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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]

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]

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]

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.

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.

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]

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]

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]

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]

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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]

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]

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]

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]

Aims 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.Methods 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.Results 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.Conclusions 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.

BackgroundThe mechanism underlying new-onset postoperative atrial fibrillation (POAF) in adult cardiac surgery is not well understood. However, efficient pharmacological methods to prevent and treat arrhythmic complications are still lacking. In the present study, we explored the efficacy and safety of sacubitril/valsartan (sac/val) in the control of POAF in adult cardiac surgery patients.MethodsBetween January 2021 and December 2021, 667 eligible adult patients who underwent cardiac surgery at the Affiliated Hospital of Qingdao University were enrolled. The participants were divided into two groups according to whether sac/val was used: the sac/val group (N = 101) and the control group (N = 566). The main observational endpoints were the incidence of POAF, left ventricular ejection fraction (LVEF) recovery, in-hospital mortality, and short-term mortality.ResultsPatients in the sac/val group had a lower incidence of POAF than those in the control group (26/101 vs. 204/566, P = 0.045). Patients in the sac/val group also showed a higher communicative risk for POAF incidence using the Kaplan–Meier survival analysis. In addition, patients in the sac/val group showed better LVEF recovery, with dynamic changes in LVEF superior to that of the control group. The change in LVEF in the sac/val group was 1.78 ± 5.41, compared with −1.19 ± 10.92 in the control group (P = 0.008).ConclusionsThis is the first observational study to evaluate the efficacy and safety of sac/val in the prevention and treatment of POAF after cardiac surgery. The results demonstrated that compared with patients who did not receive sac/val treatment, those who received Sac/val treatment showed better POAF control and LVEF recovery. These results should be cautiously interpreted and further confirmed using larger sample sizes and prospective randomized controlled trials.

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

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

Abstract Aims This study sought to assess the effect of treatment of sacubitril/valsartan (S/V) on improving cardiac function and reversing cardiac remodelling in patients with acute coronary syndrome (ACS) complicated with heart failure with reduced ejection fraction after percutaneous coronary intervention (PCI). Methods and results We enrolled 275 ACS patients with reduced left ventricular ejection fraction after PCI. The patients were divided into the routine and S/V groups according to the treatment drugs. The symptoms, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) concentrations, echocardiographic parameters [left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI), left ventricular end‐diastolic volume index (LVEDVI), and left ventricular end‐systolic volume index (LVESVI)], major adverse cardiac events (MACEs), and adverse reactions were recorded at baseline and 6 months after treatment when a clinical follow‐up was performed. The S/V group was further divided into prespecified subgroups including unstable angina (UA) group, non‐ST‐elevation myocardial infarction (NSTEMI) group, and ST‐elevation myocardial infarction (STEMI) group according to the type of ACS. We analysed the changes in LVEF, LVMI, LVEDVI, LVESVI, and NT‐proBNP in both groups and evaluated the correlation between the changes in the above variables (ΔLVEF, ΔLVMI, ΔLVEDVI, ΔLVESVI, and ΔNT‐proBNP). Cox regression model was used to assess the independent risk factors of MACE. Prespecified subgroup analyses were also conducted. Compared with baseline, LVEF increased significantly (P

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]

