Angiotensin Receptor Neprilysin Inhibitor Research Articles

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.

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. 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. 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. 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.

Natriuretic Peptides: Role in the Diagnosis and Management of Heart Failure: A Scientific Statement From the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America and Japanese Heart Failure Society

Natriuretic peptides, brain (B-type) natriuretic peptide (BNP) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are globally and most often used for the diagnosis of heart failure (HF). In addition, they can have an important complementary role in the risk stratification of its prognosis. Since the development of angiotensin receptor neprilysin inhibitors (ARNIs), the use of natriuretic peptides as therapeutic agents has grown in importance. The present document is the result of the Trilateral Cooperation Project among the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America and the Japanese Heart Failure Society. It represents an expert consensus that aims to provide a comprehensive, up-to-date perspective on natriuretic peptides in the diagnosis and management of HF, with a focus on the following main issues: (1) history and basic research: discovery, production and cardiovascular protection; (2) diagnostic and prognostic biomarkers: acute HF, chronic HF, inclusion/endpoint in clinical trials, and natriuretic peptides-guided therapy; (3) therapeutic use: nesiritide (BNP), carperitide (ANP) and ARNIs; and (4) gaps in knowledge and future directions.

Natriuretic peptides: role in the diagnosis and management of heart failure: a scientific statement from the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America and Japanese Heart Failure Society.

Natriuretic peptides, brain (B-type) natriuretic peptide (BNP) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are globally and most often used for the diagnosis of heart failure (HF). In addition, they can have an important complementary role in the risk stratification of its prognosis. Since the development of angiotensin receptor-neprilysin inhibitors (ARNIs), the use of natriuretic peptides as therapeutic agents has grown in importance. The present document is the result of the Trilateral Cooperation Project among the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America and the Japanese Heart Failure Society. It represents an expert consensus that aims to provide a comprehensive, up-to-date perspective on natriuretic peptides in the diagnosis and management of HF, with a focus on the following main issues: (1) history and basic research: discovery, production and cardiovascular protection; (2) diagnostic and prognostic biomarkers: acute HF, chronic HF, inclusion/endpoint in clinical trials, and natriuretic peptide-guided therapy; (3) therapeutic use: nesiritide (BNP), carperitide (ANP) and ARNIs; and (4) gaps in knowledge and future directions.

Guideline-Directed Medical Therapy Tolerability in Patients With Heart Failure and Mitral Regurgitation: The COAPT Trial

BackgroundIn the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial, a central committee of heart failure (HF) specialists optimized guideline-directed medical therapies (GDMT) and documented medication and goal dose intolerances before patient enrollment. ObjectivesThe authors sought to assess the rates, reasons, and predictors of GDMT intolerance in the COAPT trial. MethodsBaseline use, dose, and intolerances of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) were analyzed in patients with left ventricular ejection fraction (LVEF) ≤40%, in whom maximally tolerated doses of these agents as assessed by an independent HF specialist were required before enrollment. ResultsA total of 464 patients had LVEF ≤40% and complete medication information. At baseline, 38.8%, 39.4%, and 19.8% of patients tolerated 3, 2, and 1 GDMT classes, respectively (any dose); only 1.9% could not tolerate any GDMT. Beta-blockers were the most frequently tolerated GDMT (93.1%), followed by ACEIs/ARBs/ARNIs (68.5%), and then MRAs (55.0%). Intolerances differed by GDMT class, but hypotension and kidney dysfunction were most common. Goal doses were uncommonly achieved for beta-blockers (32.3%) and ACEIs/ARBs/ARNIs (10.2%) due to intolerances limiting titration. Only 2.2% of patients tolerated goal doses of all 3 GDMT classes. ConclusionsIn a contemporary trial population with HF, severe mitral regurgitation, and systematic HF specialist-directed GDMT optimization, most patients had medical intolerances prohibiting 1 or more GDMT classes and achieving goal doses. The specific intolerances noted and methods used for GDMT optimization provide important lessons for the implementation of GDMT optimization in future clinical trials. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] [COAPT]; NCT01626079)

