Use of Sodium-Glucose Cotransporter-2 Inhibitors and Angiotensin Receptor-Neprilysin Inhibitors in Patients With Atrial Fibrillation and Heart Failure From 2021 to 2022: An Analysis of Real-World Data.

BACKGROUND: Contemporary use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitors (ARNi) in patients with atrial fibrillation (AF) and heart failure (HF) has not been described. METHODS AND RESULTS: We analyzed the MarketScan databases for the period January 1, 2021 to July 30, 2022. Validated algorithms were used to identify patients with AF and HF, and to classify patients into HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF). We assessed the prevalence of SGLT2i and ARNi use overall and by HF type. Additionally, we explored correlates of lower use, including demographics and comorbidities. The study population included 60 927 patients (mean age, 75 years; 43% women) diagnosed with AF and HF (85% with HFpEF, 15% with HFrEF). Prevalence of ARNi use was 11% overall (30% in HFrEF, 8% in HFpEF), whereas the corresponding figure was 6% for SGLT2i (13% in HFrEF, 5% in HFpEF). Use of both medications increased over the study period: ARNi from 9% to 12% (22%-29% in HFrEF, 6%-8% in HFpEF), and SGLT2i from 3% to 9% (6%-16% in HFrEF, 2%-7% in HFpEF). Female sex, older age, and specific comorbidities were associated with lower use of these 2 medication types overall and by HF type. CONCLUSIONS: Use of ARNi and SGLT2i in patients with AF and HF is suboptimal, particularly among women and older individuals, though use is increasing. These results underscore the need for understanding reasons for these disparities and developing interventions to improve adoption of evidence-based therapies among patients with comorbid AF and HF.

Knowledge domain and emerging trends in sacubitril/valsartan study from 2008 to 2023 - a visualized conclusive analysis based on novel scientometric tools.

OBJECTIVE: This study aimed to determine the evolution of sacubitril-valsartan research and analyze the publications quantitatively and qualitatively. MATERIALS AND METHODS: We used the bibliometric method and a combination of CiteSpace_6.1.6 and VOSviewer_1.6.18 to identify top authors, countries, institutions, co-cited articles, co-cited journals, keywords, and trends. This study prioritized key aspects in the existing global research on Entresto (Sacubitril/Valsartan) to assess our depth of knowledge in this field and identify potential insights. The objective was to generate a reference for the utilization of the "angiotensin receptor-neprilysin inhibitor" (ARNI). RESULTS: From 2008 to 2022, citations of sacubitril-valsartan showed an upward trend. VOSviewer keyword analysis of 3,408 publications identified 624 keywords and divided them into seven different clusters. The clustered network was constructed based on 1,191 references cited by 3,408 publications that met the terms, where the clustered network of sacubitril-valsartan was presented. These publications can be regarded as fundamental to Entresto's research. Analysis of co-cited reference clusters showed that other than Entresto's novel application in other diseases, the new combination with other medication or mechanical assistance therapies against heart failure was Entresto's latest focus. Analysis of citation bursts showed that the rank of the top 25 keywords, according to the chronological sequence, marked Entresto's research entering a new era of exploring the extended application in other diseases and novel combinations with other diverse therapies. CONCLUSIONS: We found that emerging new mechanisms in sacubitril-valsartan therapy intended for more targets in the pathogenesis of specific diseases will be the focus of further studies.

Patient-Centered Heart Failure Therapy.

Simultaneous initiation of quadruple therapy with angiotensin receptor-neprilysin inhibitor, beta-adrenergic receptor blocker, mineralocorticoid receptor antagonist, and sodium glucose cotransporter 2 inhibitor aims at prompt improvement and prevention of readmission in patients hospitalized for heart failure with reduced ejection fraction. However, titration of quadruple therapy is time consuming. Lengthy up-titration of quadruple therapy may negate the benefit of early initiation. Quadruple therapy should start with a sodium glucose cotransporter 2 inhibition and a mineralocorticoid antagonist, as both enable safe decongestion and require minimal or no titration. Depending on the level of decongestion and clinical characteristics, patients receive an angiotensin receptor-neprilysin inhibitor or a beta-adrenergic receptor blocker to be titrated after hospital discharge. Outpatient addition of an angiotensin receptor-neprilysin inhibitor to a beta-adrenergic receptor blocker or vice versa completes the quadruple therapy scheme. By focusing on decongestion and matching intervention to patients' profile, the present therapeutic sequence allows rapid implementation of quadruple therapy at fully recommended doses.

