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 -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 -blocker therapy, starting an oral -blocker before surgery and continuing throughout the perioperative period), perioperative -blockade is associated with harm. It exposes all patients to strong -blockade regardless of the hemodynamic status. When patients on -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 -blockers against perioperative myocardial ischemia, yet not increase overall risk. Specifically, the objective of this application is to determine if postoperative -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 -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 -blocker therapy.

Public Health Relevance

Public Health Relevance: It is estimated that among the 30 million Americans undergoing non-cardiac surgery each year, 63,000 die due to a major adverse cardiac event within 30 days following surgery. Based on prior evidence, the postoperative -blocker regimen proposed in this application would translate into approximately 1 in 4 postoperative MIs prevented and between 10,000 - 15,000 lives saved each year.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL126892-02
Application #
9115689
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Lee, Albert
Project Start
2015-08-01
Project End
2020-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Duma, A; Wagner, C; Titz, M et al. (2018) High-sensitivity cardiac troponin T in young, healthy adults undergoing non-cardiac surgery. Br J Anaesth 120:291-298
Samaha, Eslam; Helwani, Mohammad A; Brown, Jamie C et al. (2018) Are high-sensitivity cardiac troponin I values stable between preoperative visit and day of non-cardiac surgery? Clin Biochem 52:171-172
Duma, Andreas; Pal, Swatilika; Johnston, Joshua et al. (2017) High-sensitivity Cardiac Troponin Elevation after Electroconvulsive Therapy: A Prospective, Observational Cohort Study. Anesthesiology 126:643-652
Kopec, Michael; Duma, Andreas; Helwani, Mohammad A et al. (2017) Improving Prediction of Postoperative Myocardial Infarction With High-Sensitivity Cardiac Troponin T and NT-proBNP. Anesth Analg 124:398-405
Brown, Jamie C; Samaha, Eslam; Rao, Srikar et al. (2017) High-Sensitivity Cardiac Troponin T Improves the Diagnosis of Perioperative MI. Anesth Analg 125:1455-1462
Nagele, Peter (2016) The Case for a Revised Definition of Myocardial Infarction-Resolving the Ambiguity of Type 2 Myocardial Infarction. JAMA Cardiol 1:247-8