Clinical trial NCT03138603
Conditions: Heart Diseases
Keywords: surgery heart disease metoprolol myocardial injury coronary artery disease
Sponsor: University of Chicago
Start date: 2016-12-01; Completion date: 2023-08-29
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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).

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.

Arms: arm 1: 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). arm 2: 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).
Interventions: intervention 1: Metoprolol Tartrate intervention 2: Placebo
Intervention descriptions: intervention 1: 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). intervention 2: 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).

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 21 
 
RRESEARCH PROTOCOL - IRB19-1797 
 
 
 
 
“The ORION Trial” 
Metoprolol to Reduce Perioperative Myocardial Injury 
 
 
 
 
 
Peter Nagele, MD, MSc 
Professor and Chairman 
Department of Anesthesia & Critical Care 
5841 S. Maryland Ave. | MC 4028, Room E-422 Chicago, IL 60637-1470 
pnagele@dacc.uchicago.edu 
Tel 773-702-2545 Fax 773-702-2190 
 
 
 
Professor Paul Myles 
Director, Department of Anesthesiology & Perioperative Medicine 
The Alfred | 55 Commercial Rd, Melbourne, VIC 3004 
P.Myles@alfred.org.au 
Tel +61 3 9076 3707 
 
 
 
 
 
Version Date:  9/28/2020 
 
 
 


Page 2 of 21 
 
 
TABLE OF CONTENTS 
1. 
SYNOPSIS .........................................................................................................................................................4 
2. 
BACKGROUND AND RATIONALE ..............................................................................................................6 
3. 
STUDY METHODS ..........................................................................................................................................6 
3.1 
Study Design Summary ..............................................................................................................................6 
3.2 
Study Population ........................................................................................................................................7 
3.2.1 
Inclusion Criteria ................................................................................................................................7 
3.2.2 
Exclusion Criteria ...............................................................................................................................7 
3.2.3 
Screening and Enrollment ..................................................................................................................7 
3.2.4 
Informed Consent Process ..................................................................................................................8 
3.2.5 
Randomization and Blinding ..............................................................................................................8 
3.2.6 
Screening log of patients excluded from trial .....................................................................................8 
3.3 
Risks and Benefits ......................................................................................................................................8 
3.3.1 
Risks ...................................................................................................................................................8 
3.3.2 
Benefits ...............................................................................................................................................9 
3.4 
Withdrawal .................................................................................................................................................9 
3.4.1 
Early Withdrawal of Subjects .............................................................................................................9 
3.4.2 
How and When to Withdraw Subjects ...............................................................................................9 
3.4.3 
Follow-up for Withdrawn Subjects ....................................................................................................9 
3.5 
Study Drug ..................................................................................................................................................9 
3.5.1 
Description of Study Drug ..................................................................................................................9 
3.5.2 
Treatment Regimen .......................................................................................................................... 10 
3.5.3 
Justification for Intervention ............................................................................................................ 10 
3.5.4 
Provision, Storage, Packaging, Dispensing of Study Drug .............................................................. 11 
3.5.5 
Potential Adverse Reactions Related to Study Drug Administration ............................................... 11 
3.6 
Study Outcomes ........................................................................................................................................ 11 
3.6.1 
Primary Outcome Measures ............................................................................................................. 11 
3.6.2 
Secondary Outcome Measures ......................................................................................................... 11 
        3.6.3        Endpoint Definitions ………………………………………………………………………………11 
4. 
STUDY PROCEDURES .................................................................................................................................. 12 
4.1 
Trial Activities Prior to the Day of Surgery ............................................................................................. 12 
4.2 
Day of Surgery Study Procedures ............................................................................................................ 12 


Page 3 of 21 
 
    4.3        Post-operative Unit ................................................................................................................................... 13 
4.4 
Trial Activities Following the Day of Surgery ......................................................................................... 13 
4.5 
Summary of Trial Intervention and Procedures ........................................................................................ 14 
5. 
SAFETY AND ETHICAL CONSIDERATIONS ............................................................................................ 14 
5.1 
Protection of Human Subjects .................................................................................................................. 14 
5.1.1 
Human Subjects Involvement and Characteristics ........................................................................... 14 
5.1.2 
Potential Risks .................................................................................................................................. 15 
5.1.3 
Adequacy of protection against risks ................................................................................................ 15 
        5.1.4  
Inclusion of Women ……………………………………………………………………………...16 
        5.1.5    
Inclusion of Minorities……………………………………………………………………………16 
        5.1.6 
Inclusion of Children …………………………………………………………………………….16 
        5.1.7 
Clincaltrials.gov requirements………………………………………………………....................16 
5.2 
Data Management Practices ..................................................................................................................... 16 
5.3 
Ethical Measures Pertaining to Clinical Care ........................................................................................... 16 
    5.4 Linkages to Subjects and Access to Identifiers ……………………………………………………..…….16 
 
6. 
ADVERSE EVENT REPORTING .................................................................................................................. 16 
6.1 
Definitions of Adverse Events .................................................................................................................. 16 
6.2 
Classification of Adverse Events .............................................................................................................. 17 
6.3 
Adverse Events Data Collection Procedures ............................................................................................. 17 
    6.4 
Procedures for Serious Adverse Events ............................................................................................ 17 
6.5 
Summary of Adverse Event Classification and Reporting ....................................................................... 18 
7. 
STATISTICAL PLAN ..................................................................................................................................... 18 
7.1 
Sample Size Determination and Power .................................................................................................... 18 
7.2 
Interim Analysis and Early Stopping ........................................................................................................ 18 
7.3 
Statistical Methods and Analysis Plan ...................................................................................................... 18 
8. 
DATA AND MONITORING ........................................................................................................................... 19 
8.1 
Data Sources and Quality Assurance ........................................................................................................ 19 
8.1.1 
Sources of Material ........................................................................................................................... 19 
8.1.2 
Data Quality Assurance .................................................................................................................... 19 
8.2 
Confidentiality and Security ..................................................................................................................... 19 
8.3 
Minimization of Bias ................................................................................................................................ 20 
8.4 
Data and Safety Monitoring Board ........................................................................................................... 20 


