Journal of the American College of Cardiology Vol. 52, No.

10, 2008
© 2008 by the American College of Cardiology Foundation ISSN 0735-1097/08/$34.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2008.04.061

Heart Failure

Anemia and Mortality in Heart Failure Patients

A Systematic Review and Meta-Analysis
Hessel F. Groenveld, MD,* James L. Januzzi, MD, FACC,† Kevin Damman, MD,*
Jan van Wijngaarden, MD, PHD,‡ Hans L. Hillege, MD, PHD,*
Dirk J. van Veldhuisen, MD, PHD, FACC,* Peter van der Meer, MD, PHD†
Groningen and Deventer, the Netherlands; and Boston, Massachusetts

Objectives The aim of this study was to assess the effect of anemia on mortality in chronic heart failure (CHF).

Background Anemia is frequently observed in patients with CHF, and evidence suggests that anemia might be associated
with an increased mortality.

Methods A systematic literature search in MEDLINE (through November 2007) for English language articles was per-
formed. In addition, a manual search was performed. We included cohort studies and retrospective secondary
analyses of randomized controlled trials whose primary objective was to analyze the association between ane-
mia and mortality in CHF. Of a total of 1,327 initial studies, we included 34 studies, comprising 153,180 pa-
tients. Information on study design, patient characteristics, outcome, and potential confounders were extracted.

Results Anemia was defined by criteria used in the original articles. Of the 153,180 CHF patients, 37.2% were anemic.
After a minimal follow-up of 6 months, 46.8% of anemic patients died compared with 29.5% of nonanemic pa-
tients. Crude mortality risk of anemia was odds ratio 1.96 (95% confidence interval: 1.74 to 2.21, p ⬍ 0.001).
Lower baseline hemoglobin values were associated with increased crude mortality rates (r ⫽ ⫺0.396, p ⫽
0.025). Adjusted hazard ratios showed an increased adjusted risk for anemia (hazard ratio 1.46 [95% confi-
dence interval: 1.26 to 1.69, p ⬍ 0.001]). Subgroup analysis showed no significant difference between mortality
risk of anemia in diastolic or systolic CHF.

Conclusions Anemia is associated with an increased risk of mortality in both systolic and diastolic CHF. Anemia should,
therefore, be considered as a useful prognosticator, and therapeutic strategies aimed to increase hemoglobin
levels in CHF should be investigated. (J Am Coll Cardiol 2008;52:818–27) © 2008 by the American College of
Cardiology Foundation

Anemia is frequently observed in patients with chronic heart
failure (CHF) (1–5). Prevalence of anemia depends both on
the severity of CHF and diagnostic criteria used to define it,
but may be as high as 50% in selected patient cohorts (3,6). Of
note, anemia is not only prevalent in the CHF population, but
several studies in different patient populations found an asso-
ciation with anemia, impaired cardiac function, more health
care utilization, and morbidity (1,7–11). In addition, numerous
studies have assessed associations between anemia and mortal-
ity in CHF. Although most studies have documented higher
mortality rates in anemic CHF patients (1,3,12–17), some
From the *Department of Cardiology, University Medical Center Groningen,
Groningen, the Netherlands; †Division of Cardiology, Department of Medicine,
Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
and the ‡Department of Cardiology, Deventer Hospital, Deventer, the Netherlands.
Dr. Damman is supported by the Netherlands Heart Foundation (grant 2006B157).
Dr. van Veldhuisen is a Clinical Established Investigator of the Netherlands Heart
Foundation (D97-017). Dr. van der Meer is supported by the Dutch Scientific
Organization (Rubicon grant: 825-07-011).
Manuscript received February 19, 2008; revised manuscript received April 23,
2008, accepted April 28, 2008.
studies report the absence of an adverse effect of anemia on
mortality in CHF (4,18 –20). Therefore, better understanding
of the risk associated with the presence of anemia is necessary.
Elucidating the contribution of anemia to mortality may lead
to a more accurate risk profiling in CHF patients, especially
since several treatment options for anemia exist including
erythropoietin (EPO) and iron therapy (21,22). Ultimately,
this may lead to more effective therapeutic strategies from a
risk-benefit perspective in heart failure patients.
We, therefore, performed a rigorous systematic review
and meta-analysis of published literature to more compre-
hensively assess the effect of anemia on mortality in CHF.
In addition, we explored whether subgroups of anemic
patients were at particularly high mortality risk.
Methods
Search strategy. We adhered to the MOOSE (Meta-
analysis Of Observational Studies in Epidemiology) study
guidelines as previously published (23). To identify all relevant

