Heart Diseases
Conditions
Keywords
surgery, heart disease, metoprolol, myocardial injury, coronary artery disease
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.
Interventions
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).
DRUGPlacebo
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).
Sponsors
University of Chicago
National Heart, Lung, and Blood Institute (NHLBI)
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double blind masking
Intervention model description
Single-center, double blinded placebo controlled
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effectiveness of Beta-blocker Therapy Reducing Post-operative Myocardial Injury | 0-3 days, following surgery | Measured effectiveness of post-operative beta-blocker therapy to reduce myocardial injury by monitoring daily biomarkers (High-Sensitivity cardiac Troponin \[HS-cTn\]). Daily post-operative biomarker (hs-cTn) measurements to determine myocardial injury. Myocardial injury is defined as a new hscTn elevation \>99th percentile, or a 50% increase if the baseline hscTn is already elevated \>99th percentile |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effectiveness in Reduction of Major Adverse Cardiac Events (MACE) | 0-3 days, following surgery | MACE are defined as myocardial ischemia (MI), cardiac death or coronary revascularization |
| Monitor Post-operative Myocardial Ischemia | 0-3 days, following surgery | 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 |
| Number of Stroke Related Events Following Surgery | 0-3 days, following surgery | Stroke will be defined as focal or global cerebral, spinal, or retinal dysfunction of sudden onset |
| Number of Participants Having Vasopressor Therapy to Regulate Symptomatic Hypotension | 0-3 days, following surgery | Monitor participants with vasopressor requirements for blood pressure regulation due to symptomatic hypotension (rate/duration time). 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. |
| Number of Participant Incidence of Clinically Relevant Bradycardia | 0-3 days, following surgery | Monitored participants with cumulative events of bradycardia (rate/duration time). Bradycardia is defined as low heart rate (HR \< 50/min). |
| Participants Number of Days Spent Post-operative Hospitalization | 0-3 days following surgery | Measurement of participants number of days spent hospitalized (0-3 days) following surgery. |
| Patient Recovery Progress Events at 30-days Post-operative. | 30-days from surgery | Measured number of participant post-operative recovery events, 30-days following the surgical procedure. |
| Participant Post-operative Mortality at 1-year Following Surgery | 1-Year from surgery | Measured number of patient post-operative mortality at 1-year. Measured by 'living', 'deceased', 'date of death'. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORPeter Nagele, MD
University of Chicago Medicine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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).
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). | 34 |
| 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).
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). | 38 |
| Total | 72 |
Baseline characteristics
| Characteristic | Metoprolol | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 30 Participants | 32 Participants | 62 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 6 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 38 Participants | 71 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 5 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 26 Participants | 30 Participants | 56 Participants |
| Region of Enrollment United States | 34 participants | 38 participants | 72 participants |
| Sex: Female, Male Female | 24 Participants | 19 Participants | 43 Participants |
| Sex: Female, Male Male | 10 Participants | 19 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 38 |
| other Total, other adverse events | 8 / 34 | 3 / 38 |
| serious Total, serious adverse events | 0 / 34 | 0 / 38 |
Outcome results
Primary
Effectiveness of Beta-blocker Therapy Reducing Post-operative Myocardial Injury
Measured effectiveness of post-operative beta-blocker therapy to reduce myocardial injury by monitoring daily biomarkers (High-Sensitivity cardiac Troponin \[HS-cTn\]). Daily post-operative biomarker (hs-cTn) measurements to determine myocardial injury. Myocardial injury is defined as a new hscTn elevation \>99th percentile, or a 50% increase if the baseline hscTn is already elevated \>99th percentile
Time frame: 0-3 days, following surgery
Population: Analysis is comprised of participants meeting criteria for randomization to receive intervention, with biomarker (hs-cTn) showing increased value(s).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metoprolol | Effectiveness of Beta-blocker Therapy Reducing Post-operative Myocardial Injury | 9 participants |
| Placebo | Effectiveness of Beta-blocker Therapy Reducing Post-operative Myocardial Injury | 11 participants |
Secondary
Effectiveness in Reduction of Major Adverse Cardiac Events (MACE)
MACE are defined as myocardial ischemia (MI), cardiac death or coronary revascularization
Time frame: 0-3 days, following surgery
Population: MACE analysis is comprised of eligible participants meeting criteria for randomization to receive intervention, having myocardial ischemia, cardiac death, or coronary revascularization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metoprolol | Effectiveness in Reduction of Major Adverse Cardiac Events (MACE) | 0 participants |
| Placebo | Effectiveness in Reduction of Major Adverse Cardiac Events (MACE) | 0 participants |
Secondary
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
Time frame: 0-3 days, following surgery
Population: Analysis is comprised of eligible participants meeting criteria for randomization to receive intervention, with post-operative cardiac monitoring (ECG), showing 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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metoprolol | Monitor Post-operative Myocardial Ischemia | 0 Participants |
| Placebo | Monitor Post-operative Myocardial Ischemia | 0 Participants |
Secondary
Number of Participant Incidence of Clinically Relevant Bradycardia
Monitored participants with cumulative events of bradycardia (rate/duration time). Bradycardia is defined as low heart rate (HR \< 50/min).