Angiotensin-Neprilysin inhibition in heart failure with preserved ejection fraction: A meta-analysis of randomized controlled trials.

BACKGROUND: The effect of sacubitril/valsartan on patients with heart failure (HF) with preserved ejection fraction (HFpEF) is a topic of ongoing debate. METHODS: Medline was queried from inception through the last week of May 2023 for randomized studies assessing the effects of sacubitril/valsartan in patients with HFpEF. For continuous outcomes, we pooled either the geometric mean ratios (gMR) or weighted mean difference (WMD) with 95% confidence intervals (CI). For dichotomous outcomes, we pooled Risk ratios (RR) with 95% CI. RESULTS: Four trials were included (N=8,129). Compared to the control, sacubitril/valsartan was associated with a reduction in NT-proBNP levels (gMR: 0.84, 95% CI 0.80, 0.88) and improvement in KCCQ score (WMD: 0.85, 95% CI: 0.02, 1.67). We observed no differences for HF hospitalization (RR: 0.90, 95% CI: 0.79, 1.01), cardiovascular mortality (RR: 0.83, 95% CI: 0.52, 1.32), all-cause mortality (RR: 0.99, 95% CI: 0.86-1.13) and improvement (RR: 1.15, 95% CI: 0.93, 1.42) or worsening (RR: 0.92, 95% CI: 0.78, 1.09) of NYHA class between the sacubitril/valsartan and comparator group. Sacubitril/valsartan was generally safe, and patients were less likely to have a ≥50% decline in eGFR compared to control (RR: 0.60, 95% CI: 0.39, 0.92). CONCLUSION: Pooled analysis suggests that sacubitril/valsartan reduces natriuretic peptide levels and improves the quality of life in patients with HFpEF, which may translate into better clinical outcomes as observed by a numerical trend towards improvement in major HF outcomes with sacubitril/valsartan therapy.

Evaluation of the clinical efficacy of racecadotril in the treatment of neonatal calves with infectious diarrhea.

Racecadotril, used as an antidiarrheal drug in humans and some animals such as the dog, inhibits peripheral enkephalinase, which degrades enkephalins and enkephalinase inhibition induces a selective increase in chloride absorption from the intestines. The study material consisted of 46 calves with infectious diarrhea and 14 healthy calves in the age 2-20 days. The calves were divided into eight groups; healthy calves (HG), healthy calves administered racecadotril (HRG), calves with E.coli-associated diarrhea (ECG), calves with E.coli-associated diarrhea administered racecadotril (ECRG), calves with bovine Rotavirus/Coronavirus-associated diarrhea (VG), calves with bovine Rotavirus/Coronavirus-associated diarrhea administered racecadotril (VRG), calves with C. parvum-associated diarrhea (CG) and calves with C. parvum-associated diarrhea administered racecadotril (CRG). Calves in the racecadotril groups received oral racecadotril at a dose of 2.5 mg/kg twice a day for 3 days. A routine clinical examination of all calves was performed. Hemogram and blood gas measurements were made from the blood samples. Standard diarrhea treatment was applied to the HG, ECG, CG, and VG groups. Clinical score parameters such as appetite, feces quality, dehydration, standing and death and some blood gas and hemogram parameters were evaluated to determine the clinical efficacy of racecadotril. Clinical score parameters were determined observationally. Blood gas measurements were performed using a blood gas analyzer. The hemogram was performed using an automated hematologic analyzer. Statistically significant differences were determined in the blood pH, bicarbonate, base deficit, lactate, and total leukocyte count in calves with diarrhea compared to healthy calves. After the treatments, these parameters were found to be within normal limits. At the end of treatment, 42 of the 46 diarrheal calves recovered, while 4 died. We found that racecadotril was effective in improving both clinical recovery and feces consistency in neonatal calves with diarrhea caused by E. coli. As a result, it can be stated that racecadotril, which has an antisecretory effect, is beneficial in the treatment of bacterial diarrhea caused by such as E. coli.

