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Sickle trait in African-American hemodialysis patients and higher erythropoiesis-stimulating agent dose.

ABSTRACT: African Americans require higher doses of erythropoiesis-stimulating agents (ESAs) during dialysis to manage anemia, but the influence of sickle cell trait and other hemoglobinopathy traits on anemia in dialysis patients has not been adequately evaluated. We performed a cross-sectional study of a large cohort of adult African-American hemodialysis patients in the United States to determine the prevalence of hemoglobinopathy traits and quantify their influence on ESA dosing. Laboratory and clinical data were obtained over 6 months in 2011. Among 5319 African-American patients, 542 (10.2%) patients had sickle cell trait, and 129 (2.4%) patients had hemoglobin C trait; no other hemoglobinopathy traits were present. Sickle cell trait was more common in this cohort than the general African-American population (10.2% versus 6.5%-8.7%, respectively, P<0.05). Among 5002 patients (10.3% sickle cell trait and 2.4% hemoglobin C trait) receiving ESAs, demographic and clinical variables were similar across groups, with achieved hemoglobin levels being nearly identical. Patients with hemoglobinopathy traits received higher median doses of ESA than patients with normal hemoglobin (4737.4 versus 4364.1 units/treatment, respectively, P=0.02). In multivariable analyses, hemoglobinopathy traits associated with 13.2% more ESA per treatment (P=0.001). Within subgroups, sickle cell trait patients received 13.2% (P=0.003) higher dose and hemoglobin C trait patients exhibited a similar difference (12.9%, P=0.12). Sensitivity analyses using weight-based dosing definitions and separate logistic regression models showed comparable associations. Our findings suggest that the presence of sickle cell trait and hemoglobin C trait may explain, at least in part, prior observations of greater ESA doses administered to African-American dialysis patients relative to Caucasian patients.

SUBMITTER: Derebail VK

PROVIDER: S-EPMC3968502 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Sickle trait in African-American hemodialysis patients and higher erythropoiesis-stimulating agent dose.

Derebail Vimal K VK Lacson Eduardo K EK Kshirsagar Abhijit V AV Key Nigel S NS Hogan Susan L SL Hakim Raymond M RM Mooney Ann A Jani Chinu M CM Johnson Curtis C Hu Yichun Y Falk Ronald J RJ Lazarus J Michael JM

Journal of the American Society of Nephrology : JASN 20140123 4

African Americans require higher doses of erythropoiesis-stimulating agents (ESAs) during dialysis to manage anemia, but the influence of sickle cell trait and other hemoglobinopathy traits on anemia in dialysis patients has not been adequately evaluated. We performed a cross-sectional study of a large cohort of adult African-American hemodialysis patients in the United States to determine the prevalence of hemoglobinopathy traits and quantify their influence on ESA dosing. Laboratory and clinic ...[more]

PMID: 24459231

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Project description:The increased risks of death and adverse events with erythropoiesis-stimulating agent (ESA) therapy targeting a higher hemoglobin level are established. It is uncertain whether the adverse effects of ESA therapy are related to dose and are mitigated when a fixed low ESA dose is used. We conducted a multicenter, prospective randomized open-label, blinded-endpoint (PROBE) trial to evaluate fixed low versus high dose ESA therapy on patient outcomes. We intended to recruit 2104 hemodialysis patients >18 years with anemia or receiving ESA treated at dialysis clinics in Italy. The intervention was fixed low (4000 IU epoetin alfa equivalent weekly) or high (18,000 IU epoetin alfa equivalent weekly) dose ESA for 12 months. Primary outcomes were serum transferrin, ferritin, albumin, C-reactive protein and ESA dose. Secondary outcomes were the composite of death or cardiovascular event, all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, cardiovascular hospitalization, and quality of life. Study recruitment was terminated after inclusion of 656 participants with convergence of ESA dose between groups during follow up. Fixed low dose ESA had uncertain effects on serum ferritin (delta of delta (DD) 3.9 ng/ml, 95% CI -85.0 to 92.8), transferrin (9.2 mg/dl, -6.3 to 24.8), transferrin saturation (3.7%, -5.0 to 12.3), serum albumin (-0.03 g/dl, -0.2 to 0.1), or C-reactive protein (-0.6 mg/l, -3.3 to 2.1). In addition, fixed dose therapy had inconclusive effects on the composite endpoint of mortality and cardiovascular events (hazard ratio [HR] 0.95, 95% CI 0.66 to 1.37), death (0.98, 0.64 to 1.52), nonfatal myocardial infarction (0.52, 0.18 to 1.52), nonfatal stroke (no events), hospital admission for cardiovascular causes (0.93, 0.50 to 1.72) or health-related quality of life. A fixed low ESA dose in hemodialysis patients has uncertain effects on serum parameters, mortality, cardiovascular events, and quality of life. Hemoglobin targets may be so entrenched in nephrology practice that a trial of ESA dose is no longer possible.

