Association between treatment with sacubitril/valsartan and the risk of Alzheimer's disease: a clinical update.

Since 2014, sacubitril/valsartan (Entresto®) is widely prescribed for heart failure. Despite neprilysin inhibition's benefits in heart failure, concerns about potential amyloid-beta (Aß) 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.

Sacubitril/Valsartan Versus Enalapril in Chronic Chagas Cardiomyopathy: Rationale and Design of the PARACHUTE-HF Trial.

Chronic Chagas cardiomyopathy (CCC) has unique pathogenic and clinical features with worse prognosis than other causes of heart failure (HF), despite the fact that patients with CCC are often younger and have fewer comorbidities. Patients with CCC were not adequately represented in any of the landmark HF studies that support current treatment guidelines. PARACHUTE-HF (Prevention And Reduction of Adverse outcomes in Chagasic Heart failUre Trial Evaluation) is an active-controlled, randomized, phase IV trial designed to evaluate the effect of sacubitril/valsartan 200 mg twice daily vs enalapril 10 mg twice daily added to standard of care treatment for HF. The study aims to enroll approximately 900 patients with CCC and reduced ejection fraction at around 100 sites in Latin America. The primary outcome is a hierarchical composite of time from randomization to cardiovascular death, first HF hospitalization, or relative change from baseline to week 12 in NT-proBNP levels. PARACHUTE-HF will provide new data on the treatment of this high-risk population. (Efficacy and Safety of Sacubitril/Valsartan Compared With Enalapril on Morbidity, Mortality, and NT-proBNP Change in Patients With CCC [PARACHUTE-HF]; NCT04023227).

Trajectories of Sacubitril/Valsartan Adherence Among Medicare Beneficiaries With Heart Failure.

Background: Sacubitril/valsartan, an angiotensin receptor/neprilysin inhibitor (ARNi), improves heart failure (HF) outcomes, yet real-world adherence patterns are not well understood. Objectives: The purpose of this study was to analyze longitudinal patterns of adherence to ARNis in patients with HF and to identify factors associated with adherence patterns. Methods: Using Medicare beneficiaries from 2015 to 2018, we included patients diagnosed with HF who initiated an ARNi. A group-based trajectory model was constructed to identify adherence patterns during follow-up. We used multivariable logistic regression to investigate factors associated with membership in each adherence trajectory group. Results: Among 9,475 eligible beneficiaries (age 77 ± 7 years, 34% female), we identified 5 distinct ARNi adherence trajectories, characterized as: immediate discontinuers, who discontinued treatment within the first 3 months (12%); early discontinuers, who discontinued treatment in months 4 to 7 (10%); late discontinuers, who discontinued treatment in months 7 to 10 (12%); intermittently adherent patients (12%); and consistently adherent patients (54%). The first 4 groups were collectively categorized as nonconsistent adherents. Living in a socioeconomically disadvantaged area, ie, a county with the top 20% of Area Deprivation Index (adjusted OR [aOR]: 1.12 [95% CI: 1.00-1.24]) and Black race (aOR: 1.36, [95% CI: 1.18-1.56]) were associated with a higher likelihood of being nonconsistently adherent. Receiving prescriptions from a cardiologist (aOR: 0.64 [95% CI: 0.57-0.73]) was associated with a lower likelihood of suboptimal ARNi adherence. Conclusions: Half of ARNi users were not consistently adherent to the drug in the first year after treatment initiation. There exist significant racial and socioeconomic inequities in longitudinal adherence to ARNi.

Impact of new drug releases on heart failure management and hospitalizations in France: A repeated cross-sectional study between 2014 and 2023.

