Daprodustat and Heart Failure in CKD

Key Points Patients with CKD face meaningful risk of heart failure hospitalization. Daprodustat compared with darbepoetin was associated with a nonsignificantly greater number of heart failure hospitalizations in non-dialysis patients. Background Patients with CKD are at higher risk of heart failure. The hypoxia-inducible factor prolyl hydroxylase inhibitor daprodustat is an orally acting alternative to conventional injectable erythropoietin-stimulating agents (ESAs) for the treatment of anemia in patients with CKD. Whether daprodustat affects the risk of heart failure hospitalization is unknown. Methods The Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat–Dialysis (ASCEND-D; n =2964) and Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat–Non-Dialysis (ASCEND-ND; n =3872) trials compared daprodustat with conventional ESA in patients with anemia of CKD who did or did not require dialysis, respectively. We identified risk factors of heart failure hospitalization and assessed the effect of daprodustat compared with conventional ESA on heart failure hospitalizations. Results History of heart failure, diabetes, and higher systolic BP were independently associated with heart failure hospitalization in both trials, irrespective of treatment assignment. The number of first heart failure hospitalizations was greater in the daprodustat arm in patients not receiving dialysis (hazard ratio [HR], 1.22 [95% confidence interval (CI), 0.95 to 1.56], P = 0.12) and in patients receiving dialysis (HR, 1.10 [95% CI, 0.84 to 1.45], P = 0.47), although these differences were not statistically significant. HRs in patients with and without history of heart failure were 1.37 (95% CI, 0.89 to 2.11) versus 1.08 (95% CI, 0.79 to 1.46) ( P -interaction=0.36) in the ASCEND-ND trial and 1.52 (95% CI, 0.97 to 2.38) versus 0.93 (95% CI, 0.66 to 1.30) ( P -interaction=0.09) in the ASCEND-D trial, respectively. In post hoc analyses, daprodustat increased total (first and recurrent) heart failure hospitalizations in participants not receiving dialysis (rate ratio, 1.46 [95% CI, 1.11 to 1.92], P = 0.007) but not in participants receiving dialysis (rate ratio, 1.01 [95% CI, 0.74 to 1.39], P = 0.93). Daprodustat did not significantly affect the risk of a composite outcome of first heart failure hospitalization or death. Conclusions A greater number of first heart failure hospitalization events occurred in patients treated with daprodustat compared with conventional ESA, but this difference did not reach statistical significance. Differences in the number of heart failure hospitalization events were most apparent in patients not receiving dialysis and in patients with history of heart failure.