Canadian Journal of Cardiology - (2015) 1e9
Systematic Review/Meta-analysis
The Efficacy and Safety of Iron Supplementation in Patients
With Heart Failure and Iron Deficiency: A Systematic Review
and Meta-analysis
Cheng Qian, MD,* Baozhu Wei, MD, PhD,* Jinye Ding, MD, Huiting Wu, MD,
and Yanggan Wang, MD, PhD
Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
ABSTRACT
Background: Iron deficiency (ID) is a common comorbidity in patients
with heart failure (HF) and has been associated with increased mor-
tality and hospitalizations. However, the benefit and safety of iron
supplementation in treating HF and ID in randomized controlled trials
(RCTs) are inconclusive. We therefore performed a meta-analysis to
overcome this limitation.
Methods: PubMed, the Cochrane Library, and ClinicalTrials.gov were
systematically searched for eligible trials up to December 31, 2014.
We also searched the references of all relevant studies and reviews for
more trials. Only RCTs reporting the clinical impact of iron therapy in
patients with HF with ID compared with no iron treatment were
enrolled in our meta-analysis.
Iron deficiency (ID) is now viewed as a frequent and impor-
tant comorbidity in patients with heart failure (HF). Studies
have reported a high prevalence of ID in patients with chronic
HF of up to 30%-50%.1,2 Traditionally, the clinically related
influences of ID were considered only in the context of ane-
mia. However, ID anemia can be regarded as the end phase of
a process beginning with the gradual depletion of iron stores.3
Accordingly, even in patients with a preserved hemoglobin
level, ID may already exist in chronic HF.4 ID, with or
without anemia, is associated with exercise intolerance, low
quality of life, and increased mortality and hospitalization in
patients with HF.5-7
Besides improving erythropoiesis, intravenous iron has
been shown to maintain energy metabolism by augmenting
Received for publication April 6, 2015. Accepted June 16, 2015.
*These authors contributed equally to this work.
Corresponding author: Dr Yanggan Wang, Department of Cardiology,
Zhongnan Hospital of Wuhan University, No 169 Donghu Road, Wuchang
District, Wuhan 430071, Hubei Province, China. Tel.: þ86-27-67812844;
fax: þ86-027-67812844.
E-mail: wb000813@whu.edu.cn
See page 8 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2015.06.009
0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

RESUM 
E
Introduction : Une carence en fer (CF) est une comorbidite  fre
quente
chez les patients atteints d’insuffisance cardiaque (IC) et elle est
associe e à une augmentation de la mortalite  et des hospitalisations.
Toutefois, le be ne
fice et la se
curite
 d’une supple
mentation en fer dans
le traitement de l’IC et de la CF dans des essais contrôles randomise s
(ECR) ne sont pas concluants. Nous avons donc re alise
 une me ta-
analyse pour surmonter cette limitation.
Me thodes : PubMed, la Cochrane Library, et le site ClinicalTrials.gov
ont e te
 syste
matiquement fouille s pour des essais admissibles jus-
qu’au 31 de cembre 2014. Nous avons e galement cherche  les
 fe
re rences de toutes les e tudes et commentaires pertinents pour plus
d’essais. Seuls les ECR rapportant l’impact clinique d’un apport
aerobic metabolism and oxidative phosphorylation.8 Cells
with high-energy demand, such as cardiomyocytes and skeletal
myocytes, are particularly sensitive to ID. As the impaired
energy generation and utilization in the myocardium and the
peripheral tissue are always involved in the pathophysiological
process of HF,9 correction of ID may be an efficient treatment
for HF and ID. In the past few decades, a number of trials
have explored the effect of erythropoiesis-stimulating agents
(ESAs) and iron preparations in treating patients with chronic
HF. Treatment with ESAs alone failed to reduce mortality or
hospitalization for HF while it increased the risk of throm-
boembolic events.10 ESAs are thus not recommended to treat
anemic patients with HF.11 ESAs combined with iron have
been shown to improve cardiac function, New York Heart
Association (NYHA) functional class, and exercise
capacity.12-14 Two observational studies, together with 1 pre-
post trial, have found that monotherapy with intravenous iron
improved symptoms, cardiac remodelling and exercise
intolerance.15-17 In addition, iron therapy alone has shown to
have the same benefits as the combination of ESAs and iron in
patients with HF.18 Although almost all randomized
controlled trials (RCTs) have observed that intravenous iron
could improve the exercise capacity, functional status, and
2 Canadian Journal of Cardiology
Volume - 2015

