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

Primary Purpose

Myocardial Injury, Myocardial Ischemia

Status

Completed

Phase

Phase 4

Locations

Switzerland

Study Type

Interventional

Intervention

Ivabradine

Placebo

About this trial

This is an interventional other trial for Myocardial Injury focused on measuring ivabradine, heart rate, pilot study, myocardial injury after non-cardiac surgery, perioperative myocardial injury, feasibility study, perioperative medicine

Eligibility Criteria

45 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Geneva University Hospitals

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Ivabradine

Placebo

Arm Description

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).

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).

Outcomes

Primary Outcome Measures

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

Blinding success rate

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

Secondary Outcome Measures

Recruitment rate

Total number of eligible participants approached, the number recruited and randomised divided by the number of months that the trial recruited for

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

Qualitative research methods (shadowing and semi-structured interviews)

Perioperative myocardial injury

Variance of high-sensitive cardiac troponin T (ng/L)

Heart rate

Variance of resting heart rate

Ivabradine dosage

Variance

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)

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)

Full Information

NCT ID

NCT04436016

First Posted

June 10, 2020

Last Updated

February 25, 2022

Sponsor

University Hospital, Geneva

1. Study Identification

Unique Protocol Identification Number

NCT04436016

Brief Title

PeRiOperaTivE CardioproTection With Ivabradine in Non-cardiac Surgery

Acronym

PROTECTIN

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2022

Overall Recruitment Status

Completed

Study Start Date

October 5, 2020 (Actual)

Primary Completion Date

December 12, 2021 (Actual)

Study Completion Date

January 11, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University Hospital, Geneva

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myocardial Injury, Myocardial Ischemia

Keywords

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

7. Study Design

Primary Purpose

Other

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Model Description

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

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

78 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ivabradine

Arm Type

Experimental

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Ivabradine

Other Intervention Name(s)

Procoralan

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Mannitol will be encapsulated for adequate blinding.

Primary Outcome Measure Information:

Title

Appropriate dosage rate

Description

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

Time Frame

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).

Title

Blinding success rate

Description

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

Time Frame

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 Measure Information:

Title

Recruitment rate

Description

Total number of eligible participants approached, the number recruited and randomised divided by the number of months that the trial recruited for

Time Frame

Up to one year from the date participant screening begins.

Title

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

Description

Qualitative research methods (shadowing and semi-structured interviews)

Time Frame

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

Title

Perioperative myocardial injury

Description

Variance of high-sensitive cardiac troponin T (ng/L)

Time Frame

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.

Title

Heart rate

Description

Variance of resting heart rate

Time Frame

Title

Ivabradine dosage

Description

Variance

Time Frame

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

Title

Quality of Recovery

Description

Variance of Quality of Recovery assessed with Quality of Recovery-15 scale (range from 0 to 150, with higher scores indicating a better outcome)

Time Frame

Morning (between 6-9 am) of post-operative days 1, 3 and at day of hospital discharge.

Title

Difficulty in following study protocol and administrating study drug

Description

Time Frame

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 Pre-specified Outcome Measures:

Title

Bradycardia

Description

Number of patients with those with a heart rate <50 or requiring an intervention to increase heart rate as atropine

Time Frame

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).

Title

Atrial fibrilation

Description

Number of patients with atrial fibrilation

Time Frame

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).

Title

Phosphenes

Description

Number of patients with phosphenes

Time Frame

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).

Title

NT-proBNP

Description

Variance of NT-proBNP (pg/L)

Time Frame

Day of surgery post-operatively (between 6-9 pm) and morning (between 6-9 am) of post-operative days 1, 2 and 3.

Title

Cardiac output (CO)

Description

Variance of CO measured with the ICON monitor (L/min)

Time Frame

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.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bernardo Bollen Pinto, MD PhD

Organizational Affiliation

University Hospital, Geneva

Official's Role

Principal Investigator

Facility Information:

Facility Name

Geneva University Hospitals

City

Geneva

Country

Switzerland

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

29203498

Citation

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.

Results Reference

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PubMed Identifier

27865641

Citation

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.

Results Reference

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PubMed Identifier

32147100

Citation

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.

Results Reference

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PubMed Identifier

29077608

Citation

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.

Results Reference

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PubMed Identifier

27777223

Citation

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.

Results Reference

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PeRiOperaTivE CardioproTection With Ivabradine in Non-cardiac Surgery

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