Page 4 of 21 
 
 
SYNOPSIS 
Study Title 
The ORION Trial - Metoprolol to Reduce Perioperative Myocardial Injury 
Objectives 
a) Determine the efficacy and safety of titrated postoperative beta-blocker therapy to 
reduce myocardial injury. 
b) Determine the clinical utility of pre-operative high-sensitivity cardiac troponin 
levels for identifying patients who may benefit from postoperative beta-blocker 
therapy. 
Hypotheses 
1) In patients with high cardiovascular risk undergoing major, non-cardiac surgery, 
postoperative therapy with the beta-blocker metoprolol will significantly reduce 
postoperative myocardial injury without causing clinically significant hypotension.  
2) Postoperative β-blocker therapy is more effective in patients with elevated 
preoperative hs-cTn (“high-risk”- patients). 
Study Period 
Planned enrollment duration: 5 years 
Planned study treatment duration: Day of surgery to 3 days (72 hrs) postop 
Long term outcomes follow-up: 30-day and 1-year  postop 
Number of 
Patients 
600 randomized subjects 
Study Treatment  
Consented subjects will be randomized at approximately 15 minutes prior to 
extubation who meet ALL the following criteria:  
1) heart rate >65/min  
2) systolic blood pressure (SBP) >110 mmHg (SBP >120 mmHg if >79 yrs) 
3) minimal active bleeding, and 
4) no active wheezing; 
To one of 2 treatment groups using a 1:1 randomization for: 
A. metoprolol tartrate or 
B. placebo.  
Administration of study drug: 
a) OR prior to extubation: IV metoprolol tartrate 5mg (or placebo 5mL) to 
achieve target heart rate of 65/min; may be repeated x2 if HR > 65/min and 
SBP >110 mmHg (SBP > 120 mmHg if > 79 yrs). Total maximum dose = 15 
mg metoprolol or 15mL placebo IV);  
b) Post-operative unit: 25mg oral metoprolol tartrate or placebo prior to 
discharge from post-op; 
c) Hospital floor: 25mg oral metoprolol tartrate or placebo every 8 hours 
thereafter until end of post-operative day three (POD3).Oral metoprolol will 
not be administered if HR <65 bpm and SBP <110 mmHg (or <120 mmHg if 
age >79 yrs)   
Study Design 
Multi-center, double-blind, randomized, placebo-controlled trial 
Inclusion and 
Exclusion Criteria 
Inclusion: 
1) Age ≥ 50 years 
2) Beta-blocker naïve [30 days prior to surgery] 
3) Previously diagnosed coronary artery disease (CAD), OR  


Page 5 of 21 
 
a) History of peripheral vascular disease (PVD), OR  
b) Chronic kidney disease (CKD) [eGFR ≤60ml/min], OR 
c) History of a positive stress test, OR 
d) 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: 
1. History of stroke or transient ischemia attack (TIA) 
2. Previously diagnosed carotid disease, i.e., either 70% unilateral or 50% bilateral 
carotid stenosis. 
3. Heart rate ≤55bpm 
4. Congestive heart failure with New York Heart Association (NYHA) Functional 
Classification of III-IV or known left ventricular heart failure with ejection 
fraction ≤50% 
5. Severe valvular regurgitation 
6. Second or third degree AV block without pacemaker 
7. Active asthma or COPD with symptoms or resolving symptoms on day of surgery   
8. Anemia [Hb≤9g/dL] 
9. Allergy to beta-blockers  
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 
  Measurements 
1. 12-lead continuous Holter-ECG monitoring through 72 hours postoperative 
2. Continuous vital sign monitoring with VISI mobile through 72 hours postop (heart 
rate, blood pressure, respiratory rate, pulse oximetry) 
3. 12-lead ECGs: preoperative; postop.; daily on post op days 1 - 3  
4. Serial cardiac biomarkers including high-sensitivity cardiac troponin plasma levels 
[hs-cTn] at 7 time points: preoperative clinic visit, preoperative holding area, prior 
to first IV metoprolol dose in OR, post-operative unit arrival, and approx. 24 hrs, 
48 hrs, and 72 hrs postop 
5. Daily adverse event monitoring until discharge from hospital 
6. Long-term follow-up at 30 days and 1 year 
Study Endpoints 
Primary efficacy endpoint: Myocardial injury (new hs-cTn elevation) 
Primary safety endpoint: Clinically relevant hypotension  
Secondary study endpoints are:  
a) MACE (Major Adverse Cardiac Events), including myocardial infarction; 
cardiac arrest; death 
b) Myocardial ischemia duration (based on 12-lead Holter ECG) 
c) Stroke 
d) Cumulative vasopressor requirements post-operatively  
e) Incidence rate and cumulative bradycardia duration (HR <50/min) 
f) Unplanned ICU admission 
g) Length of hospital stay, and  
h) Length of ICU stay 
 


Page 6 of 21 
 
1. 
BACKGROUND AND RATIONALE 
Perioperative adverse cardiac events are a significant public health concern. Often referred to as a “hidden 
epidemic”, perioperative adverse cardiac events kill twice as many Americans per year as all motor vehicle deaths 
combined (2011: 32,367 motor vehicle deaths compared to an estimated 63,000 postoperative cardiac deaths after 
non-cardiac surgery).6 Despite the substantial incidence and associated mortality of perioperative adverse cardiac 
events, few recommended preventive therapies exist. In fact, there is currently no medical treatment that can be 
recommended for the prevention of perioperative adverse cardiac events based on robust scientific evidence. 
Preoperative β-blocker therapy has become highly controversial (the new 2014 AHA guidelines no longer 
recommend preoperative β-blockers for the majority of patients).8,9 Perioperative statin therapy has nearly 
exclusively been explored in retrospective studies,42-44 and the only randomized controlled trial in patients 
undergoing non-cardiac surgery was performed by the same group whose research has been questioned for 
potential misconduct.45 Two recent large clinical trials showed that neither clonidine (an α2 adrenergic agonist; 
hazard ratio [HR] 1.08, 95% CI 0.93 – 1.26) nor aspirin (HR 0.99, 95% CI 0.86-1.15), prevent perioperative 
adverse cardiac events. Thus, there is currently no evidence-based treatment for prevention of perioperative 
adverse cardiac events and therefore the critical unmet need to identify such treatment that is both safe and 
effective. 
This research is significant because it studies an important public health problem and provides a potential 
treatment option to the vexing problem of perioperative β-blocker therapy. If successful, our novel approach 
would translate into approximately 1 in 4 postoperative MIs prevented and approximately 15,000 lives saved each 
year without increasing the risk of stroke and death in the general U.S. surgical population (assuming a similar 
effectiveness as seen in the POISE trial: absolute risk reduction from 5.1% to 3.6%, relative risk reduction ~30%, 
number needed to treat = 66 to prevent one MI). 
2. STUDY METHODS 
2.1 
Study Design Summary 
This is a multi-center (University of Chicago Medicine [USA]; The Alfred Health [Australia]), double-blind 
clinical trial that will randomize 600 patients with CAD (or at high risk for CAD), and undergoing major non-
cardiac surgery, to postoperative metoprolol tartrate or placebo. All patients will be beta-blocker naïve for at least 
30 days prior to surgery and be randomized 1:1 to receive metoprolol tartrate or placebo. Patients will receive up 
to 3 IV doses of study drug (placebo or IV metoprolol tartrate 5mg) prior to extubation, and subsequently an oral 
dose (placebo or 25mg metoprolol tartrate) in the post-operative unit, and then oral dosing at approx. every 8 
hours thereafter through postop day 3 (72 hrs). From arrival in the preop holding area through up to 72 hours 
postop or end of study treatment (whichever occurs first), patients will be continuously monitored with Holter 
ECG, a mobile hemodynamic monitor (VisiMobile), daily follow-up visits to include 12-lead ECG, and blood 
collections for serial cardiac biomarkers for high-sensitivity troponin. Primary efficacy endpoints are myocardial 
ischemia and myocardial injury as determined by ST-depression/elevation on 12-lead ECG, and hs-cTn elevation. 
Primary safety endpoint is clinically relevant hypotension. Secondary outcomes include major adverse cardiac 
events, stroke, and 30-day and 1-year mortality. 
Due to feasibility and accessibility restrictions, The Alfred Health (TAH), will not be using the continuous 
monitoring device (VisiMobile), nor will it use any form of continuous telemetry for ECG recording. However, 


