Pfeffer 2009

new england
The
journal of medicine
established in 1812 november 19, 2009 vol. 361 no. 21
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*
A BS T R AC T
BACKGROUND
Anemia is associated with an increased risk of cardiovascular and renal events The affiliations of the authors are listed
among patients with type 2 diabetes and chronic kidney disease. Although darbe- in the Appendix. Address reprint requests
to Dr. Pfeffer at the Cardiovascular Divi-
poetin alfa can effectively increase hemoglobin levels, its effect on clinical out- sion, Brigham and Women’s Hospital,
comes in these patients has not been adequately tested. 75 Francis St., Boston, MA 02115, or at
mpfeffer@rics.bwh.harvard.edu.
METHODS
In this study involving 4038 patients with diabetes, chronic kidney disease, and *The Trial to Reduce Cardiovascular Events
with Aranesp Therapy (TREAT) com-
anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemo- mittees and teams are listed in the Ap-
globin level of approximately 13 g per deciliter and 2026 patients to placebo, with pendix, and investigators and individual
rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. sites are listed in the Supplementary
Appendix, available with the full text of
The primary end points were the composite outcomes of death or a cardiovascular this article at NEJM.org.
event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospital-
ization for myocardial ischemia) and of death or end-stage renal disease. This article (10.1056/NEJMoa0907845)
was published on October 30, 2009, at
RESULTS NEJM.org.
Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa N Engl J Med 2009;361:2019-32.
and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, Copyright © 2009 Massachusetts Medical Society.
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 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.)
n engl j med 361;21 nejm.org november 19, 2009 2019
The New England Journal of Medicine
Downloaded from nejm.org at UNIVERSITY OF CALGARY on July 11, 2012. For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
The n e w e ng l a n d j o u r na l of m e dic i n e
T
ype 2 diabetes mellitus and chronic committee at each site approved the protocol,
kidney disease frequently coexist, and each and all patients provided written informed con-
disease independently increases the risk of sent. Enrollment occurred from August 25, 2004,
cardiovascular events and end-stage renal dis through December 4, 2007.
ease.1,2 Intensive treatment of concomitant con- The trial was sponsored by Amgen and de-
ventional risk factors such as hypertension and signed in collaboration with an academic execu-
elevated levels of low-density lipoprotein reduces tive committee. Data collection and management
fatal and nonfatal cardiovascular complications were the responsibility of the sponsor, with over-
and slows the progression of kidney disease.3-8 sight by the executive committee. The Statistical
Observational studies suggest that anemia can Data Analysis Center at the University of Wis-
be considered another biomarker of risk, since a consin prepared the interim unblinded reports
lower hemoglobin level is independently associ- for the independent data and safety monitoring
ated with a higher rate of cardiovascular and re- committee, which oversaw patient safety and the
nal events,9-11 especially among patients with quality of trial conduct. The independent aca-
diabetes.12,13 Whether the use of erythropoiesis- demic statistical center also performed all analy-
stimulating agents (ESAs) to increase hemoglo- ses for this article and provided the writing
bin levels lowers this risk is not known.14 group with unrestricted access to the data. The
Early studies involving the use of recombinant manuscript was prepared by the principal inves-
human erythropoietin in patients with severe tigator and subsequently revised and edited by
anemia who were undergoing dialysis showed a all the authors. All the authors decided to submit
reduced requirement for blood transfusions and the article for publication and assume responsi-
improved quality-of-life assessments, which were bility for the accuracy and completeness of the
considered major advances.15,16 Extrapolations reported data.
from these favorable effects to other populations,
including patients with anemia and earlier stages Study Population
of chronic kidney disease, led to the wider use Patients with type 2 diabetes, chronic kidney dis-
of ESAs. The presumption of the benefits associ- ease (an estimated glomerular filtration rate [GFR]
ated with the use of ESAs was so pervasive that of 20 to 60 ml per minute per 1.73 m2 of body-
major clinical trials considered the use of pla- surface area, calculated with the use of the four-
cebo unnecessary or even unethical.17-19 In fact, variable Modification of Diet in Renal Disease
there were no placebo-controlled trials in a recent formula), anemia (hemoglobin level, ≤11.0 g per
meta-analysis of the use of ESAs in patients with deciliter), and a transferrin saturation of 15% or
chronic kidney disease.20 Although ESAs have more were eligible for enrollment. Patients with
been available for more than two decades, the any of the following factors were excluded: un-
hypothesis that this treatment approach would controlled hypertension; previous kidney trans-
lower the risks associated with anemia and im- plantation or scheduled receipt of a kidney trans-
prove the prognosis has not been examined.21 plant from a living related donor; current use of
We conducted the Trial to Reduce Cardiovascu- intravenous antibiotics, chemotherapy, or radiation
lar Events with Aranesp Therapy (TREAT) to test therapy; cancer (except basal-cell or squamous-
the hypothesis that, in patients with type 2 dia- cell carcinoma of the skin); diagnosed human
betes, chronic kidney disease that does not re- immunodeficiency virus infection; active bleed-
quire dialysis, and concomitant anemia, increasing; a hematologic disease; or pregnancy. Patients
ing hemoglobin levels with the use of this agent who had had a cardiovascular event or grand mal
would lower the rates of death, cardiovascular seizure, had undergone major surgery, or had re-
events, and end-stage renal disease.22 ceived an ESA in the 12 weeks before randomiza-
tion were also ineligible.
Me thods
Study Procedures
The TREAT was a randomized, double-blind, During a 2-week screening period, prestudy labo-
placebo-controlled trial conducted at 623 sites in ratory assessments were obtained and the eligi-
24 countries (see the Supplementary Appendix, bility of patients who had provided consent was
available with the full text of this article at NEJM. confirmed. Patients were randomly assigned with
org). The institutional review board or ethics the use of a computer-generated, permuted-block
2020 n engl j med 361;21 nejm.org november 19, 2009

