Angiotensin Receptor Neprilysin Inhibitor In Patients Research Articles

Sacubitril/valsartan reduces proteinuria depending on blood pressure in patients with stage 4-5 chronic kidney disease.

Blood pressure (BP) control is an important factor in the management of chronic kidney disease (CKD). Several studies have shown that BP in many patients with CKD remained uncontrolled even with multiple medications. Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), has been newly approved for treating hypertension in Japan. However, the renoprotective effects remain unclear, particularly in patients with advanced CKD. Here, we investigated the effects on proteinuria of this ARNI in patients with stage 4-5 CKD. We retrospectively collected data from outpatients with stage 4-5 CKD who started ARNI from January until December 2023. The primary outcome was the change in urine protein creatinine ratio (UPCR) at 6months after ARNI initiation. Secondary outcomes were systolic and diastolic BP, estimated glomerular filtration rate (eGFR), serum potassium, and serum uric acid (UA). We analyzed factors associated with 50% UPCR reduction by multivariate analysis. In total, 47 patients were analyzed. ARNI reduced UPCR from 2.14g/gCr (interquartile range; 1.09-2.91) to 1.05g/gCr (0.42-1.95; p < 0.001). Systolic BP fell from 150.0mmHg (139.5-160.0) to 134.0mmHg (124.5-140.0; p < 0.001). No significant changes in eGFR, serum potassium, and serum uric acid were observed, except for a slight decrease in eGFR among patients with conversion from a renin-angiotensin system inhibitor to ARNI. In multivariate regression analysis, higher systolic BP (per 10-mmHg increase) was significantly associated with reduced proteinuria (odds ratio 2.51, 95% confidence interval 1.35-4.66; p = 0.004). ARNI reduced proteinuria in patients with stage 4-5 CKD, particularly for those with uncontrolled hypertension.

Efficacy and safety of angiotensin receptor-neprilysin inhibition in heart failure patients with end-stage kidney disease on maintenance dialysis: A systematic review and meta-analysis.

Angiotensin receptor-neprilysin inhibitor (ARNI) has played an increasingly important role in the management of heart failure (HF). However, the evidence on the benefits of ARNI in HF patients with end-stage kidney disease (ESKD) undergoing dialysis is limited. This study aimed to investigate the efficacy and safety of ARNI in patients with concomitant HF and ESKD on maintenance dialysis. We systematically searched the MEDLINE, Embase, Web of Science, Cochrane, and ClinicalTrials.gov databases for studies reporting outcomes after ARNI treatment in HF patients with ESKD on dialysis. All meta-analyses were performed using the random effects model. Twenty-six studies comprising 2494 patients with concomitant HF and ESKD undergoing dialysis were included. Our synthesis showed a significant improvement in left ventricular ejection fraction (LVEF) between before and after ARNI treatment (mean change: 8.05%; 95% confidence interval [CI] 5.57-10.54). Compared to the conventional group, the ARNI group showed a greater improvement in LVEF (mean difference: 4.03%; 95% CI 2.90-5.16). This effect was more pronounced in patients with HF with reduced ejection fraction (pinteraction < 0.0001). Patients treated with ARNI had a lower risk of all-cause mortality (risk ratio [RR] 0.64; 95% CI 0.45-0.92; p = 0.01) but had a similar rate of HF hospitalization (RR 0.71; 95% CI 0.43-1.18; p = 0.19). ARNI treatment showed benefits in the improvement of left ventricular end-systolic diameter, left ventricular mass index, left atrial diameter, and E/e' ratio (p < 0.05), while it did not significantly increase the risk of severe hyperkalaemia (p = 0.33) or symptomatic hypotension (p = 0.53). This meta-analysis provided insights into the benefits of ARNI in HF patients with ESKD undergoing dialysis by improving left ventricular function, reversing left ventricular remodelling, and reducing the risk of all-cause mortality, without increasing the risk of HF hospitalizations, severe hyperkalaemia, and symptomatic hypotension.

Efficacy of early administration of sacubitril/valsartan after coronary artery revascularization in patients with acute myocardial infarction complicated by moderate-to-severe mitral regurgitation: a randomized controlled trial.

