“Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease”
by the Investigators in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR)
N Engl J Med. 2006 Nov 16;355(20):2085-98. [free full text]
Anemia is a highly prevalent condition in CKD and ESRD. The anemia is largely attributable to the loss of erythropoietin production due to the destruction of kidney parenchyma. Thus erythropoiesis-stimulating agents (ESAs) were introduced to improve this condition. Retrospective data and small interventional trials suggested that treatment to higher hemoglobin goals (such as > 12g/dL) was associated with improved cardiovascular outcomes. However, a prospective trial in ESRD patients on HD with a hemocrit treatment target of 42% vs. 30% demonstrated a trend toward increased rates of non-fatal MI and death in the higher-target group. In an effort to clarify the hemoglobin goal in CKD patients, the 2006 CHOIR trial was designed. It was hypothesized that treatment of anemia in CKD to a target of 13.5g/dL would lead to fewer cardiac events and reduced mortality when compared to a target of 11.3g/dL.
Population: adults with CKD (eGFR 15-50ml/min) and Hgb < 11.0 g/dL
Notable exclusion criteria: active cancer, prior therapy with epo.
Patients who developed a requirement for dialysis were terminated from the study.
Intervention: target hemoglobin 13.5 g/dL with a regimen of epo support
Comparison: target hemoglobin 11.3 g/dL with a regimen of epo support
Primary – composite of death, MI, hospitalization for CHF, or stroke
- each of the four components of the composite primary endpoint
- need for renal replacement therapy
- hospitalization for any cause
- quality of life as measured by the Linear Analogue Self-Assessment (LASA), Kidney Disease Questionnaire (KDQ), and Medical Outcomes Study 36-item Short-Form Health Survey (SF-36)
This study was terminated early due to an interim analysis revealing a < 5% chance that there would be a demonstrated benefit for the high-hemoglobin group by the scheduled end of the study.
Results from 715 high-hemoglobin and 717 low-hemoglobin patients were analyzed.
Baseline characteristics were similar among the two groups aside from for higher rates of HTN (p=0.03) and CABG (p=0.05) in the high-hemoglobin group. Rates of iron supplementation during the study were similar among the two groups (~50%).
The mean change in hemoglobin was +2.5 g/dL in the high-hemoglobin group versus +1.2g/dL in the low-hemoglobin group (p<0.001).
The primary endpoint occurred in 125 of the high-hemoglobin patients (17.5%) versus 97 of the low-hemoglobin patients (13.5%) [HR 1.34, 95% CI 1.03-1.74, p=0.03; number needed to harm = 25].
There were no significant group differences among the four components of the primary endpoint when analyzed as individual secondary outcomes. Rates of renal replacement therapy (thus requiring termination from the study protocol) were 21.7% in the high-hemoglobin group versus 18.7% in the low-hemoglobin group (p=0.15). Any-cause hospitalization rates were 51.6% in the high-hemoglobin group versus 46.6% in the low-hemoglobin group (p=0.03).
Quality-of-life scores were assessed by the LASA, KDQ, and SF-36. Both groups demonstrated similar, statistically significant improvements from their respective baseline values, with the exception of a higher improvement in the emotional subset of SF-36 within the low-hemoglobin group.
The mean weekly dose of epoetin alfa required to maintain the target hemoglobin was 11,215 units/week in the high-hemoglobin group versus 6.276 units/week in the low-hemoglobin group.
In patients with anemia and CKD, treatment to a higher hemoglobin goal of 13.5g/dL was associated with an increased incidence of a composite endpoint of death, MI, hospitalization for CHF, or stroke relative to a treatment goal of 11.3g/dL. The higher treatment goal also led to higher utilization of epoetin alfa. There were no differences between the two groups in hospitalization rates or progression to renal replacement therapy, and the improvement in quality of life was similar among the two treatment groups.
Thus this study demonstrated no additional benefit and some harm with the higher treatment goal.
The authors note that “this study did not provide a mechanistic explanation for the poorer outcome with the use of a high target hemoglobin level.”
Limitations of this trial included its non-blinded nature and relatively high patient withdrawal rates.
Following this trial, the KDOQI guidelines for the management of anemia in CKD were changed to state that “in dialysis and nondialysis patients with CKD receiving ESA therapy, the selected Hb target should generally be in the range of 11.0 to 12.0 g/dL.”
Expert opinion at UpToDate recommends administration of ESAs in iron-replete CKD and ESRD patients with Hgb < 10 g/dL with the goal of maintaining Hgb between 10 and 11.5 g/dL. Treatment should be individualized in patients with concurrent malignancy.
1. Wiki Journal Club
2. 2 Minute Medicine
3. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease: 2007 Update of Hemoglobin Target
4. Pfeffer et al. “A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.” N Engl J Med. 2009;361(21):2019.
5. UpToDate, “Treatment of anemia in nondialysis chronic kidney disease”
6. UpToDate, “Treatment of anemia in hemodialysis patients”
Summary by Duncan F. Moore, MD