Sacubitril/Valsartan Off-Label Uses for Heart Failure

Sacubitril/valsartan is an angiotensin receptor/neprilysin inhibitor that the Food and Drug Administration has indicated to reduce the risk of cardiovascular hospitalization and death in patients with left ventricular ejection fraction below normal and with no specified ejection-fraction cut-off. However, clinically significant patient groups were excluded or minimally represented in sacubitril/valsartan's pivotal clinical trials. Clinicians often encounter scenarios in which a sacubitril/valsartan off-label use may be beneficial, but limited resources are available to evaluate the efficacy and safety in these patients. This state-of-the-art review describes contemporary literature for sacubitril/valsartan Food and Drug Administration off-label indications to help clinicians assess its appropriateness in these selected, clinically important groups of patients: those with acute decompensated heart failure, acute coronary syndrome, peripartum cardiomyopathy, chemotherapy-induced cardiomyopathy, adult congenital heart disease, cardiomyopathy in dialysis patients, right ventricular failure, or durable left ventricular assist device.     

沙库巴曲缬沙坦在心血管疾病中应用研究进展

近年来,多项研究表明沙库巴曲缬沙坦治疗射血分数降低的心力衰竭(HFrEF)效果优于传统药物血管紧张素转换酶抑制剂(ACEI)/血管紧张素Ⅱ受体阻滞剂(ARB)。2019年欧洲心脏病学会专家共识会议报告指出,沙库巴曲缬沙坦可作为新发HFrEF或失代偿性心力衰竭〔左心室射血分数(LVEF)<40%〕住院或门诊患者的起始治疗方案。本文综述沙库巴曲缬沙坦在多种心血管疾病如HFrEF、射血分数中间值的心力衰竭、射血分数保留的心力衰竭、急性失代偿性心力衰竭、急性心肌梗死、高血压、慢性肾脏病、糖尿病、儿童心力衰竭中的研究进展,并分析其安全性和不良反应,同时指出未来研究方向。     

A narrative review on sacubitril/valsartan and ventricular arrhythmias

Sacubitril/valsartan, the first angiotensin receptor neprilysin inhibitor approved by the Food and Drug Administration for marketing, has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms in patients with chronic heart failure with a reduced ejection fraction. However, some researchers have also found that sacubitril/valsartan has an antiarrhythmic effect. The mechanism by which sacubitril/valsartan reduces the mortality associated with malignant ventricular arrhythmias is not precise. Many studies have concluded that ventricular arrhythmia is associated with a reduction in myocardial fibrosis. This article reviews the current understanding of the effects of sacubitril/valsartan on the reduction of ventricular arrhythmia and explains its possible mechanisms. The results of this study suggest that sacubitril/valsartan reduces the occurrence of appropriate implantable cardioverter-defibrillator shocks. Meanwhile, sacubitril/valsartan may reduce the occurrence of ventricular arrhythmias by affecting 3 pathways of B-type natriuretic peptide, Angiotensin II, and Bradykinin. The conclusion of this study is that sacubitril/valsartan reduces the number of implantable cardioverter-defibrillator shocks and ventricular arrhythmias in heart failure with reduced ejection fraction patients.     

The Effect of Sacubitril/Valsartan on Left Ventricular Myocardial Deformation in Heart Failure with Preserved Ejection Fraction (PARAMOUNT trial)

BackgroundGlobal longitudinal strain (GLS) and global circumferential strain (GCS) have been shown to be impaired in heart failure with preserved ejection fraction. We sought to assess whether treating patients with heart failure with preserved ejection fraction with sacubitril/valsartan would significantly improve GLS and GCS compared with valsartan alone.Methods and ResultsPARAMOUNT (Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction Trial) was a phase II, randomized, parallel-group, double-blind multicenter trial in 301 patients with New York Heart Association functional class II–III heart failure, a left ventricular ejection fraction of 45%, and an N-terminal pro-B-type natriuretic peptide of ≥400 pg/mL. Participants were randomly assigned (1:1) to sacubitril/valsartan titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily for 36 weeks. We assessed changes in the GLS and the GCS from baseline to 36 weeks, adjusting for baseline value, in patients with sufficient imaging quality for 2-dimensitonal speckle tracking analysis at both timepoints (n = 60 sacubitril/valsartan, n = 75 valsartan only). GCS was significantly improved at 36 weeks in the sacubitril/valsartan group when compared with the valsartan group (Δ4.42%, 95% confidence interval [CI] 0.67–8.17, P = .021), with no significant difference observed in GLS (Δ0.25%, 95% CI, –1.19 to 1.70, P = .73). Patients with a history of hospitalization for heart failure had a differentially greater improvement in GCS when treated with sacubitril/valsartan.ConclusionsIn patients with heart failure with preserved ejection fraction, sacubitril/valsartan improved GCS but not GLS when compared with valsartan during a 36-week period. This trial is registered at ClinicalTrials.gov, NCT00887588.     