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studies, we performed a literature search in MEDLINE
accessed by PubMed (1966 through November 2007). Two of the
authors (H.G. and P.v.d.M.) developed a search strategy. To
identify heart failure patients and anemia, we used both the
Medical Subject Heading term (MeSH) and text word search
(Table 1). In addition, we identified potentially relevant
studies using a manual search of references lists from all
eligible studies and review articles. We consulted experts in
the field and searched the Institute for Scientific Informa-
tion Web of Sciences for publications that cited key
publications.
Study selection. We included cohort studies and retro-
spective secondary analyses of randomized controlled trials
whose primary objective was to analyze the association
between anemia and mortality in CHF. Titles and abstracts
of all articles were evaluated and rejected on initial screen if
they: 1) included subjects other than CHF patients; 2) had
no evaluation of hemoglobin (Hb) or hematocrit (Ht) levels;
3) did not include all-cause mortality as outcome; 4) were
published only in abstract form; 5) included patients ⱕ18
years old; 6) had follow-up of ⬍6 months; or 7) were
published in another language than English.
After obtaining full reports of candidate studies, the same
reviewers independently assessed eligibility. Differences in
data between the 2 reviewers were solved by rereviewing
corresponding articles, and the final set was agreed on by
consensus. For studies in which not all data were published,
or data was insufficient, authors were addressed and asked
for additional information (3,4,12,19,24 –26).
Quality assessment and data abstraction. Each study was
evaluated on quality according to the guidelines provided by
the United States Preventive Task Force (27) and published
recommendations (28). The following characteristics were
assessed: 1) duration of follow-up ⬎12 months; 2) reporting
loss of follow-up; 3) adjustment of possible confounders in
multivariate analysis; 4) definition of anemia; 5) full speci-
fication of outcome; 6) study sample representative for
mentioned population; 7) full specification of clinical and
demographic variables; 8) explanation of sample selection;
9) temporality (Hb measured at baseline, not at time of
outcomes assessment); and 10) clear inclusion and exclusion
criteria. Studies were graded as poor quality if they met ⬍5
Terms Used in the Search Query
Table 1 Terms Used in the Search Query
Text words
Congestive heart failure, CHF, anemia, anaemia, hemoglobin, haemoglobin,
Hb, Hgb, hematocrit, haematocrit, Ht, Hct
MeSH terms
Heart failure, congestive; anemia; hemoglobin; hematocrit
Title and abstract search
Hemoglobins
Limits
English language
CHF ⫽ congestive heart failure; MeSH ⫽ Medical Subject Heading.
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Groenveld et al. 819
Anemia and Mortality in Heart Failure
criterion, fair if they met 5 to 7 Abbreviations
criteria, and good if they met ⱖ8 and Acronyms
criteria.
CHF ⴝ chronic heart failure
Statistical analysis. Random
CI ⴝ confidence interval
effects meta-analysis was con-
EPO ⴝ erythropoietin
ducted to estimate the magni-
tude of risk associated with ane- ESP ⴝ erythropoiesis-
stimulating protein
mia and all-cause mortality, as
measured by crude mortality Hb ⴝ hemoglobin
risks and unadjusted odds ratios HR ⴝ hazard ratio
(ORs). Where available, adjusted Ht ⴝ hematocrit
hazard ratios (HRs) were ex- OR ⴝ odds ratio
tracted from Cox regression WHO ⴝ World Health
analysis. Adjusted risk estimates Organization
included those components as
published in final multivariate
models for each study including confounding sociodemo-
graphic and clinical covariates. We performed tests of
heterogeneity between studies using a standard chi-square
test and I2 statistic. When heterogeneity was found to be
significant, pooled estimates based on random effects mod-
els were reported. To examine sources of heterogeneity, we
conducted meta-regression analysis. Bias in published stud-
ies was assessed using a funnel plot of study results against
study precision. We tested symmetry of the funnel plot by
the Egger’s test. Subgroup analysis was pre-defined for
systolic versus diastolic CHF. Statistical significance was set
at p ⬍ 0.05, and all statistical analyses were performed using
Stata 9.0 (Stata Corp., College Station, Texas).
Results
Description of included studies. The electronic search
retrieved 1,327 eligible studies. Nonelectrical search identi-
fied 4 additional studies. On initial screening, 1,142 were
rejected, based on title. Of the 185 screened abstracts, 56
studies were retrieved for detailed evaluation. Eventually 34
studies were included in this meta-analysis (Fig. 1). Sec-
ondary analysis of the Val-HeFT (Valsartan Heart Failure
Trial) study was described in 2 separate manuscripts: Anand
et al. (29) and Maggioni et al. (5). Crude mortality data
were not published by Anand et al. (29), and for this reason
this study was excluded and the data of Maggioni et al. (5)
