T H OM A S K R I L E Y
The use of [epoetin alfa to] target a hemoglobin level of 13.5 g/dL (as compared with 11.3 g/dL) [among patients with chronic kidney dis-ease] was associated with increased risk and no incremental improve-ment in the quality of life.
—Singh et al.1
Research Question: For patients with anemia due to chronic kidney disease treated with epoetin alfa, does an aggressive hemoglobin target of 13.5 g/dL lead to better outcomes than a more conservative target of 11.3 g/dL?1
Funding: Johnson & Johnson pharmaceuticals, the maker of procrit (epoetin alfa).
Year Study Began: 2002 Year Study Published: 2006
Study Location: 130 sites in the United States.
Who Was Studied: Adults with anemia due to chronic kidney disease. To be eligible, patients were required to have a hemoglobin <11 g/dL and an esti-mated glomerular filtration rate (eGFR) of 15–50 mL/min/1.73m2 calculated using the Modification of Diet in Renal Disease (MDRD) formula.
Who Was Excluded: patients on renal replacement therapy at the time of enrollment. Also excluded were patients with “uncontrolled hypertension, active gastrointestinal bleeding, an iron overloaded state, a history of frequent transfusions in the last 6 months, refractory iron deficiency anemia, active can-cer, previous therapy with epoetin alfa, or patients with unstable angina.”1 How Many Patients: 1,432
Study Overview: See Figure 18.1 for a summary of the study’s design.
Study Intervention: patients in both groups received weekly subcutaneous injections of epoetin alfa initially at a dose of 10,000 units. After the third weekly injection, the epoetin alfa dose was adjusted to target a hemoglobin level of either 13.5 g/dL or 11.3 g/dL. The maximum dose of epoetin alfa could not exceed 20,000 units in either group, and dosing could be switched to every other week for patients with stable hemoglobin levels. Importantly, patients in both groups who began renal replacement therapy were no longer eligible to participate in the study and began receiving usual care once this occurred.
Follow-Up: Mean of 16 months.
Endpoints: primary outcome: A composite of death, myocardial infarction, hospitalization for congestive heart failure (ChF), and stroke. Secondary out-comes: Time to renal replacement therapy; hospitalization for any cause; and changes in quality-of-life scores.
Randomized
Patients with Chronic Kidney Disease and Anemia
Target Hemoglobin of 13.5 g/dL Target Hemoglobin of 11.3 g/dL
Figure 18.1 Summary of the Study Design.
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RESULTS
• Baseline characteristics in both groups were similar, with an average age of 66 years and an average baseline hemoglobin of 10.1 g/dL.
• The mean dose of epoetin alfa used and mean increase in hemoglobin level were greater in the group targeting a higher hemoglobin level (Table 18.1).
• The composite of death, myocardial infarction, hospitalization for ChF, and stroke occurred more frequently in the high hemoglobin group (Table 18.1).
• There was no statistically significant difference between groups in the need for renal replacement therapy.
• In a post hoc analysis of the primary outcome combined with the need for renal replacement therapy, there continued to be more adverse outcomes in the group targeting a higher hemoglobin.
• Changes in quality-of-life scores were similar for both groups.
Criticisms and Limitations: Of the study population, 38% did not complete follow-up (21% for unlisted reasons and 17% due to the initiation of dialysis).
Because the study was unblinded, it is possible that physicians’ knowledge of patients’ study assignment impacted their decision to initiate dialysis, which could have biased the results. Reassuringly, however, the proportion of patients
Table 18.1 Summary of Key Findings
Variable High
Mean Change in hemoglobin +2.5 g/dL +1.3 g/dL <0.001 Mean Weekly Dose of
epoetin alfa 11,215 units 6,276 units not reported
primary outcomea 17.5% 13.5% 0.03
Deathb 7.3% 5.0% 0.07
hospitalization for ChFb 9.0% 6.6% 0.07
Myocardial Infarctionb 2.5% 2.8% 0.78
Strokeb 1.7% 1.7% 0.98
a patients were only counted once for occurrence of the composite primary outcome (e.g., if hospitalization for ChF occurred before a stroke, this was counted as only one event; hospitalization for ChF was counted in the primary outcome analysis).
b patients were counted for each event experienced (e.g., a patient hospitalized for ChF with subsequent stoke was counted once in each category).
who initiated dialysis was similar between the groups, and an analysis in which dialysis initiation was combined with the primary composite outcome showed results congruent with the primary analysis.
