Download Anaemia and heart failure: statement of the problem

Nephrol Dial Transplant (2005) 20 [Suppl 7]: vii3–vii6
doi:10.1093/ndt/gfh1099
Anaemia and heart failure: statement of the problem
Basil S. Lewis, Basheer Karkabi, Ronen Jaffe, Rita Yuval, Moshe Y. Flugelman and David A. Halon
Department of Cardiovascular Medicine and the Cardiovascular Clinical Research Unit, Lady Davis Carmel Medical
Center and Bruce Rappaport School of Medicine, Technion-IIT, Haifa, Israel
Abstract
While advances in treatment strategies and pharmacotherapy have produced a dramatic reduction in
the mortality of patients with heart failure during the
past 15 years, there is still a major challenge to improve
patient well being, reduce hospitalizations and reduce
mortality further. The prevalence of heart failure is
not decreasing, and heart failure is currently a cause
for hospitalization in >25% of admissions to internal
medicine and cardiology departments. It has recently
become apparent that anaemia is present in 20–30% of
patients with heart failure, and the severity of anaemia
has important implications regarding outcome and
prognosis. Anaemia may be due to a number of
causes, including iron and vitamin deficiency, insidious
blood loss, haemodilution, renal impairment and bone
marrow depression with resistance to erythropoietin.
In the presence of a damaged heart and often coronary
artery disease, anaemia may worsen contractile ability
and systolic function, while the necessary volume load
and ventricular hypertrophy which accompany anaemia contribute to diastolic dysfunction. Preliminary
data show that appropriate treatment of anaemia,
based on correction of the underlying cause, with, in
most patients, the addition of exogenous erythropoietin and iron therapy, improves ventricular function
and clinical status. Treatment of anaemia has opened
a new frontier in the management of heart failure.
We await the results of ongoing clinical trials for more
detailed imformation regarding appropriate haemoglobin targets, choice of medication and dosing and the
degree of improvement that may be expected when the
issue of anaemia is properly addressed.
Keywords: anaemia; erythropoietin; heart failure;
iron deficiency; renal failure
Correspondence and offprint requests to: Basil S. Lewis, MD,
FRCP, Louis Edelstein Professor of Medicine and Medical
Research, Department of Cardiovascular Medicine, Lady Davis
Carmel Medical Center, 7 Michal Street, Haifa 34362, Israel.
Email: [email protected]
Introduction
Although we have witnessed a dramatic reduction
in the mortality of patients with heart failure during the
last 15 years, from a 12 month mortality of 52%
in the placebo arm of the CONSENSUS I trial [1] to
17% for similar patients in the treatment arm of the
MERIT-HF study [2], the mortality and morbidity
of the disease present a continuing challenge to the
medical community. The incidence of heart failure is
increasing, with an estimated 500 000 new cases in the
USA alone each year. Heart failure was the discharge
diagnosis in 27.4%, and suspected heart failure was
present in another 6.2% of 1095 consecutive patients
hospitalized in internal medicine/cardiology departments in a recent survey in Israel (Figure 1).
The current management of heart failure includes
treatment aimed at improving cardiac function,
haemodynamics and overall patient well being. We
aim to reduce mortality and the need for repeat cardiac
hospitalizations with its inherent load on the already
overburdened health care system of most countries. In
recent years, attention has been drawn to the deleterious effect of anaemia on patients with heart failure
and the potential benefit of appropriate treatment
[3–7]. Here we will outline key issues regarding the
pathophysiology of anaemia in heart failure and
provide a physiological basis for what treatment of
anaemia may achieve in heart failure patients.
Prevalence of anaemia in heart failure patients
Anaemia, defined as a haemoglobin level of <12 g%,
has been noted in a considerable number of patients
with heart failure. We surveyed the prevalence of
anaemia in 367 consecutive patients hospitalized
with heart failure or suspected heart failure in two
major medical centres in the Haifa area. The patients
represented a typical heart failure population: age
ranged from 37 to 98 years (Table 1), 57% were males,
29% had diabetes mellitus (8% insulin dependent,
21% oral agents), in 61% there was a diagnosis of
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vii4
B. S. Lewis et al.
SUSPECTED
CHF
68 (6.2%)
NO CHF
CHF
727 (66.4%)
300 (27.4%)
Fig. 1. High prevalence of heart failure (HF) or suspected HF
in consecutive patients hospitalized over two 6 week periods in
internal medicine, cardiology and cardiac surgical departments
in two major medical centres in Israel. HF or suspected HF was
present in 33% of patients.