was used. In addition, 1 article described the effect of
anemia from 2 different studies (5). Both studies in this
published report were analyzed separately for the meta-
analysis. The 34 included studies described a total of
153,180 patients (1,3–20,24 –26,30 – 41). Characteristics of
the included studies are listed in Table 2, characteristics of
study populations are listed in Online Tables 1 and 2. Ten
different definitions of anemia were used in the included
studies. The World Health Organization (WHO) defini-
tion (Hb ⬍13.0 g/dl for males and Hb ⬍12.0 g/dl for
females) was used in the majority of the studies. Table 3
displays the different definitions of anemia in the included
studies. Anemia, as defined in the original articles, was
 820 Groenveld et al.
Anemia and Mortality in Heart Failure
Figure 1 Flow Chart for Study Selection
CHF ⫽ chronic heart failure; Hb ⫽ hemoglobin.
present in 37.2% of the CHF patients. Mean Hb from the
studies ranged from 12.2 to 14.0 g/dl. Mean Ht values
ranged from 36.6% to 42.7%.
Meta-analysis findings. Among the 34 studies, mean
follow-up ranged from a minimum of 6 months to a
maximum of 5 years. Crude mortality data were available in
33 studies. In one study, only the adjusted HR was available,
whereas the unpublished crude mortality data were lost after
hurricane Katrina (25). Analysis of the crude mortality
revealed that 26,687 (46.8%) anemic patients died com-
pared with 28,274 (29.5%) nonanemic patients. This trans-
lated into an unadjusted mortality risk of OR 1.96 (95%
confidence interval [CI]: 1.74 to 2.21, p ⬍ 0.001) in anemic
CHF patients compared with that in nonanemic CHF
patients (Fig. 2). When the 2 largest studies (Go et al. [3]
and Kosiborod et al. [4]) were excluded, the mortality risk of
anemia was identical (OR: 1.95, 95% CI: 1.78 to 2.14, p ⬍
0.001). There was no evidence for publication bias. The
funnel plot did not show asymmetry (Fig. 3), which was
confirmed by the Egger’s test (p ⫽ 0.93). We found a
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significant heterogeneity between included studies (I2 ⫽
92.4%, p ⬍ 0.001). Meta-regression analysis was performed
using sociodemographic variables, medical history, drug use,
and laboratory data as parameters. In this sensitivity analy-
sis, excluding studies not adhering to the WHO definition
of anemia, no heterogeneity was observed (I2 ⫽ 36.5%, p ⫽
NS), yet the mortality risk remained (OR: 2.22, 95% CI:
2.04 to 2.42, p ⬍ 0.001). In addition, we found an inverse
interstudy relationship between serum creatinine levels and
the effect of anemia on mortality. The effect of anemia on
mortality declined with higher serum creatinine levels.
When assessing the gradual effect of baseline Hb values on
mortality, we found a linear trend between baseline Hb
measurements and mortality rates. Lower baseline Hb
values were associated with increased annual mortality rates
(r ⫽ ⫺0.396, p ⫽ 0.025) (Fig. 4).
Confouding factors. In 127,437 patients (83.1% of the
total included patients), reported mortality risks were ad-
justed for several sociodemographic and clinical covariates.
Potential confounders that were adjusted for in the original
reports are shown in Table 4. In all but one study, age and
renal function were considered as potential confounders
(this study included 178 patients) (33). When mortality risk,
estimated by adjusted HR, was combined, anemia remained
an independent predictor of mortality HR 1.46 (95% CI:
1.26 to 1.69, p ⬍ 0.001).
Subgroup analysis. In the subgroup analysis, we assessed
the difference between mortality risk of anemia in patients
with systolic or diastolic CHF. Table 5 displays the defini-
tions of systolic and diastolic CHF used in the original
articles. Studies or substudies in patients with only diastolic
CHF included 20,924 patients of which 5,957 (28.5%)
patients died. In studies or substudies including only pa-
tients with systolic CHF, 40,025 patients were included, of
which 12,423 (31.0%) died. The mortality risk associated
with the presence of anemia was not significantly different
between patients with systolic CHF (OR: 1.96, 95% CI:
1.70 to 2.25, p ⬍ 0.001) and diastolic CHF (OR: 2.09, 95%
CI: 1.53 to 2.86, p ⬍ 0.001).
Discussion
This is the first meta-analysis to address the relationship
between anemia and mortality in patients with CHF. In our
analysis, which examined more than 150,000 subjects,
anemia was frequently observed, found in over one-third of
CHF patients. Presence of anemia in CHF patients is
associated with an increased mortality risk in patients with
systolic as well as diastolic heart failure. The adverse effect
we found is substantial and significant. When assessing the
mortality risk by using multivariate analyses, anemia re-
mains an independent risk factor for mortality in CHF
patients.
Prevalence. In prior studies, it is observed that CHF is
often accompanied by anemia. A wide range of anemia
prevalence in CHF has been reported, ranging from 7% to
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September 2, 2008:818–27 Anemia and Mortality in Heart Failure

