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Meta-analysis: Erythropoiesis-Stimulating Agents in Patients With Chronic Kidney Disease FREE

Suetonia C. Palmer, MBChB; Sankar D. Navaneethan, MD, MPH; Jonathan C. Craig, MBChB, DCH, MM, PhD; David W. Johnson, MBChB(Hons), PhD; Marcello Tonelli, MD, SM; Amit X. Garg, MD, PhD; Fabio Pellegrini, MSc; Pietro Ravani, MD, MSc, PhD; Meg Jardine, MBBS, PhD; Vlado Perkovic, MBBS, PhD; Giusi Graziano, PhD; Richard McGee, BMedSci, MBBCh, MM; Antonio Nicolucci, MD; Gianni Tognoni, MD; and Giovanni F.M. Strippoli, MD, PhD, MPH, MM
[+] Article and Author Information

From the University of Otago, Christchurch, New Zealand; Cleveland Clinic, Cleveland, Ohio; University of Sydney and George Institute for International Health, Sydney, and University of Queensland at Princess Alexandra Hospital, Brisbane, Australia; University of Alberta, Edmonton, and University of Calgary, Calgary, Alberta, Canada; University of Western Ontario, London, Ontario, Canada; Mario Negri Sud Consortium, Santa Maria Imbaro, Italy; Scientific Institute Casa Sollievo della Sofferenza, Foggia, Italy; and Diaverum, Lund, Sweden.


Acknowledgment: The authors acknowledge the help of Ruth Mitchell, Trial Search Coordinator, and Narelle Willis, Managing Director, from the Cochrane Renal Group.

Potential Conflicts of Interest: Dr. Johnson: Consultancies: Amgen, Roche, Janssen-Cilag, Sandoz; Grants/grants pending, honoraria, and travel/accommodations expenses covered or reimbursed: Amgen, Roche, Janssen-Cilag; Payment for development of educational presentations including service on speakers' bureaus: Amgen, Janssen-Cilag. Dr. Tonelli: Grants/grants pending (money to institution): Amgen. Dr. Garg: Other: Ortho Biotech funds a research scholarship (unrestricted educational grant) at the University of Western Ontario that provides partial salary support to physicians pursuing additional years of research training; Dr. Tonelli has supervised some of these research projects. Dr. Jardine: Grants received (money to institution): Royal Australasian College of Physicians Servier Staff Postdoctoral Fellowship. Dr. Perkovic: Grants/grants pending (money to institution): Australian National Health and Medical Research Council Project Grants, Baxter, Johnson & Johnson, Novartis, Roche, Servier, Amgen; Honoraria: Abbott, AstraZeneca, Roche, Servier. Dr. Strippoli: Grants/grants pending (money to institution): Italian Agency for Drugs (independent research funding body for CEDOSE [Clinical Evaluation of the Dose of Erythropoietins], independently funded by Agenzia Italiana del Farmaco). Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-0120.

Reproducible Research Statement:Study protocol, statistical code, and data set: Available from Dr. Strippoli (e-mail, strippoli@negrisud.it).

Requests for Single Reprints: Giovanni F.M. Strippoli, MD, PhD, MPH, MM, Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud and Diaverum Medical Scientific Office, Via Nazionale 8/a, 66030 S. Maria Imbaro, Italy; e-mail, strippoli@negrisud.it.

Current Author Addresses: Dr. Palmer: Renal Division, Brigham and Women's Hospital, Harvard Institute of Medicine, Room 550, 4 Blackfan Circle, Boston, MA 02215.

Dr. Navaneethan: Cleveland Clinic Main Campus, Mail Code Q7, 9500 Euclid Avenue, Cleveland, OH 44195.

Drs. Craig and McGee: Centre for Kidney Research, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia.

Dr. Johnson: Department of Renal Medicine, Level 2, Ambulatory Renal and Transplant Services Building, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Queensland 4102, Australia.

Dr. Tonelli: University of Alberta, Department of Medicine, Division of Nephrology and Immunology, Clinical Sciences Building 7-129, Edmonton, Alberta T6G 2G3, Canada.

Dr. Garg: Department of Medicine and Epidemiology, University of Western Ontario and Division of Nephrology, London Health Sciences Centre, Room ELL-101, Westminster Tower, 800 Commissioners Road East, London, Ontario N6A 4G5, Canada.

Mr. Pellegrini and Drs. Graziano, Nicolucci, Tognoni, and Strippoli: Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, Via Nazionale 8/A, 66030 S. Maria Imbaro (Chieti), Italy.

Dr. Ravani: Department of Community Health Sciences, Faculty of Medicine, University of Calgary, TRW Building, 3rd Floor, 3280 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.

Drs. Jardine and Perkovic: The George Institute for International Health, PO Box M201 Missenden Road, Sydney, Camperdown, New South Wales 2070, Australia.

Author Contributions: Conception and design: S.C. Palmer, S.D. Navaneethan, J.C. Craig, D.W. Johnson, G.F.M. Strippoli.

Analysis and interpretation of the data: S.C. Palmer, S.D. Navaneethan, J.C. Craig, D.W. Johnson, M. Tonelli, A.X. Garg, F. Pellegrini, P. Ravani, M. Jardine, G. Graziano, R. McGee, A. Nicolucci, G.F.M. Strippoli.

Drafting of the article: S.C. Palmer, S.D. Navaneethan, J.C. Craig, D.W. Johnson, V. Perkovic, R. McGee, G.F.M. Strippoli.

Critical revision of the article for important intellectual content: S.C. Palmer, S.D. Navaneethan, J.C. Craig, D.W. Johnson, M. Tonelli, A.X. Garg, F. Pellegrini, P. Ravani, M. Jardine, V. Perkovic, A. Nicolucci, G. Tognoni, G.F.M. Strippoli.

Final approval of the article: S.C. Palmer, S.D. Navaneethan, J.C. Craig, D.W. Johnson, M. Tonelli, A.X. Garg, F. Pellegrini, P. Ravani, M. Jardine, V. Perkovic, R. McGee, A. Nicolucci, G. Tognoni, G.F.M. Strippoli.

Provision of study materials or patients: G.F.M. Strippoli.

Statistical expertise: J.C. Craig, D.W. Johnson, F. Pellegrini, G. Graziano, R. McGee, G.F.M. Strippoli.

Administrative, technical, or logistic support: G. Tognoni.

Collection and assembly of data: S.C. Palmer, S.D. Navaneethan, F. Pellegrini, G.F.M. Strippoli.


Ann Intern Med. 2010;153(1):23-33. doi:10.7326/0003-4819-153-1-201007060-00252
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Background: Previous meta-analyses suggest that treatment with erythropoiesis-stimulating agents (ESAs) in chronic kidney disease (CKD) increases the risk for death. Additional randomized trials have been recently completed.

