior to enrolment. Patients were randomized to sacubitril/valsartan (titrated to the maximum dose of 97/103 mg twice daily) versus matching placebo. Co‐primary endpoints were change from baseline to 12 weeks in high‐sensitivity cardiac troponin T (hs‐cTnT) and soluble ST2 (sST2). Exploratory endpoints included change from baseline to 12 weeks in additional circulating biomarkers. Overall, 42 patients were randomized between August 2021 and March 2023 (n = 20 sacubitril/valsartan, n = 22 placebo). Median (25th–75th) time from COVID‐19 diagnosis to enrolment was 67 (48–80) days. Median age was 67 (62–71) years, 48% were female, and 91% were White. Compared with placebo, sacubitril/valsartan did not have a significant effect on the co‐primary endpoints of change from baseline in hs‐TnT and sST2 (all p ≥ 0.29). In exploratory analyses, sacubitril/valsartan led to a 46% greater reduction in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and 51% greater reduction in C‐terminal telopeptide of collagen type I (CITP). Permanent drug discontinuation occurred in four patients in the sacubitril/valsartan group and three patients in the placebo group. There were no deaths and one patient was hospitalized in each group. Conclusion: In this pilot RCT of patients who recovered from acute COVID‐19, sacubitril/valsartan did not lower hs‐cTnT or sST2 compared with placebo. Exploratory analyses suggested potential benefits of sacubitril/valsartan on cardiac wall stress and collagen turnover as measured by NT‐proBNP and CITP. Sacubitril/valsartan was well tolerated. Clinical Trial Registration: ClinicalTrials.gov NCT04883528. [ABSTRACT FROM AUTHOR]

Background: The PARADIGM HF trial showed sacubitril/valsartan (SV) to be superior to enalapril in patients with reduced ejection fraction (HFrEF). Since its publication, several other randomized trials have compared SV to either an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) in HFrEF which showed conflicting results regarding mortality, hospitalizations, and quality of life scoring. Objective: To review randomized comparative trials of SV to either ACEI or ARB in patients with HFrEF. Methods: PubMed and Embase databases were used to identify randomized comparative trials. The text terms sacubitril, angiotensin neprilysin, and LCZ696 were used for both searches. Meta-analysis, retrospective, adhoc, and cohort studies were excluded. Results: 1476 and 3983 citations were reviewed on PubMed and Embase, respectively. Of these, 11 randomized comparative trials to either ACEI or ARB were included for analysis. The mortality/quality of life benefits of SV over enalapril in the PARADIGM HF were not corroborated in any of the other trials. The effect of hospitalizations for heart failure was inconsistent among trials. Exercise tolerance was not improved with SV versus enalapril. Conclusion: The results of the PARADIGM HF trial have largely not been confirmed in subsequent randomized comparative trials. [ABSTRACT FROM AUTHOR]

• Sacubitril/valsartan (S/V) is a key treatment for heart failure. • Sleep-disordered breathing (SDB; obstructive and central) is a common co-morbidity. • SDB has an impact on the prognosis of patients with heart failure. • After only 3 months of treatment, S/V improved LV and RV function. • This was achieved via a significant increase in TAPSE and a reduction in sPAP. • The improvement in RV function was most evident in patients with central SDB. • To date, those with central SDB cannot benefit from any treatment other than drugs. Sacubitril/valsartan has been demonstrated to significantly improve left ventricular performance and remodelling in patients with heart failure. However, its effects on the right ventricle in patients with chronic heart failure and sleep-disordered breathing (SDB) have not been studied. To investigate the impact of sacubitril/valsartan treatment on right ventricular function in patients with SDB. This was a subanalysis of an observational prospective multicentre study involving 101 patients. At inclusion, patients were evaluated by echocardiography and nocturnal ventilatory polygraphy, which allowed patients to be divided into three groups: "central-SDB"; "obstructive-SDB"; and "no-SDB". After 3 months of sacubitril/valsartan therapy, a positive impact on right ventricular function was observed. In the general population, tricuspid annular plane systolic excursion increased by +1.32 ± 4.74 mm (P = 0.024) and systolic pulmonary artery pressure decreased by −3.1 ± 10.91 mmHg (P = 0.048). The central-SDB group experienced the greatest echocardiographic improvement, with a significant increase in tricuspid annular plane systolic excursion of +2.1 ± 4.9 mm (P = 0.045) and a significant reduction in systolic pulmonary artery pressure of −8.4 ± 9.7 mmHg (P = 0.001). Sacubitril/valsartan improved right ventricular function in patients with heart failure and SDB after only 3 months of treatment. The greatest improvement in right ventricular function was observed in the central-SDB group. [ABSTRACT FROM AUTHOR]