Aims: Patients with heart failure (HF) and preserved ejection fraction (HFpEF) have a particularly high prevalence of comorbidities, often necessitating treatment with many medications. The aim of this study was to evaluate the association between polypharmacy status and outcomes in PARAGON‐HF. Methods and results: In this post hoc analysis, baseline medication status was available in 4793 of 4796 patients included in the primary analysis of PARAGON‐HF. The effects of sacubitril/valsartan, compared with valsartan, were assessed according to the number of medications at baseline: 683 non‐polypharmacy (<5 medications); 2750 polypharmacy (5–9 medications), and 1360 hyper‐polypharmacy (≥10 medications). The primary outcome was total HF hospitalizations and cardiovascular deaths. Patients with hyper‐polypharmacy were older, had more severe limitations due to HF (worse New York Heart Association class and Kansas City Cardiomyopathy Questionnaire scores), and had greater comorbidity. The non‐adjusted risk of the primary outcome was significantly higher in patients taking more medications, and similar trends were seen for HF hospitalization and cardiovascular and all‐cause death. The effect of sacubitril/valsartan versus valsartan on the primary outcome from the lowest to highest polypharmacy category was (as a rate ratio): 1.19 (0.76–1.85), 0.94 (0.77–1.15), and 0.77 (0.61–0.96) (pinteraction = 0.16). Treatment‐related adverse events were more common in patients in the higher polypharmacy categories but not more common with sacubitril/valsartan, versus valsartan, in any polypharmacy category. Conclusions: Polypharmacy is very common in patients with HFpEF, and those with polypharmacy have worse clinical status and a higher rate of non‐fatal and fatal outcomes. The benefit of sacubitril/valsartan was not diminished in patients taking a larger number of medications at baseline. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the influence of aging on the effectiveness and tolerance of sacubitril/valsartan (sac/val) among hypertensive patients complicated with heart failure in a real-world setting. Methods: This multicenter, retrospective study included patients (=18 years old) admitted with a diagnosis of hypertension and heart failure, starting sac/val therapy between January 2020 and December 2021 from 3 medical centers. Patients were grouped by the cutoff age of 65 years. Outcomes were collected 31-365 days after the initiation of sac/val and were compared in a matched cohort after 1: 1 propensity score matching (PSM). Results: A total of 794 patients were finally analyzed. Blood pressure and cardiac functions improved significantly compared with values at baseline. There were 269 patients in each cohort (<65 years and ≥65 years) after PSM. After PSM, the incidence of hyperuricemia and hypotension in the elderly patients (≥65 years) was significantly higher than in those <65 years of age. Kaplan-Meier estimate suggested that the cumulative incidence of new or recurrent cardiovascular events increased significantly at the age of ≥65 years after the point of 3 months (log-rank P = .00087). Conclusion: Sac/val benefited patients in both cohorts by improving blood pressure and cardiac function. Elderly patients (=65 years) were susceptible to hypotension, low diastolic blood pressure, hyperuricemia, and underwent cardiac-related readmissions more frequently. [ABSTRACT FROM AUTHOR]

Aims: This study sought to assess the effect of treatment of sacubitril/valsartan (S/V) on improving cardiac function and reversing cardiac remodelling in patients with acute coronary syndrome (ACS) complicated with heart failure with reduced ejection fraction after percutaneous coronary intervention (PCI). Methods and results: We enrolled 275 ACS patients with reduced left ventricular ejection fraction after PCI. The patients were divided into the routine and S/V groups according to the treatment drugs. The symptoms, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) concentrations, echocardiographic parameters [left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI), left ventricular end‐diastolic volume index (LVEDVI), and left ventricular end‐systolic volume index (LVESVI)], major adverse cardiac events (MACEs), and adverse reactions were recorded at baseline and 6 months after treatment when a clinical follow‐up was performed. The S/V group was further divided into prespecified subgroups including unstable angina (UA) group, non‐ST‐elevation myocardial infarction (NSTEMI) group, and ST‐elevation myocardial infarction (STEMI) group according to the type of ACS. We analysed the changes in LVEF, LVMI, LVEDVI, LVESVI, and NT‐proBNP in both groups and evaluated the correlation between the changes in the above variables (ΔLVEF, ΔLVMI, ΔLVEDVI, ΔLVESVI, and ΔNT‐proBNP). Cox regression model was used to assess the independent risk factors of MACE. Prespecified subgroup analyses were also conducted. Compared with baseline, LVEF increased significantly (P < 0.05), NT‐proBNP, LVMI, and LVESVI decreased significantly in both groups after 6 months (P < 0.05), and LVEDVI decreased significantly in the S/V group (P = 0.001). In the S/V group, ΔLVEF (t = −2.745, P = 0.006), ΔNT‐proBNP (P = 0.009), ΔLVEDVI (t = 4.203, P = 0.001), and ΔLVESVI (t = 3.907, P = 0.001) were significantly improved than those in the routine group. In the S/V group, ΔLVEF was negatively correlated with ΔNT‐proBNP (r = −0.244, P = 0.004), ΔLVMI (r = −0.190, P = 0.028), ΔLVEDVI (r = −0.173, P = 0.045), and ΔLVESVI (r = −0.261, P = 0.002). In Cox regression model analysis, ΔLVEF {hazard ratio [HR] = 0.87 [95% confidence interval (CI) 0.80–0.95], P = 0.003}, ΔLVEDVI [HR = 1.04 (95% CI 1.01–1.06), P = 0.013], and ΔLVESVI [HR = 1.04 (95% CI 1.01–1.08), P = 0.026] were independent risk factors for MACE. Subgroup analysis showed that ΔLVEF (t = 6.290, P = 0.001), ΔLVEDVI (t = 2.581, P = 0.011), and ΔNT‐proBNP (P = 0.019) in the NSTEMI group were significantly improved than those in the UA group, ΔLVEDVI in the NSTEMI group was significantly better than that in the STEMI group (t = −3.365, P = 0.001), and ΔLVEF in the STEMI group was significantly better than that in the UA group (t = −3.928, P = 0.001). There was a significant difference in the survival probability without MACE among the three groups in the analysis of the Kaplan–Meier curve (P = 0.042). The incidence of MACE in the UA group was significantly higher than that in the NSTEMI group (32.4% vs. 6.3%, P = 0.004). Conclusions: The cardiac function is improved and cardiac remodelling is reversed significantly after treatment of S/V in ACS patients with reduced left ventricular ejection fraction after PCI, and the improvement is more obvious than the routine group. There is a significant negative correlation between the change in LVEF and the changes in NT‐proBNP, LVMI, LVEDVI, and LVESVI. The increase of LVEF and the decrease of LVEDVI and LVESVI are protective factors to improve the prognosis. Patients with myocardial infarction and reduced left ventricular ejection fraction might benefit more from the initiation of S/V as first‐line heart failure treatment after PCI. [ABSTRACT FROM AUTHOR]

