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

Background: 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. Methods/Design: 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. Discussion: 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. Trial registration: Clinicaltrials.gov NCT00827021 Background Anemia affects almost all patients with end-stage kidney disease (ESKD) receiving renal replacement therapy [1]. Established treatment options for anemia of chronic kidney disease (CKD) are Erythropoietin Stimulating Agents (ESA), including erythropoietins (EPO alfa, beta), darbepoetin (DARBO α), pegylated epoietin (continuous erythropoietin receptor activator, CERA) and biosimilar epoetins. Observational studies suggest that, compared to patients with chronic kidney disease whose haemoglobin (Hb) levels are on average 11 g/dL, CKD patients with Hb levels < 11 g/dL experience a 20-70% higher risk of death and a 20-40% higher risk of hospitalization [2] and CKD patients with Hb levels > 12 g/dL have a 15-20% lower risk of hospitalization with no survival advantage [3]. However these studies, due to their observational design, can only establish an association between Hb and * Correspondence: [email protected] 2 Department of Clinical Pharmacology and Epidemiology, Mario Negri Sud Consortium, 66030 S. Maria Imbaro (CH), Italy Full list of author information is available at the end of the article © 2010 Clinical Evaluation of the DOse of Erythropoietins Study Group (C.E. DOSE) and Strippoli; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Strippoli et al. Trials 2010, 11:70 http://www.trialsjournal.com/content/11/1/70 Page 2 of 7 survival, and do not demonstrate a causal relationship between Hb levels and risk of death or hospitalizations. Randomized clinical studies have consistently shown that Hb targets of 12.0-13.5 g/dL achieved with ESA cause an increase in adverse vascular events compared to Hb levels of 10-12 g/dL achieved with the same agents or no treatment [4-6]. A recent meta-analysis [7], including 9 trials (5143 patients), concluded that patients who achieve Hb targets around 12.5-13.5 g/dL with ESA have a 17% higher risk of death (95% confidence intervals (CI) 1%-35%) compared to those who achieve lower Hb targets (< 12 g/dL) with the same agents. The excess risk of death is mainly due to an increased rate of adverse vascular outcomes (which increased by 25%, 95% CI 9-42%). This meta-analysis was dominated by three large multicenter randomized trials: the "Normal Hematocrit Study" [4] (NHS, n = 1233), which enrolled patients receiving hemodialysis, the "Correction of Hemoglobin and Outcomes In Renal insufficiency" study (5) (CHOIR, n = 1432) and the "Cardiovascular Risk reduction by Early Anaemia Treatment with Epoietin beta" study [6] (CREATE, n = 603) both conducted in patients with CKD not receiving dialysis. These individual studies and their pooled analysis, found that higher Hb targets (13.0-15.0 g/dL) achieved with ESA, compared to giving ESA to achieve lower Hb targets (10.5-11.5 g/dL), caused either an increased risk of death for cardiovascular events (CHOIR: relative risk (RR) 1.34; CI 95%:1.03-1.74) or, at best, no reduction in the risk (CREATE: RR 0.78; CI 95%: 0.53-1.14). In summary, based upon these data, it was concluded that administering ESA to achieve Hb targets > 12.5 g/dL caused an increased risk of all-cause mortality (RR 1.17; CI 95%: 1-13.5; p = 0.031) compared to administering ESA to achieve Hb targets between 9.0 and 12.0 g/dL. The clinical practice patterns for management of anaemia of CKD still remain highly variable with conflicting recommendations from key guideline agencies relating both to optimal Hb targets (Table 1), ESA administration (including the Hb concentration at which patients should begin ESA treatment or have their ESA dose adjusted), iron management and other aspects of ESA treatment (including definitions of ESA resistance, role of inflammation in management of anaemia, etc.). The variability in clinical practice and guideline statements prompted several systematic reviews and design and conduct of additional randomized trials However, a key question that remains unanswered is what is the mechanism by which higher Hb targets cause harm. The uncertainty regarding optimal anemia management in patients with chronic kidney disease is compounded further by the recent release of the results of the "Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT)" [8]. This trial, conducted in 4038 patients with diabetes and early CKD, who were not yet receiving dialysis, found that darbepoetin alfa 'does not beat placebo' for the composite endpoint of survival and non fatal cardiovascular events (RR 1,05; CI 95%: 0,94-1,17; p = 0,41). In addition, darbepoetin alfa may cause harm (significant increase in the risk of stroke, RR 1.92; CI 95%: 1.38-2.68; p < 0,001) with no significant quality of life advantage [5,8]. Taken together, these data showing increased harm and limited evidence for benefit bring anemia management in chronic kidney disease back to its origins. Initially, ESA were introduced to treat anemia in patients with ESKD receiving hemodialysis for renal replacement therapy, and who required red blood cell transfusions to elevate severely reduced hemoglobin levels. Given this identified benefit of ESA treatment, namely a significant reduction in the rate of transfusion [8], the question