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Received: 21 December 2020    Revised: 23 January 2021    Accepted: 8 February 2021

DOI: 10.1111/jcpt.13385

ORIGINAL ARTICLE

Long-­term efficacy and safety of hypoxia-­inducible factor

prolyl hydroxylase inhibitors in anaemia of chronic kidney
disease: A meta-­analysis including 13,146 patients

Huanhuan Chen MS1,2  | Qingfeng Cheng MD3 | Jiuxiang Wang MS1 |

Xiaofang Zhao MS1 | Shenyin Zhu PhD1

1
Department of Pharmacy, The First
Affiliated Hospital of Chongqing Medical
University, Chongqing, China
2
School of Pharmacy, Chongqing Medical
University, Chongqing, China
3
Department of Endocrinology, The First
Affiliated Hospital of Chongqing Medical
University, Chongqing, China
Correspondence
Shenyin Zhu, Department of Pharmacy,
The First Affiliated Hospital of Chongqing
Medical University, 1 Youyi Road, Yuzhong
District, Chongqing 400016, China
Email: zhushenyin0486@sina.com
FUNDING INFORMATION
No funding was received for this study.
ABSTRACT
What is known and objective: Previous studies based on small-­sample clinical data
proved that short-­term use of hypoxia-­inducible factor prolyl hydroxylase (HIF-­PHD)
inhibitors increased haemoglobin levels in anaemic patients with chronic kidney dis-
ease (CKD). However, these studies reached conflicting conclusions on iron param-
eters and adverse event profiles. Our meta-­analysis aimed to evaluate the long-­term
efficacy and safety of HIF-­PHD inhibitors in renal anaemia.
Methods: Randomized controlled trials comparing treatment with HIF-­PHD inhibitors
versus placebo or erythropoiesis-­stimulating agents (ESAs) were thoroughly searched
in the PubMed, Embase, Cochrane Library and international clinical trial registries.
Meta-­analysis was performed on main outcomes with random effects models.
Results and discussion: A total of 30 studies comprising 13,146 patients were in-
cluded. The HIF-­PHD inhibitors used included roxadustat, daprodustat, vadadustat,
molidustat, desidustat and enarodustat. HIF-­PHD inhibitors significantly increased
haemoglobin levels in comparison with placebo [weighted mean difference (WMD)
1.53, 95% confidence interval (CI) 1.39 to 1.67] or ESAs (WMD 0.13, 95% CI 0.03 to
0.22). Hepcidin, ferritin and serum iron levels were decreased, while total iron binding
capacity and transferrin levels were increased in the HIF-­PHD inhibitor group versus
those in placebo or ESAs group. Additionally, HIF-­PHD inhibitors medication was as-
sociated with cholesterol-­lowering effects. As for safety, the risk of serious adverse
events in the HIF-­PHD inhibitor group was increased in comparison with placebo
group [risk ratio (RR) 1.07, 95% CI 1.01 to 1.13], but comparable to the ESAs group
(RR 1.02, 95% CI 0.94 to 1.10). Compared with placebo, the agents increased the risk
of diarrhoea (1.21, 1.00 to 1.47), nausea (1.46, 1.09 to 1.97), oedema peripheral (1.32,
1.01 to 1.59), hyperkalemia (1.27, 1.05 to 1.54) and hypertension (1.34, 1.02 to 1.76).
Compared with ESAs, the drugs increased the risk of vomiting (1.30, 1.02 to 1.65),
headache (1.27, 1.05 to 1.53) and thrombosis events (1.31, 1.05 to 1.63).
What is new and conclusion: HIF-­PHD inhibitors treatment effectively increased
haemoglobin levels and promoted iron utilization in anaemic patients with CKD, and
they were well tolerated for long-­term use. In order to avoid unfavourable effects of