Purpose: To summarize the effects of ESA treatment on clinical outcomes in patients with anemia and CKD.

Data Sources: MEDLINE (January 1966 to November 2009), EMBASE (January 1980 to November 2009), and the Cochrane database (to March 2010) were searched without language restriction.

Study Selection: Two authors independently screened reports to identify randomized trials evaluating ESA treatment in people with CKD. Hemoglobin target trials or trials of ESA versus no treatment or placebo were included.

Data Extraction: Two authors independently extracted data on patient characteristics, study risks for bias, and the effects of ESA therapy.

Data Synthesis: 27 trials (10 452 patients) were identified. A higher hemoglobin target was associated with increased risks for stroke (relative risk [RR], 1.51 [95% CI, 1.03 to 2.21]), hypertension (RR, 1.67 [CI, 1.31 to 2.12]), and vascular access thrombosis (RR, 1.33 [CI, 1.16 to 1.53]) compared with a lower hemoglobin target. No statistically significant differences in the risks for mortality (RR, 1.09 [CI, 0.99 to 1.20]), serious cardiovascular events (RR, 1.15 [CI, 0.98 to 1.33]), or end-stage kidney disease (RR, 1.08 [CI, 0.97 to 1.20]) were observed, although point estimates favored a lower hemoglobin target. Treatment effects were consistent across subgroups, including all stages of CKD.

Limitations: The evidence for effects on quality of life was limited by selective reporting. Trials also reported insufficient information to allow analysis of the independent effects of ESA dose on clinical outcomes.

Conclusion: Targeting higher hemoglobin levels in CKD increases risks for stroke, hypertension, and vascular access thrombosis and probably increases risks for death, serious cardiovascular events, and end-stage renal disease. The mechanisms for harm remain unclear, and meta-analysis of individual-patient data and trials on fixed ESA doses are recommended to elucidate these mechanisms.

Primary Funding Source: None.

Editors' Notes
Context

  • Recent studies suggest that treating anemia of chronic kidney disease can sometimes cause harm.

Contribution

  • This review compiles 27 randomized trials of erythropoiesis-stimulating agents (ESAs) in patients with anemia and chronic kidney disease. Treatment with ESAs that resulted in higher hemoglobin levels increased risks for stroke, worsening hypertension, and vascular access thrombosis more than strategies that resulted in lower hemoglobin levels (placebo, no treatment, or lower ESA dose). Effects on all-cause mortality, cardiovascular events, and quality of life were unclear.

Caution

  • Underlying mechanisms for harms were not established.

Implication

  • Therapy with ESAs that targets high hemoglobin levels is harmful for patients with chronic kidney disease.

—The Editors

Anemia frequently complicates chronic kidney disease (CKD) (1), in part because of deficient renal erythropoietin release (2). Phase 1 and 2 clinical trials first evaluated recombinant human erythropoietin replacement therapy in 1986 and 1987 in patients receiving hemodialysis. These trials demonstrated dose-dependent increases in hemoglobin levels and avoidance of red blood cell transfusions (36), but they also reported incidence of hypertension and vascular thrombosis (3, 56). Subsequent randomized, placebo-controlled trials (716) concluded that erythropoietin treatment was associated with some improvement in quality of life at the expense of increased risk for hypertension and vascular thrombosis. From 1998 until 2009, all randomized trials compared 2 active erythropoiesis-stimulating agent (ESA) regimens to achieve higher and lower hemoglobin targets.

An earlier meta-analysis of 9 randomized trials involving 5143 patients with CKD concluded that targeting a higher hemoglobin concentration (typically 120 to 150 g/L) versus a lower concentration (95 to 115 g/L) was associated with an increased risk for all-cause mortality, arteriovenous access thrombosis, and hypertension (17). Since then, a large placebo-controlled trial of darbepoetin in patients with diabetes mellitus and CKD (TREAT [Trial to Reduce Cardiovascular Events with Aranesp Therapy]) has been completed (18).

In this present systematic review, we summarize the benefits and harms of treating anemia with an ESA and included data from all existing randomized trials. Using cumulative meta-analysis, we explore when the beneficial and harmful effects of ESA treatment and hemoglobin targets first became evident.

We followed a prespecified and peer-reviewed study protocol (19) and substantively updated a previous review and added multiple additional analyses, including a cumulative meta-analysis.

Data Sources and Searches

Two independent authors searched MEDLINE (January 1966 to November 2009) and EMBASE (1980 to November 2009) by using optimally sensitive search strategies developed by the Cochrane Collaboration. They also searched the Cochrane Renal Group trial register and the Cochrane Central Register of Controlled Trials for randomized, controlled trials to November 2009. The Cochrane search was updated to March 2010. Appendix Table 1 includes the full search strategies. Two authors identified eligible trials according to the inclusion criteria and without language restriction. They resolved any disagreements by discussion with an arbitrator.

Table Jump PlaceholderAppendix Table 1.  Search Strategy
Study Selection

We included randomized, controlled trials of at least 3 months' duration that allocated patients to ESA versus placebo, no treatment, or different ESA doses to achieve a higher hemoglobin target versus a lower hemoglobin target. Trials of erythropoietin-alfa or -beta, darbepoetin, or a continuous erythropoietin receptor activator at any dose and route of administration were eligible. We assumed that placebo-controlled trials were comparing 2 treatment targets for hemoglobin, although explicit targets were not always described. Trials of populations with any stage of CKD were included.

Data Extraction and Quality Assessment

Two authors independently extracted data on characteristics of the participants, interventions, and clinical outcomes. Both reviewers also assessed the risks for bias in trials according to standard criteria (allocation concealment, blinding of patients, investigators and outcome assessors, completeness to follow-up, and use of intention-to-treat analysis) (20). The reviewers resolved any discrepancies in data extraction by discussion with an arbitrator.

Data Synthesis and Statistical Analysis

We summarized treatment effects as relative risks (RRs) for dichotomous outcomes or mean differences for continuous outcomes with 95% CIs by using the DerSimonian and Laird random-effects model to pool data. We tested for heterogeneity of treatment effects between studies with the Cochran Q and the I2 statistics (21). In cumulative meta-analysis, outcomes were accrued according to the year of publication. Through subgroup analysis and univariate random-effects meta-regression analysis, we investigated the impact of the following plausible effect modifiers on outcomes: stage of CKD (stage 2 to 5 not requiring dialysis vs. stage 5 requiring dialysis); trial design (ESA vs. ESA or ESA vs. placebo or no treatment); baseline hemoglobin concentration; age; proportion of trial participants with diabetes mellitus, hypertension, or cardiovascular disease; baseline blood pressure; duration of administration of the intervention (<6 months, 6 to 12 months, 12 to 24 months, or >24 months); blinding of patients, investigators, or outcome assessors; intention-to-treat analysis; study attrition (≥10% or <10%); and number of trial participants (0 to 100, 101 to 500, or >500). Earlier studies tended to have very low event rates in 1 or both study groups. Our primary analyses used the standard continuity correction of 0.05 to estimate the RR for these trials. We also conducted a sensitivity analysis by using continuity corrections of 0.0001, 0.001, and 0.01 to evaluate the robustness of our results. We found no changes for the point estimates for treatment effects or their 95% CIs. All analyses were conducted with SAS, release 9.1 (SAS Institute, Cary, North Carolina).

