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

Abstract

Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested.
In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.
Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group.
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. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.)

Full text

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10.1056/nejmoa0907845 nejm.org
1
The new england
journal of medicine
A Trial of Darbepoetin Alfa in Type 2 Diabetes
and Chronic Kidney Disease
Marc A. Pfeffer, M.D., Ph.D., Emmanuel A. Burdmann, M.D., Ph.D., Chao-Yin Chen, Ph.D., Mark E. Cooper, M.D.,
Dick de Zeeuw, M.D., Ph.D., Kai-Uwe Eckardt, M.D., Jan M. Feyzi, M.S., Peter Ivanovich, M.D.,
Reshma Kewalramani, M.D., Andrew S. Levey, M.D., Eldrin F. Lewis, M.D., M.P.H., Janet B. McGill, M.D.,
John J.V. McMurray, M.D., Patrick Parfrey, M.D., Hans-Henrik Parving, M.D., Giuseppe Remuzzi, M.D.,
Ajay K. Singh, M.D., Scott D. Solomon, M.D., and Robert Toto, M.D., for the TREAT Investigators*
ABSTRACT
The affiliations of the authors are listed
in the Appendix. Address reprint requests
to Dr. Pfeffer at the Cardiovascular Divi-
sion, Brigham and Women’s Hospital,
75 Francis St., Boston, MA 02115, or at
mpfeffer@rics.bwh.harvard.edu.
*The Trial to Reduce Cardiovascular Events
with Aranesp Therapy (TREAT) com-
mittees and teams are listed in the Ap-
pendix, and investigators and individual
sites are listed in the Supplementary
Appendix, available with the full text of
this article at NEJM.org.
This article (10.1056/NEJMoa0907845)
was published on October 30, 2009, at
NEJM.org.
N Engl J Med 2009;361.
Copyright © 2009 Massachusetts Medical Society.
BACKGROUND
Anemia is associated with an increased risk of cardiovascular and renal events
among patients with type 2 diabetes and chronic kidney disease. Although darbe-
poetin alfa can effectively increase hemoglobin levels, its effect on clinical out-
comes in these patients has not been adequately tested.
METHODS
In this study involving 4038 patients with diabetes, chronic kidney disease, and
anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemo-
globin level of approximately 13 g per deciliter and 2026 patients to placebo, with
rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter.
The primary end points were the composite outcomes of death or a cardiovascular
event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospital-
ization for myocardial ischemia) and of death or end-stage renal disease.
RESULTS
Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa
and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo,
1.05; 95% confidence interval [CI], 0.94 to 1.17; P = 0.41). Death or end-stage renal
disease occurred in 652 patients assigned to darbe poetin alfa and 618 patients as-
signed to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P = 0.29). Fatal or nonfatal
stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned
to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions
were administered to 297 patients assigned to darbepoetin alfa and 496 patients as-
signed to placebo (P<0.001). There was only a modest improvement in patient-report-
ed fatigue in the darbepoetin alfa group as compared with the placebo group.
CONCLUSIONS
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. For many
persons involved in clinical decision making, this risk will outweigh the potential
benefits. (ClinicalTrials.gov number, NCT00093015.)
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T
cardiovascular events and end-stage renal dis-
ease.1,2 Intensive treatment of concomitant con-
ventional risk factors such as hypertension and
elevated levels of low-density lipoprotein reduces
fatal and nonfatal cardiovascular complications
and slows the progression of kidney disease.3-8
Observational studies suggest that anemia can
be considered another biomarker of risk, since a
lower hemoglobin level is independently associ-
ated with a higher rate of cardiovascular and re-
nal events,9-11 especially among patients with
diabetes.12,13 Whether the use of erythropoiesis-
stimulating agents (ESAs) to increase hemoglo-
bin levels lowers this risk is not known.14
Early studies involving the use of recombinant
human erythropoietin in patients with severe
anemia who were undergoing dialysis showed a
reduced requirement for blood transfusions and
improved quality-of-life assessments, which were
considered major advances.15,16 Extrapolations
from these favorable effects to other populations,
including patients with anemia and earlier stages
of chronic kidney disease, led to the wider use
of ESAs. The presumption of the benefits associ-
ated with the use of ESAs was so pervasive that
major clinical trials considered the use of pla-
cebo unnecessary or even unethical.17-19 In fact,
there were no placebo-controlled trials in a recent
meta-analysis of the use of ESAs in patients with
chronic kidney disease.20 Although ESAs have
been available for more than two decades, the
hypothesis that this treatment approach would
lower the risks associated with anemia and im-
prove the prognosis has not been examined.21
We conducted the Trial to Reduce Cardiovascu-
lar Events with Aranesp Therapy (TREAT) to test
the hypothesis that, in patients with type 2 dia-
betes, chronic kidney disease that does not re-
quire dialysis, and concomitant anemia, increas-
ing hemoglobin levels with the use of this agent
would lower the rates of death, cardiovascular
events, and end-stage renal disease.22
ype 2 diabetes mellitus and chronic
kidney disease frequently coexist, and each
disease independently increases the risk of
Methods
The TREAT was a randomized, double-blind,
placebo-controlled trial conducted at 623 sites in
24 countries (see the Supplementary Appendix,
available with the full text of this article at NEJM.
org). The institutional review board or ethics
committee at each site approved the protocol,
and all patients provided written informed con-
sent. Enrollment occurred from August 25, 2004,
through December 4, 2007.
The trial was sponsored by Amgen and de-
signed in collaboration with an academic execu-
tive committee. Data collection and management
were the responsibility of the sponsor, with over-
sight by the executive committee. The Statistical
Data Analysis Center at the University of Wis-
consin prepared the interim unblinded reports
for the independent data and safety monitoring
committee, which oversaw patient safety and the
quality of trial conduct. The independent aca-
demic statistical center also performed all analy-
ses for this article and provided the writing
group with unrestricted access to the data. The
manuscript was prepared by the principal inves-
tigator and subsequently revised and edited by
all the authors. All the authors decided to submit
the article for publication and assume responsi-
bility for the accuracy and completeness of the
reported data.
Study Population
Patients with type 2 diabetes, chronic kidney dis-
ease (an estimated glomerular filtration rate [GFR]
of 20 to 60 ml per minute per 1.73 m2 of body-
surface area, calculated with the use of the four-
variable Modification of Diet in Renal Disease
formula), anemia (hemoglobin level, ≤11.0 g per
deciliter), and a transferrin saturation of 15% or
more were eligible for enrollment. Patients with
any of the following factors were excluded: un-
controlled hypertension; previous kidney trans-
plantation or scheduled receipt of a kidney trans-
plant from a living related donor; current use of
intravenous antibiotics, chemotherapy, or radiation
therapy; cancer (except basal-cell or squamous-
cell carcinoma of the skin); diagnosed human
immunodeficiency virus infection; active bleed-
ing; a hematologic disease; or pregnancy. Patients
who had had a cardiovascular event or grand mal
seizure, had undergone major surgery, or had re-
ceived an ESA in the 12 weeks before randomiza-
tion were also ineligible.
Study Procedures
During a 2-week screening period, prestudy labo-
ratory assessments were obtained and the eligi-
bility of patients who had provided consent was
confirmed. Patients were randomly assigned with
the use of a computer-generated, permuted-block
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Darbepoetin Alfa Therapy for reduction of Cardiovascular Events
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design, in a 1:1 ratio, to receive darbepoetin alfa
(Aranesp, Amgen) or placebo. Randomization was
stratified according to the study site, the baseline
level of proteinuria (with marked proteinuria de-
fined as a ratio of total protein to creatinine [cal-
culated in milligrams per deciliter] of ≥1.0 in a
spot urine sample), and an investigator-designat-
ed history of cardiovascular disease. Darbepoetin
alfa and placebo were supplied in matching pre-
filled syringes at 12 different strengths. A third
party used a point-of-care device to monitor hemo-
globin levels and enter the value into an interac-
tive voice-response system that selected the dos-
age according to a computer algorithm (see the
Supplementary Appendix). This algorithm was
designed to adjust the dose in order to maintain
the hemoglobin level at approximately 13.0 g
per deciliter in the patients assigned to darbe-
poetin alfa.
Patients in the placebo group were assigned
to receive darbepoetin alfa as a rescue agent if
the hemoglobin level fell below 9.0 g per deciliter,
with a return to placebo once the hemoglobin
level was 9.0 g per deciliter or higher. The site
