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沙库巴曲缬沙坦治疗维持性血液透析合并心力衰竭的临床疗效
孙长丽, 董洋, 王丽姣, 赵心迪, 张翥, 邵凤民
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沙库巴曲缬沙坦治疗维持性血液透析合并心力衰竭的临床疗效
Clinical efficacy of angiotensin-receptor neprilysin inhibitors in the treatment of maintenance hemodialysis with heart failure
Objective To observe the clinical efficacy of angiotensin-receptor neprilysin inhibitors (ARNI) in the treatment of maintenance hemodialysis (MHD) with heart failure. Methods The clinical data of heart failure patients who accepted MHD in Central China Fuwai Hospital were retrospectively collected. All patients accepted regular treatments of heart failure, and then the treatment group was treated with ARNI, while the control group was treated with valsartan. The treatment course was 6 months. The cardiac parameters: left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), pulmonary artery pressure, right ventricular end-diastolic dimension (RVED), right atrial end-diastolic dimension (RAED), N-terminal pro-B-type natriuretic peptide (NT-pro BNP), and serum potassium were collected and compared between the two groups. Multivariate ordered logistic regression analysis was adopted to analyze the influencing factors of treatment effect. Results A total of 60 MHD patients with heart failure were enrolled with age of (53.92±11.88) years old, 37 males (61.7%), dialysis age of (27.83±12.92) months, and blood pressure of (154.22±15.27) mmHg/(85.43±12.31) mmHg. (1) There was no significant difference of the clinical data and cardiac parameters between the treatment group (n=30) and the control group (n=30) before treatment (all P>0.05); (2) After treatment of 6 months, the total effective rate [28/30(93.3%)] in the treatment group was significantly higher than that in the control group [20/30(66.7%)] and the rehospitalization rate [2/30(6.7%)] in the treatment group was significantly lower than that in the control group [10/30(33.3%)] (both P<0.05); (3) After treatment of 6 months, LVEF, LVEDD, LVESD, pulmonary artery pressure, RVED, RAED, NT-pro BNP, and blood pressure were all improved significantly compared with the baseline in both groups (all P<0.05) and there was no significant difference of serum potassium and body weight before and after treatment in the two groups (all P>0.05); (4) After treatment of 6 months, LVEF in the treatment group was higher than that in the control group and LVEDD, LVESD, pulmonary artery pressure, NT-pro BNP, and blood pressure in the treatment group were lower than those in the control group (all P<0.05). There was no significant difference of RVED, RAED, serum potassium and body weight between the two groups after treatment (all P>0.05); (5)The difference values before and after treatment of LVEF, LVEDD, LVESD, NT-pro BNP, body weight, systolic blood pressure, and diastolic blood pressure were different between the two groups (all P<0.05); (6)Therapy method (β=-1.863, 95%CI -2.948-0.777, P=0.001) and residual urine （β=-1.686, 95%CI -3.079- -0.293, P=0.018) were independent influencing factors of treatment effect (the treatment effect of ARNI was better than that of valsartan; the treatment effect of patients with normal urine volume was better than that of patients with oliguria and anuria). Conclusions ARNI can effectively improve cardiac function in MHD patients with heart failure, inhibit ventricular remodeling, and improve disease prognosis.
缬沙坦 / 肾透析 / 心力衰竭 / 沙库巴曲缬沙坦 / 疗效 / 安全性 {{custom_keyword}} /