Co-administration of dl-3-n-butylphthalide and neprilysin is neuroprotective in Alzheimer disease associated with mild traumatic brain injury.

dl-3-n-Butylphthalide is a potent synthetic Chinese celery extract that is highly efficient in inducing neuroprotection in concussive head injury (CHI), Parkinson's disease, Alzheimer's disease, stroke as well as depression, dementia, anxiety and other neurological diseases. Thus, there are reasons to believe that dl-3-n-butylphthalide could effectively prevent Alzheimer's disease brain pathology. Military personnel during combat operation or veterans are often the victims of brain injury that is a major risk factor for developing Alzheimer's disease in their later lives. In our laboratory we have shown that CHI exacerbates Alzheimer's disease brain pathology and reduces the amyloid beta peptide (AßP) inactivating enzyme neprilysin. We have used TiO2 nanowired-dl-3-n-butylphthalide in attenuating Parkinson's disease brain pathology exacerbated by CHI. Nanodelivery of dl-3-n-butylphthalide appears to be more potent as compared to the conventional delivery of the compound. Thus, it would be interesting to examine the effects of nanowired dl-3-n-butylphthalide together with nanowired delivery of neprilysin in Alzheimer's disease model on brain pathology. In this investigation we found that nanowired delivery of dl-3-n-butylphthalide together with nanowired neprilysin significantly attenuated brain pathology in Alzheimer's disease model with CHI, not reported earlier. The possible mechanism and clinical significance is discussed based on the current literature.

Health and Economic Evaluation of Sacubitril-Valsartan for Heart Failure Management.

Importance: The US Food and Drug Administration expanded labeling of sacubitril-valsartan from the treatment of patients with chronic heart failure (HF) with reduced ejection fraction (EF) to all patients with HF, noting the greatest benefits in those with below-normal EF. However, the upper bound of below normal is not clearly defined, and value determinations across a broader EF range are unknown. Objective: To estimate the cost-effectiveness of sacubitril-valsartan vs renin-angiotensin system inhibitors (RASis) across various upper-level cutoffs of EF. Design, Setting, and Participants: This economic evaluation included participant-level data from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and the PARAGON-HF (Prospective Comparison of ARNi with ARB Global Outcomes in HF With Preserved Ejection Fraction) trials. PARADIGM-HF was conducted between 2009 and 2014, PARAGON-HF was conducted between 2014 and 2019, and this analysis was conducted between 2021 and 2023. Main Outcomes and Measures: A 5-state Markov model used risk reductions for all-cause mortality and HF hospitalization from PARADIGM-HF and PARAGON-HF. Quality-of-life differences were estimated from EuroQol-5D scores. Hospitalization and medication costs were obtained from published national sources; the wholesale acquisition cost of sacubitril-valsartan was $7092 per year. Risk estimates and treatment effects were generated in consecutive 5% EF increments up to 60% and applied to an EF distribution of US patients with HF from the Get With the Guidelines-Heart Failure registry. The base case included a lifetime horizon from a health care sector perspective. Incremental cost-effectiveness ratios (ICERs) were estimated at EFs of 60% or less (base case) and at various upper-level EF cutoffs. Results: Among 13 264 total patients whose data were analyzed, for those with EFs of 60% or less, sacubitril-valsartan was projected to add 0.53 quality-adjusted life-years (QALYs) at an incremental lifetime cost of $40 892 compared with RASi, yielding an ICER of $76 852 per QALY. In a probabilistic sensitivity analysis, 95% of the values of the ICER occurred between $71 516 and $82 970 per QALY. Among patients with chronic HF and an EF of 60% or less, treatment with sacubitril-valsartan vs RASis would be at least of economic intermediate value (ICER <$180 000 per QALY) at a sacubitril-valsartan cost of $10 242 or less per year, of high economic value (ICER <$60 000 per QALY) at a cost of $3673 or less per year, and cost-saving at a cost of $338 or less per year. The ICERs were $67 331 per QALY, $59 614 per QALY, and $56 786 per QALY at EFs of 55% or less, 50% or less, and 45% or less, respectively. Treatment with sacubitril-valsartan in only those with EFs of 45% or greater (up to ≤60%) yielded an ICER of $127 172 per QALY gained; treatment was more cost-effective in those at the lower end of this range (ICER of $100 388 per QALY gained for those with EFs of 45%-55%; ICER of $84 291 per QALY gained for those with EFs of 45%-50%). Conclusions and Relevance: Cost-effectiveness modeling provided an ICER for treatment with sacubitril-valsartan vs RASis consistent with high economic value for patients with reduced and mildly reduced EFs (≤50%) and at least intermediate value at the current undiscounted wholesale acquisition cost price at an EF of 60% or less. Treatment was more cost-effective at lower EF ranges. These findings may have implications for coverage decisions and value assessments in contemporary clinical practice guidelines.

Comparison of the effects of angiotensin receptor-neprilysin inhibitors and thiazide diuretic/renin-angiotensin system inhibitor combination therapy in hypertensive patients: a retrospective cohort study.