J Clin Pharm Ther. 2021;00:1–11. wileyonlinelibrary.com/journal/jcpt© 2021 John Wiley & Sons Ltd     1 |
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2      CHEN et al.
excessive iron consumption, it was appropriate to administer HIF-­PHD inhibitors in
combination with iron supplements for long-­term treatment.
KEYWORDS
anaemia, chronic kidney diseases, daprodustat, desidustat, enarodustat, hypoxia-­inducible
factor, meta-­analysis, molidustat, prolyl hydroxylase inhibitors, roxadustat, vadadustat
1  |  W H AT I S K N OW N A N D O B J EC TI V E
Chronic kidney disease (CKD) is one of the major diseases leading
to the increase of global disease burden, affecting 8% to 16% of the
population worldwide.1,2 Renal anaemia is a common complication
of CKD resulting from relative or absolute erythropoietin (EPO) defi-
ciency and disordered iron homeostasis related to chronic inflamma-
tion.3 Undertreatment of anaemia in patients with CKD is associated
with impaired quality of life, along with increased risk of transfusion,
4,5
hospitalization, cardiac complications and mortality.
For decades, anaemia treatment in patients with CKD has generally
included blood transfusions, use of erythropoiesis-­stimulating agents
(ESAs) along with iron supplements, and the pharmacological method
has always been the linchpin for the treatment of CKD related anaemia.
But ESAs are exogenous EPO, and a higher concentration of ESAs is usu-
ally required for EPO receptor activation. And high ESAs doses or target-
ing high haemoglobin levels with ESAs were implicated in cardiovascular
6-­8
disease and death in both hemodialysis and predialysis CKD patients.
In particular, the risk of adverse outcomes was increased in patients with
poor response to ESAs due to activation of EPO receptors outside the
hematopoietic system.9 However, ESAs play a critical contribution in
renal anaemia management, thus physicians have been cautiously using
ESAs to correct anaemia, and the goal of medication is merely to avoid
transfusions and relieve symptoms of anaemia as much as possible.10
Hypoxia-­inducible factor prolyl hydroxylase (HIF-­PHD) inhibitors
are an emerging small molecule drugs for the treatment of anaemia
secondary to CKD.11 By inhibiting PHD, the agents stabilize HIF-­α that
results in increased HIF transcriptional activity, which can stimulate
the synthesis of endogenous EPO from native kidneys or the liver and
12
regulate iron metabolism. Previous systematic reviews and meta-­
analyses based on small-­sample clinical data proved that short-­term
use of HIF-­PHD inhibitors increased haemoglobin levels in anaemic
patients with CKD and reached different conclusions on iron parame-
ters and adverse event profiles.13,14 Now, we performed a comprehen-
sive meta-­analysis to further assess the long-­term efficacy and safety
of HIF-­PHD inhibitors for the treatment of anaemia in CKD.
2  |  M E TH O D S
2.1  |  Search methods and selection criteria
Comprehensive search of the literature was conducted to iden-
tify RCTs reporting efficacy and/or safety outcomes of HIF-­PHD
inhibitors. We searched English language studies up to 1 October
2020 on the following databases: PubMed, Embase, ClinicalTrials.
gov, Cochrane Central Register of Controlled Trials, European
Union Clinical Trials Register and WHO International Clinical
Trials Registry Platform (search terms and strategies were de-
tailed in Table S1). Furthermore, drug manufacturers’ websites
were searched for relevant studies. Our inclusion criteria were
prespecified and RCTs were included: (1) anaemic patients with
CKD treated with HIF-­PHD inhibitors, (2) reported efficacy out-
comes and/or tabulated data on safety outcomes, (3) the control
group was placebo or ESAs. Additionally, unpublished data on the
global phase 3 roxadustat clinical trials (PYRENEES, SIERRAS,
HIMALAYAS, ROCKIES, ANDES, ALPS and OLYMPUS) was ac-
quired from the European Union Clinical Trials Register (https://
www.clini​c altr​ialsr​e gist​e r.eu/about.html). In the event of the
same study population being reported in different articles, only
the article with the latest or most comprehensive safety data
was selected. The literature search and study selection were per-
formed independently by two researchers. All conflicts in study
selection were resolved by consensus. This study followed the