Valsartan / Renal dialysis / Heart failure / Sacubitril/valsartan / Efficacy / Safety {{custom_keyword}} /
彭苗 , {{custom_editor}}
表1 两组患者一般临床资料比较 |
| 项目 | 治疗组(n=30) | 对照组(n=30) | t/Z/χ2 | P值 |
|---|---|---|---|---|
| 年龄(岁) | 53.13±13.07 | 54.70±10.74 | -0.507 | 0.614 |
| 男性[例(%)] | 19(63.3) | 18(60.0) | 0.071 | 0.791 |
| 透析龄(月) | 28.43±13.56 | 27.23±12.46 | 0.357 | 0.722 |
| 体重(kg) | 61.60±12.10 | 59.70±11.00 | 0.635 | 0.528 |
| 收缩压(mmHg) | 152.90±15.90 | 155.50±14.80 | -0.665 | 0.509 |
| 舒张压(mmHg) | 86.00±13.90 | 84.80±10.70 | 0.375 | 0.709 |
| Hb(g/L) | 101.20±10.80 | 103.40±10.60 | -0.799 | 0.428 |
| ALB(g/L) | 36.80±4.60 | 38.20±4.60 | -1.132 | 0.262 |
| Scr(μmol/L) | 983.90±266.10 | 920.80±232.70 | 0.978 | 0.332 |
| BUN(mmol/L) | 32.30±8.60 | 30.60±8.30 | 0.781 | 0.438 |
| Kt/V | 1.40±0.10 | 1.30±0.10 | 1.014 | 0.315 |
| URR(%) | 71.50±4.50 | 70.90±4.20 | 0.492 | 0.625 |
| ADQI分级[例(%)] | -0.130 | 0.897 | ||
| 2NR级 | 4(13.3) | 5(16.7) | ||
| 3R级 | 5(16.7) | 3(10.0) | ||
| 3NR级 | 5(16.7) | 6(20.0) | ||
| 4R级 | 6(20.0) | 5(16.7) | ||
| 4NR级 | 10(33.3) | 11(36.6) | ||
| 原发病[例(%)] | 0.640 | 0.887 | ||
| 慢性肾炎 | 11(36.6) | 9(30.0) | ||
| 糖尿病肾病 | 6(20.0) | 7(23.3) | ||
| 高血压肾损害 | 6(20.0) | 8(26.7) | ||
| 其他 | 7(23.3) | 6(20.0) | ||
| 残余尿量[例(%)] | -0.081 | 0.935 | ||
| 无尿(尿量<100 ml/d) | 15(50.0) | 16(53.3) | ||
| 少尿(100 ml/d≤尿量< 400 ml/d) | 10(33.3) | 8(26.7) | ||
| 尿量正常(尿量≥400 ml/d) | 5(16.7) | 6(20.0) |
| 注：Hb：血红蛋白；ALB：血白蛋白；Scr：血肌酐；BUN：血尿素氮；Kt/V：尿素清除指数；URR：尿素下降率；ADQI：急性透析质量倡议；2NR级：劳力性呼吸困难在透析治疗后不能改善至NYHAⅠ级水平；3R级：日常活动导致的呼吸困难在透析治疗后可改善至NYHA Ⅱ级水平；3NR级：日常活动导致的呼吸困难在透析治疗后不能改善至NYHA Ⅱ级水平；4R级：休息时的呼吸困难在透析治疗后可改善至NYHA Ⅲ级水平；4NR级：休息时的呼吸困难在透析治疗后不能改善至NYHA Ⅲ级水平；1 mmHg=0.133 kPa；数据形式除已注明外，呈正态分布的计量资料以$\bar{x}$± s形式表示 |
表2 两组患者治疗疗效比较[例（%）] |
| 指标 | 治疗组(n=30) | 对照组(n=30) | t/Z | P值 |
|---|---|---|---|---|
| 左室射血分数(%) | ||||
| 治疗前 | 36.20±3.27 | 35.57±3.26 | 0.751 | 0.455 |
| 治疗后 | 50.80±6.00a | 44.10±3.42a | 5.313 | <0.001 |
| 治疗前后差值 | 14.60±6.40 | 8.53±4.53 | 4.236 | <0.001 |
| 左心室舒张末期内径(mm) | ||||
| 治疗前 | 49.23±4.07 | 49.27±3.82 | -0.033 | 0.974 |
| 治疗后 | 44.47±4.22a | 46.80±3.89a | -2.223 | 0.030 |
| 治疗前后差值 | 4.77±2.53 | 2.47±3.99 | 2.663 | 0.010 |
| 左心室收缩末期内径(mm) | ||||
| 治疗前 | 40.63±4.96 | 41.30±5.22 | -0.506 | 0.614 |
| 治疗后 | 35.97±5.10a | 39.60±5.29a | -2.706 | 0.009 |
| 治疗前后差值 | 4.67±3.11 | 1.70±1.62 | 4.631 | <0.001 |
| 肺动脉压(mmHg) | ||||
| 治疗前 | 36.37±6.15 | 38.33±4.29 | -1.437 | 0.156 |
| 治疗后 | 28.73±4.66a | 32.67±5.66a | -2.939 | 0.005 |
| 治疗前后差值 | 7.63±4.42 | 5.67±4.36 | 1.735 | 0.088 |
| 右心室舒张末期内径(mm) | ||||
| 治疗前 | 26.60±6.19 | 27.53±5.79 | -0.603 | 0.549 |
| 治疗后 | 24.60±5.02a | 25.43±4.38a | -0.685 | 0.496 |
| 治疗前后差值 | 2.00±3.83 | 2.10±3.79 | -0.102 | 0.919 |
| 右心房舒张末期内径(mm) | ||||
| 治疗前 | 41.07±9.25 | 38.77±5.17 | 1.189 | 0.239 |
| 治疗后 | 37.43±7.96a | 37.47±4.45a | -0.020 | 0.984 |
| 治疗前后差值 | 3.63±5.84 | 1.30±1.64 | 1.744 | 0.081 |
| N末端前B型利钠肽(ng/L) | ||||
| 治疗前 | 49 907.03±4 633.67 | 37 764.83±3 896.99 | 1.099 | 0.276 |
| 治疗后 | 10 695.23±827.82a | 22 167.00±162.20a | -3.449 | 0.001 |
| 治疗前后差值 | 39 211.80±41 763.79 | 15 597.83±26 953.66 | 3.341 | 0.001 |
| 血钾(mmol/L) | ||||
| 治疗前 | 4.89±0.60 | 4.84±0.65 | 0.333 | 0.740 |
| 治疗后 | 4.90±0.56 | 4.93±0.40 | -0.208 | 0.836 |
| 治疗前后差值 | 0.01±0.70 | 0.09±0.54 | -0.495 | 0.622 |
| 体重(kg) | ||||
| 治疗前 | 61.60±12.10 | 59.70±11.00 | 0.635 | 0.528 |
| 治疗后 | 58.70±15.90 | 59.40±10.60 | -0.194 | 0.847 |
| 治疗前后差值 | 1.20±0.74 | 0.30±0.91 | 4.223 | <0.001 |
| 收缩压(mmHg) | ||||
| 治疗前 | 152.90±15.90 | 155.50±14.80 | -0.665 | 0.509 |