Role of the Funding Source

No specific funding was received for any aspect of this study. All authors had full access to the study data and had final responsibility for the decision to submit the manuscript for publication.

We identified 27 randomized trials (10 452 participants) that met the inclusion criteria (Appendix Figure). All were randomized, controlled trials that enrolled patients with CKD for treatment with ESA. The study design changed over time from smaller placebo-controlled trials with relatively lower hemoglobin targets to larger active comparator trials with higher hemoglobin targets. This change occurred around 1998, after about a decade of randomized trial research. It was heralded by the publication of a large trial (1233 patients) by Besarab and colleagues (22) conducted in patients with end-stage kidney disease requiring hemodialysis for renal replacement therapy. Between 1989 and 1998, all 10 available trials enrolled fewer than 160 patients (median, 55 patients; interquartile range [IQR], 13 to 94 patients) (716). From 1998 onward, trials were larger (median number of participants, 172; IQR, 91 to 600), and 3 trials included more than 1000 patients (18, 2223). Earlier studies were conducted both in patients requiring dialysis and in those with earlier stages of CKD. After 2003, all but 1 (24) of 11 studies were performed in patients with moderate to severe CKD (estimated glomerular filtration rate ranged from 15 to 79 mL/min per 1.73 m2).

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Appendix Figure.
Literature search and selection.

CENTRAL = Cochrane Central Register of Controlled Trials; RRT = renal replacement therapy.

* Numbers do not sum to 1637 because some articles were identified by more than 1 search.

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The treatment comparisons in the identified trials were either ESA (erythropoietin-alfa or -beta or darbepoetin) versus placebo or no treatment or different doses of ESA therapy as needed to achieve 2 (higher vs. lower) hemoglobin target levels. Doses of ESA used in the trials were not available in one third of the study reports (Appendix Table 2). Studies published before 1998 were all placebo-controlled (716), whereas trials published from 1998 until 2009 compared 2 different doses of ESA therapy (18, 2237). The exception to this more recent trend of active comparator trials was the largest study to date, published in 2009, which was again placebo-controlled (18).

Table Jump PlaceholderAppendix Table 2.  Baseline Characteristics of Participants in Trials of Hemoglobin Targets in People With CKD

Trials completed before 1998 targeted a lower hemoglobin level in the high hemoglobin versus active ESA treatment groups than that of trials published later. With the exception of a trial of 14 patients with hemoglobin level targets between 126 and 133 g/L (10), the remaining smaller trials before 1998 had higher hemoglobin targets between 95 and 120 g/L (79, 12, 14). Trials from 1998 to 2008, all using ESA as the active comparator, had higher hemoglobin targets between 120 to 150 g/L versus lower targets between 90 to 120 g/L (2237). In the more recent trials, the lower hemoglobin target range was similar to the higher range in older trials. In all trials, the median hemoglobin target achieved by treatment in the high hemoglobin groups was 130 g/L (IQR, 120 to 140 g/L) (1011, 16, 22, 2426, 28, 3133, 36); the corresponding value in the low hemoglobin target groups was 101 g/L (IQR, 92 to 110 g/L) (11, 14, 16, 22, 2426, 28, 3133, 36).

Most studies enrolled participants between 50 and 60 years of age on average. In the 3 largest trials of more than 1000 patients each, patients were generally older than 60 years (18, 2223). Two small studies were conducted in children (12, 26). We identified 3 trials (1413 patients) that included only patients with established cardiovascular disease (22, 25, 30) and 2 trials (4210 patients) that included only patients with diabetes mellitus and CKD (18, 35). Appendix Tables 2 and 3 summarize the characteristics of all trials included in our analysis.

Table Jump PlaceholderAppendix Table 3.  Characteristics of Interventions in Trials of Hemoglobin Targets in People With Chronic Kidney Disease

By current methods standards, trial quality was suboptimal. In addition, many trials were not reported according to the CONSORT (Consolidated Standards of Reporting Trials) statement (Figure 1) (3839). None of the 27 trials reported the details of allocation concealment (the method by which the person responsible for treatment allocation is made unaware of a participant's treatment assignment). Twelve of 16 trials published before 2004 did not conduct analysis by the intention-to-treat principle, whereas all but 1 of 11 trials from 2004 onward analyzed data according to randomized treatment allocation. Study attrition was higher in studies before 1998 (median, 15%; IQR, 2 to 32%) than in studies from 1998 onward (median, 2%; IQR, 0 to 9%). Larger trials that explored major patient-level outcomes (all-cause mortality or major adverse cardiovascular events) were generally of better methodological quality.

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Figure 1.
Risks for bias in included studies.

We assessed study risk for bias according to recommendations from the Cochrane Collaboration (20).

* Whether the study reported methods to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been predicted in advance of patient enrollment.

† Methods by which patients, investigators, or outcomes assessors are protected from being aware of the treatment allocations after patients are included in the study.

‡ Whether the study conducted the major analyses according to the patients' treatment assignment at the time of randomization.

§ Whether the study described the completeness of outcome data for the primary outcomes.

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Meta-analysis

Risks for fatal and nonfatal stroke, vascular access thrombosis, and worsening hypertension were increased with a higher hemoglobin target than with a lower hemoglobin target (Figure 2). Important heterogeneity among trials for hypertension findings was explored through meta-regression. Patients randomly assigned to a higher hemoglobin target were less likely to require a blood transfusion (8 trials; 6482 patients) (RR, 0.61 [95% CI, 0.49 to 0.77]) (8, 10, 14, 18, 22, 26, 29, 37) but were more likely to receive intravenous iron therapy (6 trials; 2283 patients) (RR, 1.57 [CI, 1.13 to 2.20]) (7, 13, 22, 24, 31, 33). Heterogeneity in the analysis for iron treatment (heterogeneity chi-square = 21.38; P < 0.001) was possibly due to more frequent use of iron supplementation in older, placebo-controlled trials.

