PeRiOperaTivE CardioproTection With Ivabradine in Non-cardiac Surgery (PROTECTIN)

Effect of Heart Rate Control With Ivabradine on Myocardial Injury After Non-cardiac Surgery: a Single Center, Randomized Controlled, Double-blind Feasibility Pilot Trial

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.

Study Overview

• Status: Completed
• Conditions: Myocardial Ischemia; Myocardial Injury
• Intervention / Treatment: Drug: Ivabradine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Phase 4

Contacts and Locations

Study Locations

• Switzerland
  • Geneva, Switzerland
    • Geneva University Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 43 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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).

Exclusion Criteria:

• Inability to provide informed consent;
• History of hypersensitivity or allergy to ivabradine;
• Emergency surgery (to be done within 24h of diagnosis);
• Shock or acute decompensated heart failure at trial inclusion;
• 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;
• Treatment with a strong cytochrome P450 3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin; josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone;
• Treatment with verapamil or diltiazem which are moderate CYP3A4 inhibitors and PGP inducers with heart rate reducing properties;
• Women who are pregnant or breast feeding;
• Childbearing potential (Of note, woman with history of hysterectomy, surgical sterilization or menopause for longer than 2 years are not considered with childbearing potential, independent of their age);
• Participation in another study with investigational drug within the 30 days preceding and during the present study;
• Previous enrolment into the current study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ivabradine; 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; Ivabradine pills will be crushed and encapsulated for adequate dosing (0, 2.5mg, 5mg or 7.5 mg) and blinding.; Other Names: Procoralan; Drug: Placebo; Mannitol will be encapsulated for adequate blinding.
Placebo Comparator: Placebo; 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; Mannitol will be encapsulated for adequate blinding.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment rate	Total number of eligible participants approached, the number recruited and randomised divided by the number of months that the trial recruited for	Up to one year from the date participant screening begins.
Participant satisfaction regarding information about the study, informed consent, recruitment procedures and study participation	Qualitative research methods (shadowing and semi-structured interviews)	Screening, morning of the day surgery pre-operatively and post-operative days 1, 2 and 3.
Perioperative myocardial injury	Variance of high-sensitive cardiac troponin T (ng/L)	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	Variance of resting 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	Variance	Day of surgery pre-operatively (between 6-9 am) and morning (between 6-9 am) of post-operative days 1 and 2.
Quality of Recovery	Variance of Quality of Recovery assessed with Quality of Recovery-15 scale (range from 0 to 150, with higher scores indicating a better outcome)	Morning (between 6-9 am) of post-operative days 1, 3 and at day of hospital discharge.
Difficulty in following study protocol and administrating study drug	4-point Likert scale (Study personnel will be asked "The decision to administer the study drug according to the patient's heart rate was straightforward". Answers range from Strongly agree, Agree, Disagree to Strongly disagree)	Morning (between 6 and 9 am) and evening (between 6 and 9 pm) of day of sugery and post-operative days 1 and 2.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bradycardia	Number of patients with those with a heart rate <50 or requiring an intervention to increase heart rate as atropine	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	Number of patients with 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	Number of patients with 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).
NT-proBNP	Variance of NT-proBNP (pg/L)	Day of surgery post-operatively (between 6-9 pm) and morning (between 6-9 am) of post-operative days 1, 2 and 3.
Cardiac output (CO)	Variance of CO measured with the ICON monitor (L/min)	Day of surgery post-operatively (between 6-9 pm) and morning (between 6-9 am) and evening (betwee 6-9pm) of post-operative days 1, 2 and 3.

Collaborators and Investigators

• Sponsor: University Hospital, Geneva
• Investigators: Principal Investigator: Bernardo Bollen Pinto, MD PhD, University Hospital, Geneva

Publications and helpful links

General Publications

• 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.
• 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. Erratum In: Can J Cardiol. 2017 Dec;33(12 ):1735.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 5, 2020
• Primary Completion (Actual): December 12, 2021
• Study Completion (Actual): January 11, 2022

Study Registration Dates

• First Submitted: June 10, 2020
• First Submitted That Met QC Criteria: June 15, 2020
• First Posted (Actual): June 17, 2020

Study Record Updates

• Last Update Posted (Actual): March 2, 2022
• Last Update Submitted That Met QC Criteria: February 25, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: pilot study; feasibility study; ivabradine; heart rate; myocardial injury after non-cardiac surgery; perioperative myocardial injury; perioperative medicine
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Ischemia; Ischemia; Wounds and Injuries
• Other Study ID Numbers: PROTECTIN Pilot; SNCTP000003728 (Registry Identifier: Swiss Federal Office of Public Health's portal for human research)

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