Results: Five clinical trials comprising a total of 907 patients were therapeutique de fer pour des patients en IC avec CF, comparative-
finally included. Compared with placebo or no treatment, additional ment à aucun apport en fer, ont e  te
 inclus dans notre me ta-analyse.
iron therapy was associated with a significantly reduced rate of hos- Resultats : Cinq essais cliniques comprenant un total de 907 patients
pitalization for HF (odds ratio [OR], 0.28; 95% confidence interval [CI], ont finalement e te
 inclus. Comparativement au placebo ou aucun
0.16-0.49), though all-cause mortality was not significantly different traitement, une therapie supplemente e en fer a ete
 associe e à un taux
(OR, 0.81; 95% CI, 0.42-1.57). In 4 studies where these endpoints significativement re duit d’hospitalisation en cas d’IC (ratio d’incidence
were combined, the incidence of hospitalization for HF and death was approche  [RIA], 0,28; intervalle de confiance [IC] à 95 %, de 0,16 à
lowered in the iron supplementation group (OR, 0.47; 95% CI, 0.29- 0,49), bien que la mortalite  toutes causes confondues n’e tait pas sig-
0.76). There was no increase in the risk of adverse events. nificativement diffe rente (RIA, 0,81; IC à 95 %, 0,42 à 1,57). Dans
Conclusions: Iron supplementation significantly reduced the risk of (a) quatre etudes où ces points limites ont e te combine s, l’incidence des
hospitalization for HF and (b) the combined endpoint of hospitalization hospitalisations pour IC et de la mortaliteetait diminuee dans le groupe
for HF and death, without increasing the risk of adverse events in avec une supple mentation en fer (RIA, 0,47; IC à 95 %, 0,29 à 0,76). Il
patients with symptomatic systolic HF and ID. However, the current n’y avait pas d’augmentation du risque d’e venements inde sirables.
data are inadequate to make a clear determination upon mortality. Conclusions : La supple mentation en fer re duit significativement le
risque (a) d’une hospitalisation pour IC et (b) du critère combine  des
hospitalisations pour IC et de la mort, sans augmenter le risque d’ef-
fets indesirables chez les patients pre sentant des symptômes d’IC
systolique et de CF. Cependant, les donne es actuelles sont insuffi-
santes pour obtenir un avis tranche  concernant la mortalite .

quality of life in iron-deficient patients with HF, whether it [OR]) were also recorded for the pooled analysis. All dis-
has benefit in terms of reducing mortality or hospitalization crepancies between the two reviewers were resolved by dis-
remains unknown. Individual RCTs also have not been large cussion with a third reviewer (J.D.).
enough to detect the prognostic effects of iron supplementa-
tion. Therefore, a meta-analysis pooling the data from RCTs
is needed to overcome this limitation. Quality assessment and study outcome
The quality of the included articles was assessed according
Methods to Cochrane collaboration’s tool for assessing the risk of
bias.20 The efficacy endpoints for this analysis included hos-
Data sources and search strategy pitalization for HF, all-cause mortality, and a combined
endpoint of hospitalization for HF and death, whereas adverse
This study was conducted according to Preferred Report-
events (AEs) were recorded as the safety endpoint. We
ing Items for Systematic Reviews and Meta-Analyses state-
collected the quantitative data on only severe AEs reported in
ment.19 We performed systematic literature searches in the
each RCT for synthesis, because their concrete definition was
database of PubMed, the Cochrane Library, and
stated only in 1 eligible study.21
ClinicalTrials.gov for eligible studies. The reference lists of
relevant studies and reviews were also checked to find addi-
tional trials. We combined the following search terms: “iron”
or “ferrous” or “ferric,” and “heart failure” or “cardiac failure”
or “myocardial failure” or “heart decompensation.” Our
search was limited to human and English articles published
until December 31, 2014.