| 治疗后 | 142.70±11.90a | 150.50±11.18a | -2.604 | 0.012 |
| 治疗前后差值 | 10.17±7.87 | 5.03±8.44 | 2.435 | 0.018 |
| 舒张压(mmHg) | ||||
| 治疗前 | 86.00±13.90 | 84.80±10.70 | 0.375 | 0.709 |
| 治疗后 | 76.70±9.67a | 81.97±9.18a | -2.162 | 0.035 |
| 治疗前后差值 | 9.33±9.60 | 2.87±4.57 | 3.329 | 0.002 |
表3 两组患者治疗前后心功能相关指标比较（$\bar{x}$ ± s） |
| 疗效 | 治疗组(n=30) | 对照组(n=30) | χ2 | P值 |
|---|---|---|---|---|
| 显效 | 18(60.0) | 7(23.3) | 8.297 | 0.004 |
| 有效 | 10(33.3) | 13(43.3) | 0.635 | 0.426 |
| 无效 | 2(6.7) | 10(33.3) | 6.667 | 0.010 |
| 总有效率 | 28(93.3) | 20(66.7) | 6.667 | 0.010 |
| 再住院率 | 2(6.7) | 10(33.3) | 6.667 | 0.010 |
| 注：1 mmHg=0.133 kPa；与本组治疗前比较，aP<0.05 |
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The incidence and prevalence of heart failure (HF) and chronic kidney disease (CKD) are increasing, and as such a better understanding of the interface between both conditions is imperative for developing optimal strategies for their detection, prevention, diagnosis, and management. To this end, Kidney Disease: Improving Global Outcomes (KDIGO) convened an international, multidisciplinary Controversies Conference titled Heart Failure in CKD. Breakout group discussions included (i) HF with preserved ejection fraction (HFpEF) and nondialysis CKD, (ii) HF with reduced ejection fraction (HFrEF) and nondialysis CKD, (iii) HFpEF and dialysis-dependent CKD, (iv) HFrEF and dialysis-dependent CKD, and (v) HF in kidney transplant patients. The questions that formed the basis of discussions are available on the KDIGO website http://kdigo.org/conferences/heart-failure-in-ckd/, and the deliberations from the conference are summarized here.Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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The study objective was to assess the association between angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use and mortality in patients with chronic kidney disease (CKD).There is insufficient evidence about the association of ACEI or ARBs with mortality in patients with CKD.A logistic regression analysis was used to calculate the propensity of ACEI/ARB initiation in 141,413 U.S. veterans with nondialysis CKD who were previously unexposed to ACEI/ARB treatment. We examined the association of ACEI/ARB administration with all-cause mortality in patients matched by propensity scores using the Kaplan-Meier method and Cox models in "intention-to-treat" analyses and in generalized linear models with binary outcomes and inverse probability of treatment weights in "as-treated" analyses.The age of the patients at baseline was 75 ± 10 years, 8% of patients were black, and 22% were diabetic. ACEI/ARB administration was associated with a significantly lower risk of mortality both in the intention-to-treat analysis (hazard ratio: 0.81, 95% confidence interval: 0.78 to 0.84; p < 0.001) and the as-treated analysis with inverse probability of treatment weights (odds ratio: 0.37, 95% confidence interval: 0.34 to 0.41; p < 0.001). The association of ACEI/ARB treatment with lower risk of mortality was present in all examined subgroups.In this large contemporary cohort of nondialysis-dependent patients with CKD, ACEI/ARB administration was associated with greater survival.Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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中华医学会心血管病学分会心力衰竭学组, 中国医师协会心力衰竭专业委员会, 中华心血管病杂志编辑委员会. 中国心力衰竭诊断和治疗指南2018[J]. 中华心血管病杂志, 2018, 46(10): 760-789. DOI: 10.3760/cma.j.issn.0253-3758.2018.10.004.
