Download Anaemia as a contributor to morbidity and mortality in congestive

Nephrol Dial Transplant (2005) 20 [Suppl 7]: vii11–vii15
doi:10.1093/ndt/gfh1101
Anaemia as a contributor to morbidity and mortality
in congestive heart failure
Dov Wexler, Donald Silverberg, Miriam Blum, David Sheps, Gad Keren, Yoram Wollman,
Doron Schwartz and Adrian Iaina
Departments of Cardiology and Nephrology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Abstract
Anaemia is present in 40% of cases of congestive
heart failure (CHF) and is associated with a higher
mortality, a lower left ventricular ejection fraction,
a lower cardiac functional status, a higher rate of
hospitalization, signs of malnutrition, a lower exercise
capacity, a progressive fall in renal function, an
increased need for high dose diuretics, hyponatraemia,
an increased plasma volume, a reduced red cell volume
and a lower quality of life. In both uncontrolled and
controlled studies, correction of the anaemia with
subcutaneous erythropoietin and, in some cases, with
the addition of intravenous iron, has been shown to
improve these parameters. A vicious circle is present
between CHF, chronic kidney insufficiency (CKI) and
anaemia, each capable of causing or being caused
by the other, the so-called cardio renal syndrome.
If larger randomized, controlled, double-blind studies
confirm these observations, correction of the anaemia
may prove to be a useful addition to the prevention
and progression of both CHF and CKI. Cooperation
between nephrologists, cardiologists and other internists to identify and treat these anaemic CHF patients
early will help prevent progression of both the cardiac
and renal disease.
Keywords: anaemia, erythropoietin; heart failure;
iron; kidney failure
CHF in the community
Congestive heart failure (CHF) is present in 2%
of the population, 5% of the population above age
65 years and 10% of the population above age
80 years [1]. Despite all the advances in the therapy
Correspondence and offprint requests to: Dov Wexler MD, Heart
Failure Clinic, Tel Aviv Sourasky Medical Center, Weizman 6, Tel
Aviv 64239, Israel. Email: [email protected]
of this disease, the 1-year mortality in men in the
Framingham study fell from 30% in the period
1950–1969 to only 28% in the period 1990–1999 [2].
Although part of this disappointing result may be due
to lack of an aggressive approach to therapy with CHF
medications [3,4], it is possible that another factor is
also contributing, i.e. lack of treatment of the anaemia
which is often seen in CHF.
The relationship between anaemia
and CHF manifestations
Anaemia (which is defined in different ways by
different investigators) is found in 9–61% of CHF
cases [5–15]. On average 40% of CHF cases are
anaemic. Anaemia is more common and more severe
in the elderly, in those with more severe compared
with milder heart failure, in those who are hospitalized
compared with those in out-patient clinics, and in
those with associated renal insufficiency. Anaemia in
CHF is associated with a higher rate of hospitalization or rehospitalization [5–7] and mortality [5–13]
than patients without anaemia and is an independent
risk factor for these complications even when other
factors such as age, sex and renal function have
been taken into consideration [5–13]. Anaemia and
chronic kidney insufficiency (CKI) have an additive
effect on the mortality [8,9] and on the need for
dialysis [16] in CHF. The anaemia in CHF has
been associated with worsening New York Heart
Association (NYHA) functional status [6,10,14],
hyponatraemia [7], rapid progression of renal failure
[5,6,17,18], signs of malnutrition such as a low body
mass index (BMI) and serum albumin [10] as well
as with more severe haemodynamic changes such
as reduced oxygen utilization [10,14,19], reduced
exercise capacity [10,14,19], lower blood pressure
[10], higher heart rate [10], higher pulmonary
capillary wedge pressure [10] and signs of peripheral
hypoperfusion [20].
ß The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please email: [email protected]
vii12
How does anaemia cause or worsen CHF?
Anaemia causes peripheral ischaemia which results in
a fall in blood pressure that activates both sympathetic
and renin–angiotensin, aldosterone and vasopressin
activity, resulting in reduced renal blood flow, reduced
glomerular filtration rate (GFR) and increased
sodium and water absorption [21]. The expanded
extracellular volume will cause haemodilution and
a lower haemoglobin (Hb) concentration [13]. The
increased plasma volume causes ventricular dilation
which puts a further stress on the heart already
stressed by tachycardia and increased stroke volume.