Preferred Reporting Items for Systematic Reviews and Meta-­
analyses (PRISMA) guideline.
2.2  |  Outcome measures
The primary efficacy outcome was change in haemoglobin from
baseline. The secondary efficacy outcomes included changes from
baseline in iron parameters [hepcidin, transferrin saturation (TSAT),
ferritin, serum iron, total iron binding capacity (TIBC), transferrin]
and cholesterol [total cholesterol (TC) and low-­density lipoprotein
cholesterol (LDL-­C)]. Safety outcomes were adverse events (AEs)
and serious adverse events (SAEs).
2.3  |  Data extraction and quality assessment
Identified studies were screened based on title and abstract, and
the full texts were reviewed by two researchers. The following rel-
evant data were extracted from the main text and supplementary
files in duplicate using a predesigned data collection form: first
author/trial name, registration number, trial design, patients’ de-
mographics and clinical characteristics, number of patients, HIF-­
PHD inhibitors dose, treatment duration, comparator, efficacy and
safety outcomes. On account of many less frequently observed AEs
not being reported, only the AEs that occurred in more than 5% of
CHEN et al.
the patients in either group were included for safety analysis. The
quality of included RCTs was evaluated by the Cochrane risk-­of-­
bias tool.15
2.4  |  Statistical analysis
For efficacy outcomes, weighted mean differences (WMD) or stand-
ardized mean differences (SMD) and 95% confidence intervals (CI)
were calculated with inverse variance random effects model. For
safety outcomes, risk ratios (RR) and 95% CI were calculated with
Mantel-­Haenszel random effects. For trials containing multiple in-
tervention with different dose, we combined them to create a sin-
gle comparison group. Missing data were calculated from the raw
data given in tables or estimated from bar charts. Heterogeneity
among trials was assessed by the Cochran Q test and quantified by
I2 statistic, with I2 < 50%, 50%-­75%, >75% indicating mild, moderate,
high heterogeneity, respectively. Publication bias were examined by
funnel plots and Egger's test. In addition, sensitivity analyses were
performed to evaluate the robustness of the efficacy and safety
outcomes by the leave-­one-­out method. All analyses were carried
out by STATA 16.0 statistical software (Stata Corporation, College
Station, Texas, USA).
F I G U R E 1  Flow diagram of evidence
acquisition during study.
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3  |  R E S U LT S
3.1  |  Literature search and study characteristics
A total of 951 related articles were retrieved based on the prelimi-
nary search strategy. After screening and eligibility assessment, 30
studies with 38 comparisons comprising 13,146 patients were in-
cluded for the meta-­analysis. The flow diagram of evidence acquisi-
tion is shown in Figure 1.
Out of 38 comparisons, 21 were placebo-­controlled, while 17
were ESAs-­controlled, with follow-­up durations ranging from 4 to
52  weeks. Twenty comparisons were conducted in patients not un-
dergoing dialysis and 18 comparisons in patients on dialysis. The HIF-­
PHD inhibitors used included roxadustat, daprodustat, vadadustat,
molidustat, desidustat and enarodustat. All of the studies were funded
by industry. Characteristics of included RCTs are presented in Table 1.
The risk of bias for included studies is detailed in Figure S1.
3.2  |  Changes in haemoglobin from baseline
Compared with placebo, HIF-­PHD inhibitors treatment significantly
increased haemoglobin levels (WMD 1.53, 95% CI 1.39 to 1.67,
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4      CHEN et al.
p  <  0.001, 21 comparisons, I2  =  74.5%; Figure  2). Compared with
ESAs, HIF-­PHD inhibitors treatment showed a slight increase in
haemoglobin levels (WMD 0.13, 95% CI 0.03 to 0.22, p = 0.001, 17
comparisons, I2 = 68.9%; Figure 2). We further conducted subgroup
analyses to explore potential effects on haemoglobin outcome
measures of the following conditions: patient population, treatment
duration, mean age of patients and proportion of diabetics in in-
cluded studies (Figure 3).
In the comparison of HIF-­PHD inhibitors with placebo, subgroup
analyses did not show significant differences among the patient pop-
ulation or treatment duration. However, HIF-­PHD inhibitors treated
