Comparative Effectiveness of Ivabradine Versus Digoxin in Patients With Heart Failure With Reduced Ejection Fraction and Chronic Kidney Disease: A Real-World Multicenter Cohort Study.

INTRODUCTION: Heart failure with reduced ejection fraction (HFrEF) commonly coexists with chronic kidney disease (CKD), conferring a markedly increased risk of adverse outcomes. Ivabradine and digoxin are both used for heart rate control in HFrEF, but their comparative effectiveness in patients with CKD remains uncertain. Therefore, this study aimed to compare the risk of major adverse cardiovascular events (MACE), including heart failure exacerbation (HFE) and all-cause mortality, between ivabradine and digoxin in patients with concomitant HFrEF and CKD. METHODS: Using the TriNetX global research network, we conducted a retrospective cohort study including adults with HFrEF and CKD between 2015 and 2025. Patients prescribed ivabradine were propensity score-matched 1:1 to those receiving digoxin based on demographic, clinical, laboratory, and medication variables. The primary outcome was MACE (composite of HFE or all-cause mortality). Secondary outcomes included each component separately. Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: After matching, 3,140 patients were included (1,570 per group). Ivabradine use was associated with a significantly lower risk of MACE compared with digoxin (26.8% vs. 31.6%; HR: 0.79, 95% CI: 0.70-0.90; p < 0.001). Ivabradine also reduced the risk of HFE (HR: 0.83, 95% CI: 0.72-0.97; p = 0.015) and all-cause mortality (HR: 0.69, 95% CI: 0.56-0.85; p < 0.001). Subgroup and negative-control analyses yielded consistent results. CONCLUSIONS: In this large, real-world cohort of patients with HFrEF and CKD, ivabradine was associated with lower risks of MACE, HFE, and all-cause mortality compared with digoxin. Ivabradine may represent a safer and more effective heart rate-lowering option for this high-risk population.