investigator was to be notified if any patient had
a hemoglobin value of 7.0 g per deciliter or less, a
value of 16.0 g per deciliter or more, or a decrease
of 2.0 g per deciliter or more in a 4-week period.
Measurements of hemoglobin levels and vital
signs were performed every 2 weeks during the
study-drug–titration period and monthly there-
after. Transferrin saturation and ferritin levels
were measured quarterly; other laboratory assess-
ments and spot urine collections were performed
at 24-week intervals. Patient-reported outcomes
and health resource utilization were assessed at
weeks 1, 13, and 25 and every 24 weeks thereafter.
At each visit, information was gathered regard-
ing adverse events, hospitalization, transfusions,
and the concomitant use of other medications.
Evaluation of Outcomes
The primary end points were the time to the
composite outcome of death from any cause or a
cardiovascular event (nonfatal myocardial infarc-
tion, congestive heart failure, stroke, or hospital-
ization for myocardial ischemia) and the time to
the composite outcome of death or end-stage re-
nal disease (see the Supplementary Appendix).
The overall alpha level for the primary end points
was split: 0.048 for the cardiovascular composite
outcome and 0.002 for the renal composite out-
come. All potential end points were adjudicated
by a clinical end-point committee whose mem-
bers were unaware of the treatment assignments,
and the hematocrit and hemoglobin values were
redacted from the documents under review. Im-
portant secondary end points included time to
death, death from cardiovascular causes, and the
components of the primary end points, as well as
the rate of decline in the estimated GFR and
changes in patient-reported outcomes at week 25
measured with the use of the Functional Assess-
ment of Cancer Therapy–Fatigue (FACT-Fatigue)
instrument (on which scores range from 0 to 52,
with higher scores indicating less fatigue) and the
36-Item Short-Form General Health Survey ques-
tionnaire (calculated with norm-based scoring so
that 50 is the average score, with higher scores
indicating a better quality of life) (added after the
second protocol amendment in May 2005).
Monitoring
The independent data and safety monitoring com-
mittee reviewed safety reports monthly with for-
mal interim analyses scheduled when approxi-
mately 20, 40, 60, and 80% of the total expected
cardiovascular composite events had occurred.
Initial guidelines for early discontinuation in-
cluded a symmetric O’Brien–Fleming alpha-spend-
ing function. In April 2006, data from a non–
placebo-controlled trial of a different ESA in
patients with chronic kidney disease showed that
treatment aimed at achieving a higher hemoglo-
bin level (13.5 g per deciliter vs. 11.3 g per deci-
liter) was associated with increased rates of ad-
verse clinical events.17 This information and more
equivocal results from a related, smaller trial18
were proactively communicated to our patients,
investigators, and the data and safety monitoring
committee. The committee made no recommen-
dation to alter or terminate the study on the basis
of interim data that already reflected more clin-
ical events than the numbers of events in these
related trials. The consent form was modified
with the addition of the new information regard-
ing potential harm, and all study participants
were asked to provide written informed consent
again. The executive committee requested that
the data and safety monitoring committee adopt
a more cautious stopping rule, with the use of a
one-sided alpha of 0.05 for harm at each assess-
ment (without adjustment for multiple testing)
for either the cardiovascular composite outcome
or death. The boundaries for efficacy remained
unchanged, and with this new mandatory stop-
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4
ping rule for harm, the committee made no rec-
ommendation to terminate the trial before its
scheduled conclusion.
Statistical Analysis
The trial was event driven, with a total of 1203
cardiovascular composite events required to pro-
vide 80% statistical power to detect a 20% risk
reduction for this outcome, with a two-sided type
I error of 0.048 (unadjusted for interim analyses).
We aimed to enroll approximately 4000 patients;
assumptions included an annualized rate of events
in the placebo group of 12.5%, a 15% loss to
follow-up, and attenuation of the treatment ef-
fect due to the anticipated use of ESAs in patients
who had progression to end-stage renal disease.
Time-to-event analyses were performed with
the use of life-table methods according to the
intention-to-treat principle. Kaplan–Meier cumu-
lative incidence curves were compared with the
use of a two-sided log-rank test, stratified accord-
ing to the baseline proteinuria level and the pres-
ence or absence of a history of cardiovascular
disease. Estimated hazard ratios (for darbepoetin
alfa vs. placebo) and 95% confidence intervals
were obtained with the use of stratified Cox
proportional-hazards models. Patients who dis-
continued either study drug early, including pa-
tients who began treatment with dialysis or un-
derwent transplantation, were followed for study
end points.
Categorization of adverse events was based on
groupings of preferred terms defined by the
standardized queries in the Medical Dictionary
for Regulatory Activities.23 Analyses of patient-
reported outcomes were prespecified to impute
missing data with the last-observation-carried-
forward method and to use t-tests for treatment
comparisons, with means and standard devia-
tions. Reported P values are nominal and have
not been adjusted for multiple comparisons. Ad-
ditional statistical methods are described in the
Supplementary Appendix.
Results
Patients
We enrolled a total of 4047 patients, but before
unblinding, we excluded all information regard-
ing 9 patients from two sites that did not adhere
to Good Clinical Practice guidelines (4 patients
who were randomly assigned to darbepoetin alfa
and 5 patients who were randomly assigned to
placebo). Of the 4038 patients evaluated, 2012
were assigned to receive darbepoetin alfa and
2026 were assigned to receive placebo. The study
was event driven and was completed on March
28, 2009, with a median follow-up duration of
29.1 months. At that time, 3523 patients (87.2%)
were either still being followed for clinical end
points or had died; this group included 1761 pa-
tients in the darbepoetin alfa group (87.5%) and
1762 patients in the placebo group (87.0%). The
vital status at study termination was unknown
for 153 patients in the darbepoetin alfa group
(7.6%) and 164 in the placebo group (8.1%) (see
the Consolidated Standards for the Reporting of
Trials [CONSORT] diagram in the Supplementa-
ry Appendix).
The median age was 68 years, and 57.3% of
the patients were women; 65.4% of the patients
had a history of cardiovascular disease, with
similar percentages of patients in each group re-
porting a history of coronary artery disease,
stroke, peripheral arterial disease, and myocar-
dial infarction. There was an imbalance in the
proportion of patients with a history of heart
failure (31.5% in the darbepoetin alfa group vs.
35.2% in the placebo group, unadjusted P = 0.01).
There were no clinically meaningful baseline im-
balances in vital signs, laboratory data, or the
use of medications for cardiovascular disease and
diabetes (Table 1).
Intervention and Hemoglobin Values
The overall median hemoglobin level at baseline
was 10.4 g per deciliter (interquartile range, 9.8 to
10.9). Between-group differences in hemoglobin
values were apparent less than 1 month after ran-
domization, and the differences were significant
by 1 month (Fig. 1). From 3 months to the end of
treatment, the median achieved hemoglobin level
(based on the area under the curve) was 12.5 g
per deciliter (interquartile range, 12.0 to 12.8) in
the darbepoetin alfa group and 10.6 g per decili-
ter (interquartile range, 9.9 to 11.3) in the placebo
group (P<0.001) (Fig. 1). A total of 84.6% of pa-
tients in the darbepoetin alfa group and 86.9% of
patients in the placebo group were switched to
monthly dosing. Over the course of the study,
46% of the patients assigned to placebo received
at least one dose of darbepoetin alfa as rescue
therapy. The median monthly dose in patients
assigned to placebo was 0 μg (interquartile range,
0 to 5) as compared with 176 μg (interquartile
range, 104 to 305) in patients assigned to darbe-
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Darbepoetin Alfa Therapy for reduction of Cardiovascular Events
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Table 1. Baseline Characteristics of the Patients.*
Characteristic
Darbepoetin Alfa
(N = 2012)
Placebo
(N = 2026)P Value†
Age (yr)
Median
Interquartile range
Female sex (%)
Race or ethnic group (%)‡
White
Black
Hispanic
Other
Known duration of diabetes (yr)
Median
Interquartile range
Body-mass index§
Median
Interquartile range
Retinopathy (%)
Laser treatment (%)
Diabetic neuropathy (%)
Amputation
History of cardiovascular disease (%)¶
Coronary artery disease‖
Heart failure
Myocardial infarction
Stroke
Peripheral arterial disease**
Use of pacemaker
Use of automatic implantable cardioverter–defibrillator
Atrial fibrillation (%)
Smoking status (%)
Current smoker
Former smoker
Blood pressure (mm Hg)
Systolic
Median
Interquartile range
Diastolic
Median
Interquartile range
Serum creatinine (mg/dl)
Median
Interquartile range
Estimated GFR (ml/min/1.73 m2)
Median
0.22
6868
60–75
58.5
60–75
56.0 0.10
0.84
63.1
20.6
13.6
2.7

