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Cardiovascular complications are the major cause of diabetes mellitus-related morbidity and mortality. Increased renin–angiotensin–aldosterone system activity and decreased β-adrenergic receptor (β-AR) responsiveness contribute to diabetic cardiac dysfunction. We evaluated the effect of sacubitril/valsartan (neprilysin inhibitor plus angiotensin receptor antagonist combination) and valsartan treatments on the diabetic cardiac function through β-AR responsiveness and on protein expression of diastolic components. Six-week-old male Sprague Dawley rats were divided into control, diabetic, sacubitril/valsartan (68 mg/kg)-, and valsartan-treated (31 mg/kg) diabetic groups. Diabetes was induced by a high-fat diet plus low-dose streptozotocin (30 mg/kg, intraperitoneal). After 10 weeks of diabetes, rats were treated for 4 weeks. Systolic/diastolic function was assessed by in vivo echocardiography and pressure–volume loop analysis. β-AR-mediated responsiveness was assessed by in vitro papillary muscle and Langendorff heart experiments. Protein expression of sarcoplasmic reticulum calcium ATPase2a, phospholamban, and phosphorylated phospholamban was determined by Western blot. Sacubitril/valsartan improved ejection fraction and fractional shortening to a similar extent as valsartan alone. None of the treatments affected in vivo diastolic parameters or the expression of related proteins. β1-/β2-AR-mediated responsiveness was partially restored in treated animals. β3-AR-mediated cardiac relaxation (an indicator of diastolic function) responses were comparable among groups. The beneficial effect of sacubitril/valsartan on systolic function may be attributed to improved β1-/β2-AR responsiveness. [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]

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]

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]

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.

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]

Aims: The PIONEER‐HF and PARAGLIDE‐HF trials aimed to determine the efficacy and safety of the in‐hospital initiation of sacubitril/valsartan in patients hospitalized for AHF. However, whether the inclusion and exclusion criteria of the trials apply to patients encountered in real‐world routine care is unclear. This study aimed to investigate the applicability of the PIONEER‐HF and PARAGLIDE‐HF trials to real‐world AHF patients. Methods and results: We identified 28 293 AHF hospitalized patients between August 2008 to August 2017 from the Chang Gung Research Database and classified them into four groups based on left ventricular ejection fraction (LVEF) and trial criteria. Cox proportional hazards models were used to compare the risk of HF hospitalization and cardiovascular (CV) death. We defined PIONEER‐HF eligible (n = 3683) and non‐eligible (n = 3502) patients with an LVEF ≤40%, and PARAGLIDE‐HF eligible (n = 5191) and non‐eligible (n = 5832) patients with an LVEF >40%. Over a mean follow‐up of 3.5 years, the PIONEER‐HF non‐eligible and eligible groups exhibited similar rates of HF hospitalization and CV death (41.1% vs. 41.8%, adjusted hazard ratio [aHR]: 0.95; 95% CI: 0.88–1.04). No significant difference was found in the composite outcome between PARAGLIDE‐HF non‐eligible and eligible groups (36.7% vs. 38.6%; aHR: 0.97; 95% CI: 0.90–1.04). Conclusions: Using trial criteria, only 31.3% of AHF patients were eligible for sacubitril–valsartan. Yet, non‐eligible patients demonstrated similar outcomes to eligible patients, indicating a need for further evaluation of sacubitril–valsartan benefits in non‐eligible AHF patients. [ABSTRACT FROM AUTHOR]

Aims: The effects of initiating sacubitril/valsartan in patients with stable heart failure with reduced ejection fraction (HFrEF) on response to fluid and sodium expansion are unknown. Methods and results: We have explored changes in natriuresis, diuresis, and congestion in response to the administration of intravenous fluid/sodium load in patients with HFrEF before as compared to after the initiation of sacubitril/valsartan. At baseline (before sacubitril/valsartan initiation) and 2 and 3 months after the initiation, patients underwent an evaluation that consisted of three phases of 3 h: the rest phase (0–3 h), the load phase (3–6 h) in which 1 L of intravenous Ringer solution was administered, and the diuretic phase (6–9 h) at the beginning of which furosemide was administered. Overall, 216 patients completed the study. In comparison to baseline values, at 2 and 3 months after sacubitril/valsartan initiation, patients' diuresis and natriuresis in response to Ringer administration significantly increased (mean difference: 38.8 [17.38] ml, p = 0.0040, and 9.6 [2.02] mmol, p < 0.0001, respectively). Symptoms and signs of congestion after the fluid/sodium challenge were significantly decreased at months 2 and 3 compared to baseline. Compared to baseline, there was also an increment of natriuresis after furosemide administration on sacubitril/valsartan (9.8 [5.13] mmol, p = 0.0167). There was a significant decrease in body weight in subsequent visits when compared to baseline values (−0.50 [−12.7, 7.4] kg at 2 months, and −0.75 [−15.9, 7.5] kg at 3 months; both p < 0.0001). Conclusions: The initiation of sacubitril/valsartan in HFrEF patients was associated with improvements in natriuresis, diuresis, and weight loss and better clinical adaptation to potentially decongestive stressors. [ABSTRACT FROM AUTHOR]