Angiotensin receptor-neprilysin inhibitors (ARNIs) have been approved as antihypertensive agents in Japan, and thiazide diuretics (TZDs) are widely used concomitantly with renin-angiotensin system inhibitors (RASIs) for hypertension. This retrospective study included patients with hypertension who switched from RASI to ARNI therapy (ARNI group) and those who were prescribed TZDs with RASIs (TZD/RASI group). Drug-related changes in the estimated glomerular filtration rate (eGFR), blood pressure (BP), body weight (BW), serum electrolytes, uric acid (UA), and triglyceride levels were compared between the two groups. Overall, 70 participants (31 and 39 in the ARNI and TZD/RASI groups, respectively) were enrolled and observed for a median of 2 months. According to linear mixed models, compared with the TZD/RASI group, the ARNI group exhibited a significant change in mean eGFR of 3.71 mL/min/1.73 m2 [95% confidence interval (CI), 0.57-6.84; P = 0.02] from the time of switching drug to the next outpatient visit. Further, compared with the TZD/RASI group, the ARNI group exhibited significant changes in mean serum UA (-1.27; 95% CI, -1.66 to -0.88), sodium (1.22; 95% CI, 0.12 to -2.32), chloride (2.14; 95% CI, 0.75-3.52), and triglyceride (-52.1; 95% CI, -100.9 to -3.29) levels. Conversely, serum potassium levels, BW, and systolic and diastolic BP did not differ significantly between the two groups (P = 0.69, 0.44, 0.49, and 0.66, respectively). Compared with the combination therapy of TZD and RASI, ARNI therapy causes less renal dysfunction, hyperuricemia, and hypertriglyceridemia with fewer electrolyte abnormalities and no significant difference in antihypertensive effects.

Frailty and uptake of angiotensin receptor neprilysin inhibitor for heart failure with reduced ejection fraction.

BACKGROUND: Frail older adults may be less likely to receive guideline-directed medical therapy (GDMT)-renin-angiotensin blockers, beta-blockers, and mineralocorticoid receptor antagonists-for heart failure with reduced ejection fraction (HFrEF). We aimed to examine the uptake of angiotensin receptor neprilysin inhibitor (ARNI) and GDMT in frail older adults with HFrEF. METHODS: Using 2015-2019 Medicare data, we estimated the proportion of beneficiaries with HFrEF receiving ARNI and GDMT each year by frailty status, defined by a claims-based frailty index. Logistic regression was used to identify clinical characteristics associated with ARNI initiation. Cox proportional hazards regression was used to examine the association of GDMT use in 2015 and death or heart failure hospitalization in 2016-2019. RESULTS: Among 147,506-180,386 beneficiaries with HFrEF (mean age: 77 years; 27% women; 42.6-49.1% frail) in 2015-2019, the proportion of patients receiving ARNI increased in both non-frail (0.4%-16.4%) and frail (0.3%-13.7%) patients (p for yearly-trend-by-frailty = 0.970). Among those not receiving a renin-angiotensin system blocker, patients with age ≥ 85 years (odds ratio [95% CI], 0.89 [0.80-0.99]), dementia (0.88 [0.81-0.96]), and frailty (0.87 [0.81-0.94]) were less likely to initiate ARNI. The proportion of patients receiving all 3 GDMT classes increased in non-frail patients (22.0%-27.0%) but changed minimally in frail patients (19.6%-21.8%). Regardless of frailty status, treatment with at least 1 class of GDMT was associated with lower death or heart failure hospitalization than no GDMT medications (hazard ratio [95% CI], 0.94 [0.91-0.97], 0.92 [0.89-0.94], 0.94 [0.91-0.97] for 1, 2, and 3 classes, respectively). CONCLUSIONS: Our results suggest an evidence-practice gap in the use of ARNI and GDMT in Medicare beneficiaries with HFrEF, particularly those with frailty. Efforts to narrow this gap are needed to reduce the burden of HFrEF in older adults.

Angiotensin-Neprilysin Inhibition in Patients With Mildly Reduced or Preserved Ejection Fraction and Worsening Heart Failure.

