MO534: Associations of Haemoglobin Values and Rate of Changes With Mace in the ASCEND-D Randomised Clinical Trial
Authors: Obrador Gregorio , Macdougall Iain , Johansen Kirsten , Jha Vivekanand , Correa-Rotter Ricardo , Del Vecchio Lucia , Cases Amenos Aleix , Robertson Michele , Mallett Steve , K. Bailey Christine , Cobitz Alexander , K. Singh Ajay 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Preliminary analyses suggest that absolute haemoglobin (Hb) values and rapid Hb changes may be associated with adverse outcomes in patients with anaemia of chronic kidney disease (CKD) treated with erythropoiesis-stimulating agents (ESAs) [1–3]. In this exploratory post-hoc analysis of the ASCEND-D trial, we investigated the association between absolute Hb values or Hb changes over 4-week periods and the occurrence of the first adjudicated major adverse cardiovascular event (MACE) in patients with CKD on dialysis who were treated with either daprodustat or ESAs.

METHOD
ASCEND-D was an event-driven cardiovascular outcomes trial conducted in over 30 countries that randomized 2964 CKD patients undergoing dialysis with a baseline Hb of 8.0–11.5 g/dL to receive oral, once-daily daprodustat (1487 patients), or a conventional ESA (epoetin alfa or darbepoetin; 1477 patients). Available doses were daprodustat 1–24 mg once-daily, epoetin alfa 1500–60 000 U total weekly dose, and darbepoetin 20–400 µg total 4-weekly dose. The co-primary endpoints of non-inferiority for first occurrence of adjudicated MACE and mean Hb change from baseline to weeks 28 through 52 were met and have been reported recently [4]. MACE was a composite of death from any cause, non-fatal myocardial infarction or non-fatal stroke. An independent clinical events committee, blind to treatment assignment, adjudicated the events. To examine the association of post-randomization absolute Hb values and Hb changes with first adjudicated MACE, we divided each patient's time in the study before a first MACE or end of follow-up into distinct 4-week intervals. We then calculated a post-randomization mean Hb value and Hb rate of increase or decrease at each 4-week interval. Separately for each treatment arm, we grouped these 4-week periods into quintiles of mean Hb values and Hb rates of increase or decrease (see Table 1), and calculated MACE rates for each quintile. This analysis did not include MACE that occurred before Week 4, as this was the time for the first scheduled post-randomization Hb collection. We used the average of Hb values imputed by the multiple imputation method to impute missing Hb values.

RESULTS
This analysis included 361 and 389 first MACE in the daprodustat and ESA treatment groups, respectively. When evaluating rates of the first occurrence of adjudicated MACE by absolute Hb value quintiles and irrespective of Hb change (‘All’ column in Figure 1), the MACE rate was higher in the low Hb quintile than in the high Hb quintile across both treatment groups. In the evaluation of rates of the first MACE by Hb change quintile and irrespective of absolute Hb value (‘All’ row in Figure 1), rates of MACE were comparable across Hb change quintiles within each treatment group. When MACE risk was evaluated by both absolute Hb value and Hb change quintiles, the highest MACE rate was observed in the lowest Hb quintile (Q1 row) with the largest positive change (Q5 increase column), and this was more pronounced in the ESA group.

CONCLUSION
This exploratory analysis suggests a possible association between Hb quintile and MACE outcome for both absolute and fluxes in Hb values. However, this analysis has several limitations including a small number of events in each quintile, possible confounding by severity of disease and the choice of assessment window. Further studies are needed to confirm these findings.