Background: Sacubitril-valsartan has been widely reported for reducing the risk of cardiovascular death and improving left ventricular remodeling in patients with heart failure (HF). However, the effect of sacubitril-valsartan in patients with acute myocardial infarction (AMI) remains controversial. Therefore, we conducted this meta-analysis to investigate whether sacubitril-valsartan could reverse left ventricular remodeling and reduce cardiovascular adverse events in AMI patients after primary percutaneous coronary intervention (PPCI). Materials and methods: Two researchers independently retrieved the relevant literature from PubMed, Embase, The Cochrane Library, China National Knowledge Infrastructure (CNKI), and the Wanfang database. The retrieval time was limited from inception to 1 June 2023. Randomized controlled trials (RCTs) meeting the inclusion criteria were included and analyzed. Results: In total, 21 RCTs involving 2442 AMI patients who underwent PPCI for revascularization were included in this meta-analysis. The meta-analysis showed that compared with the angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB), sacubitril-valsartan treatment in AMI patients after PPCI significantly reduced left ventricular end-diastolic dimension (LVEDD) (weighted mean difference (WMD) -3.11, 95%CI: -4.05~-2.16, p < 0.001), left ventricular end-diastolic volume (LVEDV) (WMD -7.76, 95%CI: -12.24~-3.27, p = 0.001), left ventricular end-systolic volume (LVESV) (WMD -6.80, 95%CI: -9.45~-4.15, p < 0.001) and left ventricular end-systolic dimension (LVESD) (WMD -2.53, 95%CI: -5.30-0.24, p < 0.001). Subgroup analysis according to the dose of sacubitril-valsartan yielded a similar result. Meanwhile, PPCI patients using sacubitril-valsartan therapy showed lower risk of major adverse cardiac events (MACE) (OR = 0.36, 95%CI: 0.28-0.46, p < 0.001), myocardial reinfarction (OR = 0.54, 95% CI: 0.30-0.98, p = 0.041) and HF (OR = 0.35, 95%CI: 0.26-0.47, p < 0.001) without increasing the risk of renal insufficiency, hyperkalemia, or symptomatic hypotension. At the same time, the change of LV ejection fraction (LVEF) (WMD 3.91, 95%CI: 3.41-4.41, p < 0.001), 6 min walk test (6MWT) (WMD 43.56, 95%CI: 29.37-57.76, p < 0.001) and NT-proBNP level (WMD -130.27, 95%CI: -159.14~-101.40, p < 0.001) were statistically significant. Conclusion: In conclusion, our meta-analysis indicates that compared with ACEI/ARB, sacubitril-valsartan may be superior to reverse left ventricular remodeling, improve cardiac function, and effectively reduce the risk of MACE, myocardial reinfarction, and HF in AMI patients after PPCI during follow-up without increasing the risk of adverse reactions including renal insufficiency, hyperkalemia, and symptomatic hypotension. [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: Chronic inflammation is a constant phenomenon which accompanies the heart failure pathophysiology. In all phenotypes of heart failure, irrespective of the ejection fraction, there is a permanent low-grade activation and synthesis of proinflammatory cytokines. Many classes of anti-remodelling medication used in the treatment of chronic heart failure have been postulated to have an anti-inflammatory effect. Methods: This retrospective study enrolled 220 patients and focused on evaluating the effect of the most used active substances from these classes in reducing the level of inflammatory biomarkers (C reactive protein, erythrocyte sedimentation rate and fibrinogen) after initiation or up-titration. Our research is evaluating if this anti-inflammatory effect intensifies while raising the dose. The evaluation was performed at two visits with an interval between them of 6 months. Results: From the beta-blockers class, carvedilol showed a reduction in erythrocyte sedimentation rate (ESR), in low (6.25 mg, bi daily) and medium (12.5 mg, bi daily) doses. At the same time, sacubitril/valsartan showed a reduction in CRP levels. This effect was obtained only in the medium (49/51 mg, bi daily) and high (97/103 mg, bi daily) doses, with the maximum reduction being observed in the high dose. Conclusions: From the classes of medication evaluated, the study showed a significant reduction in ESR levels in the low and medium doses of carvedilol and a reduction in CRP values in the cases of medium and high doses of ARNI. [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/Aim: Sacubitril/valsartan (SV), a novel pharmacological class of angiotensin receptor neprilysin inhibitors, is effective in treating heart failure (HF) by inhibiting the degradation of natriuretic peptides and the renin--angiotensin--aldosterone system. However, no studies have observed the long-term effects of SV on patients with HF and preserved left ventricular ejection fraction (LVEF) undergoing hemodialysis (HD) over a long period. Patients and Methods: This single-center retrospective study of 21 months duration involved consecutive patients with HF and preserved LVEF undergoing HD, who received 50-200 mg/day. All patients were followed up regularly, and clinical, biochemical, and echocardiographic parameters were recorded at baseline and during follow-up. The efficacy and safety of SV were also analyzed. Results: This longitudinal study included nine patients, with a median age of 76 years. The median HD duration was 7 years. At baseline, the mean brain natriuretic peptide (BNP) was 133±73.6 pg/ml and that of LVEF was 66%±9%. After SV therapy, the systolic blood pressure, diastolic blood pressure, and heart rate decreased, albeit without statistical significance. BNP levels, LVEF, left atrial anteroposterior dimension, and left ventricular mass index did not change, compared to baseline values. No adverse effects were observed in any of the patients. Conclusion: SV tended to decrease blood pressure and heart rate in patients with HF and preserved LVEF undergoing HD but did not alter cardiac function assessments, such as BNP or echocardiography. [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]

Background and aim: Heart failure with preserved ejection fraction (HFpEF) is associated with an increased risk of heart failure (HF) hospitalizations and cardiovascular death (CVD). Both dapagliflozin and sacubitril-valsartan have recently shown convincing reductions in the combined risk of CVD and HF hospitalizations in patients with HF and mildly reduced ejection fraction (HFmrEF) or HFpEF. We aimed to investigate the cost-per-outcome implications of dapagliflozin vs sacubitril-valsartan in the treatment of HFmrEF or HFpEF patients. Methods: We compared the annualized cost needed to treat (CNT) to prevent the composite outcome of total HF hospitalizations and CVD with dapagliflozin or sacubitril-valsartan. The CNT was estimated by multiplying the annualized number needed to treat (aNNT) by the annual cost of therapy. The aNNT was calculated based on data collected from the DELIVER trial for dapagliflozin and a pooled analysis of the PARAGLIDE-HF and PARAGON-HF trials for sacubitril-valsartan. Costs were based on 2022 US prices. Scenario analyses were performed to attenuate the differences in the studies' populations. s Results: The aNNT with dapagliflozin in DELIVER was 30 (95% confidence interval [CI]: 21-62) versus 44 (95% CI: 25-311) with sacubitril-valsartan in a pooled analysis of PARAGLIDE-HF and PARAGON-HF, with an annual cost of $4,951 and $5,576, respectively. The corresponding CNTs were $148,547.13 (95% CI: $103,982.99-$306,997.39) for dapagliflozin and $245,346.77 (95% CI: $139,401.58-1,734,155.60) for sacubitril-valsartan for preventing the composite outcome of CVD and HF hospitalizations. The CNT for preventing all-cause mortality was lower for dapagliflozin than sacubitril-valsartan $1,128,958.15 [CI: $401,077.24-8] vs $2,185,816.71 [CI: $607,790.87-8]. Conclusion: Dapagliflozin provides a better monetary value than sacubitril-valsartan in preventing the composite outcome of total HF hospitalizations and CVD among patients with HFmrEF or HFpEF. [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]