Background: Impaired renal function is frequently observed in patients with heart failure and reduced ejection fraction (HFrEF). The differential effect of sacubitril/valsartan and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (ACEIs/ARBs) on the clinical and renal outcomes in patients with HFrEF and chronic kidney disease (CKD) remains unknown. Aims: This study aimed to explore the differential effect of sacubitril/valsartan and ACEI/ARB on the clinical and renal outcomes as well as renal function over a 12-month follow-up period in HFrEF patients with and without CKD. Methods: Patients with HfrEF (LVEF ≤35%) and NYHA class ≥II were enrolled from the Chang Gung Research Database between 2017 and 2020. Baseline characteristics were compared between patients prescribed sacubitril/valsartan and ACEI/ARB. After propensity score matching, the following clinical and renal outcomes were compared between the two groups in patients with and without CKD over a 12-month follow-up period: acute kidney injury (AKI), emergent dialysis/renal death, HF hospitalization, cardiovascular mortality, and all-cause mortality. Results: This study enrolled 3735 HFrEF patients with a mean left ventricular EF of 27.56 ± 5.86%, who had been prescribed sacubitril/valsartan (N = 1708) or ACEI/ARB (N = 2027). After propensity score matching, the clinical and renal outcomes did not differ between the sacubitril/valsartan and ACEI/ARB groups in patients without CKD. In patients with CKD, the ACEI/ARB group had a significantly higher incidence of all-cause mortality than the sacubitril/valsartan group (14.89% vs. 10.50%; hazard ratio 1.46; 95% confidence interval 1.06–2.00; p = 0.02), and the incidence of AKI, HF hospitalization, and CV mortality did not differ between the two groups. Conclusions: Sacubitril/valsartan had a lower all-cause mortality compared to ACEI/ARB in symptomatic HFrEF patients with CKD. Further prospective randomized studies are warranted to confirm our findings. [ABSTRACT FROM AUTHOR]

Background: In patients with heart failure with reduced ejection fraction (HFrEF), treatment with sacubitril–valsartan (S/V) may reverse left ventricular remodeling (rLVR). Whether this effect is superior to that induced by other renin–angiotensin system (RAS) inhibitors is not well known. Methods: HFrEF patients treated with S/V (n = 795) were compared, by propensity score matching, with a historical cohort of 831 HFrEF patients (non-S/V group) treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (RAS inhibitors). All patients were also treated with beta-blockers and shared the same protocol with repeat echocardiogram 8–12 months after starting therapy. The difference-in-difference (DiD) analysis was used to evaluate the impact of S/V on CR indices between the two groups. Results: After propensity score matching, compared to non-S/V group (n = 354), S/V group (n = 354) showed a relative greater reduction in end-diastolic and end-systolic volume index (ESVI), and greater increase in ejection fraction (DiD estimator = + 5.42 mL/m2, P = 0.0005; + 4.68 mL/m2, P = 0.0009, and + 1.76%, P = 0.002, respectively). Reverse LVR (reduction in ESVI ≥ 15% from baseline) was more prevalent in S/V than in non-S/V group (34% vs 26%, P = 0.017), while adverse LVR (aLVR, increase in ESVI at follow-up ≥ 15%) was more frequent in non-S/V than in S/V (16% vs 7%, P < 0.001). The beneficial effect of S/V on CR over other RAS inhibitors was appreciable across a wide range of patient's age and baseline end-diastolic volume index, but it tended to attenuate in more dilated left ventricles (P for interaction = NS for both). Conclusion: In HFrEF patients treated with beta-blockers, sacubitril/valsartan is associated with a relative greater benefit in LV reverse remodeling indices than other RAS inhibitors. [ABSTRACT FROM AUTHOR]

ObjectiveLevosimendan 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.MethodsCochrane 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.ResultsA 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

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 β-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