Real-life data on the impact of sacubitril-valsartan and sodium-glucose cotransporter type 2 (SGLT-2) inhibitors on heart failure (HF) in France is lacking. Using French health insurance databases, we examined the ten-year evolution in HF medication use, focusing on SGLT-2 inhibitors and sacubitril/valsartan, and incidence of HF hospitalizations during the same period. We conducted a repeated cross-sectional study using medical-administrative data from French health insurance databases between 2014 and 2023. These included "OpenMedic" for outpatient medication reimbursements and "ScanSanté" for annual hospitalization data. Medications were classified using ATC codes, and hospitalizations were identified using ICD-10 codes. Statistical analyses encompassed annual rates of users and boxes dispensed for HF medications, along with HF, ischemic heart disease and ischemic stroke hospitalization rates. Prevalence of SGLT-2 inhibitors and sacubitril-valsartan use was also studied regionally, with direct standardization by age and sex, with the French population as the standard population. Between 2014 and 2023, HF drug use increased significantly, with beta-blockers and ACE inhibitors/ARBs leading in prevalence of use. ARNi and SGLT-2 inhibitors, introduced later, showed remarkable rises: +506% and +3766% in users since their market introduction, respectively. Meanwhile, HF hospitalizations slightly increased by +3.6% between 2016 and 2019, followed by a notable decline of -12.5% during 2019-2023, coinciding with the introduction of SGLT-2 inhibitors. In contrast, hospitalizations for ischemic heart disease rose by 11.6% over the period 2016-2019 and by +5.2% over the period 2019-2023, and hospitalizations for ischemic stroke rose by 8.2% over the period 2016-2019 and declined by -0.6% over the period 2019-2023. We observed regional disparities in SGLT-2 inhibitors use, with prevalence ranging from 0.9% in Bretagne to 1.5% in Hauts-de-France. The data suggests a temporal correlation between the increase in SGLT-2 inhibitors use and the decline in HF hospitalizations since 2019. More studies are needed to measure real life effectiveness of SGLT-2 inhibitors in heart failure.

Comparison of the Efficacy of Propranolol Versus Valsartan in the Prevention of Migraine: A Randomized Controlled Trial.

BACKGROUND: Migraine is a prevalent episodic headache that affects approximately 14%-15% of the global population. Since valsartan is an antihypertensive drug, it is hypothesized that taking valsartan can prevent migraine attacks in patients with the condition. This study aimed to determine the efficacy of propranolol versus valsartan in preventing migraine attacks. MATERIAL AND METHODS: This randomized controlled trial was conducted on 56 patients with migraine from a neurology clinic. Patients were divided into two equal groups of 28 individuals, after providing informed consent. The patients then received either propranolol or valsartan treatment. The intensity and frequency of migraines were compared before and after treatment in both study groups. RESULTS: The patients' mean age was 32.78 years old (±6.9 SD), and 64% of the patients were female. After a 1-month treatment period, the results showed that valsartan patients experienced significantly fewer severe migraine attacks compared to propranolol patients. CONCLUSION: According to the results of the present study, valsartan may be at least as effective as propranolol and perhaps more effective on some measures.

Analysis of the PARAGON-HF Study Results Using Win Ratio.

BACKGROUND: The PARAGON-HF study (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction) investigated the effect of sacubitril-valsartan in heart failure (HF) with preserved ejection fraction. The results, which were analyzed using conventional statistical methods, did not find a significant reduction in the primary composite end point of cardiovascular death and total hospitalization for HF. Recent clinical trials used win ratio statistics that enable the incorporation of multiple outcome aspects into the primary end point and can detect positive outcomes with fewer patients. In this study, we assessed the effect of sacubitril-valsartan on outcomes using the win ratio to analyze results from patients included in the PARAGON-HF study. METHODS: In the PARAGON-HF study, 4822 patients with HF with preserved ejection fraction were randomized either to sacubitril-valsartan or valsartan groups. In the present study, the primary outcome was a hierarchical composite of time to cardiovascular death, total number of hospitalization for HF, time to first hospitalization for HF, time to renal composite outcome, and change in the Kansas City Cardiomyopathy Questionnaire total symptom score at 8 months analyzed using a win ratio statistical model. RESULTS: Using this approach, we found that a greater number of patients who received sacubitril-valsartan experienced clinical benefits compared with those who received valsartan (win ratio, 1.13 [95% CI, 1.04-1.23]; P=0.005). This clinical advantage was evident in patients regardless of whether the left ventricular ejection fraction was above or below the median, that is, the left ventricular ejection fraction of 57%, and regardless of sex (Pinteraction=0.76 for the left ventricular ejection fraction and 0.73 for sex). CONCLUSIONS: Employing the innovative win ratio approach, sacubitril-valsartan demonstrated significant clinical benefits among patients with HF with preserved ejection fraction. Notably, this benefit was observed irrespective of left ventricular ejection fraction and sex. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

A real-world disproportionality analysis of sacubitril/valsartan: data mining of the FDA adverse event reporting system.

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/valsartan-associated 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.