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]

Background: Sacubitril/valsartan improves heart failure (HF) outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, randomized controlled trials (RCTs) in patients with heart failure and mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) have shown inconsistent results. We conducted this meta-analysis to comprehensively evaluate the efficacy and safety of sacubitril/valsartan compared to valsartan within this specific patient population. Methods: We searched the MEDLINE database and ClinicalTrials.gov and identified four RCTs that could be included in our analysis, with 3375 patients in the sacubitril/valsartan group and 3362 in the valsartan group. Results: Our study shows that, in patients with HFmrEF and HFpEF, sacubitril/valsartan was superior to valsartan in some of the key HF outcomes, such as the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS), with a small but significant mean difference of 1.13 (95% confidence interval or CI of 0.15 to 2.11, p-value 0.024), an improvement in the New York Heart Association (NYHA) class (odds ratio or OR of 1.32, 95% CI 1.11 to 1.58, p-value 0.002), and the composite outcome of hospitalizations for HF and cardiovascular death, with a relative risk (RR) of 0.86 (95% CI 0.75 to 0.99, p-value 0.04). However, there was no additional benefit with sacubitril/valsartan compared to valsartan for the outcomes of cardiovascular death and all-cause mortality. In terms of side effects, sacubitril/valsartan was associated with a higher risk of hypotension when compared to valsartan (OR 1.67, 95% CI 1.27 to 2.19, p-value < 0.0001), but did not show an increased risk of hyperkalemia or worsening renal function. Conclusions: In individuals with HFmrEF or HFpEF, sacubitril/valsartan can result in improvements in the HF outcomes of the KCCQ CSS, the NYHA class, and the composite outcome of hospitalization for HF and cardiovascular death when compared to valsartan. While there was a higher risk of hypotension with sacubitril/valsartan compared to valsartan, there was no corresponding increase in the risk of hyperkalemia or worsening renal function. [ABSTRACT FROM AUTHOR]

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 < 10% improvement in left ventricular ejection fraction (LV EF) 6 months after the implantation. Echocardiographic parameters and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at baseline and at the end of follow-up were compared. Results: A total of 275 patients (group I, 70; group II, 70; and group III, 135) were included. After a follow-up of 7.54 ± 1.8 months (mean ± standard deviation [SD]), LV EF (%) increased in group I (25.2 ± 5.7 versus 29.4% ± 6.7; p < 0.001) and in group III (26.6 ± 6.4 versus 29.9 ± 6.7; p < 0.001). LV end-systolic diameters (mm) decreased in group I (56.6 ± 9.0 versus 54.3 ± 8.7; p = 0.004) and in group III (55.9 ± 9.9 versus 54.3 ± 11.2; p = 0.021). The levels of NT-proBNP (pg/mL) decreased in group I (2058.86 [1041.07–4502.51] versus 1121.55 [545–2541]; p < 0.001) and in group III (2223.35 [1233.03–4795.96] versus 1123.09 [500.38–2651.27]; p < 0.001). The extent of improvement was similar in groups I and III (p > 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. [ABSTRACT FROM AUTHOR]

Aims: Heart failure with reduced ejection fraction (HFrEF) poses significant challenges for clinicians and researchers, owing to its multifaceted aetiology and complex treatment regimens. In light of this, artificial intelligence methods offer an innovative approach to identifying relationships within complex clinical datasets. Our study aims to explore the potential for machine learning algorithms to provide deeper insights into datasets of HFrEF patients. Methods: To this end, we analysed a cohort of 386 HFrEF patients who had been initiated on sodium‐glucose co‐transporter‐2 inhibitor treatment and had completed a minimum of a 6‐month follow‐up. Results: In traditional frequentist statistical analyses, patients receiving the highest doses of beta‐blockers (BBs) (chi‐square test, P =.036) and those newly initiated on sacubitril‐valsartan (chi‐square test, P =.023) showed better outcomes. However, none of these pharmacological features stood out as independent predictors of improved outcomes in the Cox proportional hazards model. In contrast, when employing eXtreme Gradient Boosting (XGBoost) algorithms in conjunction with the data using Shapley additive explanations (SHAP), we identified several models with significant predictive power. The XGBoost algorithm inherently accommodates non‐linear distribution, multicollinearity and confounding. Within this framework, pharmacological categories like 'newly initiated treatment with sacubitril/valsartan' and 'BB dose escalation' emerged as strong predictors of long‐term outcomes. Conclusions: In this manuscript, we not only emphasize the strengths of this machine learning approach but also discuss its potential limitations and the risk of identifying statistically significant yet clinically irrelevant predictors. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess the correlation between alterations in the distribution width of red blood cells (RDW) and the incidence of major adverse cardiovascular events (MACEs) in patients with heart failure with reduced ejection fraction (HFRF) receiving sacubitril/valsartan therapy. Implementing Methods: After obtaining permission from the Institutional Ethics Committee, the present study was initiated. This study retrospectively examined the medical records of hospitalized patients diagnosed with HFRF. The patients were allocated into two distinct groups, namely, the traditional group and the sacubitril/valsartan group, based on whether sacubitril/valsartan was incorporated into their individual pharmacological treatment regimen. The RDW values before and after treatment with sacubitril/valsartan are documented as RDW1 and RDW2, respectively. ΔRDW is defined as the value obtained by subtracting RDW1 from RDW2. Based on ΔRDW >0 or ≤0, patients in the sacubitril/valsartan group were categorized into two subgroups. MACEs, including mortality and readmission for myocardial infarction, acute myocardial infarction, and ischemic stroke, were documented in each cohort throughout the one-year follow-up period. Findings: Patients who received sacubitril/valsartan exhibited a reduced incidence of MACE compared to those who received conventional therapy (log-rank, P<0.001). During the follow-up period, the incidence of cardiac events was significantly higher in the ΔRDW >0 group than in the ΔRDW ≤ 0 group (Breslow, P<0.001). There was a significant positive correlation between increased RDW and a decreased likelihood of developing MACE (odds ratio [OR] = 3.044, 95% confidence interval [CI]:1.592-4.357). Furthermore, for every unit increase in RDW, the risk of developing MACE increased by 23.2% (OR=2.332, 95% CI:1.185-2.499). Treatment with sacubitril/valsartan effectively reduced the incidence of MACEs in HFRF patients. In addition, variations in RDW serve as predictors of MACEs after sacubitril/valsartan treatment. [ABSTRACT FROM AUTHOR]