Design of the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor Versus Placebo in Patients With Congenital Systemic Right Ventricle Heart Failure (PARACYS-RV) Trial

The presence of a systemic right ventricle (sRV) with biventricular physiology (biV) is associated with increased patient morbidity and mortality. To date, no pharmacologic therapy for heart failure has been proven effective for patients with systolic dysfunction of the sRV-biV. We designed a randomized, double-blind, placebo-controlled crossover trial to compare sacubitril/valsartan treatment to placebo in adults (aged ≥ 18 years) with moderate-to-severe sRV-biV dysfunction and New York Heart Association functional class II to III symptoms. Two primary efficacy endpoints are assessed in the trial: exercise capacity (submaximal exercise duration) and neurohormonal activation (N-terminal prohormone brain natriuretic peptide). Secondary objectives include assessing a change in the Kansas City Cardiomyopathy Questionnaire score and evaluating the safety and tolerance of sacubitril/valsartan. A 6-week open run-in phase identifies the maximum tolerated dose of sacubitril/valsartan, up to 97 mg/103 mg twice daily. After a 2-week washout period, patients are randomized 1:1 to sacubitril/valsartan treatment vs placebo for a 24-week phase, followed by another 2-week washout period and subsequent crossover to the alternative treatment arm for an additional 24-week phase. Data to assess primary and secondary endpoints are collected at baseline and at the end of each phase. A total of 48 patients is required to provide > 80% power to detect a 30% difference in distance walked and in N-terminal prohormone brain natriuretic peptide levels with sacubitril/valsartan treatment vs placebo, each with a 2-sided P-value of 0.025. In summary, the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor vs Placebo in Patients With Congenital Systemic Right Ventricular Heart Failure Trial (PARACYS-RV) should determine the role of sacubitril/valsartan in treating heart failure in patients with sRV-biV and carries the potential to alter management of this patient population.

Effects of Angiotensin Receptor-Neprilysin Inhibitors (ARNIs) on the Glucose and Fat Metabolism Biomarkers Leptin and Fructosamine.

(1) Background: Heart failure with reduced ejection fraction (HFrEF) remains a major health burden. Angiotensin-Receptor-Neprilysin-Inhibitors (ARNIs) are an established HFrEF therapy which increases natriuretic peptide levels by inhibiting neprilysin. Leptin is a lipid metabolism parameter, which is also involved in glucose metabolism and is suggested to correlate with HF burden. While the hormone also seems to interact with neprilysin, potential associations with ARNI therapy have not been investigated yet. (2) Methods: To study this issue, we measured levels of leptin and fructosamine in consecutive 72 HFrEF patients before initiation of ARNI therapy and 3-6 months after initiation of therapy in two European centers. Biomarker levels were correlated with clinical parameters including ejection fraction, LVEF, and NYHA class. (3) Results: During a follow-up of up to 6 months, clinical parameters improved significantly (LVEF: 30.2 ± 7.8% to 37.6 ± 10.0%, (p < 0.001) and a significant improvement of the mean NYHA class with initial 32 patients in NYHA III or IV and 8 patients in NYHA class III/IV during the follow up (p < 0.001). The initial NT-proBNP levels of 2251.5 ± 2566.8 pg/mL significantly improved to 1416.7 ± 2145 pg/mL, p = 0.008) during follow up. ARNI therapy was also associated with an increase in leptin levels (17.5 ± 23.4 µg/L to 22.9 ± 29.3, p < 0.001) and furthermore, affected glucose metabolism indicated by elevation of fructosamine values (333.9 ± 156.8 µmol/L to 454.8 ± 197.8 µmol/L, p = 0.013). (4) Conclusion: while in the early phase of therapy, ARNI promotes clinical improvement of HFrEF, and it also seems to affect fat and glucose parameters, indicating significant metabolic implications of this therapy regime.

Impact of multimorbidity on mortality in heart failure with reduced ejection fraction: which comorbidities matter most? An analysis of PARADIGM-HF and ATMOSPHERE.

