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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.
Clin J Am Soc Nephrol. 2019 12 06; 14(12):1701-1710.CJ

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.

Authors+Show Affiliations

Retired from Alessandro Manzoni Hospital, ASST Lecco, Lecco, Italy; f.locatelli@asst-lecco.it.School of Medicine, University of Strasbourg, Strasbourg, France.Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Great Neck, New York.Biostatistics, F. Hoffmann-La Roche Ltd., Basel, Switzerland.Clinical Science, F. Hoffmann-La Roche Ltd., Basel, Switzerland; and.Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, Connecticut.

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31420350

Citation

Locatelli, Francesco, et al. "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." Clinical Journal of the American Society of Nephrology : CJASN, vol. 14, no. 12, 2019, pp. 1701-1710.
Locatelli F, Hannedouche T, Fishbane S, et al. 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. Clin J Am Soc Nephrol. 2019;14(12):1701-1710.
Locatelli, F., Hannedouche, T., Fishbane, S., Morgan, Z., Oguey, D., & White, W. B. (2019). 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. Clinical Journal of the American Society of Nephrology : CJASN, 14(12), 1701-1710. https://doi.org/10.2215/CJN.01380219
Locatelli F, et al. 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. Clin J Am Soc Nephrol. 2019 12 6;14(12):1701-1710. PubMed PMID: 31420350.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Locatelli,Francesco, AU - Hannedouche,Thierry, AU - Fishbane,Steven, AU - Morgan,Zoe, AU - Oguey,Delphine, AU - White,William B, Y1 - 2019/08/16/ PY - 2019/02/01/received PY - 2019/07/10/accepted PY - 2019/8/20/pubmed PY - 2020/12/2/medline PY - 2019/8/18/entrez KW - C-Reactive Protein KW - Darbepoetin alfa KW - Hematinics KW - Intention to Treat Analysis KW - Polyethylene Glycols KW - anemia KW - cardiovascular KW - cardiovascular diseases KW - chronic kidney disease KW - chronic renal insufficiency KW - clinical trial KW - continuous erythropoietin receptor activator KW - epoetin KW - erythropoietin KW - mortality risk KW - myocardial infarction KW - random allocation KW - renal dialysis KW - risk factors KW - stroke SP - 1701 EP - 1710 JF - Clinical journal of the American Society of Nephrology : CJASN JO - Clin J Am Soc Nephrol VL - 14 IS - 12 N2 - 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. SN - 1555-905X UR - https://www.unboundmedicine.com/medline/citation/31420350/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_ DB - PRIME DP - Unbound Medicine ER -