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 < 0.001). The sacubitril/valsartan group exhibited elevated levels of HDL-C and ApoA in comparison to the valsartan group (PHDL-C = 0.023, PApoA = 0.030). While TC, LDL-C, and ApoB decreased compared to baseline, the differences between groups were not statistical significance. Regarding cardiac indicators, there was an observed enhancement in the left ventricular ejection fraction (LVEF) within the sacubitril/valsartan group when compared to the baseline, and it was noticeably higher than that of the valsartan group. Spearman correlation analysis and multiple linear regression analysis revealed that medication, body mass index(BMI), and hemoglobin A1c (HbA1c) had a direct influencing effect on TG levels. Conclusion: Sacubitril/valsartan demonstrated improvements in lipid metabolism and cardiac indicators in patients with CKD and CHF. Specifically, it presented promising benefits in reducing TG levels. In addition, both BMI and HbA1c emerged as influential factors contributing to alterations in TG levels, independent of the administration of sacubitril/valsartan. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Patient Support Programmes (PSPs) are used by the pharmaceutical industry to provide education and support to consumers to overcome the challenges they face managing their condition and treatment. Whilst there is an increasing number of PSPs, limited information is available on whether these programmes contribute to safety signals. PSPs do not have a scientific hypothesis, nor are they governed by a protocol. However, by their nature, PSPs inevitably generate adverse event (AE) reports. The main goal of the research was to gather all Novartis-initiated PSPs for sacubitril/valsartan, followed by research in the company safety database to identify all AE reports emanating from these PSPs. Core data sheets (CDS) were reviewed to assess if these PSPs contributed to any new, regulatory-authority approved, validated signals. Overall, AEs entered into the safety database from PSPs confirmed no contribution to CDS updates. Detailed review of real-world data revealed tablet splitting or taking one higher dose tablet a day instead of twice daily. This research, and subsequent analyses, revealed that PSPs did not impact safety label changes for sacubitril/valsartan. It revealed an important finding concerning drug utilisation i.e. splitting of sacubitril/valsartan tablets to reduce cost. This finding suggests that PSPs may contribute important real-world data on patterns of medication usage. There remains a paucity of literature available on this topic, hence further research is required to assess if it would be worth designing PSPs for collecting data on drug utilisation and (lack of) efficacy. Such information from PSPs could be important for all stakeholders. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the renoprotective effect of sacubitril/valsartan (Sac/Val) against angiotensinconverting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB). Methods: Following PRISMA guidelines, a thorough search of PubMed, Embase, Web of Science, and Cochrane Library was performed up to May 18, 2023. Eligibility criteria included prospective, randomized, controlled trials comparing sac/Val and ACEI/ARB with regard to renal outcomes. Data extraction and quality assessment were undertaken independently by two reviewers. Fixed or random effects models were used depending on the heterogeneity among studies. Subgroup analyses were performed based on the presence or absence of heart failure. Results: Eleven trials with varied patient populations and clinical settings were included. The metaanalysis revealed that Sac/Val exhibited a significantly reduced risk of renal function decline compared to ACEI/ARB (Risk Ratio (RR) = 0.86, 95 % Confidence Interval (CI) (0.78, 0.96), p = 0.016). Subgroup analysis showed that the renoprotective effect was significant in patients with heart failure (RR = 0.84, 95 % CI (0.75, 0.94), p = 0.011), but not in non-heart failure patients (RR = 1.04, 95 % CI (0.80, 1.37), p = 0.66). Conclusions: This systematic review and meta-analysis suggest that Sac/Val confers substantial renoprotective effect compared with ACEI/ARB, particularly among heart failure patients. However, further research is required to elaborate on the full potential of Sac/Val as a nephroprotective agent. [ABSTRACT FROM AUTHOR]

