Evaluation of Ivabradine in Preventing Myocardial Injury Post-Noncardiac Surgery in Patients with or at Risk of Atherosclerotic Disease
- Trial ID
- 2024-515226-81-00
- Protocol
- PREVENT-MINS
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the PREVENT-MINS Trial is to evaluate the effect of perioperative administration of **ivabradine** in patients with, or at risk of, atherosclerotic disease undergoing noncardiac surgery. The primary outcome is the incidence of **myocardial injury after noncardiac surgery (MINS)**, defined as any myocardial infarction and any elevated postoperative cardiac troponin attributed to myocardial ischemia during or within 30 days post-surgery. This is clinically relevant as MINS is associated with increased morbidity and mortality, and understanding the impact of ivabradine could inform perioperative management strategies to mitigate these risks.
Secondary objectives include determining the impact of ivabradine on various outcomes 30 days post-surgery, such as: - A composite of vascular death, non-fatal MINS, non-fatal stroke, and non-fatal cardiac arrest - Vascular death - MINS not meeting myocardial infarction criteria - Myocardial infarction - Perioperative myocardial infarction/injury - Days alive and at home - Stroke - All-cause mortality - Health-related quality of life - Cancellation/postponement of surgery due to heart rate or troponin concerns - Intraoperative mean arterial pressure and heart rate - Clinically important atrial fibrillation - Safety outcomes including clinically significant bradycardia, hypotension, and phosphenes.
Participants
The clinical trial focuses on patients with **myocardial injury after noncardiac surgery**. The study population includes both male and female participants aged 45 years and older, who are undergoing noncardiac surgery and are expected to require at least an overnight hospital stay post-surgery. Participants are selected based on their risk of atherosclerotic disease, with key inclusion criteria requiring a history of coronary artery disease, peripheral arterial disease, stroke, or other significant risk factors such as diabetes, hypertension, or a history of smoking. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the effect of **ivabradine** on preventing myocardial injury after noncardiac surgery in patients with or at risk of atherosclerotic disease. This is a randomized, double-blind, controlled trial involving the administration of ivabradine or a placebo. The trial is expected to run from June 2022 to December 2026, with participant involvement lasting up to 30 days post-surgery. The study will include an initial screening visit to confirm eligibility based on criteria such as age, surgical requirements, and medical history related to cardiovascular conditions. Participants will be randomly assigned to receive either ivabradine or a placebo, administered orally in the form of film-coated tablets.
Study visits will be scheduled to monitor the participants' health and collect data on primary and secondary endpoints. The primary endpoint is the occurrence of myocardial injury after noncardiac surgery, defined as any myocardial infarction or elevated postoperative cardiac troponin due to myocardial ischemia. Secondary endpoints include a composite of vascular death, non-fatal myocardial injury, non-fatal stroke, and non-fatal cardiac arrest, among others. Follow-up visits will occur at regular intervals to assess these outcomes and ensure participant safety. The end-of-study visit will conclude the trial for each participant, during which final assessments will be conducted.
Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include the development of significant adverse events, withdrawal of consent, or any situation that compromises the participant's safety or the integrity of the trial. The trial's methodology ensures rigorous monitoring and data collection to achieve its objectives while maintaining participant safety and adherence to ethical standards.
Treatment
The clinical trial involves the administration of **Ivabradine Anpharm 5 mg film-coated tablets** as the experimental medication. Ivabradine is a chemical-origin active substance, and the pharmaceutical form is a film-coated tablet. The medication is administered orally. The maximum daily dose is 10 mg, with a total maximum dose of 75 mg over a treatment period of up to 7 days. The primary objective of the trial is to assess the effect of perioperative administration of ivabradine in patients with, or at risk of, atherosclerotic disease undergoing noncardiac surgery. The primary outcome is myocardial injury after non-cardiac surgery, defined as any myocardial infarction and any elevated postoperative cardiac troponin resulting from myocardial ischemia during or within 30 days after noncardiac surgery.
The study also includes a **placebo** group, which consists of capsules containing lactose monohydrate, microcrystalline cellulose, native corn starch, colloidal anhydrous silica, maltodextrin, and magnesium stearate. The capsule shell is composed of beef gelatin, glycerol, and titanium dioxide. The placebo is used to provide a comparator treatment to evaluate the efficacy of the experimental medication. The placebo administration follows the same oral route as the ivabradine tablets, ensuring blinding and maintaining the integrity of the trial design.
