NOVEL STRATEGY FOR PERIOPERATIVE BETA-BLOCKER THERAPY

 描述(由申请人提供)：非心脏手术后的主要心脏不良事件，如心肌梗塞(MI)，每年导致美国人死亡的人数超过所有机动车死亡人数的总和。围手术期阻滞剂治疗是唯一被证明可以降低围手术期心脏风险的循证干预措施。不幸的是，当像往常一样练习时(即“术前阻滞剂治疗”，在手术前开始口服阻滞剂，并在整个围手术期持续)，围手术期的阻滞剂与伤害有关。无论血流动力学状态如何，它都会使所有患者暴露在强效阻滞剂下。当服用阻滞剂的患者出现低血容量时，他们无法维持心输出量，并面临长期低血压、休克、中风和死亡的风险。这项建议将测试一种新的策略，该策略将保留？受体阻滞剂对围手术期心肌缺血的有效保护作用，但不会增加总体风险。具体地说，这项应用的目的是确定术后(而不是术前)使用阻滞剂治疗是否是降低围手术期心脏风险的安全和有效的方案。具体目标1将验证这样一种假设，即术后滴定美托洛尔方案(静脉注射，然后口服)将显著减少接受大型非心脏手术的高危患者的心肌损伤和缺血，而不会增加低血压的风险。使用高灵敏度心肌肌钙蛋白(hs-cTn)作为心肌损伤的标志物，连续12导联动态心电图用于心肌缺血，这一假设将在一个强大的单中心随机对照试验中得到验证(n=600)。主要疗效终点是心肌缺血和损伤。主要安全终点是临床上相关的低血压。最近，hs-cTn被证明可以很好地预测非心脏手术后围术期主要不良心脏事件和死亡。具体目标2将扩展这一概念，并检验术前hs-cTn浓度可以确定哪些患者可能受益于术后？阻滞剂治疗的假设。这一假设将在相同的试验队列中进行检验。本文的研究具有重要意义和创新性。 一个重要的公共卫生问题，并提供了一个新的潜在选择，以解决令人头疼的围手术期-阻滞剂治疗的问题。

 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.