Multimorbidity, the coexistence of two or more chronic conditions, is synonymous with heart failure (HF). How risk related to comorbidities compares at individual and population levels is unknown. The aim of this study is to examine the risk related to comorbidities, alone and in combination, both at individual and population levels. Using two clinical trials in HF-the Prospective comparison of ARNI (Angiotensin Receptor-Neprilysin Inhibitor) with ACEI (Angiotensin-Converting Enzyme Inhibitor) to Determine Impact on Global Mortality and morbidity in HF trial (PARADIGM-HF) and the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure trials (ATMOSPHERE)-we identified the 10 most common comorbidities and examined 45 possible pairs. We calculated population attributable fractions (PAF) for all-cause death and relative excess risk due to interaction with Cox proportional hazard models. Of 15 066 patients in the study, 14 133 (93.7%) had at least one and 11 867 (78.8%) had at least two of the 10 most prevalent comorbidities. The greatest individual risk among pairs was associated with peripheral artery disease (PAD) in combination with stroke (hazard ratio [HR] 1.73; 95% confidence interval [CI] 1.28-2.33) and anaemia (HR 1.71; 95% CI 1.39-2.11). The combination of chronic kidney disease (CKD) and hypertension had the highest PAF (5.65%; 95% CI 3.66-7.61). Two pairs demonstrated significant synergistic interaction (atrial fibrillation with CKD and coronary artery disease, respectively) and one an antagonistic interaction (anaemia and obesity). In HF, the impact of multimorbidity differed at the individual patient and population level, depending on the prevalence of and the risk related to each comorbidity, and the interaction between individual comorbidities. Patients with coexistent PAD and stroke were at greatest individual risk whereas, from a population perspective, coexistent CKD and hypertension mattered most.

Global differences in acute heart failure treatment: analysis of the STRONG-HF site feasibility questionnaire.

Acute heart failure (AHF) has an impact on human health worldwide. Despite guidelines for treatment and management of AHF, mortality rates remain high. The main objective of this study was to compare standard in-hospital treatment and management of AHF against current clinical guidelines and variations across regions. Between February 2018 and May 2021, investigators were approached to participate in the STRONG-HF study. The lead investigator at 158 sites in 20 countries completed a site feasibility questionnaire. Sites were grouped by country into five different regions: Africa and the Middle East, Eastern Europe, Russia, South America, and Western Europe. According to the questionnaires, there are large differences in how patients present due to AHF and where in the hospital they are treated. There were significant differences in reported percentage of AHF patients receiving angiotensin converting enzymes inhibitors across the regions (P<0.001), mostly due to prescription of more angiotensin II receptor blockers and angiotensin receptor-neprilysin inhibitors in South America and Western Europe. Reported beta-blocker use was high across all of the regions. Device therapy and percutaneous interventions were more common in Europe. Sites reported a 5 to 8day length of stay, while in Russia most have a 10 to 12day length of stay. Regions reported that AHF patients follow up with a community cardiologist or general practitioner post-discharge, although follow-up was commonly more than 1month post discharge, and not all sites had the capability to measure natriuretic peptides post discharge. In this analysis of feasibility questionnaires, most sites reported general adherence to ESC guidelines for treatment and management of AHF patients although percutaneous and device therapy was less common outside Europe and follow-up after discharge took place late and was not as extensive as recommended. There were wide variations seen within and across regions in some areas.

Updates for Cardio‐Kidney Protective Effects by Angiotensin Receptor‐Neprilysin Inhibitor: Requirement for Additional Evidence of Kidney Protection