Effects of angiotensin receptor/neprilysin inhibitors (ARNI) on ventricular remodeling in patients with heart failure, especially heart failure with reduced ejection fraction (HFrEF), are better than those of angiotensin-converting enzyme inhibitors (ACEI). Acute myocardial infarction (AMI) complicated by mitral regurgitation exacerbates ventricular remodeling and increases the risk of heart failure. There is limited evidence on the effects of early administration of ARNI in patients with AMI complicated by mitral regurgitation. The aim of this trial was to examine the effectiveness and the safety of early administration of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation. This was a randomized, single-blind, parallel-group, controlled trial. From June 2021 to June 2022, we enrolled 142 consecutive patients with AMI complicated by moderate-to-severe mitral regurgitation and followed them for 12months. The patients received standard treatment for AMI and were randomly assigned to receive ARNI or benazepril. The primary efficacy end points were the differences in mitral regurgitant jet area (MRJA), mitral regurgitant volume (MRV), concentration of n-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), and left ventricular end-diastolic volume and end-systolic volume (LVEDV and LVESV) between groups and within groups at baseline, 1, 3, 6, and 12months. Secondary end points included the rates of heart failure hospitalization, all-cause mortality, refractory angina, malignant arrhythmias, recurrent myocardial infarction, and stroke. Safety end points included the rates of hyperkalemia, renal dysfunction, hypotension, angioedema, and cough. The ARNI group had significantly lower NT-proBNP levels than the benazepril group at 1month and later (P < 0.001). MRJA and MRV significantly improved in the ARNI group compared with the benazepril group at 12months (MRJA: - 3.21 ± 2.18 cm2 vs. - 1.83 ± 2.81 cm2, P < 0.05; MRV: - 27.22 ± 15.22mL vs. - 13.67 ± 21.02mL, P < 0.001). The ARNI group also showed significant reductions in LVEDV and LVESV (P < 0.05) and improvement in LVEF (P < 0.05). Secondary end point analysis showed a significantly higher rate of heart failure hospitalization in the benazepril group compared with the ARNI group (HR = 2.03, 95% CI 1.12-3.68, P = 0.021). Safety end point analysis showed a higher rate of hypotension in the ARNI group (P < 0.05). Early use of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation can significantly reduce mitral regurgitation, improve ventricular remodeling, and decrease heart failure hospitalization. Nevertheless, caution is needed to avoid hypotension. Chinese Clinical Trial Registry (ChiCTR2100054255) registered on December 11, 2021.

Real-world experience of angiotensin receptor-neprilysin inhibitors in patients with heart failure and dialysis.

Although angiotensin receptor-neprilysin inhibitor (ARNI) has shown promise in patients with heart failure and reduced ejection fraction (HFrEF), the treatment effect in HFrEF patients with end-stage renal disease (ESRD) undergoing dialysis is uncertain. This study aimed to examine the real-world effects of ARNI vs. angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) in this subpopulation. This multi-institutional, retrospective study identified 349 HFrEF patients with ESRD on dialysis, who initiated either ARNI or ACEI/ARB therapy. Efficacy outcomes included rates of hospitalization for heart failure (HHF) and mortality, as well as changes in echocardiographic parameters. Safety outcomes encompassed hypotension and hyperkalemia. Treatment effects were assessed using Cox proportional hazards models, with additional sensitivity analyses for robustness. Out of 349 patients screened, 89 were included in the final analysis (42 in the ARNI group and 47 in the ACEI/ARB group). After 1 year of treatment, echocardiographic measures between the two groups were comparable. The primary composite rate of HHF or mortality was 20.6 events per 100 patient-years in the ARNI group and 26.1 in the ACEI/ARB group; the adjusted hazard ratio was 0.98 (95% CI: 0.28-3.43, P = 0.97). Their safety outcomes did not differ significantly. Sensitivity analyses, including repetitive sampling, propensity score matching, and extended follow-up, corroborated these findings. ARNI has proven effective in treating HFrEF patients; however, significant benefits were not observed in these patients with ESRD undergoing dialysis compared with ACEI/ARB in this real-world cohort. Future research employing a more extended follow-up period, larger sample size, or randomized design is warranted to investigate the treatment effects in this subpopulation.

Potential Effects of Sacubitril/Valsartan on the Cardio-ankle Vascular Index in Hypertensive Patients.