patients in trials with mean age under 60 years old was apparently
more effective than those in trials with mean age over 65 years old
in improving haemoglobin levels (WMD 1.91, 95% CI 1.57 to 2.25
vs WMD 1.28, 95% CI 1.14 to 1.43). In addition, combined results
showed that haemoglobin levels in trials with a low proportion of
diabetics (<40%) were higher than those with a high proportion of
diabetics (>60%) (WMD 1.63, 95% CI 1.42 to 1.84 vs WMD 1.16,
95% CI 0.94 to 1.38).
In the comparison of HIF-­PHD inhibitors with ESAs, subgroup
analyses suggested that haemoglobin levels were higher in pa-
tients who were undergoing dialysis and treated for more than
24 weeks. Moreover, HIF-­PHD inhibitor use increased haemoglo-
bin levels in trials with patients’ mean age under 60  years old,
but not in trials with patients’ mean age over 60 years old (WMD
0.22, 95% CI 0.07 to 0.38 vs WMD 0.08, 95% CI −0.03 to 0.19).
Likewise, a significant increase of haemoglobin levels was ob-
served in trials with the proportion of diabetics lower than 40%
(WMD 0.15, 95% CI 0.06 to 0.24), but it was not observed in trials
with the proportion of diabetics over 40% (WMD 0.07, 95% CI
−0.09 to 0.23).
3.3  |  Changes from baseline in iron parameters and
cholesterol levels
3.3.1  |  Hepcidin
The effect of HIF-­PHD inhibitors treatment on hepcidin is shown in
Figure S2. HIF-­PHD inhibitors use induced a significant reduction in
hepcidin levels in comparison with placebo (WMD −40.47, 95% CI
2
−51.17 to −29.78, p < 0.001, 14 comparisons, I  = 91.6%). Similarly,
HIF-­PHD inhibitors treatment reduced hepcidin levels in comparison
with ESAs (WMD −11.89, 95% CI −22.66 to −1.12, p  =  0.03, nine
comparisons, I2 = 71.9%).
3.3.2  |  TSAT
HIF-­PHD inhibitors induced a significant reduction in TSAT in com-
parison with placebo (WMD −3.2, 95% CI −4.36 to −2.04, p < 0.001,
nine comparisons, I2  =  28.2%; Figure S3). However, there was no
significant difference between HIF-­PHD inhibitors and ESAs in
TAST (WMD 0.76, 95% CI −0.02 to 1.54, p = 0.06, 11 comparisons,
I2 = 0%; Figure S3). Sensitivity analysis indicated that HIF-­PHD in-
hibitors increased TSAT compared with ESAs when PYRENEES (Rox,
D) or Macdougall 2019 (Mol, N) was excluded, and the pooled results
were 1.07 (95% CI 0.24 to 1.89, p = 0.011, 10 comparisons, I2 = 0%)
and 0.81 (95% CI 0.03 to 1.60, p = 0.043, 10 comparisons, I2 = 0%),
respectively.
3.3.3  |  Ferritin
Compared with placebo, HIF-­PHD inhibitors induced a significant re-
duction in ferritin levels (SMD −0.92, 95% CI −1.28 to −0.55, p < 0.001,
12 comparisons, I2 = 92.9%; Figure S4). Compared with ESAs, use of
HIF-­PHD inhibitors slightly reduced ferritin levels (SMD −0.13, 95%
CI −0.22 to −0.04, p = 0.005, 14 comparisons, I2 = 40.1%; Figure S4).
3.3.4  |  Serum iron
There were no significant differences between HIF-­PHD inhibitors
and placebo in serum iron levels (SMD −0.12, 95% CI −0.29 to 0.04,
p = 0.139, eight comparisons, I2 = 0%; Figure S5). However, HIF-­PHD
inhibitors significantly increased serum iron levels in comparison
with ESAs (SMD 0.23, 95% CI 0.10 to 0.36, p < 0.001, 14 compari-
sons, I2 = 66.9%; Figure S5). Subgroup analysis stratified by patient
population was performed in the comparison of HIF-­PHD inhibitors
with ESAs. We observed that serum iron levels in dialysis-­dependent
patients were higher than those in non-­dialysis-­dependent patients
[(SMD 0.38, 95% CI 0.32 to 0.44, p < 0.001, 10 comparisons, I2 = 0%)
vs (SMD −0.19, 95% CI −0.38 to −0.00, p = 0.046, four comparisons,
I2 = 0%)].
3.3.5  |  TIBC
HIF-­PHD inhibitors significantly increased TIBC in comparison with
placebo (SMD 2.22, 95% CI 1.47 to 2.97, p < 0.001, 12 comparisons,
I2  =  95.4%; Figure S6). Likewise, compared with ESAs, use of HIF-­
PHD inhibitors increased TIBC (SMD 0.72, 95% CI 0.46 to 0.98,
p < 0.001, 11 comparisons, I2 = 81.3%; Figure S6).
3.3.6  |  Transferrin
HIF-­PHD inhibitors significantly increased transferrin levels
in comparison with placebo (SMD 1.23, 95% CI 0.68 to 1.79,
p < 0.001, six comparisons, I2 = 85.6%; Figure S7). Similarly, HIF-­
PHD inhibitors increased transferrin levels in comparison with
ESAs (SMD 0.77, 95% CI 0.48 to 1.05, p < 0.001, six comparisons,
I2 = 70.2%; Figure S7).
TA B L E 1  Characteristics of studies included for the meta-­analysis.

