new england

The
journal of medicine
established in 1812 April 29, 2021 vol. 384  no. 17

Vadadustat in Patients with Anemia and Non–Dialysis-

Dependent CKD
G.M. Chertow, P.E. Pergola, Y.M.K. Farag, R. Agarwal, S. Arnold, G. Bako, G.A. Block, S. Burke, F.P. Castillo,
A.G. Jardine, Z. Khawaja, M.J. Koury, E.F. Lewis, T. Lin, W. Luo, B.J. Maroni, K. Matsushita, P.A. McCullough,
P.S. Parfrey, P. Roy‑Chaudhury, M.J. Sarnak, A. Sharma, B. Spinowitz, C. Tseng, J. Tumlin, D.L. Vargo, K.A. Walters,
W.C. Winkelmayer, J. Wittes, and K.-U. Eckardt, for the PRO2TECT Study Group*​​

a bs t r ac t

BACKGROUND
Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a The authors’ full names, academic degrees,
class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. and affiliations are listed in the Appen‑
dix. Address reprint requests to Dr. Cher‑
METHODS tow at the Department of Medicine, Stan‑
In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we ford University School of Medicine, 1070
Arastradero Rd., Suite 311, Palo Alto, CA
compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin 94304, or at ­gchertow@​­stanford​.­edu.
alfa in patients with non–dialysis-dependent chronic kidney disease (NDD-CKD)
*A complete list of the investigators in
not previously treated with an ESA who had a hemoglobin concentration of less the PRO2TECT Study Group is provided
than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemo- in the Supplementary Appendix, available
globin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per at NEJM.org.
deciliter (in other countries). The primary safety end point, assessed in a time-to- N Engl J Med 2021;384:1589-600.
event analysis, was the first major adverse cardiovascular event (MACE; a composite DOI: 10.1056/NEJMoa2035938
of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled Copyright © 2021 Massachusetts Medical Society.