BACKGROUND: U.S. guidelines recommend consideration of sacubitril/valsartan in chronic heart failure (HF) and mildly reduced or preserved ejection fraction (EF). Whether initiation is safe and effective in EF >40% after a worsening heart failure (WHF) event is unknown. OBJECTIVES: PARAGLIDE-HF (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF) assessed sacubitril/valsartan vs valsartan in EF >40% following a recent WHF event. METHODS: PARAGLIDE-HF is a double-blind, randomized controlled trial of sacubitril/valsartan vs valsartan in patients with EF >40% enrolled within 30 days of a WHF event. The primary endpoint was time-averaged proportional change in amino terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through Weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: 1) cardiovascular death; 2) HF hospitalizations; 3) urgent HF visits; and 4) change in NT-proBNP. RESULTS: In 466 patients (233 sacubitril/valsartan; 233 valsartan), time-averaged reduction in the NT-proBNP was greater with sacubitril/valsartan (ratio of change: 0.85; 95% CI: 0.73-0.999; P = 0.049). The hierarchical outcome favored sacubitril/valsartan but was not significant (unmatched win ratio: 1.19; 95% CI: 0.93-1.52; P = 0.16). Sacubitril/valsartan reduced worsening renal function (OR: 0.61; 95% CI: 0.40-0.93) but increased symptomatic hypotension (OR: 1.73; 95% CI: 1.09-2.76). There was evidence of a larger treatment effect in the subgroup with EF ≤60% for NT-proBNP change (0.78; 95% CI: 0.61-0.98) and the hierarchical outcome (win ratio: 1.46; 95% CI: 1.09-1.95). CONCLUSIONS: Among patients with EF >40% stabilized after WHF, sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared with valsartan alone, despite more symptomatic hypotension. (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF; NCT03988634).

Sodium-Glucose Cotransporter 2 Inhibitors First Strategy Improve Decongestion in Patients with Symptomatic Heart Failure and Reduced Ejection Fraction When Compared to Angiotensin Receptor Neprilysin Inhibitor First Strategy.

BACKGROUND: Angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) are emerging medical treatments for decompensated heart failure (HF) with reduced ejection fraction. In clinical practice, the combination of ARNI and SGLT2i cannot be administered owing to the poor hemodynamic status in patients with HF with reduced ejection fraction (HFrEF). This study aimed to compare different strategies of HF management for ARNI first or SGLT2i first in such a population. METHODS: From January 2016 to December 2021, 165 patients were diagnosed with HFrEF and New York Heart Association functional class ≥II and already received optimal medical treatment. Ninety-five patients received the ARNI-first strategy, and 70 patients received the SGLT2i-first strategy according to the physician's choice. Age, sex, hemodynamic condition, etiologies of HF, comorbidities, serum creatinine, N-terminal pro-B-type natriuretic peptide (NT-ProBNP), echocardiographic parameters, and clinical outcomes were compared between the ARNI and SGLT2i-first strategy groups. RESULTS: In the SGLT2i-first group, the median interval between the addition of the second medication was longer (ARNI-first vs. SGLT2i-first; 74 [49-100] days vs. 112 [86-138] days; p = 0.044). Improvement in left ventricular ejection fraction (LVEF), change in left atrial dimension, and change in left ventricular end-diastolic and end-systolic volume (LVESV) did not differ between the two groups. The incidence of HF hospitalization, cardiovascular mortality, and all-cause mortality did not differ between the two groups. A non-significant trend of lower NT-proBNP levels (ARNI-first vs. SGLT2i-first; 1383 [319-2507] pg/mL vs. 570 [206-1314] pg/mL; p = 0.055) and significantly higher discontinuation rate of diuretic agents (ARNI-first vs. SGLT2i- first; 6.8% vs. 17.5%; p = 0.039) were noted in the SGLT2i-first group. When early combination (≤14D) compared to late combination (>14D), better positive remodeling of LVESV presented significantly in early combination subgroups. CONCLUSIONS: In patients with symptomatic HFrEF, SGLT2i-first strategy may provide a higher possibility of discontinuing diuretic agents than the ARNI-first strategy. Changes in LV performance, progression of renal function, and clinical outcomes did not differ between the two groups. Early combination (≤14D) provided better LV remodeling.

Safety and feasibility of angiotensin receptor neprilysin inhibitor in real-world patients with acute decompensated heart failure.

