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CHAPTER II
LITERATURE
2.1 Definition
Heart failure (HF) is a frequent cause of hospitalization and, even though
there are new therapies, the mortality rate of HF patients is still high, especially
among the ones that have advanced HF. Studies show that anemia is a prevalent
morbidity among patients with heart failure. The presence of anemia worsens
progress and increases mortality. It has been known for some time that anemia
worsens HF, but in the past years, the magnitude of anemia linked with the
worsening of HF has been more evident.3
In the past, only hemoglobin levels below 9.0 mg/dl were taken into
account, but today we know that any degree of anemia can worsen the progress of
patients suffering from heart failure. The combined analysis of several studies
reveals that a decrease of 1g/dl in the level of hemoglobin (Hb) increases
mortality by 15.8%. Identifying patients with anemia among HF patients, as well
as finding the etiology of the anemic process and adopting the appropriate specific
therapy, may alter the progress of patients with HF. However, in a meta-analysis,
Hessel et al4 did not identify the actual effect of anemia correction on the
reduction of mortality and suggested that further studies are needed.3
Anemia may be the cause of HF, but it often occurs as a consequence. The
pathophysiology of anemia in patients with HF is complex and it has been the
subject of several studies. Among the mechanisms involved in its genesis, the
following can be mentioned: deficiencies in the production of erythropoietin or
erythropoietin resistance, hemodilution, neurohumoral activation,
proinflammatory state (production of cytokines - IL 1.6 and 18) and iron
deficiency. Some drugs used to treat HF can also cause anemia, such as the
inhibitors of angiotensin-converting enzyme, carvedilol and angiotensin-I receptor
blocker, because they cause the inhibition of the erythropoietin production.
Studies have shown that renal dysfunction, decrease in body mass index, old age,
female sex and left ventricular dysfunction are factors that are linked with higher
incidence of anemia who have assessed the prevalence and impact on prognosis.
However, few studies have evaluated the etiology. The iron deficiency anemia
occurs when there is a decrease in hemoglobin synthesis as a result of iron
deficiency. This type of anemia affects two thirds of world population and it is the
main cause of anemia in Brazil1. Therefore, either due to insufficient availability
of iron, or little use of one’s own reserves or insufficient intake of iron, iron
deficiency anemia is a medical condition that arouses interest in this type of
patient. The diagnosis of iron deficiency is made when the serum concentration is
lower than 100 ng/ml and the transferrin saturation is less than 20%.3
Anemia was defined by the cut-off values defined by the World Health
Organisation (WHO): haemoglobin (Hb) level lower than 12,0 g/L (corresponding
to 7.5 mmol/L) in women and 13,0 g/L (corresponding to 8.0 mmol/L) in men
denoted as WHO-anemia through out the manuscript. In order to examine if the
prognostic importance of anaemia was driven by the subgroup of patients with
most severe anaemia, the cut-off level of Hb was decreased with 1,0 and 2,0 g/L,
respectively,resulting in three subgroups of anaemic patients: Mild, moderate and
severe anaemia. Mild anaemia, corresponding for the first subgroup in each
gender, was defined as hgb. lower than 12,0 g/L (6.8 mmol/L) in women, and
lower than 13,0 g/L in men. Moderate anaemia was defined as hgb. lower than
11,0 g/L (6.8 mmol/L) in women, and lower than 12,0 g/L in men. And severe
anaemia was defined as Hb < 10,0 g/L (6.2 mmol/L) in women and < 11,0 g/L in
men.9
2.2 Prevalence and Consequences of Anemia in Heart Failure
The prevalence of anemia varies by age and gender. In an analysis of a
representative population of community-dwelling persons from the US
(NHANES-III [Third National Health and Nutrition Examination Survey]), the
prevalence of anemia in patients 65 years and older was 10.6% and rises to over
20% in 85-year-old individuals. However, in patients with congestive heart
failure, the prevalence may be much higher. In a large cohort of patients with
congestive heart failure, 37.2% were anemic. In contrast, the prevalence of anemia
was 17% in a population-based cohort of patients with new-onset congestive heart
failure (mean age 78) from Canada. The patient with heart failure who has anemia
has an increased risk of death. In a systematic review of 153,180 patients with
heart failure, 48% of anemic patients died within 6 months, compared with 29.5%
of nonanemic patients (adjusted hazard ratio 1.46; 95% CI 1.26 –1.69). This
experience is similar to the Canadian cohort in which the risk of death was 1.34