Objective Angiotensin receptor-neprilysin inhibitors (ARNIs) have been widely used as a treatment for heart failure. However, they have only been approved for the treatment of hypertension in a limited number of countries. We investigated the effect of ARNIs on arterial stiffness using the cardio-ankle vascular index (CAVI) in patients with hypertension to reveal the mechanism underlying cardiovascular interaction. Methods We investigated the utility of ARNIs in patients in whom arterial stiffness was assessed using the CAVI before and after ARNI administration. Patients In this retrospective observational study, we enrolled 50 patients with hypertension treated with ARNIs between January 2021 and 2023. Forty-eight of the 50 patients (96%) were switched from angiotensin II receptor blockers (ARBs) due to inadequate antihypertensive control. Results The systolic blood pressure (BP), diastolic BP, and CAVI were significantly decreased by ARNI administration (systolic BP: 145 [135, 162] to 131 [123, 143] mmHg [p=0.000]; diastolic BP: 92 [78, 100] to 82 [74, 89] mmHg [p=0.000]; and CAVI: 9.9 [9.1, 10.5] to 9.5 [8.8, 10.2] mmHg [p=0.005], respectively). Conclusion Hypertension treatment with ARNIs may improve not only the blood pressure but also the CAVI, reducing the afterload on the heart.

Irreversible myocardial injury attenuates the benefits of sacubitril/valsartan in heart failure patients

BackgroundDespite the established benefits of angiotensin receptor-neprilysin inhibitor (ARNI) in heart failure with reduced ejection fraction (HFrEF) across various etiologies, there are controversies regarding the effects of ARNI in patients with irreversible myocardial injury. The aim of this study is to investigate the impact of irreversible myocardial injury on the benefits of ARNI treatment in patients with HFrEF, consisted of both ischemic and non-ischemic etiologies. Methods and resultsWe conducted a retrospective single-center study including 409 consecutive patients with HFrEF treated with ARNI between March 2017 and May 2020. Irreversible myocardial injury was defined as nonviable myocardium without contractile reserve, which suggests a limited potential for recovery of left ventricular function and geometry. At baseline, irreversible myocardial injury was observed in 129 (31.5%) patients. Composite outcome was cardiovascular death or hospitalization for heart failure, which occurred in 56 (43.4%) and 61 (21.8%) patients with and without irreversible myocardial injury, respectively. On multivariable analysis, irreversible injury presence, but not ischemic etiology, was an independent predictor of composite outcome (hazard ratio 2.16, 95% confidence interval 1.33–3.49). Mediation analysis revealed that the increased risk of the composite outcome due to irreversible myocardial injury was mediated by attenuated LV reverse remodeling (Z value = 2.02, P = 0.043). ConclusionsThe presence of irreversible myocardial injury was significantly associated with the response to ARNI treatment in patients with HFrEF, regardless of etiology.

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.

Diuretic and renal effects of angiotensin receptor-neprilysin inhibitor in patients hospitalized for acute heart failure.

In patients hospitalized for acute decompensation of heart failure (HF), the impact of angiotensin receptor-neprilysin inhibitor (ARNI) on diuresis and renal function has not been fully investigated. Patients with HF and reduced ejection fraction who were hospitalized for acute decompensation and newly initiated ARNI after hemodynamic stabilization were enrolled. Changes in urine volume (UV), body weight, estimated glomerular filtration rate (eGFR), and urine N-acetyl-beta-d-glucosaminidase (uNAG) levels before and after ARNI initiation were investigated. Changes in the diuretic response [DR, calculated as urine volume/(intravenous furosemide volume/40mg)], N-terminal pro-brain natriuretic peptide (NT-proBNP), hematocrit, and plasma volume (PV) were also evaluated. A total of 60 patients were enrolled. ARNI was initiated at a median of 6 [5, 7] days after hospitalization. After initiation of ARNI, body weight, NT-proBNP, and PV decreased. UV and DR increased only on the day of ARNI initiation (delta UV 400 ± 957ml and delta DR 1100 ± 3107ml/40mg furosemide) and then decreased to baseline levels. In the multivariable linear regression analysis, younger age, higher BMI, and higher NT-proBNP levels were significantly associated with greater UV after ARNI initiation. eGFR and uNAG did not significantly change after the initiation of ARNI [delta eGFR -1.7 ± 12.0mL/min/1.73 m2 and delta uNAG 2.0 (-5.6, 6.9) IU/L]. In patients hospitalized for HF, the initiation of ARNI was associated with a small and transient increase in UV and DR, and was not associated with worsening of renal function or tubular injury.