Inclusion criteria
Clinical studies that met the following requirements were
included in our meta-analysis: (a) RCTs; (b) enrolled patients
with established HF and ID regardless of left ventricular
ejection fraction (LVEF); (c) compared iron therapy with no
iron therapy (placebo or no treatment); (d) reported data
about hospitalization for HF, all-cause mortality, a combined
endpoint of hospitalization for HF and death, and adverse
events. Trials that compared the combined treatment of ESAs
and iron with no iron treatment were excluded.

Data extraction
Two reviewers (C.Q. and B.W.) independently extracted
the details regarding study and patient characteristics, treat-
ment strategy, ID definition, and duration of follow-up. The
total number of clinical endpoints and effect sizes (odds ratio Figure 1. Flow diagram for inclusion of studies in this meta-analysis.
Qian et al. 3
Iron Supplementation for HF and Iron Deficiency

Statistical analysis

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, b-blocker; FCM, ferric carboxymaltose; Hb, hemoglobin; HF, heart failure; ID, iron deficiency; IS, iron sucrose;
Follow-up
(wk)
24

18

14

24

52
Data analysis was performed using STATA 12.0 (Stata-
Corp, College Station, TX). ORs with 95% confidence in-
tervals (CIs) for all outcomes were used to present the pooled
effect size of the individual studies. Statistical heterogeneity

Ferritin < 100 ng/mL or TSAT

300 ng/mL if TSAT < 20%)

300 ng/mL if TSAT < 20%)

300 ng/mL if TSAT < 20%)

Ferritin < 100 ng/mL (or 100-

Ferritin < 100 ng/mL (or 100-

Ferritin < 100 ng/mL (or 100-

across the studies was quantified using the I2 statistic. When I2
> 25% (indicate significant heterogeneity), we reported a

Definition of ID
pooled estimate based on the random-effects model; otherwise
the fixed-effects model was used. Sensitivity analysis was
conducted to assess the robustness of the pooled estimates by
(a) switching to the other effects model and (b) removing each

< 20%
trial one at a time from the analysis and evaluating the overall
estimates for the remaining studies. The results of the pooled

NS
effect size were considered to be statistically significant only at
P < 0.05.

Diuretic
95

71

92

90
Results

Medication (%)
ACEI/ARB
Study selection and baseline characteristics

NS
98/23

74/20

78/24
The study selection process is displayed in Fig. 1. Briefly,

IV, intravenous; LVEF, left ventricular ejection fraction; NS, not stated; NYHA, New York Heart Association; TSAT, transferrin saturation.
92z
of the initial 1512 citations, 327 were excluded because 165
studies were non-English articles, and 162 reports were not

100

89

85

90
BB
human trials. After scanning the titles and abstracts, we
excluded 1152 studies irrelevant to our participant. The
remaining 33 studies and 1 additional trial (identified by
Ischemic
HF (%)

reviewing the reference list of a study22) were selected for full-

62.5

74.3

80.2

83.4
NS
text screening, during which 29 publications did not meet the
inclusion criteria. Consequently, 5 RCTs21,23-26 performed
between 2007 and 2014 were finally included in our meta-
Hb (g/dL)

9.5-13.5
analysis.
< 11.5y
< 12.5

< 12.5

< 15
Table 1 summarizes the baseline characteristics of the
Inclusion criteria

eligible studies. All of them were designed using the ran-

domized controlled method and compared additional intra-
NYHA

NS

venous iron treatment with placebo or no treatment. Ferric

II-IV

II-III

II-III

II-III

carboxymaltose24-26 and iron sucrose21,23,24 were used in 3

separate studies (1 trial24 used both) with the dose varying
 45%*

from 200 to 1000 mg. A total of 907 participants with

 45%

 45%

 40%

 45%
LVEF

chronic HF were included, of whom 556 were assigned to the

iron group and 351 to the control group. The average age of
the participants in each study ranged from 62 to 76 years, and
Male