Eventually, left ventricular hypertrophy (LVH) occurs,
which can lead to myocardial cell death from necrosis
and apoptosis [22,23]. All this may lead to CHF. Put
simply, anaemia can cause or worsen oedema and
CHF. There are also other ways by which anaemia can
cause CHF. The lack of oxygen supply to the heart
caused by the anaemia in the face of increased heart
rate and stroke volume may cause ischaemia and
lead to myocardial cell death. In addition, the red blood
cells contain many antioxidants and, therefore, not
surprisingly, anaemia is associated with an increase
in oxidative stress [24,25] which could cause damage
to the myocardial cells. mVO2 (volume of oxygen)
utilization during peak exercise is considered one of
the most accurate tests of cardiac function [19]. In
CHF patients, peak mVO2 decreases significantly with
lower Hb levels [14,19]
The aetiology of anaemia in CHF
The main cause of anaemia is most probably renal
damage produced by poor cardiac function, with
reduced cardiac output and renal vasoconstriction
leading to prolonged renal ischaemia. This causes
renal damage and reduced production of erythropoietin (EPO) in the kidneys. However, not all patients
with anaemia and CHF have CKI [5–15]. Studies in
animals have shown that CHF itself may cause anaemia
[26]. The damaged heart may secrete cytokines such as
tumour necrosis factor-a (TNF-a [27]) which can cause
anaemia in three ways [28]: by reducing EPO production in the kidneys; by interfering with EPO activity at
the level of the bone marrow; and by inhibiting the
release of Fe from the reticuloendothelial system so that
it cannot reach the bone marrow to be utilized in Hb
production. It has been shown recently that the higher
the TNF-a in CHF, the lower the Hb level [29]. Many
patients with CHF take aspirin, which may cause
mucosal irritation and blood loss. Patients with CHF
often have proteinuria, and EPO, iron and transferrin
can all be lost in significant amounts in the urine [30],
also contributing to the anaemia. EPO production and
utilization may be inhibited by angiotensin-converting
enzyme (ACE) inhibitors, resulting in anaemia [31].
Finally, part of the anaemia in CHF may be due to
haemodilution [13,21], but the majority of CHF
patients with anaemia actually have, in addition to
D. Wexler et al.
an increased plasma volume, a reduced red cell
volume [13].
The effect of correcting the anaemia
on CHF and the associated CKI
The most important way to assess the possible causal
role of anaemia in CHF and CKI is to correct it. This
has been examined by us in several recent studies
[5,6,17,18].
We treated for several months 26 patients with
NYHA class IV who were resistant to all CHF
medications (given in recommended doses) with
subcutaneous (s.c.) EPO and intravenous (i.v.) iron
[Venofer (iron sucrose)] to correct the anaemia to a
mean of 12 g% [6]. The treatment was associated with
a marked improvement in CHF as judged by improved
NYHA functional status and increased left ventricular
ejection fraction (LVEF). Compared with the pretreatment period, the rate of rehospitalization fell
markedly and the dose of oral and i.v. diuretics
needed was greatly reduced. In addition, the rate of
fall of GFR as measured by 1/serum creatinine 100
improved. Renal function, that had been falling at
a rate of 1 ml/min/month, stabilized when the
anaemia was corrected, and the CHF improved.
In a subsequent randomized controlled (but not
double-blind) study [17], we studied 32 such resistant
anaemic CHF patients. They were assigned to two
groups. 16 received the EPO–i.v. iron combination
for several months and the other 16 were not treated.