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Structural heart disease is highly prevalent in patients with chronic kidney disease requiring dialysis. More than 80% of patients with end-stage renal disease (ESRD) are reported to have cardiovascular disease. This observation has enormous clinical relevance because the leading causes of death for patients with ESRD are of cardiovascular disease etiology, including heart failure, myocardial infarction, and sudden cardiac death. The 2 systems most commonly used to classify the severity of heart failure are the New York Heart Association (NYHA) functional classification and the American Heart Association (AHA)/American College of Cardiology (ACC) staging system. With rare exceptions, patients with ESRD who do not receive renal replacement therapy (RRT) develop signs and symptoms of heart failure, including dyspnea and edema due to inability of the severely diseased kidneys to excrete sodium and water. Thus, by definition, nearly all patients with ESRD develop a symptomatology consistent with heart failure if fluid removal by RRT is delayed. Neither the AHA/ACC heart failure staging nor the NYHA functional classification system identifies the variable symptomatology that patients with ESRD experience depending upon whether evaluation occurs before or after fluid removal by RRT. Consequently, the incidence, severity, and outcomes of heart failure in patients with ESRD are poorly characterized. The 11th Acute Dialysis Quality Initiative has identified this issue as a critical unmet need for the proper evaluation and treatment of heart failure in patients with ESRD. We propose a classification schema based on patient-reported dyspnea assessed both pre- and post-ultrafiltration, in conjunction with echocardiography.Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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林晶晶, 陈少华, 姚曦, 等. 维持性血液透析患者早期死亡率及相关危险因素分析[J]. 中华肾脏病杂志, 2020, 36(8): 595-600.
目的 分析浙江省新增终末期肾病血液透析患者早期死亡率及其相关危险因素，为降低透析患者早期死亡风险提供依据。 方法 应用浙江省血液透析登记数据库，回顾性分析2010年1月1日至2018年6月30日期间浙江省新增血液透析患者的早期死亡率及其相关因素，早期死亡的定义为患者透析后90 d内死亡。应用Cox回归模型分析血液透析患者早期死亡的相关危险因素。 结果 开始透析后第1个月死亡率最高（46.40/100人年），3个月后死亡率逐渐稳定，早期死亡率为25.33/100人年，120 d内、360 d内总体死亡率分别为21.40/100人年、11.37/100人年。年龄≥65岁患者早期高死亡现象尤为明显。老龄（≥65岁，HR=1.981，95%CI 1.319～2.977，P＜0.001）、原发病为肿瘤（HR=3.308，95%CI 1.137～5.624，P=0.028）、合并肿瘤（不含原发病为肿瘤，HR=2.327，95%CI 1.200～4.513，P=0.012）、首次透析通路为临时导管（HR=3.632，95%CI 1.806～7.307，P＜0.001）、低血白蛋白（＜30 g/L，HR=2.181，95%CI 1.459～3.260，P＜0.001）、低血红蛋白（每增加0.01 g/L，HR=0.861，95%CI 0.793～0.935，P=0.001）、高密度脂蛋白偏低（＜0.7 mmol/L，HR=1.796，95%CI 1.068～3.019，P=0.027）和C反应蛋白偏高（≥40 mg/L，HR=1.889，95%CI 1.185～3.012，P=0.008）是血液透析患者早期死亡的独立危险因素。 结论 血液透析患者开始透析后早期死亡率较高，3个月后死亡率逐渐趋于稳定。老龄、低血白蛋白、低血红蛋白、高密度脂蛋白偏低、C反应蛋白偏高、原发病为肿瘤、合并肿瘤以及首次血管通路为临时导管是维持性血液透析患者早期死亡的重要危险因素。
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Does the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers individually or as a combination confer a survival benefit in hemodialysis patients? The answer to this question is yet unclear.We performed a case-cohort study using data from the Mineral and Bone Disorder Outcomes Study for Japanese CKD stage 5D patients (MBD-5D), a 3-year multicenter prospective case-cohort study, including 8,229 hemodialysis patients registered from 86 facilities in Japan. All patients had secondary hyperparathyroidism, a condition defined as a parathyroid hormone level ≥180 pg/mL and/or receiving vitamin D receptor activators. We compared all-cause mortality rates between those receiving ACEI, ARB, and their combination and non-users with interaction testing. We used marginal structural Poisson regression (causal model) to estimate the causal effect and interaction adjusted for possible time-dependent confounding. Cardiovascular mortality was also evaluated.Among 3,762 randomly sampled subcohort patients, those taking ACEI, ARB, and their combination at baseline accounted for 4.0, 31.6, and 3.8%, respectively. Over 3 years, 1,226 all-cause and 462 cardiovascular deaths occurred. Compared to non-users, ARB-alone users had a lower all-cause mortality rate (adjusted incident rate ratio [aIRR] 0.62, 95% CI 0.50-0.76), whereas ACEI-alone users showed a statistically similar rate (aIRR 1.01, 95% CI 0.57-1.77). On the contrary, combination users had a greater mortality rate (aIRR 2.56, 95% CI 1.22-5.37), showing significant interaction (p = 0.03). Analysis for cardiovascular mortality showed similar results.Among hemodialysis patients with secondary hyperparathyroidism, unlike ACEI use, ARB use was associated with greater survival than non-use. Conversely, combination use was associated with greater mortality. Controlled trials are warranted to verify the causality factors of these associations.© 2017 The Author(s) Published by S. Karger AG, Basel.