Background: Sacubitril‐valsartan, an inhibitor of the angiotensin receptor neprilysin (ARNi), has been purported to exhibit superiority over angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in individuals diagnosed with heart failure. Hypothesis: This paper gives an updated meta‐analysis comparing the efficacy and safety of sacubitril‐valsartan to that of standard treatment for different types of heart failure. Results: The meta‐analysis comprised a total of nine randomized controlled trials (RCTs), incorporating data from a substantial sample size of 15 939 patients. The study observed a decrease in overall mortality and mortality related to cardiovascular causes among patients in the heart failure with reduced ejection fraction (HFrEF) category who were treated with sacubitril‐valsartan. However, no statistically significant variation in this outcome was seen among patients with heart failure with preserved ejection fraction and HFmrEF. Patients who were administered sacubitril‐valsartan had a notably elevated likelihood of experiencing hypotension. Nevertheless, no significant disparities were observed in terms of other adverse events among the various treatment groups. Conclusion: Current meta‐analysis provide support for use of sacubitril‐valsartan in decreasing mortality in patients with HFrEF. However, more numbers of studies are required to draw a definite conclusion on other benefits associated with sacubitril‐valsartan use over standard treatment of ACE inhibitors and ARBs. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Background: This study aimed to evaluate the effect of sacubitril valsartan (SV) on heart failure (HF) hospitalization and cardiovascular mortality in patients on hemodialysis with HF with preserved ejection fraction (EF; HFpEF). Methods: This single-center, prospective study enrolled 155 stable hemodialysis patients with EF > 40% who were followed up for 12 months. Fifty-nine patients were treated with SV; the others were matched for EF (57.89 ± 9.35 vs. 58.00 ± 11.82, P = 0.9) at a ratio of 1:1 and included as controls. The target dosage of SV was 200 mg/day. Results: Twenty-three (23/155; 14.84%) had HF with mid-range EF (HFmrEF), while 132 (85.16%) had HFpEF. After SV treatment, the peak early diastolic transmitral flow velocity/peak early diastolic mitral annular tissue velocity(E/e') improved from 17.19 ± 8.74 to 12.80 ± 5.52 (P = 0.006), the left ventricular (LV) end-diastolic diameter decreased from 53.14 ± 7.67 mm to 51.56 ± 7.44 mm (P = 0.03), and the LV mass index decreased from 165.7 ± 44.6 g/m2 to 154.8 ± 24.0 g/m2 (P = 0.02). LVEF (P = 0.08) and LV global longitudinal strain (P = 0.7) did not change significantly. The composite outcome of first and recurrent HF hospitalization or cardiovascular death showed no difference between group. However, the Acute Dialysis Quality Initiative Workgroup (ADQI) HF class improved in 39 and 15 patients and worsened in 1 and 11 patients in the SV and control groups, respectively (P < 0.001). Age, diabetes mellitus, and pulmonary arterial pressure were independent risk factors for HF hospitalization and cardiovascular mortality in patients with HFpEF. Conclusions: SV improved LV hypertrophy, diastolic function, and the ADQI class for HF; however, it failed to reduce the composite endpoints of HF hospitalization and cardiovascular disease-related mortality over 12 months of follow-up in patients on maintenance hemodialysis with EF of > 40%. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy of left bundle branch pacing (LBBP) combined with either sacubitril/valsartan or enalapril in the treatment of chronic heart failure (CHF). Methods: We retrospectively reviewed the records of 138 patients with CHF admitted to Dazhou Central Hospital between June 2020 and June 2022 to extract clinical data. We divided the data into two treatment groups for the analysis: 71 patients received LBBP combined with sacubitril/valsartan treatment (sacubitril/valsartan group), and 67 received LBBP combined with enalapril treatment (enalapril group). The levels of cardiac and cardiopulmonary function indicators, levels of myocardial injury markers, and the scores of the Minnesota Living with Heart Failure Questionnaire (MLHFQ) before and after the treatment were compared between the two groups. Results: After six months of treatment, patients in the sacubitril/valsartan group had lower myocardial injury markers, higher cardiopulmonary function indicators, and lower MLHFQ scores (P<0.05). Conclusions: In CHF patients, the combination of LBBP with sacubitril/valsartan had a better therapeutic effect compared to LBBP with enalapril, with more effective improvement of the cardiopulmonary function, reduction of myocardial injury, and improvement in quality of life. [ABSTRACT FROM AUTHOR]

Aim: It is unknown whether safety and clinical endpoints by use of sacubitril/valsartan (an angiotensin receptor–neprilysin inhibitor [ARNI]) are affected by mineralocorticoid receptor antagonists (MRA) in high‐risk myocardial infarction (MI) patients. The aim of this study was to examine whether MRA modifies safety and clinical endpoints by use of sacubitril/valsartan in patients with a MI and left ventricular systolic dysfunction (LVSD) and/or pulmonary congestion. Methods and results: Patients (n = 5661) included in the PARADISE MI trial (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) were stratified according to MRA. Primary outcomes in this substudy were worsening heart failure or cardiovascular death. Safety was defined as symptomatic hypotension, hyperkalaemia >5.5 mmol/L, or permanent drug discontinuation. A total of 2338 patients (41%) were treated with MRA. Safety of ARNI compared to ramipril was not altered significantly by ± MRA, and both groups had similar increase in symptomatic hypotension with ARNI. In patients taking MRA, the risk of hyperkalaemia or permanent drug discontinuation was not significantly altered by ARNI (p > 0.05 for all comparisons). The effect of ARNI compared with ramipril was similar in those who were and were not taking MRA (hazard ratio [HR]MRA 0.96, 95% confidence interval [CI] 0.77–1.19 and HRMRA– 0.87, 95% CI 0.71–1.05, for the primary endpoint; p = 0.51 for interaction [Clinical Endpoint Committee adjudicated]); similar findings were observed if investigator‐reported endpoints were evaluated (p = 0.61 for interaction). Conclusions: Use of a MRA did not modify safety or clinical endpoints related to initiation of ARNI compared to ramipril in the post‐MI setting in patients with LVSD and/or congestion. [ABSTRACT FROM AUTHOR]

