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

Study Overview
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Brief Summary
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This study is a multicentre, randomized controlled trial of ivabradine versus placebo.

Detailed Description
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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.

Official Title
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Ivabradine for PREVENTion of Myocardial Injury After Noncardiac Surgery

Conditions
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Myocardial Injury After Noncardiac Surgery (MINS), Myocardial Ischemia

Intervention / Treatment
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* Drug: Ivabradine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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): 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: 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 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

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ivabradine<br>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<br>* 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.<br>|
| Placebo Comparator: Placebo<br>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<br>* 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.<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| Myocardial infarction | Number of patients who experience a 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 | 
| All-cause mortality | Number of patients who die of any cause | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myocardial ischemia, Randomized controlled trial, Blinded, Noncardiac surgery, Cardiovascular events, Myocardial injury after non-cardiac surgery, Perioperative myocardial injury, Perioperative myocardial infarction, Perioperative medicine, Heart rate, Ivabradine, Cardiovascular Diseases, Troponin, Perioperative care, Physiological Effects of Drugs, Cardiovascular Agents, Cardiac Chronotropy, Heart Rate Control