脑啡肽酶抑制剂:心血管治疗领域的新利器

脑啡肽酶抑制剂(又称中性内肽酶抑制剂)是一种新型的,具有潜在改善患者心血管疾病转归的药物。脑啡肽酶抑制剂可增加钠尿肽系统活性,增加尿钠排泄、利尿以及抑制肾素-血管紧张素系统(RAS)的作用。因此,该药对慢性心衰、高血压和慢性肾病的RAS激活状态具有治疗作用。早期的脑啡肽酶抑制剂与血管紧张素转化酶抑制剂结合物由于其无法接受的血管性水肿发生率而终止。然而,新型的血管紧张素受体脑啡肽酶抑制剂——LCZ696,经大量的研究显示对心血管疾病具有有益作用。     

沙库巴曲/缬沙坦治疗心血管疾病的研究进展

沙库巴曲/缬沙坦(LCZ696)是目前最新的血管紧张素受体-脑啡肽酶抑制剂(ARNI),由血管紧张素Ⅱ的1型受体拮抗剂(缬沙坦)和脑啡肽酶抑制剂AHU377(沙库巴曲)构成,通过抑制脑啡肽酶活性和拮抗血管紧张素受体发挥作用。2015年,美国食品和药物管理局批准LCZ696用于心力衰竭一线治疗。大量研究表明,LCZ696对心力衰竭、高血压和心肌梗死后状态等有治疗作用,本文就目前LCZ696在心血管疾病中的研究进展做一综述。     

脑啡肽酶抑制剂与血管紧张素受体拮抗剂在心力衰竭患者中的应用对比研究

目的 对比研究脑啡肽酶抑制剂与血管紧张素受体拮抗剂在心力衰竭(心衰)患者应用中的临床疗效.方法 选取2017年12月至2019年12月于青海省人民医院住院治疗的心衰患者284例,分为脑啡肽酶抑制剂组和血管紧张素受体拮抗剂组,各142例,两组患者在规范应用倍他乐克、螺内酯等抗心衰基础治疗上,按分组分别予以脑啡肽酶抑制剂及...     

导读

正血管紧张素受体脑啡肽酶抑制剂能否成为改善血压控制的利器?(刘靖,p501);血管紧张素受体脑啡肽酶抑制剂沙库巴曲缬沙坦治疗高血压的研究进展(张跃,等p519)以沙库巴曲缬沙坦为代表的血管紧张素受体脑啡肽酶抑制剂(angiotensin receptor neprilysin inhibitor,ARNI)因其过硬的临床研究结果获得了众多心力衰竭指南的推荐,在心力衰竭的治疗中得到广泛应用。在心力衰竭治疗中观察到的一定程度的血压下降作用也激发了对ARNI降压效应的关注。     

心力衰竭与脑啡肽酶的研究进展

心力衰竭是一种机制复杂的临床综合征。对心力衰竭病生理机制的深入认识提示脑啡肽酶在其发生发展中起重要作用,脑啡肽酶抑制为心力衰竭治疗提供了新的方向和证据。目前血管紧张素受体脑啡肽酶抑制剂在射血分数减少心力衰竭中的治疗取得了较大进步,而射血分数保留心力衰竭尚无有效的治疗方法。2016年美国及欧洲心力衰竭指南已将血管紧张素受体脑啡肽酶抑制剂作为治疗慢性射血分数减少心力衰竭的推荐药物。本文将对心力衰竭与脑啡肽酶的研究进展作一综述。     

沙库巴曲缬沙坦治疗心力衰竭的作用机制、临床应用及指南推荐意见

心力衰竭是多数心血管疾病的归宿,已对全人类身心健康及生命安全构成严重威胁。血管紧张素转换酶抑制剂或血管紧张素受体拮抗剂、β-受体阻滞剂及醛固酮受体拮抗剂是有效治疗心力衰竭的"金三角",虽然在过去的20年内心力衰竭治疗方面取得了长足进步,但心力衰竭患者5年病死率仍高达50%。沙库巴曲缬沙坦属血管紧张素受体-脑啡肽酶抑制剂,是一种新型心力衰竭治疗药物,并有望成为治疗心力衰竭的"基石"。本文对沙库巴曲缬沙坦治疗心力衰竭的作用机制、临床应用及指南推荐意见进行了综述,旨在提高临床对该药的认识及心力衰竭治疗水平。     

