Current Drug Therapy

Anemia of chronic kidney disease: When normalcy becomes undesirable

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References

In 2006 the National Kidney Foundation modified its 1997 guidelines, suggesting an upper hemoglobin boundary of 13 g/dL. But in early 2007 it retreated to a hemoglobin target range of 11–12 g/dL, 9 after the simultaneous publication of two randomized controlled trials that found no improved outcomes with hemoglobin normalization, and some evidence of harm. 10,11

The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial randomized predialysis patients to a hemoglobin goal of either 11.3 g/dL or 13.5 g/dL. The trial was terminated early because the likelihood of benefit with the high hemoglobin goal was low. In fact, the higher-hemoglobin group had a higher incidence of the primary end point, ie, the composite of death, stroke, myocardial infarction, and hospitalization for congestive heart failure. Death and hospitalization for congestive heart failure were the main drivers of the difference in the composite end point between the groups. Quality of life was no better with the higher goal than with the lower goal. 10

The Cardiovascular Risk Reduction by Early Anemia Treatment With Epoetin Beta (CREATE) trial 11 found that the risk of cardiovascular events in predialysis patients was no lower when anemia was completely corrected (target hemoglobin range 13.0–15.0 g/dL) than with a goal of 10.5 to 11.5 g/dL. Moreover, renal function declined faster in the higher-goal group than in the lower-goal group. However, this study did show higher quality-of-life scores in the group with the higher hemoglobin goal. 11

AN FDA ALERT

On November 16, 2006, the FDA issued an alert and required that ESA product labeling include a new boxed warning with the following information 12:

  • Use the lowest dose of an ESA (Procrit, Epogen, or Aranesp) that will gradually raise the hemoglobin concentration to the lowest level sufficient to avoid the need for blood transfusion.
  • ESAs should not be given to treat symptoms of anemia or poor quality of life.
  • Maintain the hemoglobin level in the target range of 10 to 12 g/dL.
  • Decrease the dose if the hemoglobin level increases by more than 1 g/dL in any 2-week period.

ANOTHER LOOK AT THE DATA

In post hoc analyses, data from the US Normal Hematocrit and CHOIR studies were analyzed on an “as-treated” basis instead of on an intention-to-treat basis as originally reported. 13,14 Although the original studies found no survival advantage (and perhaps harm) with higher hemoglobin targets (ie, by intention-to-treat analysis), when the investigators looked at the actual hemoglobin levels achieved, they found that event rates were higher with low hemoglobin levels.

Such discordant findings highlight the importance of randomized experimental designs to avoid bias due to confounding factors (measured and unmeasured) linked to both hemoglobin level and outcome. To reconcile the above findings, we offer the following observations:

  • In each treatment group, event rates were higher among those who responded poorly to ESAs (hyporesponders). This finding undermines the intuitive assumption that higher achieved hemoglobin levels were causing volume-related events (congestive heart failure or pulmonary edema) and thrombotic events. Of note, rapid changes in hemoglobin levels in either direction further increased the frequency of events among hyporesponders (which might be associated with the more aggressive algorithm needed in the higher target group).
  • Within each treatment group, the difference in event rates is unlikely to be explained by the variation in hemoglobin within its narrow range. Rather, it was mostly due to a higher burden of disease among the hyporesponders. This problem—called targeting bias —is peculiar to therapies that are adjusted according to a target level, eg, of serum hemoglobin. 15 Therefore, any association of mortality with achieved hemoglobin within the individual target hemoglobin group is more likely due to other factors such as patient comorbidities.
  • Patients assigned to the higher hemoglobin targets received more than just higher doses of ESAs: they also got more of other interventions such as intravenous iron supplementation. Therefore, the results of the trials reflect not only the target level achieved but also the independent effects of the study drug, the co-interventions, and the treatment algorithm.

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