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Effects of the dose of erythropoiesis stimulating agents on cardiovascular events, quality of life, and health-related costs in hemodialysis patients: the clinical evaluation of the dose of erythropoietins (C.E. DOSE) trial protocol.

ABSTRACT: Anemia is a risk factor for death, adverse cardiovascular outcomes and poor quality of life in patients with chronic kidney disease (CKD). Erythropoietin Stimulating Agents (ESA) are commonly used to increase hemoglobin levels in this population. In observational studies, higher hemoglobin levels (around 11-13 g/dL) are associated with improved survival and quality of life compared to hemoglobin levels around 9-10 g/dL. A systematic review of randomized trials found that targeting higher hemoglobin levels with ESA causes an increased risk of adverse vascular outcomes. It is possible, but has never been formally tested in a randomized trial, that ESA dose rather than targeted hemoglobin concentration itself mediates the increased risk of adverse vascular outcomes. The Clinical Evaluation of the DOSe of Erythropoietins (C.E. DOSE) trial will assess the benefits and harms of a high versus a low fixed ESA dose for the management of anemia in patients with end stage kidney disease.This is a randomized, prospective open label blinded end-point (PROBE) trial due to enrol 2204 hemodialysis patients in Italy. Patients will be randomized 1:1 to 4000 IU/week versus 18000 IU/week of intravenous epoietin alfa or beta, or any other ESA in equivalent doses. The dose will be adjusted only if hemoglobin levels fall outside the 9.5-12.5 g/dL range. The primary outcome will be a composite of all-cause mortality, non fatal stroke, non fatal myocardial infarction and hospitalization for cardiovascular causes. Quality of life and costs will also be assessed.The C.E.DOSE study will help inform the optimal therapeutic strategy for the management of anemia of hemodialysis patients, improving clinical outcomes, quality of life and costs, by ascertaining the potential benefits and harms of different fixed ESA doses.Clinicaltrials.gov NCT00827021.

SUBMITTER: Strippoli GF

PROVIDER: S-EPMC2903576 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Effects of the dose of erythropoiesis stimulating agents on cardiovascular events, quality of life, and health-related costs in hemodialysis patients: the clinical evaluation of the dose of erythropoietins (C.E. DOSE) trial protocol.

Strippoli Giovanni F M GF

Trials 20100609

<h4>Background</h4>Anemia is a risk factor for death, adverse cardiovascular outcomes and poor quality of life in patients with chronic kidney disease (CKD). Erythropoietin Stimulating Agents (ESA) are commonly used to increase hemoglobin levels in this population. In observational studies, higher hemoglobin levels (around 11-13 g/dL) are associated with improved survival and quality of life compared to hemoglobin levels around 9-10 g/dL. A systematic review of randomized trials found that targe ...[more]

PMID: 20534124

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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:Targeting higher hemoglobin levels with erythropoiesis-stimulating agents (ESAs) to treat the anemia of chronic kidney disease (CKD) is associated with increased cardiovascular risk.Metaregression analysis examining the association of ESA dose with adverse outcomes independent of target or achieved hemoglobin level.Patients with anemia of CKD irrespective of dialysis status.We searched MEDLINE (inception to August 2010) and bibliographies of published meta-analyses and selected randomized controlled trials assessing the efficacy of ESAs for the treatment of anemia in adults with CKD, with a minimum 3-month duration. Two authors independently screened citations and extracted relevant data. Individual study arms were treated as cohorts and constituted the unit of analysis.ESA dose standardized to a weekly epoetin alfa equivalent, and hemoglobin levels.All-cause and cardiovascular mortality, cardiovascular events, kidney disease progression, or transfusion requirement.31 trials (12,956 patients) met the criteria. All-cause mortality was associated with higher (per epoetin alfa-equivalent 10,000-U/wk increment) first-3-month mean ESA dose (incidence rate ratio [IRR], 1.42; 95% CI, 1.10-1.83) and higher total-study-period mean ESA dose (IRR, 1.09; 95% CI, 1.02-1.18). First-3-month ESA dose remained significant after adjusting for first-3-month mean hemoglobin level (IRR, 1.48; 95% CI, 1.02-2.14), as did total-study-period mean ESA dose adjusting for target hemoglobin level (IRR, 1.41; 95% CI, 1.08-1.82). Parameter estimates between ESA dose and cardiovascular mortality were similar in magnitude and direction, but not statistically significant. Higher total-study-period mean ESA dose also was associated with increased rate of hypertension, stroke, and thrombotic events, including dialysis vascular access-related thrombotic events.Use of study-level aggregated data; use of epoetin alfa-equivalent doses; lack of adjustment for confounders.In patients with CKD, higher ESA dose might be associated with all-cause mortality and cardiovascular complications independent of hemoglobin level.

Dataset Information

Effects of the dose of erythropoiesis stimulating agents on cardiovascular events, quality of life, and health-related costs in hemodialysis patients: the clinical evaluation of the dose of erythropoietins (C.E. DOSE) trial protocol.

Publications

Effects of the dose of erythropoiesis stimulating agents on cardiovascular events, quality of life, and health-related costs in hemodialysis patients: the clinical evaluation of the dose of erythropoietins (C.E. DOSE) trial protocol.

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