across the two trials. Secondary safety end points included expanded MACE
(MACE plus hospitalization for either heart failure or a thromboembolic event).
The primary and key secondary efficacy end points in each trial were the mean
change in hemoglobin concentration from baseline during two evaluation periods:
weeks 24 through 36 and weeks 40 through 52.
RESULTS
A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated
NDD-CKD underwent randomization in the two trials. In the pooled analysis, in
which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the
hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which
did not meet the prespecified noninferiority margin of 1.25. The mean between-
group differences in the change in the hemoglobin concentration at weeks 24
through 36 were 0.05 g per deciliter (95% CI, −0.04 to 0.15) in the trial involving
ESA-untreated patients and −0.01 g per deciliter (95% CI, −0.09 to 0.07) in the
trial involving ESA-treated patients, which met the prespecified noninferiority
margin of −0.75 g per deciliter.
CONCLUSIONS
Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority
criterion for hematologic efficacy but not the prespecified noninferiority criterion for
cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics
and Otsuka Pharmaceutical; PRO2TECT ClinicalTrials.gov numbers, NCT02648347
and NCT02680574.)
n engl j med 384;17  nejm.org  April 29, 2021 1589
The New England Journal of Medicine
Downloaded from nejm.org on November 29, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l
A
nemia is a common complication of
chronic kidney disease (CKD). Among
patients with moderate-to-advanced non–
dialysis-dependent CKD (NDD-CKD), the preva-
lence of anemia, defined as a hemoglobin con-
centration below 13 g per deciliter in men and
below 12 g per deciliter in women, is approxi-
mately 30 to 40%.1,2 Conventional treatment of
anemia in patients with NDD-CKD includes cor-
rection of iron deficiency and the provision of
recombinant erythropoietin and its analogues,
referred to as erythropoiesis-stimulating agents
(ESAs), to maintain the hemoglobin concentra-
tion within the range of 9 to 12 g per deciliter.
Treatment with ESAs reduces the need for red-
cell transfusion, but an increased risk of certain
cardiovascular events has been identified when
hemoglobin concentrations in the near-normal
range are targeted.3-5
Hypoxia-inducible factor (HIF) is a tran-
scription factor that regulates many physiolog-
ical responses to hypoxia, including erythro-
poietin production by the liver and kidneys.
HIF is regulated by oxygen-dependent protea-
somal degradation, with a family of prolyl hy-
droxylases serving as oxygen sensors.6,7 HIF
prolyl hydroxylase inhibitors comprise a new
class of compounds that stabilize HIF, which
in turn stimulates endogenous erythropoietin
production.8,9
Vadadustat is an oral HIF prolyl hydroxylase
inhibitor that is under investigation for the
treatment of anemia associated with CKD. We
conducted four phase 3, international, random-
ized, controlled trials: two trials involved pa-
tients with dialysis-dependent (DD)–CKD (the
INNO2VATE trials), and two involved patients
with NDD-CKD (the PRO2TECT trials). The
­I NNO2VATE trials, which are also reported in
this issue of the Journal, showed that vadadustat
was noninferior to darbepoetin alfa with re-
spect to cardiovascular safety (major adverse
cardiovascular events [MACE]) and hematolog-
ic efficacy.10 Here, we report the results of the
two trials that examined the cardiovascular safety
and hematologic efficacy of vadadustat in pa-
tients with NDD-CKD; one trial involved patients
with anemia who had not received previous
treatment with ESAs (ESA-untreated), and the
other involved patients with anemia actively
treated with ESAs (ESA-treated).
1590 n engl j med 384;17  nejm.org  April 29, 2021
The New England Journal of Medicine
Downloaded from nejm.org on November 29, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
Me thods
Trial Design and Oversight
The design and methods of these two trials have
been described previously,11 and the protocols
are available with the full text of this article at
NEJM.org. Both trials were randomized, open-
label, active-controlled, event-driven trials that
were designed to evaluate the cardiovascular
safety and hematologic efficacy of vadadustat, as
compared with darbepoetin alfa, for the treat-
ment of anemia in patients with NDD-CKD: one
trial (previously called “Correction”) involved
ESA-untreated patients, and the other (previously
called “Conversion”) involved ESA-treated pa-
tients. In both trials, personnel at Akebia Thera-
peutics and Otsuka Pharmaceutical (the funders)
were unaware of the treatment assignments.
The target enrollment in each trial was ap-
proximately 1850 patients, randomly assigned in
a 1:1 ratio across the two treatments.11 The two
trials were designed similarly. The protocols
prespecified that the cardiovascular safety end
points would be pooled across the two trials to
achieve sufficient power. Hematologic efficacy
was prespecified to be assessed separately in
each trial (see the Supplemental Methods sec-
tion in the Supplementary Appendix, available at
NEJM.org).
Akebia Therapeutics designed the trials and
protocols with input from an executive steering
committee, and Otsuka Pharmaceutical partici-
pated in the executive steering committee meet-
ings and provided input on trial protocol amend-
ments. An independent ethics committee approved
the informed consent forms. Trial investigators
conducted the trials in collaboration with Ake-
bia Therapeutics. The executive steering com-
mittee supervised the trial conduct and prog-
ress. The trials were monitored by an independent
data and safety monitoring committee. The first
and last authors wrote the first draft of the
manuscript and made final decisions regarding
the content of the submitted manuscript. All the
authors had access to the trial data, critically
reviewed the manuscript, and approved it for
submission. The investigators vouch for the ac-
curacy and completeness of the data; the au-
thors and Akebia Therapeutics vouch for the fidel-
ity of the trials to the protocols and for the
analysis of the data.
 Vadadustat in Patients with Anemia and NDD-CKD
Participants
In both trials, eligible patients were at least 18
years of age and had NDD-CKD (defined as an
estimated glomerular filtration rate [GFR] of
≤60 ml per minute per 1.73 m2 of body-surface
area, as calculated with the use of the Chronic
Kidney Disease Epidemiology Collaboration equa-
tion, incorporating a term for patient-reported
race [Black or non-Black], as originally de-
fined12). In the trial involving ESA-untreated
patients, patients were required to have a hemo-
globin concentration of less than 10 g per deci-
liter and were excluded if they had received any
ESA within 8 weeks before randomization. In
the trial involving ESA-treated patients, patients
had to be actively receiving maintenance ESA
therapy, with at least one dose received within
6 weeks before screening or during screening,
and were also required to have a hemoglobin
concentration of 8 to 11 g per deciliter (in the
United States) or 9 to 12 g per deciliter (in other
countries).
In both trials, patients were required to have
a serum ferritin concentration of at least 100 ng
per milliliter and a transferrin saturation of at
least 20%. Patients were excluded if the investi-
gator judged that the anemia was due to causes
other than CKD or if a potential participant had
uncontrolled hypertension or had had a recent
cardiovascular event. Table S1 in the Supplemen-
tary Appendix lists all the inclusion and exclu-
sion criteria. All the patients provided written
informed consent.
Randomization and Trial Periods
Eligible patients were randomly assigned in a 1:1
ratio to receive vadadustat or darbepoetin alfa,
with stratification according to geographic region
(United States vs. Europe vs. other), New York
Heart Association (NYHA) congestive heart fail-
ure class (0 or I vs. II or III), and hemoglobin
concentration at entry (in ESA-untreated patients:
<9.5 vs. ≥9.5 g per deciliter; in ESA-treated pa-
tients: <10 vs. ≥10 g per deciliter). The trials had
four defined trial periods: a correction or con-
version period (weeks 0 through 23), a mainte-
nance period (weeks 24 through 52) that com-
prised both primary (weeks 24 through 36) and
secondary (weeks 40 through 52) efficacy evalu-
ation periods, a long-term treatment period
(weeks 53 to end of treatment), and a 4-week
n engl j med 384;17  nejm.org  April 29, 2021
The New England Journal of Medicine
Downloaded from nejm.org on November 29, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
safety follow-up period. Figure S1 shows the
schema for both trials.
End Points
The primary safety end point, assessed in a
time-to-event analysis, was the first adjudicated
MACE, which was a composite end point of
death from any cause, nonfatal myocardial in-
farction, or nonfatal stroke. Key secondary safety
end points, assessed in time-to-event analyses,
were the first occurrence of expanded MACE
(defined as a MACE plus hospitalization for ei-
ther heart failure or a thromboembolic event,
excluding vascular access failure); a composite of
death from cardiovascular causes, nonfatal myo-
cardial infarction, or nonfatal stroke (so-called
classic MACE); death from cardiovascular causes;
and death from any cause. An independent
clinical end-points committee, whose members
were unaware of the treatment assignments,
adjudicated MACE.
The primary efficacy end point was the mean
change in the hemoglobin concentration from
the baseline value to the mean concentration
during the primary evaluation period. The key
secondary efficacy end point was the mean
change in the hemoglobin concentration from
the baseline value to the mean concentration
during the secondary evaluation period.
Intervention
The starting dose of vadadustat was 300 mg
orally once daily, with doses of 150 mg, 450 mg,
and 600 mg available for adjustment to a maxi-
mum dose of 600 mg daily. Drug doses were
adjusted according to protocol-specified dose-
adjustment algorithms to achieve target hemo-
globin concentrations (in the United States: 10 to
11 g per deciliter; in other countries: 10 to 12 g
per deciliter). Darbepoetin alfa was administered
subcutaneously or intravenously. In contrast to
the initial uniform dosing in the vadadustat
group, the initial dose of darbepoetin alfa was
based on the patient’s previous dose of darbe-
poetin alfa or on the local product label for pa-
tients who had not been receiving darbepoetin
alfa before randomization. Investigators were en-
couraged to prescribe iron supplementation such
that a ferritin concentration of at least 100 ng
per milliliter or a transferrin saturation of at
least 20% would be maintained.
1591
 The n e w e ng l a n d j o u r na l
Starting at week 6, patients in the two treat-
ment groups could receive ESAs as rescue
therapy if they had worsening symptoms of
anemia with a hemoglobin concentration of
less than 9.0 g per deciliter. In a post hoc
analysis, patients who had been randomly as-
signed to receive darbepoetin alfa were also
considered to have received rescue therapy with
ESAs if the darbepoetin alfa dose was increased
to at least double the previous dose. While re-
ceiving ESAs as rescue therapy, patients tempo-
rarily discontinued vadadustat or darbepoetin
alfa, the latter only if the rescue therapy was an
ESA other than darbepoetin alfa. Receipt of
red-cell transfusions did not require discontin-
uation of the trial drug.
Statistical Analysis
All the safety and efficacy analyses were pre-
specified except where noted. Noninferiority
margins were an upper boundary of the 95%
confidence interval not exceeding 1.25 or 1.3
(both margins were prespecified in consulta-
tion with U.S. and European Union regulators,
respectively) for the hazard ratio of the pri-
mary safety end point and a lower boundary of
the 95% confidence interval for the hemo­
globin concentration that was not below −0.75 g
per deciliter for the primary efficacy end
point.
To evaluate the primary and key secondary
efficacy end points, we used analysis of covari-
ance with multiple imputation for missing data,
with baseline hemoglobin concentration (in
ESA-untreated patients: <9.5 vs. ≥9.5 g per
deciliter; in ESA-treated patients: <10 vs. ≥10 g
per deciliter), geographic region (United States
vs. Europe vs. other), and NYHA class (0 or I vs.
II or III) as covariates. We used a Cox propor-
tional-hazards model stratified according to
trial to analyze the first MACE in a time-to-
event analysis. The Cox model included the
following covariates: baseline hemoglobin con-
centration, geographic region, NYHA class, sex,
age (>65 vs. ≤65 years), race (White vs. non-
White), cardiovascular disease (yes vs. no), and
diabetes mellitus (yes vs. no). We conducted a
series of subgroup analyses, which included
subgroups defined according to the stratifica-
tion factors (see the Supplemental Methods
section).
1592 n engl j med 384;17  nejm.org  April 29, 2021
The New England Journal of Medicine
Downloaded from nejm.org on November 29, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
R e sult s
Patients
Across the two trials, 3476 patients underwent
randomization, with 1751 patients in the trial
involving ESA-untreated patients and 1725 in the
trial involving ESA-treated patients (Fig. S2). The
median duration of follow-up was 1.63 years
(interquartile range, 0.94 to 2.49) and 1.80 years
(interquartile range, 0.97 to 2.67), respectively.
The randomized groups in both trials were
generally well balanced (Table 1; Table S2 pro-
vides a more comprehensive comparison).
Primary and Key Secondary Safety End Points
We conducted all the analyses related to MACE
safety end points using the safety population (all
patients who received at least one dose of the
trial drug), pooled across the two trials; there-
fore, 1739 patients were included in the vadadu-
stat group and 1732 in the darbepoetin alfa
group. Figure 1A shows the time to the first
MACE. A first MACE occurred in 382 of 1739
patients (22.0%) in the vadadustat group and in
344 of 1732 patients (19.9%) in the darbepoetin
alfa group (hazard ratio, 1.17; 95% confidence
interval [CI], 1.01 to 1.36). The results of the
prespecified subgroup analyses of MACE are
shown in Figure S3. With regard to the compo-
nents of MACE, death from any cause occurred
in 319 patients (18.3%) in the vadadustat group
and in 307 (17.7%) in the darbepoetin alfa
group; nonfatal myocardial infarction in 67 (3.9%)
and 48 (2.8%), respectively; and nonfatal stroke
in 34 (2.0%) and 28 (1.6%), respectively.
Figure 1B shows the time to the first ex-
panded MACE, which occurred in 451 patients
(25.9%) in the vadadustat group and in 424
(24.5%) in the darbepoetin alfa group (hazard
ratio, 1.11; 95% CI, 0.97 to 1.27). Figures 1C and
1D show the time to death from cardiovascular
causes (hazard ratio, 1.01; 95% CI, 0.79 to 1.29)
and the time to death from any cause (hazard
ratio, 1.09; 95% CI, 0.93 to 1.27), respectively.
Figure S4 shows the time to the composite of
death from cardiovascular causes, nonfatal myo-
cardial infarction, or nonfatal stroke (hazard
ratio, 1.16; 95% CI, 0.95 to 1.42).
The time to CKD progression, which was
defined as the provision of maintenance dialysis,
receipt of kidney transplant, or a decrease in the
 Vadadustat in Patients with Anemia and NDD-CKD