Study Characteristics
Table 2 Study Characteristics

Author (Ref. #), Year Follow-Up n Patients End Points Major Exclusion Criteria Study Design Study
Al-Ahmad et al. (12), 2001 33.4 months 6,360 CHF, LVEF ⬍35%, Mortality Recent MI, unstable angina, Secondary analysis of Good
age 21 to 81 yrs sCR ⬎2.5 mg/dl clinical trial
(SOLVD)
Horwich et al. (9), 2002 5 yrs 1,061 Referred for heart Mortality LVEF ⬎40%, NYHA class Retrospective, Good
transplantation ⬍III, no initial Hb, “dry” observational,
evaluation weight, or adequate single-center
follow-up cohort study
McClellan et al. (38), 2002 ⬎2 yrs 633 Discharge diagnosis Mortality Dialysis, death during Retrospective, Good
of HF (ICD-9-CM) index hospitalization, observational,
missing records multicenter cohort
study
Tanner et al. (32), 2002 ⬎6 months 193 Outpatient HF clinic at Mortality, heart Secondary anemia, Retrospective, Good
university hospital transplantation hemodialysis, observational,
coronary intervention single-center
last 3 months cohort study
Kalra et al. (26), 2003 3 yrs 531 HF Mortality — Prospective Fair
observational,
single-center
cohort study
Kosiborod et al. (39), 2003 1 yr 2,281 Principal discharge Mortality, Severe AoS or MiS, HF due Retrospective, Good
diagnosis of HF hospitalization to acute illness, missing observational,
(ICD-9-CM), Htc values, in-hospital multicenter chart
age ⬎65 yrs mortality review
Mozaffarian et al. (37), 2003 15 months 1,130 LVEF ⬍30% and Mortality MI; unstable angina; stroke Secondary analysis of Good
NYHA class IIIB or or revascularization; multicenter clinical
IV HF symptoms severe pulmonary, trial (PRAISE)
renal, or hepatic disease,
sCR ⬎3.0 mg/dl
Kerzner et al. (40), 2003 25 months 367 Primary discharge Mortality — Retrospective, Fair
diagnosis of HF observational,
single-center chart
review
Szachniewicz et al. (33), 2003 529 days 176 Admitted for HF Mortality Anemia due to known Prospective, Good
secondary cause observational,
single-center,
cohort study
Sharma et al. (34), 2004 551 days 3,044 NYHA II to IV, Mortality Severe valvular disease, Secondary analysis of Good
LVEF ⱕ40%, recent PTCA, CABG, multicenter clinical
age ⬎60 yrs MI, or unstable angina, trial (ELITE II)
sCR ⬎220 ␮mol/l
Anand et al. (1), 2004 12.7 months 912 NYHA II to IV, Mortality, Surgically correctable Secondary analysis of Good
LVEF ⬍30%, hospitalization causes of HF, other clinical trial
age 18 to 55 yrs serious illness, recent or (RENAISSANCE)
planned revascularization
van der Meer et al. (30), 2004 1,100 days 74 Mild-to-severe CHF Mortality MI, CVA, severe renal Retrospective, Good
failure, valvular disease, observational,
isolated systolic single-center
dysfunction cohort study
Ezekowitz et al. (24), 2005 962 days 791 Referred for Mortality Missing Hb values Prospective Good
assessment and observational,
management single-center
of CHF cohort study
Maggioni et al. (5), Val-HeFT 23 months 5,010 Symptomatic HF Mortality, time to Rapidly deteriorating HF, Secondary analysis of Good
2005 (NYHA ⱖII), death, first acute MI, CAD likely to a randomized
clinically stable morbid event require intervention, clinical trial
unstable angina, recent (Val-HeFT)
CVA, sCR ⬎2.5 mg/dl
Maggioni et al. (5), IN-CHF 1 yr 2,411 Diagnosis of HF Mortality — Retrospective, Good
2005 according to observational,
European Society multicenter cohort
of Cardiology study
Gardner et al. (19), 2005 554 days 182 Advance HF, referred Mortality Age ⬍16 yrs, pregnancy, Prospective, Fair
for cardiac Tx known malignancy observational,
assessment single-center cohort
study