15.3
64.2
19.8
13.1
3.0

15.5
0.94
8.2–21.88.4–21.7

30.1
26.2–34.9
45.7
28.6
46.4
6.1
66.9
45.5
35.2
18.3
10.7
20.8
6.1
1.4
10.0
0.11
30.5
26.3–35.5
48.2
29.6
49.2
5.7
64.0
43.2
31.5
18.4
11.5
21.2
4.5
1.4
11.0
0.12
0.49
0.07
0.58
0.05
0.16
0.01
0.95
0.41
0.73
0.02
0.87
0.29
0.88
5.4
38.2
4.7
39.4
0.25
136 135
122–149 123–148
0.55
7170
64–8064–80

1.9
1.5–2.4
0.01
1.8
1.5–2.3
0.03
3433
Interquartile range27–4326–42
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Table 1. (Continued.)
Characteristic
Darbepoetin Alfa
(N = 2012)
Placebo
(N = 2026) P Value†
Ratio of total protein (in mg/dl) to creatinine (in mg/dl) in urine¶
Median
Interquartile range
<1 (%)
≥1 (%)
Potassium (mmol/liter)
Median
Interquartile range
Albumin (g/dl)
Median
Interquartile range
Glycated hemoglobin (%)
Median
Interquartile range
Hemoglobin (g/dl)
Median
Interquartile range
White-cell count (×10−9/liter)
Median
Interquartile range
Platelet count (×10−9/liter)
Median
Interquartile range
Transferrin saturation (%)
Median
Interquartile range
Serum ferritin (µg/liter)
Median
Interquartile range
Cholesterol (mg/dl)
Total
Median
Interquartile range
LDL
Median
Interquartile range
HDL
Median
Interquartile range
Triglycerides (mg/dl)
Median
Interquartile range
0.73
0.40.4
0.1–2.0
65.9
34.1

