PeRiOperaTivE CardioproTection With Ivabradine in Non-cardiac Surgery

NCT04436016 | Completed Phase 4

• 2 other identifiers: PROTECTIN PilotSNCTP000003728
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 1

Brief Summary

Perioperative myocardial injury (PMI) after non-cardiac surgery (NCS), i.e. the elevation of postoperative troponin, occurs in nearly 20% of patients older than 45 years undergoing NCS and is independently and strongly associated with post-operative mortality (30-day mortality up to 10%). With over 300 million surgical interventions every year worldwide, PMI has a high clinical relevance on the health of the population. Heart rate (HR) is an independent and modifiable risk factor for PMI and death after non-cardiac surgery. Numerous studies showed that beta-blockers decrease myocardial ischemia after surgery in a heart-rate dependent manner, but this beneficial effect is surpassed by an increased incidence of perioperative hypotension and death. Currently, no single intervention is available to decrease the risk of perioperative cardiac complications. Ivabradine (IVA) is a negative chronotropic agent without significant effects on contractility or vascular tone and has been shown to improve outcomes in the setting of chronic and acute heart diseases. Rationale for pilot feasibility trial: the planned definitive large trial is a multicenter trial to investigate the efficacy of ivabradine to decrease perioperative myocardial injury. The intervention planned is complex and demands important resources. The investigators designed this pilot study to inform on the feasibility of the definitive large trial. This pilot study will also provide additional information that could help investigators improve the definitive large trial regarding recruitment, refinements to the study protocol and improving the participant's experience.

Conditions

Myocardial Injury; Myocardial Ischemia

Keywords

ivabradine; heart rate; pilot study; myocardial injury after non-cardiac surgery; perioperative myocardial injury; feasibility study; perioperative medicine

Outcome Measures

Primary Outcomes (2)

• Appropriate dosage rate

  Number of correct dosages administered according to the patient's heart rate at each study visit divided by the total dosages administrated

  From the morning (6-9 am) of the day of surgery of the first study participant to the evening of the second post-operative day of the last study participant (up to 1 year from first randomization).

• Blinding success rate

  Number of times blinding code was broken divided by the total dosages administrated

  From the morning (6-9 am) of the day of surgery of the first study participant to the evening of the second post-operative day of the last study participant (up to 1 year from first randomization).

Secondary Outcomes (7)

• Recruitment rate

  Up to one year from the date participant screening begins.

• Participant satisfaction regarding information about the study, informed consent, recruitment procedures and study participation

  Screening, morning of the day surgery pre-operatively and post-operative days 1, 2 and 3.

• Perioperative myocardial injury

  Day of surgery pre-operatively (between 6-9 am) and post-operatively (between 6-9 pm or within 1h after surgery if surgery ends after 9pm) and morning (between 6-9 am) of post-operative days 1, 2, 3 and day of hospital discharge.

• Heart rate

  Day of surgery pre-operatively (between 6-9 am) and post-operatively (between 6-9 pm or within 1h after surgery if surgery ends after 9pm) and morning (between 6-9 am) of post-operative days 1, 2, 3 and day of hospital discharge.

• Ivabradine dosage

  Day of surgery pre-operatively (between 6-9 am) and morning (between 6-9 am) of post-operative days 1 and 2.

Other Outcomes (5)

• Bradycardia

  From the morning of the day of surgery when the first study intervention (between 6-9am) is adminitstered until post-operative day 3 in the morning (between 6-9am).

• Atrial fibrilation

  From the morning of the day of surgery when the first study intervention (between 6-9am) is adminitstered until post-operative day 3 in the morning (between 6-9am).

• Phosphenes

  From the morning of the day of surgery when the first study intervention (between 6-9am) is adminitstered until post-operative day 3 in the morning (between 6-9am).

Study Arms (2)

Ivabradine

EXPERIMENTAL

Ivabradine will be administered in an individualized regimen adapted to the subject's heart rate at each visit in a dosage ranging from 0-7.5mg twice daily (morning and evening) from the morning of surgery until post-operative day 2, as follows: * If heart rate is ≥101 bpm: capsule D (Ivabradine 7.5 mg); * If heart rate is 86-100 bpm: capsule C (Ivabradine 5 mg); * If HR is 71-85 bpm: capsule B (Ivabradine 2.5 mg); * If HR ≤ 70 bpm or the patient received rescue treatment for bradycardia (eg.atropine) after the previous dose: capsule A (placebo).

Drug: Ivabradine; Drug: Placebo

Placebo

PLACEBO COMPARATOR

Placebo will be administered twice daily (morning and evening) from the morning of surgery until post-operative day 2, as follows: * If heart rate is ≥101 bpm: capsule D (Placebo) * If heart rate is 86-100 bpm: capsule C (Placebo) * If HR is 71-85 bpm: capsule B (Placebo) * If HR ≤ 70 bpm or the patient received rescue treatment for bradycardia (eg.atropine) after the previous dose: capsule A (Placebo).

Drug: Placebo

Interventions

Ivabradine DRUG

Ivabradine pills will be crushed and encapsulated for adequate dosing (0, 2.5mg, 5mg or 7.5 mg) and blinding.

