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; Giovanni F.M. Strippoli, MD, PhD, MPH, MM
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.
To summarize the effects of ESA treatment on clinical outcomes in patients with anemia and CKD.
MEDLINE (January 1966 to November 2009), EMBASE (January 1980 to November 2009), and the Cochrane database (to March 2010) were searched without language restriction.
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.
Two authors independently extracted data on patient characteristics, study risks for bias, and the effects of ESA therapy.
27 trials (10Â 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.
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.
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.
Recent studies suggest that treating anemia of chronic kidney disease can sometimes cause harm.
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.
Underlying mechanisms for harms were not established.
Therapy with ESAs that targets high hemoglobin levels is harmful for patients with chronic kidney disease.
Appendix Table 1.
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.
Appendix Table 2.
Appendix Table 3.
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.
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.
Appendix Table 4.
Appendix Table 5.
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Suetonia C. Palmer, Sankar D. Navaneethan, Jonathan C. Craig, David W. Johnson, Marcello Tonelli, Amit X. Garg, et al. Meta-analysis: Erythropoiesis-Stimulating Agents in Patients With Chronic Kidney Disease. Ann Intern Med. 2010;153:23–33. doi: 10.7326/0003-4819-153-1-201007060-00252
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Published: Ann Intern Med. 2010;153(1):23-33.
Chronic Kidney Disease, Nephrology.
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