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Continued
Table 2 Continued

Author (Ref. #), Year Follow-Up n Patients End Points Major Exclusion Criteria Study Design Study
Rosolova et al. (35), 2005 4 yrs 508 Suspected HF Mortality — Retrospective, Fair
observational,
multicenter cohort
study
Grigorian et al. (14), 2006 1.5 yrs 205 Admitted to tertiary Mortality LVEF ⬍50% Retrospective, Good
center for CHF observational,
Single-center
cohort study
Kosiborod et al. (4), 2005 1 yr 50,405 Discharge diagnosis Mortality, Patients without documented Retrospective, Good
of HF hospitalization HF on admission, age observational,
for HF ⬍65 yrs, hemodialysis, multicenter cohort
severe Aos, MiS, study
Ralli et al. (16), 2005 1 yr 264 Referred to a Mortality ACS or myocarditis, Retrospective, Good
university hospital LVEF ⬎40% observational,
for HF single-center
management or cohort study
heart Tx
O’Meara et al. (36), 2006 37.7 months 2,653 Symptomatic (NYHA II Mortality sCR ⬎265 ␮mol/l, Secondary analysis of Good
to IV) HF, for at symptomatic HT, MI, CVA clinical trial
least 4 weeks, (CHARM)
age ⬎18 yrs
Felker et al. (13), 2006 3.6 yrs 4,951 Symptomatic HF Mortality Primary valvular heart Retrospective, Fair
(NYHA II) patients disease or congenital observational,
undergoing cardiac heart disease single-center
catheterization cohort study
Terrovitis et al. (31), 2006 2 yrs 160 Symptomatic HF Mortality Recent MI or CABG, Secondary analysis of Good
(NYHA II to IV), unstable angina, multicenter,
LVEF ⱕ35% anticipated cardiac prospective clinical
surgery, sCR ⬎3 mg/dl trial
Hebert et al. (25), 2006 436 days 410 LVEF ⱕ40%, enrolled Mortality Missing baseline values Retrospective, Fair
in chronic HF of Hb, sCR observational,
disease single-center
managemant cohort study
program
Formiga et al. (18), 2006 1 yr 103 Admitted for Mortality, Chronic advanced disease, Prospective, Good
symptomatic, hospitalization COPD, advanced renal observational,
previously for HF failure hemodialysis, single-center
unknown HF in-hospital mortality cohort study
Newton and Squire (15), 2006 1,257 days 528 Discharge diagnosis of Mortality Insufficient evidence of new Retrospective, Good
HF, without previous diagnosis of CHF observational,
hospitalization for single-center chart
HF review
Komajda et al. (10), 2006 58 months 2,996 NYHA class II to IV Mortality, Recent change of Secondary analysis of Good
and LVEF ⱕ35% hospitalization treatment, requirement clinical trial
of IV medication (COMET)
Go et al. (3), 2006 2 yrs 59,772 Diagnosed with CHF Mortality, — Retrospective Good
hospitalization observational,
longitudinal cohort
study
Berry et al. (7), 2006 814 days 519 Diagnosed with CHF Mortality, Primary or secondary Retrospective, Fair
or a treatment hospitalization, diagnosis of acute MI observational,
for CHF HF single-center chart
hospitalization review
de Silva et al. (42), 2006 531 days 955 LVEF ⬍45%, CHF Mortality Pregnancy, dialysis, Prospective, Fair
enrolled in a disorders resulting in observational,
community-based anemia single-center
program cohort study
Maraldi et al. (11), 2006 12 months 567 Diagnosed with HF, Mortality, Physical disability at Secondary analysis of Fair
age ⬎65 yrs physical hospital discharge, longitudinal
disability dementia, or severe observational study
cognitive impairment
Elabbassi et al. (8), 2006 1.3 yrs 437 Systolic or diastolic Mortality, No complete follow-up Prospective Good
CHF hospitalization, observational,
ED visit single-center
cohort study

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Continued
Table 2 Continued

Author (Ref. #), Year Follow-Up n Patients End Points Major Exclusion Criteria Study Design Study
Varadarajan et al. (6), 2006 5 yrs 2,246 Primary discharge of Mortality, CHF excluded with Retrospective, Good
diagnosis of CHF hospitalization, Framingham criteria, observational,
ED visit no ECG single-center,
chart review
Schou et al. (17), 2007 30 months 345 Systolic HF Mortality — Prospective, Good
(LVEF ⬍45%) observational,
single-center
cohort study

