Supplementary Material for: 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

Background: 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. Objectives: 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.