Relevant publications/ Study No. of Duration

CHEN et al.

name Registration number Located Blinded Comparator patients Dosing schedule (initial dose) (weeks)

Chen 2019 (Rox, N)25 NCT02652819 China Double-­blind Placebo 152 70 or 100 mg, TIW 8
Akizawa 2019 (Rox, N)26 NCT01964196 Japan Double-­blind Placebo 107 50, 70 or 100 mg, TIW 24
Chen 2017 (Rox, N)27 NCT01599507 China Double-­blind Placebo 91 1.1 ~ 1.75 or 1.50 ~ 2.25 mg/kg, TIW 8
ALPS (Rox, N) NCT01887600 Multiple countries Double-­blind Placebo 594 70 or 100 mg, TIW 52
OLYMPUS (Rox, N) NCT02174627 Multiple countries Double-­blind Placebo 2761 70 mg, TIW 52
ANDES (Rox, N) NCT01750190 Multiple countries Double-­blind Placebo 916 70 or 100 mg, TIW 52
28
Besarab 2015 (Rox, N) NCT00761657 United States Single-­blind Placebo 116 0.7 ~ 2.0 mg/kg, TIW or BIW 4
Martin 2017 (Vad, N)29 NCT01381094 United States Double-­blind Placebo 91 240, 370, 500 or 630 mg, QD 6
30
Pergola 2016 (Vad, N) NCT01906489 United States Double-­blind Placebo 210 450 mg, QD 20
*
Nangaku 2020 (Vad, N)31 NCT03054337 Japan Double-­blind Placebo 51 150,300 or 600 mg, QD 6
32 *
Macdougall 2019 (Mol, N) NCT02021370 Multiple countries Double-­blind Placebo 121 25, 50 or 75 mg, QD; 25 or 50 mg, 16
BID
Parmar 2019 (Des, N)23 CTRI/2017/05/008534 Indian Double-­blind Placebo 87 100, 150 or 200 mg, QOD 6
21
Holdstock 2016 (Dap, N) NCT01587898 Multiple countries Double-­blind Placebo 72 0.5, 2 or 5 mg, QD 4
Brigandi 2016 (Dap, N)33 NCT01047397 Multiple countries Single-­blind Placebo 70 10, 25, 50 or 100 mg, QD 4
34
Akizawa 2019 (Ena, N) JapicCTI−152881 Japan Double-­blind Placebo 197 2, 4 or 6 mg, QD 6
Akizawa 2017 (Dap, D)22 NCT02019719 Japan Double-­blind Placebo 97 4, 6, 8 or 10 mg, QD 4
35
Bailey 2019 (Dap, D) NCT02689206 Multiple countries Double-­blind Placebo 103 10, 15, 25 or 30 mg, TIW 4
*
Nangaku 2020 (Vad, D)31 NCT03054350 Japan Double-­blind Placebo 60 150, 300 or 600 mg, QD 6
33
Brigandi 2016 (Dap, D) NCT01047397 Multiple countries Single-­blind Placebo 37 10 and 25 mg, QD 4
Akizawa 2019 (Ena, D)36 JapicCTI−152892 Japan Double-­blind Placebo 85 2, 4 or 6 mg, QD 6
37
Chen 2019 (Rox, D) NCT02652806 China Open-­lable Epoetin alfa 304 100 or 120 mg, TIW 26
Provenzano 2016 (Rox, D)38 NCT01147666 United States Open-­lable Epoetin alfa 144 1.0 ~ 2.0 mg/kg, TIW 19
39
Akizawa 2020 (Rox, D) NCT02952092 Japan Double-­blind Darbepoetin 302 70 ~ 100 mg, TIW 24
Chen 2017 (Rox, D)27 NCT01596855 China Open-­lable Epoetin alfa 96 1.1 ~ 2.3 mg/kg, TIW 6
40
Astellas Pharma Inc (Rox, D) ISN:1517-­CL-­0304 Japan Open-­lable Darbepoetin 129 50, 70 or 100 mg, TIW 24
ROCKIES (Rox, D) NCT02174731 Multiple countries Open-­lable Epoetin alfa 2101 70 ~ 200 mg, TIW 52
PYRENEES (Rox, D) NCT02278341 Multiple countries Open-­lable rhEPO 834 70 ~ 200 mg, TIW 52
SIERRAS (Rox, D) NCT02273726 Multiple countries Open-­lable Epoetin alfa 740 70 ~ 200 mg, TIW 52
HIMALAYAS (Rox, D) NCT02052310 Multiple countries Open-­lable Epoetin alfa 1039 70 or 100 mg, TIW 52
Macdougall 2019 (Mol, D)32 NCT01975818 Multiple countries Open-­lable rhEPO 199 25, 50, 75 or 150 mg, QD 16
Akizawa 2020 (Dap, D) 41 NCT02969655 Japan Double-­blind Darbepoetin 271 1 ~ 24 mg, QD 52
|
      5