Darbepoetin Alfa Ther apy for reduction of Cardiovascular Events
design, in a 1:1 ratio, to receive darbepoetin alfa by a clinical end-point committee whose mem-
(Aranesp, Amgen) or placebo. Randomization was bers were unaware of the treatment assignments,
stratified according to the study site, the baseline and the hematocrit and hemoglobin values were
level of proteinuria (with marked proteinuria de- redacted from the documents under review. Im-
fined as a ratio of total protein to creatinine [cal- portant secondary end points included time to
culated in milligrams per deciliter] of ≥1.0 in a death, death from cardiovascular causes, and the
spot urine sample), and an investigator-designat- components of the primary end points, as well as
ed history of cardiovascular disease. Darbepoetin the rate of decline in the estimated GFR and
alfa and placebo were supplied in matching pre- changes in patient-reported outcomes at week 25
filled syringes at 12 different strengths. A third measured with the use of the Functional Assess-
party used a point-of-care device to monitor hemo- ment of Cancer Therapy–Fatigue (FACT-Fatigue)
globin levels and enter the value into an interac- instrument (on which scores range from 0 to 52,
tive voice-response system that selected the dos- with higher scores indicating less fatigue) and the
age according to a computer algorithm (see the 36-Item Short-Form General Health Survey ques-
Supplementary Appendix). This algorithm was tionnaire (calculated with norm-based scoring so
designed to adjust the dose in order to maintain that 50 is the average score, with higher scores
the hemoglobin level at approximately 13.0 g indicating a better quality of life) (added after the
per deciliter in the patients assigned to darbe- second protocol amendment in May 2005).
poetin alfa.
Patients in the placebo group were assigned Monitoring
to receive darbepoetin alfa as a rescue agent if The independent data and safety monitoring com-
the hemoglobin level fell below 9.0 g per deciliter, mittee reviewed safety reports monthly with for-
with a return to placebo once the hemoglobin mal interim analyses scheduled when approxi-
level was 9.0 g per deciliter or higher. The site mately 20, 40, 60, and 80% of the total expected
investigator was to be notified if any patient had cardiovascular composite events had occurred.
a hemoglobin value of 7.0 g per deciliter or less, a Initial guidelines for early discontinuation in-
value of 16.0 g per deciliter or more, or a decrease cluded a symmetric O’Brien–Fleming alpha-spend-
of 2.0 g per deciliter or more in a 4-week period. ing function. In April 2006, data from a non–
Measurements of hemoglobin levels and vital placebo-controlled trial of a different ESA in
signs were performed every 2 weeks during the patients with chronic kidney disease showed that
study-drug–titration period and monthly there- treatment aimed at achieving a higher hemoglo-
after. Transferrin saturation and ferritin levels bin level (13.5 g per deciliter vs. 11.3 g per deci-
were measured quarterly; other laboratory assess- liter) was associated with increased rates of ad-
ments and spot urine collections were performed verse clinical events.17 This information and more
at 24-week intervals. Patient-reported outcomes equivocal results from a related, smaller trial18
and health resource utilization were assessed at were proactively communicated to our patients,
weeks 1, 13, and 25 and every 24 weeks thereafter. investigators, and the data and safety monitoring
At each visit, information was gathered regard- committee. The committee made no recommen-
ing adverse events, hospitalization, transfusions, dation to alter or terminate the study on the basis
and the concomitant use of other medications. of interim data that already reflected more clin-
ical events than the numbers of events in these
Evaluation of Outcomes related trials. The consent form was modified
The primary end points were the time to the with the addition of the new information regard-
composite outcome of death from any cause or a ing potential harm, and all study participants
cardiovascular event (nonfatal myocardial infarc- were asked to provide written informed consent
tion, congestive heart failure, stroke, or hospital- again. The executive committee requested that
ization for myocardial ischemia) and the time to the data and safety monitoring committee adopt
the composite outcome of death or end-stage re- a more cautious stopping rule, with the use of a
nal disease (see the Supplementary Appendix). one-sided alpha of 0.05 for harm at each assess-
The overall alpha level for the primary end points ment (without adjustment for multiple testing)
was split: 0.048 for the cardiovascular composite for either the cardiovascular composite outcome
outcome and 0.002 for the renal composite out- or death. The boundaries for efficacy remained
come. All potential end points were adjudicated unchanged, and with this new mandatory stop-

ping rule for harm, the committee made no rec- placebo). Of the 4038 patients evaluated, 2012
ommendation to terminate the trial before its were assigned to receive darbepoetin alfa and
scheduled conclusion. 2026 were assigned to receive placebo. The study
was event driven and was completed on March
Statistical Analysis 28, 2009, with a median follow-up duration of
The trial was event driven, with a total of 1203 29.1 months. At that time, 3523 patients (87.2%)
cardiovascular composite events required to pro- were either still being followed for clinical end
vide 80% statistical power to detect a 20% risk points or had died; this group included 1761 pa-
reduction for this outcome, with a two-sided type tients in the darbepoetin alfa group (87.5%) and
I error of 0.048 (unadjusted for interim analyses). 1762 patients in the placebo group (87.0%). The
We aimed to enroll approximately 4000 patients; vital status at study termination was unknown
assumptions included an annualized rate of events for 153 patients in the darbepoetin alfa group
in the placebo group of 12.5%, a 15% loss to (7.6%) and 164 in the placebo group (8.1%) (see
follow-up, and attenuation of the treatment ef- the Consolidated Standards for the Reporting of
fect due to the anticipated use of ESAs in patients Trials [CONSORT] diagram in the Supplementa-
who had progression to end-stage renal disease. ry Appendix).
Time-to-event analyses were performed with The median age was 68 years, and 57.3% of
the use of life-table methods according to the the patients were women; 65.4% of the patients
intention-to-treat principle. Kaplan–Meier cumu- had a history of cardiovascular disease, with
lative incidence curves were compared with the similar percentages of patients in each group re-
use of a two-sided log-rank test, stratified accord- porting a history of coronary artery disease,
ing to the baseline proteinuria level and the pres- stroke, peripheral arterial disease, and myocar-
ence or absence of a history of cardiovascular dial infarction. There was an imbalance in the
disease. Estimated hazard ratios (for darbepoetin proportion of patients with a history of heart
alfa vs. placebo) and 95% confidence intervals failure (31.5% in the darbepoetin alfa group vs.
were obtained with the use of stratified Cox 35.2% in the placebo group, unadjusted P = 0.01).
proportional-hazards models. Patients who dis- There were no clinically meaningful baseline im-
continued either study drug early, including pa- balances in vital signs, laboratory data, or the
tients who began treatment with dialysis or un- use of medications for cardiovascular disease and
derwent transplantation, were followed for study diabetes (Table 1).
end points.
Categorization of adverse events was based on Intervention and Hemoglobin Values
groupings of preferred terms defined by the The overall median hemoglobin level at baseline
standardized queries in the Medical Dictionary was 10.4 g per deciliter (interquartile range, 9.8 to
for Regulatory Activities.23 Analyses of patient- 10.9). Between-group differences in hemoglobin
reported outcomes were prespecified to impute values were apparent less than 1 month after ran-
missing data with the last-observation-carried- domization, and the differences were significant
forward method and to use t-tests for treatment by 1 month (Fig. 1). From 3 months to the end of
comparisons, with means and standard devia- treatment, the median achieved hemoglobin level
tions. Reported P values are nominal and have (based on the area under the curve) was 12.5 g
not been adjusted for multiple comparisons. Ad- per deciliter (interquartile range, 12.0 to 12.8) in
ditional statistical methods are described in the the darbepoetin alfa group and 10.6 g per decili-
Supplementary Appendix. ter (interquartile range, 9.9 to 11.3) in the placebo
group (P<0.001) (Fig. 1). A total of 84.6% of pa-
R e sult s tients in the darbepoetin alfa group and 86.9% of
patients in the placebo group were switched to
Patients monthly dosing. Over the course of the study,
We enrolled a total of 4047 patients, but before 46% of the patients assigned to placebo received
unblinding, we excluded all information regard- at least one dose of darbepoetin alfa as rescue
ing 9 patients from two sites that did not adhere therapy. The median monthly dose in patients
to Good Clinical Practice guidelines (4 patients assigned to placebo was 0 μg (interquartile range,
who were randomly assigned to darbepoetin alfa 0 to 5) as compared with 176 μg (interquartile
and 5 patients who were randomly assigned to range, 104 to 305) in patients assigned to darbe-