4.7
4.3–5.1

4.0
3.7–4.3
0.1–1.8
64.9
35.1

4.7
4.3–5.1

4.0
3.7–4.3

6.9
6.2–7.9

10.4
9.8–10.9

6.7
5.4–8.1
0.73
0.13
0.02
7.0
6.2–8.1

10.5
9.8–11.0

6.6
5.4–8.1
0.15
0.32
0.14
241244
195–293 201–295
0.80
23 23
18–2918–28
0.17
131137
66–25468–263
0.47
169 170
142–201 142–203
0.41
84 85
64–110 63–112
0.85
4646
38–5638–56
0.97
155154
110–230109–230
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Darbepoetin Alfa Therapy for reduction of Cardiovascular Events
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poetin alfa. Among the patients who had not died
or progressed to end-stage renal disease, 93.9%
of the patients in the darbepoetin alfa group and
90.4% of those in the placebo group were receiv-
ing the assigned treatment at 6 months; 87.4%
and 83.7%, respectively, at 1 year; and 74.3% and
69.3%, respectively, at 2 years. There was no sig-
nificant difference in the proportions of patients
receiving oral iron during the study (66.8% of
those in the darbepoetin alfa group and 68.6% of
those in the placebo group, P = 0.25); however,
more patients in the placebo group received intra-
venous iron (20.4%, vs. 14.8% of patients assigned
to darbepoetin alfa; P<0.001). Red-cell transfu-
sions were administered in 297 patients in the
darbepoetin alfa group (14.8%) and in 496 pa-
tients in the placebo group (24.5%) (hazard ratio
for darbepoetin alfa vs. placebo, 0.56; 95% confi-
dence interval [CI], 0.49 to 0.65; P<0.001).
Primary Composite Outcomes and Components
Death, Myocardial Infarction, Unstable Angina,
Heart Failure, and Stroke
The primary cardiovascular composite outcome
— death or a nonfatal cardiovascular event —
occurred in 632 patients in the darbepoetin alfa
group (31.4%) and in 602 patients in the placebo
group (29.7%) (hazard ratio for darbepoetin alfa
vs. placebo, 1.05; 95% CI, 0.94 to 1.17; P = 0.41)
(Table 2 and Fig. 2A). There were no significant
Table 1. (Continued.)
Characteristic
Darbepoetin Alfa
(N = 2012)
Placebo
(N = 2026)P Value†
Medications (%)
Insulin
Oral hypoglycemic agent
Thiazolidinedione
Sulfonamide
Biguanide
Angiotensin-converting–enzyme inhibitor or angiotensin-
receptor blocker
Angiotensin-converting–enzyme inhibitor and angiotensin-
receptor blocker
Beta-blocker
Aldosterone-receptor blocker
Statin
Statin or other lipid-lowering agent
Aspirin
Aspirin or other antiplatelet agent
Vitamin K antagonist
Iron
Oral
Intravenous
Previous use of erythropoietic agent
48.7
57.5
25.2
36.3
17.1
79.7
49.8
56.1
23.5
34.5
17.2
80.0
0.49
0.36
0.22
0.24
0.91
0.82
10.3 9.80.55
49.9
5.4
59.6
64.6
42.0
48.0
7.2
48.7
4.9
57.5
64.0
42.8
48.6
6.6
0.43
0.49
0.16
0.72
0.63
0.68
0.46
41.8
1.4
8.8
42.7
1.6
10.2
0.57
0.63
0.14
* All tests for baseline laboratory values were performed by a central laboratory except hemoglobin levels, which were
measured at the site with the use of a hemoglobin point-of-care device. GFR denotes glomerular filtration rate, HDL
high-density lipoprotein, and LDL low-density lipoprotein. To convert the values for cholesterol to millimoles per liter,
multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129.
† P values have not been adjusted for multiple comparisons.
‡ Race or ethnic group was self-reported.
§ The body-mass index is the weight in kilograms divided by the square of the height in meters.
¶ These data were derived from the clinical database.
‖ This category includes coronary artery disease with or without myocardial infarction, coronary-artery bypass grafting,
and percutaneous coronary intervention.
** This category includes peripheral arterial disease with or without peripheral arterial revascularization.
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8
between-group differences in the time to the first
occurrence of the following components, when
considered individually: death from any cause,
fatal or nonfatal congestive heart failure, fatal or
nonfatal myocardial infarction, or hospitalization
for myocardial ischemia (Table 2 and Fig. 2B, 2C,
and 2D). However, fatal or nonfatal stroke was
more likely to occur in the patients assigned to
darbepoetin alfa (101 patients [5.0%] vs. 53 pa-
tients [2.6%]; hazard ratio, 1.92; 95% CI, 1.38 to
2.68; P<0.001) (Table 2 and Fig. 2E).
The prespecified stratification characteristics
of a history of cardiovascular disease and marked
proteinuria (urinary protein-to-creatinine ratio,
≥1) both identified higher-risk groups regardless
of the assigned treatment for the cardiovascular
composite outcome. The overall null effect of
darbepoetin alfa was observed in each subgroup,
with no significant interaction. Similarly, there
were no significant interactions for any of the
other five prespecified subgroups based on age,
sex, race or ethnic group, region, or baseline es-
timated GFR (see the Supplementary Appendix).
Cardiac revascularization procedures were per-
formed less frequently in the patients assigned
to darbepoetin alfa than in those assigned to
placebo (84 patients [4.2%] vs. 117 patients
[5.8%]; hazard ratio, 0.71; 95% CI, 0.54 to 0.94;
P = 0.02).
11-19-09ISSUE:
Renal Outcomes
Death or end-stage renal disease occurred in 652
patients in the darbepoetin alfa group (32.4%)
and in 618 patients in the placebo group (30.5%)
(hazard ratio for darbepoetin alfa vs. placebo,
1.06; 95% CI, 0.95 to 1.19; P = 0.29) (Fig. 3A). End-
stage renal disease occurred in 338 patients in
the darbepoetin alfa group (16.8%) and in 330 pa-
tients assigned to placebo (16.3%) (hazard ratio,
1.02; 95% CI, 0.87 to 1.18; P = 0.83) (Fig. 3B).
The stratification characteristics of a history
of cardiovascular disease and marked proteinuria
also identified groups at higher risk for the com-
posite outcome of death or end-stage renal dis-
ease, with no significant interaction in either
subgroup. No significant interactions were ob-
served in the other five prespecified subgroups,
with the exception of a nominally significant
interaction for race or ethnic group. The 653 pa-
tients described as nonwhite and nonblack in
the darbepoetin alfa group had the greatest ex-
cess risk (hazard ratio, 1.46; 95% CI, 1.10 to
Mean Hemoglobin (g/dl)
13.5
12.5
13.0
12.0
11.5
10.5
10.0
11.0
9.5
0.0
06 121824 36
48
Months since Randomization
No. of Patients
Darbepoetin alfa
Placebo
2004
2019
1768
1742
1503
1460
1300
1221
946
887
404
356
97
79
42
253
216
30
635
620
Darbepoetin alfa
Placebo
AUTHOR:
FIGURE:
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SIZE
4-C H/TLineCombo
Revised
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
Please check carefully.
1st
2nd
3rd
Pfeffer
1 of 3
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JOB: 36121
Figure 1. Mean Hemoglobin Levels through 48 Months among Patients Who Were Assigned to Receive Darbepoetin
Alfa or Placebo.
I bars represent standard errors.
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9
1.95); among the 2570 white patients, the hazard
ratio was 1.05 (95% CI, 0.92 to 1.21), and among
