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Vol. 121, No. 3-4, 2012
Issue release date: February 2013
Nephron Clin Pract 2012;121:c95–c101
(DOI:10.1159/000345158)

Treatment of Anaemia with Erythropoiesis-Stimulating Agents in Patients with Chronic Kidney Disease Does Not Lower Mortality and May Increase Cardiovascular Risk: A Meta-Analysis

Vinhas J. · Barreto C. · Assunção J. · Parreira L. · Vaz A.
Department of Nephrology, Centro Hospitalar de Setubal, Setubal, Portugal
email Corresponding Author

Abstract

Background/Aims: Interpretation of the results of earlier meta-analyses in chronic kidney disease (CKD) patients on the impact of anaemia treatment with erythropoiesis-stimulating agents (ESAs) on clinical outcomes has been hampered by the inclusion of small trials and trials of short duration. We re-evaluated the benefits and harms of treating anaemia, including only relevant clinical trials. Methods: We conducted a systematic review and meta-analysis of randomised controlled trials performed in adults with CKD which allocated patients to different doses of ESAs, and we compared the effect of these interventions on vascular access thrombosis, stroke, risk of end-stage renal disease (ESRD) and all-cause mortality. Additional inclusion criteria were studies with a duration of at least 1 year and enrolling more than 500 participants. Results: Five trials (7,902 participants) met the inclusion criteria and were included in the meta-analysis. The number of patients enrolled in each trial ranged from 596 to 4,038. The mean/median duration of follow-up ranged from 14 to 36 months. A higher haemoglobin target was associated with increased risk of vascular access thrombosis (RR 1.343; 95% CI 1.162–1.554; p = 0.0005) and stroke (RR 1.735; 95% CI 1.323–2.275; p = 0.0005), and no effect on risk of ESRD (RR 1.089; 95% CI 0.986–1.203; p = 0.094) or all-cause mortality (RR 1.148; 95% CI 0.977–1.350; p = 0.093). Conclusion: In CKD patients, treatment of anaemia with ESAs targeting a higher haemoglobin value does not lower mortality or reduce the risk of ESRD, and may increase cardiovascular risk.


 Outline


 goto top of outline Key Words

  • Chronic kidney disease
  • Erythropoiesis-stimulating agents
  • Anaemia
  • Meta-analysis

 goto top of outline Abstract

Background/Aims: Interpretation of the results of earlier meta-analyses in chronic kidney disease (CKD) patients on the impact of anaemia treatment with erythropoiesis-stimulating agents (ESAs) on clinical outcomes has been hampered by the inclusion of small trials and trials of short duration. We re-evaluated the benefits and harms of treating anaemia, including only relevant clinical trials. Methods: We conducted a systematic review and meta-analysis of randomised controlled trials performed in adults with CKD which allocated patients to different doses of ESAs, and we compared the effect of these interventions on vascular access thrombosis, stroke, risk of end-stage renal disease (ESRD) and all-cause mortality. Additional inclusion criteria were studies with a duration of at least 1 year and enrolling more than 500 participants. Results: Five trials (7,902 participants) met the inclusion criteria and were included in the meta-analysis. The number of patients enrolled in each trial ranged from 596 to 4,038. The mean/median duration of follow-up ranged from 14 to 36 months. A higher haemoglobin target was associated with increased risk of vascular access thrombosis (RR 1.343; 95% CI 1.162–1.554; p = 0.0005) and stroke (RR 1.735; 95% CI 1.323–2.275; p = 0.0005), and no effect on risk of ESRD (RR 1.089; 95% CI 0.986–1.203; p = 0.094) or all-cause mortality (RR 1.148; 95% CI 0.977–1.350; p = 0.093). Conclusion: In CKD patients, treatment of anaemia with ESAs targeting a higher haemoglobin value does not lower mortality or reduce the risk of ESRD, and may increase cardiovascular risk.

Copyright © 2012 S. Karger AG, Basel


goto top of outline Introduction

Anaemia is a common complication of chronic kidney disease (CKD) and is predominantly the result of deficient erythropoietin production by the kidney. Trials conducted in the mid-eighties in patients undergoing haemodialysis showed that recombinant human erythropoietin replacement therapy increases haemoglobin levels and reduces the need for transfusions.

Cohort-based observational studies and cross-sectional analysis of large medical databases published over the last 20 years have shown that higher haemoglobin values are associated with improved outcomes, including less severe left ventricular hypertrophy [1], and lower risk of stroke [2] and all-cause-mortality [3]. This information has had a strong influence on clinical practice guidelines and physician’s practice patterns [4] all over the world.