Table 1. Baseline Characteristics of the Patients.*
Darbepoetin Alfa Placebo

Characteristic (N = 2012) (N = 2026) P Value†
Age (yr) 0.22
Median 68 68
Interquartile range 60–75 60–75
Female sex (%) 58.5 56.0 0.10
Race or ethnic group (%)‡ 0.84
White 63.1 64.2
Black 20.6 19.8
Hispanic 13.6 13.1
Other 2.7 3.0
Known duration of diabetes (yr) 0.94
Median 15.3 15.5
Interquartile range 8.2–21.8 8.4–21.7
Body-mass index§ 0.11
Median 30.5 30.1
Retinopathy (%) 48.2 45.7 0.12
Laser treatment (%) 29.6 28.6 0.49
Diabetic neuropathy (%) 49.2 46.4 0.07
Amputation 5.7 6.1 0.58
History of cardiovascular disease (%)¶ 64.0 66.9 0.05
Coronary artery disease‖ 43.2 45.5 0.16
Heart failure 31.5 35.2 0.01
Myocardial infarction 18.4 18.3 0.95
Stroke 11.5 10.7 0.41
Peripheral arterial disease** 21.2 20.8 0.73
Use of pacemaker 4.5 6.1 0.02
Use of automatic implantable cardioverter–defibrillator 1.4 1.4 0.87
Atrial fibrillation (%) 11.0 10.0 0.29
Smoking status (%) 0.88
Current smoker 5.4 4.7
Former smoker 38.2 39.4
Blood pressure (mm Hg)
Systolic 0.25
Median 136 135
Diastolic 0.55
Median 71 70
Serum creatinine (mg/dl) 0.01
Median 1.8 1.9
Estimated GFR (ml/min/1.73 m2) 0.03
Median 34 33

Table 1. (Continued.)

Ratio of total protein (in mg/dl) to creatinine (in mg/dl) in urine¶ 0.73
Median 0.4 0.4
<1 (%) 65.9 64.9
≥1 (%) 34.1 35.1
Potassium (mmol/liter) 0.73
Median 4.7 4.7
Albumin (g/dl) 0.13
Median 4.0 4.0
Glycated hemoglobin (%) 0.02
Median 7.0 6.9
Hemoglobin (g/dl) 0.15
Median 10.5 10.4
White-cell count (×10−9/liter) 0.32
Median 6.6 6.7
−9/liter)
Platelet count (×10 0.14
Median 241 244
Transferrin saturation (%) 0.80
Median 23 23
Serum ferritin (µg/liter) 0.17
Median 131 137
Cholesterol (mg/dl)
Total 0.47
Median 169 170
LDL 0.41
Median 84 85
HDL 0.85
Median 46 46
Triglycerides (mg/dl) 0.97
Median 155 154

Table 1. (Continued.)

Medications (%)
Insulin 48.7 49.8 0.49
Oral hypoglycemic agent 57.5 56.1 0.36
Thiazolidinedione 25.2 23.5 0.22
Sulfonamide 36.3 34.5 0.24
Biguanide 17.1 17.2 0.91
Angiotensin-converting–enzyme inhibitor or angiotensin- 79.7 80.0 0.82
receptor blocker
Angiotensin-converting–enzyme inhibitor and angiotensin- 10.3 9.8 0.55
receptor blocker
Beta-blocker 49.9 48.7 0.43
Aldosterone-receptor blocker 5.4 4.9 0.49
Statin 59.6 57.5 0.16
Statin or other lipid-lowering agent 64.6 64.0 0.72
Aspirin 42.0 42.8 0.63
Aspirin or other antiplatelet agent 48.0 48.6 0.68
Vitamin K antagonist 7.2 6.6 0.46
Iron
Oral 41.8 42.7 0.57
Intravenous 1.4 1.6 0.63
Previous use of erythropoietic agent 8.8 10.2 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.
poetin alfa. Among the patients who had not died darbepoetin alfa group (14.8%) and in 496 pa-
or progressed to end-stage renal disease, 93.9% tients in the placebo group (24.5%) (hazard ratio
of the patients in the darbepoetin alfa group and for darbepoetin alfa vs. placebo, 0.56; 95% confi-
90.4% of those in the placebo group were receiv- dence interval [CI], 0.49 to 0.65; P<0.001).
ing the assigned treatment at 6 months; 87.4%
and 83.7%, respectively, at 1 year; and 74.3% and Primary Composite Outcomes and Components
69.3%, respectively, at 2 years. There was no sig- Death, Myocardial Infarction, Unstable Angina,
nificant difference in the proportions of patients Heart Failure, and Stroke
receiving oral iron during the study (66.8% of The primary cardiovascular composite outcome
those in the darbepoetin alfa group and 68.6% of — death or a nonfatal cardiovascular event —
those in the placebo group, P = 0.25); however, occurred in 632 patients in the darbepoetin alfa
more patients in the placebo group received intra- group (31.4%) and in 602 patients in the placebo
venous iron (20.4%, vs. 14.8% of patients assigned group (29.7%) (hazard ratio for darbepoetin alfa
to darbepoetin alfa; P<0.001). Red-cell transfu- vs. placebo, 1.05; 95% CI, 0.94 to 1.17; P = 0.41)
sions were administered in 297 patients in the (Table 2 and Fig. 2A). There were no significant

