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

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: (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.