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Myocardial InjuryPhase 4PROTECTINNCT04436016

PeRiOperaTivE CardioproTection With Ivabradine in Non-cardiac Surgery

A Phase 4 study testing Ivabradine in people with Myocardial Injury and Myocardial Ischemia, run by University Hospital, Geneva at 1 site in Switzerland.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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%). Read more about this study

Who is it for?
Ages 45 years and older
Conditions the study is for
Myocardial Injury, Myocardial Ischemia
What is being tested?
Ivabradine
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
78 participants
Where
1 siteSwitzerland
Study dates
5 Oct 2020to 11 Jan 2022
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 45 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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).

Who cannot join

  • 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:
Show all 22Show fewer
  • 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.

Trial locations and contacts

1 site in 1 country.

Switzerland1 site

  • Geneva University Hospitals

    Geneva

Other trials in Switzerland

About this study

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

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.

Being tested
Ivabradine, Placebo
Keywords
ivabradine, heart rate, pilot study, myocardial injury after non-cardiac surgery, perioperative myocardial injury, feasibility study, perioperative medicine
Medical subject headings
Myocardial Ischemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IvabradineDrug

    Also called Procoralan

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

  • PlaceboDrug

    Mannitol will be encapsulated for adequate blinding.

Study groups in NCT04436016
Study groupRoleWhat they receive
IvabradineExperimentalIvabradine 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).
Receives: Drug: Ivabradine; Drug: Placebo
PlaceboPlacebo comparatorPlacebo 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).
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: 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).

  2. Blinding success rate

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

    Measured: 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)

  1. Recruitment rate

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

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

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

    Qualitative research methods (shadowing and semi-structured interviews)

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

  3. Perioperative myocardial injury

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

    Measured: 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.

  4. Heart rate

    Variance of resting heart rate

    Measured: 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.

  5. Ivabradine dosage

    Variance

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

  6. 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)

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

  7. 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)

    Measured: Morning (between 6 and 9 am) and evening (between 6 and 9 pm) of day of sugery and post-operative days 1 and 2.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Jun 2020
  2. Study start5 Oct 2020
  3. Primary completion12 Dec 2021
  4. Study completion11 Jan 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Other
Allocation
Randomised
Intervention model
Parallel groups
Model description
Single center, randomized, placebo-controlled, double-blind, parallel group, feasibility pilot trial. Patients will be randomized to receive ivabradine or placebo.
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
78 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04436016
Sponsor's protocol ID
PROTECTIN Pilot
Other IDs
SNCTP000003728
Acronym
PROTECTIN
Status last verified
Feb 2022
First submitted
10 Jun 2020
Last updated
2 Mar 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 29203498

  • 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.

    PubMed 27865641

  • 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.

    PubMed 32147100

  • 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.

    PubMed 29077608

  • 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.

    PubMed 27777223

  • Acero MX, Waelli M, Gisselbaek M, Bollen Pinto B. Real-world activities of clinician-researchers in perioperative medicine: an ethnographic qualitative case study embedded in a single-centre clinical trial. BJA Open. 2026 Sep 15;20:100862. doi: 10.1016/j.bjao.2026.100862. eCollection 2026 Dec.

    PubMed 42774642

  • 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.

    PubMed 38960832

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Ivabradine in people with Myocardial Injury and Myocardial Ischemia, run by University Hospital, Geneva at 1 site in Switzerland.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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).). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04436016, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Mar 2022.

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