Table 1. Selected Demographic, Clinical, and Laboratory Characteristics of the Patients at Baseline (Randomized Population).*

Characteristic ESA-Untreated NDD-CKD ESA-Treated NDD-CKD

Vadadustat Darbepoetin Alfa Vadadustat Darbepoetin Alfa

(N = 879) (N = 872) (N = 862) (N = 863)
Age — yr 65.2±14.3 64.9±13.7 67.3±13.1 66.5±13.5
Female sex — no. (%) 475 (54.0) 506 (58.0) 468 (54.3) 488 (56.5)
Race or ethnic group — no. (%)†
White 546 (62.1) 571 (65.5) 631 (73.2) 603 (69.9)
Black 188 (21.4) 172 (19.7) 93 (10.8) 131 (15.2)
Asian 48 (5.5) 37 (4.2) 62 (7.2) 55 (6.4)
American Indian 22 (2.5) 23 (2.6) 32 (3.7) 26 (3.0)
Other 75 (8.5) 69 (7.9) 44 (5.1) 48 (5.6)
Hispanic ethnic group — no. (%)†
Hispanic 306 (34.8) 310 (35.6) 255 (29.6) 255 (29.5)
Non-Hispanic 566 (64.4) 554 (63.5) 584 (67.7) 591 (68.5)
Not reported 2 (0.2) 5 (0.6) 8 (0.9) 5 (0.6)
Unknown 5 (0.6) 3 (0.3) 15 (1.7) 12 (1.4)
Estimated GFR — ml/min/1.73 m2 21.2±12.0 21.9±12.6 22.6±11.6 22.8±12.0
Disease history — no. (%)
Diabetes mellitus 581 (66.1) 599 (68.7) 517 (60.0) 518 (60.0)
Cardiovascular disease 406 (46.2) 412 (47.2) 375 (43.5) 402 (46.6)
Hemoglobin — g/dl 9.1±0.8 9.1±0.8 10.4±0.9 10.4±0.9
Blood pressure — mm Hg
Systolic 139.1±18.5 139.2±17.8 137.1±18.0 136.4±17.5
Diastolic 73.9±12.0 73.4±12.6 73.4±11.4 74.2±10.9
Serum potassium — mmol/liter‡ 4.9±0.8 4.9±0.7 4.9±0.7 4.9±0.8
Supplemental iron use — no. (%)
Not receiving any iron 483 (54.9) 467 (53.6) 418 (48.5) 459 (53.2)
Receiving intravenous iron only 22 (2.5) 20 (2.3) 43 (5.0) 49 (5.7)

* Plus–minus values are means ±SD. ESA denotes erythropoiesis-stimulating agent, GFR glomerular filtration rate, and NDD-CKD non–dialysis-
dependent chronic kidney disease.
† Race and ethnic group were reported by the patient.
‡ The serum potassium concentration was assessed in the safety population (i.e., all the patients who received at least one dose of the trial
drug). In the trial involving patients with ESA-untreated NDD-CKD, data were available for 878 patients in the vadadustat group and for 870
in the darbepoetin alfa group; in the trial involving patients with ESA-treated NDD-CKD, data were available for 861 and 862, respectively.

