In 2009 TREAT, a large placebo-controlled trial of darbepoetin alfa, an erythropoiesis stimulating agent (ESA) was conducted in patients with type 2 diabetes who had chronic kidney disease and anemia (see TREAT). The rationale for the study was that CKD patients with anemia are at increased risk of developing adverse cardiovascular outcomes, so correction of anemia with darbepoetin alfa might reduce cardiovascular risk. However, TREAT failed to reach its endpoint of composite outcomes of death or a cardiovascular event and of death or end-stage renal disease. Furthermore, stroke occurred in twice as many patients assigned to darbepoetin alfa as compared to placebo.
Now, another trial of darbepoetin alfa has been completed and again the results are not what the investigators and the sponsor had hoped for. In the Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) trial, 2278 patients with systolic heart failure and anemia were randomized to receive either darbepoetin alfa or placebo (see RED-HR). The Hb target in the darbepoetin arm was 13 g/dL. The treatment duration was 60 months (5 years) during which a clear separation of Hb levels were achieved between the two groups. The primary outcome was a composite of death from any cause or hospitalization for worsening heart failure. The primary outcome occurred in 50.7% of darbepoetin alfa group and in 49.5% of placebo group (p=0.87). There was also no significant difference between darbepoetin alfa and placebo in any of the secondary outcomes. Thromboembolic adverse events were more common in the darbepoetin alfa-treated patients (13.5% versus 10.0%, p = 0.01). The authors concluded that treatment with darbepoetin alfa did not improve clinical outcomes in patients with systolic heart failure and mild to moderate anemia.
Commentary: Since their introduction more than 20 years ago, ESAs have had a significant impact in the life of patients with ESRD who suffer from severe anemia. However, some patients appear unresponsive to low dose ESA and require relatively high doses to maintain the Hb level within the recommended range. As a result, plasma erythropoietin levels, or more precisely plasma ESA levels have to be maintained several fold above the physiologic levels of anemic subjects without renal failure such as those with iron deficiency anemia. It is possible that these pharmacological levels of ESAs have deleterious effects, particularly on the cardiovascular system. In fact, patients with ESA-hypo-responsive anemia who require higher doses to maintain adequate Hb levels, appear to be at much higher risk of CV complications regardless of their Hb levels [Zhang et al AJKD 2004]. Since 2007, the FDA has required a “black box warning” on ESA labels (see also here), which was further restricted, following the availability of the TREAT data (see here). As we learn more about the cause or causes of ESA hypo-responsiveness, new approaches could be applied to improve ESA response.
© Copyright M. Loghman-Adham, MD