BACKGROUND: The aim of this study was to determine the safety and feasibility of in-hospital sacubitril/valsartan initiation after clinical stabilization in patients with acute decompensated heart failure (ADHF) and reduced ejection fraction (EF). METHODS: This retrospective, multicenter observational study included patients admitted for ADHF in 2 Italian centers between February 2017 and January 2022. Feasibility was evaluated by assessing the proportion of patients discharged on sacubitril/valsartan. Key safety endpoints were the incidences of adverse events during hospitalization and during follow-up planned at 1 month, 3-6 months and 12-18 months after discharge. RESULTS: One hundred and twenty-two patients were included. Median age was 71 (60-78) years, 78% male, 63% New York Heart Association (NYHA) Class III at admission with a median left ventricular ejection fraction (EF) of 25% (20-30). During hospitalization, 94 (77%) patients were treated with intravenous diuretics, 39 (32%) with inotrope/vasopressor, 51 (42%) with continuous positive airway pressure ventilation and 7 (6%) were assisted with an intra-aortic balloon pump. Median time from hospitalization to sacubitril/valsartan initiation was 4 (2-7) days. Sacubitril/valsartan was started at a dosage of 12/13 mg in 52 (43%) patients, 24/26 mg in 61 (50%) patients and 49/51 mg in 8 (7%) patients. Overall, 111 (91%) patients were discharged on sacubitril/valsartan. At 12-18-month follow-up, the vast majority of patients were still on sacubitril/valsartan therapy. CONCLUSIONS: In-hospital initiation of sacubitril/valsartan treatment in real-world ADHF patients may be a safe and feasible treatment option.

Pharmacologic Therapy for Heart Failure with Preserved Ejection Fraction.

The management of heart failure with preserved ejection fraction (HFpEF) is rapidly evolving. The pharmacologic treatment of patients with HFpEF includes symptom management with diuretics and optimization of comorbidities, including hypertension, obesity, diabetes mellitus, and atrial fibrillation. Specific therapies, including angiotensin II receptor blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, and sodium-glucose cotransporter-2 inhibitors, are well tolerated and can reduce the risk of HF hospitalization, particularly in those on the lower end of the HFpEF left ventricular ejection fraction spectrum. Ongoing trials should continue to inform optimal therapy in this evolving field.

Optimal Pharmacologic Treatment of Heart Failure With Preserved and Mildly Reduced Ejection Fraction: A Meta-analysis.

Importance: In recent years, significant progress has been made in the pharmacologic treatment of heart failure (HF) with reduced ejection fraction (HFrEF), but there is still insufficient evidence for drug therapy for HF with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF). Objective: To compare the outcomes associated with different drug combinations for the treatment of HFpEF and HFmrEF. Data Sources: A search of the PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases was conducted for studies published from inception to October 9, 2021. Study Selection: Randomized clinical trials on the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), ß-blockers, and sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with HFpEF or HFmrEF. Data Extraction and Synthesis: Data extraction and bias assessment were independently performed by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. All data for 3 outcomes were pooled with a fixed-effect model. Main Outcomes and Measures: The main outcomes were first hospitalization for HF, all-cause mortality, and cardiovascular mortality. Hazard ratios (HRs) and 95% credible intervals (CrIs) were evaluated using a bayesian network meta-analysis model. Results: In this analysis, 19 randomized clinical trials, including 20 633 patients with HF and an ejection fraction of 40% or more, without a remarkable risk of bias were included. Compared with placebo, no treatments were associated with a significant reduction in the risk of all-cause death or cardiovascular death. SGLT2 inhibitors, ARNIs, and MRAs were associated with a significant decrease in the risk of HF hospitalization compared with placebo (SGLT2 inhibitors: HR, 0.71 [95% CrI, 0.60-0.83]; ARNIs: HR, 0.76 [95% CrI, 0.61-0.95]; MRAs: HR, 0.83 [95% CrI, 0.69-0.99]), and SGLT2 inhibitors were the optimal drug class in terms of reducing the risk for HF admission. Sensitivity analysis results demonstrated a progressive decrease in the risk of HF admission and an advance in mean rank associated with the increasing use of drug classes. Conclusions and Relevance: The findings of this study suggest that SGLT2 inhibitors were the optimal drug class for HFpEF and HFmrEF, consistent with the most recent guideline recommendation. The incremental use of combinations of SGLT2 inhibitors, ACE inhibitors or ARBs, and ß-blockers may be associated with accumulative benefits in HF hospitalization rather than all-cause death among patients with HFpEF and HFmrEF.

Sacubitril/valsartan: An antiarrhythmic drug?