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Figure 2.
Meta-analysis of randomized trials comparing higher versus lower hemoglobin targets on clinical outcomes in patients with chronic kidney disease.
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Figure 2—
Continued

ACORD = Anemia Correction in Diabetes; EPO = erythropoietin; CHOIR = Correction of Hemoglobin and Outcomes in Renal Insufficiency; CREATE = Cardiovascular Risk Reduction in Early Anemia Treatment with Epoetin Beta; NHS = Normal Hematocrit Study; TREAT = Trial to Reduce Cardiovascular Events with Aranesp Therapy.

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We found no statistically significant difference in the risk for all-cause mortality, serious cardiovascular events, or fatal and nonfatal myocardial infarction between a higher hemoglobin target and a lower target (Figure 2). In the 10 studies conducted in people with CKD who were not dialysis-dependent, the risk for end-stage kidney disease requiring renal replacement therapy did not statistically significantly differ when hemoglobin target groups were compared (Figure 2). We also found no statistically significant differences between treatment groups in left ventricular mass at the end of treatment (4 trials; 1544 patients; mean difference, 0.14 g/m2 [CI, −4.60 to 4.88 g/m2]) (24, 3436).

We rated the evidence for treatment effects on quality of life to be of low quality, with high risks for bias due to selective reporting of outcomes. Appendix Table 4 summarizes the quality-of-life data reported in 15 trials. The Short Form-36 Health Survey (SF-36) was the most commonly used tool for assessment of quality of life, reported in 9 trials (18, 2224, 2930, 3537). The SF-36 assesses 8 domains: limitation of physical activity, social function, physical role, bodily pain, mental health, emotional role, vitality, and general health perception. Of importance, only 2 trials reported treatment effects on quality of life for all 8 of the SF-36 outcome domains (23, 37) and only 1 trial (7) reported treatment effects on utility. The most recent, large, and well-designed trial reported no differences in mean change in scores between groups for energy or physical function quality-of-life domains.

Table Jump PlaceholderAppendix Table 4.  Summary of Quality-of-Life Outcomes
Cumulative Meta-analysis

We performed a cumulative meta-analysis to identify when evidence for the benefits and harms of ESA therapy first became evident. Collectively, small placebo-controlled trials conducted before 1998 showed effect estimates favoring a higher hemoglobin target for all-cause mortality, serious cardiovascular events, and nonfatal and fatal stroke (Figure 3), whereas larger, active comparator trials with higher hemoglobin targets conducted from 1998 onward favored a lower hemoglobin target and showed risk for harm when targeting higher values. Specifically, when the first trial to include more than 1000 patients was completed in 1998 (22), cumulative evidence for a probable increased risk for death with a higher hemoglobin target became apparent. Across the following decade, the accrual of 12 further trials with 8233 additional patients and 1063 events did not materially influence the point estimates or confidence intervals for excess mortality that were first identified in 1998.

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Figure 3.
Cumulative meta-analysis of randomized trials comparing higher versus lower hemoglobin targets on clinical outcomes in patients with chronic kidney disease.
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Figure 3—
Continued

ACORD = Anemia Correction in Diabetes; EPO = erythropoietin; CHOIR = Correction of Hemoglobin and Outcomes in Renal Insufficiency; CREATE = Cardiovascular Risk Reduction in Early Anemia Treatment with Epoetin Beta; NHS = Normal Hematocrit Study; TREAT = Trial to Reduce Cardiovascular Events with Aranesp Therapy.

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A probable increased risk for serious cardiovascular events with a higher hemoglobin target was evident in 2006 after trials had randomly assigned 2670 patients (433 events), and this risk remained consistent across subsequent trials that enrolled 4210 patients with 1245 additional events. A probable increase in the risk for stroke with ESA treatment to a higher hemoglobin target was first indicated in 1998 and was confirmed by the placebo-controlled trial by Pfeffer and colleagues (18). Evidence for increased risks for worsening hypertension and vascular access thrombosis with a higher hemoglobin target was evident from trials conducted in 1990, with point estimates unchanged and increased precision for treatment effects available for these outcomes over time.

Investigation for Sources of Heterogeneity

We conducted subgroup analyses and univariate meta-regression to explore trial-level factors (patients, intervention, and design) that may affect the risks for all-cause mortality, worsening hypertension, and stroke (fatal and nonfatal) (Appendix Table 5). When the 2 primary trial designs were compared (placebo-controlled vs. active ESA comparator), the treatment comparison did not influence the risk for all-cause mortality or stroke. The stage of kidney disease (dialysis vs. predialysis) was not an effect modifier for any of the examined outcomes, suggesting that the findings of this meta-analysis may be generalized to any stage of CKD. When we explored the reasons for heterogeneity in the risk for worsening hypertension, we found a lower risk with a higher hemoglobin target in longer trials, trials with more participants, and trials where adjudication of outcomes was not blinded. As the prescribed ESA dose and the hemoglobin level achieved were inconsistently reported across trials (as seen in Appendix Table 2), we could not further explore the possible role of these factors on the risk for any outcome.

Table Jump PlaceholderAppendix Table 5.  Subgroup and Meta-regression Analysis Exploring the Role of Trial, Participant, or Intervention Characteristics in Trials Comparing High Versus Low Hemoglobin Targets on Risks for Mortality, Hypertension, and Stroke in People With CKD

We found that treatment with either erythropoietin or darbepoetin to higher target hemoglobin levels in patients with CKD (any stage) increased the risk for stroke, worsening hypertension, and vascular access thrombosis, compared with treatment to a lower hemoglobin target. We found no statistically significant differences between higher and lower hemoglobin targets for the risk for all-cause mortality, serious cardiovascular events, or end-stage kidney disease, but point estimates for all outcomes favored a lower hemoglobin target and effectively excluded the likelihood of any clinically relevant benefit for a higher hemoglobin target. Targeting a higher hemoglobin level was linked to a reduction in need for red blood cell transfusions but greater prescription of intravenous iron therapy. We identified no clinically important effects of ESA therapy on quality of life.

Cumulative meta-analysis demonstrated that evidence for harm associated with ESA therapy to achieve higher hemoglobin targets has remained stable since it became apparent in 1998. Before 1998, small placebo-controlled trials with relatively lower hemoglobin targets suggested that adverse clinical outcomes in CKD might be prevented with partial anemia correction compared with no treatment. In these earliest studies, ESA therapy alleviated the need for red blood cell transfusions, and therefore the need to test erythropoietin against placebo in a large trial was not advocated until more recently. A switch to larger trials in 1998 targeting higher hemoglobin values unexpectedly demonstrated that these higher hemoglobin targets were harmful. Addition of 12 further trials after 1998 did not alter the probable increased risks for mortality that was first identified by Besarab and colleagues (22), although the trials supporting this conclusion all compared 2 different doses of ESA therapy. A placebo-controlled trial of ESA therapy was conducted (TREAT [18]). Now completed, this large trial tested whether treatment with darbepoetin to achieve a hemoglobin target of about 130 g/L would “beat” placebo (rescue ESA therapy at a hemoglobin level <90 g/L) (40). It confirmed that, apart from preventing red blood cell transfusions, treating anemia with ESA therapy is not efficacious and is in fact harmful.

