NOVEL STRATEGY FOR PERIOPERATIVE BETA-BLOCKER THERAPY

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 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.