The incidence of heart failure and chronic kidney disease is increasing, and many patients develop both diseases. Angiotensin receptor-neprilysin inhibitor (ARNI) is a promising therapeutic candidate for both diseases. ARNI has demonstrated superior cardioprotective effects compared with renin-angiotensin system inhibitors (RAS-Is) in large clinical trials such as the PARADIGM-HF (Prospective Comparison of ARNI With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. It has also been suggested that ARNI can provide renoprotective effects beyond those of RAS-Is in patients with HF. ARNI might have beneficial effects on the kidneys because of its ability to improve cardiac function in patients with heart failure and affect renal hemodynamics by enhancing the effects of hormones such as natriuretic peptide. In contrast, in the PARADIGM-HF trial, ARNI was associated with more albuminuria compared with RAS-I; thus, it is unclear whether long-term ARNI therapy has renoprotective effects. Additionally, ARNI did not provide renoprotective effects beyond RAS-I in patients with chronic kidney disease in the UK HARP-III (United Kingdom Heart and Renal Protection-III) trial. In other words, the patient population in which ARNI is more renoprotective than RAS-I might be limited. Collectively, ARNI may have renoprotective effects in addition to cardioprotective effects, but the evidence to date is applicable only to heart failure. Theoretically, given the molecular mechanism of ARNI, it could also be renoprotective in conditions such as nephrosclerosis, which has low risks of albuminuria and reduced kidney perfusion, but the evidence for such effects is lacking. Further research is needed to clarify whether ARNI therapy is an acceptable treatment strategy for renal protection.

Long-term cardiac effect of sacubitril-valsartan in hemodialysis patients with a reduced ejection fraction after aortic valve replacement for aortic stenosis: a case report with literature review

BackgroundAlthough the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan has demonstrated a valuable effect on cardiac function in patients with heart failure with a reduced ejection fraction, the effect of this agent in hemodialysis patients is not well known.Case presentationSacubitril-valsartan was administered to two anuric hemodialysis patients, an 81-year-old woman and a 79-year-old man, after aortic valve replacement for aortic stenosis. Following sacubitril-valsartan administration, the two patients’ N-terminal pro-brain natriuretic peptide levels decreased from 110,373 to 47,742 and 22,723 to 7692 pg/mL within one month, respectively, and were sustained within the lower levels thereafter. Although the patients’ left ventricular ejection fractions were 40.0% and 28.4%, respectively, these values did not change at seven and four months after sacubitril-valsartan administration (41.0% and 30.0%, respectively) but increased gradually to 56.6% and 54.9% at 11 and 13 months, respectively, and were sustained at the same levels thereafter.ConclusionsLong-term sacubitril-valsartan administration can improve cardiac function in hemodialysis patients with a reduced ejection fraction.

Twenty-four-year-old patient with heart failure after myocarditis. Results of quadruple therapy: a case report

Introduction. The data of epidemiological studies indicate maintaining high prevalence of heart failure (HF) and an unfavorable prognosis for such patients, which creates the need to change the treatment approach. A feature of the case presented is the young age of the patient and a significant effect that was achieved with quadruple therapy for HF with reduced ejection fraction (EF) after myocarditis.Short description. A three-year follow-up of a patient with HFrEF was carried out. In 2019, at the age of 21, the patient had acute myocarditis, diagnosed according to magnetic resonance imaging. The outcome was postmyocarditis cardiosclerosis, complicated by HFrEF. She had two episodes of HF decompensation, followed by hospitalizations in a cardiology hospital. During the treatment, a quadruple therapy was initiated (angiotensin receptor-neprilysin inhibitor, beta-blocker, mineralocorticoid receptor antagonist, sodium-glucose cotransporter 2 inhibitor), against which a significant improve was noted in the form of decrease in congestion symptoms, natriuretic peptide level from 1956 to 501,4 pg/ml, an increase in LVEF from 33% to 39%. The patient is currently on the waiting list for a donor heart transplant.Conclusion. The case report focuses on the complexity of not only the timely diagnosis of myocarditis, but also the treatment of its consequences. The appointment of quadruple therapy for a patient with HF after myocarditis has improved the patient’s clinical condition before heart transplantation. However, this approach needs to be confirmed in a larger number of patients.

Cardiac Reverse Remodeling in Ischemic Heart Disease with Novel Therapies for Heart Failure with Reduced Ejection Fraction.