Sacubitril/Valsartan: The Newest Addition to the Toolbox for Guideline-Directed Medical Therapy of Heart Failure

Sacubitril/valsartan combines a neprilysin inhibitor with an angiotensin receptor blocker. As an inhibitor of neprilysin, an enzyme that degrades biologically active natriuretic peptides, this first-in-class therapy increases levels of circulating natriuretic peptides, resulting in natriuretic, diuretic, and vasodilatory effects. In patients with chronic New York Heart Association class II-IV heart failure with reduced ejection fraction, the PARADIGM-HF trial demonstrated that sacubitril/valsartan significantly reduced the primary endpoint of cardiovascular mortality and heart failure hospitalization, compared with enalapril. The rate of all-cause mortality was also significantly reduced. Subsequently, the American College of Cardiology/American Heart Association/Heart Failure Society of America recently updated guideline recommendations for Stage C patients with heart failure with reduced ejection fraction to recommend angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or sacubitril/valsartan in conjunction with other evidence-based therapies to reduce morbidity and mortality. Several analyses have suggested the cost-effectiveness of this new therapy. To ensure tolerability, initiating the lower dosage form of sacubitril/valsartan is warranted in patients with severe renal impairment, moderate hepatic impairment, and low blood pressure, and close monitoring is warranted in such patients. A 36-hour washout period is recommended when switching patients from an angiotensin-converting enzyme inhibitor to sacubitril/valsartan. Similarly, sacubitril/valsartan is contraindicated in patients receiving concomitant angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and those with a history of angioedema.     

沙库巴曲缬沙坦治疗心力衰竭的研究进展

沙库巴曲缬沙坦是全球近年来慢性心力衰竭（HF）治疗领域具有突破性的创新药物,它是一种血管紧张素受体-脑啡肽酶抑制剂,可同时抑制肾素-血管紧张素-醛固酮系统并调节利钠肽系统。已被证实为目前首个也是唯一一个较标准治疗显著改善HF患者预后的药物,较依那普利能够显著改善射血分数,降低HF患者的死亡风险及再入院率,目前已被各国HF治疗指南推荐为慢性HF的一线治疗药物。后续更多研究表明,沙库巴曲缬沙坦还有逆转心脏重构、保护肾功能、降低血糖等作用,临床应用范围更加广泛,是应该大力推广的抗HF药物。本文将对沙库巴曲缬沙坦治疗HF的最新研究进展做一综述。     

沙库巴曲缬沙坦的临床应用及其潜在作用

沙库巴曲缬沙坦即血管紧张素受体脑啡肽酶抑制剂(ARNI),是近年来心力衰竭领域的研究热点。多项研究显示该药可明显降低心力衰竭患者的住院率和死亡率,并对多种心血管疾病有良好获益。本文简述了沙库巴曲缬沙坦在心力衰竭、高血压、急性心肌梗死、糖尿病、心脏代谢综合征和肾功能不全等疾病中的相关研究进展,进一步表明沙库巴曲缬沙坦现已不仅局限于射血分数降低的心力衰竭的临床应用,而是对多种心血管疾病甚至非心血管疾病均有潜在的有益作用。     

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.     

Optimal Therapeutic Strategy Using Sacubitril/Valsartan in a Patient with Systolic Heart Failure and Chronic Kidney Disease - An Initial Case Report in Japan

Sacubitril/valsartan has demonstrated its prognostic advantageousness over enalapril in patients with heart failure with a reduced ejection fraction. However, the optimal therapeutic strategy using sacubitril/valsartan in real-world practice, particularly among a Japanee cohort, remains uncertain. A 75-year-old man with systolic heart failure and chronic kidney disease was administered sacubitril/valsartan. Plasma B-type natriuretic peptide transiently increased, accompanied by an increase in the urine volume, which allowed us to terminate loop diuretics. The estimated glomerular filtration rate as well as heart failure symptom improved at the one-month follow-up. Sacubitril/valsartan might be a promising option to preserve the renal function and improve clinical outcomes when the dose of concomitant diuretics can be decreased, although further large-scale studies are warranted to validate our hypothesis.     