In the 16 who were treated, the NYHA and LVEF
improved significantly, the mean serum creatinine
did not change, and the rate of hospitalization fell
significantly, as did the doses of oral and i.v.
furosemide. In the control group, the NYHA, LVEF,
hospitalization rate and needed dose of diuretics
worsened and the serum creatinine increased significantly. No deaths occurred in the treated group; four
occurred in the non-treated group, all from progressive
CHF. We have now increased our experience to
179 such patients, including both diabetics and nondiabetics, and our results were similar [18]. Our patients
were asked on their first visit and at the completion
of the study when they had reached and maintained
the target Hb of 12.5 g% to assess their fatigue and
shortness of breath on a visual analogue scale. On this
scale, 10 is the worst they could possibly feel and 0 is
the best. The score fell from a mean of 8.8 at onset to a
mean of 2.8 on completion. This striking response is
very unusual in severe CHF where quality of life tends
to deteriorate with time [19]. The mean creatinine
clearance, which was deteriorating at a mean rate
of 1.12±1.3 ml/min/month in the non-diabetics in
the months before the study, was reduced to
0.21±1.3 ml/min/month during the study, which
lasted a mean of 11.8±8.2 months. The corresponding
rates in the diabetics were –1.18±1.49 before the
intervention and þ0.13±1.54 after the intervention.
The similar rates of deterioration in non-diabetics
Anaemia and heart failure
and diabetics suggests that it was not only the diabetes
itself that is causing the deterioration in renal function
but also the anaemia and uncontrolled CHF.
Another argument for the causative effect of anaemia
in CHF is the response to EPO of other cardiovascular
parameters. In a placebo-controlled trial, patients with
severe CHF who received EPO for 3 months had a
significant improvement in peak VO2, VO2 at the
anaerobic threshold, exercise duration in seconds and
distance walked in 6 min [19]. In the control group,
none of these parameters changed significantly.
In the treated group, the quality of life based on a
questionnaire showed improvement in the treated
group and a deterioration in the placebo group. As in
the study mentioned above [14], a significant positive
linear correction was observed between the change in
Hb level and the change in peak VO2. In addition, in
those patients who initially had had excessive plasma
volume, correction of the anaemia reduced the plasma
volume to normal.
Why does CHF damage the kidneys?
In several studies of CHF, about half the patients
have CKI defined as a serum creatinine of 1.5 mg% or
higher [5,6,9,17,18]. The reduced renal blood flow
in CHF activates angiotensin, aldosterone and the
sympathetic activity. All these factors cause progressive
renal ischaemia as well as toxic effects on the renal
tissue [32,33]. All these hormones as well as other
factors also activated by ischaemia can cause damage
to the glomerulus, the mesangium, the tubular cells
and the interstitial cells, with progressive renal
fibrosis [32,33].
vii13
smoking—other risk factors also play a role in the
vascular and cardiac damage of uraemia [34–38].
These include: anaemia, hypervolaemia, malnutrition,
elevated nocturnal blood pressure, high sympathetic
activity and high blood levels of noradrenaline, renin,
angiotensin and aldosterone, inflammation, elevated
C-reactive protein, reduced fibrinolysis, low highdensity lipoprotein (HDL), increased serum Lp(a),
hyperphosphataemia,
elevated
b2-microglobulin,
calcium, elevated calcium phosphate product, parathyroid hormone, vitamin D, homocysteine, advanced
glycation end-products (AGEs), oxidative stress and
advanced oxygen protein products, cytokines, including tumour necrosis factor (TNF), interleukin-6 and
asymmetric dimethyl arginine (ADMA), with loss of
nitric oxide-mediated endothelial cell vasodilatation
leading to endothelial cell dysfunction.
Ischaemic tolerance of the heart
As a result of all the factors listed above, the heart
in uraemia has an abnormal reaction to ischaemia
[34,39]. This explains the devastating coronary prognosis of uraemic patients when they develop a
myocardial infarction [40]. Coronary ligation causes
greater infarct areas in uraemic rats compared with
sham-operated control rats [34,39]. There are many
cardiac abnormalities seen in the heart in CKI [34,39].
(i)
Why would renal failure worsen CHF?
(ii)
The heart can be damaged in many ways in renal
failure. There is a high prevalence of atherosclerotic
lesions in uraemic patients as well as a high frequency
of coronary lesions and events. This has been
documented by retrospective and prospective clinical
observations and has been confirmed in animal models
[34]. Heavily calcified plaques are found much more
often in uraemic patients than in controls, and
atherosclerotic plaques grow faster in an uraemic
environment. This process occurs early in renal disease.