13.5
13.0
Darbepoetin alfa
12.5
Mean Hemoglobin (g/dl)

12.0
11.5
11.0 Placebo
10.5
10.0
9.5
0.0
0 6 12 18 24 30 36 42 48
Months since Randomization
No. of Patients
Darbepoetin alfa 2004 1768 1503 1300 946 635 404 253 97
Placebo 2019 1742 1460 1221 887 620 356 216 79
Figure 1. Mean Hemoglobin Levels through 48 Months among PatientsRETAKE:

AUTHOR: Pfeffer
Who Were 1st
Assigned to Receive Darbepoetin
Alfa or Placebo. 2nd
I bars represent standard errors.FIGURE: 1 of 3 3rd
Revised
ARTIST: MRL
SIZE
6 col
TYPE: Line Combo 4-C H/T 33p9
between-group differences in the time to AUTHOR,
the firstPLEASE
placebo
NOTE: (84 patients [4.2%] vs. 117 patients
Figure has beenwhen
occurrence of the following components, redrawn and type hashazard
[5.8%]; been reset.
ratio, 0.71; 95% CI, 0.54 to 0.94;
Please check carefully.
considered individually: death from any cause, P = 0.02).
fatal or nonfatal congestiveJOB: 36121
heart failure, fatal or ISSUE: 11-19-09
nonfatal myocardial infarction, or hospitalization Renal Outcomes

for myocardial ischemia (Table 2 and Fig. 2B, 2C, Death or end-stage renal disease occurred in 652
and 2D). However, fatal or nonfatal stroke was patients in the darbepoetin alfa group (32.4%)
more likely to occur in the patients assigned to and in 618 patients in the placebo group (30.5%)
darbepoetin alfa (101 patients [5.0%] vs. 53 pa- (hazard ratio for darbepoetin alfa vs. placebo,
tients [2.6%]; hazard ratio, 1.92; 95% CI, 1.38 to 1.06; 95% CI, 0.95 to 1.19; P = 0.29) (Fig. 3A). End-
2.68; P<0.001) (Table 2 and Fig. 2E). stage renal disease occurred in 338 patients in
The prespecified stratification characteristics the darbepoetin alfa group (16.8%) and in 330 pa-
of a history of cardiovascular disease and marked tients assigned to placebo (16.3%) (hazard ratio,
proteinuria (urinary protein-to-creatinine ratio, 1.02; 95% CI, 0.87 to 1.18; P = 0.83) (Fig. 3B).
≥1) both identified higher-risk groups regardless The stratification characteristics of a history
of the assigned treatment for the cardiovascular of cardiovascular disease and marked proteinuria
composite outcome. The overall null effect of also identified groups at higher risk for the com-
darbepoetin alfa was observed in each subgroup, posite outcome of death or end-stage renal dis-
with no significant interaction. Similarly, there ease, with no significant interaction in either
were no significant interactions for any of the subgroup. No significant interactions were ob-
other five prespecified subgroups based on age, served in the other five prespecified subgroups,
sex, race or ethnic group, region, or baseline es- with the exception of a nominally significant
timated GFR (see the Supplementary Appendix). interaction for race or ethnic group. The 653 pa-
Cardiac revascularization procedures were per- tients described as nonwhite and nonblack in
formed less frequently in the patients assigned the darbepoetin alfa group had the greatest ex-
to darbepoetin alfa than in those assigned to cess risk (hazard ratio, 1.46; 95% CI, 1.10 to

Table 2. Composite and Component End Points.*
Darbepoetin Alfa Placebo Hazard Ratio

End Point (N = 2012) (N = 2026) (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 cause 412 (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 ischemia 41 (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
ESRD 338 (16.8) 330 (16.3) 1.02 (0.87–1.18) 0.83
Additional adjudicated end points
Death from cardiovascular causes 259 (12.9) 250 (12.3) 1.05 (0.88–1.25) 0.61
Cardiac revascularization 84 (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.
1.95); among the 2570 white patients, the hazard significantly between 1138 patients assigned to
ratio was 1.05 (95% CI, 0.92 to 1.21), and among darbepoetin alfa and 1157 patients assigned to
the 815 black patients, the hazard ratio was 0.87 placebo (mean change in the score for energy,
(95% CI, 0.68 to 1.10; P = 0.03 for the interaction, 2.6±9.9 points vs. 2.1±9.7 points; P = 0.20; mean
uncorrected for multiple comparisons). change in the score for physical functioning,
1.3±9.2 vs. 1.1±8.8; P = 0.51).
Patient-Reported Outcomes
The primary prespecified analysis for the patient- Blood Pressure
reported outcomes was the change from baseline There was no significant difference in systolic
to 25 weeks in the FACT-Fatigue score. Among blood pressure between the two groups; the me-
patients with both baseline and week-25 scores, dian systolic blood pressure over time was 134
from a baseline score of 30.2 in the group of 1762 mm Hg (interquartile range, 126 to 143) in both
patients assigned to darbepoetin alfa and a base- groups. Diastolic blood pressure was higher in
line score of 30.4 in the 1769 patients assigned to the patients assigned to darbepoetin alfa than in
placebo, there was a greater degree of improve- those assigned to placebo (median over time,
ment in the mean (±SD) score in the darbepoetin 73 mm Hg [interquartile range, 67 to 78] vs. 71
alfa group than in the placebo group (an increase mm Hg [interquartile range, 65 to 77]; P<0.001).
of 4.2±10.5 points vs. 2.8±10.3 points, P<0.001 for
between-group changes). An increase of three or Prespecified Categories of Adverse Events
more points (considered to be a clinically mean- Hypertension occurred in 491 patients in the dar-
ingful improvement) occurred in 963 of 1762 pa- bepoetin alfa group and in 446 patients in the
tients assigned to darbepoetin alfa (54.7%) and placebo group (P = 0.07) (see the Supplementary
875 of 1769 patients assigned to placebo (49.5%) Appendix). Convulsions were reported in nine pa-
(P = 0.002). Other prespecified quality-of-life as- tients in the darbepoetin alfa group and in four
sessments, in the domains of energy and physi- patients in the placebo group. No cases of anti-
cal functioning as measured with the 36-Item body-mediated pure red-cell aplasia were report-
Short-Form General Health Survey, did not differ ed in either group.

