Metoprolol to Reduce Perioperative Myocardial Injury (ORION)

The purpose of this research study is to test if a commonly used, FDA-approved medication, called metoprolol, given at the conclusion of anesthesia following surgery, and during postoperative admission, reduces the possibility of heart related complications in patients with coronary artery disease (CAD).

Study Overview

• Status: Completed
• Conditions: Heart Diseases
• Intervention / Treatment: Drug: Metoprolol Tartrate; Drug: Placebo

Detailed Description

All enrolled patients will be beta-blocker naïve for at least 30-days prior to their scheduled surgical procedure. Study patients will be randomly assigned to an interventional drug arm (metoprolol tartrate vs placebo-comparator). At the conclusion of anesthesia following the surgical procedure, patients hemodynamically stable and meeting study safety parameters (heart rate greater-than-65; systolic blood pressure greater-than-110) will receive 3-intravenous doses of interventional study drug (metoprolol tartrate 5mg or placebo-comparator), based on previously assigned study arm; then, patients remaining hemodynamically stable will receive an oral dose (25mg metoprolol vs placebo-comparator) approximately every 8-hours for up to 3-days during postoperative hospital admission.

From arrival in the preop holding area through up to 72 hours postoperative admission to hospital discharge or end of study treatment (whichever occurs first), patients will be continuously monitored through medical records assessments, Holter monitoring, mobile hemodynamic monitoring (VisiMobile), and in-person daily follow-up visits that include 12-lead ECG, and blood collections for serial cardiac biomarkers for high-sensitivity troponin.

Additional study patient postoperative assessment will be performed at 30 days and 1 year after surgery. These can be completed by interview and/or medical record review.

• Study Type: Interventional
• Enrollment (Actual): 170
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medicine
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. Age >= 50 years
2. Beta-blocker naïve [30 days prior to surgery]

3. Previously diagnosed coronary artery disease (CAD), or

   1. History of peripheral vascular disease (PVD), or
   2. Chronic kidney disease (CKD) [eGFR ≤60ml/min], or
   3. History of positive stress test or
   4. At high risk for CAD (must meet at least 2 criteria):

   i. Age >= 70 years ii. Hypertension iii. Diabetes requiring oral medication or insulin iv. Current smoker or some days smoker within the past 2 years

4. Major non-cardiac, elective surgery under general anesthesia

Exclusion Criteria

Subjects will not be enrolled if any of the following criteria exist:

1. History of stroke, or transient ischemic attack (TIA)
2. Previously diagnosed carotid disease, i.e., either 70% unilateral or 50% bilateral carotid occlusion.
3. Heart rate <=55bpm
4. Congestive heart failure with New York Heart Association(NYHA) Functional Classification of III-IV or left ventricular heart failure with ejection fraction ≤50%
5. Severe valvular regurgitation
6. Second or third degree atrioventricular (AV) block without pacemaker
7. Active asthma or chronic obstructive pulmonary disease (COPD) with symptoms or resolving symptoms on day of surgery
8. Anemia [HB<=9g/dL]
9. Allergy to beta-blockade drugs
10. Unwilling or unable to give consent for participation
11. Undergoing any carotid endarterectomy, endovascular, endoscopic, superficial, or ambulatory procedures
12. Pregnancy or lactating women
13. Prisoners

