Ivabradine for Prevention of Myocardial Injury After Noncardiac Surgery Trial (PREVENT-MINS)

Sponsor

Jagiellonian University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05279651

Collaborator

Population Health Research Institute (Other), Vanderbilt University Medical Center (Other)

2,500

Enrollment

Locations

Arms

45.6

Anticipated Duration (Months)

131.6

Patients Per Site

2.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is a multicentre, randomized controlled trial of ivabradine versus placebo.

Condition or Disease	Intervention/Treatment	Phase
Myocardial Injury After Noncardiac Surgery (MINS) Myocardial Ischemia	Drug: Ivabradine Drug: Placebo	Phase 3

Detailed Description

The PREVENT-MINS study is a 2,500 patient multicentre, superiority randomized controlled trial of ivabradine versus placebo. The primary objective of the trial is to determine the impact of ivabradine versus placebo on the risk of MINS in patients with or at risk of atherosclerotic disease who are followed for 30 days after noncardiac surgery.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

2500 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Parallel AssignmentParallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Ivabradine for PREVENTion of Myocardial Injury After Noncardiac Surgery

Actual Study Start Date :

Jun 13, 2022

Anticipated Primary Completion Date :

Mar 15, 2025

Anticipated Study Completion Date :

Mar 31, 2026

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ivabradine Patients fulfilling haemodynamic requirements (i.e. systolic blood pressure ≥90 mmHg and sinus rhythm with a heart rate ≥65 beats per minute) will receive 5mg of oral ivabradine at least 1 hour before surgery and the first postoperative dose in the evening or in the morning after surgery, at least 12 hours after the preoperative dose. Starting on the day after surgery, patients will receive 5mg oral ivabradine twice a day and continue this treatment for 7 days after surgery or until hospital discharge.	Drug: Ivabradine Patients fulfilling haemodynamic requirements (i.e. systolic blood pressure ≥90 mmHg and sinus rhythm with a heart rate ≥65 beats per minute) will receive 5mg of oral ivabradine at least 1 hour before surgery and the first postoperative dose in the evening or in the morning after surgery, at least 12 hours after the preoperative dose. Starting on the day after surgery, patients will receive 5mg oral ivabradine twice a day and continue this treatment for 7 days after surgery or until hospital discharge.
Placebo Comparator: Placebo Patients fulfilling haemodynamic requirements (i.e. systolic blood pressure ≥90 mmHg and sinus rhythm with a heart rate ≥65 beats per minute) will receive matching placebo at least 1 hour before surgery and the first postoperative dose in the evening or in the morning after surgery, at least 12 hours after the preoperative dose. Starting on the day after surgery, patients will receive matching placebo twice a day and continue this treatment for 7 days after surgery or until hospital discharge.	Drug: Placebo Patients fulfilling haemodynamic requirements (i.e. systolic blood pressure ≥90 mmHg and sinus rhythm with a heart rate ≥65 beats per minute) will receive matching placebo at least 1 hour before surgery and the first postoperative dose in the evening or in the morning after surgery, at least 12 hours after the preoperative dose. Starting on the day after surgery, patients will receive matching placebo twice a day and continue this treatment for 7 days after surgery or until hospital discharge.

Arm

Intervention/Treatment

Active Comparator: Ivabradine

Patients fulfilling haemodynamic requirements (i.e. systolic blood pressure ≥90 mmHg and sinus rhythm with a heart rate ≥65 beats per minute) will receive 5mg of oral ivabradine at least 1 hour before surgery and the first postoperative dose in the evening or in the morning after surgery, at least 12 hours after the preoperative dose. Starting on the day after surgery, patients will receive 5mg oral ivabradine twice a day and continue this treatment for 7 days after surgery or until hospital discharge.

Drug: Ivabradine

Placebo Comparator: Placebo

Patients fulfilling haemodynamic requirements (i.e. systolic blood pressure ≥90 mmHg and sinus rhythm with a heart rate ≥65 beats per minute) will receive matching placebo at least 1 hour before surgery and the first postoperative dose in the evening or in the morning after surgery, at least 12 hours after the preoperative dose. Starting on the day after surgery, patients will receive matching placebo twice a day and continue this treatment for 7 days after surgery or until hospital discharge.

Drug: Placebo

Outcome Measures

Primary Outcome Measures

MINS [30 days after randomization]
Number of patients who experience myocardial injury after non-cardiac surgery (MINS) defined as any myocardial infarction and any elevated postoperative cardiac troponin judged as resulting from myocardial ischaemia during or within 30 days after noncardiac surgery.

