Although complete correction of anemia of kidney disease with epoetin-α has been associated with increased mortality compared with partial correction,5,8
the underlying mechanisms are not clear. This post hoc
analysis of CHOIR generates the hypothesis that toxicities related to high-dose epoetin-α may contribute to worse outcomes among subjects with higher targets particularly among those who do not achieve their targeted hemoglobin. Further, this analysis demonstrates that subjects achieving their target had better outcomes than those who did not, and among subjects who achieved their randomized target, no increased risk associated with the higher hemoglobin goal was detected.
Similar to CHOIR, the Normal Hematocrit study demonstrated a relative risk of 1.28, 95% CI 0.92, 1.78, favoring the low-hematocrit group.8
Subjects achieving the higher target had a lower mortality rate than subjects in the lower-hematocrit group.7
Higher hemoglobin values alone in both the Normal Hematocrit study and CHOIR were not associated with worse outcomes. Rather, lower achieved values appeared to be associated with higher mortality. Additionally, in the Normal Hematocrit study, following cessation of the target intervention, subjects randomized to the higher arm had ‘near-identical’ rates of mortality as those randomized to the lower target.8
Thus, although being randomized to the higher hemoglobin treatment arm in each study that resulted in higher rates of adverse outcomes overall, achieving the higher hemoglobin target was associated with lower mortality. And following discontinuation of the intervention to achieve the higher target, differences in outcomes are lost. This implies that another factor must be responsible for these outcomes differences. The analysis presented here suggests that factor may be high-doses of epoetin-α.
Epoetin-α requirements are variable among anemic patients.1,7,9,10
This variability has been attributed to multiple etiologies, including iron deficiency, infection, and inflammation.9–11
Hyporesponsiveness to epoetin requires higher doses.12
Among those in the higher target hemoglobin group, the high doses of epoetin were associated with poorer outcomes, and when higher epoetin doses were considered in multivariate analyses, treatment to the higher hemoglobin target was no longer associated with increased risk, suggesting possible mediating effect of higher target via dose.
Higher doses of epoetin have been demonstrated to be an independent predictor of mortality in United States Renal Data Service data of hemodialysis patients.9
Across all hematocrit categories, significant direct relationships between dose and mortality were observed. The steepest increases in risk were found above the 72.5th dose percentile, corresponding to 18,800–29,300 U, similar to the analyses presented here. However, because of the observational nature of the United States Renal Data Service data set, the possibility that relationship between dose and outcome may reflect confounding due by comorbidity and inflammation cannot be excluded.
Defining a relationship between dose and outcomes must attempt to separate the potential contribution of increased dose requirement as a marker of comorbidity. Two observational studies have demonstrated relationships between epoetin dose requirements and clinical factors such as age, diabetes mellitus, and serum ferritin.12,13
This potential for confounding limits the ability of a data set with a single hemoglobin target or dosing strategy to discern whether the risk detected is associated with dose or with clinical factors necessitating the dose. However, a trial randomizing to two targets can take advantage of the benefits of randomization. If randomization is successful in equally distributing factors between treatment arms, by definition, factors that are reflective of inflammation and epoetin-α responsiveness will also be equally distributed at the baseline. Supporting the assertion that such factors may be still equally distributed between arms in CHOIR at the landmark time, key parameters between treatment groups were similar. To the extent that albumin and ferritin reflect inflammation, no difference between treatment groups was detected. Additionally, as a more functional marker, hemoglobin at baseline and at 3 weeks (before which both treatment groups received the same dose of epoetin-α) were also similar between groups. Together, this supports the assertion that there was a relatively equal distribution of factors reflecting epoetin-α resistance between arms. In this setting, rates of adverse events were higher among those treated to the higher hemoglobin target. Subjects in the high-hemoglobin group required the use of higher doses of epoetin, which may have predisposed these patients to a greater dose effect.
The specific mechanisms by which high-doses of epoetin-α may be associated with a greater risk of adverse outcomes remain unclear. Erythropoietin receptors have been demonstrated on human endothelial cells and multiple other sites.14,15
Additionally, receptors have been found on tumor cells, suggesting potential roles of erythropoietin as angiogenic.16–18
Therapy with large episodic doses of erythropoietin do not reflect normal erythropoietin biology and have unknown effects on erythropoietin receptors.19
Finally, the nature of the relationship as suggested by these data may not be linear as seen in previous studies11,20,21
Greater epoetin resistance or requirements in the ESRD population may alter key thresholds in this relationship and deserves additional scrutiny. However, future translational research to investigate this should allow for the potential that smaller doses may provoke differential responses or that the beneficial association with higher hemoglobin may mask the relationship with dose within certain ranges.
The Normal Hematocrit trial and other observational studies have raised concern in the renal community over potential risks associated with the use of intravenous iron.7,22–24
Although contradictory studies exist that argue the presence of this risk,25
it is noteworthy that in the Normal Hematocrit study more subjects in the higher hemoglobin arm received intravenous iron and those who received intravenous iron had a greater odds of mortality compared with those who did not receive intravenous iron. Although 990 of the 1233 subjects reported in the primary publication of the Normal Hematocrit study received intravenous iron, its use was reported in far fewer subjects in CHOIR (n
=29). To fully explore the potential confounding that may exist between intravenous iron and the relationship presented here, the use of intravenous iron was included in a multivariable model revealing stability of all point estimates.
Although this study suggests a relationship between dose and outcomes, it has limitations. It is a secondary analysis of a trial designed to test the effect of target but not dose on outcomes. The ability to generalize dose thresholds to other populations should be carefully considered given the volunteerism in trial enrollment. Landmark analyses minimize biases created by differential dropout of subjects and intervening events between the time of randomization and the inception time for the outcome measurement. However, the impact of later hemoglobin levels and doses received after the landmark time cannot be examined using this methodology. Hemoglobin target, actual hemoglobin, and dose are closely related in CHOIR due to the design. Dose is a consequence of failure to respond. Associations between outcomes and hemoglobin, dose, or both may be confounded by factors not available in the CHOIR database. Their interplay on outcome cannot be definitely isolated without future, properly designed confirmation study. The conclusions of this analysis should therefore be considered hypothesis generating. And although hyporesponsiveness and high-dose requirements for epoetin significantly attenuated the increased risk associated with a higher hemoglobin target in CHOIR, these factors do not fully explain the increase in risk. Finally, while increased parathyroid hormone levels have been associated with an increased mortality risk as well as an increased risk of ESA resistance among patients with CKD,26,27
PTH measurements were not performed as a part of the CHOIR trial and will need to be the subject of further investigation.
This secondary analysis of the CHOIR trial demonstrates a relationship between epoetin-α dose and poorer outcomes beyond the relationship previously appreciated between dose as a marker of resistance conferred by comorbidity. Current Food and Drug Administration guidance provides a goal for epoetin-α therapy focused on a target hemoglobin. Considerable discussion has recently focused on the target that balances the quality-of-life benefit1,28,29
and the poorer outcomes associated with targeting a higher hemoglobin goal in CKD and ESRD populations.5,7
These data suggest that the dose of epoetin-α should play an increasing role in discussions to determine best policy-maximizing safety. Although future investigations on the impact of dose on outcomes may suggest a maximum dose for all patients or separate maximum doses for specific subgroups, these data suggest that among patients who do not achieve their targeted goal for hemoglobin, consideration should be given toward limiting dose escalation. For patients who do not respond to lower doses of epoetin-α, the final hemoglobin achieved may not be as important as the maximum doses required.