Mechanism of Increased Mortality Risk with Erythropoietin Treatment to Higher Hemoglobin Targets

Abstract

Recent randomized, controlled trials indicate that there is a strong trend for increased risk for death or adverse composite outcomes with erythropoiesis-stimulating agent treatment in kidney disease to hemoglobin targets higher than those currently recommended. The failure of these trials to find a benefit of higher hemoglobin is in stark contrast to findings from large, observational, population-based studies that continue to demonstrate the association of low hemoglobin with adverse outcomes. The mechanisms for the adverse effect of higher hemoglobin targets that are seen in the randomized, controlled trials are poorly understood. This review explores hypotheses involving (1) the effect of achieved hemoglobin itself, (2) the role of erythropoiesis-stimulating agent treatment, (3) the use of iron supplementation, (4) increased blood pressure, and (5) erythropoiesis-stimulating agent hyporesponsiveness. Because the causal pathway has yet to be determined, further research is strongly encouraged. Clinical practice, however, should avoid erythropoiesis-stimulating agent treatment to higher hemoglobin targets, particularly in those with significant cardiovascular morbidity and those who require disproportionately high dosages of erythropoietin-stimulating agents to achieve recommended hemoglobin levels.

2009

“…We lack the clinical or biomarker-derived tools to characterize precisely risk or potential benefit and thus to individualize our Hb strategy (and this would apply of course to many other treatments, too [e.g., plasma phosphate]). What the precise mechanism(s) might be to explain rHuEPO "toxicity" remains unknown (38); Figure 3 shows some of the many possibilities. A much greater effort is now necessary to understand how, and in whom, benefit can be conferred using these important and powerful medications.…”

Pharmacologic Adjuvants to Reduce Erythropoietin Therapy Dose in Anemia of Chronic Kidney Disease and End Stage Renal Disease

“…Recently, studies targeting higher Hb levels or using higher EPO dosing regimens in the correction of anemia have shown detrimental effects including increased all cause mortality, cardiac and cerebral vascular events and vascular access thrombosis 8-10, 54 It is not clear whether this is due to higher HCT or EPO the molecule itself at higher concentration. This review article focused on adjuvant oral and parenteral agents that have been used along with EPO to reduce its dose and give foundation to research in randomized control trials.…”

Use of agents stimulating erythropoiesis in digestive diseases

“…Factors that influence the increase in mortality with higher hemoglobin targets may include the impossibility of achieving the target hemoglobin, a too high hemoglobin target, the toxic effects of high doses of ESAs, the presence of comorbidity and other features [131][132][133][134][135] . These factors were evaluated in a second analysis of the CHOIR study [136] that found no clinical factor associated with risk, after adjustment and multivariate analysis, except for high dose of epoetin (> 20 000 U/wk), which was an independent risk factor for death, myocardial infarction, heart failure, or stroke.…”