Consistent with these data, increased mortality associated with higher hemoglobin targets using ESA treatment has also been demonstrated in patients with anemia and cancer. A meta-analysis of individual-patient data of erythropoietin or darbepoetin versus placebo (53 trials; 13 933 patients) found that treatment with an ESA was associated with significantly worse overall survival than was no treatment (hazard ratio, 1.06 [CI, 1.00 to 1.12]) (4142). Although a much smaller meta-analysis of placebo-controlled trials of ESA versus placebo (7 trials; 650 patients) in patients with anemia and heart failure did not find a relationship between ESA treatment and mortality (43), a large, event-driven study of darbepoetin versus placebo is currently under way in patients with New York Heart Association class II to IV heart failure and anemia (hemoglobin target, 90 to 120 g/L) (RED-HF [Reduction of Events with Darbepoetin alfa in Heart Failure] trial) (44). The consistency of our findings compared with those identified in other populations suggests that the design of any ongoing trial in this setting must be carefully assessed. Our findings are also consistent with those of a previous meta-analysis of 8 trials evaluating target hemoglobin levels in CKD that showed an increase in the risk for all-cause mortality with higher hemoglobin levels (RR for all-cause mortality, 1.17 [CI, 1.01 to 1.35]) (17). We provide a more precise estimate (that is, a narrower confidence interval) of mortality risk (18 trials) (RR, 1.09 [CI, 0.99 to 1.20]) with higher hemoglobin targets than that previously reported by including more trials and patients. Of note, the lack of statistical significance found in the present meta-analysis for mortality is probably due to the smaller point estimate that we found (9% vs. 17%), which is, however, consistent with that reported in the larger meta-analysis of trials in patients with cancer (42).

In the absence of a survival advantage for ESA therapy, improving quality of life has become the key rationale for treating anemia in CKD. We found that evidence for quality of life was suboptimal because of selective reporting, suggesting potential overestimation of the benefits of anemia correction. Data from large and well-conducted trials did not support clinical efficacy for ESA therapy on quality of life (18). We found that ESA therapy was associated with a reduction in the need for blood transfusions, although the clinical relevance of this observation needs to be considered in light of the harms demonstrated in randomized trials of ESA to date, increased rates of intravenous iron therapy associated with higher hemoglobin targets, expense of ESA administration, and relatively low risks for transfusion-associated infection in the modern era.

Targeting higher hemoglobin levels with ESA therapy worsens hypertension. Although greater risks for hypertension were evident in smaller studies of lower quality and with shorter follow-up, larger trials with lower risks for bias also demonstrated increased risks for worsening hypertension with a higher hemoglobin target. The hypertensive effects of ESA therapy in the higher hemoglobin target group of all trials to date suggest that ESA therapy might mediate excess vascular events through nonhematopoietic erythropoietin receptor activation in vascular tissues (45), although this hypothesis remains speculative.

Using subgroup and meta-regression analysis, we identified consistent treatment-related risks for death and stroke associated with higher hemoglobin levels across all trials. Risks were similar across all stages of CKD and were not dependent on trial method quality or intervention. We could not specifically address the important question of whether the increased risk for adverse outcomes with higher hemoglobin levels was due to the ESA dose required in the individual patient to achieve the targeted hemoglobin level rather than the hemoglobin target (4648). Understanding the independent effect of ESA dose on outcomes in CKD now demands that treatment dose (and not hemoglobin target) is the randomized intervention in adequately powered trials and that dose and other data from existing trials should be made available for more refined analyses. Our findings indicate that, on the basis of the available trial evidence, the rationale for the recommended hemoglobin target of 110 to 120 g/L in the National Kidney Foundation clinical practice guideline on recommendations for anemia in CKD is unclear (4950). We found no evidence that higher hemoglobin targets in CKD are associated with benefit and conclude that anemia treatment using ESA is associated with possible or absolute harm across all major clinical outcomes.

Our review has limitations. First, the evidence for ESA therapy to improve quality of life is based largely on selective reporting of outcomes and is generally of low quality. Second, the available trial data do not identify the mechanisms by which ESA therapy may be harmful. Third, trials reported insufficient information to allow analysis of the independent effects of ESA dose on outcomes. A meta-analysis of individual-patient data might allow preliminary exploration of the specific patient and intervention characteristics that predict harm with ESA therapy.

In conclusion, ESA therapy targeting higher hemoglobin levels leads to increased risks for vascular and fatal events compared with therapy targeting lower levels. Evidence for harm when targeting higher hemoglobin values in CKD has now been available for more than 20 years, and this evidence should be incorporated in guidelines and adopted in clinical practice. The case is strong for making the best use of the considerable amount of information on hemoglobin targets available in existing trials by conducting meta-analysis of individual-patient data. The nephrology community should focus strongly on exploring these existing data and designing, conducting, and achieving funding for fixed-dose ESA trials.

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Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM.  Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet. 1986; 2:1175-8. PubMed
 
Zins B, Drüeke T, Zingraff J, Bererhi L, Kreis H, Naret C, et al..  Erythropoietin treatment in anaemic patients on haemodialysis [Letter]. Lancet. 1986; 2:1329. PubMed
 
Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW.  Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med. 1987; 316:73-8. PubMed
 
Bommer J, Alexiou C, Müller-Bühl U, Eifert J, Ritz E.  Recombinant human erythropoietin therapy in haemodialysis patients—dose determination and clinical experience. Nephrol Dial Transplant. 1987; 2:238-42.
 
