NOVEL STRATEGY FOR PERIOPERATIVE BETA-BLOCKER THERAPY

 描述（由申请人提供）：非心脏手术后的主要不良心脏事件，如心肌梗死（MI），每年杀死更多的美国人比所有机动车死亡的总和。围手术期β受体阻滞剂治疗是唯一的循证干预，已被证明可以降低围手术期心脏风险。不幸的是，当像往常一样练习时（即，作为“术前β受体阻滞剂治疗”，在手术前开始口服β受体阻滞剂并在整个围手术期持续），围手术期β受体阻滞剂与伤害相关。无论血流动力学状态如何，它都会使所有患者暴露于强血流阻断。当服用β受体阻滞剂的患者出现血容量不足时，他们无法维持心输出量，并有长期低血压、休克、中风和死亡的风险。这项提案将测试一种新的策略，该策略将保留β受体阻滞剂对围手术期心肌缺血的有效保护，但不会增加总体风险。具体而言，本申请的目的是确定术后β受体阻滞剂治疗（而非术前）是否是降低围手术期心脏风险的安全有效方案。具体目标1将检验以下假设：在接受重大非心脏手术的高风险患者中，滴定术后美托洛尔方案（IV，然后口服）将显著减少心肌损伤和缺血，而不会增加低血压的风险。采用高敏心肌肌钙蛋白（hs-cTn）作为心肌损伤的标志物，连续12导联霍尔特ECG检测心肌缺血，将在一项具有良好把握度的单中心随机对照试验（n=600）中检验该假设。主要疗效终点为心肌缺血和损伤。主要安全性终点为临床相关低血压。最近，hs-cTn已被证明可以强烈预测围手术期主要不良心脏事件和非心脏手术后死亡。具体目标2将扩展这一概念，并检验术前hs-cTn浓度可以识别可能从术后hs-cTn受体阻滞剂治疗中获益的患者的假设。该假设将在同一试验队列中进行检验。本研究既有意义又有创新性， 一个重要的公共卫生问题，并提供了一个新的潜在的选择，以解决围手术期血管紧张素受体阻滞剂治疗的棘手问题。

 DESCRIPTION (provided by applicant): Major adverse cardiac events, such as myocardial infarction (MI), after non-cardiac surgery kill more Americans each year than all motor vehicle deaths combined. Perioperative ß-blocker therapy is the only evidence-based intervention that has been shown to reduce perioperative cardiac risk. Unfortunately, when practiced as usual (i.e., as "preoperative ß-blocker therapy", starting an oral ß-blocker before surgery and continuing throughout the perioperative period), perioperative ß-blockade is associated with harm. It exposes all patients to strong ß-blockade regardless of the hemodynamic status. When patients on ß-blockers develop hypovolemia, they are unable to maintain cardiac output, and are at risk for prolonged hypotension, shock, stroke and death. This proposal will test a novel strategy that will retain the effective protection of ß-blockers against perioperative myocardial ischemia, yet not increase overall risk. Specifically, the objective of this application is to determine if postoperative ß-blocker therapy (rather than preoperative) is a safe and effective regimen to reduce perioperative cardiac risk. Specific aim 1 will test the hypothesis that a titrated postoperative metoprolol regimen (IV followed by oral) will significantly reduce myocardial injury and ischemia in high-risk patients undergoing major non-cardiac surgery, without increasing the risk of hypotension. Using high-sensitivity cardiac troponin (hs-cTn) as marker for myocardial injury and continuous 12-lead Holter ECG for myocardial ischemia, the hypothesis will be tested in a well-powered single-center randomized controlled trial (n=600). Primary efficacy endpoints are myocardial ischemia and injury. Primary safety endpoint is clinically relevant hypotension. Recently, hs-cTn has been shown to strongly predict perioperative major adverse cardiac events and death after non-cardiac surgery. Specific aim 2 will extend this concept and test the hypothesis that preoperative hs-cTn concentration can identify patients who may benefit from postoperative ß-blocker therapy. This hypothesis will be tested within the same trial cohort. This research is both significant and innovative as it studies an important public health problem and offers a novel potential option to the vexing problem of perioperative ß-blocker therapy.