A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease:
Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Study
Pfeffer M, Burdmann E, Chen C, et al. N Engl J Med 2009;361:2019-32.
Reviewed by: Gardy Mak
Purpose
Background
Primary
Endpoints
Secondary
Endpoints
Study Design
Study
Population
Exclusion
Criteria
To determine if darbepoetin alfa reduces the risk of cardiovascular and end-stage renal
disease in patients with DMII, CKD, and anemia
 Type II diabetes is one of the leading causes of chronic kidney disease
 Chronic kidney disease has many complications including cardiovascular disease
and anemia
 Anemia in chronic renal failure
o Decreased erythropoietin synthesis in the kidneys
o Erythropoietin is responsible for RBC development and maturation from
precursors in the bone marrow
o Majority of this hormone is produced in the kidneys
 Red blood cell transfusions
o Iron overload
o Volume overload
o Infection
 Recombinant human erythropoietin: Erythropoiesis-stimulating agents (ESAs)
o Increase Hgb levels
o Eliminates need for continuous transfusion
o Common SE: hypertension, edema, fatigue, hypotension, and headache
o Epoetin alfa (Epogen, Procrit)
o Darbepoetin alfa (Aranesp)
 Type II diabetes, CKD, and anemia can all individually increase the risk of
cardiovascular and end-stage renal disease
 Composite outcome of death or cardiovascular event (nonfatal MI, CHF, stroke, or
hospitalization for MI)
 Composite outcome of death or end-stage renal disease
 Time to death
 Death from cardiovascular causes
 Rate of decline in the estimated GFR
 Changes in patient-reported outcomes at week 25
o FACT-Fatigue score
o 36-Item Short-Form General Health Survey questionnaire
 Randomized
 Double-blind
 Placebo-controlled
 623 sites in 24 countries
 Event driven
 Median follow-up duration of 29.1 months
 DMII
 CKD (eGFR of 20-60 ml/min/1.73 m2) not on dialysis
 Anemia (Hgb ≤ 11.0 g/dL)
 Transferrin saturation of 15% or more
 Uncontrolled hypertension
 Previous kidney transplantation or scheduled kidney transplant
 Current IV antibiotics, chemotherapy, radiation
 Cancer
 HIV
 Active bleeding
 Hematologic disease
 Pregnancy
 History of cardiovascular event, seizure or major history
Treatment
(N = 4038)
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Statistical
Analysis
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Patient
Population
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Results
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ESA in the last 12 weeks prior to randomization
Darbepoetin alfa group: N = 2012
o 12 different strengths
o Point-of-care device to select dose using computer algorithm
o Adjust dose to maintain Hgb at ~13.0 g/dL
Placebo group: N = 2026
o Matching pre-filled syringes
o Rescue darbepoetin alfa if Hbg < 9.0 g/dL
o Return to placebo once ≥ 9.0 g/dL
Hgb levels and vital signs measured every 2 weeks during titration period then
monthly
Event driven, 1203 cardiovascular composite events required to provide 80%
statistical power to detect a 20% risk reduction
o Two-sided type I error of 0.048
Primary and secondary outcomes
o Intention-to-treat analysis
Hazard ratios with 95% confidence intervals
o Cox proportional-hazards model
Patient reported outcomes
o Last-observation-carried forward method
o T-tests
Baseline characteristics were similar between groups
o Age, history of CAD, stroke, peripheral arterial disease, MI, Hgb level, and
cardiovascular disease medications
History of heart failure more predominant in the placebo group than darbepoetin
alfa group (35.2% and 31.5% respectively, unadjusted P = 0.01)
Hemoglobin levels from baseline and end of treatment were measured
o Darbepoetin alfa: Median Hgb 12.5 g/dL (interquartile range, 12.0 to 12.8)
o Placebo: Median Hgb 10.6 g/dL (interquartile range, 9.9-11.3, P<0.001)
Red-cell transfusions
o Darbepoetin alfa: 297 patients (14.8%)