ACS ⫽ acute coronary syndromes; AoS ⫽ aortic valve stenosis; CABG ⫽ coronary arterial bypass graft surgery; CAD ⫽ coronary artery disease; CHARM ⫽ Candesartan in Heart Failure trial; CHF ⫽ chronic
heart failure; COMET ⫽ Carvedilol Or Metoprolol European Trial; COPD ⫽ chronic obstructive pulmonary disease; CVA ⫽ cerebral vascular accident; ECG ⫽ electrocardiogram; ED ⫽ emergency department;
ELITE II ⫽ Losartan Heart Failure Survival Study; F/U ⫽ follow-up; Hb ⫽ hemoglobin; HF ⫽ heart failure; HT ⫽ hypertension; Htc ⫽ hematocrit; ICD-9-CM ⫽ International Classification of Diseases, 9th
Revision, Clinical Modification; IN-CHF ⫽ Italian Network—Congestive Heart Failure trial; IV ⫽ intravenous; LVEF ⫽ left ventricular ejection fraction; MI ⫽ myocardial infarction; MiS ⫽ mitral valve stenosis;
NYHA ⫽ New York Heart Association functional class; PRAISE ⫽ Prospective Randomized Amlopidine Survival Evaluation trial; PTCA ⫽ percutaneous transluminal coronary angioplasty; RENAISSANCE ⫽
Randomized Etanercept North American Strategy to Study Antagonism of Cytokines; sCR ⫽ serum creatinine; Tx ⫽ heart transplantation; Val-HeFT ⫽ Valsartan Heart Failure Trial.

over 50% (1– 4,10,17,32,35). This range can be attributed to
multiple factors, including the use of multiple definitions of
anemia. The WHO criteria was used in the majority of
studies. In addition, administrational codes or arbitrary
boundary values to define anemia were also used. Studies
defining anemia with administrative codes (such as Inter-
national Classification of Diseases, 9th Revision, codes)
have clear limitations. The use of this coding system solely
relies on physicians to consider anemia as a possible
diagnosis leading to an underestimation of the preva-
lence. Therefore, we excluded in this meta-analysis stud-
ies without measurements of actual Hb or Ht values. This
resulted in the exclusion of only one study (2). Results of
the current meta-analysis clearly indicate the need for
standardized definitions of anemia in CHF patients. The
definition of anemia appeared to be a major source of
heterogeneity. However, despite different definitions of
anemia in the present meta-analysis, the association with
mortality was robust, using different analysis strategies.
Definitions of Anemia Used in the Original Articles
Table 3 Definitions of Anemia Used in the Original Articles
Pathophysiology. It is tempting to speculate about the
mechanisms behind the increased mortality risk observed in
anemic CHF patients. Anemia may lead to an increased
work load, resulting from an increased heart rate and stroke
volume (32,42,43). In response to the increased workload,
the heart undergoes “remodeling,” marked by left ventricu-
lar hypertrophy and dilation. This eventually may lead to
CHF with an increased mortality risk. Also, renal failure, as
a common comorbidity in CHF, might be implicated in the
pathophysiology. CHF and renal failure are 2 entities that
are often seen together with prevalences ranging from 20%
to 40% (2,38,44 – 46). With meta-regression analysis, we
found an inverse interstudy relationship between serum
creatinine levels and the effect of anemia on mortality.
However, this result does not suggest that the mortality risk
declines with higher creatinine levels. It merely illustrates a
statistical decreasing effect of anemia on mortality with
increasing creatinine levels; the decline of the effect of
anemia on mortality can be the result of an increased

Definition of Anemia Author (Ref. #)

WHO Elabbassi et al. (8), Maraldi et al. (11), De Silva et al. (42), Go et al. (3), Komajda
et al. (10), Formiga et al. (18), Hebert et al. (25), O’Meara et al. (36), Felker et
al. (13), Ralli et al. (16), Grigorian Shamagian et al. (14), Rosolova et al. (35),
Gardner et al. (19), Ezekowitz et al. (24), van der Meer et al. (30), Kerzner et
al. (40), Mozaffarian et al. (37), Schou et al. (17)
Hb ⬍11.5 g/dl Kalra et al. (26)
Hb ⬍12.0 g/dl Varadarajan et al. (6), Anand et al. (1), Szachniewicz et al. (33), Tanner et al. (32)
Hb ⬍12.3 g/dl Horwich et al. (9)
Hb ⬍13.0 g/dl Sharma et al. (34)
Hb ⬍11.0 g/dl in women Maggioni et al. (Val-HeFT) (5), Maggioni et al. (IN-CHF) (5)
and Hb ⬍12.0 g/dl in men
Hb ⬍11.5 g/dl in women Berry et al. (7), Newton and Squire (15)
and ⬍13.0 g/dl in men
Ht ⬍35% Al-Ahmad et al. (12)
Ht ⱕ37% Kosiborod et al. 2003 (39), McClellan et al. (38)
Ht ⬍37% Terrovitis et al. (31)
Ht ⬍37% in women and Kosiborod et al. 2005 (4)
⬍40% in men