the 815 black patients, the hazard ratio was 0.87
(95% CI, 0.68 to 1.10; P = 0.03 for the interaction,
uncorrected for multiple comparisons).
Patient-Reported Outcomes
The primary prespecified analysis for the patient-
reported outcomes was the change from baseline
to 25 weeks in the FACT-Fatigue score. Among
patients with both baseline and week-25 scores,
from a baseline score of 30.2 in the group of 1762
patients assigned to darbepoetin alfa and a base-
line score of 30.4 in the 1769 patients assigned to
placebo, there was a greater degree of improve-
ment in the mean (±SD) score in the darbepoetin
alfa group than in the placebo group (an increase
of 4.2±10.5 points vs. 2.8±10.3 points, P<0.001 for
between-group changes). An increase of three or
more points (considered to be a clinically mean-
ingful improvement) occurred in 963 of 1762 pa-
tients assigned to darbepoetin alfa (54.7%) and
875 of 1769 patients assigned to placebo (49.5%)
(P = 0.002). Other prespecified quality-of-life as-
sessments, in the domains of energy and physi-
cal functioning as measured with the 36-Item
Short-Form General Health Survey, did not differ
significantly between 1138 patients assigned to
darbepoetin alfa and 1157 patients assigned to
placebo (mean change in the score for energy,
2.6±9.9 points vs. 2.1±9.7 points; P = 0.20; mean
change in the score for physical functioning,
1.3±9.2 vs. 1.1±8.8; P = 0.51).
Blood Pressure
There was no significant difference in systolic
blood pressure between the two groups; the me-
dian systolic blood pressure over time was 134
mm Hg (interquartile range, 126 to 143) in both
groups. Diastolic blood pressure was higher in
the patients assigned to darbepoetin alfa than in
those assigned to placebo (median over time,
73 mm Hg [interquartile range, 67 to 78] vs. 71
mm Hg [interquartile range, 65 to 77]; P<0.001).
Prespecified Categories of Adverse Events
Hypertension occurred in 491 patients in the dar-
bepoetin alfa group and in 446 patients in the
placebo group (P = 0.07) (see the Supplementary
Appendix). Convulsions were reported in nine pa-
tients in the darbepoetin alfa group and in four
patients in the placebo group. No cases of anti-
body-mediated pure red-cell aplasia were report-
ed in either group.
Table 2. Composite and Component End Points.*
End Point
Darbepoetin Alfa
(N = 2012)
Placebo
(N = 2026)
Hazard Ratio
(95% CI)P Value†
number (percent)
Primary end points
Cardiovascular composite end point‡ 632 (31.4) 602 (29.7) 1.05 (0.94–1.17)0.41
Death from any cause412 (20.5)395 (19.5)1.05 (0.92–1.21) 0.48
Myocardial infarction§124 (6.2)129 (6.4)0.96 (0.75–1.22) 0.73
Stroke§101 (5.0)53 (2.6) 1.92 (1.38–2.68)<0.001
Heart failure§ 205 (10.2)229 (11.3)0.89 (0.74–1.08)0.24
Myocardial ischemia41 (2.0)49 (2.4) 0.84 (0.55–1.27) 0.40
Renal composite end point (ESRD or death) 652 (32.4)618 (30.5) 1.06 (0.95–1.19)0.29
ESRD338 (16.8)330 (16.3)1.02 (0.87–1.18)0.83
Additional adjudicated end points
Death from cardiovascular causes259 (12.9)250 (12.3)1.05 (0.88–1.25)0.61
Cardiac revascularization84 (4.2)117 (5.8) 0.71 (0.54–0.94)0.02
* ESRD denotes end-stage renal disease.
† P values have not been adjusted for multiple comparisons.
‡ A patient may have had multiple cardiovascular events of different types. The cardiovascular composite end point re-
flects only the first occurrence of any of the components.
§ This category includes both fatal and nonfatal events.
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Patients with Event (%)
50 4030
10
20
0
0
6
12
18
24
36
48
42
30
Months since Randomization
A Cardiovascular Composite End Point
P=0.41
No. at Risk
Darbepoetin alfa
Placebo
2012
2026
18821836
1717
1687
1515
1487
11801178
551
529
817
834
318319
130 122
Darbepoetin alfa
Placebo
Hazard ratio, 1.05 (95% CI, 0.94–1.17)
Patients with Event (%)
50 40 30
10
20
0
0
6
12
18
24
36
48
42
30
Months since Randomization
B Death from Any Cause
P=0.48
No. at Risk
Darbepoetin alfa
Placebo
2012
2026
19471943
18471839
16591652
13371345
655 636
945970
386385
164156
Darbepoetin alfa
Placebo
Hazard ratio, 1.05 (95% CI, 0.92–1.21)
Patients with Event (%)
5040 30
10
20
0
0
6
12
18
24
36
48
42
30
Months since Randomization
C Fatal or Nonfatal Congestive Heart Failure
P=0.24
No. at Risk
Darbepoetin alfa
Placebo
2012
2026
1890 1859
1742 1702
15251495
1191
1187
555
519
819
835
319
307
136
115
Darbepoetin alfa
Placebo
Hazard ratio, 0.89 (95% CI, 0.74–1.08)
Patients with Event (%)
504030
10
20
0
0
6
12
18
24
36
48
42
30
Months since Randomization
E Fatal or Nonfatal Stroke
P<0.001
No. at Risk
Darbepoetin alfa
Placebo
2012
2026
1923
1914
17871783
1581
1575
12471262
590
561
863886
341
338
141
132
Darbepoetin alfa
Placebo
Hazard ratio, 1.92 (95% CI, 1.38–2.68)
Patients with Event (%)
50 40 30
10
20
0
0
6
12
18
24
36
48
42
30
Months since Randomization
D Fatal or Nonfatal Myocardial Infarction and Myocardial Ischemia
P=0.40
P=0.73
No. at Risk
Fatal or Nonfatal Myocardial Infarction
Darbepoetin alfa
Placebo
2012
2026
19201907
17851765
15661550
12321235
577539
851
863
325324
137 123
Myocardial Ischemia
Darbepoetin alfa
Placebo
2012
2026
1924 1906
17941767
1583
1561
1255
1251
597 556
869880
347 338
146132
Darbepoetin alfa
Placebo
Darbepoetin alfa
Placebo
Fatal or Nonfatal
Myocardial Infarction
Hazard ratio, 0.96 (95% CI,
0.75–1.22)
Myocardial Ischemia
Hazard ratio, 0.84 (95% CI,
0.55–1.27)
AUTHOR:
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RETAKE:
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4-C H/T Line Combo
Revised
AUTHOR, PLEASE NOTE:
1st
2nd
3rd
Pfeffer
2 of 3
ARTIST:
TYPE:
MRL
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Darbepoetin Alfa Therapy for reduction of Cardiovascular Events
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Venous thromboembolic events were reported
in 41 patients in the darbepoetin alfa group
(2.0%), as compared with 23 patients in the pla-
cebo group (1.1%) (P = 0.02). Arterial thrombo-
embolic events (some of which were adjudicated
as cardiovascular events) were also reported more
frequently in the darbepoetin alfa group (in 178
patients [8.9%] vs. 144 patients [7.1%], P = 0.04).
Cancer
There was no significant between-group difference
in the number of patients reporting a cancer-
related adverse event: 139 in the darbepoetin alfa
group (6.9%) and 130 in the placebo group (6.4%)
(P = 0.53). Overall, 39 deaths were attributed to
cancer in the 2012 patients in the darbepoetin
alfa group and 25 deaths were attributed to cancer
in the 2026 patients in the placebo group (P = 0.08
by the log-rank test). Among patients with a his-
tory of a malignant condition at baseline, there
were 60 deaths from any cause in the 188 patients
assigned to darbepoetin alfa and 37 deaths in the
160 patients assigned to placebo (P = 0.13 by the
log-rank test). In this subgroup, 14 of the 188 pa-
tients assigned to darbepoetin alfa died from can-
cer, as compared with 1 of the 160 patients as-