(Continues)
 6      | CHEN et al.

3.3.7  |  TC and LDL-­C

Duration
(weeks) A total of 12 RCTs reported the effect of roxadustat on TC and/or

Abbreviations: BIW, twice weekly; D, dialysis-­dependent; Dap, daprodustat; Des, desidustat; Ena, enarodustat; Mol, molidustat; N, non-­dialysis-­dependent; QD, once a day; QOD, every other day;
24
4
52
24
16
LDL-­C. Compared with placebo, roxadustat induced a significant re-
duction in TC (SMD −0.84, 95% CI −1.13 to −0.55, p < 0.001, four
comparisons, I2 = 83.2%; Figure S8) and LDL-­C (SMD −0.68, 95% CI
Dosing schedule (initial dose)

−0.89 to −0.46, p < 0.001, five comparisons, I2 = 84.7%; Figure S9).

Compared with ESAs, roxadustat apparently reduced TC (SMD −0.55,
95% CI −0.81 to −0.29, p < 0.001, four comparisons, I2 = 67.9%; Figure
4, 6, 10 or 12 mg, QD

25, 50 or 75 mg, QD
0.5, 2 or 5 mg, QD

S8) and LDL-­C (SMD −0.6, 95% CI −0.75 to −0.45, p < 0.001, six com-
1, 2 or 4 mg, QD
1 ~ 24 mg, QD

parisons, I2 = 80.4%; Figure S9).

3.4  |  Safety outcomes

The risk of the main AEs in HIF-­PHD inhibitors group versus control
patients

group was pooled and presented in Figure S10 and S11. Compared
No. of

216
80
299
250
124

with placebo, HIF-­PHD inhibitors treated patients did not experi-

ence significantly more risk of AEs (RR 1.01, 95% CI 0.99 to 1.04,
p = 0.188, 19 comparisons, I2 = 0%), but these patients experienced
significantly more risk of SAEs (RR 1.07, 95% CI 1.01 to 1.13, p = 0.03,
Epoetin beta

Darbepoetin
Comparator

16 comparisons, I2 = 0%). Compared with ESAs, HIF-­PHD inhibitors

rhEPO
rhEPO

rhEPO

treated patients did not experience significantly more risk of AEs

(RR 1.01, 95% CI 0.98 to 1.04, p = 0.53, 14 comparisons, I2 = 31.7%)
or SAEs (RR 1.02, 95% CI 0.94 to 1.10, p  =  0.66, 15 comparisons,
I2 = 27.1%).
Thereafter, the most common reported AEs in the HIF-­PHD
Open-­lable
Open-­lable
Open-­lable
Open-­lable
Open-­lable

inhibitors group were further evaluated and shown in Figure  4.

Blinded

Patients treated with HIF-­PHD inhibitors were more likely to

experience diarrhoea (RR 1.21, 95% CI 1.00 to 1.47, p  =  0.04),
nausea (RR 1.46, 95% CI 1.09 to 1.97, p  =  0.01), peripheral oe-
dema (RR 1.32, 95% CI 1.01 to 1.59, p  <  0.001), hyperkalemia
Multiple countries
Multiple countries

Multiple countries
Multiple countries

(RR 1.27, 95% CI 1.05 to 1.54, p  =  0.02) and hypertension (RR

1.34, 95% CI 1.02 to 1.76, p = 0.03) than those treated with pla-
*Fixed dose; Rox, roxadustat; TIW, three times weekly; Vad, vadadustat.

cebo. Meanwhile, patients treated with HIF-­PHD inhibitors were

Located

Japan

more likely to experience vomiting (RR 1.30, 95% CI 1.02 to 1.65,

p = 0.03), headache (RR 1.27, 95% CI 1.05 to 1.53, p = 0.01) and
thrombosis events (RR 1.31, 95% CI 1.05 to 1.63, p = 0.02) than
Registration number

those treated with ESAs.

