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Completed

NCT Number: NCT04436016

PeRiOperaTivE CardioproTection With Ivabradine in Non-cardiac Surgery

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.

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Key information

Conditions

Myocardial Injury Cardiovascular Diseases Heart Diseases Myocardial Ischemia Vascular Diseases

Age range

45 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Geneva University Hospitals

Geneva, Switzerland

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Ivabradine

Drug

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

Other names: Procoralan

Placebo

Drug

Mannitol will be encapsulated for adequate blinding.

Primary outcomes

  1. Appropriate dosage rate

    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).

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

  2. Blinding success rate

    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).

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

Secondary outcomes

  1. Recruitment rate

    Time frame: Up to one year from the date participant screening begins.

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

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

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

    Qualitative research methods (shadowing and semi-structured interviews)

  3. Perioperative myocardial injury

    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.

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

  4. Heart rate

    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.

    Variance of resting heart rate

  5. Ivabradine dosage

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

    Variance

  6. Quality of Recovery

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

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

  7. Difficulty in following study protocol and administrating study drug

    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.

    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)

Other outcomes

  1. Bradycardia

    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).

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

  2. 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).

    Number of patients with atrial fibrilation

  3. 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).

    Number of patients with phosphenes

  4. NT-proBNP

    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.

    Variance of NT-proBNP (pg/L)

  5. Cardiac output (CO)

    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.

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

Sponsors and collaborators

Lead sponsor

University Hospital, Geneva

Other

Registry information

Official study 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

Acronym: PROTECTIN

Important dates

Study start
2020
Primary completion
2021
Study completion
2022
First posted
Jun 17, 2020
Registry last updated
Mar 2, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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