Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany
New England Journal of Medicine (Impact Factor: 55.87). 11/2006; 355(20):2071-84. DOI: 10.1056/NEJMoa062276
Source: PubMed


Whether correction of anemia in patients with stage 3 or 4 chronic kidney disease improves cardiovascular outcomes is not established.
We randomly assigned 603 patients with an estimated glomerular filtration rate (GFR) of 15.0 to 35.0 ml per minute per 1.73 m2 of body-surface area and mild-to-moderate anemia (hemoglobin level, 11.0 to 12.5 g per deciliter) to a target hemoglobin value in the normal range (13.0 to 15.0 g per deciliter, group 1) or the subnormal range (10.5 to 11.5 g per deciliter, group 2). Subcutaneous erythropoietin (epoetin beta) was initiated at randomization (group 1) or only after the hemoglobin level fell below 10.5 g per deciliter (group 2). The primary end point was a composite of eight cardiovascular events; secondary end points included left ventricular mass index, quality-of-life scores, and the progression of chronic kidney disease.
During the 3-year study, complete correction of anemia did not affect the likelihood of a first cardiovascular event (58 events in group 1 vs. 47 events in group 2; hazard ratio, 0.78; 95% confidence interval, 0.53 to 1.14; P=0.20). Left ventricular mass index remained stable in both groups. The mean estimated GFR was 24.9 ml per minute in group 1 and 24.2 ml per minute in group 2 at baseline and decreased by 3.6 and 3.1 ml per minute per year, respectively (P=0.40). Dialysis was required in more patients in group 1 than in group 2 (127 vs. 111, P=0.03). General health and physical function improved significantly (P=0.003 and P<0.001, respectively, in group 1, as compared with group 2). There was no significant difference in the combined incidence of adverse events between the two groups, but hypertensive episodes and headaches were more prevalent in group 1.
In patients with chronic kidney disease, early complete correction of anemia does not reduce the risk of cardiovascular events. ( number, NCT00321919 [].).

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Available from: Dimitrios Tsakiris
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    • "Singh et al. (2006) found an increased risk of a composite endpoint of several cardiovascular events and death in chronic kidney disease subjects treated to a target hemoglobin levels of 13.5 g/dl versus 11.3 g/dl. Around the same time, Drüeke et al. (2006) found no significant difference in all-cause mortality or death from cardiovascular causes between subjects randomly assigned to have their treatment target a normal hemoglobin range of 13.0 to 15.0 g/dl versus a subnormal range of 10.5 to 11.5 g/dl. More recently, Pfeffer et al. (2009) found a nonsignificant increased risk of death or nonfatal cardiovascular event in type 2 diabetes subjects with chronic kidney disease randomized to a target hemoglobin of 13 g/dl versus those in a placebo group treated only to maintain a hemoglobin of about 9.0 g/dl. "
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    ABSTRACT: Epoetin is commonly used to treat anemia in chronic kidney disease and End Stage Renal Disease subjects undergoing dialysis, however, there is considerable uncertainty about what level of hemoglobin or hematocrit should be targeted in these subjects. In order to address this question, we treat epoetin dosing guidelines as a type of dynamic treatment regimen. Specifically, we present a methodology for comparing the effects of alternative treatment regimens on survival using observational data. In randomized trials patients can be assigned to follow a specific management guideline, but in observational studies subjects can have treatment paths that appear to be adherent to multiple regimens at the same time. We present a cloning strategy in which each subject contributes follow-up data to each treatment regimen to which they are continuously adherent and artificially censored at first nonadherence. We detail an inverse probability weighted log-rank test with a valid asymptotic variance estimate that can be used to test survival distributions under two regimens. To compare multiple regimens, we propose several marginal structural Cox proportional hazards models with robust variance estimation to account for the creation of clones. The methods are illustrated through simulations and applied to an analysis comparing epoetin dosing regimens in a cohort of 33,873 adult hemodialysis patients from the United States Renal Data System.
    Full-text · Article · Feb 2015 · The Annals of Applied Statistics
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    • "In contrast to the results of early observational studies, the results of several randomized controlled trials (RCTs) using ESAs for different target Hb levels have repeatedly demonstrated an increased risk of mortality or no benefit on mortality or cardiovascular events in patients treated to achieve higher Hb level [20] [21] [22] [23]. These RCTs compared similar Hb groups with a high Hb target of 13.0–15.0 "
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    ABSTRACT: Background: Anemia is a major risk factor that contributes to mortality in patients with chronic kidney disease. There is controversy over the optimal hemoglobin (Hb) target in these patients. This study investigated the association between Hb level and mortality in a cohort of hemodialysis (HD) patients in Korea. Methods: This study was a multicenter prospective observational study of maintenance HD patients that was performed for 5 years in western Seoul, Korea. Three hundred and sixty-two participants were enrolled. Laboratory values and mortality were accessed every 6 months. Repeated measures of laboratory values in each interval were averaged to obtain one semiannual mean value. The Hb values were divided into six groups: (1) Hb<9 g/dL; (2) 9 g/dL≤Hb<10 g/dL; (3) 10 g/dL≤Hb<11 g/dL; (4) 11 g/dL≤Hb<12 g/dL; (5) 12 g/dL≤Hb<13 g/dL; and (6) Hb≥13 g/dL. We analyzed the odds ratio for all-cause mortality, based on the Hb group, and adjusted for demographics and various laboratory values. Statistics were performed with SAS, version 9.1 software (SAS Institute Inc., Cary, NC, USA). Results: Mortality odds ratios relative to the reference group (10-11 g/dL) in the fully adjusted model were 3.61 for<9 g/dL; 3.17 for 9-10 g/dL(⁎); 4.65 for 11-12 g/dL(⁎); 5.50 for 12-13 g/dL(⁎); and 2.05 for≥13 g/dL ((⁎) indicates P<0.05). Conclusion: In this study, a Hb level of 10-11 g/dL was associated with the lowest mortality among the groups with Hb level<13 g/dL. Larger interventional trials are warranted to determine the optimal Hb target for Korean HD patients.
    Full-text · Article · Jan 2015
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    • "Recent studies suggest that higher doses of ESAs, in themselves, may be at least partly responsible for an increased mortality risk in nondialysis CKD patients [26] [27]. Increasing evidence from multiple well-designed prospective randomized trials, the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR), Cardiovascular risk Reduction by Early Anaemia Treatment with Epoetin β (CREATE), and Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) trials in predialysis CKD patients suggest that Hb levels approaching the normal range, compared with levels of moderate anemia, are associated with increased risk of adverse outcomes [28] [29] [30]. In the CHOIR trial, an unadjusted analysis showed an increased risk of the primary composite endpoint (death, myocardial infarction, heart failure, or stroke) at 4 months was associated with both an inability to achieve target levels and higher doses of EPO-α (420,000 units per week). "
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    ABSTRACT: Recent evidence demonstrates that high doses of epoetin-alpha (EPO-α) can be administrated at extended intervals, despite its relatively short serum half-life. However, no prospective randomized trials on the effects of extended dosing intervals of EPO-α compared with darbepoetin-alpha (DA-α) have been performed. This study was designed to investigate whether a single biweekly (Q2W) administration of a high dose of EPO-α is as effective as DA-α for anemia in chronic kidney disease (CKD) patients not receiving dialysis.
    Full-text · Article · Dec 2014
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