times higher in anemic than in nonanemic patients with heart failure.10
It is unknown if the increased risk of death is from anemia or is just a
marker for underlying severity of disease. Previous studies demonstrated an
estimated prevalence of anemia in patients with heart failure from 23% to 48%.3,4
In a general elderly population (National Health and Nutrition Examination
Survey) with age and sex distributions similar to those in our study, the
prevalence of anemia was 10.6% in those aged 65 years or more (mean age 74.9
years, 56.6% were female). The present study extends previous reports by
demonstrating that the burden of anemia in patients with heart failure is
substantial, with more than half anemic by WHO criteria in recent years. This
prevalence is higher than previously reported, likely reflecting the unselected
population represented in our community cohorts in contrast with the highly
selective nature of trial participants and in studies limited to those with reduced
ejection fraction. Further, the prevalence of anemia increased markedly over time,
and this steady increase cannot be readily explained by changes in age and renal
function. As observed herein and consistent with previous studies the prevalence
of anemia increases with age. However, no temporal change in mean age at heart
failure diagnosis was detected. In addition, despite the known correlation between
anemia and chronic kidney disease in heart failure, in this cohort the mean
creatinine clearance increased over time. One possible contributor could be the
increase in patients with heart failure with preserved ejection fraction. Previous
data have been conflicting on whether the prevalence of anemia differs by ejection
fraction, with studies demonstrating prevalence is higher, lower, and the same in
patients with preserved versus reduced ejection fraction. Our data from 2003 to
2006 performed in an unselected population with heart failure with complete
ejection fraction ascertainment demonstrate that the prevalence of anemia is
higher in those with preserved versus reduced ejection fraction. Owan et al
recently reported that the proportion of patients with heart failure with preserved
ejection fraction is increasing over time. Given this proportionate increase in
patients with heart failure with preserved ejection fraction, and an increased
prevalence of anemia in those with preserved ejection fraction,it is plausible that
this shift in case mix is contributing to the increased prevalence of anemia in
community patients with heart failure. Because the pathogenesis of anemia in
heart failure has not been fully elucidated, further work is needed to define the
mechanisms of anemia in heart failure.6
2.3 Cause of Anemia in Heart Failure
The cause of anemia in patients with heart failure varies. Iron deficiency
(based on physician hospital discharge diagnosis) is reported in up to 21% of heart
failure patients with anemia. This most likely results from the common use of
aspirin, other platelet function inhibitors (ie, clopidogrel), and anticoagulants.
Anemia of chronic inflammation is the most common cause of anemia and occurs
in 58% of heart failure patients with anemia. Patients with congestive heart failure
have inflammatory activation, leading to higher levels of circulating inflammatory
cytokines, including tumor necrosis factor and interleukin-6, and nonspecific
markers of inflammation, such as C-reactive protein.10
Heart failure is associated with renal insufficiency, which also stimulates
cytokine production. Many patients with heart failure have concomitant renal
insufficiency from medications, such as diuretics and angiotensin- converting
enzyme inhibitors and primary renal disorders resulting from hypertension and
renal artery stenosis. Renal insufficiency is associated with anemia that results, at
least in part, from low erythropoietin levels.9
The etiology of anaemia in HF is multifactorial, including bone marrow
depression and reduced availability of iron and heamodilution secondary to
sodium and water retention. As discussed by Lewis et al. and Wexler et al. in the
current supplement, HF is accompanied by bone marrow depression, probably due
to chronic inflammation with production of proinflammatory cytokines and
induced erythropoietin resistance. The low iron level, due to reduced content of
iron in the diet and also reduced iron absorption, is often present in patients with
HF. Witte et al. explored the relationship between levels of iron, B12 and folic
acid levels. They measured the Hb levels and exercise tolerance in 173 patients
with systolic dysfunction, 123 patients with diastolic HF and 58 control patients.5
Thirty-five percent of the patients with systolic dysfunction, 33% of the
patients with diastolic dysfunction and four control patients were anaemic.
