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.

• Authors: Robert Provenzano, Lynda Szczech, Robert Leong, Khalil G Saikali, Ming Zhong, Tyson T Lee, Dustin J Little, Mark T Houser, Lars Frison, John Houghton, Thomas B Neff
• Journal: Clinical journal of the American Society of Nephrology : CJASN (Clin J Am Soc Nephrol) Vol. 16 Issue 8 Pg. 1190-1200 (08 2021) ISSN: 1555-905X [Electronic] United States
• PMID: 34362786 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 by the American Society of Nephrology.

Chemical References

• Enzyme Inhibitors
• Hemoglobins
• Isoquinolines
• Hypoxia-Inducible Factor-Proline Dioxygenases
• Glycine
• roxadustat

Topics

• Aged
• Anemia (blood, drug therapy, etiology)
• Cardiovascular Diseases (chemically induced)
• Clinical Trials, Phase III as Topic
• Enzyme Inhibitors (adverse effects, therapeutic use)
• Erythrocyte Transfusion
• Female
• Glycine (adverse effects, analogs & derivatives, therapeutic use)
• Hemoglobins (metabolism)
• Humans
• Hypoxia-Inducible Factor-Proline Dioxygenases (antagonists & inhibitors)
• Isoquinolines (adverse effects, therapeutic use)
• Male
• Middle Aged
• Mortality
• Randomized Controlled Trials as Topic
• Renal Insufficiency, Chronic (complications)