Anemia Correction in Patients with Diabetes and CKD

News from a trial of darbepoetin alfa in Type 2 diabetes and chronic kidney disease.

The treatment of anemia in patients with kidney disease or malignancy with erythrocyte-stimulating agents has received a great deal of attention in the medical and lay press over the last three years. The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), the findings of which were recently published in The New England Journal of Medicine, is the largest clinical trial involving patients with kidney disease.

TREAT is a randomized, double-blind, placebo-controlled trial in which patients with Type 2 diabetes and chronic kidney disease were assigned to receive either darbepoetin alfa (Aranesp®) or placebo for treatment of anemia. The goal for patients in the active treatment arm was a hemoglobin level of 13.0 g/dL. Patients in the placebo arm were provided with active medication if their hemoglobin levels fell below 9.0 g/dL. The primary endpoints were the composite outcomes of death, nonfatal myocardial infarction, congestive heart failure, stroke, and hospitalization for myocardial ischemia. Quality-of-life and functional assessments were measured with the Functional Assessment of Cancer Therapy-Fatigue (FACT-Fatigue) score and the 36-item Short Form (SF-36) Health Survey.

A total of 4,047 patients were enrolled, and 4,038 provided evaluable data (i.e., 2,012 in the darbepoetin alfa arm and 2,026 in the placebo arm). Patients were followed for a median of 29.1 months. At the time when the study was closed, 87.2% of patients were still being followed for clinical endpoints or had died. The median age of patients enrolled was 68 years, and 65.4% of these had a history of cardiovascular disease. Randomization successfully distributed all clinical and demographic factors, with the exception of a history of heart failure, which was present in a greater proportion of patients in the placebo group (31.5% vs 35.2%, P = .01).

In the group receiving darbepoetin alfa, the mean hemoglobin level was 12.5 g/dL, from three months to the end of treatment, and this mean hemoglobin level was achieved with a mean dose of 176 µg of darbepoetin alfa per month. The primary endpoint was reached in 31.4% of patients in the darbepoetin alfa arm and 29.7% of patients in the placebo arm (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.94-1.17; P = .41). There were no differences between the placebo arm and the darbepoetin alfa arm in the individual components of the endpoints, with the exception of stroke. Patients assigned to the darbepoetin alfa group experienced twice the risk for stroke as patients assigned to the placebo group (HR, 1.92; 95% CI, 1.38-2.68; P < .001).

With respect to patient-reported outcomes, modest differences were identified in the two groups. In response to the FACT-Fatigue survey, patients receiving darbepoetin alfa had a score 3 points higher than the patients assigned to placebo (54.7% vs 49.5%, P = .002), indicating that patients receiving active treatment experienced less fatigue. However, no other differences were noted in the quality-of-life factors measured by the SF-36 Health Survey.

Finally, there were no differences between the two groups in cancer-related adverse events. Some 39 deaths were attributed to cancer in the darbepoetin alfa group, and 25 deaths were attributed to cancer in the placebo group (P = .08). In the subgroup of patients with a history of a malignant condition at baseline, 60 of 188 patients died in the darbepoetin alfa group and 37 of 160 patients died in the placebo group (P = .002).

The study authors concluded that the risks for stroke and death among patients with a history of a malignant condition may outweigh the benefits of anemia correction.

N Engl J Med. 2009;361:2019-2032. Epub 2009 October 30