However, interventional evidence has been pointing in a different direction for several years now [5,6,7]. For example, the 2009 TREAT study [7] showed that treatment of anaemia with an erythropoiesis-stimulating agent (ESA) in nondialysis-dependent CKD patients with diabetes mellitus type 2 does not reduce the risk for the composite outcome of death or a cardiovascular event.

Earlier meta-analyses involving patients with CKD evaluating the effect of ESAs on clinical outcomes always included small trials enrolling less than 100 patients and of short duration (≤6 months), and therefore the number of some end points (stroke, ESRD, all-cause mortality) in many of these studies is zero or close to zero. It has been shown that studies of mortality rates which use insufficient sample size may bias conclusions. In studies with small sample size the probability of observing one or more deaths is close to zero, and therefore the point estimates of the so-called below-threshold mortality (or of any other end point) are highly inaccurate [8]. Studies of short duration may also bias the results for the same reason. Pooling these studies in a meta-analysis does not improve the accuracy of the estimates. A meta-analysis based on poor papers is a poor meta-analysis.

Thus, in the present meta-analysis we re-evaluated the benefits and harms of treating anaemia with ESAs in patients with CKD, using only relevant randomised controlled trials, defined as trials with duration of at least 1 year and enrolling more than 500 participants.

 

goto top of outline Methods

goto top of outline Search Strategy and Selection Criteria

Studies were considered eligible trials if they met the following inclusion criteria: randomised controlled trials performed in adults, including patients with CKD, which allocated patients to different doses of ESAs targeting two different haemoglobin levels (‘higher’ and ‘lower’), or to ESAs and to placebo, and comparing the effect of these interventions on vascular access thrombosis, stroke, risk of ESRD and all-cause mortality. Additional inclusion criteria were studies with a duration of at least 1 year and enrolling more than 500 participants.

During a preliminary search, a recently published meta-analysis on the same topic was identified [9]. This meta-analysis searched data on Medline (from January 1966 to November 2009), the Cochrane database (to March 2009) and EMBASE (January 1980 to March 2010), and included 27 trials. Although some of the periods searched made no sense to us (erythropoietin only became available in 1989), it was decided to include all the trials included in this meta-analysis and to make additional searches on Medline for the period between January 2009 and January 2012 (therefore including an overlapping period between January and November 2009). All searches included the following keywords: erythropoietin, erythropoiesis stimulating agents, darbepoetin, epoetin, randomised controlled trials, chronic kidney disease and haemodialysis. The search retrieved 603 studies (fig. 1). We supplemented the electronic search by scanning the reference list of relevant publications. Two independent authors evaluated the trials (603 + 27 trials) and screened titles and abstracts to assess eligibility. Articles were classified according to whether they were ‘randomised controlled trials’, were ‘evaluating an intervention with erythropoietin’, had information on the clinical outcomes of interest and were considered ‘relevant’, defined as studies of at least 1 year and enrolling more than 500 participants. Discrepancies were resolved by discussion among all authors. Of a total of 630 abstracts, 625 were excluded because they did not meet the inclusion criteria (fig. 1).

FIG01
Fig. 1. Literature search and selection.

goto top of outline Data Extraction and Quality Assessment

Two authors independently extracted data on patient characteristics, type of ESAs, haemoglobin target, achieved haemoglobin, duration of follow-up and clinical outcomes (tables 1 and 2). Outcomes assessed were vascular access thrombosis, stroke, ESRD and all-cause mortality.

TAB01
Table 1. Patient characteristics at baseline

TAB02
Table 2. Study design and type of intervention of included trials

The risk for bias of the included trials was assessed by two independent authors using standard criteria: the adequacy of randomisation, allocation concealment, blinding of patients, blinding of investigators, blinding of outcome assessors, use of intention-to-treat analysis, loss to follow-up, early stopping of trial, funding source, study chair and design, and Jadad score [10,11]. The quality assessment of included trials and risk for bias are depicted in table 3. The quality of trials, evaluated by current standards, was heterogeneous.

TAB03
Table 3. Quality assessment of included trials and risk for bias

goto top of outline Statistical Analysis

Treatment effects were expressed as risk ratio (RR) with 95% CIs by using the DerSimonian and Laird random effect model. Heterogeneity of treatment effects between trials was assessed with the Cochran’s Q and the I2 statistics [12]. I2 describes the percentage of total variation across studies due to heterogeneity rather than chance. A value of 0% indicates no observed heterogeneity and larger values show increasing heterogeneity [12]. All analysis was performed with the Comprehensive Meta-Analysis Version 2 (Biostat, Englewood, N.J., USA).