Empagliflozin combined with sacubitril/valsartan in hypertensive patients with heart failure: a retrospective study of efficacy and effect on blood pressure variability and cardiac function.

OBJECTIVE: To evaluate the efficacy of empagliflozin combined with sacubitril/valsartan in treating hypertensive patients with heart failure (HF), focusing on its effects on blood pressure variability (BPV) and cardiac function. METHODS: This retrospective study included 101 patients with hypertension and heart failure with reduced ejection fraction treated at Baoji High-Tech Hospital from October 2021 to October 2023. Patients were divided into two groups: an observation group (n=51), treated with both empagliflozin and sacubitril/valsartan, and a control group (n=50), treated with sacubitril/valsartan alone. We compared the therapeutic effects, BPV (including 24-hour, daytime, and nighttime systolic and diastolic BPV), cardiac function indicators, levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) before and after treatment, and the incidence of adverse reactions between the groups. Independent risk factors affecting treatment efficacy were also analyzed. RESULTS: The total effective rate of treatment in the observation group was significantly higher than in the control group (P<0.05). Both groups showed reductions in daytime and nighttime systolic and diastolic BPV after treatment, with the observation group displaying more pronounced improvements (all P<0.05). Enhancements in cardiac ultrasound measurements, NT-proBNP levels, and cTnI levels were more significant in the observation group compared to the control group post-treatment (both P<0.05). There was no significant difference in the incidence of adverse reactions during treatment between the two groups (P>0.05). Age and comorbid diabetes were identified as independent risk factors for poor prognosis, while treatment with empagliflozin combined with sacubitril/valsartan was a protective factor. CONCLUSION: Empagliflozin combined with sacubitril/valsartan significantly enhances treatment efficacy in hypertensive patients with heart failure, effectively improves cardiac function and BPV, and demonstrates good safety.

Pseudo-nephropathy and hyper-excretion of urinary C-peptide: an overlooked adverse effect of an angiotensin receptor-neprilysin inhibitor (ARNI).

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.

Novel Therapies for the Treatment of Cardiovascular Disease.

Over the last decade, randomized clinical trials of several pharmacologic agents have demonstrated a reduction in cardiovascular mortality and other important secondary outcomes. Angiotensin-Neprilysin Inhibitors and Sodium-Glucose Co-transporter 2 inhibitors have now become pillars in the treatment of heart failure. Ivabradine is a negative chronotropic agent used as an adjunctive therapy in patients with heart failure. Two new hypertension therapies, zilebresiran and aprocitentan, are currently in investigational stages. Finally, mavacamten has emerged as a pharmacologic treatment for hypertrophic obstructive cardiomyopathy. Practitioners must be familiar with the indications and side effects of newer therapies as they are now frequently prescribed.

Anti-atrial Fibrillatory and Cardiorenal Protective Effects of the Combination of Valsartan and Cilnidipine in Dahl Salt-Sensitive Rats.

The current study aimed to investigate the anti-atrial fibrillatory (AF) effects of a combination of valsartan and a calcium channel blocker (cilnidipine or amlodipine) in Dahl salt-sensitive (Dahl S) rats. Seven-week-old male Dahl S rats were fed an 8% salt diet. Six weeks later, valsartan (60 mg/kg, Val group), cilnidipine + valsartan (10 + 60 mg/kg, CV group), amlodipine + valsartan (3 + 60 mg/kg, AV group), or vehicle was orally administered daily for 5 weeks. Echocardiography and atrial electrophysiological evaluations were performed on the last day of treatment. Blood pressure in each drug treatment group was lower than in the Vehicle group. The duration of AF induced by atrial burst stimulation was shorter in the Val group (3.2 ± 1.6 s) than in the Vehicle group (11.2 ± 6.0 s), which was further shortened in the CV and AV groups (1.1 ± 0.3 and 1.3 ± 0.3 s, respectively). Left ventricular ejection fraction and left ventricular fractional shortening were greater in the CV and AV groups than those in the Vehicle group. Urinary albumin excretion in the CV group was the lowest among the drug-treated groups. The results collectively suggest that the combination of a calcium channel blocker with valsartan could be useful in terms of its anti-AF action as well as for improving cardiac and renal functions.

Acute changes in kidney function and outcomes following an acute myocardial infarction: Insights from PARADISE-MI.

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.