It has been suggested that there is also excessive
angiogenesis in the adventitial layer of the coronary
arteries leading to intramural haematoma formation
and rupture of the fibrous cap [34].
(iii)
(iv)
What causes the vascular and cardiac
damage in uraemia?
(v)
In addition to the classical risk factors seen in
renal failure—hypertension, dyslipidaemia, diabetes
and increased insulin resistance, obesity and
Microvessel disease. It appears that the growth
of capillaries in uraemia does not keep pace
with the hypertrophy of the cardiomyocytes. This
mismatch between cardiomyocytes and capillaries
increases the distance through which oxygen must
diffuse from the capillary lumen to the interior of
the myocyte.
Failure of vasodilation of the coronary arteries
due to endothelial dysfunction.
Studies of the metabolism of the heart in uraemia
have shown a decay of energy-rich nucleotides,
especially ATP. There is thus a reduction in energy
stores coupled with an increased energy demand.
Increased sympathetic activity. Chemoreceptors
and baroreceptors in the damaged kidney are
activated, sending signals to the hypothalamus
causing sympathetic efferent traffic and increased
sympathetic tone. Besides increasing heart rate
and cardiac contraction, this predisposes to the
development of arrythmias. Excessive sympathetic
activity will lead to pump failure. Compared
with sham-operated rats, the hearts of rats
subjected to subtotal nephrectomy contain fewer
myocytes in the left ventricle. In other words, there
is cardiocyte drop-out in the uraemic animals even
in the absence of ischaemia. This is probably due
primarily to excessive apoptosis.
In uraemia, there are numerous abnormalities
of cardiomyocyte function, including abnormal
cardiomyocyte calcium cycling and contractile
function.
vii14
D. Wexler et al.
The vicious circle of CHF, CKI and anaemia—
the cardio renal anaemia (CRA) syndrome
A vicious circle therefore appears to be present in CHF,
where CHF itself causes both anaemia and CKI.
The CKI causes more anaemia, and the anaemia and
CKI act back to further worsen the CHF, which then
further worsens the anaemia and CKI, and so on.
In other words, each condition can cause or be caused
by the other. We suggested calling this relationship the
cardio renal anaemia (CRA) syndrome [5].
(carvedilol, metoprolol and bisoprolol) and other CHF
agents in the correct doses than other specialties. As
suggested above, the aggressive treatment of the CHF
including correction of the anaemia may cause a
slowing or arrest of the progression of both CHF and
CKI. Randomized double-blind, placebo-controlled
studies of EPO in CHF are now in progress which
will further clarify the role of anaemia and its
correction in CHF.
Conflict of interest statement. None declared.
heart failure
ll
anaemia $ renal failure
The importance of this concept is that if the anaemia
is not treated in CHF patients, there will probably be
resistance to any other form of CHF therapy and there
will be progression of both the CHF and the CKI.
Thus, correction of anaemia may therefore be crucial
in the prevention of the progression of both CHF and
CKI. It also follows that the failing heart needs
maximal protection with all the CHF medications in
the recommended doses.
Attitude of cardiologists and internists
to anaemia in CHF
In a preliminary report from the Cleveland Clinic [41],
2011 consecutive ambulatory patients with chronic
stable heart failure seen in tertiary care cardiology or
internal medicine clinics were studied. Anaemia was
defined as a Hb 12 g% in men and 11 g% in women;
29% of the patients had or developed anaemia at
some time. Yet anaemia was only recognized as a
diagnosis in 11.1% of these cases by the internists
and in 4.4% of the cases by cardiologists. Diagnostic
evaluation was only performed in 6% of these patients
and only 10% received medical therapy for the
anaemia. The conclusion of the investigators was
that anaemia in ambulatory patients with CHF is
under-recognized, under-diagnosed and under-treated
by cardiologists and internists.
