#3715 THE EFFECT OF DAPRODUSTAT ON INTRAVENOUS IRON USE IN PATIENTS WITH CKD-RELATED ANAEMIA ON DIALYSIS IN THE ASCEND TRIALS

Abstract

Abstract Background and Aims Intravenous (IV) iron is frequently needed in patients with chronic kidney disease (CKD) to ensure sufficient iron is available for erythropoiesis. However high doses of IV iron and erythropoiesis stimulating agents (ESAs) may be associated with risks in these patients [1]. The hypoxia-inducible factor-prolyl hydroxylase domain inhibitor daprodustat was non-inferior to comparator ESAs for the primary endpoint of efficacy (change-in-Hb) in the multicentre, randomised, Phase 3 trials ASCEND-D (NCT02879305) [2] and ASCEND-TD (NCT03400033) [3], also for the safety (major adverse cardiovascular [CV] events) coprimary endpoint in ASCEND-D [2]. This analysis of ASCEND-D and ASCEND-TD compared daprodustat to active ESAs on measures of IV iron use in dialysis patients. Method Daprodustat and ESAs were compared in patients with CKD anaemia on haemodialysis/peritoneal dialysis (ASCEND-D); haemodialysis (ASCEND-TD). ASCEND-D (N = 2,964) was an open-label CV outcome study using daprodustat once daily, while ASCEND-TD (N = 407) was a double-blind, double-dummy, 52-week study investigating three times weekly dosing of daprodustat. In both studies, following randomisation, treatment dosage was titrated to achieve the Hb target range of 10.0–11.0g/dL, with Hb efficacy assessed during the evaluation period (EP), Weeks 28–52. All patients were required to have ferritin >100 ng/mL and/or transferrin saturation (TSAT) >20% at baseline for inclusion. Throughout the study, iron therapy was administered if ferritin was ≤100 ng/mL and/or TSAT was ≤20% so patients would remain iron replete throughout the study. Investigators chose the route and dose of iron administration per patient iron status and clinical judgement. Stopping threshold criteria of 800 ng/mL ferritin + TSAT >20%, or TSAT>40% were implemented to avoid iron overload, but investigators could stop administration of iron at levels below the protocol-defined stopping thresholds. The average monthly IV iron dose (mg)/patient to Week 52 was a principal secondary endpoint, while the proportion of patients who met iron management criteria with a decrease in monthly IV iron dose during the EP relative to baseline and until patients received first transfusion were exploratory endpoints. The baseline monthly IV iron dose was defined as the average monthly IV iron (mg) over the 16 weeks prior to randomisation for ASCEND-D and over the 12 weeks prior to randomisation for ASCEND-TD. Results The proportion of patients with IV iron use at baseline was similar in both treatment arms for ASCEND-D (64%) but lower in the daprodustat group in ASCEND-TD (63% vs 72% in the ESA group). In both studies the proportion of patients receiving IV iron during the EP decreased (ASCEND-D: daprodustat 49%, ESA 52%; ASCEND-TD: daprodustat 38%, ESA 40%). The average monthly IV iron dose during the EP and from Day 1 to Week 52 was lower than monthly IV iron dose at baseline, however daprodustat was not associated with a statistically significant reduction in monthly IV iron per patient to Week 52 vs ESA comparator (Table 1). After a period of IV iron requirements decreasing, based on adjustment to protocol-specified levels, IV iron dosage remained relatively stable for daprodustat and ESA (Figure 1). In ASCEND-D, 3 of 23 pre-defined subgroups (prior ESA dose group, ESA hyporesponders2, history of myocardial infarction) showed a trend towards heterogeneity (interaction p-value <0.1), with differences in monthly IV iron use in the prior ESA dose group receiving ≥7000 U/week (-21.2 mg/month) and in the ESA hyporesponder group (-31.7 mg/month) in favour of daprodustat. Fewer patients met the criteria for stopping iron while on daprodustat vs ESA, whereas the converse was observed in ASCEND-TD (Table 1). Conclusion In ASCEND-D and -TD, no clinically or statistically significant reduction in monthly IV iron use was seen with daprodustat vs ESA comparators, although there was a numerical decrease in the proportion of patients receiving IV iron during the EP for the daprodustat group in both studies.