Neprilysin Inhibition in the Prevention of Anthracycline-Induced Cardiotoxicity.

Anthracycline-induced cardiotoxicity (AIC) poses a clinical challenge in the management of cancer patients. AIC is characterized by myocardial systolic dysfunction and remodeling, caused by cardiomyocyte DNA damage, oxidative stress, mitochondrial dysfunction, or renin-angiotensin-aldosterone system (RAAS) dysregulation. In the past decade, after positive results of a PARADIGM-HF trial, a new class of drugs, namely angiotensin receptor/neprilysin inhibitors (ARNi), was incorporated into the management of patients with heart failure with reduced ejection fraction. As demonstrated in a variety of preclinical studies of cardiovascular diseases, the cardioprotective effects of ARNi administration are associated with decreased oxidative stress levels, the inhibition of myocardial inflammatory response, protection against mitochondrial damage and endothelial dysfunction, and improvement in the RAAS imbalance. However, data on ARNi's effectiveness in the prevention of AIC remains limited. Several reports of ARNi administration in animal models of AIC have shown promising results, as ARNi prevented ventricular systolic dysfunction and electrocardiographic changes and ameliorated oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and the inflammatory response associated with anthracyclines. There is currently an ongoing PRADAII trial aimed to assess the efficacy of ARNi in patients receiving breast cancer treatment, which is expected to be completed by late 2025.

Safety and effectiveness of angiotensin receptor-neprilysin inhibitors in patients with heart failure with preserved ejection fraction (ARNI-PRESERVED study)

Abstract Funding Acknowledgements Type of funding sources: None. Background The goal of this study is to look at the safety and efficacy of ARNI (valsartan/sacubitril), a combination of angiotensin II receptor blocker and neprilysin inhibitor (ARNI), in patients with heart failure with preserved ejection fraction (HFpEF). Purpose ARNI decreases the hazard of cardiovascular death and hospitalization in patients with chronic HFrEF (NYHA Class II–IV). Although there are several evidence based therapies for HFrEF, there is no effective therapy for HFpEF at the presently. In Paragon-HF trial, ARNI demonstrated a minimal evidence of additional improvements in patients with HFpEF Material and methods A retrospective research with a clinical population was carried out. A total of 154 HFpEF patients (87 females and 67 males) were treated with ARNI, which was subsequently titrated up to a maximum tolerable dose and monitored in an outpatient clinic. 56 patients were given ARNI while in the hospital for decompensated heart failure before being discharged. Results Patients were categorized as New York Heart Association (NYHA) class III (71.4%) and NYHA class II (28.6%). Diabetes mellitus was identified in 52% of patients, while hypertension was found in 78%. Symptomatic clinical improvement was observed, with a substantial decrease in NYHA class down to NYHA class II (p=0.018). A considerable decrease in NYHA class resulted in symptomatic clinical improvement as well as the rales and peripheral oedema had resolved (p&amp;lt;0.001). The NT-pro-BNP levels were considerably lowered (p&amp;lt;0.001). The echocardiographic parameters for diastolic function (E/A, E/E’ ratios) improved. In individuals with HFpEF, ARNI resulted in significant clinical benefits (Table -1). Conclusion In individuals with HFpEF, sacubitril/valsartan, ARNI resulted in significant clinical benefits A randomized research is also required to see if it results in beneficial outcomes for a wider sample.

Angiotensin Receptor-Neprilysin Inhibitors in Patients With Heart Failure With Reduced Ejection Fraction and Advanced Chronic Kidney Disease: A Retrospective Multi-Institutional Study.