Ht ⫽ hematocrit; WHO ⫽ World Health Organization definition of anemia, Hb ⬍12.0 g/dl in women, ⬍13.0 in men; other abbreviations as in Table 2.

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Figure 2 Risk of All-Cause Mortality of Anemic Versus Nonanemic CHF Patients

CHF ⫽ chronic heart failure. CI ⫽ confidence interval.

mortality risk caused by renal failure (47). From a patho-

physiological standpoint, CHF can also cause renal failure
due to a decreased cardiac output reducing renal perfusion
(i.e., forward failure); subsequent renal failure may lead to
decreased endogenous EPO levels and may ultimately
induce anemia, leading to an increased cardiac workload
completing the vicious circle. Recently this has been called
the “cardio-renal-anemia syndrome” (48).
Findings from intervention studies. Considering the in-
creased mortality risk caused by anemia, in heart failure as
well as renal failure, trials have been designed in which
patients receive erythropoiesis-stimulating proteins (ESPs)
to increase Hb levels. The first intervention study to address
the efficacy of EPO in CHF patients was performed by
Silverberg et al. (49) in 32 patients. Correction of anemia
with EPO and intravenous iron led to a significant increase
Figure 3 Funnel Plot for Publication Bias
in left ventricular ejection fraction and decrease in New
York Heart Association functional class, which was re- OR ⫽ odds ratio.
flected by almost 90% reduction in the number of hospital-

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 JACC Vol. 52, No. 10, 2008 Groenveld et al. 825
September 2, 2008:818–27 Anemia and Mortality in Heart Failure

Definitions
Diastolic HFofUsed
Systolic
in the
andOriginal Articles
Definitions of Systolic and
Table 5
Diastolic HF Used in the Original Articles

LVEF (%)
Systolic CHF
Mozaffarian et al. (37), Anand et al. (1) ⬍30
Komajda et al. (10), Terrovitis et al. (31) ⬍35
Sharma et al. (34), Ralli et al. (16), Maggioni et al. (5), ⬍40
Kerzner et al. (40), Kosiborod et al. (4), O’Meara et al. (36),
Felker et al. (13)
Schou et al. (17) ⬍45
Diastolic CHF
Kerzner et al. (40), Kosiborod et al. (4), O’Meara et al. (36), ⬎40
Felker et al. (13)
Grigorian Shamagian et al. (14) ⬎50

Abbreviations as in Table 2.

nous thromboembolism and mortality associated with re-

Relationship Between Baseline
Figure 4
Hemoglobin and Annual Mortality
The area of each circle is proportional to the sample size in each cohort. The cen-
ter line shows the estimated mortality risk per year of lower baseline Hb values on
a continuous scale. The dotted lines represent the 95% confidence intervals.
izations. A similar study showed that EPO treatment
significantly increased peak oxygen consumption and exer-
cise duration in patients with moderate-to-severe CHF
(50). Recently, 2 substantially larger multicenter phase II
studies evaluated the effects of darbepoetin (a long-acting
ESP) on surrogate cardiovascular end points (51,52). Treat-
ment with darbepoetin was safe and effectively raised Hb.
Moreover, it significantly improved clinical status; however,
no significant improvement in exercise tolerance could be
observed.
However, recently several studies showed a potentially
harmful effect of ESP treatment in patients with kidney
disease and malignancies. A meta-analysis in patients with
cancer-associated anemia showed an increased risk in ve-
Potential Confounders of Included Studies
Table 4 Potential Confounders of Included Studies
combinant EPO and darbepoetin administration (53). Fur-
thermore, concerns about the cardiovascular safety of ESP
in patients with kidney disease have been raised. Two
separate studies showed that patients targeted to a higher
Hb level had an increased incidence of cardiovascular events
(54,55). However, in these studies, no placebo groups were
included. These studies were all performed in patients with
severe renal failure, and only a minority of patients suffered
from heart failure. Consequently, the results of the studies
mentioned in the preceding text cannot be extrapolated to
the CHF population.
Larger randomized studies are clearly needed to deter-
mine the impact on morbidity and mortality in CHF.
Currently, a large phase III morbidity and mortality trial,
the RED-HF (Reduction of Events with Darbepoetin
alfa in Heart Failure) trial (56), is being conducted to
answer the question whether the use of ESPs in anemic
heart failure patients is beneficial. Besides ESP, intrave-
nous iron treatment is another intervention modality in
anemic CHF patients. Recently, 2 trials appeared show-

