Abstract | BACKGROUND: METHODS: We performed a post hoc analysis from the CHOIR trial. Inclusion criteria were Hb <11.0 g/dl and estimated glomerular filtration rates of 15-50 ml/min/1.73 m(2). To be included in the present analysis, subjects needed to be free of the composite event at 4 months, receive epoetin-alfa, and have ≥1 postbaseline Hb measurement. The mean weekly dose of epoetin-alfa received up to the time of first event or censure was the main exposure variable, while the achieved Hb at month 4 was the confounder representing the subject's underlying response to treatment. The primary outcome was the composite of death, heart failure hospitalization, stroke, or myocardial infarction. A Cox proportional hazard regression model was used in time-to-event analysis. RESULTS: Among 1,244 subjects with complete data, the average weekly dose of epoetin-alfa ranged 143.3-fold from 133 to 19,106 units/week at the time of first event or censure. Cox proportional hazard analysis found that those in the middle tertile of Hb achieved (>11.5 to <12.7 g/dl) and the lowest tertile of epoetin-alfa dose exposure level (<5,164 units/week) had the lowest risk. Irrespective of Hb achieved, the relative risk in the highest tertile (>10,095 units/week) of epoetin-alfa dose exposure level was significantly escalated (hazard ratios ranged from 2.536 to 3.572, p < 0.05, when compared to the group of middle Hb tertile and lowered dose tertile). In a multivariable model that adjusted for achieved Hb, albumin, cholesterol, age, prior heart failure, prior stroke, prior deep venous thrombosis, atrial fibrillation or malignancy, the average weekly dose had a significant (p = 0.005) relative risk of 1.067 per 1,000 units of epoetin-alfa for the primary end point. CONCLUSIONS: In the CHOIR trial, average epoetin-alfa doses >10,095 units/week were associated with increased risks for cardiovascular events irrespective of the Hb achieved within the first 4 months of treatment. These data suggest the weekly epoetin-alfa dose and not the Hb achieved was a principal determinant in the primary outcome observed implicating a cardiovascular toxicity of this erythrocyte-stimulating agent.
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Authors | Peter A McCullough, Huiman X Barnhart, Jula K Inrig, Donal Reddan, Shelly Sapp, Uptal D Patel, Ajay K Singh, Lynda A Szczech, Robert M Califf |
Journal | American journal of nephrology
(Am J Nephrol)
Vol. 37
Issue 6
Pg. 549-58
( 2013)
ISSN: 1421-9670 [Electronic] Switzerland |
PMID | 23735819
(Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 S. Karger AG, Basel. |
Chemical References |
- Hematinics
- Hemoglobins
- Recombinant Proteins
- Erythropoietin
- Epoetin Alfa
|
Topics |
- Aged
- Aged, 80 and over
- Anemia
(drug therapy, etiology)
- Dose-Response Relationship, Drug
- Epoetin Alfa
- Erythropoietin
(adverse effects)
- Female
- Heart Failure
(chemically induced)
- Hematinics
(adverse effects)
- Hemoglobins
- Humans
- Male
- Middle Aged
- Myocardial Infarction
(chemically induced)
- Proportional Hazards Models
- Recombinant Proteins
(adverse effects)
- Renal Insufficiency, Chronic
(complications)
- Risk Factors
- Stroke
(chemically induced)
- Treatment Outcome
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