Targeted heart rate control using ivabradine to reduce disease in patients undergoing non-cardiac surgery

Plain English Summary

Background and study aims
Increasingly complex surgical treatments are offered to more patients than ever before. In particular, older patients with serious medical problems are far more likely to undergo surgery today than even 20 years ago. Patients frequently develop medical complications in the days following surgery, including pneumonia and damage to the heart (which is usually undetected by doctors and nurses). Even temporary harm to other parts of the body after surgery prevents individuals from recovering to their normal levels of function. For many patients, this delays further necessary treatments, especially cancer therapies, and increases the risk of dying even after leaving the hospital. The impact of these complications can last months and years, contributing to the increasing number of patients struggling to cope with multiple medical problems (called "multi-morbidity"). Multi-morbidity after surgery is an increasing and unmet healthcare need affecting millions of individuals worldwide each year.

An early feature after surgery in many patients is damage to the heart, which reflects cell damage that is happening at the same time to many other parts of the body. Problems with a specialised nerve called the vagus nerve which helps control the speed at which the heart beats, are often linked to heart damage and other complications after surgery. Poor vagus nerve activity causes a higher heart rate, which is strongly linked to heart damage and coincides with other organs of the body not working normally. Our aim is to protect both the heart and other body organs by lowering heart rate after surgery, to ensure that patients gain the best possible result from surgery with rapid recovery and as few complications as possible. In this trial, ivabradine will be used to slow heart rate with minimal effects on other functions including blood pressure.

FUNNY is a clinical trial to establish whether the targeted lowering of heart rate is beneficial for patients aged 55 years and over undergoing elective or urgent non-cardiac surgery. 350 patients will be enrolled over a three-year recruitment window across all hospitals. We aim to address the following research question does slowing the speed of the heart beating reduce damage caused to the heart after surgery? We will also look into the number of harmful events including postoperative infections, kidney damage and respiratory complications within 30 days of surgery.

Who can participate?
Adults aged 55 years and over who are undergoing elective or urgent non-cardiac surgery requiring general and/or regional anaesthesia with sedation, expected to take longer than 120 minutes from the induction of anaesthesia, with at least one medical risk factor for perioperative myocardial injury and history of hypertension or hypertension recorded at the pre-assessment clinic.

What does the study involve?
Before surgery, participants are randomly allocated to either receive ivabradine or placebo. The study is blinded so the trial participants, healthcare staff, local investigators collecting outcome data, and investigators at the central coordinating centre will not know which treatment the patients are receiving. The treatment will be administered twice a day with a 12 hour (± 2 hours) gap in-between the administrations starting on the day of surgery before the induction of anaesthesia and continue on postoperative day one and day two. The treatment will last for a maximum of three days or less if the patient in discharged. The number of tablets per dose is dependent on the heart rate recorded within one hour before dosing. To assess whether the patient’s heart shows any signs of stress, additional blood samples will be collected on the following time points: preoperatively before induction of anaesthesia on the day of surgery, on postoperative day one, postoperative day two and postoperative day three provided the patient has not been discharged earlier than these timepoints. At selected centres, heart rate will be measured using a Holter and blood pressure using an ambulatory blood pressure monitor cuff. The patient will wear these monitors for at least one hour before induction of anaesthesia until postoperative day three or discharge (whichever is earlier).

At postoperative day one, intraoperative information, administration of drug and safety events will be measured. Similar assessments will be made on day two and day three postoperatively. On hospital discharge, there will be a review of the medical notes for complications and adverse events will be assessed. 30 days after surgery, the research team will review the patient’s medical record to assess specific postoperative complications and any treatments received as a result. The research team will contact the patient to conduct a brief telephone interview on their recovery. At 180 days after surgery the mortality status of the patient will be confirmed by reviewing their hospital records.

What are the possible benefits and risks of participating?
There are no guaranteed benefits to the trial participants however the study might benefit patients undergoing surgery in the future. Ivabradine is a licensed drug commonly used to treat chronic heart failure and the symptoms of chronic angina. It is generally safe and most people do not have any problems. But like all medicines, it can cause side effects in some people. The side effects of ivabradine include:
• Very common (may affect more than 1 in 10 people): Luminous visual phenomena (brief moments of increased brightness, most often caused by sudden changes in light intensity). They can also be described as a halo, coloured flashes, image decomposition or multiple images. They generally occur within the first two months of treatment after which they may occur repeatedly and resolve during or after treatment.
• Common (may affect up to 1 in 10 people): Modification in the heart functioning (the symptoms are a slowing down of the heart rate). They particularly occur within the first 2 to 3 months of treatment initiation. Other common side effects include headache, dizziness, blurred vision (cloudy vision), irregular rapid contraction of the heart, abnormal perception of heartbeat and uncontrolled blood pressure.
• Uncommon (may affect up to 1 in 100 people): Fainting, double vision, impaired vision, spinning sensation (vertigo), palpitations and cardiac extra beats, low blood pressure, difficulty breathing (dyspnoea), feeling sick (nausea), constipation, diarrhoea, abdominal pain, skin rash, muscle spasms, feeling of tiredness, feeling of weakness, swollen face, tongue or throat, difficulty in breathing or swallowing (angioedema), changes in laboratory parameters: an excess of eosinophils (a type of white blood cell), high blood levels of uric acid, elevated creatinine in blood (a breakdown product of muscle), abnormal ECG heart tracing.
• Rare (may affect up to 1 in 1,000 people): Skin reddening, itching, urticaria, feeling unwell.
• Very rare (may affect up to 1 in 10,000 people): Irregular heartbeats.

Where is the study run from?
Critical Care and Perioperative Medicine Research Group (CCPMG) at the Royal London Hospital (UK).

When is the study starting and how long is it expected to run for?
February 2021 to March 2026

Who is funding the study?
National Institute for Health Research (NIHR) (UK).

Who is the main contact?
1. Ms Tasnin Shahid (public), t.shahid@qmul.ac.uk
2. Dr Priyanthi Dias (scientific), p.dias@qmul.ac.uk

Study website

Contact information

Study information

Eligibility

Locations

Countries of recruitment

• England
• United Kingdom

Study participating centres

Sponsor information

Queen Mary University of London
University/education

Mile End Road
London
E1 4NS
England
United Kingdom

Phone	+44 (0)20 7882 7275
Email	research.governance@qmul.ac.uk
Website	http://www.jrmo.org.uk/
"ROR"	https://ror.org/026zzn846

Funders

Funder type

Government

Results and Publications

Study outputs

Editorial Notes

11/03/2025: Publication reference added.
07/03/2025: The recruitment end date was changed from 31/03/2025 to 06/03/2025 and the total final enrolment was added.
19/02/2024: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/02/2024 to 31/03/2025.
2. The overall end date was changed from 01/02/2025 to 31/03/2026.
3. The intention to publish date was changed from 01/08/2025 to 31/03/2026.
4. The plain English summary was updated to reflect these changes.
07/03/2023: The following updates have been made to the study record and the plain English summary updated accordingly:
1. The inclusion criteria have been changed.
2. The exclusion criteria have been changed.
07/12/2021: The recruitment start date was changed from 01/12/2021 to 21/12/2021.
03/11/2021: The recruitment start date has been changed from 01/11/2021 to 01/12/2021.
22/10/2021: Internal review.
22/09/2021: Trial's existence confirmed by London Westminster Research Ethics Committee.