Despite the improvements in the treatment of coronary artery disease (CAD) and acute myocardial infarction (MI) over the past 20 years, ischemic heart disease (IHD) continues to be the most common cause of heart failure (HF). In clinical trials, over 70% of patients diagnosed with HF had IHD as the underlying cause. Furthermore, IHD predicts a worse outcome for patients with HF, leading to a substantial increase in late morbidity, mortality, and healthcare costs. In recent years, new pharmacological therapies have emerged for the treatment of HF, such as sodium-glucose cotransporter-2 inhibitors, angiotensin receptor-neprilysin inhibitors, selective cardiac myosin activators, and oral soluble guanylate cyclase stimulators, demonstrating clear or potential benefits in patients with HF with reduced ejection fraction. Interventional strategies such as cardiac resynchronization therapy, cardiac contractility modulation, or baroreflex activation therapy might provide additional therapeutic benefits by improving symptoms and promoting reverse remodeling. Furthermore, cardiac regenerative therapies such as stem cell transplantation could become a new therapeutic resource in the management of HF. By analyzing the existing data from the literature, this review aims to evaluate the impact of new HF therapies in patients with IHD in order to gain further insight into the best form of therapeutic management for this large proportion of HF patients.

Sacubitril/Valsartan in Heart Failure Hospitalization: Two Pills a Day to Keep Hospitalizations Away?

Heart failure (HF) is a clinical syndrome with signs and symptoms that result from any structural or functional deterioration of ventricular filling or ejection of blood. It is the final stage of various cardiovascular diseases (e.g., coronary artery disease, hypertension, previous myocardial infarction) and remains one of the leading causes of hospitalization. It poses severe health and economic burden worldwide. Patients usually present with shortness of breath due to impaired cardiac ventricular filling and decreased cardiac output. Cardiac remodeling due to the renin-angiotensin-aldosterone system overactivation is the final pathological mechanism leading to these changes. The natriuretic peptide system is also activated to stop the remodeling. Sacubitril/valsartan, an angiotensin-receptor neprilysin inhibitor, has prompted a substantial conceptual change in HF treatment. Its primary mechanism is the inhibition of cardiac remodeling and the prevention of natriuretic peptide degradation by inhibiting the enzyme neprilysin. It is an efficacious, safe, and cost-effective therapy that improves the quality of life and survival rate in patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction. It has been demonstrated to significantly reduce hospitalization rates and rehospitalization for HF when compared to enalapril. In this review, we have discussed the benefits of sacubitril/valsartan in treating patients with HFrEF, particularly in reducing hospitalizations and readmissions. We have also compiled studies to examine the drug's effect on adverse cardiac events. Finally, the cost benefits of the drug and optimal dosing strategies are also reviewed. Our review article, combined with the recommendations of the 2022 American Heart Association guidelines for heart failure, strongly suggests that sacubitril/valsartan is a cost-effective strategy that reduces hospitalizations for HFrEF patients when started early with optimal doses. There is still much uncertainty regarding the optimal usage of this drug, its use in HFrEF, and the cost benefits when used alone compared with enalapril.

Angiotensin Receptor-Neprilysin Inhibitor Therapy and Cardiac Remodeling in Heart Failure: Consensus Statement from India

Adverse cardiac remodeling refers to progressive structural and functional modifications in the heart because of increased wall stress in the myocardium, loss of viable myocardium, and neurohormonal stimulation. The guideline-directed medical therapy for Heart failure (HF) includes Angiotensin receptor-neprilysin inhibitor (ARNI) (sacubitril/valsartan), β-blockers, sodium-glucose co-transporter 2 (SGLT2) inhibitors, and mineralocorticoid receptor antagonists (MRA). ARNI is under-prescribed in India despite its attractive safety and efficacy profile. Therefore, the consensus discusses objectives and topics related to ARNI in the management of cardiac remodeling, and experts shared their views on the early timely intervention of effective dosage of ARNI to improve the diagnosis and enhance mortality and morbidity benefits in cardiac reverse remodeling (CRR).