Page 7 of 21 
 
all other methods of data collection and monitoring will be done, including a daily stat 12-lead ECG recording, 
blood draws, and other information determining the patients’ recovery progress during hospital admission.  
The aim of the ORION trial is to compare the use of post-operative metoprolol to placebo for efficacy 
(myocardial ischemia and myocardial injury) and safety (clinically relevant hypotension) outcomes in Beta-
blocker naïve patients with high cardiac risk undergoing elective, major, non-cardiac surgery with general 
anesthesia. 
Additional sites may be added to the study at a later date to also assist in recruitment, Ethics committee approval 
will be obtained then from each, but no data/samples will be shared until that approval and/or agreements have 
been confirmed.  
Additional Australian sites include:  
Fiona Stanley 
Dandenong 
Geelong Hospital 
Waikato 
 
2.2 
Study Population 
Participants will be recruited from patients with planned, elective, non-cardiac surgery, to be performed at the 
University of Chicago Medicine, Chicago IL [USA]; and The Alfred Health, Melbourne, [AU]. 
2.2.1 
Inclusion Criteria 
1. 
Age ≥ 50 years 
2. 
Beta-blocker naïve [30 days prior to surgery] 
3. 
Previously diagnosed CAD, or 
a) History of PVD, or 
b) CKD [eGFR ≤60ml/min], or 
c) History of positive stress test or 
d) 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 
2.2.2 
Exclusion Criteria 
Subjects will not be enrolled if any of the following criteria exist: 
1. History of stroke, or 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 


Page 8 of 21 
 
6. Second or third degree AV block without pacemaker 
7. Active asthma or 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 
 
2.2.3 
Screening and Enrollment 
Screening and recruitment at UCM Anesthesia Perioperative Medicine Clinic (APMC), which conducts 
preoperative visits for approx. 19-35 patients/day; or during a preoperative stay in the hospital for eligible 
inpatients. The purpose of the APMC is to perform standardized assessments prior to surgery..Pre-screening will 
be conducted by coordinator review of the APMC schedule to identify patients who meet the criteria for age, 
eligible surgical procedure, and planned general anesthesia. If a patient is deemed eligible, the patient’s medical 
history will be further evaluated by review of the electronic medical record (EMR) to apply inclusion and 
exclusion criteria. Eligible patients will be approached in APMC by a study team member who will discuss study 
aims, procedures, risks, and benefits of participation. 
The screening and recruitment plan at TAH will be approved and in accordance with their local Ethics 
Committee; while following institutional guidelines regarding research patient enrollment in a pre-operative 
clinical setting, 
Occasionally, patients undergoing elective surgery will be recruited from inpatient hospital units. These patients 
will be identified by routine screening of the OR schedule then following the same process as described above, 
utilizing the EMR to further assess inclusion/exclusion criteria prior to approaching for informed consent and 
study participation.  
2.2.4 
Informed Consent Process 
After determining clinical eligibility, the study will be discussed with patients, including all research related 
procedures, subject involvement, risks and benefits. Patients will be provided the opportunity to ask questions and 
if agreeable and demonstrate verbal understanding, we will obtain written informed consent prior to any study 
related procedures. Subjects will be provided with a signed and dated copy of the consent form document.  
After obtaining informed consent, patients will be enrolled in the trial. Final decision for randomization will be 
made in the operating room when patient meets criteria for study drug administration. 
2.2.5 
Randomization and Blinding 
Randomization will be performed respectively by UCM Investigational Drug Services (IDS), and TAH drug 
services), using a 1:1 computer-generated randomization sequence, which will be concealed from investigators 
and the research team through study completion. Consented patients will be randomly assigned to receive 
metoprolol tartrate or an identical appearing placebo in a 1:1 ratio using permutation blocks (n=4 per block). 
Study subjects, clinicians and research team will be blinded to the randomization assignment. Similarly, the 
adjudicators, whom will determine severity and relatedness of potential adverse events (AEs) and serious adverse 
events, will be blinded and only receive the information necessary to make a decision regarding relatedness to 
study treatment. 


Page 9 of 21 
 
Perioperative intravenous doses of study drug will be prepared respectively by each institutions drug services 
department, using identical syringes for administration of 5mg metoprolol tartrate in 5mL (1mg/mL) or 5mL 
placebo (normal saline). Post-operative oral doses will be dispensed in identical capsules; active capsules will 
contain an over-encapsulated metoprolol tartrate 25 mg tablet with lactose monohydrate backfill and placebo 
capsules will contain lactose monohydrate for equal weight and feel. 
It’s the responsibility of the respective research pharmacies to maintain documentation of medication procurement 
and preparation, as well as randomization, dispensing, and accountability logs. All medications and blinding 
supplies will be stored in a secure location within the research pharmacy and maintained under controlled 
environmental conditions. 
2.2.6 
Screening log of patients excluded from trial 
The study team will maintain a log of all patients screened for this trial to include: 
• 
Eligible and consented 
• 
Eligible and non-consented (reason for refusal) 
• 
Ineligible due to exclusion criteria, indicating the unmet exclusion criteria 
2.3 
Risks and Benefits 
2.3.1 
Risks 
Risks associated with metoprolol: Metoprolol is one of the most commonly used β-blockers. 
Likely:  
Reduction in heart rate and blood pressure,  
Less likely: 
Bronchospasm, clinically significant hypotension and bradycardia, dizziness nausea, diarrhea 
Rare:  
Stroke, death, heart failure, cardiac arrhythmias, blurred vision, hepatitis, psoriasis flare up, 
itching, rash 
 
Risks associated with blood collection: The blood draw may cause bleeding, bruising, or pain. There is also a rare 
risk of infection from venipuncture. Risk from blood collection from a catheter is primarily infection. Maximum 
blood collection is up to approx 37mL collected for up to 72 hours postop. 
 