Canadian Erythropoietin Study Group.  Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. BMJ. 1990; 300:573-8. PubMed
 
Bahlmann J, Schöter KH, Scigalla P, Gurland HJ, Hilfenhaus M, Koch KM, et al..  Morbidity and mortality in hemodialysis patients with and without erythropoietin treatment: a controlled study. Contrib Nephrol. 1991; 88:90-106. PubMed
 
Clyne N, Jogestrand T.  Effect of erythropoietin treatment on physical exercise capacity and on renal function in predialytic uremic patients. Nephron. 1992; 60:390-6. PubMed
 
Kleinman KS, Schweitzer SU, Perdue ST, Bleifer KH, Abels RI.  The use of recombinant human erythropoietin in the correction of anemia in predialysis patients and its effect on renal function: a double-blind, placebo-controlled trial. Am J Kidney Dis. 1989; 14:486-95. PubMed
 
Kuriyama S, Tomonari H, Yoshida H, Hashimoto T, Kawaguchi Y, Sakai O.  Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Nephron. 1997; 77:176-85. PubMed
 
Morris KP, Skinner JR, Hunter S, Coulthard MG.  Short term correction of anaemia with recombinant human erythropoietin and reduction of cardiac output in end stage renal failure. Arch Dis Child. 1993; 68:644-8. PubMed
 
Nissenson AR, Korbet S, Faber M, Burkart J, Gentile D, Hamburger R, et al..  Multicenter trial of erythropoietin in patients on peritoneal dialysis. J Am Soc Nephrol. 1995; 5:1517-29. PubMed
 
Revicki DA, Brown RE, Feeny DH, Henry D, Teehan BP, Rudnick MR, et al..  Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am J Kidney Dis. 1995; 25:548-54. PubMed
 
Sikole A, Polenakovic M, Spirovska V, Polenakovic B, Masin G.  Analysis of heart morphology and function following erythropoietin treatment of anemic dialysis patients. Artif Organs. 1993; 17:977-84. PubMed
 
Watson AJ, Gimenez LF, Cotton S, Walser M, Spivak JL.  Treatment of the anemia of chronic renal failure with subcutaneous recombinant human erythropoietin. Am J Med. 1990; 89:432-5. PubMed
 
Phrommintikul A, Haas SJ, Elsik M, Krum H.  Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet. 2007; 369:381-8. PubMed
 
Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al., TREAT Investigators.  A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009; 361:2019-32. PubMed
 
Strippoli GF, Navaneethan SD, Craig JC.  Haemoglobin and haematocrit targets for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2006; CD003967. PubMed
 
. Higgins JP, Green S Cochrane Handbook for Systematic Reviews of Interventions. Version 5.0.2. The Cochrane Collaboration. 2009.
 
Higgins JP, Thompson SG, Deeks JJ, Altman DG.  Measuring inconsistency in meta-analyses. BMJ. 2003; 327:557-60. PubMed
 
Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, 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; 339:584-90. PubMed
 
Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al., CHOIR Investigators.  Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006; 355:2085-98. PubMed
 
Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D.  Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol. 2005; 16:2180-9. PubMed
 
Berns JS, Rudnick MR, Cohen RM, Bower JD, Wood BC.  Effects of normal hematocrit on ambulatory blood pressure in epoetin-treated hemodialysis patients with cardiac disease. Kidney Int. 1999; 56:253-60. PubMed
 
Brandt JR, Avner ED, Hickman RO, Watkins SL.  Safety and efficacy of erythropoietin in children with chronic renal failure. Pediatr Nephrol. 1999; 13:143-7. PubMed
 
Cianciaruso B, Ravani P, Barrett BJ, Levin A, ITA-EPO-7 investigators.  Italian randomized trial of hemoglobin maintenance to prevent or delay left ventricular hypertrophy in chronic kidney disease. J Nephrol. 2008; 21:861-70. PubMed
 
Conlon PJ, Kovalik E, Schumm D, Minda S, Schwab SJ.  Normalization of hematocrit in hemodialysis patients with cardiac disease does not increase blood pressure. Ren Fail. 2000; 22:435-44. PubMed
 
Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al., CREATE Investigators.  Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006; 355:2071-84. PubMed
 
Foley RN, Parfrey PS, Morgan J, Barré PE, Campbell P, Cartier P, et al..  Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy. Kidney Int. 2000; 58:1325-35. PubMed
 
Furuland H, Linde T, Ahlmén J, Christensson A, Strömbom U, Danielson BG.  A randomized controlled trial of haemoglobin normalization with epoetin alfa in pre-dialysis and dialysis patients. Nephrol Dial Transplant. 2003; 18:353-61. PubMed
 
Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC.  Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int. 2004; 66:753-60. PubMed
 
Levin A, Djurdjev O, Thompson C, Barrett B, Ethier J, Carlisle E, et al..  Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD. Am J Kidney Dis. 2005; 46:799-811. PubMed
 
Macdougall IC, Temple RM, Kwan JT.  Is early treatment of anaemia with epoetin-alpha beneficial to pre-dialysis chronic kidney disease patients? Results of a multicentre, open-label, prospective, randomized, comparative group trial. Nephrol Dial Transplant. 2007; 22:784-93. PubMed
 
Ritz E, Laville M, Bilous RW, O'Donoghue D, Scherhag A, Burger U, et al., Anemia Correction in Diabetes Study Investigators.  Target level for hemoglobin correction in patients with diabetes and CKD: primary results of the Anemia Correction in Diabetes (ACORD) Study. Am J Kidney Dis. 2007; 49:194-207. PubMed
 
Roger SD, McMahon LP, Clarkson A, Disney A, Harris D, Hawley C, et al..  Effects of early and late intervention with epoetin alpha on left ventricular mass among patients with chronic kidney disease (stage 3 or 4): results of a randomized clinical trial. J Am Soc Nephrol. 2004; 15:148-56. PubMed
 
Rossert J, Levin A, Roger SD, Hörl WH, Fouqueray B, Gassmann-Mayer C, et al..  Effect of early correction of anemia on the progression of CKD. Am J Kidney Dis. 2006; 47:738-50. PubMed
 
Moher D, Schulz KF, Altman D, CONSORT Group (Consolidated Standards of Reporting Trials).  The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA. 2001; 285:1987-91. PubMed
 
Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, et al., CONSORT GROUP (Consolidated Standards of Reporting Trials).  The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med. 2001; 134:663-94. PubMed
 
Pfeffer MA.  Critical missing data on erythropoiesis-stimulating agents in CKD: first beat placebo [Editorial]. Am J Kidney Dis. 2008; 51:366-9. PubMed
 
Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, et al..  Erythropoietin or darbepoetin for patients with cancer—meta-analysis based on individual patient data. Cochrane Database Syst Rev. 2009; CD007303. PubMed
 
Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, et al..  Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009; 373:1532-42. PubMed
 
van der Meer P, Groenveld HF, Januzzi JL Jr, van Veldhuisen DJ.  Erythropoietin treatment in patients with chronic heart failure: a meta-analysis. Heart. 2009; 95:1309-14. PubMed
 
McMurray JJ, Anand IS, Diaz R, Maggioni AP, O'Connor C, Pfeffer MA, et al., RED-HF Committees and Investigators.  Design of the Reduction of Events with Darbepoetin alfa in Heart Failure (RED-HF): a phase III, anaemia correction, morbidity-mortality trial. Eur J Heart Fail. 2009; 11:795-801. PubMed
 
Bode-Böger SM, Böger RH, Kuhn M, Radermacher J, Frölich JC.  Recombinant human erythropoietin enhances vasoconstrictor tone via endothelin-1 and constrictor prostanoids. Kidney Int. 1996; 50:1255-61. PubMed
 
Cotter DJ, Stefanik K, Zhang Y, Thamer M, Scharfstein D, Kaufman J.  Hematocrit was not validated as a surrogate end point for survival among epoetin-treated hemodialysis patients. J Clin Epidemiol. 2004; 57:1086-95. PubMed
 
Himmelfarb J, Szczech LA.  Resolved: Targeting a higher hemoglobin is associated with greater risk in patients with CKD anemia: con. J Am Soc Nephrol. 2009; 20:1441-3. PubMed
 
Zhang Y, Thamer M, Stefanik K, Kaufman J, Cotter DJ.  Epoetin requirements predict mortality in hemodialysis patients. Am J Kidney Dis. 2004; 44:866-76. PubMed
 
National Kidney Foundation.  KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease: 2007 Update of Hemoglobin Target. New York: National Kidney Foundation; 2007. Accessed atwww.kidney.org/professionals/KDOQI/guidelines_anemiaUP/index.htmon 23 February 2010.
 