Project description:BackgroundEpoetin alfa and darbepoetin alfa are erythropoiesis-stimulating agents (ESAs) indicated for the treatment of anemia in chronic renal failure, including patients on dialysis and patients not on dialysis. Clinical experience demonstrates that the dose conversion ratio (DCR) between epoetin alfa and darbepoetin alfa is nonproportional across the dosing spectrum. However, previous calculations of the dose relationship between epoetin alfa and darbepoetin alfa, described in previous work as the "dose ratio" (DR), (a) used cross-sectional designs (i.e., compared mean doses for patient groups using each ESA) and were therefore vulnerable to confounding or (b) did not adjust for the nonproportional dose relationship. DRs reported in the literature range from 217:1 to 287:1 epoetin alfa (Units [U]):darbepoetin alfa (micrograms [micrograms]). Payers may need a single DCR that accounts for the nonproportional dose relationship to evaluate the economic implications of converting a nondialyzed patient population with chronic kidney disease (CKD) from epoetin alfa to darbepoetin alfa.ObjectiveTo estimate a single mean maintenance DCR between epoetin alfa and darbepoetin alfa in subjects with CKD not receiving dialysis, using methods that take into account the nonproportional dose relationship between the 2 ESAs.MethodsThis was a post-hoc analysis of a subset of patients enrolled in an unpublished, open-label, single arm phase 3 clinical trial (ClinTrial. gov identifier NCT00093977) that was completed in 2006. Although the clinical trial enrolled both dialyzed and nondialyzed patients, the present study used a patient subset comprising nondialyzed patients with CKD previously receiving weekly or every-other-week (Q2W) epoetin alfa who were switched to Q2W darbepoetin alfa to maintain hemoglobin (Hb) levels between 11.0 and 13.0 grams per deciliter. A population mean DCR was estimated using 2 methods: (a) a regression-based method in which the log-transformed (natural logarithm) mean weekly darbepoetin alfa dose over the evaluation period of the study (weeks 25 to 33) was regressed on the log-transformed (natural logarithm) weekly epoetin alfa dose over the 2-week screening period; and (b) a mean ratio method in which the DCR was calculated for each individual patient and then averaged for the study population to give a population-level DCR. Sensitivity analyses estimated the DCR in various subgroups.ResultsOf 1,127 patients enrolled in clinical trial NCT00093977, 567 patients on dialysis were excluded. Of the remaining 560 patients, 104 received weekly or Q2W epoetin alfa, were switched to Q2W darbepoetin alfa, received at least 1 non-zero dose of darbepoetin alfa during the evaluation period, and were included in the DCR calculation for the present study. Analysis of the log-log plot for the regression-based method indicated 2 or more possible regression lines with separate slopes. However, based on our a priori analysis plan to estimate a single DCR for the patient sample, the estimated sample mean maintenance DCR in the regression analysis was 330.6 U epoetin alfa to 1 micrograms darbepoetin alfa. In the mean ratio analysis, the DCR was 375.6 U:1 micrograms. Sensitivity analyses in which DCRs were calculated for different subgroups with different baseline differences identified a variable DCR range of 302-380 U:1 micrograms.ConclusionsThe methodology used in estimating the DCR accounts for the nonproportional dose relationship between epoetin alfa and darbepoetin alfa and may represent an advance over the methods used in previous research. The mean maintenance DCR between the 2 ESAs exceeds a threshold of 300 U:1 micrograms, which is greater than previously reported DRs. This methodology provides payers the means to compare ESA doses in CKD patients not receiving dialysis.

Dataset Information

Sickle trait in African-American hemodialysis patients and higher erythropoiesis-stimulating agent dose.

Publications

Sickle trait in African-American hemodialysis patients and higher erythropoiesis-stimulating agent dose.

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