Secondary Outcome Measures

A composite of vascular death, non-fatal MINS, non-fatal stroke, and non-fatal cardiac arrest [30 days after randomization]
Number of patients who have at least one of the following: vascular death, non-fatal MINS, non-fatal stroke, and non-fatal cardiac arrest
MINS not fulfilling the 4th universal definition of myocardial infarction [30 days after randomization]
Number of patients who experience MINS not fulfilling the 4th universal definition of myocardial infarction
Myocardial infarction [30 days after randomization]
Number of patients who experience a myocardial infarction
Vascular death [30 days after randomization]
Number of patients who die of vascular cause
Stroke [30 days after randomization]
Number of patients who experience a stroke
All-cause mortality [30 days after randomization]
Number of patients who die of any cause
Days alive and at home [30 days after randomization]
Average number of days when a patient is alive and out of hospital within 30 days after randomization
Health-related quality of life [30 days after randomization]
Average health-related quality of life (based on EuroQol 5 Dimension, five-level version [EQ-5D])
Clinically important atrial fibrillation [30 days after randomization]
Number of patients who experience clinically important atrial fibrillation
Clinically significant bradycardia [30 days after randomization]
Number of patients who experience clinically significant bradycardia
Clinically significant hypotension [30 days after randomization]
Number of patients who experience clinically significant hypotension
Phosphenes [30 days after randomization]
Number of patients who experience phosphenes
Cancellation or postponement of surgery due to concerns about patient's heart rate [30 days after randomization]
Number of surgeries cancelled or postponed due to heart rate concerns
Peak troponin concentration [30 days after randomization]
Peak troponin concentration during the index hospitalization
Area under the curve troponin [30 days after randomization]
Area under the curve of troponin concentrations measured during the hospitalization

Other Outcome Measures

Cardiac revascularization [30 days after randomization]
Number of patients who undergo cardiac revascularization
Re-hospitalization for vascular reasons [30 days after randomization]
Number of patients re-hospitalized for vascular reasons
Acute myocardial injury according to Fourth Universal Definition of Myocardial Infarction [30 days after randomization]
Number of patients who experience an acute myocardial injury according to Fourth Universal Definition of Myocardial Infarction
Non-fatal cardiac arrest [30 days after randomization]
Number of patients who experience non-fatal cardiac arrest
Acute congestive heart failure [30 days after randomization]
Number of patients who experience acute congestive heart failure
Any symptomatic or asymptomatic episode of deep vein thrombosis or pulmonary embolism [30 days after randomization]
Number of patients who experience any (symptomatic or asymptomatic) episode of deep vein thrombosis or pulmonary embolism
International Society on Thrombosis and Haemostasis (ISTH) major bleeding [30 days after randomization]
Number of patients who experience major bleeding (as defined by ISTH)
BIMS [30 days after randomization]
Number of patients who experience bleeding independently associated with mortality after noncardiac surgery (BIMS)
Infection/Sepsis [30 days after randomization]
Number of patients who experience infection/sepsis
Acute kidney injury fulfilling Kidney Disease Improving Global Outcomes (KDIGO) criteria [30 days after randomization]
Number of patients who experience an acute kidney injury (fulfilling KDIGO criteria)
Acute kidney injury requiring dialysis [30 days after randomization]
Number of patients who experience an acute kidney injury requiring dialysis
Amputation [30 days after randomization]
Number of patients who undergo an amputation
Days outside of intensive care unit [30 days after randomization]
Average number of days alive outside of intensive care/cardiac care unit within 30 days after randomization
Length of hospital stay [30 days after randomization]
Average length of hospital stay
Length of intensive care unit stay [30 days after randomization]
Average length of intensive care unit stay
Discharge destination from the hospital [30 days after randomization]
Number of patients discharge to home/long-term care facility/other
All-cause mortality [1 year after randomization]
Number of patients who die of any cause
Vascular death [1 year after randomization]
Number of patients who die of vascular cause
Myocardial infarction [1 year after randomization]
Number of patients who experience a myocardial infarction
Cardiac revascularization [1 year after randomization]
Number of patients who undergo cardiac revascularization
Non-fatal cardiac arrest [1 year after randomization]
Number of patients who experience non-fatal cardiac arrest
Stroke [1 year after randomization]
Number of patients who experience a stroke
Health-related quality of life [1 year after randomization]
Average health-related quality of life (based on EuroQol 5 Dimension, five-level version [EQ-5D])
Amputation [1 year after randomization]
Number of patients who have an amputation
Re-hospitalization for vascular reasons [1 year after randomization]
Number of patients who experience a re-hospitalization for vascular reasons

