Targeted heart rate control using the funny current inhibitor ivabradine to reduce morbidity in patients undergoing noncardiac surgery: study protocol for a phase 2a, triple-blind, placebo-controlled randomised trial
Bernardo Bollen Pinto,
Benjamin Shelley,
Priyanthi Dias,
Salma Begum,
Florence Ennahdi-Elidrissi,
Tom E.F. Abbott,
Russell Hewson,
Akshaykumar Patel,
Kamran Khan,
Rupert M. Pearse,
Gareth L. Ackland,
Bernardo Bollen Pinto,
Benjamin Shelley,
Priyanthi Dias,
Salma Begum,
Florence Ennahdi-Elidrissi,
Russell Hewson,
Anna Wozniak,
Shaun M. May,
Mareena Joseph,
Agustine Miguel Saavedra,
Tim Martin,
Onika Ottley,
Ana Santos,
Fatima Seidu,
Stéphanie Mulin,
Stéphane Luise,
Isabelle Pichon,
John Daniels,
Béatrice Gil-Wey,
Soraya Bicher,
Gaël Rais,
Christene Aitken,
Elizabeth Boyd,
Patricia Griffen,
Charlene Hamilton,
Kathryn Valdeavella,
Rhiannon McAreavey,
Phillip McCall,
Alfie Lloyd,
Jocelyn Barr,
Julie Buckley,
Anne Marie Tiah,
Henrike Janssen,
Lisa Kandala,
Angela Fitzpatrick,
Alexander Lysomirski,
Ahmed Ahltobi,
Ana Gutierrez del Arroyo,
Tom E.F. Abbott,
Akshaykumar Patel,
Kamran Khan,
Rupert M. Pearse,
Gareth L. Ackland
Affiliations
Bernardo Bollen Pinto
Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals, Geneva, Switzerland
Benjamin Shelley
Department of Cardiothoracic Anaesthesia and Intensive Care, Golden Jubilee National Hospital, Clydebank, UK; Anaesthesia, Perioperative Medicine and Critical Care Research Group, University of Glasgow, Glasgow, UK
Priyanthi Dias
Faculty of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK
Salma Begum
Faculty of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK
Florence Ennahdi-Elidrissi
Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals, Geneva, Switzerland
Tom E.F. Abbott
Faculty of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK
Russell Hewson
Faculty of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK
Akshaykumar Patel
Faculty of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK
Kamran Khan
Faculty of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK
Rupert M. Pearse
Faculty of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK
Gareth L. Ackland
Faculty of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK; Corresponding author.
Background: Myocardial injury is strongly associated with excess morbidity and mortality after noncardiac surgery. Higher heart rate may result in perioperative myocardial injury through demand–supply mismatch. Alternatively, higher heart rates may reflect autonomic dysfunction that promotes myocardial injury independently of heart rate. The specific hyperpolarisation-activated, cyclic nucleotide-gated (HCN)-4 (funny) channel inhibitor ivabradine slows the heart rate without altering autonomic control, blood pressure, or myocardial contractility. We hypothesise that individuals with autonomic dysfunction may benefit most from ivabradine reducing heart rate control to minimise myocardial injury-associated morbidity. Methods: This triple-blind, international, multicentre, randomised, placebo-controlled, parallel group randomised trial will recruit 350 patients, aged ≥55 yr, with cardiovascular risk factors for myocardial injury during elective noncardiac surgery. To achieve the target heart rate <70 beats min−1 (sinus rhythm), patients will be randomly allocated in a 1:1 ratio using minimisation and will receive either ivabradine (2.5–7.5 mg) or placebo tablet twice daily, from the morning of surgery for 72 h. High-sensitivity troponin T concentrations will be measured before and up to 72 h after surgery, blinded to participants, clinicians, and investigators. The primary outcome is myocardial injury associated with morbidity within 7 days of randomisation (defined by Postoperative Morbidity Survey). Secondary outcomes include peak troponin concentrations, complications within 30 days, and mortality within 6 months of surgery. Pre-specified analyses will include resting and orthostatic heart rate plus N-terminal prohormone of brain natriuretic peptide concentrations before surgery. Conclusions: This phase 2b study will explore whether targeted heart rate control reduces morbidity after surgery, using ivabradine to selectively slow the heart rate without altering perioperative autonomic control. Clinical trial registration: ISRCTN12903789.