 

goto top of outline Results

goto top of outline Search

We identified 5 randomised controlled trials, including 7,904 participants, which met the prespecified criteria [5,6,7,13,14]. The number of patients in each trial ranged from 596 to 4,038. The mean/median duration of follow-up ranged from 14 to 36 months. Patient characteristics and study design and type of intervention of included trials are shown in tables 2 and 3. All studies were conducted in patients with CKD treated with ESAs.

goto top of outline Trial, Participant and Intervention Characteristics, and Clinical Outcomes

Tables 1 and 2 summarise participants, trial and intervention characteristics.

goto top of outline Vascular Access Thrombosis

Two studies, NHT [5] and Parfrey et al. [13], including 1,829 haemodialysis patients, provided data on vascular access thrombosis. The NHT study [5] assigned 618 patients to receive increasing doses of epoetin alfa to achieve and maintain a haematocrit of 42% and assigned 615 to receive doses of epoetin alfa sufficient to maintain a haematocrit of 30% throughout the study. The study period ranged from 4 days to 30 months (median 14 months). The second study, Parfrey et al. [13], assigned 300 patients to receive epoetin alfa to maintain a lower haemoglobin target (9.5–11.5 g/dl) and 296 to receive epoetin alfa to maintain a higher haemoglobin target (13.5–14.5 g/dl). The mean times in the study were 73.4 weeks for the higher and 74.0 weeks for the lower target group.

Meta-analysis (fig. 2) showed that patients randomly assigned to a higher haemoglobin target had a higher risk of vascular access thrombosis than those assigned to a lower haemoglobin target (RR 1.343; 95% CI 1.162–1.554; p = 0.0005). There was no heterogeneity or inconsistency between the trials (χ2 0.483; p = 0.487; I2 0%).

FIG02
Fig. 2. Risk of vascular access thrombosis in the higher compared with lower haemoglobin target.

goto top of outline Stroke

Four studies [5,6,7,14] enrolling 7,306 patients provided data on stroke, with 1,233 patients on haemodialysis (NHT) and 6,073 nondialysis-dependent CKD patients. Three studies were conducted in nondialysis-dependent CKD patients: the first study, CHOIR [6], included 1,432 patients, 715 of whom were assigned to receive doses of epoetin alfa sufficient to maintain a higher haemoglobin target (13.5 g/dl) and 717 of whom were assigned to receive epoetin alfa to maintain a lower haemoglobin target (11.3 g/dl). The mean duration of follow-up was 16 months. The second study, TREAT [7], included 4,038 patients, 2,012 assigned to darbepoetin alfa to achieve a haemoglobin target of 13.0 g/dl and 2,026 assigned to receive placebo, with rescue darbepoetin alfa when the haemoglobin level was less than 9.0 g/dl. The median duration of follow-up was 29.1 months. The last study, CREATE [14], included 603 patients, 301 of whom were assigned to receive doses of epoetin beta to maintain a haemoglobin target between 13.0 and 15.0 g/dl and 302 of whom were assigned to receive epoetin beta to maintain a haemoglobin target between 10.5 and 11.5 g/dl. The mean duration of observation for the primary end point was 3 years.

Meta-analysis (fig. 3) showed patients randomly assigned to a higher haemoglobin target had a higher risk of stroke as compared with those assigned to a lower haemoglobin target or no treatment (RR 1.735; 95% CI 1.323–2.275; p = 0.0005). There was no significant heterogeneity across trials (χ2 2.298; p = 0.513; I2 0%).

FIG03
Fig. 3. Risk of stroke in the higher compared with lower haemoglobin target.

goto top of outline End-Stage Renal Disease

Three studies, CHOIR, TREAT and CREATE [6,7,14], enrolling 6,073 patients provided data on risk of ESRD. Meta-analysis (fig. 4) showed no difference in the effect of ESA on risk of ESRD between patients assigned to a higher haemoglobin target and those assigned to a lower haemoglobin target or no treatment (RR 1.089; 95% CI 0.986–1.203; p = 0.094). There was no significant heterogeneity across trials (χ2 1.221; p = 0.543; I2 0.0%).