Severity of
Author (Ref. #) Number of Patients Age Gender Renal Function Heart Failure Medical History Medication
Elabbassi et al. (8) 437 ⫻ ⫻ ⫻ ⫻ ⫻
Maraldi et al. (11) 567 ⫻ ⫻ ⫻ ⫻ ⫻
Berry et al. (7) 519 ⫻ ⫻ ⫻
Newton and Squire (15) 528 ⫻ ⫻ ⫻
Hebert et al. (25) 410 ⫻ ⫻ ⫻ ⫻ ⫻
Felker et al. (13) 4,951 ⫻ ⫻ ⫻ ⫻
Kosiborod et al. (4) 50,405 ⫻ ⫻ ⫻ ⫻ ⫻ ⫻
Maggioni-V et al. (5) 5,010 ⫻ ⫻ ⫻ ⫻ ⫻ ⫻
Maggioni-I et al. (5) 2,411 ⫻ ⫻ ⫻ ⫻ ⫻ ⫻
van der Meer et al. (30) 74 ⫻ ⫻ ⫻ ⫻ ⫻
Szachniewicz et al. (33) 176 ⫻
Mozaffarian et al. (37) 1,130 ⫻ ⫻ ⫻ ⫻ ⫻
Go et al. (3) 59,772 ⫻ ⫻ ⫻ ⫻ ⫻ ⫻
Kalra et al. (26) 531 ⫻ ⫻ ⫻
Schou et al. (17) 345 ⫻ ⫻ ⫻

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 826 Groenveld et al.
Anemia and Mortality in Heart Failure
ing that intravenous iron without ESPs increased Hb
levels in patients with CHF. Moreover, they showed an
improved exercise capacity and decreased NT-proBNP
levels (57,58). Further research is needed to study the
effect of intravenous iron on morbidity and mortality in
anemic CHF patients.
Study limitations. Limitations of meta-analyses include
differences in designs and populations used in included
trials, quality of studies, and heterogeneity (59). However,
the quality of all studies was graded according to published
guidelines and all met at least 7 of 12 criteria.
Evaluation of anemia was only at baseline in all
included studies. Tang et al. (60) recently reported a
study with serial hemoglobin measurements and showed
that persistent anemia has a larger effect on mortality
than transient anemia. No evaluation of Hb was per-
formed during the studies; thus, it remains unknown
whether anemia in the included studies was persistent or
transient. Furthermore, heterogeneity in our study is
substantial and can be attributed to differences in dura-
tion of follow-up, type of patients included, study design,
and definition of anemia. Definition of anemia was a
major cause of heterogeneity. When mortality risk was
assessed using studies that defined anemia by WHO
criteria, heterogeneity was no longer significant, while
the increased mortality risk caused by anemia remained.
Furthermore, our meta-analysis could not exclude resid-
ual confounding from studies in the adjusted analyses,
although most studies adjusted for many known major
confounders. However, this limitation emphasizes the
inability of our analysis to prove causality.
Previously, it has been argued that a larger meta-analysis
(e.g., ⬎1,000 events) is clinically more meaningful (59); our
study, which includes over 50,000 events, is therefore of
particular note. Besides the overall size, the individual
studies in the present analysis were of considerable size, with
14 including more than 1,000 patients. These strengths
make our findings all the more firm.
Conclusions
Anemia is present in one-third of the CHF population
and is an independent risk prognosticator for mortality in
subjects so affected, irrespective of a systolic versus
diastolic etiology of CHF. Further research is needed to
assess the effect of correcting anemia in CHF patients.
Reprint requests and correspondence: Dr. Peter van der Meer,
Cardiovascular Research Center, Massachusetts General Hospital,
Charles River Plaza, 185 Cambridge Street, Boston, Massachu-
setts 02114. E-mail: pvandermeer@partners.org.
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Key Words: heart failure y anemia y prognosis.
APPENDIX
For the Acknowledgments and supplementary Tables 1 and 2, please see
the online version of this article.