estimated GFR to below 15 ml per minute per
1.73 m2 or a decrease of 40% or more in the
estimated GFR (with the two estimated GFR
criteria confirmed after ≥4 weeks), was similar
in the two treatment groups in the two trials
(Fig. S5). The mean systolic and diastolic blood
pressures in the two treatment groups were
similar over the course of both trials (Fig. S6).
Figure S7 shows the median doses of the trial
drugs in both trials.
Prespecified Subgroup Analyses of Safety End
Points According to Region
Figure 2 shows the time to the first MACE and
the time to the first expanded MACE in the U.S.
and non-U.S. populations. Figure S8 shows the
time to death from any cause in the U.S. and non-
U.S. populations. Table S3 shows a breakdown of
first MACE events in these two populations, and
Table S4 shows the components of first MACE as
well as death from any cause in these populations.

n engl j med 384;17  nejm.org  April 29, 2021 1593

The New England Journal of Medicine
Downloaded from nejm.org on November 29, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
 A MACE B Expanded MACE

1594
100 100
90 90
80 80
70 70
60 60
50 Vadadustat (382 events) 50 Vadadustat (451 events)
40 Hazard ratio, 1.17 (95% CI, 1.01–1.36) 40 Hazard ratio, 1.11 (95% CI, 0.97–1.27)
30 30
20 20 Darbepoetin alfa (424 events)

Cumulative Incidence (%)

Cumulative Incidence (%)
10 Darbepoetin alfa (344 events) 10
0 0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 58 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 58
Months since Randomization Months since Randomization
No. at Risk No. at Risk
Vadadustat 1739 1668 1587 1301 1108 931 759 588 459 311 185 97 30 4 1 0 Vadadustat 1739 1636 1535 1247 1057 882 718 554 429 296 175 91 30 4 1 0
Darbepoetin alfa 1732 1674 1618 1329 1129 961 774 621 505 346 213 103 43 6 0 Darbepoetin alfa 1732 1639 1565 1270 1070 906 722 573 462 320 193 91 35 6 0
The

C Death from Cardiovascular Causes D Death from Any Cause

100 100
90 90
80 80
70 70
60 60

n engl j med 384;17

50 50
Vadadustat
40 40
30 Hazard ratio, 1.01 (95% CI, 0.79–1.29) 30 Hazard ratio, 1.09 (95% CI, 0.93–1.27)

nejm.org
20 Vadadustat 20

Cumulative Incidence (%)

Cumulative Incidence (%)
Darbepoetin alfa
n e w e ng l a n d j o u r na l

10 10

The New England Journal of Medicine

Darbepoetin alfa
of

0 0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 58 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 58
Months since Randomization Months since Randomization

April 29, 2021

No. at Risk No. at Risk
Vadadustat 1739 1689 1617 1329 1137 967 796 623 487 334 204 106 34 4 1 0 Vadadustat 1739 1689 1617 1329 1137 967 796 623 487 334 204 106 34 4 1 0

Copyright © 2021 Massachusetts Medical Society. All rights reserved.

m e dic i n e

Darbepoetin alfa 1732 1686 1637 1349 1151 988 799 646 523 361 221 108 44 7 0 Darbepoetin alfa 1732 1686 1637 1349 1151 988 799 646 523 361 221 108 44 7 0

Figure 1. MACE, Expanded MACE, Death from Cardiovascular Causes, and Death from Any Cause in the Pooled Safety Population of the Two Trials.
Shown are the cumulative incidences of a first adjudicated major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or non‑
fatal stroke), a first adjudicated expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event, excluding vascular access failure), death from car‑

Downloaded from nejm.org on November 29, 2021. For personal use only. No other uses without permission.
diovascular causes, and death from any cause. The safety end points were assessed in the safety population (all the patients who received at least one dose of trial drug) pooled
across the two trials. Tick marks indicate censored data. CI denotes confidence interval.
 Vadadustat Darbepoetin alfa

A MACE, U.S. Population B MACE, Non-U.S. Population

100 100
90 90
80 80
70 70
60 60
50 50
40 Hazard ratio, 1.06 (95% CI, 0.87–1.29) 40 Hazard ratio, 1.30 (95% CI, 1.05–1.62)
30 30
20 20

Cumulative Incidence (%)

Cumulative Incidence (%)
10 10
0 0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 58 0 4 8 12 16 20 24 28 32 36 40 44 46
Months since Randomization Months since Randomization
No. at Risk No. at Risk
Vadadustat 861 824 778 677 575 505 421 342 276 203 139 87 30 4 1 0 Vadadustat 878 844 809 624 533 426 338 246 183 108 46 10 1
Darbepoetin alfa 862 826 792 674 583 510 424 346 302 235 168 96 43 6 0 Darbepoetin alfa 870 848 826 655 546 451 350 275 203 111 45 7 0

C Expanded MACE, U.S. Population D Expanded MACE, Non-U.S. Population

100 100
90 90
80 80
70 70
60 60
Hazard ratio, 1.02 (95% CI, 0.86–1.21) 50

n engl j med 384;17  nejm.org  April 29, 2021

50

The New England Journal of Medicine

Hazard ratio, 1.24 (95% CI, 1.01–1.52)
40 40
30 30
20 20
Cumulative Incidence (%)
Vadadustat in Patients with Anemia and NDD-CKD

Cumulative Incidence (%)

10 10
0 0

Copyright © 2021 Massachusetts Medical Society. All rights reserved.

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 58 0 4 8 12 16 20 24 28 32 36 40 44 46
Months since Randomization Months since Randomization
No. at Risk No. at Risk
Vadadustat 861 797 742 634 535 468 387 312 249 189 130 81 30 4 1 0 Vadadustat 878 839 793 613 522 414 331 242 180 107 45 10 1
Darbepoetin alfa 862 798 747 625 534 468 383 310 269 214 151 84 35 6 0 Darbepoetin alfa 870 841 818 645 536 438 339 263 193 106 42 7 0

Downloaded from nejm.org on November 29, 2021. For personal use only. No other uses without permission.
Figure 2. MACE and Expanded MACE in U.S. and Non-U.S. Populations.
Shown are the cumulative incidences of a first adjudicated MACE in the U.S. trial population and in the non-U.S. trial population (i.e., patients in Europe or elsewhere) and a first
adjudicated expanded MACE in the U.S. and non-U.S. trial populations. Tick marks indicate censored data.

