Iron deficiency and risk of heart failure and cardiovascular events in CKD: Insights from the ASCEND-ND trial

Background and aims Iron deficiency occurs commonly in chronic kidney disease (CKD), but its association with heart failure and other cardiovascular outcomes, independent of anemia, is not well defined. Methods We conducted a post-hoc analysis of the Anaemia Studies in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial. We assessed the independent associations of transferrin saturation (TSAT) and ferritin levels with cardiovascular and mortality outcomes using time-updated multivariable Cox regression models. The primary outcome was heart failure hospitalization (HFH) or cardiovascular death. Results Among 3,872 participants (median age 67 years, 56% women, median estimated glomerular filtration rate 18 mL/min/1.73m2), those with lower TSAT were more likely to be women, have diabetes, atrial fibrillation, and a history of cardiovascular disease. In fully adjusted models (including hemoglobin), compared to TSAT >30-≤40%, time-updated TSAT ≤20% was associated with a 2-fold higher risk of the primary outcome (HR 2.13, 95% CI 1.62-2.80), with similar associations observed for HFH (HR 1.97, 95% CI 1.40-2.79) and for cardiovascular death (HR 2.19, 95% CI 1.45-3.29), as well as all-cause mortality (HR 1.60, 95% CI 1.25-2.03). Ferritin levels ≤100 ng/mL (vs >100 to ≤300 ng/mL) were not associated with a higher risk of any cardiovascular or mortality outcomes. Conclusions Iron deficiency defined by low transferrin saturation, but not low ferritin levels, is associated with increased risk of heart failure and cardiovascular death in CKD, independent of hemoglobin.