NCT02021409
NCT01587924
NCT01977482

NCT01977573
NCT02791763

3.5  |  Bias assessment and sensitivity analyses

The analysis of funnel plots is shown in Figure S12, and Egger's

test did not show any evidence of publication bias for haemo-
Meadowcroft 2019 (Dap, D) 42
Relevant publications/ Study

globin, hepcidin, transferrin, TSAT, ferritin, AEs or SAEs, but

Macdougall 2019 (Mol, N)32
44
Holdstock 2016 (Dap, D)21
43

Holdstock 2019 (Dap, N)

indicated that there was obvious publication bias for ferritin

NCT02791763 (Dap, N)
TABLE 1 (Continued)

(p  =  0.009; placebo-­c ontrolled comparison), TIBC (p = 0.002;

placebo-­c ontrolled comparison) and serum iron (p  =  0.046;
ESAs-­c ontrolled comparison). Sensitivity analyses showed that
the pooled results of changes in haemoglobin, iron parameters
name

other than TSAT, cholesterol levels and adverse events were

robust.
CHEN et al. |
      7

F I G U R E 2  Forest plot comparing effect of HIF-­PHD inhibitors versus Placebo (A) or ESAs (B) on haemoglobin.
 |
8      CHEN et al.

F I G U R E 3  Subgroup analyses of comparing effect of HIF-­PHD inhibitors versus Placebo (A) or ESAs(B) on haemoglobin.

4  |  D I S C U S S I O N Anaemia is common in the older population, as well as in diabet-