INTRODUCTION: Heart failure (HF) is a major cause of morbidity and mortality, with nearly half of all HF-related deaths resulting from sudden cardiac death (SCD), most often from an arrhythmic event. The pathophysiologic changes that occur in response to the hemodynamic stress of HF may lead to increased arrhythmogenesis. Theoretically, medications that block these arrhythmogenic substrates would decrease the risk of SCD. The combined angiotensin receptor and neprilysin inhibitor (ARNi; tradename Entresto) is the newest commercially available medication for the treatment of heart failure. METHODS AND RESULTS: We reviewed and synthesized the available literature regarding sacubitril/valsartan and its effects on cardiac rhythm. ARNi has been shown to decrease cardiovascular mortality and hospitalization in patients with HF with reduced ejection fraction (HFrEF). Emerging evidence suggests that ARNi also may play a role in reducing arrhythmogenesis and thereby SCD. CONCLUSION: This review summarizes the current data regarding this ARNi and its potential antiarrhythmic effects.

Sacubitril/valsartan attenuates myocardial ischemia/reperfusion injury via inhibition of the GSK3ß/NF-κB pathway in cardiomyocytes.

In ischemia/reperfusion (I/R) injury, both inflammation and apoptosis play a vital role, and the inhibition of excessive inflammation and apoptosis show substantial clinical potential in the treatment of I/R disease. The role of sacubitril/valsartan (SAC/VAL)-a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI)-in inflammation regulation and apoptosis in the context of I/R injury needs to be further explored. In this study, we investigate the short- and long-term effects of SAC/VAL administration in treating adult murine I/R injury both in vivo and in vitro. Our results verified that the application of SAC/VAL could reduce infarct size and suppress apoptosis and the inflammatory response in the acute phase post I/R. Long-term application of SAC/VAL for four weeks significantly improved ventricular function and reversed pathological ventricular remodeling. Mechanistically, SAC/VAL treatment induces the inhibition of the GSK3ß-mediated NF-κB pathway through synergistically blocking angiotensin 1 receptor (AT1R) and activating natriuretic peptide receptor (NPR). In summary, we reported the therapeutic role of SAC/VAL in regulating the GSK3ß/NF-κB signaling pathway to suppress the inflammatory response and apoptosis, thereby reducing cardiac dysfunction and remodeling post I/R.

Consensus statement on the current pharmacological prevention and management of heart failure.

INTRODUCTION: This consensus statement of Australian clinicians provides new recommendations for the pharmacological management of heart failure based on studies reported since the publication of the 2018 Australian heart failure guidelines. MAIN RECOMMENDATIONS: ▪Use of sodium-glucose cotransporter 2 (SGLT2) inhibitors to prevent hospitalisation for heart failure in type 2 diabetes mellitus can be extended to patients with multiple cardiovascular risk factors, albuminuric chronic kidney disease, or atherosclerotic cardiovascular disease. ▪New evidence supports the use of a mineralocorticoid receptor antagonist (finerenone) to prevent heart failure in type 2 diabetes mellitus associated with albuminuric chronic kidney disease. ▪In addition to renin angiotensin system inhibitors (angiotensin receptor neprilysin inhibitor preferred), beta blockers and mineralocorticoid receptor antagonists, an SGLT2 inhibitor (dapagliflozin or empagliflozin) is recommended in all patients with heart failure with reduced left ventricular ejection fraction (LVEF ≤ 40%) (HFrEF). Lower quality evidence supports these therapies in patients with heart failure with mildly reduced LVEF (41-49%) (HFmrEF). ▪A soluble guanylate cyclase stimulator (vericiguat), selective cardiac myosin activator (omecamtiv mecarbil) and, if iron deficient, intravenous iron (ferric carboxymaltose) provide additional benefits in persistent HFrEF. ▪An SGLT2 inhibitor (empagliflozin) should be considered in patients with heart failure with preserved LVEF (≥ 50%) (HFpEF). Key changes in management from this statement: This document broadens the scope of angiotensin receptor neprilysin inhibitor use in patients with HFrEF and HFmrEF. SGLT2 inhibitor use expands to become a cornerstone therapy in HFrEF, with increasing evidence to support its use in HFmrEF and HFpEF.

[Angiotensine Receptor-Neprilysin Inhibitor combination is not the preferred medication for patients after acute myocardial infarction]. / Sacubitril/valsartan verdient geen voorkeur boven ACE-remmer na een hartinfarct.

