Table 7.

Clinical studies of HCN channel blocker.

Drug	Study Population	Treatment	Primary and Secondary Endpoints	Main Findings and Conclusions
Ivabradine (BEAUTIFUL trial) [117]	▪Patients with CAD and LV systolic dysfunction ▪LVEF < 40% ▪Resting HR ≥ 60 bpm (N = 10,917)	Ivabradine 5–7.5 mg BID or placebo	Primary: ▪A composite of CV death, admission to hospital for acute MI, and admission to hospital for new-onset or worsening HF.	▪Ivabradine reduced HR of 6 and 5 bpm at 12 and 24 months, respectively. ▪Reduction in HR could be used to reduce the incidence of CAD outcomes in patients who have HR ≥ 70 bpm.
Ivabradine (Echo substudy of BEAUTIFUL) [118]	Subgroup analysis of the BEAUTIFUL trial (N = 590)		Primary: ▪Change in LV end-systolic volume index (LVESVI). Secondary: ▪Changes in LVEF, LVEDVI, and NT-proBNP.	▪Ivabradine was associated with a decrease in LVESVI and an increase in LVEF. ▪Ivabradine may reverse detrimental LV remodeling.
Ivabradine (SHIFT trial) [119]	▪Patients with symptomatic HF and LVEF ≤ 35% ▪HR ≥ 70 bpm (N = 6558)	Ivabradine titrated to a maximum of 7.5 mg BID or placebo	Primary: ▪A composite of CV death or hospital admission for worsening HF.	▪Ivabradine reduced major risks associated with HF. ▪Ivabradine reduced the risk of the primary endpoint. ▪No difference in reducing CV and all-cause deaths.
Ivabradine (Echo substudy of SHIFT) [120]	Subgroup analysis of the SHIFT trial (N = 411)		Primary: ▪Change in LVESVI from baseline to 8 months. Secondary: ▪Changes in LVEF, LVEDVI, LVESV, and LVEDV	▪Ivabradine reduced LVESVI. ▪Ivabradine reverses cardiac remodeling in HF patients with LV systolic dysfunction.