There is ample evidence on the benefit of angiotensin receptor-neprilysin inhibitors (ARNIs) in heart failure, yet data regarding the potential protective action of ARNIs in hypertensive heart disease are sparse. The aim of this study was to show whether an ARNI exerts a protective effect in a model of Nω-nitro-L-arginine methyl ester (L-NAME)-induced hypertension with a hypertensive heart and to compare this potential benefit with an angiotensin-converting enzyme inhibitor, captopril. Five groups of adult male Wistar rats were studied (14 per group) for four weeks: untreated controls; ARNI (68 mg/kg/day); L-NAME (40 mg/kg/day); L-NAME treated with ARNI; and L-NAME treated with captopril (100 mg/kg/day). L-NAME administration induced hypertension, accompanied by increased left ventricular (LV) weight and fibrotic rebuilding of the LV in terms of increased concentration and content of hydroxyproline in insoluble collagen and in total collagen and with a histological finding of fibrosis. These alterations were associated with a compromised systolic and diastolic LV function. Treatment with either an ARNI or captopril reduced systolic blood pressure (SBP), alleviated LV hypertrophy and fibrosis, and prevented the development of both systolic and diastolic LV dysfunction. Moreover, the serum levels of prolactin and prolactin receptor were reduced significantly by ARNI and slightly by captopril. In conclusion, in L-NAME-induced hypertension, the dual inhibition of neprilysin and AT1 receptors by ARNI reduced SBP and prevented the development of LV hypertrophy, fibrosis, and systolic and diastolic dysfunction. These data suggest that ARNI could provide protection against LV structural remodeling and functional disorders in hypertensive heart disease. [ABSTRACT FROM AUTHOR]

Angiotensin receptor neprilysin inhibitor is the standard of care for systolic heart failure in adults. In addition, its use in adults with failing systemic right ventricles and diastolic heart failure is promising. This study reports our experience with this drug for protein-losing enteropathy secondary to Fontan failure in pediatrics.

Background: As the survival of patients with malignant neoplasms is improving, the urgent need for cardioprotective agents to counteract toxic effects of chemotherapy is growing.Objective: To compare the cardioprotective efficacy of sacubitril/valsartan and candesartan in women with chronic heart failure and baseline reduced left ventricular ejection fraction (LVEF) during a 5-year prospective follow-up after chemotherapy for breast cancer.Materials and methods: In this randomized study, 127 women with chronic heart failure and reduced LVEF after radical surgical treatment of breast cancer received potentially cardiotoxic adjuvant polychemotherapy (fluorouracil+ doxorubicin + cyclophosphamide). In addition, the patients received sacubitril/valsartan at a dose of up to 97/103 mg twice daily (n = 63) or candesartan at a dose of up to 32 mg once daily (n = 65), and this treatment was monitored for 5 years.Results: The combination of sacubitril/valsartan was significantly superior to candesartan in improving left ventricular function and reducing the burden of ventricular arrhythmias and the risk of cardiovascular death (P = .039) at the long-term follow-up. Sacubitril/valsartan group and candesartan group did not differ in terms of mortality due to breast cancer progression or recurrence (P = .628).Conclusions: Sacubitril/valsartan can be considered an effective and safe option for protecting the cardiovascular system during potentially cardiotoxic polychemotherapy for breast cancer in patients with chronic heart failure and baseline reduced LVEF.