Time frame: 0-3 days, following surgery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metoprolol | Number of Participant Incidence of Clinically Relevant Bradycardia | 0 Participants |
| Placebo | Number of Participant Incidence of Clinically Relevant Bradycardia | 1 Participants |
Secondary
Number of Participants Having Vasopressor Therapy to Regulate Symptomatic Hypotension
Monitor participants with vasopressor requirements for blood pressure regulation due to symptomatic hypotension (rate/duration time). 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.
Time frame: 0-3 days, following surgery
Population: Analysis is comprised of eligible participants meeting criteria for randomization to receive intervention, having significant post-operative hypotension (systolic BP \< 90 mmHg), requiring therapeutic intervention (vasopressor).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metoprolol | Number of Participants Having Vasopressor Therapy to Regulate Symptomatic Hypotension | 0 Participants |
| Placebo | Number of Participants Having Vasopressor Therapy to Regulate Symptomatic Hypotension | 0 Participants |
Secondary
Number of Stroke Related Events Following Surgery
Stroke will be defined as focal or global cerebral, spinal, or retinal dysfunction of sudden onset
Time frame: 0-3 days, following surgery
Population: Analysis is comprised of eligible participants meeting criteria for randomization to receive intervention, with post-operative sudden onset of neurological effects from cerebral dysfunction.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metoprolol | Number of Stroke Related Events Following Surgery | 0 Participants |
| Placebo | Number of Stroke Related Events Following Surgery | 0 Participants |
Secondary
Participant Post-operative Mortality at 1-year Following Surgery
Measured number of patient post-operative mortality at 1-year. Measured by 'living', 'deceased', 'date of death'.
Time frame: 1-Year from surgery
Population: Analysis is comprised of eligible participants meeting criteria for randomization to receive intervention, deceased within 1-year of post-operative discharge.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metoprolol | Participant Post-operative Mortality at 1-year Following Surgery | 0 Participants |
| Placebo | Participant Post-operative Mortality at 1-year Following Surgery | 0 Participants |
Secondary
Participants Number of Days Spent Post-operative Hospitalization
Measurement of participants number of days spent hospitalized (0-3 days) following surgery.
Time frame: 0-3 days following surgery
Population: Analysis is comprised of eligible participants meeting criteria for randomization to receive intervention, with post-operative length of hospital stay in days.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Metoprolol | Participants Number of Days Spent Post-operative Hospitalization | Participant post-operative hospitalization in days | 2.5 days |
| Metoprolol | Participants Number of Days Spent Post-operative Hospitalization | Participant post-operative Intensive Care Unit (ICU) hospitalization in days | 2 days |
| Placebo | Participants Number of Days Spent Post-operative Hospitalization | Participant post-operative hospitalization in days | 2.5 days |
| Placebo | Participants Number of Days Spent Post-operative Hospitalization | Participant post-operative Intensive Care Unit (ICU) hospitalization in days | 3 days |
Secondary
Patient Recovery Progress Events at 30-days Post-operative.
Measured number of participant post-operative recovery events, 30-days following the surgical procedure.
Time frame: 30-days from surgery
Population: Analysis is comprised of eligible participants meeting criteria for randomization to receive intervention, with post-operative 1-month follow up showing readmission since surgical discharge.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metoprolol | Patient Recovery Progress Events at 30-days Post-operative. | 0 Participants |
| Placebo | Patient Recovery Progress Events at 30-days Post-operative. | 0 Participants |
Other Pre-specified
Measured Number of Patient Adverse Events
Number of measured participant 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.
Time frame: Post-operatively, 0-3 days, and day-30
Population: Analysis is comprised of eligible participants meeting criteria for randomization to receive intervention, having post-operative adverse events.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Metoprolol | Measured Number of Patient Adverse Events | Hypotension | 7 Participants |
| Metoprolol | Measured Number of Patient Adverse Events | Bradycardia | 0 Participants |
| Metoprolol | Measured Number of Patient Adverse Events | Death | 0 Participants |
| Metoprolol | Measured Number of Patient Adverse Events | Cardiac Arrest | 0 Participants |
| Placebo | Measured Number of Patient Adverse Events | Cardiac Arrest | 0 Participants |
| Placebo | Measured Number of Patient Adverse Events | Hypotension | 2 Participants |
| Placebo | Measured Number of Patient Adverse Events | Death | 0 Participants |
| Placebo | Measured Number of Patient Adverse Events | Bradycardia | 1 Participants |