European Journal of Heart Failure 2006 8(1):54-57; doi:10.1016/j.ejheart.2005.05.004
© 2005 European Society of Cardiology
Anaemia and coronary artery disease severity in patients with heart failure
G. Michael Felker*,
Wendy Gattis Stough,
Linda K. Shaw and
Christopher M. O'Connor
Duke Clinical Research Institute PO Box 17969, Durham, NC 27715, USA
* Corresponding author. Tel.: +1 919 668 8919; fax: +1 919 668 7058. E-mail address: michael.felker{at}duke.edu
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Abstract
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Background: Anaemia is common in heart failure (HF) and associated with
higher mortality. Exacerbation of myocardial ischemia in patients
with heart failure, coronary disease, and anaemia patients has
been suggested as a potential mechanism underlying this association.
Aims: The aim of this study was to evaluate the hypothesis that greater CAD severity would exacerbate the adverse effects of anaemia in HF.
Methods: We examined data on patients with symptomatic heart failure (NYHA class 
II) undergoing coronary angiography between 1995 and 2003 (n=4951). Patients with primary valvular or congenital heart disease were excluded. Cox proportional hazards modeling was used to evaluate the relationship between coronary disease severity (as defined by no. of diseased vessels) and hemoglobin concentration.
Results and conclusions: In patients with symptomatic HF undergoing coronary angiography, we found an interaction between hemoglobin and CAD severity (p=0.003 for interaction). Contrary to our hypothesis, the mortality hazard associated with anaemia was greatest in patients without CAD and progressively lower with increasing CAD severity. These data suggest that anaemia may exert its effect on HF outcomes through mechanisms beyond simply the exacerbation of myocardial ischemia.
Key Words: Anaemia • Heart failure • Coronary artery disease • Survival
Received November 23, 2004; Revised March 16, 2005; Accepted May 5, 2005
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1. Background
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Anaemia is associated with impaired survival in patients with
heart failure, and pilot studies evaluating anaemia treatment
in heart failure have suggested the possibility of benefit
[1-6].
Although potential explanations for the interaction between
anaemia and survival in heart failure have been proposed, the
underlying mechanisms remain poorly understood
[7]. Since hemoglobin
level is a major determinant of oxygen carrying capacity and
heart failure is a state of impaired oxygen delivery, anaemia
may be particularly poorly tolerated in heart failure patients.
Other insults to myocardial oxygen delivery, such as the presence
of significant coronary artery disease (CAD), could potentiate
the adverse effects of anaemia in heart failure and lead to
impaired survival. This theoretical concern has lead to recommendations
for an arbitrary "transfusion trigger" (typically a hemoglobin
level <10 g/dl) in patients with significant cardiovascular
disease
[8,
9]. Whether more severe CAD is associated with greater
mortality in anaemic patients with heart failure has not been
previously investigated.
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2. Aims
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The aim of this study was to evaluate the hypothesis that the
impact of anaemia on mortality would be greater in heart failure
patients with more severe coronary artery disease.
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3. Methods
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Patient data was obtained from the Duke Databank for Cardiovascular
Diseases, which collects data on all patients undergoing diagnostic
cardiac catheterization at our institution. Patients were included
if they had symptomatic heart failure (NYHA
II) and had undergone
coronary angiography between 1995 and 2003. The diagnosis of
heart failure was based on the history and physical examination
of the treating physician. Patients were included without regard
to ejection fraction, but ejection fraction was adjusted for
in multivariable analyses. Patients with primary congenital
or valvular heart disease were excluded. Baseline clinical data
and long term follow-up were obtained as previously described
[10].
Baseline characteristics were described with medians or percentages as appropriate. Pearson's 
2 tests were used for group comparisons of unordered categorical variables and Wilcoxon's rank-sum tests were used for continuous measures. Survival curves were constructed using the method of Kaplan and Meier and compared using the log-rank test. Multivariable Cox proportional hazards analysis was used to adjust for baseline differences between groups. The possibility of a differential effect of anaemia in patients with varying CAD severity was evaluated using an interaction term in the Cox proportional hazards model (hemoglobin*CAD severity). The hemoglobin level immediately prior to the cardiac catheterization was used as the index hemoglobin. For the display of baseline characteristics, anaemia was defined using the WHO definition (hemoglobin <12 g/dl for women, and Hb <13 g/dl for men) [11]. In order to limit bias introduced by the use of an arbitrary definition of anaemia, hemoglobin was considered as a continuous variable in all analyses. In order to identify any potential non-linear relationship between hemoglobin and mortality (as has been proposed by other studies), patients were divided into quintiles of hemoglobin and adjusted hazard ratios computed for each quintile [12,13]. Heart failure etiology was defined using previously published criteria [14]. Coronary disease severity was quantified by the number of epicardial vessels with 75% stenosis (0, 1, 2, or 3). A p-value 
0.05 was used to indicate statistical significance for all comparisons.