Eligibility Criteria

Criteria

Ages Eligible for Study:

45 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Undergoing noncardiac surgery
≥45 years of age
Expected to require at least an overnight hospital admission after surgery
Provide written informed consent to participate in the PREVENT-MINS Trial, AND
Fulfill ≥1 of the following 5 criteria (A-E):

History of coronary artery disease B. History of peripheral arterial disease C. History of stroke D. Undergoing major vascular surgery, OR

E. Any 3 of 9 risk criteria:

Undergoing major surgery ii. History of congestive heart failure iii. History of a transient ischaemic attack iv. Diabetes and currently taking an oral hypoglycemic agent or insulin v. Age ≥70 years vi. History of hypertension vii. Serum creatinine >175 µmol/L (>2.0 mg/dl) viii. History of smoking within 2 years of surgery ix. Undergoing emergent/urgent surgery

Exclusion Criteria:

Conduction abnormalities:

Non-sinus rhythm on ECG B. Sinoatrial or AV (2nd and 3d degree) blocks C. Sick sinus syndrome D. Long QT syndrome E. Pacemaker dependent

Transplanted heart (or on waiting list)
Use of a selected class I or III antiarrhythmic drug (quinidine, disopyramide, sotalol, ibutilide, amiodarone) or diltiazem/verapamil
Resting heart rate <65 beats per minute on the day of surgery
Systolic blood pressure <90 mmHg on the day of surgery
Acute decompensated heart failure, cardiogenic shock, acute myocarditis
Acute coronary syndrome within 2 months before surgery;
Stroke or transient cerebral ischaemia within 1 month before surgery
Known severe liver or kidney disease (MDRD creatinine clearance <15 mL/min)
Inability to tolerate oral intake
Recent use of ivabradine (<1 month)
Known allergy or hypersensitivity to ivabradine
Low-risk surgical procedure based on individual physician's judgment
Investigator considers the patient unreliable regarding requirement for study compliance
Women of childbearing potential who are not taking effective contraception, pregnant or breast-feeding
Previously enrolled in the PREVENT-MINS study

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	ZZOZ Szpital Śląski w Cieszynie	Cieszyn	Poland	43-400
2	Uniwersyteckie Centrum Kliniczne im. Prof. Kornela Gibińskiego Śląski Uniwersytet Medyczny	Katowice	Poland	40-752
3	5 Wojskowy Szpital Kliniczny z Polikliniką Samodzielny Publiczny Zakład Opieki Zdrowotnej w Krakowie	Kraków	Poland	30-901
4	Szpital Zakonu Bonifratrów św. Jana Grandego w Krakowie	Kraków	Poland	31-061
5	Krakowski Szpital Specjalistyczny im. Jana Pawła II	Kraków	Poland	31-202
6	Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie sp. z o.o.	Kraków	Poland	31-826
7	Szpital Specjalistyczny Stefana Żeromskiego w Krakowie	Kraków	Poland	31-913
8	Samodzielny Publiczny Szpital Kliniczny 1 w Lublinie	Lublin	Poland	20-081
9	Wojewódzki Szpital Specjalistyczny w Olsztynie	Olsztyn	Poland	10-561
10	Uniwersytecki Szpital Kliniczny w Opolu	Opole	Poland	45-401
11	Samodzielny Publiczny Szpital Kliniczny Nr 2 Pomorskiego Uniwersytetu Medycznego	Szczecin	Poland	70-111
12	Samodzielny Publiczny Szpital Kliniczny Nr 1 Pomorskiego Uniwersytetu Medycznego	Szczecin	Poland	72-252
13	Specjalistyczny Szpital im. Edwarda Szczeklika w Tarnowie	Tarnów	Poland	33-100
14	Uniwersyteckie Centrum Kliniczne Warszawskiego Uniwersytetu Medycznego	Warszawa	Poland	02-097
15	Wojskowy Instytut Medyczny Centralny Szpital Kliniczny MON	Warszawa	Poland	04-141
16	Uniwersytecki Szpital Kliniczny we Wrocławiu	Wrocław	Poland	50-556
17	Samodzielny Publiczny Szpital Kliniczny Nr 1 im. Prof. Stanisława Szyszko Śląskiego Uniwersytetu Medycznego w Katowicach	Zabrze	Poland	41-800
18	Szpital Uniwersytecki im. Karola Marcinkowskiego w Zielonej Górze	Zielona Góra	Poland	65-001
19	Centralny Szpital Kliniczny Uniwersytetu Medycznego w Łodzi	Łódź	Poland	92-213