Risks involving ECG: and hemodynamic monitoring includes mild skin irritation from the electrodes.  
 
Risk of confidentiality breach is also possible.  
The patient will not be penalized or accrue any additional risks if they are randomized to the "placebo" group. No 
standard of care will be affected by this study. If deemed necessary, an un-blinding of the primary care team by 
investigational pharmacy may be activated to ensure the appropriate care can be given to the patient. 
2.3.2 
Benefits 
Participation in this clinical trial may provide additional benefit from continuous hemodynamic monitoring and 
daily post-operative ECGs which help detect silent cardiac events that otherwise may go unnoticed. Subjects will 
also receive daily post-operative follow-up visits from a member of the study team for assessment of any AEs and 
SAEs.  
This clinical trial has the potential to significantly reduce risk of adverse perioperative cardiac events for patients 
in the metoprolol group. The anticipated additional benefit of this research is to provide validation of an evidence-
based approach utilizing hs-cTn assays in clinical practice to improve preoperative cardiac risk stratification. 


Page 10 of 21 
 
2.4 
Withdrawal 
2.4.1 
Early Withdrawal of Subjects  
Early withdrawal may occur per PI discretion if deemed in the best interest of the subject. Subjects may also 
withdraw from study participation at any time. At the time of withdrawal, the metoprolol (or placebo) will be 
stopped.  Patients who desire withdrawal from the protocol will be asked if they may be contacted at 30-days and 
12-months to complete follow up. 
2.4.2 
How and When to Withdraw Subjects Before Randomization 
Patients who do not meet criteria to receive study drug in the OR prior to extubation will be withdrawn per 
protocol and will not undergo any further interventional study related procedures or treatments.  
3.4.3 
Follow-up for Withdrawn Subjects 
The research team may continue to monitor withdrawn subjects for adverse events and serious adverse events 
during hospitalization.  
2.5 
Study Drug 
2.5.1 
Description of Study Drug 
Metoprolol is a β1-selective β-blocker. The estimated oral bioavailability of immediate-release metoprolol tartrate 
tartrate is about 50%.56 Median elimination half-life of oral immediate-release metoprolol tartrate is between 3-5 
hours in normal metabolizers. Peak plasma concentrations are reached after 2-3 min. for IV and 1-2 hours for oral 
metoprolol tartrate.  
2.5.2 
Treatment Regimen 
At approx. 15 minutes before planned extubation in the OR, the patient’s hemodynamic status will be assessed to 
determine if randomization criteria are met to allow study drug administration. These criteria are: 
1) heart rate >65/min  
2) systolic blood pressure > 110 mmHg (if subject > 79 yrs, SBP target is > 120) 
3) minimal active bleeding 
4) no active wheezing; 
 
Subjects who meet randomization criteria will receive the study drug. Subjects that do not meet the randomization 
criteria will be withdrawn. 
Participants will be administered study drug using a double-blind, randomization as described above. Subjects 
will be randomized to one of the following two groups: 
• 
In the Beta-Blocker arm, patients will receive up to 3 doses of 5mg IV Metoprolol tartrate prior to 
extubation to achieve target heart rate of 65/min, for a total of up to 15mg IV Metoprolol tartrate, 
followed by 25mg immediate-release oral 25mg Metoprolol tartrate in the post-operative unit and every 8 
hours thereafter for up to POD 3 (72 hours) 
• 
In the Placebo arm, patients will receive up to 3 doses of 5mL IV normal saline (placebo) prior to 
extubation, for a total of up to 15mL IV placebo followed by an oral matching placebo capsule (lactulose) 
in the PACU and every 8 hours thereafter for up to POD 3 (72 hours) 
At least 2 hours after the first intraoperative dose and while in the Post-operative unit, the patient may receive an 
oral dose of study drug (placebo vs oral metoprolol tartrate 25mg) if HR >65 bpm and SBP >110 mmHg (if 
subject > 79 yrs, SBP target is > 120) and no active or minimal bleeding or no active wheezing. This regimen will 


Page 11 of 21 
 
be repeated on the floor every 8 hours with oral study drug (placebo vs 25mg metoprolol tartrate) through 
postoperative day 3. Patients who cannot receive oral medications per clinical orders, may receive IV study drug 
(metoprolol tartrate 5mg or placebo 5mL) to be administered over 2 minutes. If IV study drug is administered on 
the floor, additional monitoring via hospital telemetry should be active. Of note, the first oral dose administered 
on the floor should be given at least 4 hours following the Post-operative unit dose. 
Rescue Medication 
If patients develop clinically significant hypotension (defined as systolic blood pressure < 90 mmHg), clinicians 
are encouraged to raise and maintain a systolic blood pressure > 110 mmHg. We will provide clinicians with an 
optional rescue protocol that includes administration of IV drugs (e.g. phenylephrine, ephedrine, etc.) and/or IV 
fluid bolus. Likewise, if patients develop clinically significant bradycardia (defined as HR < 50/min), clinicians 
are encouraged to raise the heart rate >60/min. Options may include IV glycopyrrolate, ephedrine, and atropine.  
2.5.3 
Justification for Metoprolol Intervention 
The rationale for the metoprolol regimen is the following: 
1. IV metoprolol is the only AHA-recommended standard of care parenteral β-blocker for acute MI in non-
surgical settings  
2. The IV dosing regimen is identical to the MIAMI trial and COMMIT trial 
3. Data for bisoprolol are sparse and an IV formulation is not FDA-approved 
4. Atenolol has lower effectiveness compared to metoprolol and is no longer considered a first-line β-
blocker; furthermore, atenolol depends on renal excretion which may be affected by perioperative acute 
kidney injury 
5. Esmolol (ultra-short acting IV β-blocker) must be administered via IV infusion which excludes discharge 
of postoperative patients to a regular floor; thus, using esmolol would severely limit the eligible patient 
population to patients being admitted to an ICU or other monitored environment 
6. All perioperative MI studies have shown that >90% of perioperative adverse cardiac events occur 
between the day of surgery and postoperative day 3; therefore, we decided on a short-term β-blocker 
intervention (3 days) that will cover this high-risk period compared to a 30-day course 
7. The daily oral metoprolol dose in this trial is 25% lower than in the POISE trial (150 mg vs. 200 mg) 
which we expect to retain the effectiveness of β-blockade while lowering the risk of hypotension and 
stroke. 
2.5.4 
Provision, Storage, and Packaging, Dispensing of Study Drug 
Drug procurement and dispersing will be in accordance with respective institutional guidelines. Formulations of 
metoprolol tartrate and placebo will be prepared and provided by respective institutional drug services 
department. Active study drug (metoprolol tartrate) will be provided in IV formulation in 3 separate syringes each 
containing 5mg at a concentration of 1mg/mL.  
2.5.5 
Potential Adverse Reactions Related to Study Drug Administration 
Likely:  Reduction in heart rate and blood pressure,  
Less likely:  Bronchospasm, clinically significant hypotension, dizziness, bradycardia, nausea, and diarrhea 
Rare:   Stroke, death, cardiac arrhythmias, depression, heart failure, blurred vision, hepatitis, psoriasis flare up, 
itching, rash 
2.6 
Study Outcomes 
2.6.1 
Primary Outcome Measures 
Primary efficacy endpoint:  
Myocardial injury (hs-cTn elevation) 