A Cardiovascular Composite End Point B Death from Any Cause
2028
50 50
Hazard ratio, 1.05 (95% CI, 0.94–1.17) Hazard ratio, 1.05 (95% CI, 0.92–1.21)
40 P=0.41 40 P=0.48
Darbepoetin alfa Darbepoetin alfa
30 Placebo 30
Placebo
20 20
10 10
Patients with Event (%)

0 0
0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
Months since Randomization Months since Randomization
No. at Risk No. at Risk
Darbepoetin alfa 2012 1882 1717 1515 1180 817 551 318 130 Darbepoetin alfa 2012 1947 1847 1659 1337 945 655 386 164
Placebo 2026 1836 1687 1487 1178 834 529 319 122 Placebo 2026 1943 1839 1652 1345 970 636 385 156
C Fatal or Nonfatal Congestive Heart Failure D Fatal or Nonfatal Myocardial Infarction and Myocardial Ischemia
50 50 Fatal or Nonfatal
Downloaded from nejm.org at UNIVERSITY

Hazard ratio, 0.89 (95% CI, 0.74–1.08)
Myocardial Infarction Myocardial Ischemia
The
40 P=0.24 40
FIGURE: 2 of
TYPE: OF
Hazard ratio, 0.96 (95% CI, Hazard ratio, 0.84 (95% CI,
AUTHOR: Pfeffer
Line
0.75–1.22) 0.55–1.27)
30 30
P=0.73 P=0.40
20 20 Darbepoetin alfa Darbepoetin alfa
Placebo Placebo
CALGARY
10 Placebo 10
Darbepoetin alfa

0 0
n 3engl j med 361;21

0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
Combo on July
Months since Randomization Months since Randomization
No. at Risk No. at Risk
AUTHOR, PLEASE NOTE:

4-C 11,H/T
Darbepoetin alfa 2012 1890 1742 1525 1191 819 555 319 136 Fatal or Nonfatal Myocardial Infarction
nejm.org
Placebo 2026 1859 1702 1495 1187 835 519 307 115 Darbepoetin alfa 2012 1920 1785 1566 1232 851 577 325 137
Placebo 2026 1907 1765 1550 1235 863 539 324 123
RETAKE:
n e w e ng l a n d j o u r na l
Myocardial Ischemia
Revised
ARTIST: MRLThe New England Journal of Medicine
col
SIZE
33p9
of
Placebo 2026 1906 1767 1561 1251 880 556 338 132
november
1st
2012. For 6personal

2nd
3rd 19,
E Fatal or Nonfatal Stroke
50
2009
Hazard ratio, 1.92 (95% CI, 1.38–2.68)

P<0.001
m e dic i n e
40
30
20
10 Darbepoetin alfa
Placebo

0
0 6 12 18 24 30 36 42 48
No. at Risk
use only. No other uses without permission.

Placebo 2026 1914 1783 1575 1262 886 561 338 132
per deciliter) versus placebo (with darbepoetin