Efficacy of Sacubitril/Valsartan versus Losartan in Heart Failure Patients with Respect to Improvements in Ejection Fraction and New York Heart Association Functional Class

Background: Heart failure (HF) is a complicated clinical disease that develops when the Left ventricular becomes symptomatic due to anatomical or functional ventricular malfunction. The symptoms emerge from a cardiac output that is insufficient to meet the body's metabolic needs. Globally, HF has emerged as a major health issue, with an estimated prevalence of &gt;37.7 million. While HF with reduced ejection fraction (HFrEF) is more frequently seen in Indian patients, HF with preserved EF seems to be more prevalent in the western population. Objective: This study was conducted to determine the efficacy of sacubitril/valsartan (S/V) versus losartan in patients with HF with respect to improvements in EF and New York Heart Association (NYHA) functional class symptoms. Materials and Methods: A prospective cohort study was conducted on 62 HF patients who are either on angiotensin receptor-neprilysin inhibitor or angiotensin receptor blocker therapy for a period of 6 months, i.e., November 2021 to April 2022, who attended the Inpatient Cardiology Department of Narayana Medical College and Hospital. By using a semi-structured questionnaire, the data was gathered. The 2013 edition of Microsoft Excel and SPSS version 20.0 software were used for data analysis. Results: Subjects in the S/V group showed a 56% reduction in subjects with HFrEF from the beginning to end of the follow-up, while subjects in the losartan group showed only 16% reduction. With respect to NYHA functional class, subjects in the S/V group showed greater reduction in subjects in NYHA class III and NYHA class IV by the end of follow-up when compared to the losartan group. Conclusion: S/V showed better efficacy in improving EF and NYHA functional class when compared to losartan.

Effects of angiotensin receptor-neprilysin inhibitor on insulin resistance in patients with heart failure.

Although the haemodynamic effects of angiotensin receptor-neprilysin inhibitor (ARNI) on patients with heart failure have been demonstrated, the effect on glucose metabolism has not been fully elucidated. We retrospectively investigated the effect of ARNI on abnormal glucose metabolism in patients with stable chronic heart failure using an additional structural equation model (SEM) analysis. We analysed 34 patients who regularly visited to the outpatient department of our institute with heart failure from October 2021 and July 2022 and who were taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Seventeen patients switched from ACE inhibitors or ARBs to an ARNI (ARNI group), and the other 17 patients continued treatment with ACE inhibitors or ARBs (control group). At baseline, although the ARNI group included fewer patients with heart failure with preserved ejection fraction in comparison with the control group (P=0.004), patients with heart failure with mildly reduced ejection fraction, and heart failure with reduced ejection fraction were mostly biased towards the ARNI group (although not statistically significant). The baseline insulin resistance in the ARNI group was already significantly higher in comparison with the control group [fasting blood insulin, 9.7 (7.4, 11.6) vs. 7.8 (5.2, 9.2) μU/mL, P=0.033; homoeostasis model assessment of insulin resistance (HOMA-IR), 3.10 (1.95, 4.19) vs. 2.02 (1.56, 2.42), P=0.014]. Three months later, the fasting blood insulin and the HOMA-IR levels were both found to have decreased in comparison with the baseline values [baseline to 3months: insulin, 9.7 (7.4, 11.6) to 7.3 (4.6, 9.4) μU/mL, P<0.001; HOMA-IR, 3.10 (1.95, 4.19) to 1.96 (1.23, 3.09), P<0.001]. An additional SEM analysis demonstrated that the initiation of ARNI had caused a reduction in the fasting blood insulin and the HOMA-IR levels at 3months independently of the baseline fasting blood insulin and HOMA-IR levels, respectively. Similarly, the initiation of ARNI resulted in a significant reduction in serum uric acid levels (6.28±0.35 to 5.80±0.30mg/dL, P=0.008). In conclusion, even in a short period of only 3months, the administration of ARNI improved insulin resistance and consequently reduced the serum uric acid levels in patients with stable chronic heart failure. Although the ARNI group already had high insulin resistance at baseline, an additional SEM analysis revealed that the decreased insulin resistance was truly due to the effect of ARNI.