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4. Results
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Four thousand nine hundred and fifty one patients met criteria
for the study. Using the WHO definition, anaemia was present
in 1946 (39%) and absent in 3005 (61%). The mean hemoglobin
in study cohort was 12.8 g/dl. Frequency plots of hemoglobin
levels for men and women are shown in
Fig. 1, and baseline characteristics
stratified by the WHO anaemia definition are shown in
Table 1.
Anaemic patients were more likely to be older, female, and to
have an ischemic etiology of heart failure and greater severity
of CAD (
p<0.001 for all comparisons). After adjustment for
baseline differences, both hemoglobin (adjusted HR=1.12 per
1 g/dl decrease in hemoglobin) and CAD severity (adjusted HR=1.15
per diseased vessel,
p<0.0001) were significant predictors
of worse survival. When hemoglobin was divided into quintiles,
we did not identify a "U shaped" relationship between hemoglobin
and mortality, although the hazard for death with hemoglobin
levels >12 g/dl was essentially flat (
Fig. 2).
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Fig. 2 Adjusted mortality hazard by quintiles of hemoglobin. Vertical bars represent 95% confidence intervals. The highest quintile of hemoglobin is set as the reference value (hazard ratio=1). Values displayed on the X-axis represent median hemoglobin values for each quintile.
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As we hypothesized, a statistically significant interaction
was identified between hemoglobin and CAD severity (
p=0.003
for interaction term). Contrary to our initial hypothesis, however,
the risk of morality associated with greater anaemia was highest
in patients without CAD (adjusted HR=1.19 per g/dl of hemoglobin)
and lowest in patients with 3 vessel disease (adjusted HR=1.07
per g/dl of hemoglobin). As shown in
Fig. 3, a "dose-response"
relationship was observed between the mortality hazard associated
with anaemia and increasing levels of CAD severity. This interaction
was seen whether defining hemoglobin as categorical (anaemic
vs. not) or continuous, and whether CAD was quantified as a
categorical (ischemic vs. non-ischemic etiology of heart failure)
or ordinal (number of diseased vessels).
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5. Limitations
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Our analysis is based on a cohort of patients with symptomatic
heart failure undergoing coronary angiography. We do not have
sufficiently detailed clinical data in our database to evaluate
what proportion of patients had their index hemoglobin level
measured during an acute state of volume overload (such as an
acute heart failure decompensation), which might increase the
observed prevalence of anaemia due to plasma volume expansion
and hemodilution. Our findings were not altered by adjustment
of the hospitalization status of patients at the time of the
index angiogram, suggesting that hemodilution from acute volume
overload is unlikely to explain the results of our study. Our
study is strengthened by the availability of detailed coronary
angiographic data on all patients, allowing adjustment for CAD
severity to a greater extent that has been possible in previous
studies.
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6. Conclusions
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The primary finding of our study is that the mortality risk
associated with anaemia in patients with heart failure was greatest
in patients without coronary artery disease, and was progressively
lower in patients with greater degrees of CAD severity. These
data contradict our initial hypothesis, namely that greater
severity of CAD would potentiate the adverse effects of anaemia
on mortality. Our findings suggest that mechanisms other than
impairment of oxygen delivery may play a role in the association
between anaemia and mortality in chronic heart failure. Such
mechanisms remain speculative, but could include bone marrow
suppression from circulating inflammatory cytokines, hemodilution,
renal dysfunction, or malnutrition
[7]. Additionally, our data
call into question traditional thinking about the need for blood
transfusions to maintain an arbitrary hematocrit in patients
with cardiovascular disease, and support recently published
data suggesting that red blood cell transfusions may not be
beneficial in patients with acute ischemic heart disease
[15].
Future research will be required to further understand the mechanisms
underlying the association between anaemia and heart failure,
as well as to determine the potential benefit of therapies designed
to treat anaemia in patients with heart failure.
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Notes
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This work was funded independently by the Duke Clinical Research
Institute. Dr. Felker is supported in part by NIH K23 HL72357-01A1.
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References
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Abstract
1. Background