signed to placebo (P = 0.002 by the log-rank test).
Discussion
The main purpose of the TREAT was to determine
whether treatment of a low hemoglobin level with
darbepoetin alfa would reduce the risk of death
and major cardiovascular and renal events among
patients with type 2 diabetes mellitus, chronic
kidney disease, and anemia. There was no signifi-
cant difference in the overall rates of either the
primary cardiovascular composite end point or
the primary renal composite end point with the
use of the therapeutic strategy of increasing the
hemoglobin level with darbepoetin alfa (to at-
tempt to reach a target hemoglobin level of 13.0 g
per deciliter) versus placebo (with darbepoetin
alfa as rescue therapy if hemoglobin values de-
creased below 9.0 g per deciliter). In this study
involving 4038 patients randomly assigned to a
study group, with 9941 patient-years of follow-up
and with 1234 patients who had a composite out-
come of a cardiovascular event and 1270 patients
who had a composite outcome of a renal event,
we found no overall significant differences in the
hazard rates for these clinically important out-
comes or in the rates of death, heart failure, myo-
cardial infarction, admission for myocardial is-
chemia, or end-stage renal disease.
Although there was no significant increase in
the overall cardiovascular composite outcome in
the group assigned to darbepoetin alfa, there was
an increased incidence of stroke (annualized event
rate, 2.1%, vs. 1.1% in the placebo group). Data
from a study of patients undergoing dialysis sug-
gested this risk of stroke19; however, this risk
was not identified in either the Correction of
Hemoglobin and Outcomes in Renal Insufficien-
cy (CHOIR) study (ClinicalTrials.gov number,
NCT00211120)17 or a meta-analysis.24 This pre-
viously undocumented and clinically important
finding of a heightened risk of stroke is not ex-
plained by an increase in systolic blood pressure.
In a recent report of a randomized, placebo-con-
trolled trial of intravenous erythropoietin in the
early phase of an acute ischemic stroke,25 there
were more deaths in the group assigned to the
ESA (42 of 256 patients [16.4%]) as compared
with the group assigned to placebo (24 of 266
patients [9.0%]). This study also provides support
for an adverse relationship between ESAs and
stroke. We also confirmed previous findings of
increased rates of venous thromboembolic events
among patients treated with ESAs.
Our findings appear to differ from those of
the CHOIR trial, the next largest trial involving
patients with chronic kidney disease who were
not undergoing dialysis, which used epoetin alfa
and was discontinued prematurely after a median
follow-up of 16 months and after 222 patients
had a primary event.17 Both groups in the CHOIR
trial were randomly assigned to receive epoetin
alfa, and in that study, there was a higher risk of
cardiovascular events in the group assigned to a
target hemoglobin level of 13.5 g per deciliter
than in the group assigned to a target level of
11.3 g per deciliter (hazard ratio, 1.34; 95% CI,
1.03 to 1.74; P = 0.03). This excess of cardiovas-
Figure 2 (facing page). Kaplan–Meier Estimates of the
Probability of the Primary and Secondary End Points.
Panel A shows the primary cardiovascular composite
end point. The secondary end points of deaths from
any cause (Panel B), fatal or nonfatal congestive heart
failure (Panel C), fatal or nonfatal myocardial infarction
and myocardial ischemia (Panel D), and fatal or non-
fatal stroke (Panel E) are also shown. P values are not
adjusted for multiple comparison.
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Darbepoetin Alfa Therapy for reduction of Cardiovascular Events
cular events was largely accounted for by more
deaths and heart-failure events; only 12 patients
in each group had a stroke. These findings led
to the suggestion that our trial should be discon-
tinued.26 However, by that time, there were more
accumulated cardiovascular composite events in
our trial than in the CHOIR trial, and the inde-
pendent data and safety monitoring committee
recommended continuation.27 The TREAT execu-
tive committee updated the consent form to re-
flect the results from the CHOIR trial, and our
patients again were asked to provide written in-
formed consent. The final results of our study
demonstrate the importance of completing the
planned follow-up of trials and the potential to
draw misleading conclusions when premature dis-
continuation results in an insufficient number
of events to allow for a reliable estimation of the
effect of treatment.28,29
Before we conducted our study, there was a
suggestion that ESAs might increase mortality
among patients with cancer, so patients with an
active malignant condition were excluded from
our trial.30 During the trial, mounting concern led
to new regulatory warnings about the use of ESAs
in patients with “anemia of cancer,”31 prompting
a protocol amendment to discontinue the study
drug in patients in whom cancer developed. Al-
Patients with Event (%)
50
40
30
10
20
0
0612 182436
48
Months since Randomization
A Renal Composite (ESRD or Death)
P=0.29
No. at Risk
Darbepoetin alfa
Placebo
2012
2026
1910
1915
1762
1748
1544
1519
1207
1193
552
540
134
123
30
42
820
842
309
312
Darbepoetin alfa
Placebo
Hazard ratio, 1.06 (95% CI, 0.95–1.19)
Patients with Event (%)
50
40
30
10
20
0
0612 18 2436
48
Months since Randomization
B ESRD
P=0.83
No. at Risk
Darbepoetin alfa
Placebo
2012
2026
1908
1907
1755
1729
1527
1491
1187
1162
535
513
129
115
30
42
802
811
296
292
Darbepoetin alfa
Placebo
Hazard ratio, 1.02 (95% CI, 0.87–1.18)
AUTHOR:
FIGURE:
RETAKE:
SIZE
4-C H/T Line Combo
Revised
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
Please check carefully.
1st
2nd
3rd
Pfeffer
3 of 3
ARTIST:
TYPE:
MRL
xx-xx-09JOB: 361xxISSUE:
Figure 3. Kaplan–Meier Estimates of the Probability of Renal Outcomes.
Panel A shows the primary renal composite end point (end-stage renal disease [ESRD] or death), and Panel B shows
the end-point component of ESRD. P values have not been adjusted for multiple comparisons.
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Darbepoetin Alfa Therapy for reduction of Cardiovascular Events
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13
though the number of these patients did not dif-
fer significantly between the study groups, among
the 348 patients with a history of cancer at base-
line, mortality was higher among those assigned
to darbepoetin alfa than among those assigned
to placebo; these findings are consistent with
those in a recent meta-analysis.32
Our trial provides long-term, placebo-controlled
data on the use of ESAs in patients with diabetes,
chronic kidney disease, and moderate anemia
who are not undergoing dialysis. No single trial
can address the multitude of pertinent issues
without limitations, and our data may not be