Comparison of Efficacy and Safety of Angiotensin Receptor-Neprilysin Inhibitors in Patients With Heart Failure With Reduced Ejection Fraction: A Meta-Analysis.

The present meta-analysis was conducted to compare the safety and efficacy of angiontensin receptor neprilysin inhibitor (ARNI) with angiotensin receptor blockers (ARBs) and angiotensin-converting-enzyme inhibitors (ACEi) in patients with heart failure with reduced ejection fraction (HFrEF).This meta-analysis was conducted and reported in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement.Two authors carried out a scientific literature search on online databases, including EMBASE, PubMed, and the Cochrane Library. The following keywords or corresponding Medical Subject Headings (MeSH) were used for the search of relevant articles: "heart failure with reduced ejection fraction," "angiotensin receptor-neprilysin inhibitor," "Angiotensin receptor blockers," and "clinical outcomes."Outcomes assessed in the present meta-analysis included changes in ejection fraction (EF) from baseline in percentage. Other outcomes assessed in the present meta-analysis included all-cause mortality, cardiovascular death, and hospitalization due to heart failure. Adverse events assessed in the present meta-analysis included hypokalemia, acute kidney injury, and hypotension. Total 10 studies were included. This meta-analysis showed that treatment with ARNI was associated with a significantly lower risk of all-cause mortality and cardiovascular death compared to control groups. There was no significant difference between the two groups in terms of change of EF from baseline or hospitalization related to heart failure. However, the risk of hypotension was significantly higher in patients receiving ARNI. The study findings support the use of ARNI as first-line therapy for heart failure with reduced ejection fraction. Further studies are required to determine the optimal use of ARNI in heart failure management and to investigate the mechanisms underlying the increased risk of hypotension.

Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors Use among Heart Failure Patients and the Role of Pharmacists in Early Initiation of Therapy.

Heart failure (HF) is a growing major public health and economic concern in the United States and worldwide. Heart failure mortality rates can be as high as 75% despite advances in therapies. HF is expected to be the fastest growing among all cardiovascular diseases, with HF-associated direct medical costs projected to nearly double over the next 10 years. Hospital admissions, re-admission, and medical cost are a huge burden to the healthcare system, and this is estimated to have increased gradually over the past decades despite the available advances in HF treatment and prevention. Many heart failure therapies have shown improvement in terms of mortality, morbidity, and symptomatic management. Guideline-directed medical therapy (GDMT) for heart failure has proven its ability to reduce morbidity and mortality by 66%. GDMT is recommended to be used among all HF patients when appropriate. In recent years, two new drug classes, angiotensin receptor-neprilysin inhibitor (ARNi) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, were approved by the United States Food and Drug Administration (US FDA) for the management of heart failure. The exact mechanism by which the SGLT-2 inhibitors attenuate the inflammatory process remains unclear. Several mechanisms have been suggested related to the cardiovascular benefit of SGLT-2 inhibitors, including a reduction in inflammation, improvement in natriuresis/diuresis, and promotion of the use of ketones as a secondary energy source. Clinical data showed that SGLT-2 inhibitors have morbidity and mortality benefits within 30 days of initiation. Studies have proven that clinical pharmacists practicing in HF inpatient and outpatient settings resulted in a reduction of HF hospitalization and an increase in the uptake of GDMT by initiating or up-titrating GDMT agents as well as providing patient education.

A comparative study between angiotensin receptor neprilysin inhibitor (thiorphan/irbesartan) with each of nitrate and carvedilol in a rat model of myocardial ischemic reperfusion injury.