BackgroundData regarding using angiotensin receptor-neprilysin inhibitor (ARNI) in patients with both heart failure with reduced ejection fraction (HFrEF) and advanced chronic kidney disease (CKD) are limited.Methods and ResultsBetween January 2016 and December 2018, patients with HFrEF and advanced CKD (estimated glomerular filtration rate [eGFR] ≤ 30 mL/min/1.73 m2) were identified from a multi-institutional database in Taiwan. Patients who had never been prescribed with an ARNI, angiotensin-converting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB) were excluded. We used inverse probability of treatment weighting (IPTW) to balance baseline covariates, and compared outcomes between ARNI and ACEI/ARB users. There were 206 patients in the ARNI group and 833 patients in the ACEI/ARB group. After IPTW adjustment, the mean ages (65.1 vs. 66.6 years), male patients (68.3 vs. 67.9%), left ventricular ejection fraction (30.5 vs.31.2%), eGFR (20.9 vs. 20.3 mL/min/1.73 m2) were comparable in the ARNI and ACEI/ARB groups. Over 85% of the patients had beta-blockers prescriptions in both groups (86.2 vs. 85.5%). After IPTW adjustment, the mean follow-up durations were 7.3 months and 6.6 months in the ARNI and ACEI/ARB groups, respectively. ARNI and ACEI/ARB users had a comparable risk of the composite clinical event (all-cause mortality or heart failure hospitalization) (hazard ratio [HR], 1.31; 95% confidence interval (CI) 0.91–1.88) and progression to dialysis (HR 1.04; 95% CI 0.54–2.03). In subgroup analysis, dialysis patients who used ARNIs were associated with higher incidence of heart failure hospitalization (subdistribution HR, 1.97; 95% CI 1.36–2.85).ConclusionsCompared with ACEIs or ARBs, ARNIs were associated with comparable clinical and renal outcomes in patients with HFrEF and advanced CKD (eGFR ≤ 30 mL/min/1.73 m2). In short-term, HF hospitalization may occur more frequently among ARNI users, especially in patients on dialysis.

Angiotensin receptor-neprilysin inhibitor in patients with heart failure and chronic kidney disease.

Despite significant advances in the management of heart failure with reduced ejection fraction (HFrEF), there remains an enormous health problem with high morbidity and mortality over the last few decades. The neprilysin inhibitor enhances the activity of natriuretic peptides, producing vasodilation, natriuresis, and diuresis. Angiotensin receptor blockers inhibit the renin-angiotensin-aldosterone system. Sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI), has been shown to improve cardiovascular outcomes in HFrEF and delay the progression of chronic kidney disease (CKD) in patients with HFrEF. The PARADIGM-HF study showed a reduction in diuretic need in the ARNI group. While the use of diuretics is effective in volume control in patients with HFrEF, their use has the potential to adversely affect renal function. Therefore, ARNI therapy could benefit patients with heart failure and CKD by reducing cardiovascular morbidity and mortality and possibly retarding the progression of CKD, although more clinical evidence is required in patients with severe CKD and end-stage renal disease.

Abstract 10044: Efficacy of Sacubitril-Valsartan in Patients with Reduced Left Ventricular Ejection Fraction

Introduction: Angiotensin receptor-neprilysin inhibitor (ARNI) reduces death and heart failure (HF) hospitalization in patients with HF and reduced ejection fraction (HFrEF). In addition to the PARADIGM-HF, PARADISE-MI and LIFE trial has recently tested the safety and efficacy of ARNI in subgroups of patients with reduced left ventricular ejection fraction (LVEF) such as those patients at risk for HFrEF after myocardial infarction (without prior HF) and advanced HF patients. Methods: We performed a random-effects model meta-analysis of three randomized controlled trails investigating the effect of ARNI in patients with reduced LVEF. The main endpoints were the composite of cardiovascular death and HF hospitalization, and HF hospitalization. Results: A total of 14,395 patients were included in our analysis. The characteristics of the included studies are demonstrated on Table 1. The composite endpoint and HF hospitalization were non-significantly reduced with ARNI compared with angiotensin-converting enzyme inhibitor or angiotensin II receptor blockers (composite endpoint adjusted hazard ratio [HR] 0.9, 95% confidence intervals 0.75-1.08 and HF hospitalizations: HR 0.87, 0.72-1.04, Figure 1). The heterogeneity among trials was high (I 2 &gt;50%). Conclusions: In line with the recently reported trials, our findings support the use of ARNI in patients with HFrEF that meet the inclusion criteria of PARADIGM-HF trial. It is important to tailor medical therapy by matching individual patient profiles to inclusion criteria of the published randomized clinical trials.