Aims: We sought to evaluate the mechanism of angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan therapy and compare it with a valsartan‐only control group in patients with heart failure with reduced ejection fraction (HFrEF). Methods and results: The study was a phase IV, prospective, randomized, double‐blind, parallel‐group study in patients with New York Heart Association class II–III heart failure and left ventricular ejection fraction (LVEF) ≤35%. During a 6‐week run‐in period, all patients received valsartan therapy, which was up‐titrated to the highest tolerated dose level (80 mg bid or 160 mg bid) and then randomized to either valsartan or sacubitril/valsartan. Myocardial oxygen consumption, energetic efficiency of cardiac work, cardiac and systemic haemodynamics were quantified using echocardiography and 11C‐acetate positron emission tomography before and after 6 weeks of therapy (on stable dose) in 55 patients (ARNI group: n = 27, mean age 63 ± 10 years, LVEF 29.2 ± 10.4%; and valsartan‐only control group: n = 28, mean age 64 ± 8 years, LVEF 29.0 ± 7.3%; all p = NS). The energetic efficiency of cardiac work remained unchanged in both treatment arms. However, both diastolic (−4.5 mmHg; p = 0.026) and systolic blood pressure (−9.8 mmHg; p = 0.0007), myocardial perfusion (−0.054 ml/g/min; p = 0.045), and left ventricular mechanical work (−296; p = 0.038) decreased significantly in the ARNI group compared to the control group. Although myocardial oxygen consumption decreased in the ARNI group (−5.4%) compared with the run‐in period and remained unchanged in the control group (+0.5%), the between‐treatment group difference was not significant (p = 0.088). Conclusions: We found no differences in the energetic efficiency of cardiac work between ARNI and valsartan‐only groups in HFrEF patients. However, ARNI appears to have haemodynamic and cardiac mechanical effects over valsartan in heart failure patients. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to investigate the efficacy and safety of sacubitril/valsartan in abnormal renal function (eGFR < 60ml/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 60ml/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. [ABSTRACT FROM AUTHOR]

Introduction: Mycophenolate mofetil (MMF), an inactive prodrug of mycophenolic acid (MPA), is an immunosuppressive drug used widely in the treatment of lupus nephritis. In this case report, the area under the blood concentration time curve (AUC) of MPA was significantly decreased by the concomitant use of sacubitril/valsartan. Case Presentation: The patient was a man in his 40s with a diagnosis of lupus nephritis class IVa/c+V. MMF dose was 1.5 g/day at admission, and AUC of MPA on day 14 was 25.1 μg⋅h/mL. Owing to poor blood pressure control, sacubitril/valsartan was initiated at 97/103 mg/day on day 29. On day 37, AUC of MPA was significantly decreased to 8.7 μg⋅h/mL, suggesting drug interaction with the newly initiated sacubitril/valsartan. Sacubitril/valsartan was decreased to 49/51 mg/day, and AUC of MPA on day 67 was 37.6 μg⋅h/mL, achieving the target range. The final MMF dose was set at 1.75 g/day. A possible mechanism of drug interaction between sacubitril/valsartan and MPA involves an organic anion transporting polypeptide (OATP). The inhibition of OATPs by sacubitril may have interrupted the enterohepatic circulation of MPA, resulting in a lower plasma concentration. Conclusion: Since lupus nephritis is often associated with hypertension, the drug interaction observed in this report may also occur in other cases. However, it is impossible to conclude that the decrease in plasma MPA levels was due to the concomitant use of sacubitril/valsartan, and more cases and basic findings are needed. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the clinical effectiveness of beta-blockers (BBs) and renin-angiotensin-aldosterone system (RAAS) inhibitors in chronic heart failure with preserved ejection fraction (HFpEF). Methods: 100 patients with HFpEF admitted to The Third Affiliated Hospital of Qiqihar Medical University, China, between April and June 2023 were stratified into five groups. Beta-blocker (BB) group received bisoprolol, angiotensin-converting enzyme inhibitor (ACEI) group received benazepril hydrochloride, angiotensin II receptor blocker (ARB) group received candesartan, angiotensin receptor neprilysin inhibitor (ARNI) group received sacubitril valsartan, and mineralocorticoid receptor antagonist (MRA) group received spironolactone. Differences in clinical effectiveness, six-minute walking distance (6MWD), cardiac functionality, quality of life, and survival rate were compared among the groups. Results: Beta-blocker group showed the highest efficacy. After treatment, all groups except MRA showed significant improvement in 6MWD. Also, ACEI, ARB, and ARNI groups exhibited significantly longer 6 MWD than MRA group (p < 0.05). Left ventricular ejection fraction levels showed significant improvement in the ACEI, ARNI, and MRA groups (p < 0.05), while pulmonary artery pressure (PAP) decreased in the BB, ACEI, ARNI, and MRA groups (p < 0.05). After treatment, the Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores of BB, ACEI, ARB, and ARNI groups were significantly lower than before treatment (p < 0.05). All five groups significantly exhibited decline in NTproBNP levels after treatment (p < 0.05). However, at 18-month follow-up, there was no significant difference in survival rates among the groups (p > 0.05). Conclusion: Beta-blockers (BBs) and RAAS inhibitors show promising activity in HFpEF, bisoprolol enhances cardiac function, benazepril improves symptoms, candesartan aids exercise and sacubitril valsartan elevates cardiac class. However, none of these drugs significantly improves clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: 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. [ABSTRACT FROM AUTHOR]

Objectives: Heart failure (HF) is a serious disease associated with increased morbidity and mortality. Hepatic dysfunction secondary to hepatic congestion and ventricular arrhythmia (VA) are frequently observed in patients with HF. The albuminbilirubin (ALBI) score, which predicts liver damage, is a parameter that has been used in patients with HF in recent years. In this study, we investigated the predictive value of the ALBI score in detecting VA in patients with HF. Materials and Methods: This study was planned as a single-center retrospective study. The study included 150 consecutive HF patients with reduced ejection fraction who had an implantable cardioverter-defibrillator. The ALBI score was calculated using the following formula: [log10 TB (mg/dL) × 0.66] + [albumin (g/dL) × -0.085]. Patients were divided into two groups: those with and without VA. A receiver operator characteristic (ROC) curve analysis was used to define the cut-off level of the ALBI score to predict VA. Results: The mean age of the group was 55.3±10.8 years, and 78.7% of the patients were male. 28 patients (18.7%) had VAs. Male gender and HF hospitalization in the previous year were more common in the arrhythmia group. ALBI score was higher in the arrhythmia group (p<0.001). Sacubitril-valsartan and digoxin use were higher in the arrhythmia group, whereas beta-blocker and statin use were higher in the non-arrhythmia group. In multivariate logistic regression analysis, the ALBI score was found to be an independent predictor of VA. Male gender, hospitalization in the previous year, sacubitril-valsartan use, and digoxin use were other independent predictors of VA. ALBI score at a cut-off point of -3.66, predicts ventricular tachycardia with 74% sensitivity and 70% specificity in ROC curve analysis (area under the curve=0.732, p<0.001). Conclusion: The ALBI score is associated with VA in patients with HF. It can be easily assessed and used as a predictor of VA in this patient group. [ABSTRACT FROM AUTHOR]