1595
 The n e w e ng l a n d j o u r na l of m e dic i n e

Vadadustat Darbepoetin alfa

A Hemoglobin Concentration in ESA-Untreated Patients

4
Mean Change from Baseline (g/dl)

–1
0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 64 76 88 104 116 128 140 156 168
Weeks since Randomization
No. at Risk
Vadadustat 821 804 776 779 742 770 750 734 712 676 675 641 594 555 543 530 469 396 334 252 201 148 110 76 48
Darbepoetin alfa 811 806 778 772 758 769 766 743 731 698 690 671 614 583 559 543 496 422 355 271 216 176 138 97 62

B Hemoglobin Concentration in ESA-Treated Patients

3
Mean Change from Baseline (g/dl)

–1
0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 64 76 88 104 116 128 140 156 168
Weeks since Randomization
No. at Risk
Vadadustat 811 801 791 781 778 773 771 761 744 718 712 674 617 586 545 542 477 415 362 300 235 190 143 89 49
Darbepoetin alfa 811 807 792 799 781 794 786 773 767 751 744 713 637 604 573 519 519 459 399 326 276 234 181 107 46

Figure 3. Mean Change from Baseline in Hemoglobin Concentrations in the Randomized Populations of the Two Trials.
Shown are the mean changes in the hemoglobin concentrations in the trial involving patients who had not been treated with erythropoiesis-
stimulating agents (ESAs) (Panel A) and in the trial involving ESA-treated patients (Panel B). The figures are based on observed data only.
Given the large sample size, the mean values with standard deviations (I bars) are presented here to show the extent of variability, which
may have been less apparent if mean values with standard errors had been presented.

Efficacy End Points hemoglobin concentration from the baseline val-

Trial Involving ESA-Untreated Patients ue to the mean of the values in weeks 24 through
Figure 3A shows the mean hemoglobin concen- 36 were 1.43±0.05 g per deciliter in the vadadu-
trations over time in the two treatment groups. stat group and 1.38±0.05 g per deciliter in the
The least-squares mean (±SE) changes in the darbepoetin alfa group; the corresponding least-

1596 n engl j med 384;17  nejm.org  April 29, 2021

The New England Journal of Medicine

Downloaded from nejm.org on November 29, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
 Vadadustat in Patients with Anemia and NDD-CKD
squares mean difference between the groups was
0.05±0.05 g per deciliter (95% CI, −0.04 to 0.15).
The least-squares mean (±SD) change in the hemo-
globin concentration from the baseline value to
the mean of the values in weeks 40 though 52 was
1.52±0.05 g per deciliter in the vadadustat group
and 1.48±0.05 g per deciliter in the darbepoetin
alfa group; the corresponding least-squares mean
between-group difference was 0.04±0.05 g per
deciliter (95% CI, −0.06 to 0.14). Thus, for both
the primary and secondary efficacy end points,
the lower boundaries of the 95% confidence
intervals (−0.04 and −0.06, respectively) were
above −0.75 g per deciliter, which showed the
noninferiority of vadadustat to darbepoetin alfa.
The percentage of patients who received red-
cell transfusions was 2.7% in the vadadustat
group and 2.2% in the darbepoetin alfa group
during weeks 24 through 36. The corresponding
percentages were 2.4% and 2.2% during weeks
40 through 52. Table S5 shows the percentages of
patients with a mean hemoglobin concentration
within the region-specific target range during
weeks 24 through 36 and weeks 40 through 52.
Trial Involving ESA-Treated Patients
Figure 3B shows the mean hemoglobin concen-
trations in the two treatment groups. The least-
squares mean (±SE) changes in the hemoglobin
concentration from the baseline value to the
mean of the values in weeks 24 through 36 were
0.41±0.04 g per deciliter in the vadadustat group
and 0.42±0.04 g per deciliter in the darbepoetin
alfa group; the corresponding least-squares mean
difference between the groups was −0.01±0.04 g
per deciliter (95% CI, −0.09 to 0.07). The least-
squares mean (±SD) change in the hemoglobin
concentration from the baseline value to the
mean of the values in weeks 40 through 52 was
0.43±0.04 g per deciliter in the vadadustat group
and 0.44±0.04 g per deciliter in the darbepoetin
alfa group; the corresponding least-squares mean
between-group difference was 0.00±0.05 g per
deciliter (95% CI, −0.10 to 0.09). Thus, for both
the primary and secondary efficacy end points,
the lower boundaries of the 95% confidence in-
tervals (−0.09 and −0.10, respectively) were above
−0.75 g per deciliter, which showed the noninfe-
riority of vadadustat to darbepoetin alfa.
The percentage of patients who received red-
cell transfusions was 1.6% in the vadadustat
group and 1.2% in the darbepoetin alfa group
n engl j med 384;17  nejm.org  April 29, 2021
The New England Journal of Medicine
Downloaded from nejm.org on November 29, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
during weeks 24 through 36 and 2.4% and 1.9%,
respectively, during weeks 40 through 52. Table
S5 shows the percentages of patients with a mean
hemoglobin concentration within the region-
specific target range during weeks 24 through
36 and weeks 40 through 52.
Rescue Therapy with an ESA
Table S6 shows the percentages of patients ran-
domly assigned to receive vadadustat or darbe-
poetin alfa who received ESA rescue therapy for
symptomatic anemia with a hemoglobin concen-
tration below the target range. The use of ESA
rescue therapy was less common among patients
who had been randomly assigned to the vadadu-
stat group than among those who had been ran-
domly assigned to the darbepoetin alfa group.
Adverse Events
Table 2 shows a summary of the adverse events
that occurred after the start of trial treatment,
including the adverse events that were reported
in at least 10% of the patients in either treatment
group in both trials. A full list of all the adverse
events in the trials is provided in Table S7.
Discussion
The pooled results from these two randomized
trials involving patients with NDD-CKD in which
we compared vadadustat, a HIF prolyl hydroxy-
lase inhibitor, with darbepoetin alfa, a commonly
prescribed ESA — with one trial involving pa-
tients who had not previously received treatment
with ESAs and the other involving patients who
were receiving active ESA therapy — showed that
vadadustat did not meet its prespecified nonin-
feriority margin with respect to MACE, defined
as death from any cause, nonfatal myocardial
infarction, or nonfatal stroke. Vadadustat met its
noninferiority margin with respect to hemato-
logic efficacy in each trial.
The safety and efficacy of vadadustat in pa-
tients with NDD-CKD have previously been ex-
amined in several smaller studies, none of which
suggested a cardiovascular safety signal.13-15
The pooled results of our trials contrast with
those reported in patients with DD-CKD (the
INNO2VATE trials),10 which compared vadadustat
and darbepoetin alfa for the treatment of ane-
mia in 3923 patients with DD-CKD, including
3554 patients who had been undergoing mainte-
1597
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Adverse Events and Serious Adverse Events (Safety Population).

