Clinical trial NCT04436016: PeRiOperaTivE CardioproTection With Ivabradine in Non-cardiac Surgery
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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Myocardial Injury
Myocardial Ischemia
Keywords: ivabradine
heart rate
pilot study
myocardial injury after non-cardiac surgery
perioperative myocardial injury
feasibility study
perioperative medicine
Lead sponsor: University Hospital, Geneva
Sponsor class: OTHER
First posted: 2020-06-17
Enrollment: 78
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Single center, randomized, placebo-controlled, double-blind, parallel group, feasibility pilot trial.

Patients will be randomized to receive ivabradine or placebo.
Primary purpose: OTHER

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.


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.

Primary outcomes:
measure: Appropriate dosage rate
timeFrame: 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).
measure: Blinding success rate
timeFrame: 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:
measure: Recruitment rate
timeFrame: Up to one year from the date participant screening begins.
measure: Participant satisfaction regarding information about the study, informed consent, recruitment procedures and study participation
timeFrame: Screening, morning of the day surgery pre-operatively and post-operative days 1, 2 and 3.
measure: Perioperative myocardial injury
timeFrame: 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.
measure: Heart rate
timeFrame: 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.
measure: Ivabradine dosage
timeFrame: Day of surgery pre-operatively (between 6-9 am) and morning (between 6-9 am) of post-operative days 1 and 2.
measure: Quality of Recovery
timeFrame: Morning (between 6-9 am) of post-operative days 1, 3 and at day of hospital discharge.
measure: Difficulty in following study protocol and administrating study drug
timeFrame: 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 outcomes:
measure: Bradycardia
timeFrame: 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).
measure: Atrial fibrilation
timeFrame: 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).
measure: Phosphenes
timeFrame: 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).
measure: NT-proBNP
timeFrame: Day of surgery post-operatively (between 6-9 pm) and morning (between 6-9 am) of post-operative days 1, 2 and 3.
measure: Cardiac output (CO)
timeFrame: 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.
Locations:
city: Geneva
country: Switzerland
facility: Geneva University Hospitals
Study officials:
affiliation: University Hospital, Geneva
name: Bernardo Bollen Pinto, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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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.
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.