McMahon L, Caring for Australians with Renal Impairment (CARI), The CARI guidelines.  Biochemical and haematological targets. Haemoglobin. Nephrology (Carlton). 2008; 13:Suppl 2S44-56. PubMed
 

Figures

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Appendix Figure.
Literature search and selection.

CENTRAL = Cochrane Central Register of Controlled Trials; RRT = renal replacement therapy.

* Numbers do not sum to 1637 because some articles were identified by more than 1 search.

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Figure 1.
Risks for bias in included studies.

We assessed study risk for bias according to recommendations from the Cochrane Collaboration (20).

* Whether the study reported methods to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been predicted in advance of patient enrollment.

† Methods by which patients, investigators, or outcomes assessors are protected from being aware of the treatment allocations after patients are included in the study.

‡ Whether the study conducted the major analyses according to the patients' treatment assignment at the time of randomization.

§ Whether the study described the completeness of outcome data for the primary outcomes.

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Figure 2.
Meta-analysis of randomized trials comparing higher versus lower hemoglobin targets on clinical outcomes in patients with chronic kidney disease.
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Figure 2—
Continued

ACORD = Anemia Correction in Diabetes; EPO = erythropoietin; CHOIR = Correction of Hemoglobin and Outcomes in Renal Insufficiency; CREATE = Cardiovascular Risk Reduction in Early Anemia Treatment with Epoetin Beta; NHS = Normal Hematocrit Study; TREAT = Trial to Reduce Cardiovascular Events with Aranesp Therapy.

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Figure 3.
Cumulative meta-analysis of randomized trials comparing higher versus lower hemoglobin targets on clinical outcomes in patients with chronic kidney disease.
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Figure 3—
Continued

ACORD = Anemia Correction in Diabetes; EPO = erythropoietin; CHOIR = Correction of Hemoglobin and Outcomes in Renal Insufficiency; CREATE = Cardiovascular Risk Reduction in Early Anemia Treatment with Epoetin Beta; NHS = Normal Hematocrit Study; TREAT = Trial to Reduce Cardiovascular Events with Aranesp Therapy.

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Tables

Table Jump PlaceholderAppendix Table 1.  Search Strategy
Table Jump PlaceholderAppendix Table 2.  Baseline Characteristics of Participants in Trials of Hemoglobin Targets in People With CKD
Table Jump PlaceholderAppendix Table 3.  Characteristics of Interventions in Trials of Hemoglobin Targets in People With Chronic Kidney Disease
Table Jump PlaceholderAppendix Table 4.  Summary of Quality-of-Life Outcomes
Table Jump PlaceholderAppendix Table 5.  Subgroup and Meta-regression Analysis Exploring the Role of Trial, Participant, or Intervention Characteristics in Trials Comparing High Versus Low Hemoglobin Targets on Risks for Mortality, Hypertension, and Stroke in People With CKD

References

Hsu CY, McCulloch CE, Curhan GC.  Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the Third National Health and Nutrition Examination Survey. J Am Soc Nephrol. 2002; 13:504-10. PubMed
CrossRef
 
McGonigle RJ, Wallin JD, Shadduck RK, Fisher JW.  Erythropoietin deficiency and inhibition of erythropoiesis in renal insufficiency. Kidney Int. 1984; 25:437-44. PubMed
 
Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM.  Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet. 1986; 2:1175-8. PubMed
 
Zins B, Drüeke T, Zingraff J, Bererhi L, Kreis H, Naret C, et al..  Erythropoietin treatment in anaemic patients on haemodialysis [Letter]. Lancet. 1986; 2:1329. PubMed
 
Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW.  Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med. 1987; 316:73-8. PubMed
 
Bommer J, Alexiou C, Müller-Bühl U, Eifert J, Ritz E.  Recombinant human erythropoietin therapy in haemodialysis patients—dose determination and clinical experience. Nephrol Dial Transplant. 1987; 2:238-42.
 
Canadian Erythropoietin Study Group.  Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. BMJ. 1990; 300:573-8. PubMed
 
Bahlmann J, Schöter KH, Scigalla P, Gurland HJ, Hilfenhaus M, Koch KM, et al..  Morbidity and mortality in hemodialysis patients with and without erythropoietin treatment: a controlled study. Contrib Nephrol. 1991; 88:90-106. PubMed
 
Clyne N, Jogestrand T.  Effect of erythropoietin treatment on physical exercise capacity and on renal function in predialytic uremic patients. Nephron. 1992; 60:390-6. PubMed
 
Kleinman KS, Schweitzer SU, Perdue ST, Bleifer KH, Abels RI.  The use of recombinant human erythropoietin in the correction of anemia in predialysis patients and its effect on renal function: a double-blind, placebo-controlled trial. Am J Kidney Dis. 1989; 14:486-95. PubMed
 
Kuriyama S, Tomonari H, Yoshida H, Hashimoto T, Kawaguchi Y, Sakai O.  Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Nephron. 1997; 77:176-85. PubMed
 
Morris KP, Skinner JR, Hunter S, Coulthard MG.  Short term correction of anaemia with recombinant human erythropoietin and reduction of cardiac output in end stage renal failure. Arch Dis Child. 1993; 68:644-8. PubMed
 
Nissenson AR, Korbet S, Faber M, Burkart J, Gentile D, Hamburger R, et al..  Multicenter trial of erythropoietin in patients on peritoneal dialysis. J Am Soc Nephrol. 1995; 5:1517-29. PubMed
 
Revicki DA, Brown RE, Feeny DH, Henry D, Teehan BP, Rudnick MR, et al..  Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am J Kidney Dis. 1995; 25:548-54. PubMed
 
Sikole A, Polenakovic M, Spirovska V, Polenakovic B, Masin G.  Analysis of heart morphology and function following erythropoietin treatment of anemic dialysis patients. Artif Organs. 1993; 17:977-84. PubMed
 
Watson AJ, Gimenez LF, Cotton S, Walser M, Spivak JL.  Treatment of the anemia of chronic renal failure with subcutaneous recombinant human erythropoietin. Am J Med. 1990; 89:432-5. PubMed
 
Phrommintikul A, Haas SJ, Elsik M, Krum H.  Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet. 2007; 369:381-8. PubMed
 
Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al., TREAT Investigators.  A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009; 361:2019-32. PubMed
 
Strippoli GF, Navaneethan SD, Craig JC.  Haemoglobin and haematocrit targets for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2006; CD003967. PubMed
 
. Higgins JP, Green S Cochrane Handbook for Systematic Reviews of Interventions. Version 5.0.2. The Cochrane Collaboration. 2009.
 