Other Relevant Studies and Information:
• The Normal Hematocrit Trial evaluated 1,233 patients with cardiovascular disease who were on hemodialysis and found that targeting a hematocrit of 42% compared to 30% yielded no cardiovascular or mortality advantage and was associated with increased risk of thrombosis of grafts and fistulas.2
• In studies done after the CHOIR study of patients with chronic kidney disease and anemia who were not yet on dialysis, similar results to ChoIR’s were observed; some of these studies also demonstrate an increased risk of stroke and thrombosis when targeting a higher hemoglobin level.3,4 These trials achieved mean hemoglobin levels of 11.5 g/dL and 10.5 g/dL in the less aggressive group.
• A meta-analysis of 27 trials and 10,452 patients comparing high hemoglobin targets versus low hemoglobin targets or placebo found statistically significant increases in stoke, hypertension, and vascular thrombosis in the high hemoglobin target groups and nonstatistically significant increases in mortality and cardiovascular morbidity.5
• The 2012 Kidney Disease Improving Global Outcomes guidelines recommend considering initiation of erythrocyte-stimulating agents (eSAs) in patients with anemia due to chronic kidney disease who are not receiving dialysis only when hemoglobin levels fall below 10 g/dL. The decision to start treatment should be based on the rate of fall in hemoglobin and a discussion of risks and benefits with the patient. When using eSAs, the target hemoglobin should be less than 11.5 g/dL for most patients.6 guidelines for patients on hemodialysis recommend similar hemoglobin targets.
Summary and Implications: In patients with anemia and chronic kidney dis-ease who are not on dialysis, using ESAs to target a hemoglobin of 13.5 g/dL is associated with increased risk compared to a target hemoglobin of 11.3 g/
dL. Based on this and other research, practice guidelines recommend initiating ESAs only when the hemoglobin drops below 10 g/dL with a target hemoglo-bin <11.5 g/dL in most patients.
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References
1. Singh AK et al. Correction of anemia with epoetin alfa in chronic kidney disease.
N Engl J Med. 2006 Nov 16;355(20):2085–2098.
2. Besarab A 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.
3. Drüeke TB et al. Normalization of hemoglobin level in patients with chronic kid-ney disease and anemia. N Engl J Med. 2006;355:2071.
4. Pfeffer MA et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019.
5. palmer SC et al. Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. Ann Intern Med. 2010;153:23.
6. Kidney Disease: Improving global outcomes (KDIgo) Anemia Work group.
KDIgo clinical practice guidelines for anemia in chronic kidney disease. Kidney Int Suppl. 2012;2:288.
CLINICAL CASE: ANEMIA AND EPOETIN THERAPY Case History:
A 67-year-old man with a history of hypertension, hyperlipidemia, and chronic kidney disease presents with complaints of malaise and fatigue. The patient is found to have a hemoglobin level of 10.6 g/dL with a mean cell vol-ume (MCV) of 77 and an estimated gFR of 44 using the MDRD formula.
Iron studies are ordered, which show decreased ferritin, decreased serum iron, and increased transferrin. Based on the results on the ChoIR trial, how should this patient’s anemia be treated?
Suggested Answer:
Anemia associated with chronic kidney disease is typically normocytic and normochromic and related to decreased production of erythropoietin by the kidneys. The patient in this vignette, however, has microcytic anemia with iron studies suggesting iron deficiency. prior to considering an eSA, this patient should be evaluated for iron loss and his iron stores should be repleted.
If his anemia persists after treatment of his iron deficiency, an eSA still would not be recommended according to current guidelines because his hemoglo-bin is not <10 g/dL.