58.6% were women. The mean duration of follow-up ranged

47.7
45.2
(%)
NS
NS

NS

NS
71
73

33

26

from 14 to 52 weeks. All patients in the included trials had

Table 1. Baseline characteristics of the included studies

established chronic HF with an LVEF  45% and NYHA

class II-III (except one study23 that enrolled patients with
 14
 11

68  10
67  11
69  10
Age (y)
7
8

70  9

*  40% for NYHA II and  45% for NYHA III.

NS

NS

NYHA class IV). In the included studies, the hemoglobin cut-

Percentage of patients receiving ACEI or ARB.
76
74
64
62

off value varied from 11.5 to 15.0 g/dL. ID was defined as

ferritin < 100 ng/mL or transferrin saturation (TSAT) <
< 12.5 for men and < 11.5 for women.
20
20
24
11
27
30
15
304
155
150

151

20% in 1 study,23 and 3 trials21,25,26 diagnosed ID with

N

ferritin < 100 ng/mL or between 100 and 300 ng/mL if

TSAT < 20%. In addition, 2 studies23,24 enrolled patients
Iron and control

IV FCM 200 mg

IV FCM 200 mg

IV FCM 500 or

with chronic renal failure, but the mean creatinine clearance

IV IS 200 mg

IV IS 200 mg

IV IS 200 mg
No treatment

No treatment

was greater than 30 mL/min.

1000 mg

Quality assessment
Saline

Saline

Saline

The Cochrane risk of bias assessment was used to perform

quality assessment (shown in Fig. 2). Overall, random
Ponikowski
Arutyunov
200723