FIG04
Fig. 4. Risk of ESRD in the higher compared with lower haemoglobin target.

goto top of outline All-Cause Mortality

Five studies, NHT, CHOIR, TREAT [5,6,7], Parfrey et al. [13] and CREATE [14], including 7,902 patients, 1,829 patients on haemodialysis and 6,073 nondialysis-dependent CKD patients, provided data on all-cause mortality. Meta-analysis (fig. 5) showed no difference in the effect of ESA on all-cause mortality between patients assigned to a higher or a lower (including no treatment) haemoglobin target (RR 1.148; 95% CI 0.977–1.350; p = 0.093). There was no significant heterogeneity across studies (χ2 6.669; p = 0.154), although there was a moderate degree of inconsistency among them (I2 40.0%). Sub-group analysis showed no difference in mortality risk between patients assigned to a higher or a lower haemoglobin target (including no treatment), either in patients undergoing haemodialysis (RR 1.164; 95% CI 0.974–1.391; p = 0.095), or in nondialysis-dependent CKD patients (RR 1.095; 95% CI 0.975–1.229; p = 0.124).

FIG05
Fig. 5. Risk of all-cause mortality in the higher compared with lower haemoglobin target.

 

goto top of outline Discussion

Meta-analysis is a pooling of multiple trials to increase statistical power, often pooling data from randomised trials with small sample size and of short duration. However, the inclusion of trials with small sample size and of short duration evaluating clinical end points such as all-cause mortality often decreases the probability of observing one or more of these end points. When the number of deaths is close to zero, the point estimates of the so-called below-threshold mortality (or of any other end point) are highly inaccurate [8].

The current meta-analysis, pooling 5 randomised controlled trials on treatment of anaemia with ESAs in CKD patients, included only relevant randomised controlled trials with a duration of at least 1 year and enrolling more than 500 participants. The quality of the trials, evaluated by current standards, was heterogeneous.

This meta-analysis showed that, in patients with CKD, treatment of anaemia with ESAs targeting a higher haemoglobin value does not lower mortality or reduce the risk of ESRD, and may increase cardiovascular risk, as compared with targeting a lower haemoglobin value or no treatment.

When, during a preliminary search, we identified a recently published meta-analysis on the same topic [9], we wondered whether a new meta-analysis would add new knowledge to the literature. However, our aim was to perform a meta-analysis including only relevant clinical trials, therefore avoiding the potential bias of including studies with zero or close to zero end points. The meta-analysis of Palmer et al. [9] included 27 randomised controlled trials, many of which had a ‘below threshold’ number of end points. Additionally, some of the point estimates in this recent meta-analysis were calculated using inappropriate populations at risk: calculations of risk of vascular access thrombosis were performed including studies that enrolled nondialysis-dependent CKD patients, where most of the patients did not have a vascular access in place, and therefore the risk was largely underestimated.

Furthermore, when analysing the risk of stroke, the meta-analysis of Palmer et al. [9] did not include data from the CREATE trial [14], which included information on the number of cerebrovascular accidents and transient ischemic attacks. Therefore, selection bias is an issue in that meta-analysis. Finally, the inclusion of small trials in that meta-analysis meant that, by current standards, trial quality was sub-optimal.

Nonetheless, despite these methodological problems, the results of the Palmer et al. [9] meta-analysis were quite similar to those of the present meta-analysis: higher haemoglobin targets (haemoglobin between 13.0 and 15.0 g/dl) were associated with increased risk of stroke and vascular access thrombosis, and no effect on risk either of ESRD or all-cause mortality, as compared with lower haemoglobin targets (haemoglobin between 9.5 and 11.5 g/dl) or no treatment.

While the interpretation of earlier systematic reviews and meta-analyses of randomised trials has been hampered by the inclusion of small trials and trials of short duration that could potentially bias the results, this problem has been overcome in our meta-analysis by only including relevant clinical trials. Our findings have obvious implications for clinical decision making and should influence future clinical practice patterns.

However, our meta-analysis has some limitations. First, issues related to study design, namely the open label design of some of the trials, could be relevant to the internal validity of those studies, and therefore, of this meta-analysis. Second, pooling of trials enrolling patients undergoing haemodialysis with trials that included nondialysis-dependent CKD patients could be a source of bias. However, when nondialysis-dependent CKD patients and haemodialysis patients were analysed separately, the results of sub-group analysis were concordant with the global results, as far as all-cause mortality is concerned.