o Placebo: 496 patients (24.5%) [hazard ratio 0.56, 95% CI, 0.49 to 0.65,
P<0.001]
Primary Outcomes
Endpoint
Darbepoetin
Alfa
(N=2012)
Cardiovascular
632 (31.4)
composite
endpoint
Stroke
101 (5.0)
Renal composite
endpoint
ESRD
Placebo
(N=2026)
Hazard Ratio
(95% CI)
P
Value
NNH
602 (29.7)
1.05 (0.941.17)
0.41
59
53 (2.6)
1.92
(1.3802.68)
1.06 (0.951.19)
1.02 (0.871.18)
<0.001
42
0.29
53
0.83
200
652 (32.4)
618 (30.5)
338 (16.8)
330 (16.3)
Secondary Outcomes
 FACT-Fatigue score
o Only assessed patients with both baseline and week-25 scores
o Darbepoetin alfa: 963 of 1762 patients (54.7%) had an increase of 3 or more
points
o Placebo: 875 of 1769 patients (49.5%)
o P=0.002
o NNT=20
Conclusion
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Short-Form General Health Survey
o No significant difference between groups
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Darbepoetin alfa significantly increased Hgb levels and had clinical benefits in
improving fatigue score compared to placebo
Fewer transfusions required in the darbepoetin alfa group than the placebo group
However, darbepoetin alfa did not demonstrate significant effect in reducing
cardiovascular events and the time to end stage renal disease in comparison to
placebo
Instead, there is an increase in one of the cardiovascular components when Hgb
target is 13 g/dL
o Higher incidence of stroke in the darbepoeitin alfa group (5% vs 2.6% in the
placebo group)
Pts with DMII, CKD and anemia not on dialysis are not likely to benefit from ESAs
at a Hgb of 13 g/dL
Long-term study
Randomization
Blinding
Multinational, multicenter
Large sample size
Higher Hgb target than current recommended goal of 10 to 12 g/dL (FDA, 2007
update) and 11 to 12 g/dL (National Kidney Foundation Dialysis Outcomes Quality
Initiative) in patients treated with darbepoetin alfa
o Uncertain whether the Hgb level or ESA use is causing the increase stroke
incidences
Baseline imbalances
Baseline Hgb was 10.4 and 10.5 in darbepoetin alfa and placebo group, respectively
Rate of darbepoetin alfa adjustment not specified
Funded by Amgen, a company that manufactures Aranesp
Correction of Hemoglobin and Outcomes in Renal Insufficency (CHOIR) study
o Similar patient population
o Discontinued prematurely due to increase cardiovascular events in the higher
Hgb group
Current guidelines recommend darbepoetin alfa use in patients with anemia and
CKD
o FDA indication: patients with CRF not on dialysis should have a Hgb less than
10 g/dL prior to starting treatment
Studies show that ESAs might increase mortality and disease progression in patients
with certain cancers and anemia
o June 2008 European Medicines Agency recommended blood transfusions over
ESAS in cancer patients on chemotherapy and expected to live reasonably long
o FDA mandated changes to ESA indications: ESAs are not indicated in patients
on myelosuppressive agents if cure is the expected outcome
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Strengths
Limitations
Clinical
Relevance
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NEPHRODIAB2: ongoing clinical trial comparing target Hgbs level in
patients with DMII, CKD, and anemia
Schrier, Stanley et al. Role of erythopoiesis-stimulating agents in the treatment of anemia in patients with cancer. UpToDate. Jan 2010.
http://www.uptodate.com.proxy.westernu.edu/online/content/topic.do?topicKey=genl_onc/14286&selectedTitle=1~150&source=search_resu
lt#H14
Berns, Jeffrey. Anemia of chronic kidney disease: Target hemoglobin/hematocrit for patients treated with erythropoietic agents. UpToDate.
Feb 2010.
http://www.uptodate.com.proxy.westernu.edu/online/content/topic.do?topicKey=dialysis/36521&source=see_link#H10
Pham, David. PHRM 6202 Pharmacy Practice II: Anemia Lecture. Sept 2008.
Darbepoetin. Lexicomp. http://online.lexi.com.proxy.westernu.edu/crlsql/servlet/crlonline