Treating Anemia Does Not Reduce the Risk for Cardiovascular or Renal Events in Diabetics With Renal Disease

Norra MacReady

November 03, 2009

November 3, 2009 (San Diego, California) — A rigorously designed and conducted trial has shown that anemia treatment with darbepoetin alfa (Aranesp) is no better than placebo at reducing mortality, heart failure, heart attacks, or the need for dialysis in patients with diabetes, anemia, and chronic kidney disease (CKD).

If anything, darbepoetin alfa was associated with a higher risk for stroke and cancer-related mortality, said Marc A. Pfeffer, MD, PhD, who presented the data in a plenary session here at Renal Week 2009: American Society of Nephrology (ASN) 2009 Annual Meeting. Dr. Pfeffer is a senior physician in cardiovascular medicine at Brigham and Women's Hospital in Boston, Massachusetts.

He predicted that these findings would prompt clinicians to reconsider their use of darbepoetin. "One would have to ask themselves: What am I trying to achieve now that I know there's a risk?"

Several studies have shown that the "triple whammy" of diabetes, CKD, and anemia greatly increases the risk for all-cause mortality, Dr. Pfeffer explained. Anemia was considered a marker of risk because low hemoglobin is an independent risk factor for renal and cardiovascular events, especially among people with diabetes.

The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) was launched in 2004 to determine whether raising hemoglobin with darbepoetin in patients with diabetes, anemia, and CKD not requiring dialysis would lower the risk for death, cardiovascular morbidity, or death from end-stage renal disease. The trial was conducted at 623 centers in 24 countries; Dr. Pfeffer was the principle investigator.

A total of 4038 patients were randomized to receive darbepoetin alfa (n = 2012) or placebo (n = 2026). At baseline, the groups were comparable in age, sex, race, ethnicity, duration of diabetes, and history of cardiovascular disease, except for a significantly higher history of heart failure in the placebo group. The target hemoglobin level was 13 g/dL, and rescue therapy was instituted any time a patient's hemoglobin dropped below 9 g/dL. Double-blinding was maintained by having a computer determine who needed rescue therapy and directing clinicians to use prefilled syringes.

TREAT had 2 composite primary end points: a cardiovascular composite, consisting of death, myocardial ischemia, congestive heart failure, and stroke; and a renal composite, consisting of death and end-stage renal disease. Participants had type 2 diabetes, CKD, defined as an estimated glomerular filtration rate of 20 to 60 mL/min per 1.73 m2, anemia, defined as serum hemoglobin of 11 g/dL or less, and transferring saturation of 15% or more. Subjects were followed for 48 months.

Darbepoetin alfa had a marked effect on hemoglobin level. The overall median hemoglobin level at baseline was 10.4 g/dL. Three months into the study, median hemoglobin was 12.5 g/dL in the darbepoetin group and 10.6 g/dL in the placebo group (P < .001). These levels persisted to the end of the trial.

However, correcting anemia had no effect on outcome. From the beginning of the study, the curves from the 2 groups showing the percent of patients experiencing cardiovascular or renal events overlapped nearly perfectly. In all, 632 patients in the darbepoetin group (31.4%) experienced some type of cardiovascular event, compared with 602 patients in the placebo group (29.7%; P = .41). For the renal composite, 652 of the darbepoetin patients (32.4%) experienced an event, compared with 618 (30.5%) of the people in the placebo group (P = .29). Among diabetic patients at risk for a cardiovascular event or mortality, darbepoetin "did not alter their journey" toward that outcome, Dr. Pfeffer said.

A particularly troubling finding was a doubling in the risk for stroke associated with darbepoetin. Over the course of the trial, 101 patients in the darbepoetin group (5%) experienced a fatal or nonfatal stroke, compared with 53 patients in the placebo group (2.6%; P < .001).

Composite and Component Event Rates in TREAT

End Point Darbepoetin Alfa (%) Placebo (%) P
End-stage renal disease or death 32.4 30.5 0.29
Cardiovascular events or death 31.4 29.7 0.41
All-cause death 20.5 19.5 0.48
MI 6.2 6.4 0.73
Heart failure 10.2 11.3 0.24
Stroke 5.0 2.6 <.001

The trial excluded patients with active malignancy, but 348 participants had a history of malignancy. Of those patients, some developed cancer during the study. Deaths attributable to malignancy in that group was higher among people taking darbepoetin than among those taking placebo (P = .002).

Darbepoetin did relieve fatigue. Patients in the darbepoetin group reported a mean increase of 4.2 points on the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) score, compared with a mean of 2.8 points reported by the placebo group (P = .002). Changes of 3 points or more are considered to be clinically significant, said Dr. Pfeffer. However, there were no differences in energy level or physical function in the 2 groups.

The TREAT findings could have an impact on clinical practice, said president of the ASN, Thomas M. Coffman, MD, from Durham, North Carolina, who was not involved in this research. "This was a very well-designed study, and people will have to make therapeutic decisions based on this new information. Darbepoetin failed to show evidence of cardiovascular benefit across the board. It will likely lead to a reduction in the use of erythropoietin-stimulating agents."

Dr. Pfeffer concluded that "these findings mean that, for many patients, the risks of darbepoetin outweigh the modest benefits."

American Society of Nephrology (ASN) Renal Week: Abstract 7010. Presented October 30, 2009.

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