Table 1. Haemoglobin and creatinine values in patients hospitalized
for heart failure in Haifa
Age (years)
LVEF (%)
Hb (g/dl)
Creatinine (mg/dl)
Median
First
quartile
Third
quartile
Range
78
35
12.4
1.30
71
25
11.0
1.00
86
50
14.0
1.72
37–98
4–70
5.1–17.7
0.1–9.0
red blood cell and plasma volume. Patients with
haemodilution tended to do worse than patients with
true anaemia, which suggests that volume overload
may be an important mechanism contributing to the
poor outcome in anaemic congestive heart failure
(CHF) patients.
A number of other factors contribute to anaemia
in patients with heart failure. Iron deficiency is not
uncommon following poor nutrition and decreased
absorption, with gastrointestinal blood loss in a
population of patients almost universally treated with
antiplatelet drugs such as aspirin and/or chronic
anticoagulation with warfarin. Renal failure is
common due to common disease aetiology (diabetes
mellitus, systemic hypertension and atherosclerotic
vascular disease) or due to unrelated causes. In addition
and importantly, the immunomodulator role of tissue
necrosis factor and interleukins in heart failure is
associated with resistance to erythropoietin at a bone
marrow level, with decreased haemoglobin production.
Under these circumstances, circulating erythropoietin
levels should be very high. Thus, while measured circulating erythropoietin levels may be normal or mildly
elevated in heart failure patients, exogenous erythropoietin is effective in raising haemoglobin. Since most
heart failure patients are elderly, there may be other
unrelated causes for the development of anaemia, and
these should be carefully looked for.
Ventricular function in heart failure
hypertension, and 8.2% had suffered a recent episode
of acute myocardial infarction. Systolic left ventricular
(LV) function was reduced in most patients. The
median LF ejection fraction (EF) was 35%.
Haemoglobin values in these heart failure patients
ranged from 5.1 to 17.7 g/dl. The median value was
12.4 g/dl, lower quartile <11.0 g/dl, upper quartile
>14.0 g/dl (Table 1), meaning that in almost half the
patients, haemoglobin was <12.0 g/dl. The findings
were similar but slightly worse than those reported in
the European Heart Failure Survey [8], where haemoglobin values were <11 g/dl in 18% of men and 23% of
women. Renal dysfunction was very common. Mean
serum creatinine was 1.6±1.2 (range 0.1–9.0) mg% and
the median value 1.3 mg%, implying abnormal renal
function in at least half the patients. In the European
survey, renal dysfunction was reported to have
complicated the management of patients with known
or suspected heart failure in 18% of cases [8].
Aetiology of anaemia in heart failure
There are many potential reasons for development of
anaemia in chronic heart failure, including bone
marrow depression, reduced intestinal iron uptake,
and dilution as a consequence of sodium and water
retention [9]. Androne et al. [10] examined the prevalence of haemodilution in a subset of 37 ambulatory
anaemic patients with 131I-tagged albumin to measure
The contractile state of the LV may be assessed
from the instantaneous relationships between force,
velocity and fibre length. The Starling series of curves
characterizes the systolic contractile potential of
the heart and may be estimated at catheterization or
semi-invasively by construction of pressure–volume
loops, by the end-systolic pressure–volume relationship
or on a more simple daily basis by measurement of
LVEF by invasive or non-invasive methodology. The
nature of the contraction abnormality depends on the
aetiology of the disease. Heart failure due to coronary
artery disease is characterized by regional ventricular
contraction abnormalities, hypertensive heart failure or
valvular disease by global reduction in LV contraction.
Diastolic ventricular function may be described in
terms of the diastolic pressure–volume curve, itself the
result of a number of determinants including inherent
LV relaxation properties, the compliance of the
ventricle and the extraneous influences of the right
ventricle and pericardial system, where the parallel
elastic component represents the distensile abilities
of the interstitial and other para-myocardial LV
structures [11]. Abnormal diastolic function (decreased
compliance/increased stiffness) is represented by an
upward and leftward shift to the pressure–volume
curve. An increased ventricular volume (volume
load) shifts the patients upward and to the right
along the pressure–volume curve, and in patients
with decreased compliance, LV end-diastolic pressure
The problem of anaemia in heart failure
may indeed rise very sharply since the diastolic compliance curve is exponential. The three major causes
of diastolic dysfunction—ischaemia, fibrosis and ventricular hypertrophy—are frequently present in heart
failure patients.