200821

200924

200925

201426

sequence generation was observed in 4 studies, and 2 of them

Okonko
Toblli

Anker

had reported allocation concealment. Three trials were double

Study

y
z

blinded and had performed a blinded assessment of the

4 Canadian Journal of Cardiology
Figure 2. Risk of bias assessment in the included studies.
outcomes. Neither incomplete outcome data nor selective
reporting was present in any of the included studies. We also
did not observe other significant bias during quality assess-
ment. However, there are no data available for appraising the
risk of bias in 1 study.24
Hospitalization for HF
Four included studies reported the risk of hospitalization
for HF, and no evidence of heterogeneity was observed across
them (I2 ¼ 0%, P ¼ 0.723). In total, there were 18 (3.6%)
hospitalizations due to HF in the iron group (n ¼ 499),
compared with 47 (14.0%) hospitalizations in the control
group (n ¼ 336, Supplemental Table S1). The pooled esti-
mates using fixed-effect meta-analysis showed a significantly
reduced rate of hospitalization for HF among the iron sup-
plementation patients compared with the non-iron treatment
group (OR, 0.28; 95% CI, 0.16-0.49; P < 0.001) (Fig. 3A).
All-cause mortality
Four studies reported data for all-cause mortality, and there
was no significant heterogeneity across them (I2 ¼ 0%, P ¼
0.962). In general, 19 (3.5%) patients in the iron group (n ¼
536) reached this endpoint compared with 18 (5.4%) patients
in the control group (n ¼ 331, Supplemental Table S1).
Pooling across the 4 trials using fixed-effect meta-analysis
showed no significant difference in all-cause mortality
Volume - 2015
between iron and non-iron groups (OR, 0.81; 95% CI, 0.42-
1.57; P ¼ .53) (Fig. 3B).
Hospitalization for HF and death
Four studies reported the composite of hospitalization for
HF and death, and no proof of heterogeneity was found (I2 ¼
0%, P ¼ 0.574). Overall, 31 (6.2%) patients reached the
combined endpoint in the iron group (n ¼ 499), whereas 49
(14.6%) patients reached the endpoint in the control group
(n ¼ 336, Supplemental Table S1). Pooling across the 4 trials
using fixed-effect meta-analysis indicated that iron supple-
mentation was associated with a significant decrease in the risk
of this combined endpoint (OR, 0.47; 95% CI, 0.29-0.76;
P ¼ 0.002) (Fig. 4).
Adverse events
Data for severe AEs were provided in 4 studies, and sta-
tistical heterogeneity across them was not significant (I2 ¼
19%, P ¼ 0.295). In summary, there were 52 (9.7%) par-
ticipants with at least one severe AE in the iron group (n ¼
538), whereas 62 (18.7%) participants in the control group
had at least one severe AE (n ¼ 332, Supplemental Table S2).
Meta-analytic pooling for this safety outcome using a fixed-
effects model revealed that the iron group had a statistically
lower rate of severe AEs than the control group (OR, 0.50;
95% CI, 0.34-0.75; P ¼ 0.001) (Fig. 5). Of the AEs reported
Qian et al.
Iron Supplementation for HF and Iron Deficiency
Figure 3. Forest plot showing the effect of iron supplementation on (A) hospitalization for HF and (B) all-cause mortality in patients with HF and ID.
in the included studies, such as cardiac, nervous system,
gastrointestinal, and vascular disorders, none was observed to
occur more frequently in the iron group. In addition, no se-
vere allergic reactions related to the iron treatment were re-
ported in each included trial.
Sensitivity analysis
When switching to random-effects model analysis, the
overall ORs are consistent with the direction and size of the
ones calculated by the fixed-effects model. Elimination of each
trial one at a time from the analysis did not have any relevant
influence on the overall results with the exception of the effect
variable regarding severe AEs, which confirmed in direction
and magnitude the major results of the present study and
suggested that there was only a nominal reduction in the risk
of severe AEs in this meta-analysis (shown in Table 2).
5
Discussion
In the present meta-analysis, we summarize the available
evidence on the prognostic effect and safety of iron treatment
in patients with HF and ID. The results demonstrate that iron
supplementation is associated with a significant reduction in
(a) hospitalization because of HF and (b) the combined
endpoint of hospitalization for HF and death. However, we
failed to detect the superiority in terms of all-cause mortality
of iron therapy to non-iron treatment or placebo. Addition-
ally, iron supplementation is not associated with an increased
risk of adverse events in patients with chronic HF.
Similar benefits of iron therapy were also observed in 2
previous meta-analyses.27,28 Although our study additionally
included only one large and well-designed RCT published
recently, the sample size of our meta-analysis increased by
about half. Moreover, the most recent meta-analysis enrolled
patients were treated in combination with ESAs and lost the
significance of prognostic endpoints after exclusion of some
6 Canadian Journal of Cardiology
Volume - 2015

Figure 4. Forest plot showing the effect of iron supplementation on the combined outcome of hospitalization for HF and death in patients with HF
and ID.

trials.28 Conversely, we conducted a reliable sensitivity anal-
ysis and evaluated more endpoints (eg, the combined out-
comes of death and HF hospitalization). The above points
increase accuracy and robustness of our findings.
Several studies have confirmed the negative effects of ID on
aerobic capacity, endurance, energetic efficiency, and work
productivity.29 According to the experimental data, iron
treatment improves the impaired electron transport of
myocardial mitochondria and exercise performance in iron-
deficient rats,30,31 indicating its role as an important
cofactor in energy metabolism. In addition, long-term iron-
deficiency anemia can induce cardiac maladaptation,
including cardiac dilatation and myocardial fibrosis.32 For the
patients with chronic HF and ID (with or without anemia),
iron therapy has been shown to improve quality of life and
exercise tolerance.11 In Ferinject Assessment in Patients With
Iron Deficiency and Chronic Heart Failure (FAIR-HF)25 and
Ferric Carboxymaltose Evaluation on Performance in Patients
With Iron Deficiency in Combination With Chronic Heart
Failure (CONFIRM-HF)26 studies, significant improvements
were observed with intravenous iron preparation for 6-minute
walk distance, quality-of-life assessment, and NYHA func-
tional class. Moreover, hospitalizations for worsening HF are
always related to unfavorable clinical outcomes. Therefore,
our finding that additional iron use significantly reduced the
risk of hospitalization for HF, consistent with the results of
the CONFIRM-HF26 study, is physiologically and clinically
credible.

