Cardiovascular Safety and All-Cause Mortality of Methoxy Polyethylene Glycol-Epoetin Beta and Other Erythropoiesis-Stimulating Agents in Anemia of CKD: A Randomized Noninferiority Trial

Abstract

Background and objectives: Erythropoiesis-stimulating agents correct anemia of CKD but may increase cardiovascular risk. We compared cardiovascular outcomes and all-cause mortality associated with monthly methoxy polyethylene glycol-epoetin beta with those of the shorter-acting agents epoetin alfa/beta and darbepoetin alfa in patients with anemia of CKD.

Design, setting, participants, & measurements: We conducted a multicenter, open-label, noninferiority trial in which patients were randomized to receive methoxy polyethylene glycol-epoetin beta or reference erythropoiesis-stimulating agents, stratified by maintenance or correction treatment status and C-reactive protein level. The trial had a prespecified noninferiority margin of 1.20 for the hazard ratio (HR) for the primary end point (a composite of all-cause mortality, nonfatal myocardial infarction or stroke, adjudicated by an independent blinded committee). This trial is registered with ClinicalTrials.gov, number NCT00773513.

Results: In total, 2818 patients underwent randomization, received methoxy polyethylene glycol-epoetin beta or a reference agent, and were followed for a median of 3.4 years (maximum, 8.4 years). In the modified intention-to-treat analysis, a primary end point event occurred in 640 (45.4%) patients in the methoxy polyethylene glycol-epoetin beta arm, and 644 (45.7%) in the reference arm (HR 1.03; 95% confidence interval [95% CI], 0.93 to 1.15, P=0.004 for noninferiority). All-cause mortality was not different between treatment groups (HR 1.06; 95% CI, 0.94 to 1.19). Results in patient subgroups on dialysis or treated in the correction or maintenance settings were comparable to the primary analysis.

Conclusions: In patients with anemia of CKD, once-monthly methoxy polyethylene glycol-epoetin beta was noninferior to conventional, shorter-acting erythropoiesis-stimulating agents with respect to rates of major adverse cardiovascular events or all-cause mortality.

Keywords: C-Reactive Protein; Darbepoetin alfa; Hematinics; Intention to Treat Analysis; Polyethylene Glycols; anemia; cardiovascular; cardiovascular diseases; chronic kidney disease; chronic renal insufficiency; clinical trial; continuous erythropoietin receptor activator; epoetin; erythropoietin; mortality risk; myocardial infarction; random allocation; renal dialysis; risk factors; stroke.

Copyright © 2019 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

Patient disposition. The most common reason for discontinuation in patients in the ‘other’ category was the patient moving away from participating dialysis units. *Kidney transplant was a prespecified reason for withdrawal from the trial.

Figure 2.

Hematologic and iron parameters during the study. (A) Hemoglobin, (B) ferritin, and (C) transferrin saturation. Values shown are median with IQRs.

Figure 3.

Time-to-event curves. (A) Death from any cause, nonfatal stroke, or nonfatal myocardial infarction (primary end point) and (B) death from any cause.

Figure 4.

Subgroup analysis of the primary end point by baseline patient and disease factors.