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The purpose of the study was to compare the risk of de novo cardiovascular disease (CVD) between hemodialysis (HD) and peritoneal dialysis (PD) in patients with incident end-stage renal disease (ESRD).From a Taiwanese universal insurance claims database, we identified 45309 incident ESRD patients without preexisting CVD from 2000 to 2010. Using the propensity score matching method, we included 6516 patients in HD and PD groups, respectively. All patients were followed up until the end of 2011. The Cox proportional hazards regression model was employed to calculate the impact of dialysis modality on the risk of new onset cardiovascular events including ischemic heart disease, and congestive heart failure (CHF).No difference was observed in the overall risk of de novo ischemic heart disease between the propensity score-matched HD and PD groups (HD versus PD, adjusted hazard ratio [HR]: 1.03, 95% confidence interval [CI]: 0.86-1.22). However, HD was associated with a higher risk of de novo CHF (adjusted HR: 1.29, 95% CI: 1.13-1.47) than PD was. The risk of de novo CHF was particularly high in the first year under dialysis treatment for propensity score-matched HD patients, compared to PD patients.No difference was observed in the overall risk of de novo major ischemic heart events between HD and PD patients. However, HD was associated with a higher risk of de novo CHF than PD in the first year under dialysis treatment.Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
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Angiotensin converting enzyme inhibitors (ACE-I), are beneficial both in heart failure with reduced ejection fraction (HF-REF) and after myocardial infarction (MI). We examined the effects of the angiotensin-receptor neprilysin inhibitor sacubitril/valsartan, compared with the ACE-I enalapril, on coronary outcomes in PARADIGM-HF.We examined the effect of sacubitril/valsartan compared with enalapril on the following outcomes: i) the primary composite endpoint of cardiovascular (CV) death or HF hospitalization, ii) a pre-defined broader composite including, in addition, MI, stroke, and resuscitated sudden death, and iii) a post hoc coronary composite of CV-death, non-fatal MI, angina hospitalization or coronary revascularization. At baseline, of 8399 patients, 3634 (43.3%) had a prior MI and 4796 (57.1%) had a history of any coronary artery disease. Among all patients, compared with enalapril, sacubitril/valsartan reduced the risk of the primary outcome (HR 0.80 [0.73-0.87], P<.001), the broader composite (HR 0.83 [0.76-0.90], P<.001) and the coronary composite (HR 0.83 [0.75-0.92], P<.001). Although each of the components of the coronary composite occurred less frequently in the sacubitril/valsartan group, compared with the enalapril group, only CV death was reduced significantly.Compared with enalapril, sacubitril/valsartan reduced the risk of both the primary endpoint and a coronary composite outcome in PARADIGM-HF. Additional studies on the effect of sacubitril/valsartan on atherothrombotic outcomes in high-risk patients are merited.Copyright © 2017 Elsevier Inc. All rights reserved.
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| [17] |
Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women compared with men.In a prespecified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), which compared sacubitril-valsartan and valsartan in patients with heart failure with preserved ejection fraction. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes.Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older and had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI, 0.59-0.90) in women and 1.03 (95% CI, 0.84-1.25) in men ( interaction = 0.017). The benefit from sacubitril-valsartan was attributable to reduction in heart failure hospitalization. The improvement in New York Heart Association class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score was less in women than in men. The difference in adverse events between sacubitril-valsartan and valsartan was similar in women and men.As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding.https://www.clinicaltrials.gov. Unique identifier: NCT01920711.
