Pooled Analysis of Roxadustat for Anemia in Patients With Kidney Failure Incident to Dialysis

Abstract

Introduction: Erythropoiesis-stimulating agents are associated with increased cardiovascular risk when higher doses are used toward higher hematocrit targets. Patients new to dialysis are at higher risk for morbidity and mortality. Systematic evaluation of this population was predefined in the roxadustat clinical development program. Roxadustat is a hypoxia-inducible prolyl hydroxylase inhibitor.

Methods: Data were pooled from 3 phase 3, randomized, open-label, active-controlled trials. Eligible adults had kidney failure and initiated dialysis for 2 weeks to ≤ 4 months prior to randomization to roxadustat or epoetin alfa. Efficacy was assessed as mean change in hemoglobin from baseline averaged over weeks 28 to 52, regardless of rescue therapy. Key cardiovascular safety endpoints were major adverse cardiovascular events (MACE; all-cause mortality [ACM], myocardial infarction, and stroke), and MACE+ (MACE plus unstable angina or congestive heart failure requiring hospitalization), and ACM.

Results: This study included 1530 patients with kidney failure incident to dialysis. Mean (SD) changes in hemoglobin from baseline averaged over weeks 28 to 52, regardless of rescue therapy, were 2.12 (1.45) versus 1.91 (1.42) g/dl in the roxadustat and epoetin alfa groups (least-squares mean difference: 0.22; 95% CI, 0.05 to 0.40; P = 0.0130). Risks of MACE and MACE+ were lower in the roxadustat group (hazard ratio [HR], 0.70; 95% CI, 0.51 to 0.96) than the epoetin alfa group (HR, 0.66; 95% CI, 0.50 to 0.89); the HR for ACM was 0.76 (95% CI, 0.52 to 1.11).

Conclusion: Roxadustat was at least as efficacious as epoetin alfa. Roxadustat had a lower risk of MACE/MACE+ in patients new to dialysis.

Keywords: anemia; chronic kidney disease; dialysis; roxadustat.

Graphical abstract

Figure 1

CONSORT flow diagram.

Figure 2

Hemoglobin levels by treatment arm (Full Analysis Set).

Figure 3

Forest plot of cardiovascular safety analyses in incident-dialysis patients on dialysis for 2 week to ≤4 months prior to randomization. (a) MACE using all-cause mortality. (b) MACE using cardiovascular mortality. (c) Individual events. ∗OT-7: events that occurred during the treatment period and within 7 days of the last dose of study drug. ^†PEY for each patient = (last dose date − first dose date + 1) / 365.25. Incidence rate (per 100 PEY) = 100 × number of subjects with events / PEY. ^‡HR derived using a meta-analysis method combining individual study log-HRs with weights inversely proportional to the variants of the study-specific log-HRs. ^§P value reported when the point estimate of HR was <1.0. ACM, all-cause mortality; CHF, congestive heart failure; CI, confidence interval; CVM, cardiovascular mortality; HR, hazard ratio; MACE, major adverse cardivascular event; MACE+, MACE plus unstable angina and CHF requiring hospitalization; MI, myocardial infarction; OT+7, on treatment plus 7 days after last study drug; PEY, patient-exposure years.

Figure 4

Kaplan-Meier curves for MACE, MACE+, and ACM. ACM, all-cause mortality; CHF, congestive heart failure; CI, confidence interval; CVM, cardiovascular mortality; HR, hazard ratio; MACE, major adverse cardivascular event; MACE+, MACE plus unstable angina and CHF requiring hospitalization; MI, myocardial infarction; OT+7, on treatment plus 7 days after last study drug.