Impact of Once-Daily Ivabradine on Average Resting Heart Rate in Patients With Reduced Ejection Fraction With Systolic Dysfunction: A Multicenter, Post-marketing Observational Study

Background: An elevated resting heart rate (RHR) is associated with an increased risk of morbidity and mortality in patients with cardiovascular (CV) diseases. Twice-daily (BD) dosing of ivabradine effectively lowers RHR and reduces HF-related hospitalizations and mortality. However, benefits depend on dosing frequency, which is vital in ensuring medication adherence. Aim: This study aims to determine whether a once-daily (OD) prolonged-release formulation of ivabradine maintains effective RHR control over 12 months in patients with HF with reduced ejection fraction (HFrEF) and systolic dysfunction who were previously stabilized on BD ivabradine therapy. Materials and methods: This was a multicenter, post-marketing, observational clinical study that enrolled 500 patients aged ≥18 years with stable chronic HF, New York Heart Association Class II to III, who were stabilized on a conventional IV ivabradine BD formulation for at least one month. The patients on BD were transitioned to ivabradine OD dosing (10 mg/15 mg) and followed for 12 months (at baseline, 3, 6, 9, and 12 months), with dose adjustments made as required during follow-up. The primary endpoint was the maintenance of a reduced RHR from baseline through 12 months after switching to OD dosing. Secondary endpoints were changes in average RHR at each visit, changes in HR-lowering medication use, and adverse events (AEs). Incidence and time of CV death, all-cause mortality, and hospitalization for worsening HF were prespecified exploratory clinical endpoints. Results: Of the 500 patients (females: 149, males: 351, mean age: 55.9 ± 11.7 years), 435 patients completed the study. At 12 months, OD ivabradine maintained RHR below baseline, with a mean difference of 3.6 beats per minute (95% confidence interval: -5.058 to -2.338; p < 0.0001). RHR remained consistently below baseline at all follow-up visits, with a significant reduction at each time point (p < 0.0001). Five deaths (1.0%) (four due to CV diseases, one due to a fall) were reported at 12 months. Two patients (0.4%) required hospitalization for worsening HF. The mean time to CV death, all-cause mortality, and hospitalization due to worsening HF were 134.75, 118.8, and 276 days, respectively. AEs were reported in 10 patients (2.0%), and serious AEs in 9 patients (1.8%), all of which were unrelated to study treatment. Conclusions: Ivabradine administered OD over 12 months effectively maintained RHR in patients previously stabilized on a BD regimen when used alongside other HR-lowering therapies. The observed AE profile was consistent with findings in the published literature, in which most AEs are attributed to underlying conditions or concomitant medications rather than to the drug itself. This supports the overall tolerability and known safety profile of OD dosing of ivabradine, positioning it as a viable and convenient alternative for managing HFrEF.