Acute Tubular Necrosis Associated with Angiotensin Receptor-neprilysin Inhibitor

Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), significantly reduces mortality and morbidity in patients with chronic heart failure with a reduced ejection fraction (HFrEF). However, a considerable number of patients treated with sacubitril/valsartan experience hypotension, oliguria, progressive azotemia, and renal failure as adverse events. These issues have been linked to significant gaps in the usage and dosing of guideline-directed medical therapy with ARNI in patients with HFrEF. We herein report a relevant case of pathologically proven acute tubular necrosis after the first dose of sacubitril/valsartan, highlighting the importance of optimizing the medical therapy in an outpatient with HFrEF.

New ACC guidance focuses on optimizing care in patients with HFrEF

Management of patients with heart failure (HF) has evolved over the past few years, prompting the American College of Cardiology (ACC) to release an updated Expert Consensus Decision Pathway to provide guidance and recommendations on the clinical care of patients with HF with a reduced ejection fraction (HFrEF). The update focuses on 10 pivotal issues in patients with HFrEF (see sidebar). “New therapies for HFrEF have emerged that expand the armamentarium for the treatment of patients with HFrEF,” wrote the guideline authors. “In particular, the emergence of angiotensin receptor–neprilysin inhibitors (ARNIs), sodium–glucose cotransporter-2 (SGLT2) inhibitors, and percutaneous therapy for mitral regurgitation represent significant advances in the treatment of HFrEF.” Following the publication of the previous guideline in 2017, data have emerged to support the expanded role of ARNIs in patients with HFrEF. ACC’s updated guideline notes that the ARNI sacubitril/valsartan (Entresto—Novartis) is the preferred agent, with an angiotensin-converting enzyme in-hibitor (ACEI)/angiotensin receptor blocker (ARB) recommended for those in whom ARNI administration is not possible. The guidance states that the totality of the data supports a direct-to-ARNI approach and gives recommendations on how to initiate therapy in ACEI/ARB–naive patients or those who may be switching from an ACEI/ARB treatment to an ARNI. To avoid the potential for angioedema, a 36-hour waiting period is required before initiating an ARNI in patients who were previously on an ACEI, the guideline states. No waiting period is needed if switching from an ARB to an ARNI. The guideline recommends that ARNIs be given in conjunction with evidence-based beta-blockers—carvedilol, metoprolol succinate, or bisoprolol—and a diuretic agent. The guideline also discusses the emerging data with use of SGLT2 inhibitors in patients with HFrEF. Data for dapagliflozin (Farxiga’AstraZeneca) and empagliflozin (Jardiance’Boehringer Ingelheim, Lilly) show a reduced risk of major events in patients with HFrEF regardless of the presence of diabetes. These agents can be used in conjunction with guideline-directed medical therapy in patients meeting specific eGFR criteria. Ivabradine (Corlanor’Amgen) can be used as an add-on for patients with a resting heart rate of 70 or higher who are on a maximally tolerated dose of a beta-blocker and in sinus rhythm. The importance of titrating medications is also discussed, with adjustments to treatments recommended every 2 weeks, after an HF diagnosis (as tolerated). The goal is to achieve optimal treatment doses within 3 to 6 months after the initial diagnosis. Follow-up assessments should focus on the patient’s clinical status, blood pressure measurements, and kidney function (and electrolytes). In a section on strategies to improve adherence in patients with HFrEF, the guideline suggests simplifying the medication regimen whenever possible; considering the cost of medications and access (e.g., proactively discuss out-of-pocket costs with patients); educating using practical, patient-friendly information; and anticipating problems that may arise (e.g., communicate adverse effects, discuss when to refill prescriptions). The guidance notes that the language has shifted from one of “compliance” to “adherence” and now to “activation,” “engagement,” and “empowerment.” It adds that the integration of pharmacists, patient navigators, and registered nurses in collaborative practice may help with optimization of guideline-directed medication therapy for patients with HFrEF. 10 pivotal issues in patients with HFrEF▪How to initiate, add, or switch therapies to new evidence-based, guideline-directed treatments▪How to achieve optimal therapy given multiple drugs for HF▪When to refer to an HF specialist▪How to address challenges in coordination of care▪How to improve medication adherence▪What is needed in specific patient cohorts (e.g., Black Americans, older adults)▪How to manage costs and access to HF medications▪How to manage increasing complexity of HF▪How to manage common comorbidities▪How to integrate palliative care and the transition into hospice careSource: www.jacc.org/doi/pdf/10.1016/j.jacc.2020.11.022. ▪How to initiate, add, or switch therapies to new evidence-based, guideline-directed treatments▪How to achieve optimal therapy given multiple drugs for HF▪When to refer to an HF specialist▪How to address challenges in coordination of care▪How to improve medication adherence▪What is needed in specific patient cohorts (e.g., Black Americans, older adults)▪How to manage costs and access to HF medications▪How to manage increasing complexity of HF▪How to manage common comorbidities▪How to integrate palliative care and the transition into hospice care Source: www.jacc.org/doi/pdf/10.1016/j.jacc.2020.11.022.

