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Original ArticlesChronic Kidney Disease
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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

Francesco Locatelli, Thierry Hannedouche, Steven Fishbane, Zoe Morgan, Delphine Oguey and William B. White
CJASN December 2019, 14 (12) 1701-1710; DOI: https://doi.org/10.2215/CJN.01380219
Francesco Locatelli
1Retired from Alessandro Manzoni Hospital, ASST Lecco, Lecco, Italy;
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Thierry Hannedouche
2School of Medicine, University of Strasbourg, Strasbourg, France;
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Steven Fishbane
3Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Great Neck, New York;
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Zoe Morgan
4Biostatistics, F. Hoffmann-La Roche Ltd., Basel, Switzerland;
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Delphine Oguey
5Clinical Science, F. Hoffmann-La Roche Ltd., Basel, Switzerland; and
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William B. White
6Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, Connecticut
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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.

  • anemia
  • chronic kidney disease
  • epoetin
  • clinical trial
  • cardiovascular
  • mortality risk
  • Darbepoetin alfa
  • Hematinics
  • C-Reactive Protein
  • cardiovascular diseases
  • Intention to Treat Analysis
  • random allocation
  • renal dialysis
  • risk factors
  • continuous erythropoietin receptor activator
  • erythropoietin
  • myocardial infarction
  • chronic renal insufficiency
  • stroke
  • Polyethylene Glycols
  • Received February 1, 2019.
  • Accepted July 10, 2019.
  • Copyright © 2019 by the American Society of Nephrology
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Clinical Journal of the American Society of Nephrology: 14 (12)
Clinical Journal of the American Society of Nephrology
Vol. 14, Issue 12
December 06, 2019
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Cardiovascular Safety and All-Cause Mortality of Methoxy Polyethylene Glycol-Epoetin Beta and Other Erythropoiesis-Stimulating Agents in Anemia of CKD
Francesco Locatelli, Thierry Hannedouche, Steven Fishbane, Zoe Morgan, Delphine Oguey, William B. White
CJASN Dec 2019, 14 (12) 1701-1710; DOI: 10.2215/CJN.01380219

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Cardiovascular Safety and All-Cause Mortality of Methoxy Polyethylene Glycol-Epoetin Beta and Other Erythropoiesis-Stimulating Agents in Anemia of CKD
Francesco Locatelli, Thierry Hannedouche, Steven Fishbane, Zoe Morgan, Delphine Oguey, William B. White
CJASN Dec 2019, 14 (12) 1701-1710; DOI: 10.2215/CJN.01380219
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Keywords

  • anemia
  • chronic kidney disease
  • epoetin
  • clinical trial
  • cardiovascular
  • mortality risk
  • Darbepoetin alfa
  • Hematinics
  • C-Reactive Protein
  • cardiovascular diseases
  • intention to treat analysis
  • Random Allocation
  • renal dialysis
  • risk factors
  • continuous erythropoietin receptor activator
  • erythropoietin
  • Myocardial Infarction
  • chronic renal insufficiency
  • Stroke
  • Polyethylene Glycols

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