Page 12 of 21 
 
Primary safety endpoints:  
Clinically relevant hypotension 
2.6.2 
Secondary Outcome Measures 
1) MACE (Major Adverse Cardiac Events), including myocardial infarction, cardiac arrest, death 
2) Myocardial ischemia (ST-depression/elevation duration) 
3) Stroke 
4) Cumulative vasopressor requirements in post-operative unit  
5) Incidence rate and cumulative bradycardia duration (HR <50/min)  
6) Unplanned ICU admission  
7) Length of hospital stay 
8) Length of ICU stay 
 
2.6.3 
Endpoint Definitions 
 
Myocardial Injury: for statistical purposes, we will use the Δhs-cTn = difference between baseline and peak 
postoperative hs-cTn as continuous variable. To define an “event”, myocardial injury will be defined as a new 
hscTn elevation >99th percentile, or a 50% increase if the baseline hscTn is already elevated >99th percentile. 
 
Clinically relevant hypotension is defined as cumulative hypotensive time (duration of syst. BP <90 mmHg); 
Symptomatic hypotension as event is defined when there was a clinical intervention due to hypotension and/or the 
patient developed clinical symptoms due to hypotension. 
 
MACE are defined as MI, cardiac death or coronary revascularization  
 
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 
 
Myocardial infarction will be assessed according to the Third Universal Definition of myocardial infarction 
(rising pattern of cTn with at least one elevation > 99th percentile plus new ECG changes indicative of 
myocardial ischemia and/or clinical symptoms). New Q-waves, ST-segment depression or T-wave inversion ≥ 
0.1mV, or ST-elevation ≥ 0.2 mV in at least two contiguous leads are considered indicative of myocardial 
ischemia. The diagnosis of MI will be made and adjudicated by an attending cardiologist.  
 
Deaths will be reviewed by two independent physicians and classified as either cardiac or non-cardiac 
 
Sudden unexplained deaths will be classified as cardiac unless evidence to the contrary (e.g. autopsy) 
 
Stroke will be defined as focal or global cerebral, spinal, or retinal dysfunction of sudden onset that either: 1) 
persists for > 24 hours and has no known corresponding hemorrhage on brain imaging, or 2) persists for < 24 hrs 
and is associated with infarction of central nervous system tissue documented on brain imaging.  
3. 
STUDY PROCEDURES 
3.1 
Trial Activities Prior to the Day of Surgery 
• 
Subject will have provided written informed consent  
• 
Research team will document medical/surgical history, relevant laboratory and radiological results, 
planned surgery and concomitant medications 
• 
Preop vital signs and 12 lead ECG will be obtained 
• 
Blood sample #1 (5mL) will be conducted for hs-cTn  


Page 13 of 21 
 
4.2 
Day of surgery study procedures 
• 
The research team will confirm subject continues to meet all inclusion/exclusion criteria per protocol and 
wishes to continue with study participation 
• 
Research team will inform clinical team of study participation and procedures 
• 
Medical history and concomitant medications will be reviewed for any changes in health status since date 
of consent 
• 
Study subject will undergo preop collection of blood for hs-cTn and 12 lead ECG if not already obtained 
prior to day of surgery. 
• 
Holter monitoring will be initiated 
• 
A member of the study team will be present in the OR for hemodynamic data collection at induction and 
to evaluate for randomization criteria prior to administration of study drug (Sect 3.5.2)  
• 
Prior to extubation and before administration of study drug, blood sample #2 (5mL) may be collected for 
hs-cTn 
• 
At approx 15 minutes prior to extubation and if the patient meets hemodynamic criteria, the anesthesia 
team will follow guidelines to administer the study drug per protocol: 
 A slow injection over 1 minute of IV study drug (5mL IV metoprolol tartrate (5mg) or normal saline 
(placebo) 
 If after 5 min, HR >65 bpm and SBP >110 mmHg, administer a second dose of IV study drug (5mL) 
 If after an additional 5 min, HR >65 bpm and SBP >110 mmHg, admin a third dose of IV study drug  
• 
Total dose of intra-operative study drug is up to 15mg IV metoprolol tartrate or 15mL normal saline 
placebo, for a targeted HR of 65 bpm 
• 
NOTE: If the patient is greater than 79 years old, the systolic BP target will be >120 mmHg. 
4.3  
Post-operative Unit  
• 
Upon arrival to post-op unit blood sample #3 (5mL) will be collected to measure hs-cTn. An additional 
5mL sample of blood will be collect for DNA isolation, if not drawn previously.  
• 
A 12 lead ECG will be obtained by a member of the study team 
• 
ViSi Mobile continuous hemodynamic monitoring will be initiated (at UCM) 
• 
Following a minimum of 2 hours after the first intraoperative dose of study drug, and if still in the post-
operative unit, the patient may receive one dose of oral study drug (placebo vs 25mg oral over-
encapsulated metoprolol tartrate) if HR >65 bpm and SBP >110 mmHg and no active or minimal 
bleeding. If the patient is greater than 79 years old, the SBP parameter will be >120 mmHg. The target 
HR is 65 bpm. 
• 
If the subject cannot tolerate oral medication, study drug may be administered intravenously as 5mg IV 
metoprolol tartrate. 
4.4 
Trial Activities for post-operative treatment period (POD1 – POD3) 
• 
At least 4 hours after receiving study drug in the post-operative unit, and 6-8 hours after the first 
intraoperative dose, the patient will be assessed for oral study drug treatment. If the HR >65 bpm and 
SBP >110 mmHg and there is no active or minimal bleeding, the patient will be given 25mg over-
encapsulated, oral metoprolol tartrate or matching placebo (or by IV route as stated above with telemetry 
monitoring requirements). If the patient is greater than 79 years old, the systolic BP target will be >120 
mmHg. The target HR is 65 bpm. 