The aim of this study is to evaluate the cost-effectiveness of 2 different therapies of cardiomyopathy (CM) after COVID -19. The focus of the study is fixed dose combination (FDC) of sacubitril/valsartan and standard therapy in Kazakhstan. This is written from the point of view of the health insurance institution. Information for the age, gender, CM therapy, number of hospitalizations, COVID-19 infection, and past cardiovascular surgeries of 237 patients with incidents of CM which required a hospitalization after a COVID-19 infection was collected. Selected patients were divided into two groups: the cost of FDC and standard therapy and the annual cost of their therapy was calculated. The incremental cost-effectiveness ratio was calculated by dividing the cost of medication therapy by the number of hospitalizations between the two compared groups. Robustness of the results was tested with deterministic and probabilistic sensitivity analyses. The study was performed in City cardiology centre of Almaty in Kazakhstan during 2020-2022. Results show that FDC is more costly but more effective, leading to fewer hospitalizations. ICER accounts for €-2,743.08 per hospitalization saved in the group on FDC vs standard of therapy. Sacubitril/valsartan is cost-effective in ambulatory conditions in comparison with standard therapy of cardiomyopathy after COVID-19 leading to savings due to the decrease in the number of hospitalizations. [ABSTRACT FROM AUTHOR]

Data on angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan (SV) in patients undergoing maintenance dialysis is scarce. Our study aimed to investigate the effect of SV on patients undergoing dialysis. We retrospectively reviewed the data of end-stage kidney disease (ESRD) patients undergoing either peritoneal dialysis (PD) or hemodialysis (HD) in our center. A total of 51 patients receiving SV treatment were enrolled in the SV group. Another 51 age and sex-matched patients on dialysis without SV treatment were selected as the control group. All the patients were regularly followed up in the dialysis clinic. Their clinical, biochemical, and echocardiographic parameters were all recorded at baseline and during follow-up. The effect and safety of SV were further analyzed. A total of 102 ESRD patients on dialysis (51 patients in the SV group and 51 patients in the control group) were finally enrolled. The median follow-up time was 349 days (interquartile range [IQR]: 217–535 days). The level of B-type natriuretic peptide (BNP) (median [IQR] before and after SV treatment: 596.35 pg/ml [190.6–1714.85] vs. 188.7 pg/ml [83.34–600.35], p < 0.001) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) (median [IQR]: 6316.00 pg/ml [4552.00–28598.00] vs. 5074.00 pg/ml [2229.00–9851.00], p = 0.022) were significantly decreased after treatment with SV. The variant rate of left ventricular ejection fraction (LVEF) was significantly higher in the SV group compared to the control group, especially in the PD subgroup. No significant difference was found in other echocardiographic parameters between SV and control group. Subgroup analysis of the PD group showed an increase in daily PD ultrafiltration (median [IQR]: 400 ml/d [200-500] vs. 500 ml/d [200–850], p = 0.114) after SV treatment. Variant rate of overhydration (OH) measured by the body composition monitor (BCM) of the SV group were significantly different from the control group (median [IQR]: −13.13% [−42.85%–27.84%] vs. 0% [−17.95%–53.85%], p = 0.049). The rate of hyperkalemia was slightly higher but without significant difference before and after the introduction of SV (19.6% vs. 27.5%, p = 0.350). No event of hypotension and angioedema were observed. SV might have a cardio-protective role in ESRD patients undergoing dialysis, especially in PD patients. Serum potassium should be monitored during the treatment. [ABSTRACT FROM AUTHOR]

Background and objective: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and soluble interleukin 1 receptor-like 1 ST2 (sST2) are biomarkers used to grade heart failure with reduced ejection fraction (HFrEF) severity. Both are potential targets of HFrEF treatment, but the first is associated with the patient's hemodynamic status, while the second is more indicative of the inflammatory status and of myocardial fibrosis. The aim of this study was to assess the kinetics of these biomarkers after treatment with sacubitril/valsartan in HFrEF. Methods: We analyzed blood samples of patients with HFrEF at baseline (before sacubitril/valsartan treatment), after 1, 2, and 3 months (respectively, after a month taking the 24/26 – 49/51 – 97/103 mg twice daily, or b.i.d., doses), and 6 months after the maximum-tolerated dose was reached (end study). Results: We obtained samples from 72 patients with HFrEF (age 64.0 ± 10.5 years, 83% males). NT-proBNP and sST2 values progressively and significantly reduced to 37% and 16%, respectively, with a greater reduction for NT-proBNP (p < 0.001). Specifically, NT-proBNP reduced from 1144 [593–2586] pg/mL to 743 [358–1524] pg/mL and sST2 from 27.3 [20.5–35.0] ng/mL to 23.1 [15.9–30.7] ng/mL, p for trend < 0.001 in both cases. The reduction of the two biomarkers over time occurred with statistically significant different kinetics: deferred for sST2 and faster for NT-proBNP. No significant changes in renal function and potassium levels were recorded. Conclusion: These findings suggest that, in patients with HF, sacubitril/valsartan effects on the cardiovascular system share a double pathway: a first, hemodynamic, faster pathway and a second, non-hemodynamic anti-fibrotic, delayed one. Both likely contribute to the sacubitril/valsartan benefits in HFrEF. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the association between red blood cell distribution width (RDW) changes and major adverse cardiovascular event (MACE) occurrences during sacubitril/valsartan treatment in patients with heart failure with reduced ejection fraction (HFrEF).Methods: This study retrospectively analyzed the medical records of patients with HFrEF hospitalized from April 2018 to February 2021. The patients were divided into two groups according to the inclusion of sacubitril/valsartan in the personal drug treatment regimen, the traditional and the sacubitril/valsartan group. RDW values before and after sacubitril/valsartan treatment were recorded respectively as RDW1 and RDW2. ΔRDW was defined as the difference between RDW2 and RDW1. The patients in the sacubitril/valsartan group were divided into two subgroups according to ΔRDW > 0 or ≤ 0. MACEs, such as readmission for HF, acute myocardial infarction, ischemic stroke, and malignant arrhythmia and death, were recorded during the 1-year follow-up period in each group.Results: MACE development was lower in patients treated with sacubitril/valsartan than those treated with conventional therapy (log-rank, P< 0.001). The incidence of cardiac events during the follow-up period was greater in the group with ΔRDW > 0 than in the group with ΔRDW ≤ 0 (Breslow, P< 0.001). Increased RDW was associated with a higher likelihood of developing MACE than decreased RDW (odds ratio [OR] =2.055, 95% confidence interval [CI]:1.301– 3.246), and the risk of developing MACE increased by 22.1% for each unit increase in RDW (OR=1.221, 95% CI:1.074– 1.389).Conclusion: Sacubitril/valsartan treatment is effective in reducing the risk of MACEs in HFrEF. Additionally, RDW changes are predictors of MACEs after sacubitril/valsartan treatment. [ABSTRACT FROM AUTHOR]