Exercise tolerance and peak oxygen consumption during effort correlated with Hb
levels. There was no difference in the levels of iron, B12 and folic acid among the
different groups of patients. Altogether, 6% had vitamin B12 deficiency, 13% had
iron deficiency and 8% folate deficiency. Anaemia can be also iatrogenic due to
repeated blood testing. Smoller et al. studied 50 HF patients who were
hospitalized in intensive care units and found that a volume of 762 ml of blood
was withdrawn during their hospitalization. It is clear that every blood test should
be ordered only if necessary and not only by routine. IHD is the most common
cause of HF. Zeidman et al. compared 317 anaemic IHD patients with 50 anaemic
patients without IHD and 50 IHD patients without anaemia (control). Patients
with combined IHD and anaemia had more severe clinical presentations, with
44% presenting with acute coronary syndrome and 36% with acute myocardial
infarction, compared with 26 and 20% in the group of IHD patients with normal
Hb levels. HF was more common in IHD patients with anaemia compared with
IHD patients without anaemia (31 vs 18%). Mortality was also significantly
higher in IHD patients with anaemia (13 vs 4%). In their discussion, the authors
raise the possibility that the more severe clinical manifestation is due to more
severe chronic inflammation, leading both to anaemia and to more advanced
atherosclerosis.5
Recently, Iversen et al. demonstrated a decreased haematopoiesis in the
bone marrow of mice with HF. The HF mice had a 60% reduction in the amount
of progenitor cells compared with control mice. A 3-fold increase in apoptosis
was probably the reason for the paucity in progenitor cells. As measured in vitro,
the proliferative capacity of progenitor cells in mice with HF was only 50% of the
control. The authors also found that the expression of TNF-a was markedly
increased in bone marrow natural killer cells and T cells and these lymphocytes
exhibited increased cytolytic activity against progenitor cells in vitro, indicating
that anaemia is related to increased inflammatory activity. Wexler et al. (this
supplement), who performed several pioneering studies on the frequency and
significance of anaemia in HF patients, found that anaemia is present in _40% of
HF patients. This is in concordance with the findings of Lewis et al. [this
supplement], who reported an incidence of almost 50% of anaemia (defined as
Hb<12 g/dl) in HF patients. In the European Heart Failure Survey [16], an Hb of
<11 g/dl was found in 23% of the women and 18% of the men. These authors
suggest that in HF patients, the main cause of the anaemia is the renal damage
caused by the reduced cardiac output. Several other reports have demonstrated
reduced renal function in anaemic HF patients [3,17,18]. Ezekowitz et al. [18]
analysed the data from a large cohort of 12 065 patients hospitalized in Alberta,
Canada with new onset HF. Seventeen percent of these patients were found to be
anaemic, 58% of whom had anaemia of chronic disease, 21% of iron deficiency
and 8% of other causes. Anaemia was more common in older patients, females,
hypertensive or chronic renal failure patients. The hazard ratio for mortality was
1.34 in anaemic patients.5
2.4 Treatment
2.4.1 Iron Therapy
It is important to understand the reason why symptoms in heart failure
patients improve with treatment of iron. It does not appear that treating anemia is
the explanation or the only explanation. Most patients in these trials were either
not anemic or had mild anemia,and there were small increases in the hemoglobin
concentration after treatment. Most of the experimental evidence suggests that
iron improves muscle function. Finch and colleagues 12 compared work
performance of rats with and without iron deficiency while controlling for
hemoglobin concentration. Work performance increased to normal when the
hemoglobin was corrected, but only after iron therapy. In iron-deficient rats,
marked impairment in running ability persisted even after hemoglobin was
corrected. In mitochondrial preparations of skeletal muscle, the rate of
phosphorylation with glycerophosphate as substrate was associated with increase
in work performance with treatment of the iron-deficient rats. These results were
confirmed in two other experimental studies. In severely iron-deficient rats with a
hemoglobin concentration of 4.1 to 5.2 g/dL, walking duration increased 6- to 10-
fold for 15 to 18 hours after iron dextran therapy. This rapid improvement in
exercise capacity without change in hemoglobin concentration suggests that iron
is a cofactor needed for exercise. In a second study in rats, exercise training did
not increase VO2max or change hemoglobin concentration in iron-deficient rats.10
There is limited data that iron deficiency may alter cardiac muscle function. Two
studies fed iron-deficient diets to rats and examined cardiac muscle. Rats
receiving iron-deficient diet were anemic. Cardiac muscle examined by
transmission electron microscopy showed mitochondrial swelling and abnormal
sarcomere structure. In another study, iron deficiency was associated with
impairment of myocardial mitochondrial electron transport in rat heart.10
Three randomized clinical trials have been performed evaluating
intravenous iron therapy in patients with anemia and heart failure. The first trial
randomly allocated 40 patients to placebo or intravenous iron.9 Patients were
eligible with (a) ejection fraction less than 35%, (b) New York Heart Association
functional class 2 to 4; (c) iron deficiency anemia defined as hemoglobin
concentration 12.5 g/dL for men and 11.5 g/dL for women, and either ferritin
100 ng/mL and/or with transferrin saturation less than 20%; and (d) normal renal
function. After a follow-up of 6 months, the hemoglobin concentration increased
in the iron-treated group from 10.3 to 11.8 g/dL and was stable in the placebo
group. All the outcomes significantly improved with iron therapy, including NT-
probrain natriuretic peptide, C-reactive protein, ejection fraction (31.3% – 35.7%),
and a 6-minute walk (192.3–240.1 meters). It is unclear how iron therapy reduces
inflammatory markers, such as C-reactive protein.10
The second trial enrolled 35 patients with congestive heart failure and
administered 16 weeks of intravenous iron or placebo.10Patients either had a
serum ferritin 100 ng/mL or transferrin saturation less than 20%, if the ferritin was
between 100 to 300 ng/mL. About half of the patients had hemoglobin
concentration less than 12.5 g/dL, and the remaining patients were not anemic.