Page 14 of 21 
 
• 
This dosing regimen will be repeated every 8 hours with 25mg oral metoprolol tartrate or placebo through 
post-operative day 3 
• 
On the morning of POD 1-3, subjects will undergo blood collection for hs-cTn, blood samples #4, #5, and 
#6 (or through hospital discharge, whichever occurs first) 
• 
12-lead ECG will be obtained on POD 1-3 and will be evaluated by a member of the study team for 
outcomes measures and AEs/SAEs 
 
Total blood collection during the study treatment will be up to 6 blood samples (approx. 30 mL) and 1 blood 
collection for DNA (7mL) for a total of approx. 37mL or about 3 tablespoons. Continuous hemodynamic 
monitoring using the Visi-Mobile will be performed through end of treatment on POD3 (approx. 72 hours 
postop) or hospital discharge, whichever occurs first. Patients will be followed through hospital discharge for 
any AEs/SAEs. 
30-day Follow-Up 
• 
Approximately 30 days following day of surgery, patients will be contacted by telephone to assess for 
outcome measures, adverse events, and changes in medications. If a patient cannot be contacted after 
multiple attempts at up to 5 varying time points, a chart review will be conducted to complete the 30-day 
follow-up. 
1-year Follow-Up 
• 
Approximately 1 year following the day of surgery, patients will be contacted by telephone for an 
assessment of 1-year morbidity and mortality, using the same survey tool for outcomes measured at Day 
30, inclusive of major vascular events.  
• 
This will be the final contact with study participants 
 
 
4.5 
Summary of Trial Intervention and Procedures 
An overview of trial flow is summarized in the diagram below 
 


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5 
SAFETY AND ETHICAL CONSIDERATIONS 
5.1  
Protection of Human Subjects 
5.1.1 
Human Subjects Involvement and Characteristics 
The principal investigators will submit this protocol to the UC Human Research Protection Office for Internal Review 
Board approval. Research personnel will approach all potentially eligible patients who fulfil inclusion and 
exclusion criteria for consent. As defined in the eligibility criteria, patients with conditions that predispose them 
to risk of adverse events associated with decreased heart rate or blood pressure secondary to the administration of 
a Beta-blocker will be excluded. These conditions include but are not limited to history of stroke, TIA, carotid 
disease, and hemodynamic instability. Patient participation will be at the discretion of the PI and clinical care 
team and all other aspects of routine clinical care will not be affected by their participation in the study. 
This trial will not include vulnerable populations and will not enroll children (<18 yrs of age). All participants 
must be able to provide verbal understanding and informed consent. Prisoners will not be enrolled in this study. 
5.1.2 
Potential Risks 
• 
Protocol-specific risks associated with participation may include minor bruising and/or discomfort from 
blood draws 
• 
Study-drug specific risks include:  
o Likely: hypotension, bradycardia,  
o Less likely: Bronchospasm, allergic reaction, dizziness nausea, diarrhea, severe hypotension or 
bradycardia 
o Rare: stroke, death, cardiac arrhythmias, blurred vision, heart failure, psoriasis flare up, severe allergic 
reaction 
Informed Consent                                                          End of Surgery 
                                             IV Metoprolol           Oral Metoprolol  
                                                             
                                   R            IV Placebo               Oral Placebo 
                                                                                      
                                  ViSi & Holter Monitoring                         
          Baseline Blood/ECG                                                 ECG                      ECG                         ECG                         ECG 
                                                           Blood Draw        Blood Draw        Blood Draw            Blood Draw            Blood Draw 
    APMC             Pre-op           Intra-op        Post-op            POD1                 POD2                POD3 


Page 16 of 21 
 
Participants risk the possibility of confidential information accidentally being disclosed 
5.1.3 
Adequacy of protection against risks 
• 
All subjects that participate will provide verbal understanding of risks and sign informed consent prior to 
enrollment in the study. Subjects will be informed that participation is voluntary, and they may refuse to 
participate and withdraw from the study at any time without penalty. Subjects will be told that in the 
event of a physical injury as the direct result of study procedures, the team will do everything to limit the 
injury at no cost to the patient, within the limits of the respective study sites.  
• 
All patients will receive general anesthesia by a team led by Board-certified/eligible anesthesiology 
faculty that operates at the highest standards of current medical practice and has an extensive experience 
in perioperative care for major vascular and other non-cardiac surgery. Patients will be fully monitored 
according to and exceeding of the American Society of Anesthesiology standards to quickly assess any 
adverse event or complication from the time in the preoperative holding area through operating room and 
post-anesthesia care unit. 
• 
Blood draws will be completed by clinical staff with extensive experience in phlebotomy and blood 
collections.  
• 
Patient’s participation will be continuously assessed with ongoing study treatment at the discretion of the 
PI and the clinical care team. 
• 
Hemodynamic parameters designed to ensure subjects receive study drug as appropriate and when 
indicated (HR >65bpm and SBP >110 mmHg. If a patient is over 79 year of age, the SBP target will be 
120 mmHg.)  
• 
The clinical care team will be provided with the guidelines for providing rescue medications if a patient 
develops clinically significant hypotension (defined as SBP <90 mmHg) or bradycardia (HR <50 bpm). 
• 
Serious adverse events will be reported to the respective institutional IRB/Ethics committee according to 
current IRB/Ethics committee guidelines. Adequate clinical care readily available at the University of 
Chicago Medicine, and The Alfred Health, major tertiary care hospitals with around-the-clock anesthesia 
attending staffing and ICU availability. 
• 
The attending surgeon and the surgery staff caring for the subject will be informed of the subject’s 
participation and provided detailed information related to study drug administration 
• 
The research team will be in open and continuous discussion with clinical team to ensure that there is no 
disruption in routine medical supervision, comfort, and recovery 
• 
Extensive measures will be taken to prevent any confidentiality breach of participants’ information as 
described below 
5.1.4 
Inclusion of Women 
There is no exclusion of any sex/gender or racial/ethnic group for these studies. This study actively encourages the 
participation of women.  The study goal is equivalent numbers of women and men.  
5.1.5 
Inclusion of Minorities 
This study actively encourages the participation of minorities. Minority recruiting will typically match the 
demographic composition of the University of Chicago community from which subjects will be recruited. 
5.1.6 
Inclusion of Children 
Subjects <18 yrs will not be studied in these investigations.  