Angiotensin-Neprilysin Inhibition as a Paradigm for All?

Composite angiotensin receptor-neprilysin inhibition (ARNi) represents a novel pharmacologic strategy for treatment of heart failure with reduced ejection fraction (HFrEF). In the PARADIGM-HF (Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial of 8399 subjects with HFrEF, treatment with the ARNi LCZ696 (sacubitril/valsartan) was associated with statistically important reductions in cardiovascular death, all-cause mortality, and the composite of cardiovascular death or heart failure hospitalization in comparison with enalapril. These data have supported the US and European regulatory approval of sacubitril/valsartan and guideline-based recommendations for its use in the treatment of selected patients with HFrEF. In this review, we discuss the evidence supporting use of ARNi in preference to angiotensin-converting enzyme-inhibitors or angiotensin receptor blockers in patients with HFrEF and identify a strategy for selection of appropriate patients for transition to ARNi in clinical practice.     

沙库巴曲缬沙坦在低收缩压心力衰竭患者中的临床研究

目的 探究沙库巴曲缬沙坦在低收缩压（90~100） mmHg心力衰竭患者中的耐受剂量、治疗效果和安全性。 方法 选取2018年12月~2019年12月就诊于空军军医大学西京医院心内科的心衰患者116例,患者收缩压（90~100）mmHg,随机分为对照组和试验组。对照组在基础治疗上加用缬沙坦,起始剂量20 mg,1次/d;试验组在基础治疗上加用沙库巴曲缬沙坦,起始剂量25 mg,2次/d;接受过ACEI或ARB治疗的患者需停药36 h进行药物洗脱,两组患者治疗开始后每周电话随访血压情况,密切检测不良反应,治疗6个月后评估相关指标。 结果 治疗6个月后,沙库巴曲缬沙坦显著改善患者NYHA心功能分级、左室射血分数（LVEF）、N末端B型利钠肽原(NT-proBNP)、6分钟步行距离(6MWD)、明尼苏达心衰量表评分（MHFQL）等指标（均P<0.05）,且改善程度优于对照组（均P<0.05）。两组心血管不良事件和药物相关不良事件发生率无统计学差异。 结论 收缩压（90~100）mmHg的心衰患者持续接受沙库巴曲缬沙坦滴定治疗能够显著改善心脏功能和生活质量,且改善程度优于缬沙坦。     

血管紧张素受体-脑啡肽酶抑制剂治疗射血分数保留型心力衰竭的研究进展

随着目前人口老龄化的加剧,射血分数保留型心力衰竭(HFpEF)在心力衰竭患者中占比日益升高,而传统治疗慢性心力衰竭的药物未能显著改善HFpEF患者的预后。近年来观察到在射血分数降低型心力衰竭(HFrEF)患者中有明确疗效的血管紧张素受体-脑啡肽酶抑制剂(ARNI)被认为有可能改善HFpEF患者的现况。考虑到HFpEF给社会带来的经济负担,及心力衰竭治疗领域需不断创新发展,ARNI在HFpEF患者中的疗效被寄予厚望。然而,全世界与此相关的大型临床研究屈指可数。本综述旨在探讨ARNI的代表药物沙库巴曲缬沙坦在延缓HFpEF进程中可能的作用机制及临床应用进展。     

Sleep Outcomes From AWAKE-HF: A Randomized Clinical Trial of Sacubitril/Valsartan vs Enalapril in Patients With Heart Failure and Reduced Ejection Fraction