BackgroundPeripartum cardiomyopathy (PPCM) is a common cause of heart failure (HF) in the peripartum. Some medications are considered safe while breastfeeding. However, sacubitril/valsartan (Entresto), while efficacious, is not recommended in breastfeeding women due to concerns about adverse infant development, and no published data suggest otherwise.ObjectivesThis study aimed to assess the transfer of sacubitril/valsartan into human milk and evaluate the infant’s risk of drug exposure.MethodsThe InfantRisk Human Milk Biorepository released samples and corresponding health information from five breastfeeding maternal–infant dyads exposed to sacubitril/valsartan. Sacubitril, valsartan, and LBQ657 (sacubitril active metabolite) concentrations were determined using liquid chromatography-mass spectrometry (LC/MS/MS) from timed samples 0, 1, 2, 4, 6, 8, 10, and 12 h following medication administration at steady state conditions.ResultsValsartan levels were below the detection limit of 0.19 ng/mL in all milk samples. Sacubitril was measurable in all milk samples of the five participants, peaking 1 h after drug administration at a mean concentration of 1.52 ng/mL for a total infant dose of 0.00049 mg/kg/12 h and a relative infant dose (RID) calculated at 0.01%. The maximum concentration of its active metabolite LBQ657 in the milk samples was observed 4 h after medication administration and declined over the remaining 12-h dosing interval, for an average concentration of 9.5 ng/mL. The total infant dose was 0.00071 mg/kg/12 h, and the RID was 0.22%. Two mothers reported continuing to breastfeed while taking sacubitril/valsartan; both mothers stated observing no negative effects in their breastfed infants.ConclusionThe transfer of sacubitril/valsartan into human milk is minimal. These concentrations are unlikely to pose a significant risk to breastfeeding infants, with a combined calculated RID of

A study published in the European Journal of Heart Failure compared the effectiveness of sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor (ARNI), with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB) in patients with newly diagnosed heart failure (HF) and preserved or mildly reduced ejection fraction. The study used a large real-world dataset from the United States and found that patients initiated on sacubitril/valsartan had significantly lower rates of all-cause and cardiovascular hospitalizations compared to those initiated on ACEi/ARB. These findings support the potential benefit of early initiation of sacubitril/valsartan in a diverse and high-risk HF population. However, the study acknowledges limitations, including its retrospective nature and the possibility of unmeasured confounding. The study was funded by Novartis AG, and some of the authors reported conflicts of interest. [Extracted from the article]

Medication adherence in chronic conditions is a long-term process. Modeling longitudinal trajectories using routinely collected prescription data is a promising method for describing adherence patterns and identifying at-risk groups. The study aimed to characterize distinct long-term sacubitril/valsartan adherence trajectories and factors associated with them in patients with heart failure (HF). Subjects with incident HF starting sac/val in 2017–2018 were identified from the Campania Regional Database for Medication Consumption. We estimated patients' continuous medication availability (CMA9; R package AdhereR) during a 12-month period. We selected groups with similar CMA9 trajectories (Calinski-Harabasz criterion; R package kml). We performed multinomial regression analysis, assessing the relationship between demographic and clinical factors and adherence trajectory groups. The cohort included 4455 subjects, 70% male. Group-based trajectory modeling identified four distinct adherence trajectories: high adherence (42.6% of subjects; CMA mean 0.91 ± 0.08), partial drop-off (19.6%; CMA 0.63 ± 0.13), moderate adherence (19.3%; CMA 0.54 ± 0.11), and low adherence (18.4%; CMA 0.17 ± 0.12). Polypharmacy was associated with partial drop-off adherence (OR 1.194, 95%CI 1.175–1.214), while the occurrence of ≥1 HF hospitalization (OR 1.165, 95%CI 1.151–1.179) or other hospitalizations (OR 1.481, 95%CI 1.459–1.503) were associated with low adherence. This study found that tailoring patient education, providing support, and ongoing monitoring can boost adherence within different groups, potentially improving health outcomes. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a significant event for public health. It has a prevalence between 1-2%, mortality rate between 7-17%, and hospitalization between 32-44%. This implies a risk to health and quality of life, but also great financial efforts for health systems. Sacubitril/valsartan is a medication recognized for its efficacy, and this consensus seeks to synthesize the available information regarding its use for the benefit of patients. This document consists of a description of the epidemiology of HF, pharmacology of the drug, clinical trials, use of the drug in cases with reduced ejection fraction, mildly reduced ejection frac- tion and preserved ejection fraction, available literature on HF guidelines, recommendations and conclusions. [ABSTRACT FROM AUTHOR]