Event ESA-Untreated NDD-CKD ESA-Treated NDD-CKD

Vadadustat Darbepoetin Alfa Vadadustat Darbepoetin Alfa

(N = 878) (N = 870) (N = 861) (N = 862)

number of patients (percent)

Any adverse event 798 (90.9) 797 (91.6) 767 (89.1) 756 (87.7)
Any drug-related adverse event 95 (10.8) 57 (6.6) 100 (11.6) 44 (5.1)
Any serious adverse event 573 (65.3) 561 (64.5) 504 (58.5) 488 (56.6)
Any drug-related serious adverse 23 (2.6) 15 (1.7) 13 (1.5) 9 (1.0)
event
Any adverse event leading to discon‑ 84 (9.6) 60 (6.9) 79 (9.2) 44 (5.1)
tinuation of trial treatment
Any drug-related adverse event lead‑ 13 (1.5) 4 (0.5) 16 (1.9) 2 (0.2)
ing to discontinuation of trial
treatment
Any adverse event leading to death 177 (20.2) 165 (19.0) 135 (15.7) 137 (15.9)
Death 180 (20.5) 168 (19.3) 139 (16.1) 139 (16.1)
Common adverse event*
Diarrhea 122 (13.9) 87 (10.0) 119 (13.8) 76 (8.8)
End-stage renal disease 305 (34.7) 306 (35.2) 237 (27.5) 245 (28.4)
Fall 84 (9.6) 87 (10.0) 69 (8.0) 65 (7.5)
Hyperkalemia 108 (12.3) 136 (15.6) 81 (9.4) 85 (9.9)
Hypertension 155 (17.7) 192 (22.1) 124 (14.4) 128 (14.8)
Peripheral edema 110 (12.5) 91 (10.5) 85 (9.9) 87 (10.1)
Pneumonia 86 (9.8) 75 (8.6) 86 (10.0) 84 (9.7)
Urinary tract infection 113 (12.9) 104 (12.0) 105 (12.2) 125 (14.5)
Nausea 88 (10.0) 71 (8.2) 73 (8.5) 58 (6.7)

* Common adverse events were those that occurred in at least 10% of the patients in either treatment group.

nance dialysis and had been receiving treatment
with ESAs and 369 patients who were new to
dialysis and had had limited previous exposure
to ESAs. Pooled across those two trials, the haz-
ard ratios for MACE and expanded MACE were
0.96 (95% CI, 0.83 to 1.11) and 0.96 (95% CI,
0.84 to 1.10), respectively. Point estimates for all
components of MACE, as well as cardiovascular
death, were below 1.0.
The difference in outcomes between the current
pooled trials involving patients with NDD-CKD
and the pooled trials involving patients with
DD-CKD10 is not the first example in which the
relative safety of drugs used to treat anemia dif-
fered between DD-CKD and NDD-CKD popula-
tions. In the EMERALD (Efficacy and Safety of
Peginesatide for the Maintenance Treatment of
Anemia in Patients with Chronic Renal Failure
Who Were Receiving Hemodialysis and Were Pre-
viously Treated with Epoetin) trials, peginesatide,
a synthetic peptide-based erythropoietin receptor
agonist, was shown to be noninferior to epoetin
alfa in patients with DD-CKD with respect to
safety, on the basis of a composite end point that
was not unlike our expanded MACE (death from
any cause, nonfatal myocardial infarction or
stroke, or serious adverse events of congestive
heart failure, unstable angina, or arrhythmia)
(hazard ratio, 0.95; 95% CI, 0.77 to 1.17).16 In
contrast, in the PEARL (Peginesatide for the
Correction of Anemia in Patients with Chronic
Renal Failure Not on Dialysis and Not Receiving
Treatment with Erythropoiesis-Stimulating Agents)
trials, which involved patients with NDD-CKD,
peginesatide did not meet its noninferiority mar-
gin for safety as compared with darbepoetin alfa