BackgroundHeart failure and sleep-disordered breathing have been increasingly recognized as co-occurring conditions. Their bidirectional relationship warrants investigation into whether heart failure therapy improves sleep and sleep-disordered breathing. We sought to explore the effect of treatment with sacubitril/valsartan on sleep-related endpoints from the AWAKE-HF study.Methods and ResultsAWAKE-HF was a randomized, double-blind study conducted in 23 centers in the United States. Study participants with heart failure with reduced rejection fraction and New York Heart Association class II or III symptoms were randomly assigned to receive treatment with either sacubitril/valsartan or enalapril. All endpoints were assessed at baseline and after 8 weeks of treatment. Portable sleep-monitoring equipment was used to measure the apnea-hypopnea index, including obstructive and central events. Total sleep time, wake after sleep onset and sleep efficiency were exploratory measures assessed using wrist actigraphy.The results were as follows140 patients received treatment in the double-blind phase (sacubitril/valsartan, n = 70; enalapril, n = 70). At baseline, 39% and 40% of patients randomly assigned to receive sacubitril/valsartan or enalapril, respectively, presented with undiagnosed, untreated, moderate-to-severe sleep-disordered breathing (≥ 15 events/h), and nearly all had obstructive sleep apnea. After 8 weeks of treatment, the mean 4% apnea-hypopnea index changed minimally from 16.3/h to 15.2/h in the sacubitril/valsartan group and from 16.8/h to 17.6/h in the enalapril group. Mean total sleep time was long at baseline and decreased only slightly in both treatment groups at week 8 (–14 and –11 minutes for sacubitril/valsartan and enalapril, respectively), with small changes in wake after sleep onset and sleep efficiency in both groups.ConclusionsIn a cohort of patients with heart failure with reduced rejection fraction who met prescribing guidelines for sacubitril/valsartan, one-third had undiagnosed moderate-to-severe obstructive sleep apnea. The addition of sacubitril/valsartan therapy did not significantly improve sleep-disordered breathing or sleep duration or efficiency. Patients who meet indications for treatment with sacubitril/valsartan should be evaluated for sleep-disordered breathing.     

Sacubitril/Valsartan Initiation and Postdischarge Adherence Among Patients Hospitalized for Heart Failure

BackgroundWe investigated associations between timing of sacubitril/valsartan initiation and postdischarge adherence among patients hospitalized for heart failure with reduced ejection fraction (HFrEF). Clinical trials support initiation of sacubitril/valsartan among patients hospitalized with HFrEF. The association between timing of initiation and postdischarge adherence is unknown.Methods and ResultsWe analyzed patients hospitalized for HFrEF (EF of ≤40%) within the Get With The Guidelines Heart Failure registry linked with Medicare claims between October 2015 and September 2017 who were eligible for sacubitril/valsartan. Follow-up was through December 2018. Patients were grouped by timing of sacubitril/valsartan initiation. Sacubitril/valsartan adherence at 90 and 365 days after discharge was assessed by calculating proportion of days covered (PDC) using medication fills. Among 4666 patients, 108 (2.3%) were continued on sacubitril/valsartan (on sacubitril/valsartan at admission and discharge), 191 (4.1%) were initiated as inpatients, 130 (2.8%) were initiated at discharge, and 4237 (90.1%) were discharged without sacubitril/valsartan. Median (25th, 75th) proportion of days covered through 90 days among those continued, initiated as inpatients, and initiated at discharge was 0.9 (0.6–0.1), 0.3 (0.0–0.7), and 0.0 (0.0–0.7), respectively (P < .001). Patients discharged without sacubitril/valsartan had very low rates of any sacubitril/valsartan fills within 90 and 365 days of discharge (2.1% and 7.7% of surviving patients, respectively).ConclusionsIn 2015–2017 US clinical practice, more than 90% of eligible patients hospitalized for HFrEF were discharged without sacubitril/valsartan. Patients initiated as inpatients had a higher postdischarge proportion of days covered than patients initiated at discharge. Patients discharged without sacubitril/valsartan were unlikely to receive it during follow-up. These findings highlight the importance of initiating sacubitril/valsartan during hospitalization to improve the quality of care.     

The role of angiotensin receptor–neprilysin inhibitors in cardiovascular disease—existing evidence,knowledge gaps,and future directions

Although traditional renin–angiotensin system antagonists including angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers have revolutionized the treatment of cardiovascular disease (CVD), the pivotal PARADIGM‐HF trial demonstrated that sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor (ARNI), was superior to an angiotensin‐converting enzyme inhibitor in reducing cardiovascular morbidity and mortality in patients with heart failure and reduced ejection fraction. However, despite international regulatory approval and strong recommendations in the guidelines, uptake of sacubitril/valsartan has been disappointing. Sacubitril/valsartan is now the focus of a large programme of clinical trials testing the hypothesis that ARNIs may supplant conventional renin–angiotensin system inhibitors across the spectrum of CVD, including hypertension, secondary prevention after myocardial infarction, and heart failure with preserved ejection fraction. This review summarizes the existing evidence, knowledge gaps, and future directions of ARNIs in CVD based on discussions between clinical trialists, industry representatives, and regulatory authorities at the 2016 Global CardioVascular Clinical Trialists Forum in Washington, D.C.     