fully applicable to other patient populations. It is
possible that other dosing strategies could be
developed to mitigate the risk of stroke while
conserving the modest benefits of treatment. In
light of the baseline imbalances between the
study groups, additional sensitivity analyses were
conducted, and they did not alter our results.
More extensive analyses of the patient-reported
outcome measures are needed to assess the dura-
bility of the rather modest improvement we ob-
served only in the FACT-Fatigue score.
The long-standing presumption of a benefit of
ESAs in this patient population led to non–pla-
cebo-controlled trials, which, by design, cannot
provide a reliable assessment of risk and bene-
fit.21 The present trial supplies these missing data,
which may assist physicians and patients in mak-
ing more informed decisions about individual
care. It is our view that, in many patients with
diabetes, chronic kidney disease, and moderate
anemia who are not undergoing dialysis, the in-
creased risk of stroke and possibly death among
patients with a history of a malignant condition
will outweigh any potential benefit of an ESA.
Supported by Amgen, which provided independent statistical
support through a contract with the board of regents for the
University of Wisconsin System for data analysis for the TREAT
Data and Safety Monitoring Committee as well as for the study.
Dr. Pfeffer reports receiving consulting fees from Abbott,
Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Boston
Scientific, Bristol-Myers Squibb, Centocor, CVRx, Genentech,
Cytokinetics, Daiichi Sankyo, Genzyme, Medtronic, Novartis,
Roche, Sanofi-Aventis, Servier, and VIA Pharmaceutics and grant
support from Amgen, Baxter, Celladon, Novartis, and Sanofi-
Aventis, and being named coinventor on a patent for the use of
inhibitors of the renin–angiotensin system in selected survivors
of myocardial infarction; Dr. Burdmann, receiving consulting
fees from Amgen and Sigma Pharma and grant support from
Amgen and Roche; Drs. Chen and Kewalramani, being employ-
ees of and owning stock in Amgen; Dr. Cooper, receiving con-
sulting fees from Amgen; Dr. de Zeeuw, receiving consulting
fees from Amgen and Novartis and lecture fees from Amgen; Dr.
Eckardt, receiving consulting fees from Amgen, Ortho Biotech,
Roche, Affymax, Stada, and Sandoz–Hexal and lecture fees from
Amgen, Ortho Biotech, and Roche; Dr. Ivanovich, receiving con-
sulting fees from Amgen, Baxter, Biogen, and Reata; Dr. Levey,
receiving grant support from Amgen; Dr. Lewis, receiving con-
sulting fees from Amgen and grant support from Amgen and
the Robert Wood Johnson Foundation; Dr. McGill, receiving con-
sulting fees from Amgen and Boehringer Ingelheim, lecture fees
from Novartis, and grant support from Novartis and Boehringer
Ingel heim; Dr. McMurray, receiving consulting fees from Me-
narini, Bristol-Myers Squibb, Roche, Novocardia, Boehringer
Ingelheim, Novartis, BioMérieux, and Boston Scientific, lecture
fees from AstraZeneca, Solvay, Takeda, Novartis, BMS Sanofi,
and Vox Media, and grant support from BMS, Novartis, Amgen,
AstraZeneca, Cytokinetics, Hoffmann–La Roche, Pfizer, Scios,
and GlaxoSmithKline; Dr. Parfrey, receiving consulting and
lecture fees from Amgen and lecture fees from Ortho Biotech;
Dr. Parving, receiving consulting fees from Amgen and Novartis
and lecture fees from Novartis; Dr. Singh, receiving consulting
fees from Johnson & Johnson and Watson, lecture fees from John-
son & Johnson, Amgen, and Watson, and grant support from
Johnson & Johnson, Amgen, Roche, AMAG Pharmaceuticals, and
Watson; Dr. Solomon, receiving grant support from Amgen;
and Dr. Toto, receiving consulting and lecture fees from Amgen
and grant support from Novartis, Reata, and Abbott. No other
potential conflict of interest relevant to this article was reported.
Appendix
From the Department of Medicine, Brig ham and Women’s Hospital, Harvard Medical School (M.A.P., E.F.L., A.K.S., S.D.S.); and the
Division of Nephrology, Tufts Medical Center (A.S.L.) — both in Boston; Hospital de Base, Faculdade de Medicina de São José do Rio
Preto, São José do Rio Preto, Brazil (E.A.B.); Global Biostatistics and Epidemiology and Global Clinical Development, Amgen, Thousand
Oaks, CA (C.-Y.C., R.K.); Baker Heart Research Institute, Melbourne, VIC, Australia (M.E.C.); the Division of Clinical Pharmacology,
University Medical Center, Groningen, the Netherlands (D.Z.); the Department of Nephrology and Hypertension, University of Erlan-
gen-Nuremberg, Erlangen, Germany (K.-U.E.); the Department of Biostatistics and Medical Informatics, University of Wisconsin,
Madison (J.M.F.); the Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago (P.I.); the Department
of Medicine, Washington University School of Medicine, St. Louis (J.B.M.); the Department of Cardiology, British Heart Foundation
Glasgow Cardiovascular Research Centre, Glasgow, United Kingdom (J.J.V.M.); the Division of Nephrology, Health Sciences Centre, St.
John’s, NF, Canada (P.P.); the Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, and Fac-
ulty of Health Science, Aarhus University, Aarhus (H.-H.P.) — both in Denmark; Mario Negri Institute for Pharmacological Research,
Bergamo, Italy (G.R.); and the Department of Medicine, University of Texas Southwestern Medical Center, Dallas (R.T.).
The TREAT committees and teams are as follows: protocol development committee — R. Brenner and M. Pfeffer (cochairs), N.
Abrouk, W. Carroll, D. Green, P. Klassen, J. Lubina, J. McMurray, L. Messer, R. Newmark, P. Parfrey, S. Solomon; executive committee
— M. Pfeffer (chair), E. Burdmann, M. Cooper, D. de Zeeuw, K.-U. Eckardt, P. Ivanovich, A. Levey, J. McGill, J. McMurray, P. Parfrey,
H.-H. Parving, B. Pereira, G. Remuzzi, A. Singh, S. Solomon, R. Toto; hemoglobin monitoring committee — P. Ivanovich (chair), S.
Fishbane, A. Nissenson; statistical data analysis center — R. Bechhofer, D. DeMets, J. Feyzi; data and safety monitoring committee — C.
Hennekens (chair), G. Chertow, E. Frohlich, P. O’Brien, J. Rouleau; clinical end-point center — S. Solomon (chair), E. Lewis (cochair),
A. Desai, C. Duong, P. Finn, L.H. Hartley, S. Kesari, J. Lin, J. Meadows, L. Mielniczuk, F. Shamshad, A. Singh, O. Vasyleyeva, L. Wein-
rauch; study team — A. Adee, A. Ahmed, P. Blaisdell, P. Brady, L. Bucker, J. Cap, W. Carroll, D. Chaparro, C.-Y. Chen, B. Condon, R.
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Darbepoetin Alfa Therapy for reduction of Cardiovascular Events
Cravario, R. Damato, K. Dellacroce, K. DiRocco, D. Donovan, B. Doria, M. Dougherty, J. Droge, A. Grewal, L. Guimaraes, P. Haynes,
J. Hevy, T. Jambusaria, N. James, A. Kacprzak, M. Kasenda, S.R.K. Reddy, R. Kewalramani, H. Kirby, C. Klacker, T. Kocsis, A. Kondo,
M. Lauw, M. Liebelt, P. McElligott, B. Mesquita, C. Mix, A. Mueller, S. O’Callaghan, H. Ocampo, K. Olson, S. Perez, J. Pillai, A. Pollock,