Page 17 of 21 
 
5.1.7 
Clincaltrials.gov requirements 
The proposed research will be registered in ClinicalTrials.gov once the protocol has been reviewed and approved 
by UC IRB. 
 
5.2 Data Management Practices 
All research data will be recorded and saved to a secure password protected research designated server at the resptive 
study sites. Data will be de-identified and stored under lock and key (secured building, locked office, locked cabinet) 
and only the research team will access.   
5.3 
Ethical Measures Pertaining to Clinical Care 
The research team will inform the clinical team of any relevant information that is ascertained as a result of the 
research monitoring (Holter, 12 lead ECG, VisiMobile hemodynamic monitoring, patient self-reported symptoms, 
etc).  
5.4 
Linkages to Subjects and Access to Identifiers 
Any information that is obtained in connection with research that can be identified with a subject will remain 
confidential. Medical information, case report forms, pharmacokinetic and genetic data will be given a code and 
only the research personnel will have access to this information. The original informed consent forms will be kept 
by the PI for 7 years and a copy will be given to all subjects. 
6 
ADVERSE EVENT REPORTING 
6.1 
Definitions of Adverse Events 
An Adverse Event is an unfavorable change in health that occurs in a patient during their enrollment in the 
clinical trial, even if it is not associated with the investigational study drug. 
An Unanticipated Problem is an incident, experience, or outcome that meets all of the following criteria: 
1. Is unexpected in nature, severity, or frequency 
2. Is related or possibly related to participation in the research 
3. Suggests that the research places subjects or other  
A Serious Adverse Event is an unfavorable change in health that: 
• 
Results in death 
• 
Is life-threatening 
o In the definition of serious adverse-events, the term “life-threatening” refers to an event during which 
the subject was at risk of death at the time of the event. It does not include an event which 
hypothetically may have caused death, had it been more severe. 
• 
Requires hospitalization or prolongation of the existing hospitalization, unless 
o The hospitalization was pre-planned before the study 
o Emergency room visits without hospital admission 
o Hospitalization for elective surgery for a condition that was pre-existing at the time of initial 
enrollment. 
• 
Results in a persistent or significant disability or incapacity 
o This refers to an event which causes a substantial disruption of a person’s ability to conduct normal 
life functions. This does not include events of relatively minor significance such as uncomplicated 
nausea and vomiting, diarrhea, or accidental trauma (e.g. sprained ankle) which may interfere or 
prevent daily life functions but is temporary or does not constitute a substantial disruption. 


Page 18 of 21 
 
• 
Resulting in a congenital anomaly or birth defect 
6.2 
Classification of Adverse Events  
Adverse events assessment will be performed by the PI to assign a rating for severity and causality, per 
institutional and federal guidelines. The PI will consider alternative causes for the event, including underlying 
medical conditions, concurrent medical therapy, risk factors, prior reactions of similar nature within this class of 
drugs, and the temporal relationship of the event in context of the study drug pharmacokinetics.  
Relationship to study drug will be classified as: 
• 
None – An event for which there is no causal relationship between the study drug and the event and an 
alternative explanation is more likely. 
• 
Unlikely – An event for which the relationship between the event and the study drug is not clearly 
established or uncertain. 
• 
Probable – An event for which there is most likely a causal relationship between the study drug and the 
event and an alternative explanation is less likely. 
 
Severity for adverse events will be based on the PIs clinical judgment. Severity will be classified as: 
• 
Mild – An event that causes minimal discomfort to the subject and does not interfere with the functions of 
daily living. 
• 
Moderate – An event that interferes with, but does not prevent the subject from performing the functions 
of daily living. 
• 
Severe – An event that is incapacitating and prevents the subject from performing functions of daily 
living. 
6.3  
Adverse Events Data Collection Procedures 
The investigators will closely monitor subjects for evidence of adverse events.  All adverse events will be 
reported and followed until satisfactory resolution.  The description of the adverse experience will include the 
time of onset, duration, severity, etiology, relationship to the study drug (none, unlikely, probable) and any 
treatment required. The clinicians will manage any postoperative event related to the patient’s surgical procedure 
as standard of care. 
6.4      Procedures for Serious Adverse Events  
All Serious Adverse Events or Unanticipated Problems will be reported to the IRB/Ethics committee and 
respective study site DSMB in accordance with institutional and federal guidelines. Unblinding will be at the 
discretion of the PI with the collaborative efforts of the primary care team to determine the necessity. Study drug 
storage, logging, and distribution is the responsibility of the respective institutional drug service departments, and 
they will be responsible for notifying the care team of the patient’s randomized study arm. 
 
6.5 
Summary of Adverse Event Classification and Reporting 
• 
All serious adverse events will be reported to the IRB within 7 calendar days of initial receipt of the 
information 
• 
All unanticipated problems will be reported to the IRB within 10 calendar days of initial receipt of the 
information 