The PARADISE-MI study compared standard treatment with an ACE inhibitor (ramipril) after an acute myocardial infarction with the newer sacubitril/ valsartan combination (so-called ARNI) medication in 5661 patients. Most patients had a reduced cardiac function (40% ejection fraction or less) and in about 50% of patients it was accompanied by complaints of congestion. The expected 15% reduction in primary endpoint cardiovascular death or rehospitalization or extra visits for heart failure was not met after 22 months. The study is characterized by an increased incidence of symptomatic hypotension of 28,3% in the group treated with the ARNI, compared to an incidence of 21,9% in the group treated with the ACE inhibitor. The interpretation of the trial is hampered by the mixed design of prevention and treatment trial for heart failure. A continuing careful approach is advised with ACE inhibitors as first choice in the first week(s) after myocardial infarction.

Angiotensin receptor/Neprilysin inhibitor effects in CRTd non-responders: From epigenetic to clinical beside.

OBJECTIVES: We evaluated whether Angiotensin receptor/Neprilysin inhibitors (ARNI) reduce heart failure (HF) hospitalizations and deaths in cardiac resynchronization therapy with defibrillator (CRTd) non-responders patients at 12 months of follow-up, modulating microRNAs (miRs) implied in adverse cardiac remodeling. BACKGROUND: adverse cardiac remodeling characterized by left ventricle ejection fraction (LVEF) reduction, left ventricular end-systolic volume (LVESv) increase, and the 6-minute walking test (6MWT) reduction are relevant pathological mechanisms in CRTd non-responders and could be linked to changes in miRNAs (miRs), regulating cardiac fibrosis, apoptosis, and hypertrophy. METHODS: miRs levels and clinical outcomes (LVEF, cardiac deaths, and 6MWT) were evaluated at baseline and one year of follow-up in CRTd non-responders divided into ARNI-users and Non-ARNI users. RESULTS: At baseline, there were no differences in levels of inflammatory markers, miR-18, miR-145, and miR-181 (p > 0.05) between Non-ARNI users (n 106) and ARNI-users (n 312). At one year of follow-up, ARNI-users vs. Non-ARNI users showed lowest inflammatory markers (p < 0.01) and miR-181 levels (p < 0.01) and higher values of miR-18 (p < 0.01)and miR-145 (p < 0.01). At one year of follow-up, ARNI-users had a higher increase of LVEF (p < 0.01) and 6MWT (p < 0.01) along with a more significant reduction of LVESv (p < 0.01) compared to Non-ARNI users. Cox regression analysis evidenced that ARNI-based therapies increase the probability of anti-remodeling effects of CRTd. Based on symptomatic improvements, echocardiographic and functional classification improvements, 37 (34.9%) patients among ARNI-users became responders, while only twenty (6.4%) patients became responders among Non-ARNi-users. CONCLUSIONS: ARNI might influence epigenetic mechanisms modulating miRs implicated in the adverse cardiac remodeling responses to CRTd.

Targeting and Modulation of the Natriuretic Peptide System in Covid-19: A Single or Double-Edged Effect?

Natriuretic peptide system (NPS) is a group of peptide hormones or paracrine factors, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and natriuretic peptide precursor C (NPC), that are structurally related. The physiological effects of NPS include natriuresis, increased glomerular filtration rate, inhibition release of renin, vasopressin, and aldosterone, sympathetic inhibition, vasodilatations, and prevents cardiac hypertrophy and remodeling. ANP has immunological effects, as it is produced locally from immune cells; it regulates innate and adaptive immune responses. Metabolism and degradation of ANP are achieved by neutral endopeptidase (NEP), also known as neprilysin. Coronavirus disease 2019 (Covid-19) pandemic may lead to acute lung injury (ALI) and/or respiratory distress syndrome (ARDS). The underlying causes of inflammatory and immunological disorders in patients with severe Covid-19 are connected to the immune over-stimulation with the subsequent release of pro-inflammatory cytokines. Covid-19 severity is linked with high ANP serum levels regardless of acute cardiac injury. Inflammatory stimuli appear to be linked with the release of NPs, which anti-inflammatory effects prevent the development of ALI/ARDS in Covid-19. Therefore, neprilysin inhibitors like sacubitril increase endogenous NPs and may reduce the risk of ALI in Covid-19 due to the potentiation of endogenous anti-inflammatory effects of NPs. However, sacubitril increases gastrin-releasing peptide, cathepsin G and release of pro-inflammatory cytokines that are inactivated by neprilysin. In conclusion, NPs and neprilysin have cardio-pulmonary protective effects against Covid-19-induced ALI/ARDS. Neprilysin inhibitor sacubitril has dual protective and harmful effects regarding metabolizing vasoactive peptides by neprilysin. These findings require potential reevaluation of the effect of neprilysin inhibitors in managing Covid-19.