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Erythropoietin Dose and Mortality in Hemodialysis Patients: Marginal Structural Model to Examine Causality.

ABSTRACT: It has been previously reported that a higher erythropoiesis stimulating agent (ESA) dose in hemodialysis patients is associated with adverse outcomes including mortality; however the causal relationship between ESA and mortality is still hotly debated. We hypothesize ESA dose indeed exhibits a direct linear relationship with mortality in models of association implementing the use of a marginal structural model (MSM), which controls for time-varying confounding and examines causality in the ESA dose-mortality relationship. We conducted a retrospective cohort study of 128?598 adult hemodialysis patients over a 5-year follow-up period to evaluate the association between weekly ESA (epoetin-?) dose and mortality risk. A MSM was used to account for baseline and time-varying covariates especially laboratory measures including hemoglobin level and markers of malnutrition-inflammation status. There was a dose-dependent positive association between weekly epoetin-? doses ?18?000?U/week and mortality risk. Compared to ESA dose of <6?000?U/week, adjusted odds ratios (95% confidence interval) were 1.02 (0.94-1.10), 1.08 (1.00-1.18), 1.17 (1.06-1.28), 1.27 (1.15-1.41), and 1.52 (1.37-1.69) for ESA dose of 6?000 to <12?000, 12?000 to <18?000, 18?000 to <24?000, 24?000 to <30?000, and ?30?000?U/week, respectively. High ESA dose may be causally associated with excessive mortality, which is supportive of guidelines which advocate for conservative management of ESA dosing regimen in hemodialysis patients.

SUBMITTER: Streja E

PROVIDER: S-EPMC4889858 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Erythropoietin Dose and Mortality in Hemodialysis Patients: Marginal Structural Model to Examine Causality.

Streja Elani E Park Jongha J Chan Ting-Yan TY Lee Janet J Soohoo Melissa M Rhee Connie M CM Arah Onyebuchi A OA Kalantar-Zadeh Kamyar K

International journal of nephrology 20160519

It has been previously reported that a higher erythropoiesis stimulating agent (ESA) dose in hemodialysis patients is associated with adverse outcomes including mortality; however the causal relationship between ESA and mortality is still hotly debated. We hypothesize ESA dose indeed exhibits a direct linear relationship with mortality in models of association implementing the use of a marginal structural model (MSM), which controls for time-varying confounding and examines causality in the ESA ...[more]

PMID: 27298736

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Project description:Background:There is no consensus on intravenous (IV) iron supplement dose, schedule, and serum ferritin target in functional iron deficiency anemia to maintain optimum target levels of iron stores by several guidelines. Objective:To examine the effect of IV iron supplementation to different targets of serum ferritin on erythropoietin dose and inflammatory markers in chronic hemodialysis (HD) patients with functional iron deficiency anemia. Design:A multicenter, randomized, open-label study. Setting:In a developing country, Thailand. Patients:Chronic HD patients with functional iron deficiency anemia. Measurements:Erythropoietin resistance index, high-sensitivity C-reactive protein, and fibroblast growth factor 23. Methods:Two hundred adult chronic HD patients with transferrin saturation less than 30% and serum ferritin of 200 to 400 ng/mL were randomized 1:1 to maintain serum ferritin 200 to 400 ng/mL (low-serum ferritin group, N = 100) or 600 to 700 ng/mL (high-serum ferritin group, N = 100). During a 6-week titration period, participants randomized to the high-serum ferritin group initially received 600 mg IV iron (100 mg every week), while the participants in the low-serum ferritin group did not receive IV iron. During the 6-month follow-up period, the dose of IV iron was adjusted by protocol. Results:The mean dose of IV iron was 108.3 ± 28.2 mg/month in the low-serum ferritin group and 192.3 ± 36.2 mg/month in the high-serum ferritin group. The mean serum ferritin was 367.0 ± 224.9 ng/mL in the low ferritin group and 619.6 ± 265.2 ng/mL in the high ferritin group. The erythropoietin resistance index was significantly decreased in the high-serum ferritin group compared to the low-serum ferritin group after receiving IV iron in the 6-week titration period (mean difference: -113.43 ± 189.14 vs 41.08 ± 207.38 unit/week/g/dL; P < .001) and 3-month follow-up period (mean differences: -88.88 ± 234.43 vs -10.48 ± 217.75 unit/week/g/dL; P = .02). Limitations:Short follow-up period. Conclusion:Maintaining a serum ferritin level of 600 to 700 ng/mL by IV iron administration of approximately 200 mg per month as a maintenance protocol can decrease erythropoietin dose requirements in chronic HD patients with functional iron deficiency anemia. Trials registration:The study was registered with the Thai Clinical Trials Registry TCTR20180903003.

Project description:Background and objectivesRecombinant human erythropoietin (epoetin) is used routinely to increase blood hemoglobin levels in patients with ESRD and anemia. Although lower doses of epoetin are required to achieve equivalent hemoglobin responses when administered subcutaneously rather than intravenously, standard practice has been to administer epoetin to patients on hemodialysis intravenously. Randomized trials of alternative epoetin treatment regimens in patients with kidney failure have shown that risks of cardiovascular complications and death are related to the dose levels of epoetin used. Therefore, given the dose-sparing advantages of subcutaneous epoetin administration, the possibility that treatment of patients on hemodialysis with subcutaneous epoetin might be associated with more favorable outcomes compared with intravenous treatment was investigated.Design, setting, participants, & measurementsA retrospective cohort study of 62,710 adult patients on hemodialysis treated with either intravenous or subcutaneous epoetin-? and enrolled in the Centers for Medicare and Medicaid Services ESRD Clinical Performance Measures Project from 1997 to 2005 was carried out. Risks of death and/or hospitalization for cardiovascular complications (adverse composite event outcomes) during 2 years of follow-up were determined in relationship to epoetin dose and route of administration (intravenous versus subcutaneous) by multivariate Cox proportional hazard modeling adjusted for demographics and clinical parameters.ResultsEpoetin doses used to achieve equivalent hemoglobin responses in study patients were, on average, 25% higher when epoetin was administered intravenously rather than subcutaneously (as expected). Moreover, adverse composite event outcomes were found to be significantly more likely to occur during follow-up for patients on hemodialysis managed with intravenous rather than subcutaneous epoetin (adjusted hazard ratio for adverse events within 1 year [intravenous versus subcutaneous] was 1.11 [95% confidence interval, 1.04 to 1.18]).ConclusionsThis study finds that treatment of patients on hemodialysis with subcutaneous epoetin is associated with more favorable clinical outcomes than those associated with intravenous epoetin treatment.

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Erythropoietin Dose and Mortality in Hemodialysis Patients: Marginal Structural Model to Examine Causality.

Publications

Erythropoietin Dose and Mortality in Hemodialysis Patients: Marginal Structural Model to Examine Causality.

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