血管紧张素受体脑啡肽酶抑制剂在心力衰竭治疗中的回顾与进展研究

心力衰竭是心脏疾病的终末阶段,其病死率高,预后差,为社会经济带来巨大负担。传统的心力衰竭治疗主要以抑制肾素-血管紧张素-醛固酮系统和交感神经系统为基础,近年来研究发现,联合脑啡肽酶抑制剂和血管紧张素受体阻滞剂可明显改善心力衰竭患者预后,成为心力衰竭治疗发展史中的重要转折点。     

沙库巴曲缬沙坦在心力衰竭治疗中作用研究的进展

沙库巴曲缬沙坦作为一种新型抗心力衰竭药物,是一种血管紧张素受体-脑啡肽酶抑制剂(ARNI)。其通过调控利钠肽系统和肾素-血管紧张素-醛固酮系统(RAAS),既可有效降低血管紧张素Ⅱ受体活性,又能提高利钠肽水平,其治疗作用优于传统心血管疾病治疗药物。因其卓越的临床疗效,越来越受到人们关注,现就沙库巴曲缬沙坦作用机理、临床研究成果、临床指南推荐及实际使用方案等几个方面做一阐述。     

规范化、个体化使用心力衰竭治疗新药

在心力衰竭多种改善预后药物可供选择的时代,临床决策更具挑战性。心力衰竭的治疗已经从传统的“金三角”（β受体阻滞剂、血管紧张素转换酶抑制剂或血管紧张素Ⅱ受体阻滞剂和醛固酮受体拮抗剂）发展为“金四角”（“金三角”+脑啡肽酶抑制剂）,或有更多的综合治疗。应遵循指南,平衡获益-风险比,做出规范化和个体化选择,使患者获益最大化。     

射血分数中间值的心力衰竭研究进展

心力衰竭是由心脏结构或功能异常所致的一种临床综合征,各种原因的初始心肌损害可引起心室舒张和（或）收缩能力受损导致循环淤血和组织灌流不足。目前指南推荐将心力衰竭根据左心室射血分数值分为三种亚型。射血分数中间值心力衰竭的临床特点介于另两种亚型之间,其治疗措施多缺乏循证医学证据支持。目前的经验治疗如β受体阻滞剂,血管紧张素转换酶抑制剂/血管紧张素Ⅱ受体拮抗剂等效果确切;使用盐皮质激素受体拮抗剂可获得显著收益;血管紧张素受体-脑啡肽酶抑制剂的效果值得期待;其它如基于运动锻炼的心脏康复也能改善预后指标。     

Potential effects and application prospect of angiotensin receptor-neprilysin inhibitor in diabetic kidney disease

Diabetic kidney disease (DKD) is one of the main causes of end-stage renal disease (ESRD) and all-cause mortality in diabetic patients, despite the extensive use of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB). Angiotensin receptor-neprilysin inhibitor (ARNI), combining ARB and neutral endopeptidase inhibitor (NEPI), is likely to have potential favorable effects in DKD. This review summarizes existing preclinical and clinical studies on mechanism of ARNI and its potential effects on DKD. In preclinical studies, ARNI manifested its renoprotective effects by improving natriuresis, ameliorating inflammation, oxidative stress and renal dysfunction, and slowing down glomerulosclerosis and tubulointerstitial injury of kidney, but its effect on proteinuria is still controversial. Beneficial effects of ARNI on blood glucose regulation and glycometabolism have also been reported. There are no clinical studies of ARNI that specifically focus on DKD patients so far. ARNI has application potential in DKD, but there still need clinical studies that focus on DKD patients to determine its effectiveness, safety and underlying mechanism.     

Pharmacogenomics of angiotensin receptor/neprilysin inhibitor and its long‐term side effects

The development of the promising agent sacubitril/valsartan, known as an angiotensin receptor blocker‐neprilysin inhibitor (ARNI), to improve heart failure (HF) management, may benefit morbidity, mortality, and readmission rates in patients with HF. The PARADIGM‐HF trial demonstrated that the ARNI can reduce morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), while ongoing PARAMOUNT and PARAGON‐HF trials determined whether the ARNI has morbidity and mortality benefits in patients with heart failure with preserved ejection fraction (HFpEF). However, the risk of long‐term side effects of the ARNI such as cognitive dysfunction or Alzheimer's disease (AD) remains unknown. In fact, neprilysin (NEP), encoded by NEP or MME gene, is a principal peptidase involved in the degradation of β‐amyloid (Aβ) protein. Several studies have demonstrated that polymorphisms of the NEP gene may be associated with AD and cerebral amyloid angiopathy (CAA). Pharmacogenomics, the study of variability in drug response due to genetic polymorphisms, can potentially explain the variability in the effect of the ARNI and their side effects. Therefore, we have attempted to highlight pharmacogenomic factors and potential long‐term side effects of the ARNI. Physicians should carefully monitor elderly patients with genetic risk factors for AD and CAA. In the future, genetic testing and genomic testing for NEP polymorphisms may play an important role in monitoring long‐term side effects in ARNI‐treated HF patients.     

