Risks outweighed benefits of darbepoetin alfa in patients with type 2 diabetes, CKD, anemia

Renal Week 2009

Darbepoetin alfa did not decrease the risk for death, cardiovascular or renal events in patients with type 2 diabetes, chronic kidney disease and moderate anemia enrolled in the Trial to Reduce CV Events with Aranesp Therapy (TREAT). Further, darbepoetin alfa was associated with an increased risk for stroke.

“There was no significant difference in the overall rates of either the primary CV composite endpoint or the primary renal composite endpoint with the use of the therapeutic strategy of increasing the hemoglobin level with darbepoetin alfa (Aranesp, Amgen) vs. placebo,” the TREAT researchers wrote in The New England Journal of Medicine.

TREAT researchers randomly assigned 4,038 patients with type 2 diabetes, CKD and anemia to either darbepoetin alfa or placebo, with a target hemoglobin level of 13 g/dL. Rescue darbepoetin alfa was administered when the hemoglobin level was <9 g per deciliter, with a return to placebo once the hemoglobin level was ≥9 g per deciliter.

The results were released during a late-breaking clinical trials session at Renal Week 2009 and published simultaneously in The New England Journal of Medicine.

Cardiovascular, renal events

The researchers gathered HbA1c levels and vital sign measurements every two weeks during the drug titration period and every month after, and assessed patient-reported outcomes and health resource utilization at 24-week intervals.

Death or a CV event occurred in 632 patients assigned to darbepoetin alfa (n=2,012) vs. 602 patients assigned to placebo (n=2,026; HR=1.05; 95% CI, 0.94 to1.17). Death or end-stage renal disease was reported in 652 patients assigned to treatment vs. 618 patients assigned to placebo (HR=1.06; 95% CI, 0.95 to 1.19).

Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa compared with 53 patients assigned placebo (HR=1.92; 95% CI, 1.38-2.68).

The darbepoetin alfa group achieved a median hemoglobin concentration of 12 g/dL (interquartile range, 12.0 to 12.8) and the placebo group achieved a median concentration of 10.6 g/dL (interquartile range, 9.9 to 11.3).

Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa compared with 496 patients assigned to placebo during the study period (P<.001). Researchers reported only a modest improvement in patient-reported fatigue in the darbepoetin alfa group when compared with the placebo group.

“It is our view that, in many patients with diabetes, chronic kidney disease and moderate anemia who are not undergoing dialysis, the increased risk of stroke and possibly death among patients with a history of a malignant condition will outweigh any potential benefit of erythropoiesis-stimulating agents,” the researchers concluded.

Key study

“The TREAT will be a key study in the treatment of patients with CKD,” Philip A. Marsden, MD, of Keenan Research Centre of the Li Ka Shing Knowledge Institute at St. Michaels Hospital and the University of Toronto, wrote in an accompanying editorial.

“Despite a reduction in red-cell transfusions and modest improvement in patient-reported fatigue, the current study does not confirm the findings of the earlier Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial, which studied the use of epoetin alfa treatment to achieve two different target hemoglobin levels. Therefore, in retrospect, it is ironic that others had argued that because of its placebo group, the TREAT should be discontinued.”

Marsden noted that the risk for death or a major CV event was 31% in the overall cohort, “a reminder of the incredible burden of CV disease in patients with CKD.”

However, he cautioned that the TREAT data may not be applied to other populations such as those undergoing dialysis, and alternative dosing strategies may be required to alleviate the risk for stroke and conserve the benefits observed in quality of life.

This trial was sponsored by Amgen. – by Jennifer Southall

Marsden PA. N Engl J Med. 2009;doi:10.1056/NEJMe0909664.
Pfeffer MA. N Engl J Med. 2009;doi:10.1056/NEJMoa0907845.

This is a very thoughtful study that addresses the issue of correcting hemoglobin in people with advanced nephropathy with an erythropoietin-type drug. The evidence is clear there is no benefit and the risk for stroke is increased. This is consistent with previous outcomes in dialysis patients. While this seems antithetical, this observation may have much more to do with the erythropoietin preparation itself. There is evidence that giving large doses of erythropoetin increases clotting and platelet adhesion and, thus, stroke risk should be increased. Investigation of a different erythropoetin release mechanism or different way to increase hemoglobin should be investigated. Also note that the hemoglobin level in TREAT was similar to the group with higher CV events in CHOIR. Again, a relationship of higher erythropoetin dose and CV events. Until better preparations or release systems of erythropoetin are available, it would be the better part of valor to keep hemoglobin levels <11.5 g/dL based on the available data.

– George Bakris, MD

Endocrine Today Editorial Board member