Also known as: Procoralan

Ivabradine

Placebo DRUG

Mannitol will be encapsulated for adequate blinding.

Ivabradine; Placebo

Eligibility Criteria

• Age: 45 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Informed Consent as documented by signature of patient; AND
• Undergoing intermediate or high-risk non-cardiac surgery (as defined in European Society of Anaesthesiology guidelines) AND;
• One of the following:
• o≥ 75 years old OR; o≥ 45 years old AND at least 1 risk factors independently associated with perioperative myocardial injury (history of coronary artery disease, chronic heart failure, peripheral artery disease, ischemic stroke, hypertension, diabetes mellitus, chronic kidney disease).

You may not qualify if:

• Inability to provide informed consent;
• History of hypersensitivity or allergy to ivabradine;
• Emergency surgery (to be done within 24h of diagnosis);
• Low cardiac output syndrome;
• Arrhythmia:
• Atrial fibrillation or flutter;
• AV-block of 3rd degree;
• Sick sinus syndrome;
• Sino-atrial block;
• Pacemaker dependency;
• Unstable angina;
• Acute myocardial infarction in the 3 months preceding the trial;
• Stroke in the 3 months preceding the trial;
• Cirrhosis Child B and C;
• Renal failure with a Estimated Glomerular filtration rate ≤ 15 ml/min/1.73m2;

Sponsors & Collaborators

• University Hospital, Geneva: lead

Study Sites (1)

Geneva University Hospitals

Geneva, Switzerland

Location

Related Publications (6)

• Puelacher C, Lurati Buse G, Seeberger D, Sazgary L, Marbot S, Lampart A, Espinola J, Kindler C, Hammerer A, Seeberger E, Strebel I, Wildi K, Twerenbold R, du Fay de Lavallaz J, Steiner L, Gurke L, Breidthardt T, Rentsch K, Buser A, Gualandro DM, Osswald S, Mueller C; BASEL-PMI Investigators. Perioperative Myocardial Injury After Noncardiac Surgery: Incidence, Mortality, and Characterization. Circulation. 2018 Mar 20;137(12):1221-1232. doi: 10.1161/CIRCULATIONAHA.117.030114. Epub 2017 Dec 4.

  PMID: 29203498 BACKGROUND

• Duceppe E, Parlow J, MacDonald P, Lyons K, McMullen M, Srinathan S, Graham M, Tandon V, Styles K, Bessissow A, Sessler DI, Bryson G, Devereaux PJ. Canadian Cardiovascular Society Guidelines on Perioperative Cardiac Risk Assessment and Management for Patients Who Undergo Noncardiac Surgery. Can J Cardiol. 2017 Jan;33(1):17-32. doi: 10.1016/j.cjca.2016.09.008. Epub 2016 Oct 4.

  PMID: 27865641 BACKGROUND

• Chen A, Elia N, Dunaiceva J, Rudiger A, Walder B, Bollen Pinto B. Effect of ivabradine on major adverse cardiovascular events and mortality in critically ill patients: a systematic review and meta-analyses of randomised controlled trials with trial sequential analyses. Br J Anaesth. 2020 Jun;124(6):726-738. doi: 10.1016/j.bja.2020.01.027. Epub 2020 Mar 6.

  PMID: 32147100 BACKGROUND

• Abbott TEF, Pearse RM, Archbold RA, Ahmad T, Niebrzegowska E, Wragg A, Rodseth RN, Devereaux PJ, Ackland GL. A Prospective International Multicentre Cohort Study of Intraoperative Heart Rate and Systolic Blood Pressure and Myocardial Injury After Noncardiac Surgery: Results of the VISION Study. Anesth Analg. 2018 Jun;126(6):1936-1945. doi: 10.1213/ANE.0000000000002560.

  PMID: 29077608 BACKGROUND

• Eldridge SM, Chan CL, Campbell MJ, Bond CM, Hopewell S, Thabane L, Lancaster GA; PAFS consensus group. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. BMJ. 2016 Oct 24;355:i5239. doi: 10.1136/bmj.i5239.

  PMID: 27777223 BACKGROUND

• White MJ, Zaccaria I, Ennahdi-Elidrissi F, Putzu A, Dimassi S, Luise S, Diaper J, Mulin S, Baudat AD, Gil-Wey B, Elia N, Walder B, Bollen Pinto B. Personalised perioperative dosing of ivabradine in noncardiac surgery: a single-centre, randomised, placebo-controlled, double-blind feasibility pilot trial. Br J Anaesth. 2024 Oct;133(4):738-747. doi: 10.1016/j.bja.2024.05.020. Epub 2024 Jul 2.

  PMID: 38960832 DERIVED

MeSH Terms

Conditions

Myocardial Ischemia

Interventions

Ivabradine

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Bernardo Bollen Pinto, MD PhD

  University Hospital, Geneva

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Registrar and Research Fellow

Model Details: Single center, randomized, placebo-controlled, double-blind, parallel group, feasibility pilot trial. Patients will be randomized to receive ivabradine or placebo.

Study Record Dates

• First Submitted: June 10, 2020
• First Posted: June 17, 2020
• Study Start: October 5, 2020
• Primary Completion: December 12, 2021
• Study Completion: January 11, 2022
• Last Updated: March 2, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)