Higgins JP, Thompson SG, Deeks JJ, Altman DG.  Measuring inconsistency in meta-analyses. BMJ. 2003; 327:557-60. PubMed
 
Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, 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; 339:584-90. PubMed
 
Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al., CHOIR Investigators.  Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006; 355:2085-98. PubMed
 
Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D.  Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol. 2005; 16:2180-9. PubMed
 
Berns JS, Rudnick MR, Cohen RM, Bower JD, Wood BC.  Effects of normal hematocrit on ambulatory blood pressure in epoetin-treated hemodialysis patients with cardiac disease. Kidney Int. 1999; 56:253-60. PubMed
 
Brandt JR, Avner ED, Hickman RO, Watkins SL.  Safety and efficacy of erythropoietin in children with chronic renal failure. Pediatr Nephrol. 1999; 13:143-7. PubMed
 
Cianciaruso B, Ravani P, Barrett BJ, Levin A, ITA-EPO-7 investigators.  Italian randomized trial of hemoglobin maintenance to prevent or delay left ventricular hypertrophy in chronic kidney disease. J Nephrol. 2008; 21:861-70. PubMed
 
Conlon PJ, Kovalik E, Schumm D, Minda S, Schwab SJ.  Normalization of hematocrit in hemodialysis patients with cardiac disease does not increase blood pressure. Ren Fail. 2000; 22:435-44. PubMed
 
Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al., CREATE Investigators.  Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006; 355:2071-84. PubMed
 
Foley RN, Parfrey PS, Morgan J, Barré PE, Campbell P, Cartier P, et al..  Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy. Kidney Int. 2000; 58:1325-35. PubMed
 
Furuland H, Linde T, Ahlmén J, Christensson A, Strömbom U, Danielson BG.  A randomized controlled trial of haemoglobin normalization with epoetin alfa in pre-dialysis and dialysis patients. Nephrol Dial Transplant. 2003; 18:353-61. PubMed
 
Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC.  Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int. 2004; 66:753-60. PubMed
 
Levin A, Djurdjev O, Thompson C, Barrett B, Ethier J, Carlisle E, et al..  Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD. Am J Kidney Dis. 2005; 46:799-811. PubMed
 
Macdougall IC, Temple RM, Kwan JT.  Is early treatment of anaemia with epoetin-alpha beneficial to pre-dialysis chronic kidney disease patients? Results of a multicentre, open-label, prospective, randomized, comparative group trial. Nephrol Dial Transplant. 2007; 22:784-93. PubMed
 
Ritz E, Laville M, Bilous RW, O'Donoghue D, Scherhag A, Burger U, et al., Anemia Correction in Diabetes Study Investigators.  Target level for hemoglobin correction in patients with diabetes and CKD: primary results of the Anemia Correction in Diabetes (ACORD) Study. Am J Kidney Dis. 2007; 49:194-207. PubMed
 
Roger SD, McMahon LP, Clarkson A, Disney A, Harris D, Hawley C, et al..  Effects of early and late intervention with epoetin alpha on left ventricular mass among patients with chronic kidney disease (stage 3 or 4): results of a randomized clinical trial. J Am Soc Nephrol. 2004; 15:148-56. PubMed
 
Rossert J, Levin A, Roger SD, Hörl WH, Fouqueray B, Gassmann-Mayer C, et al..  Effect of early correction of anemia on the progression of CKD. Am J Kidney Dis. 2006; 47:738-50. PubMed
 
Moher D, Schulz KF, Altman D, CONSORT Group (Consolidated Standards of Reporting Trials).  The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA. 2001; 285:1987-91. PubMed
 
Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, et al., CONSORT GROUP (Consolidated Standards of Reporting Trials).  The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med. 2001; 134:663-94. PubMed
 
Pfeffer MA.  Critical missing data on erythropoiesis-stimulating agents in CKD: first beat placebo [Editorial]. Am J Kidney Dis. 2008; 51:366-9. PubMed
 
Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, et al..  Erythropoietin or darbepoetin for patients with cancer—meta-analysis based on individual patient data. Cochrane Database Syst Rev. 2009; CD007303. PubMed
 
Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, et al..  Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009; 373:1532-42. PubMed
 
van der Meer P, Groenveld HF, Januzzi JL Jr, van Veldhuisen DJ.  Erythropoietin treatment in patients with chronic heart failure: a meta-analysis. Heart. 2009; 95:1309-14. PubMed
 
McMurray JJ, Anand IS, Diaz R, Maggioni AP, O'Connor C, Pfeffer MA, et al., RED-HF Committees and Investigators.  Design of the Reduction of Events with Darbepoetin alfa in Heart Failure (RED-HF): a phase III, anaemia correction, morbidity-mortality trial. Eur J Heart Fail. 2009; 11:795-801. PubMed
 
Bode-Böger SM, Böger RH, Kuhn M, Radermacher J, Frölich JC.  Recombinant human erythropoietin enhances vasoconstrictor tone via endothelin-1 and constrictor prostanoids. Kidney Int. 1996; 50:1255-61. PubMed
 
Cotter DJ, Stefanik K, Zhang Y, Thamer M, Scharfstein D, Kaufman J.  Hematocrit was not validated as a surrogate end point for survival among epoetin-treated hemodialysis patients. J Clin Epidemiol. 2004; 57:1086-95. PubMed
 
Himmelfarb J, Szczech LA.  Resolved: Targeting a higher hemoglobin is associated with greater risk in patients with CKD anemia: con. J Am Soc Nephrol. 2009; 20:1441-3. PubMed
 
Zhang Y, Thamer M, Stefanik K, Kaufman J, Cotter DJ.  Epoetin requirements predict mortality in hemodialysis patients. Am J Kidney Dis. 2004; 44:866-76. PubMed
 
National Kidney Foundation.  KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease: 2007 Update of Hemoglobin Target. New York: National Kidney Foundation; 2007. Accessed atwww.kidney.org/professionals/KDOQI/guidelines_anemiaUP/index.htmon 23 February 2010.
 
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NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

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