Efficacy and Cardiovascular Safety of Roxadustat for Treatment of Anemia in Patients with Non-Dialysis-Dependent CKD: Pooled Results of Three Randomized Clinical Trials

Abstract

Background and objectives: We evaluated the efficacy and cardiovascular safety of roxadustat versus placebo by analyzing data pooled from three phase 3 studies of roxadustat in patients with non-dialysis-dependent CKD and CKD-related anemia.

Design, setting, participants, & measurements: In the three phase 3, double-blind studies of roxadustat versus placebo evaluating the treatment of CKD-related anemia in patients not requiring dialysis, the primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28-52, regardless of rescue therapy. The primary cardiovascular safety end point was a composite measure of major adverse cardiovascular events (MACE; all-cause mortality, myocardial infarction, stroke). MACE plus (MACE+; MACE plus unstable angina and heart failure requiring hospitalization) and all-cause mortality were key secondary safety end points. These safety end points were adjudicated.

Results: A total of 4277 patients with non-dialysis-dependent CKD were randomized (roxadustat, n=2391; placebo, n=1886). Baseline characteristics were comparable between groups; the mean (SD) hemoglobin was 9.1 (0.7) g/dl and mean eGFR was 20 (12) ml/min per 1.73 m2. Patients treated with roxadustat versus those treated with placebo showed a mean change from baseline in hemoglobin averaged over weeks 28-52, regardless of rescue therapy, of 1.9 versus 0.2 g/dl, a treatment difference of 1.7 (95% confidence interval [95% CI], 1.7 to 1.8). Roxadustat reduced the need for red blood cell transfusion in the first 52 weeks versus placebo (6.1 versus 20.4 per 100 patient-exposure years, respectively; hazard ratio [HR], 0.26; 95% CI, 0.21 to 0.32). There were no increased risks of MACE (HR, 1.10; 95% CI, 0.96 to 1.27), MACE+ (HR, 1.07; 95% CI, 0.94 to 1.21), all-cause mortality (HR, 1.08; 95% CI, 0.93 to 1.26), or individual MACE+ components in patients treated with roxadustat versus those treated with placebo.

Conclusions: Roxadustat was more effective than placebo at increasing hemoglobin in patients with non-dialysis-dependent CKD and anemia, while decreasing transfusion rate and being noninferior to placebo with respect to risk of MACE.

Clinical trial registry name and registration number: A Study of FG-4592 for the Treatment of Anemia in Chronic Kidney Disease Patients Not Receiving Dialysis, NCT01750190; Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not Requiring Dialysis (ALPS), NCT01887600; Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease (CKD), Not on Dialysis, NCT02174627.

Keywords: MACE; anemia; chronic kidney disease; efficacy; roxadustat; safety.

Copyright © 2021 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

CONSORT flow diagram.§In study 001 (OLYMPUS), 2781 patients were randomized but 20 were excluded from statistical analysis because of system technical issues and major good clinical practice violations. In study 608 (ALPS), 597 patients were randomized but three were excluded from statistical analysis because of good clinical practice violations. **Includes adverse event and progressive disease. †Patients who died while on study drug or after discontinuation of study drug were categorized as completing the study in study 001. ‡Development of study-specific discontinuation criteria: either the patient’s decision (the patient is, at any time, free to discontinue treatment, without prejudice to further treatment) or investigator’s decision (including but not limited to these examples: incorrectly randomized patient in whom the inclusion/exclusion criteria violation would put the patient at undue risk, adverse event for which the investigator thinks continued treatment may put the patient at undue risk, severe nonadherence to study protocol, pregnancy, patients who have received two courses of erythropoietin analogue rescue therapy and for whom there is a need for a third course of rescue with erythropoietin analogue, for patients initiating dialysis during the study and for whom there is a need for rescue with erythropoietin analogue). *Vital status was ascertained at the end of the study among 91% of the roxadustat arm and 91% of the placebo arm. CONSORT, Consolidated Standards of Reporting Trials; ITT, intention to treat; SAF, safety analysis set.

Figure 2.

Hemoglobin levels in the overall non–dialysis-dependent patient population over time (weeks 0–52) (full analysis set).

Figure 3.

Forest plots for the cardiovascular safety analyses in patients who were not dependent on dialysis (safety analysis set, ITT analysis). ITT analysis refers to analyses comprising both on-treatment and long-term follow-up events. †Follow-up–adjusted incidence rate per 100 patient years: 100×number of patients with events/patient years. Patient years for each patient: (first event occurrence or censor date–first dose date+1)/365.25. 95% CI, 95% confidence interval; H, hospitalization; HR, hazard ratio; MACE, major adverse cardiovascular event defined as all-cause mortality, myocardial infarction, or stroke; MACE+, MACE plus unstable angina and congestive heart failure requiring hospitalization.

Figure 4.

Kaplan–Meier curves for MACE, MACE+, and all-cause mortality in patients who were not dependent on dialysis (safety analysis set, ITT analysis). MACE was defined as all-cause mortality, myocardial infarction, or death.