The challenge of interdisciplinary cooperation
This lack of awareness of the importance of anaemia
in CHF among internists and cardiologists is a major
challenge to the one group of physicians who are
most experienced in anaemia correction in patients
with CKI and CHF, i.e. nephrologists. Another
advantage that will be accrued to nephrologists by
cooperation with them will be that CHF itself may
be better treated. Cardiologists are much more likely
to find reversible causes of CHF and are more likely
to treat CHF aggressively with proven b blockers
References
1. Miller LW, Missov ED. Epidemiology of heart failure. Cardiol
Clin 2001; 19: 547–555
2. Levy D, Kenchaiah S, Larson MG et al. Long term trends in
the incidence of and survival with heart failure. N Engl J Med
2002; 347: 1397–1402
3. Cleland FGF, Cohen-Solal A, Aguillar JC et al. Management
of heart failure in primary care (the IMPROVEMENT of heart
failure programme): an international survey. Lancet 2002; 360:
1631–1639
4. Stafford RS, Radley DC. The underutilization of cardiac
medications of proven benefit, 1990–2002. J Am Coll Cardiol
2003; 41: 56–61
5. Silverberg DS, Wexler D, Blum M, Iaina A. The cardio renal
anemia syndrome: correcting anemia inpatients with resistant
congestive heart failure can improve both cardiac and renal
function and reduces hospitalization. Clin Nephrol 2003; 60
[Suppl 1]: S93–S102
6. Silverberg DS, Wexler D, Blum M et al. The use of
subcutaneous erythropoietin and intravenous iron for the
treatment of the anemia of severe, resistant congestive heart
failure improves cardiac and renal function, functional cardiac
class, and markedly reduces hospitalizations. J Am Coll Cardiol
2000; 35: 1737–1744
7. Kosiborod M, Smith GL, Radford MJ et al. The prognostic
importance of anemia in patients with heart failure. Am J Med
2003; 114: 112–119
8. Al-Ahmad A, Rand WM, Manjunath G et al. Reduced kidney
function and anemia as risk factors for mortality in patients
with left ventricular dysfunction. J Am Coll Cardiol 2001; 38:
955–962
9. McClellan WM, Flanders WD, Langston RD et al. Anemia
and renal insufficiency are independent risk factors for death
among patients with congestive heart failure admitted to
community hospitals: a population-based study. J Am Soc
Nephrol 2002; 13: 1928–1936
10. Horwich TB, Fonarow GC, Hamilton MA et al. Anemia
is associated with worse symptoms, greater impairment in
functional capacity and a significant increase in mortality in
patients with advanced heart failure. J Am Coll Cardiol 2002;
39: 1780–1786
11. Ezekowitz J, McAlister FA, Armstrong PW. Anemia is
common in heart failure and is associated with poor outcomes.
Circulation 2003; 107: 223–225
12. Mozaffarian D, Nye R, Levy WC. Anemia predicts
mortality in severe heart failure. J Am Coll Cardiol 2003; 41:
1933–1939
13. Androne AS, Katz SD, Lund L et al. Hemodilution is common
in patients with advanced heart failure. Circulation 2003; 107:
226–229
14. Kalra PR, Bolger AP, Francis DP et al. Effect of anemia on
exercise tolerance in chronic heart failure. Am J Cardiol 2003;
91: 888–891
Anaemia and heart failure
15. Kalra PR, Collier T, Cowie MR et al. Haemoglobin
concentration and prognosis in new cases of heart failure.