Abstract Aims To explore the role and mechanism of Notch signaling and ERK1/2 pathway in the inhibitory effect of sacubitril/valsartan on the proliferation of vascular smooth muscle cells (VSMCs). Main methods Human aortic vascular smooth muscle cells (HA-VSMCs) were cultured in vitro. The proliferating VSMCs were divided into three groups as control group, Ang II group and Ang II + sacubitril/valsartan group. Cell proliferation and migration were detected by CCK8 and scratch test respectively. The mRNA and protein expression of PCNA, MMP-9, Notch1 and Jagged-1 were detected by qRT-PCR and Western blot respectively. The p-ERK1/2 expression was detected by Western blot. Key findings Compared with the control group, proliferation and migration of VSMCs and the expression of PCNA, MMP-9, Notch1, Jagged-1 and p-ERK1/2 was increased in Ang II group. Sacubitril/valsartan significantly reduced the proliferation and migration. Additionally, pretreatment with sacubitril/valsartan reduced the PCNA, MMP-9, Notch1, Jagged-1 and p-ERK1/2 expression.

Abstract Background Tubulointerstitial fibrosis plays an important role in the progression of diabetic kidney disease (DKD). Sacubitril/valsartan (Sac/Val) exerts a robust beneficial effect in DKD. However, the potential functional effect of Sac/Val on tubulointerstitial fibrosis in DKD is still largely unclear. Methods Streptozotocin-induced diabetic mice were given Sac/Val or Val by intragastric administration once a day for 12 weeks. The renal function, the pathological changes of tubule injury and tubulointerstitial fibrosis, as well as mitochondrial morphology of renal tubules in mice, were evaluated. Genome-wide gene expression analysis was performed to identify the potential mechanisms. Meanwhile, human tubular epithelial cells (HK-2) were cultured in high glucose condition containing LBQ657/valsartan (LBQ/Val). Further, mitochondrial functions and Sirt1/PGC1α pathway of tubular epithelial cells were assessed by Western blot, Real-time-PCR, JC-1, MitoSOX or MitoTracker. Finally, the Sirt1 specific inhibitor, EX527, was used to explore the potential effects of Sirt1 signaling in vivo and in vitro. Results We found that Sac/Val significantly ameliorated the decline of renal function and tubulointerstitial fibrosis in DKD mice. The enrichment analysis of gene expression indicated metabolism as an important modulator in DKD mice with Sac/Val administration, in which mitochondrial homeostasis plays a pivotal role. Then, the decreased expression of Tfam and Cox IV;, as well as changes of mitochondrial function and morphology, demonstrated the disruption of mitochondrial homeostasis under DKD conditions. Interestingly, Sac/Val administration was found to restore mitochondrial homeostasis in DKD mice and in vitro model of HK-2 cells. Further, we demonstrated that Sirt1/PGC1α, a crucial pathway in mitochondrial homeostasis, was activated by Sac/Val both in vivo and in vitro. Finally, the beneficial effects of Sac/Val on mitochondrial homeostasis and tubulointerstitial fibrosis was partially abolished in the presence of Sirt1 specific inhibitor. Conclusions Taken together, we demonstrate that Sac/Val ameliorates tubulointerstitial fibrosis by restoring Sirt1/PGC1α pathway-mediated mitochondrial homeostasis in DKD, providing a theoretical basis for delaying the progression of DKD in clinical practice.

Abstract Background and objective Dyslipidemia is significantly more common in those with concurrent chronic kidney disease (CKD) and chronic heart failure (CHF). Sacubitril/valsartan has showcased its influence on both cardiac and renal functions, extending its influence to the modulation of lipid metabolism pathways. This study aimed to examine how sacubitril/valsartan affects lipid metabolism within the context of CKD and CHF. Methods This study adopted a retrospective design, focusing on a single center and involving participants who were subjected to treatment with sacubitril/valsartan and valsartan. The investigation assessed the treatment duration, with a particular emphasis on recording blood lipid indicators, including triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A (ApoA), and apolipoprotein B (ApoB). Furthermore, cardiac and renal functions, blood pressure, potassium levels, and other factors influencing the blood lipids were analyzed in both groups at identical time points. Results After 16 weeks of observation, the sacubitril/valsartan group exhibited lower TG levels compared to the valsartan group. Noteworthy was the fact that individuals undergoing sacubitril/valsartan treatment experienced an average reduction of 0.84 mmol/L in TG levels, in stark contrast to the valsartan group, which registered a decline of 0.27 mmol/L (P