F. Poloni, K. Polu, R. Poston, G. Ramirez, A. Rasmussen, L. Reeves, M. Rocha, A.P. Ross, J. Rossert, B. Sahl, T. See, S. Shahinfar, K.
Shart, C. Stehman-Breen, A. Teh, L. Tierra, M. Vaghela, C. White. Enrollment by country was as follows (numbers of patients are in
parentheses): Argentina (84), Australia (58), Austria (3), Brazil (190), Bulgaria (28), Canada (176), Chile (14), Czech Republic (96),
Denmark (10), Estonia (16), France (11), Germany (135), Hungary (70), Italy (87), Latvia (51), Mexico (150), Poland (213), Portugal
(17), Romania (47), Russia (117), Slovakia (65), Slovenia (12), United Kingdom (49), United States (2339).
References
Stamler J, Vaccaro O, Neaton JD,
1.
Wentworth D. Diabetes, other risk fac-
tors, and 12-yr cardiovascular mortality
for men screened in the Multiple Risk Fac-
tor Intervention Trial. Diabetes Care 1993;
16:434-44.
Booth GL, Kapral MK, Fung K, Tu JV.
2.
Relation between age and cardiovascular
disease in men and women with diabetes
compared with non-diabetic people: a pop-
ulation-based retrospective cohort study.
Lancet 2006;368:29-36.
Turnbull F, Neal B, Algert C, et al. Ef-
3.
fects of different blood pressure-lowering
regimens on major cardiovascular events
in individuals with and without diabetes
mellitus: results of prospectively designed
overviews of randomized trials. Arch In-
tern Med 2005;165:1410-9.
Baigent C, Keech A, Kearney PM, et al.
4.
Efficacy and safety of cholesterol-lower-
ing treatment: prospective meta-analysis
of data from 90,056 participants in 14 ran-
domised trials of statins. Lancet 2005;366:
1267-78. [Errata, Lancet 2005;366:1358,
2008;371:2084.]
Gaede P, Lund-Andersen H, Parving
5.
H-H, Pedersen O. Effect of a multifacto-
rial intervention on mortality in type 2
diabetes. N Engl J Med 2008;358:580-91.
Brenner BM, Cooper ME, de Zeeuw D,
6.
et al. Effects of losartan on renal and car-
diovascular outcomes in patients with
type 2 diabetes and nephropathy. N Engl J
Med 2001;345:861-9.
Lewis EJ, Hunsicker LG, Clarke WR,
7.
et al. Renoprotective effect of the angio-
tensin-receptor antagonist irbesartan in
patients with nephropathy due to type 2
diabetes. N Engl J Med 2001;345:851-60.
Tonelli M, Isles C, Craven T, et al. Ef-
8.
fect of pravastatin on rate of kidney func-
tion loss in people with or at risk for coro-
nary disease. Circulation 2005;112:171-8.
Locatelli F, Pisoni RL, Combe C, et al.
9.
Anaemia in haemodialysis patients of five
European countries: association with mor-
bidity and mortality in the Dialysis Out-
comes and Practice Patterns Study (DOPPS).
Nephrol Dial Transplant 2004;19:121-32.
[Erratum, Nephrol Dial Transplant 2004;
19:1666.]
Foley RN, Parfrey PS, Harnett JD, Kent
10.
GM, Murray DC, Barre PE. The impact of
anemia on cardiomyopathy, morbidity, and
mortality in end-stage renal disease. Am J
Kidney Dis 1996;28:53-61.
Keane WF, Brenner BM, de Zeeuw D,
11.
et al. The risk of developing end-stage re-
nal disease in patients with type 2 diabe-
tes and nephropathy: the RENAAL study.
Kidney Int 2003;63:1499-507.
Vlagopoulos PT, Tighiouart H, Weiner
12.
DE, et al. Anemia as a risk factor for car-
diovascular disease and all-cause mortal-
ity in diabetes: the impact of chronic kid-
ney disease. J Am Soc Nephrol 2005;16:
3403-10.
Tong PCY, Kong APS, So W-Y, et al.
13.
Hematocrit, independent of chronic kid-
ney disease, predicts adverse cardiovascu-
lar outcomes in Chinese patients with
type 2 diabetes. Diabetes Care 2006;29:
2439-44.
Pfeffer MA, Solomon SD, Singh AK,
14.
Ivanovich P, McMurray JJ. Uncertainty in
the treatment of anemia in chronic kidney
disease. Rev Cardiovasc Med 2005;Suppl 3:
S35-S41.
Eschbach JW, Abdulhadi MH, Browne
15.
JK, et al. Recombinant human erythro-
poietin in anemic patients with end-stage
renal disease: results of a phase III multi-
center clinical trial. Ann Intern Med
1989;111:992-1000.
Canadian Erythropoietin Study Group.
16.
Association between recombinant human
erythropoietin and quality of life and exer-
cise capacity of patients receiving haemo-
dialysis. BMJ 1990;300:573-8.
Singh AK, Szczech L, Tang KL, et al.
17.
Correction of anemia with epoetin alfa in
chronic kidney disease. N Engl J Med
2006;355:2085-98.
Drueke TB, Locatelli F, Clyne N, et al.
18.
Normalization of hemoglobin level in pa-
tients with chronic kidney disease and
anemia. N Engl J Med 2006;355:2071-84.
Parfrey PS, Foley RN, Wittreich BH,
19.
Sullivan DJ, Zagari MJ, Frei D. Double-
blind comparison of full and partial ane-
mia correction in incident hemodialysis
patients without symptomatic heart dis-
ease. J Am Soc Nephrol 2005;16:2180-9.
Phrommintikul A, Haas SJ, Elsik M,
20.
Krum H. Mortality and target haemoglo-
bin concentrations in anemic patients with
chronic kidney disease treated with eryth-
ropoietin: a meta-analysis. Lancet 2007;
369:381-8.
Pfeffer MA. Critical missing data in
erythropoiesis-stimulating agents in CKD:
first beat placebo. Am J Kidney Dis 2008;
51:366-9.
Pfeffer MA, Burdmann EA, Chen CY,
22.
et al. Baseline characteristics in the Trial
to Reduce Cardiovascular Events With
Aranesp Therapy (TREAT). Am J Kidney
Dis 2009;54:59-69.
Mozzicato P. Standardised MedDRA
23.
queries: their role in signal detection.
Drug Saf 2007;30:617-9.
Strippoli GF, Navaneethan SD, Craig
24.
JC. Haemoglobin and haematocrit targets
for the anaemia of chronic kidney dis-
ease. Cochrane Database Syst Rev 2006;4:
CD003967.
Ehrenreich H, Weissenborn K, Prange
25.
H, et al. Recombinant human erythro-
poietin in the treatment of acute ischemic
stroke. Stroke 2009 October 15 (Epub
ahead of print).
Strippoli GFM, Tognoni G, Navanee-
26.
than SD, Nicolucci A, Craig JC. Hemoglo-
bin targets: we were wrong, time to move
on. Lancet 2007;369:349-50.
Pfeffer MA. An ongoing study of ane-
27.
mia correction in chronic kidney disease.
N Engl J Med 2007;356:959-61.
DeMets DL, Pocock SJ, Julian DG. The
28.
agonising negative trend in monitoring of
clinical trials. Lancet 1999;354:1983-8.
Califf RM, DeMets DL. Principles from
29.
clinical trials relevant to clinical practice:
Part I. Circulation 2002;106:1015-21.
Leyland-Jones B, Semiglazov V, Pawl-
30.
icki M, et al. Maintaining normal hemo-
globin levels with epoetin alfa in mainly
nonanemic patients with metastatic breast
cancer receiving first-line chemotherapy:
a survival study. J Clin Oncol 2005;23:5960-
72.
FDA black box warning for Aranesp.
31.
Silver Spring, MD: Food and Drug Admin-
istration. (Accessed October 23, 2009, at
http://www.accessdata.fda.gov/drugsatfda
_docs/label/2008/103951s5195PI.pdf.)
Bohlius J, Schmidlin K, Brillant C, et
32.
al. Recombinant human erythropoiesis-
stimulating agents and mortality in pa-
tients with cancer: a meta-analysis of ran-
domised trials. Lancet 2009;373:1532-42.
[Erratum, Lancet 2009;374:28.]
Copyright © 2009 Massachusetts Medical Society.
21.
Downloaded from www.nejm.org on November 2, 2009 . Copyright © 2009 Massachusetts Medical Society. All rights reserved.