Page 19 of 21 
 
SAEs will also be assessed for causality and severity per the Division of Clinical & Translational Research 
Standard Operating Procedures.  
7 
STATISTICAL PLAN 
7.1 Sample Size Determination and Power 
This trial will randomize 600 study subjects to achieve a minimum of 500 evaluable subjects, which would 
provide a power (1-β) of 0.99. For the primary efficacy analysis, we have based our estimate of the needed sample 
size based on our experience in the VINO trial conducted by Nagele et al. at WU School of Medicine. We 
observed a standard deviation of 4.0 ng/L for the peak change in cTn from baseline. Using a two-sided α=.025, a 
difference between the two groups of 1.5 ng/L, and a conservative estimate of 250 usable peak values in each 
group we calculated a power (1-β) of 0.99.  
7.2 
Interim Analysis  
A blinded interim analysis for safety after 50% of patients have been enrolled, will be conducted. The interim 
analysis will not assess futility or early stopping other than for safety concerns. The DSMB will review the safety 
record and formally assess a statistically significant trend in increased rates of strokes and deaths at an alpha-level 
of 0.025. It is at the discretion of the DSMB to stop the trial for other safety concerns, such as in-creased 
hypotension. 
7.3 
Statistical Methods and Analysis Plan 
a) Hypothesis 1 (In patients with high cardiovascular risk undergoing major, non-cardiac surgery, 
postoperative therapy with the beta-blocker metoprolol will significantly reduce postoperative myocardial 
injury without causing clinically significant hypotension): The primary analysis will be intention-to-treat. 
The main comparison between metoprolol and placebo arm for the primary efficacy endpoints will be 
comparing the Δhs-cTn between both arms (Δhs-cTn = difference between baseline and peak postoperative 
hs-cTn). These will be tested with a simple t-test (α= 0.05). For the analysis of the primary safety endpoint 
(hypotension) the difference in cumulative hypotensive time will be tested with a t-test. Transformations will 
be used if there are substantial departures from the distributional assumptions for these t-tests. For secondary 
analyses of the hs-cTn values, we will fit a repeated measures analysis of variance model showing the time 
course of the average elevation and allow a test of the area under the curve with the use of an appropriate 
contrast statement. Secondary endpoints will be analyzed like the safety endpoint. We will also augment all 
analyses by repeating all analyses with an appropriate vector of covariates to an ANOVA model for 
continuous outcomes and for logistic regression for dichotomous variables. 
b) Hypothesis 2 (Postoperative β-blocker therapy is more effective in patients with elevated preoperative hs-
cTn (“high-risk”- patients). To determine if postoperative β-blocker therapy is more effective in patients 
with elevated preoperative hs-cTn, we plan the following analyses: The first goal will be to identify a cutoff 
preoperative hs-cTn concentration that defines high-risk patients using ROC analyses. Using this hs-cTn 
cutoff, we will compute the interaction of being in the high risk group and randomization group on the Δhs-
cTn (difference between baseline and peak postoperative hs-cTn) We will consider a two-sided p-value < 
0.05 for the interaction term (high-risk group * metoprolol) as statistically significant. Exploratory analyses 
will extend this model adjusting for known covariates of perioperative cardiac risk such as age, sex, eGFR, 
heart failure, etc. 
 


Page 20 of 21 
 
8 
DATA AND SAFETY MONITORING 
8.1  
Data Sources and Quality Assurance 
8.1.1 
Sources of Material 
The following “materials” will be obtained from all study patients for research purposes only: 
• 
Blood tests for hs-cTn: approximately 5mL at up to 6 time points over a 3-day period and an additional 
7mL for DNA, for a total of up to approximately 37 ml blood 
• 
12-lead ECG and digital recording of continuous Holter ECG (up to 72 hours postop) 
• 
Monitoring of vital signs: VisiMobile provides continuous hemodynamic monitoring (for 72 hours 
postop)  
• 
Daily post-op assessments for AEs/SAEs 
• 
Information from the patient’s medical record including progress notes, lab results and diagnostic testing 
 
Results from some of these tests will not available until several weeks after the patient has completed the study 
and will not enter the patient’s clinical record. Blood samples will be stored in a -80⁰ F freezer in a secure 
location, allowing only research team access. All samples will be de-identified with a study ID. All data will be 
for research purposes only. In the event of an incidental finding, the PI will discuss such findings with the clinical 
team and/or primary care physician. 
8.1.2 
Data Quality Assurance 
In order to optimize the accuracy and quality of data, we will: 
• 
Educate all members of the study team to study protocol, manual of procedures and work in accordance 
with good clinical practice 
• 
Provide manual of procedures and guidelines for data acquisition and the completion of the CRF to ensure 
consistency 
• 
Utilize a system of validation measures for the CRF to help protect against user error  
8.2 
Confidentiality and Security 
All electronic data (except for an electronic key linking study ID to PHI) will be de-identified of protected health 
information that could link the data or blood samples to an individual subject. We will only use pre-assigned 
patient study ID numbers to label blood samples, Holter ECG, and hemodynamic information. The numbers are 
linked to subject data and identifiers using an electronic key. Only the research team will have access to the 
electronic key, which will be kept password-protected on a secured network. All research files will be stored in a 
locked and secure location only accessible to the study team. Electronically stored info will be encrypted and 
stored in a password protected database. 
8.3 
Minimization of Bias 
Potential biases will be minimized by the study design of this double-blinded randomized controlled trial. 
Randomization will be performed by respective study site drug services department, utilizing a 1:1 randomization 
sequence, which will be concealed from investigators until the completion of the study. Health care providers, 
study personnel and patients will be blinded to the assigned intervention group (placebo vs. metoprolol). 
Similarly, the adjudicators will also be blinded and only receive information necessary to make a decision. Patient 
recruitment from preoperative clinics reduce selection bias since this is a clearly defined and easily accessible 
population that is well-representative of patient undergoing non-cardiac surgery with high cardiac risk. All 
patients attending the preoperative clinics will be screened according to routine operating procedures, with 
IRB/Ethics committee approval for a partial waiver of consent, irrespective of race, sex and religion. A 


Page 21 of 21 
 
standardized method of assessing reasons for dropouts and withdrawals will be utilized at multiple time-points 
throughout the study. This will be an intention to treat analysis to avoid bias during data analysis. 
8.4 
Data and Safety Monitoring Board 
A data and safety monitoring board (DSMB) will be established for this study at each site consisting of two 
senior anesthesiologists who are not directly involved in the study, one biostatistician, and one cardiologist. The 
DSMB is responsible for overseeing the overall safety of the study and will meet before the start of the trial to 
discuss the study protocol and DSMB charter. The board will meet annually to review all adverse and serious 
adverse events. Should there be a serious adverse event that potentially increases the risks to the participants, the 
study will be stopped, an investigation will be conducted, and a findings report will be generated before the study 
is resumed. These individuals will review; make decisions on adverse event data, other safety data, quality and 
completeness of study data, and enrollment data at each meeting to ensure proper trial conduct. The DSMB will 
review the consent periodically and/or as needed consider whether the consent form requires revision. At 
intervals, as noted above, the DSMB will also review formal interim analyses. In addition to regular meetings, it 
may be necessary to convene the DSMB urgently on an ad hoc basis to discuss new data or other information that 
raises questions about equipoise, safety, or conduct of the trial. 
It is expected that all DSMB members will attend every meeting and conference call. However, it is recognized 
that this may not always be possible. A quorum for voting is half of the standing members plus one. The board 
may wish to decide if particular expertise is needed with the quorum for a particular meeting. All standing 
monitoring board members are voting members. The board may decide in advance whether ad hoc members can 
vote and whether absent members can vote electronically on proposed issues in advance.