Comparison of the Efficacy and Safety of Sacubitril/Valsartan and Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers in Patients With Reduced Ejection Fraction Combined With Moderate-to-Severe Chronic Kidney Disease.

Background and Objectives: The efficacy and safety of a lower target dose of sacubitril/valsartan (angiotensin receptor neprilysin inhibitor [ARNI]) for treating heart failure with reduced ejection fraction (HFrEF) in Chinese patients with moderate-to-severe chronic kidney disease (CKD) remain unknown. We performed a retrospective study to compare the efficacy of ARNI with that of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) in patients with HFrEF and moderate-to-severe CKD. Methods: This retrospective study included 129 patients. An inverse probability of treatment weighting (IPTW) analysis was performed to compare the baseline characteristics and outcomes between the 2 groups. The incidence of death due to cardiovascular disease, rehospitalization due to heart failure after treatment, and improvement in cardiac function symptoms (New York Heart Association [NYHA]) were assessed after 12 months. Improvements of ejection fraction (EF), N-terminal pro-brain natriuretic peptide (NT-proBNP) level, left ventricular end-systolic diameter (LVESD), and left ventricular end-diastolic diameter (LVEDD) were compared. Results: Compared with the ACEI/ARB group, the ARNI group, with 90.77% (59/65) in the lower target dose group, showed a lower rate of death due to cardiovascular disease (6.6% vs 0.9% after IPTW) and a lower incidence of rehospitalization (46.5% vs 30.4% after IPTW). NYHA class, estimated glomerular filtration rate, EF, NT-ProBNP levels, LVEDD, and LVESD improved in the ARNI group. None of the patients withdrew from treatment because of adverse drug reactions. Conclusion: Our study showed that ARNI resulted in a greater improvement in heart failure than ACEIs/ARBs in patients with HFrEF and moderate-to-severe CKD.

Effects of Heart Failure Therapies on Atrial Fibrillation: Biological and Clinical Perspectives.

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.

Effects of sacubitril-valsartan on aging-related cardiac dysfunction.

Heart failure (HF) remains a huge medical burden worldwide, with aging representing a major risk factor. Here, we report the effects of sacubitril/valsartan, an approved drug for HF with reduced EF, in an experimental model of aging-related HF with preserved ejection fraction (HFpEF). Eighteen-month-old female Fisher 344 rats were treated for 12 weeks with sacubitril/valsartan (60 mg/kg/day) or with valsartan (30 mg/kg/day). Three-month-old rats were used as control. No differential action of sacubitril/valsartan versus valsartan alone, either positive or negative, was observed. The positive effects of both sacubitril/valsartan and valsartan on cardiac hypertrophy was evidenced by a significant reduction of wall thickness and myocyte cross-sectional area. Contrarily, myocardial fibrosis in aging heart was not reduced by any treatment. Doppler echocardiography and left ventricular catheterization evidenced diastolic dysfunction in untreated and treated old rats. In aging rats, both classical and non-classical renin-angiotensin-aldosterone system (RAAS) were modulated. In particular, with respect to untreated animals, both sacubitril/valsartan and valsartan showed a partial restoration of cardioprotective non-classical RAAS. In conclusion, this study evidenced the favorable effects, by both treatments, on age-related cardiac hypertrophy. The attenuation of cardiomyocyte size and hypertrophic response may be linked to a shift towards cardioprotective RAAS signaling. However, diastolic dysfunction and cardiac fibrosis persisted despite of treatment and were accompanied by myocardial inflammation, endothelial activation, and oxidative stress.

Protein-Losing Enteropathy in the Failing Fontan: Treatment With Angiotensin Receptor Neprilysin Inhibitor.

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.

Impact of Sacubitril/ Valsartan on quality of life and ejection fraction of heart failure patients with and without chronic kidney disease.