The TREAT study has shown that treatment of anaemia with an ESA in nondialysis-dependent CKD patients with diabetes does not reduce the risk of either the combined primary end point of death or a cardiovascular event, or of death or a renal event, and is only associated with a modest improvement in patient-reported fatigue [7]. Additionally, this meta-analysis shows that treatment of anaemia in the CKD population with ESAs targeting a higher haemoglobin level does not reduce the risk of either ESRD or all-cause mortality, and is potentially harmful to patients, as compared with targeting a lower haemoglobin level or no treatment.

The studies included in this meta-analysis show that the availability of ESA did not eliminate the need for red cell transfusion, even when high haemoglobin values are targeted (13.0–15.0 g/dl). Therefore, in anaemia management in CKD patients, there is more than ESA therapy to consider. It is noteworthy that red cell transfusion rates in these studies showed a huge variability within low as well as within high haemoglobin target groups (data not shown). However, in nondialysis-dependent CKD patients, low haemoglobin target groups showed an increase in the red cell transfusion rate of 23.3% [14] and 96.6% [7], as compared with high haemoglobin target groups. In haemodialysis patients, low haemoglobin target groups showed an increase in red cell transfusion rate of 50.0% [5] and 253.0% [13], as compared with high haemoglobin target groups (data not shown).

However, there is more to life than red cell transfusion. When weighing risk and benefit, patients and physicians alike will probably give more weight to stroke and VA thrombosis when balancing between the risk of these events and that of red cell transfusion. Therefore, in patients with CKD, physicians should carefully consider when to start as well as when to interrupt treatment with an ESA, bearing in mind that the primary goal of treatment is to decrease the need for blood transfusions, and that treatment may be associated with increased risk for serious cardiovascular events. When beginning an ESA, physicians should actively monitor haemoglobin concentration, bearing in mind the goals and risks of this therapy. In each case, physicians should discuss with their patients the potential benefits and harms of the treatment. Choosing between these options requires nuanced individualized judgment, and in the end, it is up to patients to decide.

 

goto top of outline Disclosure Statement

José Vinhas has received consultancy fees from Abbott, Amgen, F. Hoffmann-La Roche, Janssen-Cilag and NephroCare. He has received speaker’s honoraria from Amgen, F. Hoffmann-La Roche and Renal Pharma. All other authors declare no conflicts of interest.


 goto top of outline References
  1. Levin A, Thompson CR, Ethier J, et al: Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. Am J Kidney Dis 1999;34:125–134.
  2. Abramson JL, Jurkovitz CT, Vaccarino V, et al: Chronic kidney disease, anemia, and incident stroke in a middle-aged, community-based population: the ARIC Study. Kidney Int 2003;64:610–615.
  3. Pisoni RL, Bragg-Gresham JL, Young EW, et al: Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2004;44:94–111.
  4. KDOQI, National Kidney Foundation: KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 2006;47(suppl 3):S1–S85.
  5. Besarab A, Bolton WK, Browne JK, et al: The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998;339:584–590.
  6. Singh AK, Szczech L, Tang KL, et al: Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085–2089.
  7. Pfeffer MA, Burdmann EA, Chen CY, et al: A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019–2032.
  8. Promislow DEL, Tatar M, Pletcher S, Carey JR: Below-threshold mortality: implications for studies in evolution, ecology and demography. J Evol Biol 1999;12:314–328.
  9. Palmer SC, Navaneethan SD, Craig JC, et al: Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. Ann Intern Med 2010;153:23–33.
  10. Schulz KF, Chalmers I, Hayes RJ, Altman DG: Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408–412.
  11. Higgins JP, Green S (eds): Cochrane Handbook for Systematic Reviews of Interventions, version 5.0.2. The Cochrane Collaboration, 2009. Available from www.cochrane-handbook.org.
  12. Higgins JPT, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analysis. BMJ 2003;327:557–560.
  13. Parfrey PS, Foley RN, Wittreich BH, et al: Double-blind comparison of full and partial anemia correction in incident haemodialysis patients without symptomatic heart disease. J Am Soc Nephrol 2005;16:2180–2189.
  14. Drüeke TB, Locatelli F, Clyne N, Eckardt KU, et al: Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355:2071–2084.

 goto top of outline Author Contacts

J. Vinhas, MD
Centro Hospitalar de Setubal
Rua Camilo Castelo Branco
PR–2910-446 Setubal (Portugal)
E-Mail jose.m.vinhas@gmail.com


 goto top of outline Article Information

Received: July 10, 2012
Accepted: October 6, 2012
Published online: November 22, 2012
Number of Print Pages : 7
Number of Figures : 5, Number of Tables : 3, Number of References : 14


 goto top of outline Publication Details

Nephron Clinical Practice

Vol. 121, No. 3-4, Year 2012 (Cover Date: February 2013)

