Personalized Perioperative Dosing of Ivabradine in Noncardiac Surgery: A Single-Centre, Randomised, Placebo-Controlled, Double-Blind Feasibility Pilot Trial

Academic Background

Perioperative myocardial injury (PMI) is a common complication following noncardiac surgery and is closely associated with postoperative mortality and morbidity. Studies have shown that heart rate (HR) is an independent risk factor for perioperative myocardial injury. Although beta-blockers have been used to modulate perioperative HR to prevent cardiac complications, their use may lead to side effects such as hypotension and bradycardia, especially when administered immediately before surgery. Therefore, finding a safer and more effective HR-modulating drug has become a research priority.

Ivabradine, a selective inhibitor of the sinoatrial node If channel, can reduce HR without affecting myocardial contractility or vascular tone. Recent studies in acute care settings have shown that ivabradine has a safe HR-modulating effect. However, the pharmacokinetics and pharmacodynamics of ivabradine in the perioperative period have not been fully studied, and its optimal dosage and administration regimen remain unclear. Therefore, this study aims to evaluate the feasibility of personalized perioperative ivabradine dosing through a randomized, double-blind, placebo-controlled feasibility trial, providing a basis for future large-scale clinical trials.

Source of the Paper

This paper was co-authored by researchers from the Department of Anaesthesiology, Pharmacology, Intensive Care, and Emergency Medicine at Geneva University Hospitals, Switzerland, including Marion J. White, Isabelle Zaccaria, Florence Ennahdi-Elidrissi, and others. The paper was published on July 2, 2024, in the British Journal of Anaesthesia, titled Personalised perioperative dosing of ivabradine in noncardiac surgery: a single-centre, randomised, placebo-controlled, double-blind feasibility pilot trial.

Study Design and Methods

Study Process

This study was a single-center, randomized, double-blind, placebo-controlled feasibility trial aimed at evaluating the feasibility of personalized perioperative ivabradine dosing. The study was conducted at Geneva University Hospitals and included patients aged 75 years or older, or 45 years or older with cardiovascular risk factors, scheduled for intermediate- or high-risk noncardiac surgery. Patients were randomized to receive either ivabradine (2.5 mg, 5.0 mg, or 7.5 mg) or placebo twice daily from the morning of surgery until postoperative day 2, based on their HR.

Study Subjects and Sample

A total of 78 patients were enrolled, with 39 receiving ivabradine and 39 receiving placebo. Baseline characteristics of the patients included age, sex, body mass index, and cardiovascular history. The primary endpoints of the study were the appropriate dosing rate and the success rate of blinding.

Experimental Methods

The study employed a personalized dosing regimen, adjusting the dose of ivabradine based on the patient’s HR. The specific dosing regimen was as follows: - Patients with HR ≤70 beats/min or those who received rescue treatment for bradycardia: placebo (Pill A). - Patients with HR 71-85 beats/min: ivabradine 2.5 mg or placebo (Pill B). - Patients with HR 86-100 beats/min: ivabradine 5.0 mg or placebo (Pill C). - Patients with HR ≥101 beats/min: ivabradine 7.5 mg or placebo (Pill D).

Data Analysis

The primary endpoints of the study were the appropriate dosing rate and the success rate of blinding. The appropriate dosing rate was defined as the proportion of correct doses administered according to the patient’s HR out of the total doses administered, while the success rate of blinding was defined as the proportion of doses administered without unblinding out of the total doses administered. Secondary endpoints included the incidence of postoperative myocardial injury and the incidence of bradycardia.

Results

Primary Results

A total of 444 doses were administered, with 439 doses being appropriate, resulting in an appropriate dosing rate of 98.9%. The success rate of blinding was 100%, indicating that the double-blind design of the study was effectively implemented. Placebo was administered 137 times (31%) due to HR ≤70 beats/min or the use of rescue treatment for bradycardia. The incidence of postoperative myocardial injury was 11.5%, with bradycardia occurring 9 times in the ivabradine group and 8 times in the placebo group.

Secondary Results

The study also found that the HR in the ivabradine group was significantly lower than that in the placebo group on postoperative day 2 (73.5 beats/min vs. 78 beats/min). The incidence of postoperative myocardial injury was 7.7% in the ivabradine group, lower than the 15.4% in the placebo group. Additionally, no serious adverse events were observed, confirming the safety of ivabradine.

Conclusions and Significance

This study confirmed the feasibility of personalized perioperative ivabradine dosing, with both the appropriate dosing rate and the success rate of blinding meeting the expected targets. The results suggest that ivabradine can effectively reduce postoperative HR without increasing the incidence of adverse effects such as bradycardia. However, the low incidence of postoperative myocardial injury indicates that future studies should include higher-risk patients to enhance the clinical significance of the findings.

Scientific and Application Value

This study provides important feasibility data for future large-scale clinical trials, supporting the safety and efficacy of personalized perioperative ivabradine dosing. The results suggest that ivabradine may be an effective drug for preventing perioperative myocardial injury, especially in high-risk patients. Additionally, the study highlights the importance of perioperative HR modulation, offering new insights for future clinical practice.

Research Highlights

• Personalized Dosing Regimen: The study employed a personalized ivabradine dosing regimen, adjusting the dose based on the patient’s HR, avoiding a “one-size-fits-all” approach.
• High Success Rate of Blinding: The double-blind design of the study was effectively implemented, with a 100% success rate of blinding, ensuring the reliability of the results.
• Low Incidence of Postoperative Myocardial Injury: Although the incidence of postoperative myocardial injury was low, it was significantly lower in the ivabradine group than in the placebo group, suggesting its potential clinical value.

Other Valuable Information

The study also noted that future research should consider including higher-risk patients and optimizing sample size calculations to improve the statistical power of the study. Additionally, the study suggested the use of intravenous ivabradine in future trials to address difficulties with oral administration postoperatively.

This study provides important scientific evidence for the development and application of perioperative HR-modulating drugs, with broad clinical application prospects.