of potential treatment efficacy was expanded and explored in the predialysis setting where subsequently no beneficial effects and the potential for harm have been clearly demonstrated. In light of the absence of benefit from targeting hemoglobin levels for patients with CKD, it is now important to understand whether alternative therapeutic strategies to manage anaemia in CKD can be found and whether a fixed dose ESA strategy (high or low) might increase hemoglobin levels without signifcant harm (adverse vascular events and mortality). The mechanism by which targeting Hb levels above 12.5 g/dL causes an increase in the risk of death and cardiovascular events remains uncertain. It is possible that the ESA dose required to achieve and maintain higher Hb targets is directly linked with adverse events, most particularly in patients who are resistant to the actions of administered ESA [9,10]. Further, evaluating differing fixed doses of ESA is difficult because Hb levels inextricably link to ESA dose and demonstrably affect patient outcomes. Trial Hypothesis We will test the hypothesis that fixed doses of ESA are feasible and provide improvements in clinical events and quality of life in individuals with end-stage kidney disease, without increasing adverse outcomes. The Clinical Evaluation of the DOSe of Erythropoietins (C.E. DOSE) trial is the first study to test this hypothesis and assess the feasibility of two therapeutic strategies for the management of anemia in ESKD. The trial has two therapeutic strategies. These are two fixed ESA doses. The first is based on the prescription of a minimum ESA dose (4000 I/U per week) and the second is based on the administration of a maximum ESA dose (18000 I/U per week), independent of the Hb target level which is achieved. Both strategies include a rescue mechanism for dose tapering when Hb levels fall outside the range of 9,5 to 12,5 g/dL. Strippoli et al. Trials 2010, 11:70 http://www.trialsjournal.com/content/11/1/70 Page 3 of 7 Aims of the study 1) To evaluate the comparative efficacy of two fixed ESA doses (high versus low) on a composite of major cardiovascular endpoints and on safety endpoints; 2) to evaluate the effects of two fixed ESA doses on quality of life in hemodialysis patients by means of a validated quality of life assessment tool; 3) to evaluate the feasibility of each of the fixed-dose therapeutic strategies; and 4) to conduct a cost-effectiveness analysis for the two therapeutic approaches. Methods/Design Study population Patients > 18 years who fulfil the following criteria: 1) Presence of anemia related to ESKD. Anemia is defined by the National Kidney Foundation as having a Hb level below 12.0 g/dL in women and 13.5 g/L in men. In the interest of a common definition for recruitment in the C.E. DOSE trial, any patient who is already receiving ESA will be eligible for randomization, as well as any patient in which the managing physician would initiate ESA treatment. Patients will be excluded if they have a Hb > 10 g/dL and are not currently receiving ESA treatment. For these individuals, ESA initiation would not be recommended based on current evidence; 2) Renal replacement therapy with hemodialysis (bicarbonate dialysis, hemofiltration, hemodiafiltration, on-line hemodiafiltration, or acetate-free biofiltration); 3) No contraindication to ESA treatment. Patients who are already receiving treatment with any ESA may participate in the trial and will be directly enrolled and randomized into the trial without a washout period. This study will be conducted in agreement with the Declaration of Helsinki. Patients will provide written informed consent before commencement of the study. The following Ethics Committee approved the study: Comitato indipendente di etica medica dell'AUSL BR/1 di Brindisi, Italy. Study design This will be a pragmatic, multicenter, centrally randomized, controlled trial (Figure 1) based upon the intentionto-treat principle. To achieve allocation concealment, randomization will be carried out centrally by the coordinating study center. Independent of baseline Hb level, participants will be allocated to ESA 4000 IU/week intravenously versus 18000 IU/week intravenously of erythropoietin alfa, beta, or equivalent doses of any other commercially available agent (including darbepoetin alfa, C.E.R.A. or biosimilars and other agents, which may Figure 1 Flow chart describing the selection, randomization and follow-up process of the Clinical Evaluation of the Dose of Erythropoietins (C.E. DOSE) trial. Randomization 4000 IU/week iv. EPO alfa or beta or equivalent doses of any other ESA 18000 IU/week iv. EPO alfa or beta or equivalent doses of any other ESA Assessment of clinical outcomes (composite of major cardiovascular events, cardiovascular mortality, safety of treatments), quality of life, and costs Male or female individuals (age ≥18 years) with ESKD, receiving hemodialysis, treated with ESA or without side effects to ESA treatment Assessment of clinical outcomes (composite of major cardiovascular events, cardiovascular mortality, safety of treatments), quality of life, and costs Table 1: Guidelines on hemoglobin (Hb) targets in patients with CKDa. Guidelines Country Year Target Hb level (g/L) European medicines Agency (EMEA) Europe 2008 100-120 National Kidney Foundation-Dialysis Outcome Quality Initiative (NKF-DOQI) USA 2007 110-120 Italian Society of Nephrology Italy 2006 110-115