Figure 2 (facing page). Kaplan–Meier Estimates of the
Probability of the Primary and Secondary End Points. alfa as rescue therapy if hemoglobin values de-
Panel A shows the primary cardiovascular composite creased below 9.0 g per deciliter). In this study
end point. The secondary end points of deaths from involving 4038 patients randomly assigned to a
any cause (Panel B), fatal or nonfatal congestive heart study group, with 9941 patient-years of follow-up
failure (Panel C), fatal or nonfatal myocardial infarction and with 1234 patients who had a composite out-
and myocardial ischemia (Panel D), and fatal or non
come of a cardiovascular event and 1270 patients
fatal stroke (Panel E) are also shown. P values are not
adjusted for multiple comparison. who had a composite outcome of a renal event,
we found no overall significant differences in the
hazard rates for these clinically important out-
Venous thromboembolic events were reported comes or in the rates of death, heart failure, myo-
in 41 patients in the darbepoetin alfa group cardial infarction, admission for myocardial is
(2.0%), as compared with 23 patients in the pla- chemia, or end-stage renal disease.
cebo group (1.1%) (P = 0.02). Arterial thrombo Although there was no significant increase in
embolic events (some of which were adjudicated the overall cardiovascular composite outcome in
as cardiovascular events) were also reported more the group assigned to darbepoetin alfa, there was
frequently in the darbepoetin alfa group (in 178 an increased incidence of stroke (annualized event
patients [8.9%] vs. 144 patients [7.1%], P = 0.04). rate, 2.1%, vs. 1.1% in the placebo group). Data
from a study of patients undergoing dialysis sug-
Cancer gested this risk of stroke19; however, this risk
There was no significant between-group difference was not identified in either the Correction of
in the number of patients reporting a cancer- Hemoglobin and Outcomes in Renal Insufficien-
related adverse event: 139 in the darbepoetin alfa cy (CHOIR) study (ClinicalTrials.gov number,
group (6.9%) and 130 in the placebo group (6.4%) NCT00211120)17 or a meta-analysis.24 This pre-
(P = 0.53). Overall, 39 deaths were attributed to viously undocumented and clinically important
cancer in the 2012 patients in the darbepoetin finding of a heightened risk of stroke is not ex-
alfa group and 25 deaths were attributed to cancer plained by an increase in systolic blood pressure.
in the 2026 patients in the placebo group (P = 0.08 In a recent report of a randomized, placebo-con-
by the log-rank test). Among patients with a his- trolled trial of intravenous erythropoietin in the
tory of a malignant condition at baseline, there early phase of an acute ischemic stroke,25 there
were 60 deaths from any cause in the 188 patients were more deaths in the group assigned to the
assigned to darbepoetin alfa and 37 deaths in the ESA (42 of 256 patients [16.4%]) as compared
160 patients assigned to placebo (P = 0.13 by the with the group assigned to placebo (24 of 266
log-rank test). In this subgroup, 14 of the 188 pa- patients [9.0%]). This study also provides support
tients assigned to darbepoetin alfa died from can- for an adverse relationship between ESAs and
cer, as compared with 1 of the 160 patients as- stroke. We also confirmed previous findings of
signed to placebo (P = 0.002 by the log-rank test). increased rates of venous thromboembolic events
among patients treated with ESAs.
Discussion Our findings appear to differ from those of
the CHOIR trial, the next largest trial involving
The main purpose of the TREAT was to determine patients with chronic kidney disease who were
whether treatment of a low hemoglobin level with not undergoing dialysis, which used epoetin alfa
darbepoetin alfa would reduce the risk of death and was discontinued prematurely after a median
and major cardiovascular and renal events among follow-up of 16 months and after 222 patients
patients with type 2 diabetes mellitus, chronic had a primary event.17 Both groups in the CHOIR
kidney disease, and anemia. There was no signifi- trial were randomly assigned to receive epoetin
cant difference in the overall rates of either the alfa, and in that study, there was a higher risk of
primary cardiovascular composite end point or cardiovascular events in the group assigned to a
the primary renal composite end point with the target hemoglobin level of 13.5 g per deciliter
use of the therapeutic strategy of increasing the than in the group assigned to a target level of
hemoglobin level with darbepoetin alfa (to at- 11.3 g per deciliter (hazard ratio, 1.34; 95% CI,
tempt to reach a target hemoglobin level of 13.0 g 1.03 to 1.74; P = 0.03). This excess of cardiovas-

A Renal Composite (ESRD or Death)

50
Darbepoetin alfa
40

Placebo
Hazard ratio, 1.06 (95% CI, 0.95–1.19)
30
P=0.29
20
10
0
0 6 12 18 24 30 36 42 48
No. at Risk
Placebo 2026 1915 1748 1519 1193 842 540 312 123
B ESRD
50
40
Hazard ratio, 1.02 (95% CI, 0.87–1.18)

30
P=0.83 Darbepoetin alfa
Placebo
20
10
0
0 6 12 18 24 30 36 42 48
No. at Risk
Placebo 2026 1907 1729 1491 1162 811 513 292 115
Figure 3. Kaplan–Meier Estimates of the Probability of Renal Outcomes.

AUTHOR: Pfeffer RETAKE: 1st
Panel A shows the primary renal composite end point (end-stage renal disease [ESRD]
2nd or death), and Panel B shows
FIGURE:
the end-point component of ESRD. 3 of 3have not been adjusted for multiple comparisons.
P values 3rd
Revised
ARTIST: MRL
SIZE
6 col
TYPE: Line Combo 4-C H/T 33p9
cular events was largely accounted for by more planned follow-up of trials and the potential to
AUTHOR, PLEASE NOTE:
deaths and heart-failure events; Figure
only has
12 been
patients draw
redrawn and type misleading
has been reset. conclusions when premature dis-
in each group had a stroke. These findings Pleaseled
checkcontinuation
carefully. results in an insufficient number
to the suggestion that our trial should be discon- of events to
JOB: 361xx allow
ISSUE: for a reliable estimation of the
xx-xx-09
tinued.26 However, by that time, there were more effect of treatment.28,29
accumulated cardiovascular composite events in Before we conducted our study, there was a
our trial than in the CHOIR trial, and the inde- suggestion that ESAs might increase mortality
pendent data and safety monitoring committee among patients with cancer, so patients with an
recommended continuation.27 The TREAT execu- active malignant condition were excluded from
tive committee updated the consent form to re- our trial.30 During the trial, mounting concern led
flect the results from the CHOIR trial, and our to new regulatory warnings about the use of ESAs
patients again were asked to provide written in- in patients with “anemia of cancer,”31 prompting
formed consent. The final results of our study a protocol amendment to discontinue the study
demonstrate the importance of completing the drug in patients in whom cancer developed. Al-