Crossing the chasm: caution for use of angiotensin receptor-neprilysin inhibition in patients with cardiogenic shock- a case report.

BackgroundVasoplegia has been reported in patients receiving angiotensin receptor-neprilysin inhibitors (ARNI) with heart failure with reduced ejection fraction (HFrEF). We present a case of vasoplegic shock after initiation of ARNI in a hospitalized 65-year-old man recovering from cardiogenic shock (CS) and acute kidney injury (AKI).Case summaryA 65-year-old man with HFrEF presented to a community hospital with CS with evidence of poor perfusion with a lactate of 5.6 mmol/L and creatinine (Cr) 125 µmol/L. He was treated with intravenous furosemide infusion. Subsequently, his lactate normalized but he developed an AKI with a Cr of 176 µmol/L. He was then started on ARNI and beta blockers. Over the next 24 h, he developed a vasoplegic shock necessitating multiple vasopressors and a transfer to a tertiary academic centre. With supportive therapy, his vasoplegic shock improved and he was discharged home.DiscussionPARADIGM-HF found that the introduction of an ARNI in patients with ambulatory symptomatic HFrEF reduces the risk of death and heart failure hospitalization. Most recently, PIONEER-HF showed that ARNI reduced N-terminal pro-B-type natriuretic peptide levels at 4 and 8 weeks, without significantly different rates of medication-related adverse effects. However, thus far, no clinical trials have examined the role of ARNI in CS. Our case report highlights the risk of vasoplegic shock caused by initiation of ARNI in patients hospitalized with CS especially in whom renal and hepatic impairment is present.

Changes in QRS Duration Are Associated with a Therapeutic Response to Sacubitril-valsartan in Heart Failure with Reduced Ejection Fraction.

BACKGROUNDRecent studies have demonstrated that angiotensin receptor neprilysin inhibitors (ARNIs) can reverse the cardiac remodeling effects that occur in heart failure with reduced ejection fraction (HFrEF). These studies have also suggested that ARNIs have favorable effects on ventricular dyssynchrony. We assessed the changes in QRS duration associated with ARNIs in patients with HFrEF.METHODSWe retrospectively investigated patients with HFrEF (defined by a left ventricular ejection fraction [LVEF] ≤ 35%) who were treated with ARNIs for at least six months. We divided the patients into QRS shortening and non-QRS shortening groups according to their electrocardiogram (ECG) findings. We also compared changes in echocardiographic parameters between the groups.RESULTSA total of 68 patients with HFrEF were included (mean age: 62.5 years, 74.6% male). Twenty-one patients had significant ischemic heart disease (IHD). Thirty-five patients exhibited QRS-duration shortening on follow-up ECGs (mean change: −7.8 msec), and 33 patients showed no changes or increased QRS duration (mean change: 5.1 msec). The QRS shortening group exhibited significant improvement in LVEF (12.5 ± 15.3% vs. 1.7 ± 9.5%; p < 0.001) when compared with the non-QRS shortening group. The QRS shortening group also had significantly lower LV end-diastolic dimension (LVEDD), LV end-systolic dimension (LVESD) and LV mass index (LVMI) than did the non-QRS shortening group. The change in QRS duration was significantly correlated with the change in LVEF (r = -0.329, p = 0.011) and LVESD (r = 0.298, p = 0.022).CONCLUSIONSAmong patients with HFrEF treated with ARNIs, the QRS shortening group showed favorable LV systolic function recovery, and reversal of cardiac remodeling compared to those of the non-QRS shortening group. Change in the QRS duration, which reflects LV synchrony, may be associated with response to ARNIs in patients with HFrEF.