Efficacy
Efficacy in the clinical trial titled "Ivabradine for PREVENTion of Myocardial Injury after Noncardiac Surgery (MINS) - PREVENT-MINS Trial" will be assessed using specific primary and secondary endpoints. The primary endpoint is the occurrence of **myocardial injury after non-cardiac surgery (MINS)**, defined as any myocardial infarction and any elevated postoperative cardiac troponin judged as resulting from myocardial ischemia during or within 30 days after noncardiac surgery. This will be measured through clinical assessments and laboratory tests to detect myocardial infarction and elevated cardiac troponin levels.
Secondary endpoints include a composite of vascular death, non-fatal MINS, non-fatal stroke, and non-fatal cardiac arrest, as well as individual outcomes such as vascular death, MINS not fulfilling the criteria of myocardial infarction, myocardial infarction, days alive and at home, and stroke. Additional secondary outcomes involve health-related quality of life, cancellation or postponement of surgery due to heart rate concerns, intraoperative mean arterial pressure, intraoperative heart rate, and clinically important atrial fibrillation. Safety outcomes will also be monitored, including clinically significant bradycardia, clinically significant hypotension, and phosphenes.
The efficacy parameters will be collected and analyzed at specified timepoints, including during the perioperative period and up to 30 days post-surgery. The trial will utilize validated clinical assessments and laboratory tests to ensure accurate measurement of these endpoints. The data collected will be analyzed to determine the effect of perioperative administration of ivabradine in patients with, or at risk of, atherosclerotic disease undergoing noncardiac surgery.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Undergoing noncardiac surgery
- ≥45 years of age
- Expected to require at least an overnight hospital stay after surgery
- Written informed consent to participate in the PREVENT-MINS Trial provided
- Fulfil ≥1 of the following 5 criteria (A-E): A. Current or prior history of coronary artery disease as defined by any one of the following 7 criteria: i. History of angina; ii. History of acute coronary syndrome; iii. History of a segmental cardiac wall motion abnormality on echocardiography or a segmental fixed defect on radionuclide imaging; iv. History of a positive radionuclide exercise, echocardiographic exercise, or pharmacological cardiovascular stress test demonstrating cardiac ischaemia; v. History of a coronary angiographic or CT coronary angiographic evidence of atherosclerotic stenosis ≥50% of the diameter of any coronary artery; vi. ECG with pathological Q waves in at least two contiguous leads; OR vii. Previous coronary artery revascularization, (i.e. percutaneous coronary intervention [PCI] or coronary artery bypass graft surgery [CABG]);
- Fulfil ≥1 of the following 5 criteria (A-E): B. Peripheral arterial disease as defined by a physician diagnosis of a current, or prior history of any of the following 4 criteria: i. Intermittent claudication; ii. Vascular surgery OR percutaneous transluminal angioplasty (PTA) for atherosclerotic disease; iii. An ankle/brachial systolic blood pressure ratio <0.90 in either leg at rest; OR iv. Angiographic, CT angiographic or doppler findings demonstrating >70% stenosis in a noncardiac artery;
- Fulfil ≥1 of the following 5 criteria (A-E): C. History of stroke as defined by any one of the following 2 criteria: i. A physician diagnosis of stroke; OR ii. CT or MRI evidence of a prior stroke;
- Fulfil ≥1 of the following 5 criteria (A-E): D. Undergoing major vascular surgery defined as all vascular surgeries (including any above foot amputation) with the exception of arteriovenous shunt, vein stripping procedures (varicose vein surgery), carotid endarterectomies, endovascular abdominal aortic aneurysm repair (EVAR); OR
- Fulfil ≥1 of the following 5 criteria (A-E): E. Any 3 of 9 risk criteria: i. Undergoing major surgery defined as: intraperitoneal, intrathoracic, retroperitoneal, or major orthopaedic; ii. History of congestive heart failure defined as a physician diagnosis of a current or prior episode of congestive heart failure OR prior radiographic evidence of vascular redistribution, interstitial pulmonary edema, or frank alveolar pulmonary oedema; iii. History of a transient ischaemic attack; iv. Diabetes diagnosis and currently taking hypoglycemic agent; v. Age ≥70 years; vi. History of hypertension; vii. Serum creatinine >175 μmol/L (>2.0 mg/dl) based on the most recent values before randomisation; viii. History of smoking within 2 years of surgery; and ix. Undergoing emergent/urgent surgery, defined as surgery that a surgeon schedules to go to the operating room within 48 hours from an acute presentation to the hospital.
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 trial
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Not Recruiting | 13 Jun 2022 | 2500 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Ivabradine Anpharm 5 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 10 | 7 | PRD3250284 |
Placebo: lactose monohydrate, microcrystalline cellulose, native corn starch, colloidal anhydrous silica, maltodextrin, magnesium stearate
Capsule: Beef gelatin, Glycerol, Titanium dioxide | Placebo | N/A | — | — | — | N/A |