Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.
Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.
复制标题
DOI：
10.1161/circulationaha.115.018622
复制
发表时间：
2016-03-15
期刊：
影响因子：
37.8
通讯作者：
Brown NJ
中科院分区：
文献类型：
--
作者：
Hubers SA;Brown NJ
心力衰竭仅在美国就影响了大约570万人。血管紧张素转换酶抑制剂、血管紧张素受体阻滞剂、β受体阻滞剂和醛固酮拮抗剂可改善心力衰竭和射血分数降低患者的死亡率，但死亡率仍然很高。2015年7月，FDA批准了第一种用于治疗心力衰竭的新药;缬沙坦/沙库巴曲（原名LCZ 696，目前由诺华公司以Entresto销售）将血管紧张素受体阻滞剂缬沙坦和脑啡肽酶抑制剂前药沙库巴曲以1：1的比例组合在钠超分子复合物中。沙库巴曲通过酯酶转化为LBQ 657，LBQ 657抑制脑啡肽酶，脑啡肽酶负责利钠肽和许多其他血管活性肽的降解。因此，这种组合的血管紧张素受体拮抗剂和脑啡肽酶抑制剂解决了心力衰竭的两种病理生理机制-激活肾素-血管紧张素-醛固酮系统和降低对利钠肽的敏感性。在ARNI与ACEI的前瞻性比较以确定心力衰竭对全球死亡率和发病率的影响（PARADIGM-HF）试验中，与依那普利相比，缬沙坦/沙库巴曲显著降低了心力衰竭患者的死亡率和住院率，以及血压，射血分数降低，脑钠肽或N末端脑钠肽前体循环水平升高。正在进行的临床试验正在评估缬沙坦/沙库巴曲在治疗射血分数保留的心力衰竭和高血压中的作用。本文综述了缬沙坦/沙库巴曲的作用机制、药物的药理学特性及其治疗心力衰竭和高血压的有效性和安全性。
Heart failure affects approximately 5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the FDA approved the first of a new class of drugs for the treatment of heart failure; valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses two of the pathophysiologic mechanisms of heart failure - activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared to enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacologic properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.