Figure 5. Forest plot showing the impact of iron supplementation on severe adverse events (defined as deaths, all-cause hospitalizations, and life-
threatening events) in patients with HF and ID.
Qian et al.
Iron Supplementation for HF and Iron Deficiency
Table 2. Sensitivity analysis
Hospitalization for HFy All-cause mortalityy
Study* or
effect model OR (95% CI) P OR (95% CI)
Toblli23 0.30 (0.17-0.54) < 0.001 NA
Okonko21 0.27 (0.15-0.49) < 0.001 0.79 (0.40-1.55)
Arutyunov24 NA NA 0.81 (0.41-1.59)
Anker25 0.24 (0.12-0.49) < 0.001 0.88 (0.41-1.87)
Ponikowski26 0.29 (0.12-0.70) 0.006 0.73 (0.23-1.88)
Random 0.29 (0.16-0.52) < 0.001 0.81 (0.42-1.56)
CI, confidence interval; HF, heart failure; NA, not assessed; OR, odds ratio.
* Removing each study (author’s name) one at a time.
y
Evaluating the overall estimate of each endpoint for the remaining studies or random-effects model.
There is a trend towards lower mortality in iron-treated
patients although not reaching statistical significance, as
shown in the present analysis. Nevertheless, it should be
mentioned that we observed that only 4.3% of the overall
cohort experienced this outcome that is mainly due to the
small sample size and short follow-up duration in all of the
included trials, which may be inadequate to detect potential
differences. To evaluate the composite prognostic effects, we
pooled the combined endpoint of hospitalization for HF and
death and found that iron supplementation was related to a
significant reduction in the risk of this composite outcome.
The positive finding further confirmed the prognostic benefit
of additional iron therapy in patients with chronic HF
and ID.
We did not observe that intravenous iron supplementation
was associated with an increased risk of AEs, including car-
diovascular, nervous system, and gastrointestinal disorders.
Conversely, intravenous iron seems to result in fewer severe
AEs, but this statistically significant benefit was not well
established because of vague results in the sensitivity analysis.
The FAIR-HF25 and CONFIRM-HF26 studies are 2 large-
scale RCTs that may drive the results of our meta-analysis.
Both of them showed benefit in terms of a reduction in HF
hospitalizations, or approximately the same magnitude.
However, by removing each one of them in sensitivity anal-
ysis, we did not find statistically substantial changes in overall
results. The etiology of HF does not seem to be an important
confounder for the pooled estimates, because the high pro-
portions (approximately 65%-80%) of patients with ischemic
causes of HF are similar between iron and control groups in
all included trials. Moreover, in the 2 large-scale RCTs,25,26 a
consistent benefit regarding the 6-minute walk distance was
observed in patients with HF with and without ischemic
causes.
There are extremely limited data about the efficacy and
safety of oral iron in treating HF. Despite being a relatively
cheap preparation, oral iron is poorly absorbed, particularly in
patients with chronic diseases, such as chronic HF, and is not
well tolerated because of adverse gastrointestinal effects.33,34
In a recent study with a small sample size, improvement in
VO2max was found with intravenous iron but not oral iron.35
In addition, a meta-analysis indicates that intravenous iron is
indeed more effective than oral iron in chronic kidney dis-
ease.36 Thus, intravenous iron may be superior to the oral iron
in terms of clinical efficacy and safety.
The therapy for patients with HF with ID should also be
optimized. Regarding this issue, a proper definition of ID is of
great importance. As mentioned above, ID was defined as
7
Combined endpointy Severe adverse eventsy
P OR (95% CI) P OR (95% CI) P
NA 0.52 (0.31-0.85) 0.009 NA NA
0.49 0.45 (0.28-0.74) 0.002 0.50 (0.33-0.74) < 0.001
0.54 NA NA 0.50 (0.33-0.75) < 0.001
0.73 0.44 (0.25-0.79) 0.005 0.75 (0.42-1.35) 0.34
0.59 0.43 (0.20-0.92) 0.03 0.37 (0.22-0.63) < 0.001
0.52 0.49 (0.30-0.80) 0.004 0.51 (0.31-0.85) 0.009