Abstract Aims The current European Society of Cardiology (ESC) guidelines provide clear indications for the treatment of acute and chronic heart failure (HF). Nevertheless, there is a constant need for real‐world evidence regarding the effectiveness, adherence, and persistence of drug therapy. We investigated the use of sacubitril/valsartan for the treatment of HF with reduced ejection fraction in real‐world clinical practice in Italy. Methods and results An observational, retrospective, non‐interventional cohort study based on electronic medical records from nine specialized hospital HF centres in Italy was carried out on patients with prescription of sacubitril/valsartan. Overall, 948 patients had a prescription of sacubitril/valsartan, with 924 characterized over 6 months and followed up for 12 months. Pharmacoutilization data at 1 year of follow‐up were available for 225 patients {mean age 69.7 years [standard deviation (SD) = 10.8], 81.8% male}. Of those, 398 (45.2%) reached the target dose of sacubitril/valsartan of 97/103 mg in a mean time of 6.9 (SD = 6.2) weeks. Blood pressure and hypotension in 61 patients (65%) and worsening of chronic kidney disease in 10 patients (10.6%) were the main reasons for not reaching the target dose. Approximatively 50% of patients had a change in sacubitril/valsartan dose during follow‐up, and 158 (70.2%) were persistent with the treatment during the last 3 months of follow‐up. A sensitivity analysis (persistence during the last 4 months of follow‐up) showed persistence for 162 patients (72.0%). Adherence data, available for 387 patients, showed full adherence for 205 (53%). Discontinuation (102/717 patients, 14.2%) was mainly due to hypotension and occurred after a mean time of 34.3 (SD = 28.7) weeks. During follow‐up, out of 606 patients with available data, 434 patients (71.6%) had an HF add‐on drug or drugs concomitant with sacubitril/valsartan. HF‐related hospitalization during follow‐up was numerically higher in non‐persistent (16/67 patients, 23.9%) vs. patients persistent to sacubitril/valsartan (30/158, 19%) (P = 0.405). Conclusions Real‐world data on the use of sacubitril/valsartan in clinical practice in Italy show a rapid titration to the target dose, high therapeutic adherence enabling a good level of therapeutic management in line with ESC guidelines for patients with reduced ejection fraction.

Abstract Introduction Non-responders to cardiac resynchronization therapy (CRT-NR) have poor prognosis. Sacubitril/valsartan (SV) treatment improved the outcome of patients with heart failure with reduced left ventricular (LV) ejection fraction (HFrEF) in randomized trials with no data on the specific cohort of CRT-NRs. The aim of this study was to compare the echocardiographic and biomarker changes in CRT-NR patients treated with versus without SV, and in patients with HFrEF on SV therapy. Methods CRT-NR patients initiated on SV (group I), CRT-NR patients on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB) (group II), and patients with HFrEF (without CRT) initiated on SV (group III) were identified in our heart failure (HF) registry. CRT-NR was defined as 0.05). No significant changes were detected in group II. Conclusion SV therapy induced similar improvements in echocardiographic parameters and in NT-proBNP levels in CRT-NR patients and in patients with HFrEF without resynchronization.

Abdullah Alshammari,1 Basmah Ahmed Qasem,1 Nouf Ahmed Almatrafi,1 Lujain Mofareh Alharbi,1 Abeer Abdulhadi Alhuthali Snr,2 Attiah Abdulrahman Khobrani,2 Mohammed Alnuhait1 1Clinical Pharmacy Department, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia; 2Clinical Pharmacy Department, King Abdullah Medical City, Makkah, Saudi ArabiaCorrespondence: Mohammed Alnuhait, Clinical Pharmacy Department, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia, Email manuhait@uqu.edu.saBackground: Chemotherapy-induced cardiotoxicity is a significant problem, ranking as the second most frequent cause of mortality in cancer patients. This adverse outcome encompasses many cardiovascular problems, such as heart failure. Sacubitril/valsartan has shown potential in the management of heart failure, however, its effectiveness in treating chemotherapy-induced heart failure has not been extensively explored. We performed a case series to investigate the safety and effectiveness of sacubitril/valsartan in treating chemotherapy-induced cardiomyopathy in Saudi Arabia.Methods: The case series was conducted at a single medical center in Makkah, Saudi Arabia. The data gathered included patient demographics, clinical features, laboratory results, echocardiographic findings, and medication information. The data underwent analysis using descriptive statistics.Results: Out of the total of eight patients who were part of the investigation, a notable majority of six individuals exhibited substantial enhancements in their ejection fraction (EF) after receiving sacubitril/valsartan medication.Conclusion: Our case series provides significant insights by revealing improvements in ejection fraction (EF) in six out of eight patients who had chemotherapy-induced cardiomyopathy after receiving sacubitril/valsartan treatment.Keywords: oncology, sacubitril/valsartan, cardiotoxicity, chemotherapy, Saudi Arabia