Ivabradine for Heart Rate Reduction During Exercise in Healthy Adults

Heart rate and stroke volume are generally considered as two independent factors which influence cardiac output, yet they are interlinked by cellular (e.g., calcium handling) and hemodynamic (e.g., diastolic pressure decay) mechanisms. Delineating how heart rate and stroke volume influence cardiac output and exercise capacity, even within healthy individuals, has historically been experimentally difficult as pharmacologic perturbations, such as beta-adrenergic antagonists, influence both heart rate and heart muscle performance. Ivabradine selectively reduces heart rate in a dose-dependent manner, without impacting myocardial contractility, cardiac afterload, or venous return. However, it has largely been studied in clinical outcome trials in adults with heart failure, or safety studies in younger healthy adults. As such, there is a knowledge gap on how ivabradine influences heart rate and exercise capacity in healthy younger and older adults.

Study Purpose To characterize the effects of two single doses of ivabradine (7.5 mg and 12.5 mg) on heart rate during incremental exercise in younger and older healthy adults.

Exploratory Aim To assess the safety and tolerability of two single doses of ivabradine (7.5 mg and 12.5 mg) in younger and older healthy adults.

Hypothesis Ivabradine will produce dose-dependent reductions in peak exercise heart rate and heart rate/work-rate relationships (anticipated to be approximately 10-15%, on average).

Research Design Unblinded, non-randomized, repeated measures design.

Study Visits Visit 1 (1.5 hours): Screening, consent, assessments of anthropometrics, seated heart rate and blood pressure, a resting 12-lead electrocardiogram, and a cardiopulmonary exercise test with 12-lead electrocardiogram. Pre-menopausal females will also be required to complete a urine pregnancy test and confirm a negative result prior to participation.

Visits 2 and 3 (4 hours each): A single oral dose of ivabradine will be administered at each visit: 7.5 mg at Visit 2 and 12.5 mg at Visit 3. Doses are administered in this fixed order so that all participants are observed at the lower dose before proceeding to the higher dose.

Following drug administration, participants will be seated and observed for 90 minutes with continuous heart rate monitoring and blood pressure recorded at 15-minute intervals. Participants will then complete an incremental exercise test on a cycle ergometer with 12-lead ECG monitoring, following the same work-rate protocol used in Visit 1. Following exercise, participants will be seated and observed for 120 minutes with continuous heart rate monitoring and blood pressure recorded at 15-minute intervals.

Statistical Analysis Data will be analyzed using SPSS Statistics (v.30, IBM Inc). Normality will be assessed by the Shapiro-Wilk test. Omnibus testing will be conducted using analysis of variance (ANOVA), the Friedman test, or the Kruskal-Wallis test with significant effects tested post hoc. If all compared groups or conditions approximate a normal distribution, data will be presented as mean ± standard deviation with paired comparisons made using t-tests. Otherwise, data will be presented as median (inter-quartile range) with paired comparisons made using the Mann-Whitney U or Wilcoxon Signed Rank tests. Associations will be explored with Pearson correlations and linear regression.

Sample Size Justification Based on existing literature describing the effect of ivabradine on heart rate during exercise in healthy adults, a sample size of 20 provides 95% power to detect a 5 beats per minute difference between 7.5 mg and 12.5 mg trials, assuming a standard deviation of 5 beats per minute and a two-tailed alpha of 0.05 adjusted for three post-hoc paired t-tests.

Inclusion criteria

• Healthy males and females aged 19-39 years, and 60-79 years
• Engaging in regular aerobic exercise (e.g., running, cycling, swimming, hiking, field, ice, or racquet sports) at least once per week

Exclusion criteria

• History of any cardiovascular condition, including hypertension
• Use of any chronic medication
• History of any respiratory condition, including asthma
• Smoking, including cannabis or vaping in the past year
• History of diabetes mellitus, cancer, hepatic, renal or any other chronic illness
• Seated blood pressure ≥130/90 or <100/60 mmHg
• Body mass index <20 or >32 kg/m2
• Non-sinus rhythm or abnormalities on 12-lead electrocardiogram (ECG)
• Pregnant, breastfeeding, or women of childbearing potential not using appropriate contraception
• Current or recent (past year) participation in >150 minutes per week of moderate-vigorous intensity exercise (to avoid endurance training-related bradycardia)
• Any condition that prevents vigorous exercise from being performed safely
• Seated resting heart rate <60 beats per minute
• Prolonged QT interval (e.g., long QT syndrome)
• Sick sinus syndrome, sino-atrial block or third-degree atrio-ventricular block
• Use of strong cytochrome P450 (CYP3A4) inhibitors (e.g., nirmatrelvir and ritonavir, ketoconazole), which can increase ivabradine levels in the blood to potentially unsafe levels
• Use of verapamil or diltiazem, which are moderate CYP3A4 inhibitors and also lower heart rate, posing a risk of excessive bradycardia when combined with ivabradine
• Lactose intolerance, as ivabradine contains lactose
• Known allergy/hypersensitivity to ivabradine or to any ingredient in the formulation or component of the container