1598 n engl j med 384;17  nejm.org  April 29, 2021

The New England Journal of Medicine

Downloaded from nejm.org on November 29, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
 Vadadustat in Patients with Anemia and NDD-CKD
(hazard ratio, 1.32; 95% CI, 0.97 to 1.81).17 The
reasons for these discrepant results among pa-
tients with DD-CKD and those with NDD-CKD
remain unclear.
Other studies of ESAs in patients with NDD-
CKD have shown higher risks with hemoglobin
targets in the normal or near-normal range
than with lower targets3,4 or placebo.5 In the
PRO2TECT trials, we chose to use region-specific
hemoglobin target ranges to account for differ-
ences in regional guidelines and usual clinical
practice. In the United States, the results of
these trials were in line with what was observed
in the INNO2VATE trials (hazard ratio for MACE,
1.00 [95% CI, 0.84 to 1.18]; hazard ratio for ex-
panded MACE, 0.99 [95% CI, 0.85 to 1.15]). In
contrast, in the non-U.S. regions, the risks of
MACE and expanded MACE in the PRO2TECT
trials were considerably higher among patients
who had been randomly assigned to the vadadu-
stat group than among those assigned to the
darbepoetin alfa group. Whether this difference
between regions is causally related to the differ-
ence in hemoglobin targets or other factors is
unclear.
Analysis of events in the current trials re-
vealed that the higher risk that was observed
among patients who had been randomly assigned
to the vadadustat group than among those in the
darbepoetin alfa group was due largely to an
excess of nonfatal myocardial infarctions and a
higher incidence of death from noncardiovascu-
lar causes. We could not identify a reason for the
excess in noncardiovascular deaths. Adverse
events were evenly distributed between the vada-
dustat group and the darbepoetin alfa group.
The cumulative incidences of pulmonary hyper-
tension and cancer, which are theoretical conse-
quences of HIF pathway activation, were similar
in the two treatment groups.
The current trials have many strengths, in-
cluding — in combination — the relatively large
sample size, the diverse population of patients
(according to age, sex, race or ethnic group, and
primary cause of kidney disease), and the inclu-
sion of a sizable fraction of patients with stage
G4 or G5 CKD.18 The use of region-specific in-
clusion criteria and target hemoglobin concen-
trations was a strength with respect to general-
izability to different regions but hampered the
trial in that treatment was not uniform. Limita-
tions included the fact that, on the basis of guid-
n engl j med 384;17  nejm.org  April 29, 2021
The New England Journal of Medicine
Downloaded from nejm.org on November 29, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
ance from regulatory agencies, these two trials
were not placebo-controlled.
In these two trials, we found that, among
patients with NDD-CKD, vadadustat was non-
inferior to darbepoetin alfa with regard to hema-
tologic efficacy but did not meet the prespecified
noninferiority criterion for cardiovascular safety,
which was a composite of death from any cause,
nonfatal myocardial infarction, or nonfatal stroke.
Supported by Akebia Therapeutics and Otsuka Pharmaceutical.
Dr. Chertow reports receiving advisory board fees and own-
ing stock options in Ardelyx, Miromatrix Medical, and Unicycive
Therapeutics, receiving steering committee fees from AstraZen-
eca, Gilead Sciences, Sanifit, and Vertex Pharmaceuticals, re-
ceiving advisory board fees from Baxter, Cricket Health, Dia-
Medica Therapeutics, and Reata Pharmaceuticals, serving on an
advisory board and owning stock options in CloudCath, Durect,
and Outset Medical, receiving fees for serving on a data and
safety monitoring board from Angion, Bayer, and ReCor Medi-
cal, and receiving grant support, paid to his institution, from
Amgen; Dr. Pergola, receiving consulting fees and fees for serv-
ing on a speaker’s bureau from AstraZeneca, consulting fees
and advisory board fees from Bayer, Gilead Sciences, Corvidia
Therapeutics, FibroGen, Tricida, Ardelyx, and Unicycive Thera-
peutics, and consulting fees and honoraria from Reata Pharma-
ceuticals and being employed by Renal Associates; Dr. Farag,
being employed by Akebia Therapeutics; Dr. Agarwal, receiving
steering committee fees, adjudication committee fees, consult-
ing fees, and travel support from Bayer HealthCare Pharmaceu-
ticals and Janssen Research and Development, steering commit-
tee fees, consulting fees, and travel support from Vifor Fresenius
Medical Care Renal Pharma, Sanofi US Services, Sanofi Aventis
US, and Reata Pharmaceuticals, adjudication committee fees,
consulting fees, and travel support from Boehringer Ingelheim
International, consulting fees and travel support from Eli Lilly,
AstraZeneca Pharmaceuticals, Boehringer Ingelheim, Boehringer
Ingelheim Pharma, and Merck, fees for serving on a data and
safety monitoring board from AstraZeneca, Ironwood Pharma-
ceuticals, and Chinook Therapeutics, lecture fees and travel
support from Fresenius USA Marketing, meal reimbursement
from Otsuka America Pharmaceutical, OPKO Pharmaceuticals,
and E.R. Squibb and Sons, and consulting fees from Lexicon
Pharmaceuticals and DiaMedica Therapeutics; Dr. Block, receiv-
ing grant support, steering committee fees, and travel support
from Akebia Therapeutics and being employed by U.S. Renal
Care; Dr. Burke, being employed by and owning stock in Akebia
Therapeutics; Dr. Khawaja, being employed by Akebia Therapeu-
tics; Dr. Koury, receiving consulting fees from FibroGen, fees
for serving on a data safety and management committee from
TG Therapeutics, and consulting fees and fees for serving on a
data and safety management committee from Micelle BioPhar-
ma; Dr. Lewis, receiving grant support from Akebia Therapeu-
tics; Dr. Luo, being employed by Akebia Therapeutics; Dr. Ma-
roni, being employed by and receiving consulting fees from
Akebia Therapeutics and holding a pending patent (number, PCT/
US16/25235) on compositions and methods for treating anemia,
licensed to Akebia Therapeutics; Dr. Matsushita, receiving grant
support and consulting fees from Kyowa Kirin and grant sup-
port and honoraria from Fukuda Denshi; Dr. Parfrey, receiving
advisory board fees from Vifor Pharma; Dr. Roy-Chaudhury, re-
ceiving consulting fees from W.L. Gore, BD, Medtronic, Akebia
Therapeutics, Bayer, CorMedix, Reata Pharmaceuticals, Huma-
cyte, and Eko and being employed by Inovasc; Dr. Sarnak, re-
ceiving advisory board fees from Bayer and consulting fees from
Cardurion Pharmaceuticals; Dr. Sharma, being employed by
Bayer U.S. Pharma; Dr. Spinowitz, receiving advisory board fees
1599
 Vadadustat in Patients with Anemia and NDD-CKD

from Akebia Therapeutics and Otsuka Pharmaceutical; Dr. Vargo,
being employed by Akebia Therapeutics; Dr. Walters, being em-
ployed by Statistics Collaborative; Dr. Winkelmayer, receiving
steering committee fees from Akebia, advisory fees from Astra-
Zeneca, Janssen, Merck, Otsuka Pharmaceutical, and Reata
Pharmaceuticals, steering committee fees and advisory fees from
Bayer, and advisory fees and consulting fees from Vifor Fresenius
Medical Care Renal Pharma (including Relypsa); Dr. Wittes, being
employed by Statistics Collaborative; and Dr. Eckardt, receiving
grant support from Amgen and Fresenius, lecture fees from
Astellas Pharma, grant support and lecture fees from Astra-
Zeneca, Bayer, and Genzyme, consulting fees from Boehringer
Ingelheim, advisory board fees from Retrophin, and grant sup-
port, advisory board fees, and lecture fees from Vifor Pharma.
No other potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.