though the number of these patients did not dif- patients with a history of a malignant condition
fer significantly between the study groups, among will outweigh any potential benefit of an ESA.
the 348 patients with a history of cancer at base- Supported by Amgen, which provided independent statistical
support through a contract with the board of regents for the
line, mortality was higher among those assigned University of Wisconsin System for data analysis for the TREAT
to darbepoetin alfa than among those assigned Data and Safety Monitoring Committee as well as for the study.
to placebo; these findings are consistent with Dr. Pfeffer reports receiving consulting fees from Abbott,
32 Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Boston
those in a recent meta-analysis. Scientific, Bristol-Myers Squibb, Centocor, CVRx, Genentech,
Our trial provides long-term, placebo-controlled Cytokinetics, Daiichi Sankyo, Genzyme, Medtronic, Novartis,
data on the use of ESAs in patients with diabetes, Roche, Sanofi-Aventis, Servier, and VIA Pharmaceutics and grant
support from Amgen, Baxter, Celladon, Novartis, and Sanofi-
chronic kidney disease, and moderate anemia Aventis, and being named coinventor on a patent for the use of
who are not undergoing dialysis. No single trial inhibitors of the renin–angiotensin system in selected survivors
can address the multitude of pertinent issues of myocardial infarction; Dr. Burdmann, receiving consulting
fees from Amgen and Sigma Pharma and grant support from
without limitations, and our data may not be Amgen and Roche; Drs. Chen and Kewalramani, being employ-
fully applicable to other patient populations. It is ees of and owning stock in Amgen; Dr. Cooper, receiving con-
possible that other dosing strategies could be sulting fees from Amgen; Dr. de Zeeuw, receiving consulting
fees from Amgen and Novartis and lecture fees from Amgen; Dr.
developed to mitigate the risk of stroke while Eckardt, receiving consulting fees from Amgen, Ortho Biotech,
conserving the modest benefits of treatment. In Roche, Affymax, Stada, and Sandoz–Hexal and lecture fees from
light of the baseline imbalances between the Amgen, Ortho Biotech, and Roche; Dr. Ivanovich, receiving con-
sulting fees from Amgen, Baxter, Biogen, and Reata; Dr. Levey,
study groups, additional sensitivity analyses were receiving grant support from Amgen; Dr. Lewis, receiving con-
conducted, and they did not alter our results. sulting fees from Amgen and grant support from Amgen and
More extensive analyses of the patient-reported the Robert Wood Johnson Foundation; Dr. McGill, receiving con-
sulting fees from Amgen and Boehringer Ingelheim, lecture fees
outcome measures are needed to assess the dura- from Novartis, and grant support from Novartis and Boehringer
bility of the rather modest improvement we ob- Ingelheim; Dr. McMurray, receiving consulting fees from Me-
served only in the FACT-Fatigue score. narini, Bristol-Myers Squibb, Roche, Novocardia, Boehringer
Ingelheim, Novartis, BioMérieux, and Boston Scientific, lecture
The long-standing presumption of a benefit of fees from AstraZeneca, Solvay, Takeda, Novartis, BMS Sanofi,
ESAs in this patient population led to non–pla- and Vox Media, and grant support from BMS, Novartis, Amgen,
cebo-controlled trials, which, by design, cannot AstraZeneca, Cytokinetics, Hoffmann–La Roche, Pfizer, Scios,
and GlaxoSmithKline; Dr. Parfrey, receiving consulting and
provide a reliable assessment of risk and bene- lecture fees from Amgen and lecture fees from Ortho Biotech;
21
fit. The present trial supplies these missing data, Dr. Parving, receiving consulting fees from Amgen and Novartis
which may assist physicians and patients in mak- and lecture fees from Novartis; Dr. Singh, receiving consulting
fees from Johnson & Johnson and Watson, lecture fees from John-
ing more informed decisions about individual son & Johnson, Amgen, and Watson, and grant support from
care. It is our view that, in many patients with Johnson & Johnson, Amgen, Roche, AMAG Pharmaceuticals, and
diabetes, chronic kidney disease, and moderate Watson; Dr. Solomon, receiving grant support from Amgen;
and Dr. Toto, receiving consulting and lecture fees from Amgen
anemia who are not undergoing dialysis, the in- and grant support from Novartis, Reata, and Abbott. No other
creased risk of stroke and possibly death among potential conflict of interest relevant to this article was reported.
Appendix
From the Department of Medicine, Brigham 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. Vasylyeva, 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.

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
1. Stamler J, Vaccaro O, Neaton JD, mortality in end-stage renal disease. Am J 21. Pfeffer MA. Critical missing data in
Wentworth D. Diabetes, other risk fac- Kidney Dis 1996;28:53-61. erythropoiesis-stimulating agents in CKD:
tors, and 12-yr cardiovascular mortality 11. Keane WF, Brenner BM, de Zeeuw D, first beat placebo. Am J Kidney Dis 2008;
for men screened in the Multiple Risk Fac- et al. The risk of developing end-stage re- 51:366-9.
tor Intervention Trial. Diabetes Care 1993; nal disease in patients with type 2 diabe- 22. Pfeffer MA, Burdmann EA, Chen CY,
16:434-44. tes and nephropathy: the RENAAL study. et al. Baseline characteristics in the Trial
2. Booth GL, Kapral MK, Fung K, Tu JV. Kidney Int 2003;63:1499-507. to Reduce Cardiovascular Events With
Relation between age and cardiovascular 12. Vlagopoulos PT, Tighiouart H, Weiner Aranesp Therapy (TREAT). Am J Kidney
disease in men and women with diabetes DE, et al. Anemia as a risk factor for car- Dis 2009;54:59-69.
compared with non-diabetic people: a pop- diovascular disease and all-cause mortal- 23. Mozzicato P. Standardised MedDRA
ulation-based retrospective cohort study. ity in diabetes: the impact of chronic kid- queries: their role in signal detection.
Lancet 2006;368:29-36. ney disease. J Am Soc Nephrol 2005;16: Drug Saf 2007;30:617-9.
3. Turnbull F, Neal B, Algert C, et al. Ef- 3403-10. 24. Strippoli GF, Navaneethan SD, Craig
fects of different blood pressure-lowering 13. Tong PCY, Kong APS, So W-Y, et al. JC. Haemoglobin and haematocrit targets
regimens on major cardiovascular events Hematocrit, independent of chronic kid- for the anaemia of chronic kidney dis-
in individuals with and without diabetes ney disease, predicts adverse cardiovascu- ease. Cochrane Database Syst Rev 2006;4:
mellitus: results of prospectively designed lar outcomes in Chinese patients with CD003967.
overviews of randomized trials. Arch In- type 2 diabetes. Diabetes Care 2006;29: 25. Ehrenreich H, Weissenborn K, Prange
tern Med 2005;165:1410-9. 2439-44. H, et al. Recombinant human erythro-
4. Baigent C, Keech A, Kearney PM, et al. 14. Pfeffer MA, Solomon SD, Singh AK, poietin in the treatment of acute ischemic
Efficacy and safety of cholesterol-lower- Ivanovich P, McMurray JJ. Uncertainty in stroke. Stroke 2009 October 15 (Epub
ing treatment: prospective meta-analysis the treatment of anemia in chronic kidney ahead of print).
of data from 90,056 participants in 14 ran- disease. Rev Cardiovasc Med 2005;Suppl 3: 26. Strippoli GFM, Tognoni G, Navanee-
domised trials of statins. Lancet 2005;366: S35-S41. than SD, Nicolucci A, Craig JC. Hemoglo-
1267-78. [Errata, Lancet 2005;366:1358, 15. Eschbach JW, Abdulhadi MH, Browne bin targets: we were wrong, time to move
2008;371:2084.] JK, et al. Recombinant human erythro on. Lancet 2007;369:349-50.
5. Gaede P, Lund-Andersen H, Parving poietin in anemic patients with end-stage 27. Pfeffer MA. An ongoing study of ane-
H-H, Pedersen O. Effect of a multifacto- renal disease: results of a phase III multi- mia correction in chronic kidney disease.
rial intervention on mortality in type 2 center clinical trial. Ann Intern Med N Engl J Med 2007;356:959-61.
diabetes. N Engl J Med 2008;358:580-91. 1989;111:992-1000. 28. DeMets DL, Pocock SJ, Julian DG. The
6. Brenner BM, Cooper ME, de Zeeuw D, 16. Canadian Erythropoietin Study Group. agonising negative trend in monitoring of
et al. Effects of losartan on renal and car- Association between recombinant human clinical trials. Lancet 1999;354:1983-8.
diovascular outcomes in patients with erythropoietin and quality of life and exer- 29. Califf RM, DeMets DL. Principles from
type 2 diabetes and nephropathy. N Engl J cise capacity of patients receiving haemo- clinical trials relevant to clinical practice:
Med 2001;345:861-9. dialysis. BMJ 1990;300:573-8. Part I. Circulation 2002;106:1015-21.
7. Lewis EJ, Hunsicker LG, Clarke WR, 17. Singh AK, Szczech L, Tang KL, et al. 30. Leyland-Jones B, Semiglazov V, Pawl-
et al. Renoprotective effect of the angio- Correction of anemia with epoetin alfa in icki M, et al. Maintaining normal hemo-
tensin-receptor antagonist irbesartan in chronic kidney disease. N Engl J Med globin levels with epoetin alfa in mainly
patients with nephropathy due to type 2 2006;355:2085-98. nonanemic patients with metastatic breast
diabetes. N Engl J Med 2001;345:851-60. 18. Drueke TB, Locatelli F, Clyne N, et al. cancer receiving first-line chemotherapy:
8. Tonelli M, Isles C, Craven T, et al. Ef- Normalization of hemoglobin level in pa- a survival study. J Clin Oncol 2005;23:5960-
fect of pravastatin on rate of kidney func- tients with chronic kidney disease and 72.
tion loss in people with or at risk for coro- anemia. N Engl J Med 2006;355:2071-84. 31. FDA black box warning for Aranesp.
nary disease. Circulation 2005;112:171-8. 19. Parfrey PS, Foley RN, Wittreich BH, Silver Spring, MD: Food and Drug Admin-
9. Locatelli F, Pisoni RL, Combe C, et al. Sullivan DJ, Zagari MJ, Frei D. Double- istration. (Accessed October 23, 2009, at
Anaemia in haemodialysis patients of five blind comparison of full and partial ane- http://www.accessdata.fda.gov/drugsatfda
European countries: association with mor- mia correction in incident hemodialysis _docs/label/2008/103951s5195PI.pdf.)
bidity and mortality in the Dialysis Out- patients without symptomatic heart dis- 32. Bohlius J, Schmidlin K, Brillant C, et
comes and Practice Patterns Study (DOPPS). ease. J Am Soc Nephrol 2005;16:2180-9. al. Recombinant human erythropoiesis-
Nephrol Dial Transplant 2004;19:121-32. 20. Phrommintikul A, Haas SJ, Elsik M, stimulating agents and mortality in pa-
[Erratum, Nephrol Dial Transplant 2004; Krum H. Mortality and target haemoglo- tients with cancer: a meta-analysis of ran-
19:1666.] bin concentrations in anemic patients with domised trials. Lancet 2009;373:1532-42.
10. Foley RN, Parfrey PS, Harnett JD, Kent chronic kidney disease treated with eryth- [Erratum, Lancet 2009;374:28.]
GM, Murray DC, Barre PE. The impact of ropoietin: a meta-analysis. Lancet 2007; Copyright © 2009 Massachusetts Medical Society.
anemia on cardiomyopathy, morbidity, and 369:381-8.


Pfeffer 2009

Uploaded by

Copyright:

Available Formats

Pfeffer 2009

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Pfeffer 2009

Uploaded by

Copyright:

Available Formats

new england

A Trial of Darbepoetin Alfa in Type 2 Diabetes

2020 n engl j med 361;21 nejm.org november 19, 2009

The New England Journal of Medicine

n engl j med 361;21 nejm.org november 19, 2009 2021

2022 n engl j med 361;21 nejm.org november 19, 2009

The New England Journal of Medicine

Table 1. Baseline Characteristics of the Patients.*

Darbepoetin Alfa Placebo

n engl j med 361;21 nejm.org november 19, 2009 2023

Darbepoetin Alfa Placebo

2024 n engl j med 361;21 nejm.org november 19, 2009

The New England Journal of Medicine

Darbepoetin Alfa Placebo

n engl j med 361;21 nejm.org november 19, 2009 2025

Mean Hemoglobin (g/dl)

Figure 1. Mean Hemoglobin Levels through 48 Months among PatientsRETAKE:

nonfatal myocardial infarction, or hospitalization Renal Outcomes

2026 n engl j med 361;21 nejm.org november 19, 2009

The New England Journal of Medicine

Table 2. Composite and Component End Points.*

Darbepoetin Alfa Placebo Hazard Ratio

* ESRD denotes end-stage renal disease.

n engl j med 361;21 nejm.org november 19, 2009 2027

Patients with Event (%)

Downloaded from nejm.org at UNIVERSITY

Patients with Event (%)

n 3engl j med 361;21

AUTHOR, PLEASE NOTE:

2012. For 6personal

Copyright © 2009 Massachusetts Medical Society. All rights reserved.

Patients with Event (%)

use only. No other uses without permission.

per deciliter) versus placebo (with darbepoetin

n engl j med 361;21 nejm.org november 19, 2009 2029

A Renal Composite (ESRD or Death)

Patients with Event (%)

Hazard ratio, 1.02 (95% CI, 0.87–1.18)

Figure 3. Kaplan–Meier Estimates of the Probability of Renal Outcomes.

2030 n engl j med 361;21 nejm.org november 19, 2009

The New England Journal of Medicine

n engl j med 361;21 nejm.org november 19, 2009 2031

2032 n engl j med 361;21 nejm.org november 19, 2009

The New England Journal of Medicine

You might also like