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metoprolol; Metoprolol group, 3-intravenous doses of 5mg metoprolol tartrate (over 15-minutes), and oral dose(s) of 25mg metoprolol approximately every 8 hours postoperatively for up to 3-days (or 72 hrs).	Drug: Metoprolol Tartrate; Patients will be randomly assigned to receive up-to-three intravenous doses of 5mg metoprolol tartrate (over 15-minutes) at the end of their surgical procedure, and a scheduled oral dose regimen of 25mg metoprolol approximately every 8-hours postoperatively for up to 3-days (or 72 hrs).; Other Names: Beta-blocker
Placebo Comparator: Placebo; Placebo comparator group, up-to-three intravenous doses of placebo comparator (over 15-minutes), and oral dose(s) of a placebo comparator approximately every 8 hours postoperatively for up to 3-days (or 72 hrs).	Drug: Placebo; Patients will be randomly assigned to receive up-to-three intravenous doses of a placebo-comparator (over 15-minutes) at the end of their surgical procedure, and scheduled oral dose regimen of a placebo-comparator approximately every 8-hours postoperatively for up to 3-days (or 72 hrs).; Other Names: Control; Sham; Placebo-comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction of Myocardial Injury following Post-op Beta-blocker therapy	Measure effectiveness of post-operative beta-blocker therapy to reduce myocardial injury by monitoring daily biomarkers (High-Sensitivity cardiac Troponin [HS-cTn]). Myocardial injury is defined as a new hscTn elevation >99th percentile, or a 50% increase if the baseline hscTn is already elevated >99th percentile	Up to 72 hours following surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Clinically Relevant Bradycardia	Monitor cumulative events of bradycardia rate/duration time. Bradycardia is defined as low heart rate (HR < 50/min).	Up to 72 hours following surgery
Monitor Post-operative Myocardial ischemia	Post-operative cardiac monitoring via ECG to evaluate if myocardial ischemia is present. Myocardial Ischemia is defined as ST depression or elevation of ≥0.2 mV in one lead or ≥0.1 mV in two contiguous leads lasting ≥10 min	Up to 72 hours following surgery
Stroke related events following surgery	Stroke will be defined as focal or global cerebral, spinal, or retinal dysfunction of sudden onset	Up to 72 hours following surgery
Vasopressor Therapy to Regulate Symptomatic Hypotension	Monitor vasopressor requirements for blood pressure regulation due to symptomatic hypotension. Symptomatic hypotension (systolic BP < 90 mmHg) can be determined by clinical intervention due to low blood pressure and/or patient developed clinical symptoms due to hypotension.	Up to 72 hours following surgery
Recovery Progress 30-day Post-operative	Monitor post-operative recovery 30-days following the procedure to determine if changes to medications, readmissions, or other events have occurred since hospital discharge.	30-days from surgery
Post-operative Mortality at 1-year	Collect 1-year post-operative mortality of study population. Measured by 'living', 'deceased', 'date of death'.	1-Year from surgery
Reduction in Major Adverse Cardiac Events (MACE)	MACE are defined as myocardial ischemia (MI), cardiac death or coronary revascularization	Up to 72 hours following surgery
Length of Post-operative Hospitalization	Measure post-operative length of admission associated with level of care until discharge (regular floor, intensive care unit, observation unit).	Up to 72 hours following surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Monitor adverse events and severity associated with low blood pressure (hypotension), low heart heart (bradycardia), nausea and vomiting; or other symptoms determined 'probably', 'possibly', 'unrelated', or 'related' to the study intervention. This includes any unplanned escalation of care admissions (e.g., Intensive Care Unit [ICU]). Study patient safety is monitored by the investigators (MD) with experience in critical care anesthesia, as well as an experienced clinical research team responsible for data collection and reporting of events.	Length of participation

Collaborators and Investigators

• Sponsor: University of Chicago
• Collaborators: Washington University School of Medicine; National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Peter Nagele, MD, University of Chicago Medicine

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Actual): April 18, 2023
• Study Completion (Actual): August 29, 2023

Study Registration Dates

• First Submitted: April 26, 2017
• First Submitted That Met QC Criteria: April 28, 2017
• First Posted (Actual): May 3, 2017

Study Record Updates

• Last Update Posted (Actual): October 23, 2023
• Last Update Submitted That Met QC Criteria: October 17, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: myocardial injury; surgery; coronary artery disease; heart disease; metoprolol
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Metoprolol
• Other Study ID Numbers: IRB19-1797; 5R01HL126892 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No