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evident
Original paper
2009NEJMNephrology

TREAT

A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease

RCTAnemia in CKD

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Overview

In diabetes, CKD, and anemia not on dialysis, darbepoetin did not reduce either primary composite and increased stroke.

Clinical takeaway

Do not use darbepoetin alfa to push hemoglobin toward 13 g/dL for cardiovascular or kidney protection. Both primary composites were null, and stroke was more common.

Key result

Primary: death or a cardiovascular event HR 1.05 (95% CI 0.94-1.17; P=0.41); death or ESRD HR 1.06 (95% CI 0.95-1.19; P=0.29). Stroke (not a primary end point): 101 vs 53 events (HR 1.92; 95% CI 1.38-2.68; P<0.001).

Practice impact

Do not target hemoglobin near 13 g/dL with darbepoetin in nondialysis diabetic CKD; stroke risk rose without outcome benefit.

Evidence

Study design

Randomized trial of darbepoetin alfa versus placebo, with rescue darbepoetin alfa if hemoglobin fell below 9.0 g per deciliter, in patients with diabetes, chronic kidney disease, and anemia.

Enrollment

4,038

Follow-up

Not listed

Geography

Not listed

Clinical question

Does darbepoetin alfa targeted to a hemoglobin of about 13 g/dL reduce death or cardiovascular events, or death or end-stage renal disease, compared with placebo in diabetes, CKD, and anemia?

Population

  • 4038 patients with diabetes, chronic kidney disease, and anemia who were not undergoing dialysis.

Intervention

Darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter (2012 patients).

Comparator

Placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter (2026 patients).

Primary outcome

Two primary composite outcomes: death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia), and death or end-stage renal disease.

Darbepoetin alfa did not reduce either primary composite. Death or a cardiovascular event: HR 1.05 (95% CI 0.94-1.17; P=0.41). Death or end-stage renal disease: HR 1.06 (95% CI 0.95-1.19; P=0.29).

Hazard ratio (death or a cardiovascular event) / 1.05 / 95% CI 0.94-1.17 / p=0.41

Key results

  • Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 assigned to placebo; hazard ratio 1.05 (95% CI 0.94-1.17; P=0.41).
  • Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 assigned to placebo; hazard ratio 1.06 (95% CI 0.95-1.19; P=0.29).
  • Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 assigned to placebo; hazard ratio 1.92 (95% CI 1.38-2.68; P<0.001).
  • Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue with darbepoetin alfa.

Harms

  • Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 assigned to placebo (hazard ratio 1.92; 95% CI 1.38-2.68; P<0.001).

Clinical Use

Practice impact

  • Do not start darbepoetin alfa in nondialysis diabetic CKD to chase a hemoglobin near 13 g/dL for cardiovascular or renal protection.
  • The authors concluded that for many decision-makers the stroke risk outweighs the potential benefits (fewer transfusions and a modest fatigue change).

Applicability

  • Most applicable to patients with diabetes, CKD, and moderate anemia who are not on dialysis.
  • The comparison was an approximately 13 g/dL hemoglobin target versus placebo with rescue below 9.0 g/dL, not a trial of treating severe symptomatic anemia.

Limitations

  • Follow-up duration is not stated in the abstract.
  • Event counts for the composites are given without percentages or person-time.
  • Fatigue improvement is described only as modest, without a numeric effect size.

Common misinterpretations

  • A lower transfusion rate is not a substitute for the null primary composites.
  • This does not test darbepoetin for hemoglobin values below 9 g/dL; the placebo group received rescue therapy at that threshold.
  • Stroke was not a primary end point, but the estimate is large and the confidence interval excludes no effect.

Citation

Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019-2032. doi:10.1056/NEJMoa0907845

The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke.