TREAT

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Pfeffer MA, et al. "A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease". The New England Journal of Medicine. 2009. 361(21):2019-32.
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Clinical Question

In patients with type 2 diabetes mellitus, chronic kidney disease, and anemia, what is the efficacy of erythrocyte-stimulating agents in decreasing mortality, CV events, or advancement to ESRD?

Bottom Line

TREAT demonstrated that targeting a hemoglobin of >13 g/dL with erythrocyte-stimulating agents does not confer a survival benefit in T2DM with CKD, but does increase the risk of stroke.

Major Points

Erythrocyte-stimulating agents (ESA) increase hemoglobin concentration, though their effects on clinical outcomes in non-dialysis-dependent patients was unclear. The 2006 CHOIR trial demonstrated an increased risk of HF and hospitalizations in patients with CKD randomized to ESA therapy targeting a hemoglobin of 13.5 g/dL when compared to a target of 11.3 g/dL. CREATE[1] demonstrated that higher hemoglobin targets were associated with more rapid progression to ESRD. ESAs did not appear to influence the rate of CV events.

The 2009 Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) trial randomized 4,038 patients with T2DM, CKD, and anemia to darbepoetin or placebo. The darbepoetin group received therapy to maintain a hemoglobin >13 g/dL, while the placebo group received rescue darbepoetin if hemoglobin fell below 9 g/dL. With a mean follow-up of 29.1 months, there was no difference between the groups for the coprimary outcome of death or CV events and death or ESRD. The darbepoetin group had a higher rate of strokes (5% vs. 2.5%; NNH 40). The results from TREAT make an argument against such high hemoglobin targets with ESA therapy in patients with these constellation of diseases.

Guidelines

The National Kidney Foundation guidelines[2] have not been updated since 2007. However, The American Society of Nephrology's contributions to Choosing Wisely (2012)[3] recommends against ESA-targeted hemoglobin levels above 9-11 g/dL in asymptomatic patients with CKD.

Design

  • Multicenter, double-blinded, parallel-group, randomized, placebo-controlled trial
  • N=4,038
    • Darbepoeitin alfa (n=2,012)
    • Placebo (n=2,026)
  • Setting: 623 centers in 24 countries
  • Enrollment: 2004-2007
  • Median follow-up: 29.1 months
  • Analysis: Intention-to-treat
  • Primary outcomes:
    • Death or CV event
    • Death or ESRD

Population

Inclusion Criteria

  • Type 2 diabetes mellitus
  • GFR 20-60ml/min (by MDRD)
  • Hemoglobin ≤11g/dl
  • Transferrin saturation >15%

Exclusion Criteria

  • Uncontrolled hypertension
  • Previous kidney transplantation or scheduled receipt from living donor
  • Current IV antibiotic use
  • Chemotherapy or radiation therapy
  • Cancer (except basal-cell or squamous cell carcinoma of skin)
  • HIV
  • Active bleeding
  • Hematologic disease
  • Pregnancy
  • Coronary event, grand mal seizure, major surgery, or receipt of ESA in the 12 weeks prior to randomization

Interventions

  • Patients randomized to darbepoetin alfa or placebo
  • Darbepoetin group had dose adjusted to maintain hemoglobin 13g/dL
  • Placebo group received darbepoetin alfa as rescue agent for hemoglobin <9g/dL
  • Hemoglobin and vital signs were measured every 2 weeks, transferring saturation and ferritin levels measured quarterly, and others at 24-week intervals

Outcomes

Comparisons are darbepoetin vs. placebo.

Primary Outcomes

Death or CV event
31.4% vs. 29.7% (HR 1.05; 95% CI, 0.94 to 1.17; P=0.41)
Death or ESRD
32.4% vs. 30.5% (HR 1.06; 95% CI, 0.95 to 1.19; P=0.29)

Secondary Outcomes

Stroke
5% vs. 2.5% (HR 1.92; 95% CI 1.38-2.68; P<0.001; NNH 40)
Increase of ≥3 points in patient-reported FACT-Fatigue symptom score

Higher score indicates less fatigue.

54.7% vs. 49.5% placebo (P=0.002)

Criticisms

  • Did not target different hemoglobin levels for different sexes[4]
  • Incomplete details pertaining to stroke[4]
  • Unclear effect of iron administration in placebo group[4]

Funding

  • Amgen, the manufacturers of Aranesp (the brand name of darbepoetin alfa)

Further Reading

  1. Drueke TB, et al. "Normalization of hemoglobin level in patients with chronic kidney disease and anemia." The New England Journal of Medicine. 2006;355(20):2071-2084.
  2. KDOQI guidelines for CKD care. Kidney.org. Accessed 2014-08-25.
  3. American Society of Nephrology. "Five things physicians and patients should question." Choosing Wisely Campaign. Released 2012-04-04. Choosingwisely.org. Accessed 2014-08-25.
  4. 4.0 4.1 4.2 Multiple authors. "Correspondence: Darbepoetin alfa and chronic kidney disease." The New England Journal of Medicine. 2010;362:653-655.