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

Ivabradine for PREVENTion of Myocardial Injury After Noncardiac Surgery

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

Study Overview

• Status: Active, not recruiting
• Conditions: Myocardial Ischemia; Myocardial Injury After Noncardiac Surgery (MINS)
• Intervention / Treatment: Drug: Ivabradine; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 2146
• Phase: Phase 3

Contacts and Locations

Study Locations

• Poland
  • Bydgoszcz, Poland, 85-094
    • Szpital Uniwersytecki Nr 1 im. dr Antoniego Jurasza w Bydgoszczy
  • Ciechanów, Poland, 06-400
    • Specjalistyczny Szpital Wojewódzki w Ciechanowie
  • Cieszyn, Poland, 43-400
    • ZZOZ Szpital Śląski w Cieszynie
  • Gdansk, Poland, 80-952
    • Uniwersyteckie Centrum Kliniczne Gdańskiego Uniwersytetu Medycznego
  • Gmina Końskie, Poland, 26-200
    • Szpital Specjalistyczny św. Łukasza w Końskich
  • Katowice, Poland, 40-752
    • Uniwersyteckie Centrum Kliniczne im. Prof. Kornela Gibińskiego Śląski Uniwersytet Medyczny
  • Krakow, Poland, 31-501
    • Sp Zoz Szpital Uniwersytecki W Krakowie
  • Krakow, Poland, 31-202
    • Krakowski Szpital Specjalistyczny im. Jana Pawła II
  • Krakow, Poland, 30-693
    • Szpital św. Rafała w Krakowie
  • Krakow, Poland, 30-901
    • 5 Wojskowy Szpital Kliniczny z Polikliniką Samodzielny Publiczny Zakład Opieki Zdrowotnej w Krakowie
  • Krakow, Poland, 31-061
    • Szpital Zakonu Bonifratrów św. Jana Grandego w Krakowie
  • Krakow, Poland, 31-826
    • Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie sp. z o.o.
  • Krakow, Poland, 31-913
    • Szpital Specjalistyczny im. Stefana Żeromskiego w Krakowie
  • Lodz, Poland, 92-213
    • Centralny Szpital Kliniczny Uniwersytetu Medycznego w Łodzi
  • Lublin, Poland, 20-081
    • Samodzielny Publiczny Szpital Kliniczny 1 w Lublinie
  • Olsztyn, Poland, 10-561
    • Wojewodzki Szpital Specjalistyczny w Olsztynie
  • Opole, Poland, 45-401
    • Uniwersytecki Szpital Kliniczny w Opolu
  • Szczecin, Poland, 70-111
    • Samodzielny Publiczny Szpital Kliniczny Nr 2 Pomorskiego Uniwersytetu Medycznego
  • Szczecin, Poland, 72-252
    • Samodzielny Publiczny Szpital Kliniczny Nr 1 Pomorskiego Uniwersytetu Medycznego
  • Tarnów, Poland, 33-100
    • Specjalistyczny Szpital im. Edwarda Szczeklika w Tarnowie
  • Warsaw, Poland, 02-097
    • Uniwersyteckie Centrum Kliniczne Warszawskiego Uniwersytetu Medycznego Centralny Szpital Kliniczny
  • Warsaw, Poland, 02-005
    • Uniwersyteckie Centrum Kliniczne Warszawskiego Uniwersytetu Medycznego Szpital Kliniczny Dzieciątka Jezus
  • Warsaw, Poland, 04-141
    • Wojskowy Instytut Medyczny Centralny Szpital Kliniczny MON
  • Wroclaw, Poland, 50-556
    • Uniwersytecki Szpital Kliniczny we Wrocławiu
  • Zabrze, Poland, 41-800
    • Samodzielny Publiczny Szpital Kliniczny Nr 1 im. Prof. Stanisława Szyszko Śląskiego Uniwersytetu Medycznego w Katowicach
  • Zielona Góra, Poland, 65-001
    • Szpital Uniwersytecki im. Karola Marcinkowskiego w Zielonej Górze

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Undergoing noncardiac surgery
2. ≥45 years of age
3. Expected to require at least an overnight hospital admission after surgery
4. Provide written informed consent to participate in the PREVENT-MINS Trial, AND
5. Fulfill ≥1 of the following 5 criteria (A-E):

A. 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:

i. 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:

1. Conduction abnormalities:

   A. 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

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MINS	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.	30 days after randomization

Secondary Outcome Measures

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

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: Jagiellonian University
• Collaborators: Vanderbilt University Medical Center; Population Health Research Institute
• Investigators: Principal Investigator: Wojciech Szczeklik, Professor, Centre for Intensive Care and Perioperative Medicine, Jagiellonian University Medical College

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2022
• Primary Completion (Actual): April 30, 2025
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: March 4, 2022
• First Submitted That Met QC Criteria: March 4, 2022
• First Posted (Actual): March 15, 2022

Study Record Updates

• Last Update Posted (Estimated): September 3, 2025
• Last Update Submitted That Met QC Criteria: August 26, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Cardiovascular Diseases; Randomized controlled trial; Perioperative care; Ivabradine; Physiological Effects of Drugs; Myocardial ischemia; Heart rate; Cardiovascular events; Troponin; Cardiovascular Agents; Blinded; Heart Rate Control; Perioperative medicine; Noncardiac surgery; Perioperative myocardial infarction; Myocardial injury after non-cardiac surgery; Perioperative myocardial injury; Cardiac Chronotropy
• Additional Relevant MeSH Terms: Vascular Diseases; Heart Diseases; Cardiovascular Diseases; Myocardial Ischemia; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Substandard Drugs; Pharmaceutical Preparations; Benzazepines; Counterfeit Drugs; Ivabradine
• Other Study ID Numbers: PREVENT-MINS

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

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