ferritin < 100 ng/mL (absolute ID) or TSAT < 20% in one
included study. But when ferritin is between 100 and 300 ng/
mL, the diagnosis of ID is complex and only functional ID
can be diagnosed (with TSAT < 20%).37 Definitions con-
cerning absolute and functional ID should thus be combined,
which has been applied in 3 late trials we included. Agents for
treating HF including b-blockers, angiotensin-converting
enzyme inhibitors and/or angiotensin receptor blockers, and
diuretics were widely used in the included trials. The high
proportions of patients receiving these recommended HF
medications, comparable to what was seen in large HF trials,
were not significantly different across the studies, suggesting
their critical role in the management of HF. Nevertheless,
because of the negative prognostic value of ID, it is insuffi-
cient that only using these agents to treat patients with HF
with the comorbidity. Therefore, intravenous iron should be
considered for optimal treatment of patients with HF who are
iron deficient.
Although advances in the management of HF have made
great contributions to improving the outcomes of systolic HF,
postdischarge mortality and readmission rates in patients with
HF remain unacceptably high.38 Moreover, the rate of reho-
spitalization continues to rise and approach 30% within 60 to
90 days of discharge.39 What’s worse is that the mean cost of
HF-related hospitalization has imposed a huge economic
burden on health care resources.40 Intravenous iron prepara-
tion, such as ferric carboxymaltose, has been estimated to be
cost-effective in treating patients with HF and ID.41 There-
fore, the results of our meta-analysis showing that iron sup-
plementation was associated with a significant reduction in
hospitalization because of HF are of particular clinical
significance.
There are some limitations in our meta-analysis. First, we
did not consider the influences of the iron preparation dose,
the hemoglobin level, and the NYHA class on therapeutic
effects because of the absence of relevant data. Second,
because only 2 trials administered ferric carboxymaltose, 2
trials administered iron sucrose, and 1 trial administered both
without some relevant data, analyzing the class-specific effects
of iron preparations on clinical outcomes is inappropriate.
Third, the sample size and follow-up duration in these clinical
trials were small and short, respectively, resulting in a lack of
statistical power; hence, a larger sample size and a longer
duration of follow-up may be needed to observe significant
changes in prognostic endpoints. Forth, it must be mentioned
that all included trials enrolled patients with symptomatic HF
with an LVEF below 45%, so generalization of our findings
should be used with caution.
8 Canadian Journal of Cardiology
Conclusions
Based on the results of our meta-analysis, iron supple-
mentation significantly reduced risk of (a) rehospitalizations
because of HF and (b) the combined endpoint of rehospi-
talizations for HF and death, without increased adverse events
in patients with symptomatic systolic HF and ID. However,
the current data are inadequate to make a conclusive deter-
mination upon total mortality. Additional well-designed and
large RCTs with long-term follow-up duration are certainly
needed to confirm our findings especially regarding mortality,
in terms of the effects of different iron preparations and doses,
different hemoglobin levels and NYHA classes, and different
baseline LVEF values.
Funding Sources
This work was supported by the National Natural Science
Foundation of China (Grant no. 81270304).
Disclosures
The authors have no conflicts of interest to disclose.
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Supplementary Material
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article, visit the online version of the Canadian Journal of
Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10.
1016/j.cjca.2015.06.009.