Effect of anaemia on haemodynamics of the
damaged left ventricle
Patients with anaemia suffer from volume load of the
cardiovascular system, while oxygen carrying capacity
is reduced. Heart rate is increased. This means that
ventricular volumes are larger, with greater demands
on energy expenditure. The increased plasma volume
produces eccentric hypertrophy, where ventricular
dimensions increase disproportionally to the ability
to increase wall thickness. Cardiac mass in anaemic
animals increased by as much as 25% [12]. Wall stress
increases [13,14]. While systolic cardiac function may
be unaltered (or even compensatorily enhanced) in the
presence of moderate anaemia and in the absence of
underlying heart disease [15,16], systolic function may
indeed be considerably reduced in the damaged heart
of patients in heart failure or in patients with very
severe anaemia. In children with severe iron deficiency
anaemia, the ratio of LV end-systolic wall stress to the
LV volume index (and cardiac index) decreased when
the haemoglobin concentration was 6 g/dl, indicating
a decrease in LV contractility and LV dysfunction,
and resulted in circulatory congestion [17]. After iron
repletion, LV function was shown to improve before
the rise in haemoglobin level, suggesting that correction
of functional abnormalities may also be the result of
correction of iron metabolism at the tissue level [18].
In diastole, the increased volume is associated with
further deterioration regarding filling pressures in the
presence of an already compromised end-diastolic
pressure–volume relationship (Figure 2).
Relationship between anaemia and
clinical outcome
The severity of anaemia is an independent predictor
of outcome [19–21]. A lower baseline haemoglobin
value was associated with increased risk of short-term
adverse clinical events [22]. In population studies,
the cause of anaemia has not always been well defined.
This is potentially important because iron deficiency
anaemia may alter endothelial function [23]. In contrast
to studies in established chronic heart failure, the
haemoglobin level in new cases of heart failure was not
always independently associated with prognosis when
age and serum creatinine concentration were included
in the analysis [24]. The adverse effects of anaemia
on survival might be a consequence of chronic heart
failure rather than a separate process causing disease
progression. In a large series of 12 065 patients with
new-onset heart failure studied in Canada [25], anaemia
vii5
Anemia
LVEDP
Fig. 2. Ventricular pressure–volume loops in health (control
loop), in patients with decreased compliance (filled loop) and in
patients with anaemia (dotted line). Anaemia is associated with
volume load and shift of the loop to the right. Systolic function
may be preserved (as shown) or reduced if anaemia decreases
systolic contraction. Left ventricular end-diastolic pressure (LVEDP)
is increased following the exponential nature of the diastolic
pressure–volume curve.
was common and an independent prognostic factor
for mortality. In our series of hospitalized heart failure
patients in Haifa, 12 month mortality/repeat hospitalization was more frequent in patients with haemoglobin
<11 g/dl (lowest quartile vs all others) (51 vs 41%,
P ¼ 0.07), while 12 month mortality was marginally but
not significantly higher (36 vs 27%, P ¼ 0.12). The very
high 36% 12 month mortality and 51% mortality/
cardiac rehospitalization rates were staggering and
imposed a heavy burden on health care resources.
Similar data were reported by Kosiborod et al. [26],
who found that after adjusting for demographic and
clinical factors, each 1% reduction in haematocrit was
associated with a 2% greater 1-year mortality.
Effect of treatment and role of erythropoetin
in heart failure patients
At a clinical level, anaemia has an important effect
on exercise tolerance in chronic heart failure [27].
Mancini et al. [28] showed that in a placebo-controlled
study, administration of erythropoetin was associated
with a significant increase in haemoglobin, peak VO2
and exercise duration. Resting and hyperaemic forearm
vascular resistance and indices of the rate of muscle
oxidative capacity were unchanged in both groups,
suggesting that erythropoietin enhances exercise
capacity by increased oxygen delivery from increased
haemoglobin concentration. In addition, erythropoietin has potentially beneficial effects on the endothelium,
including anti-apoptotic and pro-angiogenic activities
[29]. Erythropoetin may be associated with an increase
in circulating endothelial progenitor cells [30,31], and
these are currently the subject of extensive investigation
as potentially therapeutic targets in patients with acute
and chronic myocardial ischaemia and/or damage.
Reports that erythropoietin may have pro-thrombotic
or platelet-activating effects, or produce hypertension
appear to be less important clinically in light of
vii6
preliminary clinical trials [3,4] based on administration
of erythropoietin and iron therapy in heart failure
patients.
Implications for treatment and management
The high prevalence of anaemia in heart failure patients
presents both a new challenge and a new therapeutic
opportunity in the management of patients with heart
failure. Treatment of anaemia, using a judicious combination of iron and erythropoetin therapy, improves
ventricular function and clinical status in patients
with chronic renal failure. It now appears that the
same is true in patients with heart failure, many of
whom suffer from additional renal impairment. The
inter-relationships between heart failure, anaemia and
renal insufficiency are currently the subject of intense
research activity [6] and is also the theme of this
Supplement. We await the results of new trials to define
the advantage to be gained in terms of mortality,
morbidity and cost savings [32] by treating anaemia in
heart failure patients.
Conflict of interest statement. None declared.
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