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| [18] |
\n Salt-sensitive hypertension (SSH) is characterized by impaired sodium excretion and subnormal vasodilatory response to salt loading. Sacubitril/valsartan (LCZ696) was hypothesized to increase natriuresis and diuresis and result in superior blood pressure control compared with valsartan in Asian patients with SSH. In this randomized, double-blind, crossover study, 72 patients with SSH received sacubitril/valsartan 400 mg and valsartan 320 mg once daily for 4 weeks each. SSH was diagnosed if the mean arterial pressure increased by ≥10% when patients switched from low (50 mmol/d) to high (320 mmol/d) sodium diet. The primary outcome was cumulative 6- and 24-hour sodium excretion after first dose administration. Compared with valsartan, sacubitril/valsartan was associated with a significant increase in natriuresis (adjusted treatment difference: 24.5 mmol/6 hours, 50.3 mmol/24 hours, both\n P\n <0.001) and diuresis (adjusted treatment difference: 291.2 mL/6 hours,\n P\n <0.001; 356.4 mL/24 hours,\n P\n =0.002) on day 1, but not on day 28, and greater reductions in office and ambulatory blood pressure on day 28. Despite morning dosing of both drugs, ambulatory blood pressure reductions were more pronounced at nighttime than at daytime or the 24-hour average. Compared with valsartan, sacubitril/valsartan significantly reduced N-terminal pro B-type natriuretic peptide levels on day 28 (adjusted treatment difference: −20%;\n P\n =0.001). Sacubitril/valsartan and valsartan were safe and well tolerated with no significant changes in body weight or serum sodium and potassium levels with either treatments. In conclusion, sacubitril/valsartan compared with valsartan was associated with short-term increases in natriuresis and diuresis, superior office and ambulatory blood pressure control, and significantly reduced N-terminal pro B-type natriuretic peptide levels in Asian patients with SSH.\n
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| [19] |
Sacubitril/valsartan (Entresto™; LCZ696) is an orally administered supramolecular sodium salt complex of the neprilysin inhibitor prodrug sacubitril and the angiotensin receptor blocker (ARB) valsartan, which was recently approved in the US and the EU for the treatment of chronic heart failure (NYHA class II-IV) with reduced ejection fraction (HFrEF). In the large, randomized, double-blind, PARADIGM-HF trial, sacubitril/valsartan reduced the incidence of death from cardiovascular causes or first hospitalization for worsening heart failure (composite primary endpoint) significantly more than the angiotensin converting enzyme (ACE) inhibitor enalapril. Sacubitril/valsartan was also superior to enalapril in reducing death from any cause and in limiting the progression of heart failure. Sacubitril/valsartan was generally well tolerated, with no increase in life-threatening adverse events. Symptomatic hypotension was significantly more common with sacubitril/valsartan than with enalapril; the incidence of angio-oedema was low. Therefore, sacubitril/valsartan is a more effective replacement for an ACE inhibitor or an ARB in the treatment of HFrEF, and is likely to influence the basic approach to treatment.
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| [20] |
Although pain is one of the most common afflictions, it is often inadequately managed because the available analgesic options are relatively limited due to insufficient efficacy, unacceptable adverse effects or the potential for misuse or abuse. However, recent publications suggest that an alternative approach-indirect enhancement of endogenous pain-relieving pathways-might be desirable. We review this approach, in particular the dual enkephalinase inhibitors (DENKIs).Published literature and Internet sources were searched for information related to the basic science and clinical data on inhibition of metabolic pathways of endogenous analgesic agents. The identified sources were reviewed, assessed and synthesized. Emphasis was placed on the benefits of the approach, as well as on the individual agents.Inhibition of the enzymes that degrade the endogenous opioid ligands Met- and Leu-enkephalin results in an increased synaptic concentration of the enkephalins and an analgesic effect in a variety of animal models of pain and in preliminary trials in humans. The design of compounds that inhibit both of the two major enkephalin-degrading enzymes (neprilysin and aminopeptidase N) has been found to be better than those that inhibit only one of the enzymes. These dual-acting enkephalinase inhibitors yield analgesia with less adverse effects than current opioid drugs.Unlike currently available analgesics, inhibitors of the metabolic degradation of endogenous analgesic substances attempt to elicit a more "natural" and targeted analgesic effect. This indirect approach offers an opportunity for novel additions to the otherwise relatively limited choice of analgesic classes.© 2018 John Wiley & Sons Ltd.
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蒋红利, 姚丽, 陈蕾, 等. 中国透析患者慢性心力衰竭管理指南[J]. 中华肾脏病杂志, 2022.
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陈香美, 丁小强, 王荣, 等. 血液净化标准操作规程(2020版)[M]. 北京: 人民军医出版社, 2020: 261.
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| [23] |
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The aim of this report is to describe the feasibility and tolerability of medical treatment with sacubitril/valsartan in a patient treated with hemodialysis. We describe the case of a 67-year-old man with heart failure with reduced ejection fraction due to an ischemic cardiomyopathy and renal insufficiency undergoing hemodialysis. Because of worsening heart failure with no other therapeutic options, a treatment with sacubitril/valsartan was started. Although this patient had a very low systolic blood pressure, he could tolerate a moderate dose of 49/51 mg twice daily. After initiation of sacubitril/valsartan, there was a symptomatic improvement with a clear reduction NT-proBNP, accompanied by a decrease in filling pressures. In conclusion, in this patient with severe heart failure undergoing hemodialysis, treatment with sacubitril/valsartan was feasible, safe, and improved heart failure symptoms.© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.