The combined angiotensin receptor neprilysin inhibitor is a promising cardioprotective pharmacological agent. This study investigated the beneficial effects of thiorphan (TH)/irbesartan (IRB), in myocardial ischemia-reperfusion (IR) injury, compared to each of nitroglycerin and carvedilol. Male Wistar rats were divided into five groups (10 rats/group): Sham, untreated I/R, TH/IRB + IR (0.1/10mg/kg), nitroglycerin + IR (0.2mg/kg), and carvedilol + IR (10mg/kg). Mean arterial blood pressure, cardiac functions and arrhythmia incidence, duration and score were assessed. Cardiac levels of creatine kinase-MB (CK-MB), oxidative stress, endothelin-1, ATP, Na+ /K+ ATPase pump activity and mitochondria complexes activities were measured. Histopathological examination, Bcl/Bax immunohistochemistry studies and electron microscopy examination of left ventricle were performed. TH/IRB preserved the cardiac functions and mitochondrial complexes activities, mitigated cardiac damage, reduced oxidative stress and arrhythmia severity, improved the histopathological changes and decreased cardiac apoptosis. TH/IRB showed a comparable effect to each of nitroglycerin and carvedilol in alleviating the IR injury consequences. TH/IRB showed significant preservation of mitochondrial complexes activity I and II compared to nitroglycerin. TH/IRB significantly increased LVdP/dtmax and decreased oxidative stress, cardiac damage and endothelin-1 along with increasing the ATP content, Na+ /K+ ATPase pump activity and mitochondrial complexes activity when compared to carvedilol. TH/IRB showed a cardioprotective effect in reducing IR injury that is comparable to each of nitroglycerin and carvedilol that could be explained in part by its ability to preserve mitochondrial function, increase ATP, decrease oxidative stress as well as endothelin 1.

The impact of heart failure therapy in patients with mildly reduced ejection fraction: a network meta-analysis.

Recent heart failure (HF) guidelines have re-classified HF patients with left ventricular ejection fraction (LVEF) between 41% and 49% as HF with mildly reduced ejection fraction (HFmrEF). HFmrEF treatment is often considered a grey zone as no randomized controlled trials (RCTs) were conducted exclusively on these patients. A network meta-analysis (NMA) was performed to compare treatment effect of mineralocorticoid receptor antagonists (MRA), angiotensin receptor neprilysin inhibitor (ARNi), angiotensin receptor blockers (ARB), angiotensin-converting-enzyme inhibitors (ACEi), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and beta-blockers (BB) in HFmrEF cardiovascular (CV) outcomes. RCTs sub-analyses evaluating the efficacy of pharmacological treatment in HFmrEF patients were searched. Hazard ratios (HRs) and their variance were extracted from each RCT for (i) composite of CV death or HF hospitalizations, (ii) CV death, and (iii) HF hospitalizations. A random-effects NMA was performed to compare and assess the treatment efficiency. Six RCTs with subgroup analysis according to participants' ejection fraction, a patient-level pooled meta-analysis of two RCTs, and an individual patient-level analysis of eleven BB RCTs were included, totalling 7966 patients. To our primary endpoint, SGLT2i vs. placebo was the only comparison with significant results, with a 19% risk reduction in the composite of CV death or HF hospitalizations [HR 0.81, 95% confidence interval (CI) 0.67-0.98]. In HF hospitalizations, the impact of the pharmacological therapies was more notorious, and ARNi reduced in 40% the risk of HF hospitalizations (HR 0.60, 95% CI 0.39-0.92), SGLT2i in 26% (HR 0.74, 95% CI 0.59-0.93) and renin-angiotensin system inhibition (RASi) with ARB and ACEi in 28% (HR 0.72, 95% CI 0.53-0.98). Although BBs were globally less beneficial, they were the only class that supported a reduced risk of CV death (HR vs. placebo: 0.48, 95% CI 0.24-0.95). We did not observe a statistically significant difference in any comparison between active treatments. There was a sound reduction with ARNi on the primary endpoint (HR vs. BB: 0.81, 95% CI 0.47-1.41; HR vs. MRA 0.94, 95% CI 0.53-1.66) and on HF hospitalizations (HR vs. RASi 0.83, 95% CI 0.62-1.11; HR vs. SGLT2i 0.80, 95% CI 0.50-1.30). In addition to SGLT2i, pharmacological treatment recommended for HF with reduced LVEF, namely, ARNi, MRA, and BB, can also be effective in HFmrEF. This NMA did not show significant superiority over any pharmacological class.