Appendix
The authors’ full names and academic degrees are as follows: Glenn M. Chertow, M.D., M.P.H., Pablo E. Pergola, M.D., Ph.D.,
Youssef M.K. Farag, M.D., Ph.D., M.P.H., Rajiv Agarwal, M.D., Susan Arnold, M.B., B.Ch., M.Med., Gabriel Bako, M.D., Geoffrey A.
Block, M.D., Steven Burke, M.D., Fausto P. Castillo, M.D., Alan G. Jardine, M.B., Ch.B., M.D., Zeeshan Khawaja, M.D., Mark J. Koury,
M.D., Eldrin F. Lewis, M.D., M.P.H., Tim Lin, Ph.D., Wenli Luo, Ph.D., Bradley J. Maroni, M.D., Kunihiro Matsushita, M.D., Ph.D.,
Peter A. McCullough, M.D., Ph.D., Patrick S. Parfrey, M.B., B.Ch., Prabir Roy‑Chaudhury, M.D., Ph.D., Mark J. Sarnak, M.D., Amit
Sharma, M.D., Bruce Spinowitz, M.D., Carol Tseng, Ph.D., James Tumlin, M.D., Dennis L. Vargo, M.D., Kimberly A. Walters, Ph.D.,
Wolfgang C. Winkelmayer, M.D., M.P.H., Sc.D., Janet Wittes, Ph.D., and Kai‑Uwe Eckardt, M.D.
The authors’ affiliations are as follows: Stanford University School of Medicine, Palo Alto, CA (G.M.C., E.F.L.); Renal Associates, San
Antonio (P.E.P.), U.S. Renal Care, Plano (G.A.B.), Baylor University Medical Center, Baylor Heart and Vascular Hospital, Baylor Heart
and Vascular Institute, Dallas (P.A.M.), and the Section of Nephrology, Baylor College of Medicine, Houston (W.C.W.) — all in Texas;
Akebia Therapeutics, Cambridge (Y.M.K.F., S.B., Z.K., W.L., B.J.M., A.S., D.L.V.), and the Division of Nephrology, Tufts Medical Cen-
ter, Tufts University School of Medicine, Boston (M.J.S.) — both in Massachusetts; the Department of Medicine, Division of Nephrol-
ogy, Indiana University School of Medicine, Indianapolis (R.A.); Excellentis Clinical Trial Consultants, George, South Africa (S.A.);
Bihor County Hospital Oradea, Oradea, Romania (G.B.); Qway Research, Hialeah, FL (F.P.C.); the Institute of Cardiovascular and
Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.G.J.); the Department of Medicine, Vanderbilt University Medi-
cal Center, Nashville (M.J.K.); Firma Clinical Research, Hunt Valley (T.L.), and the Department of Epidemiology, Johns Hopkins Bloom-
berg School of Public Health, Baltimore (K.M.) — both in Maryland; the Department of Medicine, Memorial University of Newfound-
land, St. John’s, Canada (P.S.P.); the Division of Nephrology and Hypertension, University of North Carolina Kidney Center, Chapel Hill,
and the W.G. (Bill) Hefner Veterans Affairs Medical Center, Salisbury — both in North Carolina (P.R.-C.); the Division of Nephrology,
New York–Presbyterian Queens, Flushing (B.S.); Firma Clinical Research, Chicago (C.T.); Emory University School of Medicine,
Atlanta (J.T.); Statistics Collaborative, Washington, DC (K.A.W., J.W.); and the Department of Nephrology and Medical Intensive Care,
Charité–Universitätsmedizin Berlin, Berlin (K.-U.E.).

References
1. Stauffer ME, Fan T. Prevalence of ane-
mia in chronic kidney disease in the United
States. PLoS One 2014;​9(1):​e84943.
2. Hsu C, McCulloch CE, Curhan GC.
Epidemiology of anemia associated with
chronic renal insufficiency among adults
in the United States: results from the
Third National Health and Nutrition Ex-
amination Survey. J Am Soc Nephrol 2002;​
13:​504-10.
3. Singh AK, Szczech L, Tang KL, et al.
Correction of anemia with epoetin alfa in
chronic kidney disease. N Engl J Med 2006;​
355:​2085-98.
4. Drüeke TB, Locatelli F, Clyne N, et al.
Normalization of hemoglobin level in pa-
tients with chronic kidney disease and
anemia. N Engl J Med 2006;​355:​2071-84.
5. Pfeffer MA, Burdmann EA, Chen C-Y,
et al. A trial of darbepoetin alfa in type 2
diabetes and chronic kidney disease. N Engl
J Med 2009;​361:​2019-32.
6. Kaelin WG Jr, Ratcliffe PJ. Oxygen
sensing by metazoans: the central role of
the HIF hydroxylase pathway. Mol Cell
2008;​30:​393-402.
7. Semenza GL. Hypoxia-inducible fac-
tors in physiology and medicine. Cell 2012;​
148:​399-408.
8. Bernhardt WM, Wiesener MS, Scigalla
P, et al. Inhibition of prolyl hydroxylases
increases erythropoietin production in
ESRD. J Am Soc Nephrol 2010;​21:​2151-6.
9. Haase VH. Regulation of erythropoi-
esis by hypoxia-inducible factors. Blood
Rev 2013;​27:​41-53.
10. Eckardt KU, Agarwal R, Aswad A, et al.
Safety and efficacy of vadadustat for ane-
mia in patients undergoing dialysis. N Engl
J Med 2021;​384:1601-12.
11. Chertow GM, Pergola PE, Agarwal R,
et al. Cardiovascular safety and efficacy of
vadadustat for the treatment of anemia in
non-dialysis-dependent CKD: design and
baseline characteristics. Am Heart J 2020;​
235:​1-11.
12. Levey AS, Stevens LA, Schmid CH, et al.
A new equation to estimate glomerular
filtration rate. Ann Intern Med 2009;​150:​
604-12.
13. Martin ER, Smith MT, Maroni BJ,
Zuraw QC, deGoma EM. Clinical trial of
vadadustat in patients with anemia sec-
ondary to stage 3 or 4 chronic kidney dis-
ease. Am J Nephrol 2017;​45:​380-8.
14. Pergola PE, Spinowitz BS, Hartman
CS, Maroni BJ, Haase VH. Vadadustat, a
novel oral HIF stabilizer, provides effec-
tive anemia treatment in nondialysis-
dependent chronic kidney disease. Kidney
Int 2016;​90:​1115-22.
15. Nangaku M, Farag YMK, deGoma E,
Luo W, Vargo D, Khawaja Z. Vadadustat,
an oral hypoxia-inducible factor prolyl
hydroxylase inhibitor, for treatment of
anemia of chronic kidney disease: two
randomized phase 2 trials in Japanese pa-
tients. Nephrol Dial Transplant 2020 July
28 (Epub ahead of print).
16. Fishbane S, Schiller B, Locatelli F, et al.
Peginesatide in patients with anemia un-
dergoing hemodialysis. N Engl J Med 2013;​
368:​307-19.
17. Macdougall IC, Provenzano R, Sharma
A, et al. Peginesatide for anemia in pa-
tients with chronic kidney disease not re-
ceiving dialysis. N Engl J Med 2013;​368:​
320-32.
18. Kidney Disease: Improving Global
Outcomes Chronic Kidney Disease Guide-
line Development Work Group. KDIGO
2012 clinical practice guideline for the
evaluation and management of chronic
kidney disease. Kidney Int Suppl 2013;​3:​
1-150.
Copyright © 2021 Massachusetts Medical Society.

1600 n engl j med 384;17  nejm.org  April 29, 2021

The New England Journal of Medicine

Downloaded from nejm.org on November 29, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.