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| [25] |
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| [26] |
Sacubitril/valsartan (SV) reduced heart failure hospitalization and cardiovascular mortality compared with enalapril in the Prospective Comparison of ARNI with ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure trial. However, this trial excluded patients with end stage of renal disease (ESRD); thus, the efficacy and safety of SV in heart failure with reduced ejection fraction (HFrEF) with ESRD remains uncertain.We retrospectively analysed the clinical and laboratory data of 501 HFrEF patients who administered with SV from March 2017 to April 2019 in a single tertiary university hospital. A total of 23 HFrEF patients with ESRD on dialysis [58.3% non-ischaemic heart failure; left ventricular ejection fraction (LVEF): 29.7 ± 4.4%] were included in this study. At baseline and follow-up visit, we evaluated cardiovascular biomarkers such as high-sensitive troponin T (hsTnT), soluble ST2 (sST2), echocardiographic parameters, and clinical and adverse events. The mean dose of SV was 90 ± 43 mg/day at baseline and 123 ± 62 mg/day at last follow-up (follow-up duration: median 132 days). The level of hsTnT was significantly reduced from 236.2 ± 355.3 to 97.0 ± 14.0 pg/mL (P = 0.002), and the sST2 level was significantly reduced from 40.4 ± 44.0 to 19.6 ± 14.1 ng/mL (P = 0.005). LVEF was significantly improved from 29.7 ± 4.4% to 40.8 ± 10.4% (P = 0.002). During the follow-up, up-titration, down-titration, and maintenance of SV dosing were observed in 7 (30%), 5 (21.7%), and 11 patients (47.8%), respectively. SV down-titration group had adverse events including symptomatic hypotension (systolic blood pressure <100 mmHg) (n = 4) and dizziness (n = 1), but they did not discontinue SV therapy.We found that SV could safely reduce the hsTnT and sST2 levels and improve LVEF in HFrEF patients with ESRD. As far as we know, this is the first study to show the efficacy and safety of SV in HFrEF with ESRD on dialysis. Larger prospective, long-term follow-up study should be warranted.© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.
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王学忠. 缬沙坦/沙库比曲在心力衰竭临床治疗中的应用[J]. 中华心血管病杂志, 2017, 45(6): 538-541. DOI: 10.3760/cma.j.issn.0253-3758.2017.06.018.
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| [28] |
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| [29] |
Angiotensin II has been implicated in maladaptive right ventricular (RV) hypertrophy and fibrosis associated with pulmonary hypertension (PH). Natriuretic peptides decrease RV afterload by promoting pulmonary vasodilation and inhibiting vascular remodeling but are degraded by neprilysin. We hypothesized that angiotensin receptor blocker and neprilysin inhibitor, sacubitril/valsartan (Sac/Val, LCZ696), will attenuate PH and improve RV function by targeting both pulmonary vascular and RV remodeling.
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| [30] |
A majority of patients with hypertension fail to achieve blood pressure (BP) control despite treatment with commonly prescribed drugs. This randomized, double-blind phase III trial assessed the superiority of sacubitril/valsartan 200 mg (97/103 mg) to continued olmesartan 20 mg in reducing ambulatory systolic BP after 8-week treatment in patients with mild to moderate essential hypertension uncontrolled with olmesartan 20 mg alone. A total of 376 patients were randomized to receive either sacubitril/valsartan (n = 188) or olmesartan (n = 188). Superior reductions in 24-hour mean ambulatory systolic BP were observed in the sacubitril/valsartan group vs the olmesartan group (-4.3 mm Hg vs -1.1 mm Hg, P < .001). Reductions in 24-hour mean ambulatory diastolic BP and pulse pressure and office systolic BP and diastolic BP were significantly greater with sacubitril/valsartan vs olmesartan (P < .014). A greater proportion of patients achieved BP control with sacubitril/valsartan vs olmesartan. The overall incidence of adverse events was comparable between the groups. Compared with continued olmesartan, sacubitril/valsartan was more effective and generally safe in patients with hypertension uncontrolled with olmesartan 20 mg.©2018 Wiley Periodicals, Inc.
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| [31] |
The safety of LCZ696, a novel angiotensin receptor-neprilysin inhibitor, was evaluated for the first time in patients with severe hypertension in this 8-week, multicenter, open-label study. Thirty-five Japanese patients with either office systolic blood pressure (SBP) ≥180 mm Hg or diastolic blood pressure (DBP) ≥110 mm Hg received LCZ696 200 mg. If blood pressure was uncontrolled, the LCZ696 dose was increased to 400 mg after 2 weeks (if there were no safety concerns; n=32), followed by an optional addition of another antihypertensive drug (except angiotensin receptor blocker and angiotensin-converting enzyme inhibitor) after 4 weeks (n=21). Reductions in office SBP/DBP (baseline, 173.4 mm Hg/112.4 mm Hg) and pulse pressure (baseline, 61.0 mm Hg) at week 8 were 35.3/22.1 mm Hg and 13.2 mm Hg, respectively. The overall incidence of adverse events was 48.6% with no reports of dizziness, hypotension, or angioedema. The LCZ696-based regimen was generally well-tolerated and could present a treatment option for severe hypertension in Asian patients especially in reducing SBP and pulse pressure. © 2015 Wiley Periodicals, Inc.