Lancet 2003; 362: 211–212
16. Gilbertson, D, Li S, Murray AM, Herzog CA, Collins AJ.
Competing risks of death vs ESRD in Medicare beneficiaries
age 65þ with chronic kidney disease, CHF and anemia. J Am
Soc Nephrol 2002; 13: SA848 [abstract]
17. Silverberg DS, Wexler WD, Sheps D et al. The effect of
correction of mild anemia in severe, resistant congestive heart
failure using subcutaneous erythropoietin and intravenous
iron: a randomized controlled study. J Am Coll Cardiol 2001;
37: 1775–1780
18. Silverberg DS, Wexler D, Blum M et al. The effect of
correction of anemia in diabetic and non diabetics with severe
resistant congestive heart failure and chronic renal failure by
subcutanous erythropoietin and intravenous iron. Nephrol Dial
Transplant 2003; 18: 141–146
19. Mancini DM, Katz SD, Lang C et al. Effect of erythropoietin
on exercise capacity in patients with moderate to severe chronic
heart failure. Circulation 2003; 107: 294–299
20. Macin SM, Perna ER, Farias EF et al. Anemia is a
highly prevalent condition in decompensated heart failure
with prognostic implication. Eur J Heart Fail Suppl 2003; 2:
295A
21. Anand IS, Chandrashekhar Y, Ferrari R, Poole-Wilson PA,
Harris PC. Pathogenesis of oedema in chronic anemia: studies
of body water and sodium, renal function, haemodynamics and
plasma hormones. Br Heart J 1993; 70: 357–362
22. Johnson DB, Dell’Italia LJ. Cardiac hypertrophy and failure
in hypertension. Curr Opin Nephrol Hypertens 1996; 5: 186–191
23. Katz AM. The cardiomyopathy of overload: an unnatural
growth response in the hypertrophied heart. Ann Intern Med
1994; 121: 363–371
24. Grune T, Sommerburg O, Siems WG. Oxidative stress in
anemia. Clin Nephrol 2000; 53 [Suppl 1]: S18–S22
25. Siems WG, Sommerburg O, Grune T. Erythrocyte free
radical and energy formation. Clin Nephrol 2000; 53 [Suppl 1]:
S9–S17
26. Iverson PO, Woldbaek PR, Tonnessen T, Christensen G.
Decreased hematopoiesis in bone marrow of mice with
congestive heart failure. Am J Physiol 2002; 282: R166–R172
27. Herrera-Garza EH, Stetson SJ, Cubillos-Garzon A,
Vooltich MT, Farmer JA, Torre-Amione G. Tumor necrosis
vii15
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
factor: a mediator of disease progression in the failing human
heart. Chest 1999; 115: 1170–1174
Means RT. Advances in the anemia of chronic disease. Int J
Hematol 1999; 70: 7–12
Bolger AP, Doehner W, Sharma R, Coate JS, Anker S. Anemia
in chronic heart failure: the relationship to inflammatory
cytokine production and prognostic importance. Circulation
2002; 106 [Suppl]: 2819A [abstract]
Vaziri ND Erythropoietin and transferrin metabolism in
nephrotic syndrome. Am J Kidney Dis 2001; 38: 1–8
Macdougall IC. The role of ACE inhibitors and angiotensin II
receptor blockers in the response to erythropoietin. Nephrol
Dial Transplant 1999; 14: 1836–1841
Fine L, Dandyopadhay D, Norman JT. Is there a common
mechanism for the progression of different types of renal
diseases other than proteinuria? Towards the unifying theme of
chronic hypoxia. Kidney Int 2000; 57 [Suppl 75]: S22–S26
Yu HT. Progression of chronic renal failure. Arch Intern Med
2003; 163: 1417–1429
Amann K, Ritz C, Adamczak M, Ritz E. Why is coronary
heart disease of uraemic patients so frequent and so
devastating? Nephrol Dial Transplant 2003; 18: 631–640
Zoccali C, Mallamaci F, Tripepi G. Traditional and emerging
cardiovascular risk factors in end-stage renal disease. Kidney Int
2003; 63 [Suppl 85]: S105–S110
McCullough PA, Why is chronic kidney disease the ‘spoiler’ for
cardiovascular disease outcomes? J Am Coll Cardiol 2003; 41:
725–728
Stenvinkel P, Pecoits-Filho R, Lindholm B. Coronary artery
disease in end-stage renal disease: no longer a simple plumbing
question. J Am Soc Nephrol 2003; 14: 1927–1939
Mann JFE, Gerstein HC, Dulau-Florea I, Lonn E.
Cardiovascular risk in patients with mild renal insufficiency.
Kidney Int 2003; 63 [Suppl 84]: S192–S196
Tyralla K, Amann K. Morphology of the heart and arteries in
renal failure. Kidney Int 2003; 63 [Suppl 84]: S80–S83
Herzog CA, Ma JZ, Collins AJ. Poor long term survival after
acute myocardial infarction among patients on long term
dialysis. N Engl J Med 1998; 339: 799–805
Tang WHW, Miller H, Partin M et al. Anemia in ambulatory
patients with chronic heart failure: a single-center clinical
experience derived from electronic medical records. J Am Coll
Cardiol 2003; 41 [Suppl A]: 157A [abstract]