Journal Editor: McIntyre C. (Derby)
ISSN: 1660-2110 (Print), eISSN: 1660-2110 (Online)

For additional information: http://www.karger.com/NEC


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background/Aims: Interpretation of the results of earlier meta-analyses in chronic kidney disease (CKD) patients on the impact of anaemia treatment with erythropoiesis-stimulating agents (ESAs) on clinical outcomes has been hampered by the inclusion of small trials and trials of short duration. We re-evaluated the benefits and harms of treating anaemia, including only relevant clinical trials. Methods: We conducted a systematic review and meta-analysis of randomised controlled trials performed in adults with CKD which allocated patients to different doses of ESAs, and we compared the effect of these interventions on vascular access thrombosis, stroke, risk of end-stage renal disease (ESRD) and all-cause mortality. Additional inclusion criteria were studies with a duration of at least 1 year and enrolling more than 500 participants. Results: Five trials (7,902 participants) met the inclusion criteria and were included in the meta-analysis. The number of patients enrolled in each trial ranged from 596 to 4,038. The mean/median duration of follow-up ranged from 14 to 36 months. A higher haemoglobin target was associated with increased risk of vascular access thrombosis (RR 1.343; 95% CI 1.162–1.554; p = 0.0005) and stroke (RR 1.735; 95% CI 1.323–2.275; p = 0.0005), and no effect on risk of ESRD (RR 1.089; 95% CI 0.986–1.203; p = 0.094) or all-cause mortality (RR 1.148; 95% CI 0.977–1.350; p = 0.093). Conclusion: In CKD patients, treatment of anaemia with ESAs targeting a higher haemoglobin value does not lower mortality or reduce the risk of ESRD, and may increase cardiovascular risk.



 goto top of outline Author Contacts

J. Vinhas, MD
Centro Hospitalar de Setubal
Rua Camilo Castelo Branco
PR–2910-446 Setubal (Portugal)
E-Mail jose.m.vinhas@gmail.com


 goto top of outline Article Information

Received: July 10, 2012
Accepted: October 6, 2012
Published online: November 22, 2012
Number of Print Pages : 7
Number of Figures : 5, Number of Tables : 3, Number of References : 14


 goto top of outline Publication Details

Nephron Clinical Practice

Vol. 121, No. 3-4, Year 2012 (Cover Date: February 2013)

Journal Editor: McIntyre C. (Derby)
ISSN: 1660-2110 (Print), eISSN: 1660-2110 (Online)

For additional information: http://www.karger.com/NEC


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Levin A, Thompson CR, Ethier J, et al: Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. Am J Kidney Dis 1999;34:125–134.
  2. Abramson JL, Jurkovitz CT, Vaccarino V, et al: Chronic kidney disease, anemia, and incident stroke in a middle-aged, community-based population: the ARIC Study. Kidney Int 2003;64:610–615.
  3. Pisoni RL, Bragg-Gresham JL, Young EW, et al: Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2004;44:94–111.
  4. KDOQI, National Kidney Foundation: KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 2006;47(suppl 3):S1–S85.
  5. Besarab A, Bolton WK, Browne JK, et al: The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998;339:584–590.
  6. Singh AK, Szczech L, Tang KL, et al: Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085–2089.
  7. Pfeffer MA, Burdmann EA, Chen CY, et al: A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019–2032.
  8. Promislow DEL, Tatar M, Pletcher S, Carey JR: Below-threshold mortality: implications for studies in evolution, ecology and demography. J Evol Biol 1999;12:314–328.
  9. Palmer SC, Navaneethan SD, Craig JC, et al: Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. Ann Intern Med 2010;153:23–33.
  10. Schulz KF, Chalmers I, Hayes RJ, Altman DG: Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408–412.
  11. Higgins JP, Green S (eds): Cochrane Handbook for Systematic Reviews of Interventions, version 5.0.2. The Cochrane Collaboration, 2009. Available from www.cochrane-handbook.org.
  12. Higgins JPT, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analysis. BMJ 2003;327:557–560.
  13. Parfrey PS, Foley RN, Wittreich BH, et al: Double-blind comparison of full and partial anemia correction in incident haemodialysis patients without symptomatic heart disease. J Am Soc Nephrol 2005;16:2180–2189.
  14. Drüeke TB, Locatelli F, Clyne N, Eckardt KU, et al: Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355:2071–2084.