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。     

沙库巴曲缬沙坦对慢性心力衰竭合并肾功能不全患者容量管理的优化作用

[摘要] 目的 观察慢性心力衰竭（心衰）合并肾功能不全患者应用沙库巴曲缬沙坦后容量状态变化及其对心脏结构和功能的影响。方法 连续入选84例慢性心衰合并肾功能不全患者,分为沙库巴曲缬沙坦（ARNI）组48例和对照组36例。ARNI组接受沙库巴曲缬沙坦治疗,对照组接受单一的缬沙坦治疗。测量2组患者服药6个月后24小时尿量、利尿剂用量,检测血浆B型脑钠肽（BNP）水平,随访纽约心脏病协会（NYHA）分级变化,并以超声心动图评价心脏结构及功能的改善情况。结果 （1）两组患者基线临床资料差异均无统计学意义（P?0.05）。（2）ARNI组服药后与对照组比较,患者24小时尿量明显增多（P<0.01）;NYHA分级明显改善（P=0.032）。ARNI组服药后与服药前比较,患者服用利尿剂剂量、BNP水平明显降低（P均<0.01）;24小时尿量明显增加（P<0.01）。（3）ARNI组服药后与对照组比较,患者每搏输出量（SV）、心输出量（CO）、左室射血分数（LVEF）、二尖瓣环E峰与A峰比值（E/A）明显升高（P均<0.05）,左房内径（LA）缩小（P<0.05）;ARNI组服药后与服药前比较,患者左室舒张末内径（LVDD）、左室收缩末内径（LVSD）、LA明显缩小（P均<0.01）;SV、CO、E/A、LVEF明显升高（P均<0.01）。结论 与单一使用缬沙坦比较,沙库巴曲缬沙坦可明显改善合并肾功能不全的慢性心衰患者的容量超负荷,优化容量管理措施,超声心动图证实了其对心脏收缩及舒张功能的改善。     

A clinical experience of Indian patients with heart failure with reduced left ventricular ejection fraction using an angiotensin receptor-neprilysin inhibitor [ARNI] on an outpatient basis

The goal of this study is to portray an initial experience with the efficacy, safety, and, acceptance of ARNI in ambulatory cardiology practices in India. The research is a retrospective review of single-centre data who began therapy with ARNI in HFrEF between 2019 and 2020. The analysis included data for 454 symptomatic patients, aged 57 ± 20.8 years in NYHA class II-III. During follow-up, patients experienced significant improvement in HF symptoms determined by using Kansas City Cardiomyopathy Questionnaire (KCCQ) and a considerable reduction in NT-proBNP levels. ARNI is associated with substantial clinical benefit in an outpatient setting in HFrEF.     

沙库巴曲缬沙坦钠对射血分数减低型心力衰竭患者肾功能、血压及血清电解质的影响

目的探究沙库巴曲缬沙坦对射血分数减低型心力衰竭(HFrEF)患者的肾功能、血压及电解质的影响并分析造成肾功能恶化(WRF)的相关危险因素。方法选取2019年10月至2020年1月于徐州医科大学附属医院心内科就诊的HFrEF患者104例,根据用药不同分为两组,其中观察组为接受沙库巴曲缬沙坦钠治疗者54例(ARNI组),对照组为接受盐酸贝那普利治疗者50例(ACEI组),分别对两组患者进行6个月的随访,观察治疗前后两组患者血清尿素氮(BUN)、肌酐(SCr)、胱抑素C(CysC)、尿酸(UA)、收缩压(SBP)、舒张压(DBP)及血电解质的变化,分析造成WRF的相关危险因素。结果随访6个月后,两组患者SCr水平较用药前均明显升高(P<0.05),但ARNI组SCr水平增加幅度明显低于ACEI组(5.76μmol/L vs.14.54μmol/L,P<0.05),且WRF发生率(16.7%)低于ACEI组(22.0%),而两组间BUN、CysC及UA的变化无明显差异(P>0.05)。ARNI组患者血压较基线平均降低12.11/4.68 mmHg(1 mmHg=0.133kPa),ACEI组患者血压较基线平均降低6.63/3.04 mmHg,两组相比,ARNI组SBP下降幅度更大(P<0.05),而DBP的下降幅度组间无明显差异(P>0.05)。治疗前后,ARNI组及ACEI组血钾、血钠、血钙及血磷水平无显著改变(P>0.05),组间也无明显差异。通过单因素及多因素Logistic回归分析发现,年龄≥75岁是造成WRF的重要危险因素。结论与ACEI相比,ARNI能延缓HFrEF患者肾功能进展,降压效果较强。     