Objective: Chronic kidney disease (CKD) patients are at high risk of heart failure (HF) and both share similar risk factors, including diabetes and elevated blood Pressure (B.P). Aim of this study was to determine the impact of sacubitril/valsartan on the quality of life (QOL) and ejection fraction (EF) of patients with HF with and without CKD. Methods: Single center (Doctors Hospital Lahore), observational study with longitudinal follow up, on 104 HF patients from July 2019 to July 2020. HF was diagnosed on both clinical and echo parameters. New York Heart Association Class II-IV, EF less than or equal to 40% HF with reduced EF and stage three CKD patients were included. Sacubitril/Valsartan was prescribed at a starting daily dose of 50mg and then up titrated to 400mg. Patients were followed up with clinical evaluation, QOL assessment, echocardiography and biochemical profile at one, four, eight and 12 months. Results: Gender, age, and diabetes mellitus between CKD and non-CKD patients were noted to be statistically different, defined as p<0.05. CKD patients' QOL increased from 45.15 to 57.57 from baseline to 12 months (p-value<0.01). Non-CKD patients' QOL increased from 48.07 to 56.25. In CKD patients, EF increased from 27.87% to 29.29% from baseline to 12 months (p-value 0.03) whereas in non-CKD patients EF improved from 29.42% to 31.43%. Conclusion: Sacubitril/ valsartan improves QOL in patients of HF with reduced EF both with and without CKD. Clinical improvement was independent of Left Ventricular EF as measured by QOL. Thus, QOL is a useful tool to assess the drug's beneficial effect.

Roselle (Hibiscus sabdariffa L.) extract as an adjunct to valsartan in patients with mild chronic kidney disease: A double-blind randomized controlled clinical trial.

Objective: The objective of this study was to evaluate the effectiveness of Hibiscus sabdariffa L. extract (HS) as an adjunct to valsartan in the treatment of high blood pressure in patients with mild chronic kidney disease (CKD). Materials and Methods: This trial was conducted in Gorgan, Iran. Seventy-two participants with CKD and high blood pressure were randomly assigned to either the HS group, receiving a 350 mg pill every 12 hr for 90 days along with 40 mg of valsartan every 12 hr, or the control group (40 mg valsartan + 12.5 mg hydrochlorothiazide). The primary objective was to assess the improvement of hypertension, while secondary objectives included the evaluation of proteinuria, albuminuria, kidney function, lipid profile, and electrolyte levels. Molecular docking analysis was performed to examine the mechanisms of action of the isolated components of HS. Results: Out of 80 initial participants, 72 were included in the analysis. Both groups showed a significant reduction in blood pressure (p<0.001). The HS group demonstrated a statistically significant decrease in lipid profile (p<0.001). There were no statistically significant differences between the groups regarding the reduction of renal markers. Molecular docking analysis revealed that the compounds present in HS, particularly its anthocyanins and flavonoids, exhibited greater angiotensin-converting enzyme (ACE) inhibitory potential than hydrochlorothiazide in both domains. Moreover, the compounds met the criteria for drug likeness and Lipinski rules. Conclusion: Adjunctive therapy with HS showed promising results in reducing hypertension and improving lipid profile in patients with CKD.

Sacubitril/Valsartan Improves Cardiac Function in Dialysis Patients.

Heart failure (HF) is characterized by the activation of adverse neurohormonal systems and a high mortality rate. Noteworthy, HF is a well-known complication of chronic kidney disease (CKD), especially in end-stage kidney disease (ESKD), where dialysis patients are seven to eight times more likely to encounter cardiac arrest than the general population. Therefore, it is important to develop efficient treatments to improve cardiac function in dialysis patients and eventually reduce the cardiovascular death toll. Sacubitril/valsartan (Sac/Val) is a dual inhibitor/blocker of the neprilysin and angiotensin II receptors, which exert cardioprotective effects among patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved EF (HFpEF). Unfortunately, the drug is not approved for subjects with advanced CKD or dialysis patients due to safety concerns. The current study examined the cardiac effects of Sac/Val in HD patients. Administration of Sac/Val (100-400 mg/day) to 12 hemodialysis (HD) patients with HFrEF for six months gradually improved ejection fraction (EF) independently of morphological changes in cardiac geometry, as assessed by echocardiography (ECHO), and hemodynamic alterations. Interestingly, the Cardiomyopathy Questionnaire (Kansas City KCCQ-12) revealed that quality of life significantly improved after Sac/Val treatment. No major adverse effects were reported in the present study, supporting the safety of Sac/Val at least in these patients and for the applied follow-up period. Collectively, these findings support the use of Sac/Val as a cardioprotective agent in both HD and peritoneal dialysis (PD) patients. Yet, a more comprehensive study is required to establish these findings and to extend the follow-up period for 12 months in order to solidify these encouraging results.

Status and timing of angiotensin receptor-neprilysin inhibitor implementation in patients with heart failure and reduced ejection fraction: Data from the Swedish Heart Failure Registry.

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.