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| [32] |
This 8-week, multi-center, open-label study assessed the safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Patients (n=32) with mean sitting systolic blood pressure (msSBP) ⩾140 mm Hg (after a 2-5-week washout of previous antihypertensive medications) and estimated glomerular filtration rate (eGFR) ⩾15 and <60 ml min(-1) 1.73 m(-2) received LCZ696 100 mg with an optional titration to 200 and 400 mg in a sequential manner starting from Week 2 in patients with inadequate BP control (msSBP ⩾130 mm Hg and mean sitting diastolic blood pressure (msDBP) ⩾80 mm Hg) and without safety concerns. Safety was assessed by monitoring and recording all adverse events (AEs) and change in potassium and creatinine. Efficacy was assessed as change from baseline in msSBP/msDBP. The mean baseline BP was 151.6/86.9 mm Hg, urinary albumin/creatinine ratio (UACR) geometric mean was 7.3 mg mmol(-1) and eGFR was ⩾30 and <60 in 25 (78.1%) patients and was ⩾15 and <30 in 7 (21.9%) patients. Fourteen (43.8%) patients reported at least one AE, which were mild in severity. No severe AEs or deaths were reported. There were no clinically meaningful changes in creatinine, potassium, blood urea nitrogen and eGFR. The geometric mean reduction in UACR was 15.1%, and the mean reduction in msSBP and msDBP was 20.5±11.3 and 8.3±6.3 mm Hg, respectively, from baseline to Week 8 end point. LCZ696 was generally safe and well tolerated and showed effective BP reduction in Japanese patients with hypertension and renal dysfunction without a decline in renal function.
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| [33] |
We evaluated the role of sacubitril/valsartan in heart rate variability, T-peak to T-end index, external cell mass, internal cell mass and total body water in elderly patients with heart failure with reduced ejection fraction (HFrEF).Eleven elderly patients (9 males; mean age 77 years, range 70-87; 2 females, mean age 60 years, range 50-71) with HFrEF (<35%) were included in this analysis. Four patients presented moderate chronic kidney failure (creatinine clearance [CrCl] 30-59 mL/min) and four patients with diabetes (HbA1c >6.5%). All patients had hypertension and dyspnoea due to HF. Clinical outcomes of this investigation were kidney function, glucose, brain-natriuretic peptide, heart rate variability, T-peak to T-end index and markers of body water composition with bioelectrical impedance analysis (BIA).One-month therapy with sacubitril/valsartan 24/26 mg/bid was associated with an improved redistribution of body water (extracellular mass: 19.4 ± 3.0 at baseline vs 18.4 ± 2.6 Kg/m at 1 month; p = .001), body weight reduction (81 ± 8 vs 78 ± 8 Kg; p = .002) and improved clinical outcomes (i.e. reduction of dyspnoea, mean duration of symptoms and walking test).Based on our preliminary results, sacubitril/valsartan could be a new effective approach in the treatment of elderly patients with chronic HFrEF. However, further studies are necessary to confirm these preliminary findings.
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Natriuretic peptides (NP) are widely recognized as key regulators of blood pressure, water and salt homeostasis. In addition, they play a critical role in physiological cardiac growth and mediate a variety of biological effects including antiproliferative and anti-inflammatory effects in other organs and tissues. The cardiac release of NPs ANP and BNP represents an important compensatory mechanism during acute and chronic cardiac overload and during the pathogenesis of heart failure where their actions counteract the sustained activation of renin-angiotensin-aldosterone and other neurohormonal systems. Elevated circulating plasma NP levels correlate with the severity of heart failure and particularly BNP and the pro-peptide, NT-proBNP have been established as biomarkers for the diagnosis of heart failure as well as prognostic markers for cardiovascular risk. Despite activation of the NP system in heart failure it is inadequate to prevent progressive fluid and sodium retention and cardiac remodeling. Therapeutic approaches included administration of synthetic peptide analogs and the inhibition of NP-degrading enzyme neutral endopeptidase (NEP). Of all strategies only the combined NEP/ARB inhibition with sacubitril/valsartan had shown clinical success in reducing cardiovascular mortality and morbidity in patients with heart failure.
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所有作者声明无利益冲突
孙长丽、董洋：研究设计、数据收集、论文撰写；王丽姣、赵心迪：数据收集、整理、统计学分析；张翥：论文指导及修改；邵凤民：研究指导、论文修改及经费支持
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