Safety and efficacy of ARNI (valsartan/sacubitril) vs ACEI (enalapril) in acute heart failure – A prospective observational study

ObjectiveTo compare the safety and efficacy of valsartan/sacubitril (angiotensin receptor neprilysin inhibitor [ARNI]) against enalapril (angiotensin-converting enzyme inhibitor [ACEI]) in patients with acute heart failure at 6-month follow-up.MethodsIn this prospective, single centre, and observational study conducted between September 2017 and February 2020 in India, patients with acute decompensated heart failure with reduced ejection fraction (<40%) were included. Patients were divided in two groups: valsartan/sacubitril (ARNI) group and enalapril (ACEI). Patients were followed up for at least 6 months after administration of first dose and were evaluated for safety, efficacy, and tolerability of target drug. Student's independent t-test was employed for comparing continuous variables. Chi-square test or Fisher's exact test, whichever appropriate, was applied for comparing categorical variables.ResultsA total of 200 patients were included in the present study, 100 each in ARNI and ACEI group. The mean age of the population was 61.2 ± 8.4 years and 62.6 ± 8.6 years in ARNI group and ACEI group, respectively. The mean maximum tolerated dose by population in ARNI group was 203.6 mg and 8.9 mg in ACEI group. Readmission for heart failure were seen significantly higher in ACEI group than ARNI group (p value = 0.001). Parameters like ejection fraction, left ventricular end diastolic and systolic dimensions, 6 min walk test and Kansas City Cardiomyopathy Questionnaires (KCCQ) showed p values < 0.05 between the groups.ConclusionThe ARNI study group showed better safety and efficacy outcomes at the end of 6 months follow-up compared to ACEI group.     

Risk of Acute Kidney Injury Among Older Adults With Heart Failure and With Reduced Ejection Fraction Treated With Angiotensin-Neprilysin Inhibitor vs Renin-Angiotensin System Inhibitor in Routine Clinical Care

BackgroundThe acute hemodynamic effects of sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), may result in early changes in kidney function, raising concerns about acute kidney injury (AKI), particularly in those who are naïve to renin-angiotensin system inhibitors (RASis).MethodsWe conducted a cohort study using U.S. Medicare fee-for-service claims data (2014–2017). Patients with HFrEF ≥ 65 years newly initiating ARNI or RASi, with no prior use of either drug class, were included. The primary outcome was hospitalization due to AKI as the primary discharge diagnosis, and the secondary outcome included AKI as a primary or secondary discharge diagnosis. AKI risks were described under an as-treated follow-up approach, with censoring on treatment discontinuation, switch, insurance disenrollment, death, or administrative censoring as well as an intent-to-treat approach. Propensity-score–based fine-stratification weighting was used to account for potential confounding by 81 pre-exposure characteristics. Cumulative incidence functions were used to report absolute risks, and Cox proportional hazards models were used to provide hazard ratios (HR) and 95% confidence intervals (CI).ResultsWe included 27,166 patients with a mean (SD) age of 73 (7.3) years, and 4155 (15.3%) were initiating ARNI. After propensity score weighting, the 180-day cumulative incidence was 2.7% (2.4%–3.1%) among RASi initiators and 2.7% (2.2%–3.5%) among ARNI initiators for the primary outcome, and it was 6.5% (6.0%–7.1%) and 6.1% (5.2%–7.1%), respectively, for the secondary outcome under as-treated follow-up. HR (95% CI) comparing ARNI with RASi were 0.91 (95% CI: 0.72–1.16) for the primary outcome and 0.92 (95% CI: 0.79–1.08) for the secondary outcome. Similar results were observed in the intent-to-treat analysis.ConclusionsAmong a large cohort of U.S. Medicare beneficiaries with HFrEF, ARNI treatment was not associated with higher rates of AKI than RASi treatment. These results provide reassurance for providers considering ARNI initiation in older patients who are RASi-naïve.