This meta-­analysis, based on 38 comparisons including 13,146 pa-
tients, evaluated the totality of evidence investigating the efficacy
and safety of HIF-­PHD inhibitors versus placebo or ESAs in anaemic
patients with CKD. The major findings were as follows. Firstly, HIF-­
PHD inhibitors could effectively improve haemoglobin levels during
the long-­term as well as the short-­term use, although the beneficial
effect on haemoglobin improvement would be affected by age and
diabetes. Secondly, HIF-­PHD inhibitor treatment remarkably pro-
moted iron utilization and was associated with cholesterol-­lowering
effects. Finally, HIF-­PHD inhibitors were generally well tolerated for
long-­term use.
ics. Unexplained anaemia is more common in persons age 65 years
and older, which is mainly caused by age-­related physiological mech-
anisms such as a decline in red blood cell production or shortened
survival alongside a decreased response to EPO stimulation.16,17 For
diabetic patients, systemic inflammation and microvascular dam-
age in the bone marrow might result in EPO hyporesponsiveness.18
Moreover, hyperglycemia and elevated levels of advanced glycation
end products would lead to abnormal red blood cells in diabetes mel-
litus.19 Therefore, we should pay more attention to HIF-­PHD inhibi-
tor management in these anaemic patients with CKD.
In the placebo-­controlled comparison, there were no differences
in serum iron levels between the two groups, while the HIF-­PHD
CHEN et al.
F I G U R E 4  Forest plot comparing effect of HIF-­PHD inhibitors versus Placebo (A) or ESAs (B) on adverse events.
inhibitors group increased TIBC. Therefore, the decrease in TSAT
and ferritin indicated that HIF-­PHD inhibitors increased iron uti-
lization. In the ESAs-­controlled comparison, serum iron levels in
dialysis-­dependent patients were higher than those in non-­dialysis-­
dependent patients due to the active iron supplementation mea-
sures in the former. For non-­dialysis-­dependent patients, HIF-­PHD
inhibitors therapy improved iron utilization, but it was more likely to
cause iron deficiency due to excessive iron consumption. And thus
we believed that it was appropriate to receive iron supplementation
when patients were treated long-­term with HIF-­PHD inhibitors.
HIF activation would promote the uptake of lipoprotein and the
degradation of 3-­hydroxy-­3-­methylglutaryl coenzyme A reductase
that inhibited synthesis of cholesterol. 20 TC, LDL-­C and HDL-­C low-
ering effects were also reported in two studies of daprodustat, 21,22
23
besides, Parmar et al found that desidustat reduced LDL-­C .
However, cholesterol-­lowering effects were not reported with other
HIF-­PHD inhibitors, such as vadadustat or molidustat. It is unclear
whether cholesterol-­lowering effects were specific to certain com-
pounds or a class effect.
Of note, the adverse event profile of HIF-­PHD inhibitors is an
important factor in therapy options for anaemic patients with CKD.
In this meta-­analysis including large-­sample clinical data, the risk
|
      9
of hyperkalemia in the HIF-­PHD inhibitors group was increased in
comparison with placebo group. Studies reporting hyperkalemia
mostly came from roxadustat, and few studies reported treatment
emergent hyperkalemia caused by vadadustat and molidustat.
Additionally, the risk of hypertension was increased in the HIF-­PHD
inhibitor group versus that in the placebo group, which might be due
to EPO-­induced hypertension or HIF activation. 24 It was notewor-
thy that long-­term use of HIF-­PHD inhibitors increased the risk of
thrombosis events compared with ESAs. The cause of the increased
risk of thrombosis events remains unclear, however, we should be
alert to the possibility of high haemoglobin levels caused by HIF-­
PHD inhibitors, especially for patients who switch from ESAs to
HIF-­PHD inhibitors, the initial dose of HIF-­PHD inhibitors should be
selected more carefully to avoid high haemoglobin levels. Our find-
ings on the safety profile of HIF-­PHD inhibitors came from RCTs,
while more comprehensive safety conclusions remain to be further
confirmed by postmarketing surveillance and pharmacovigilance.
There were several limitations in our meta-­analysis. Firstly, the
different dose groups in trials were combined into one comparison
group, and thus, the effect of dose on outcomes was not taken into
consideration. Secondly, most trials were conducted in patients
not on dialysis in the placebo-­controlled trials, while most studies
 |
10      CHEN et al.
were conducted in dialysis-­dependent patients in ESAs-­controlled
studies, which perhaps cover up the relationship between patient
population and efficacy as well as safety outcomes to some extent.
Finally, concomitant iron therapies in the analysed studies were not
available; therefore, it was unknown the changes in iron parameters
to which extent affected the therapy outcomes.
5  |  W H AT I S N E W A N D CO N C LU S I O N
This extensive meta-­analysis confirmed that HIF-­PHD inhibitors
were capable of effectively correcting and maintaining haemo-
globin levels and promoting iron utilization in anaemic patients
with CKD. And it was appropriate to receive iron supplementation
when patients were long-­term treated with HIF-­PHD inhibitors.
In addition, HIF-­PHD inhibitors were generally well tolerated dur-
ing short-­term and long-­term treatment, but it is necessary to pay
close attention to its potential adverse effects in continued phar-
macovigilance data.
AC K N OW L E D G E M E N T
We would like to express our gratitude to AstraZeneca
Pharmaceutical (China) Co., Ltd., since they provided us with more
information about the outcomes of the roxadustat global clinical
trials.
C O N FL I C T O F I N T E R E S T
The authors declare no conflict of interest.
AU T H O R C O N T R I B U T I O N S
H.H.C., Q.F.C. and S.Y.Z. conceived and designed the study. X.F.Z.,
J.X.W. contributed to the study selection and data collection. H.H.C.
contributed to the data analysis and manuscript written and edition.
S.Y.Z. contributed to the supervision and review. All authors read
and approved the final manuscript.
DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from
the corresponding author upon reasonable request.
ORCID
Huanhuan Chen  https://orcid.org/0000-0002-8620-6493
Shenyin Zhu  https://orcid.org/0000-0001-5739-5603
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S U P P O R T I N G I N FO R M AT I O N
Additional supporting information may be found online in the
Supporting Information section.
How to cite this article: Chen H, Cheng Q, Wang J, Zhao X,
Zhu S. Long-­term efficacy and safety of hypoxia-­inducible
factor prolyl hydroxylase inhibitors in anaemia of chronic
kidney disease: A meta-­analysis including 13,146 patients. J
Clin Pharm Ther. 2021;00:1–11. https://doi.org/10.1111/
jcpt.13385