Sacubitril/Valsartan: From Clinical Trials to Real-world Experience

Purpose of review

Compared to enalapril, use of angiotensin-receptor blocker and neprilysin inhibitor sacubitril/valsartan to treat patients with heart failure and reduced ejection fraction (HFrEF) is associated with substantial reductions in both cardiovascular mortality and heart failure progression. The purpose of this review is to discuss the real-world experience of sacubitril/valsartan.

Recent findings

In the years following the publication of the landmark PARADIGM-HF trial in 2014 and its subsequent FDA approval, a growing evidence base supports the safety and efficacy of sacubitril/valsartan in a broad spectrum of patients with HFrEF. Updated clinical practice guidelines have embraced the use of sacubitril/valsartan in preference to ACE inhibitors or ARBs in selected patients.

Summary

In this review, we highlight the clinical trials that led to these key updates to clinical guidelines, offer practical strategies for patient selection and utilization in clinical practice, and identify important areas of uncertainty that require future research.

     

Sacubitril/valsartan: A practical guide

Renin-angiotensin-aldosterone system (RAAS) inhibitors are a cornerstone in the treatment of heart failure with reduced ejection fraction (HFrEF). Sacubitril/valsartan modulates the neurohormonal axis by inhibiting both angiotensin receptors and neprilysin, and improves neurohormonal balance more than blocking the RAAS alone.The PARADIGM-HF trial validated this new treatment option for patients with HFrEF. Sacubitril/valsartan was also more effective than enalapril in slowing disease progression by decreasing the risk of worsening heart failure requiring hospitalization or emergency admission and the need for intensified therapy, heart failure devices or cardiac transplantation. More than 70% of patients included in PARADIGM-HF were in NYHA class II, and overall, the results indicate that sacubitril/valsartan should be started in the earliest symptomatic stages of the disease.As PARADIGM-HF has excellent robustness for a cardiovascular trial, sacubitril/valsartan has been included as a new treatment option with a strong level of recommendation in the main international guidelines.This expert task force proposes a practical guide to the use of this new drug that has been endorsed by the Working Group on Heart Failure of the Portuguese Society of Cardiology.     

Heart Failure Duration and Mechanistic Efficacy of Sacubitril/Valsartan in Heart Failure With Reduced Ejection Fraction

BackgroundAlthough sacubitril/valsartan (Sac/Val) is indicated for the treatment of heart failure with reduced ejection fraction (HFrEF), gaps in care continue to exist for those with newer onset HFrEF vs those with longer durations of disease.Methods and ResultsWe categorized 794 persons with HFrEF (EF of ≤40%) according to a HF duration of less than 12 months, 12–24 months, 24–60 months, and more than> 60 months. After the initiation of Sac/Val, concentrations of N-terminal pro-B type natriuretic peptide, high sensitivity cardiac troponin T, and soluble ST2 were measured, and Kansas City Cardiomyopathy Questionnaire 23 scores were obtained serially from baseline to 12 months. The left ventricular ejection fraction was measured by echocardiography. Significant decreases in the concentrations of N-terminal pro-B type natriuretic peptide, high sensitivity cardiac troponin T, and soluble ST2 were observed regardless of HF duration (P < .001). Comparable gains in Kansas City Cardiomyopathy Questionnaire 23 scores were achieved in all HF duration categories. Moreover, consistent reverse cardiac remodeling in all HF duration categories occurred, with the absolute left ventricular ejection fraction improvement by 12 months across HF duration groups of 12.2%, 6.9%, 8.5%, and 8.6% for HF duration of less than 12 months, 12–24 months, 24–60 months, and more than 60 months, respectively.ConclusionsThe initiation of Sac/Val decreases prognostic biomarkers, improves health status, and reverses cardiac remodeling processes, regardless of HF duration.Brief lay summaryWe categorized 794 persons with heart failure owing to a low ejection fraction according to disease duration into 4 groups: less than 12 months, 12–24 months, 24–60 months, and more than 60 months. After the initiation of sacubitril/valsartan (Entresto), we found that regardless of the duration of heart failure significant improvements occurred in cardiac biomarkers, patients felt better with improved health status and on testing with cardiac ultrasound examination, improvement in heart size, and function occurred. These results suggest that, regardless of heart failure duration, patients with a reduced ejection fraction would benefit from use of sacubitril/valsartan for their care.