The primary outcome, change in absolute peak oxygen consumption, did not
reach statistical significance (placebo, -21 120; iron 75 156; P .08) nor did
treadmill exercise duration (placebo–15 109, iron 45 84; P .08). However,
change in New York Heart Association function class improved (placebo 0.2 0.4,
iron -0.4 0.6; P .007), and patient global assessment (placebo -0.2 1.6, iron 1.5
1.2; P .002) was improved in patients administered intravenous iron.10
In the third, and largest trial, Anker and colleagues 1 enrolled 459 patients
with (a) hemoglobin concentration between 9.5 to 13.5 g/dL; (b) New York Heart
Association functional class 2; (c) ejection fraction 40%; or (d) New York Heart
Association functional class 3, with ejection fraction 45% fraction; and (e) a
diagnosis of iron deficiency, which was defined as a ferritin of 100 g/L or
between 100 to 200 g/L if the transferrin saturation was 20%. Patients were
randomly allocated to placebo or iron repletion based on Ganzoni’s formula11
and the hemoglobin concentration at the start of the trial. Ferric carboxymaltose
was given in doses of 200 mg on a weekly basis until iron repletion and every 4
weeks for maintenance. Blinding of treatment assignment was maintained by
administering iron with a black syringe using a curtain or equivalent to shield the
patient. Study personnel involved with implementing the iron therapy reviewed
laboratory results. Iron was administered weekly until ferritin exceeded 800 g/L or
was between 500 to 800, with iron saturation 50%, or if hemoglobin was 16 g/dL.
Iron was reinitiated when the following three criteria were met: (1) the serum
ferritin fell to _ 400 _g/L, (2) the transferrin saturation was_45%, and (3) the
hemoglobin was 16 g/dL. At baseline, the hemoglobin concentration was 11.9 ,
mean ferritin in the two groups was 52.5 and 60.1, and transferrin saturation was
between 6.7 to 17.7. Efficacy was assessed up to 24 weeks.10
The primary outcomes were self-reported Patient Global Assessment, which
was moderately or much improved in 50% of the iron group and in 28% of the
control group, and the New York Heart Association class improved to class 1 or
class 2 in 47% of the iron group, compared with 30% in those receiving placebo.
These outcomes were also significantly improved in the iron group at 4 and 12
weeks. The secondary outcomes of 6-minute walking distance (an increase of 35
8 meters for the iron group, compared with placebo), quality of life as measured
by EQ-5D score, and Kansas City Cardiomyopathy Score were significantly
improved in the iron-treated group. Overall, the mean difference between the iron
group and placebo group at 24 weeks for serum ferritin was 246 g/L and in
hemoglobin concentration was 0.5 g/dL. The mean difference between iron group
and placebo group for hemoglobin concentration in patients with anemia (defined
as hemoglobin concentration _ 12 g/dL) was 0.9 g/dL but only 0.1 g/dL in patients
without anemia. There was a trend toward fewer hospitalizations in patients
receiving iron therapy.10
This clinical trial has many strengths and some weaknesses. The
investigators enrolled a large number of subjects with documented heart failure
and demonstrate improvement in multiple outcomes. The trial was double-blind,
which is important given that most of the outcomes were subjective and based on
symptoms. Multiple outcomes were assessed and were consistent in showing a
positive effect of iron therapy. The hemoglobin was normal or near normal in
most patients, suggesting that correction of anemia may not be mediating the
treatment effect. However, there are several weaknesses. First, nearly all the
outcomes were subjective. If blinding was not maintained, it is possible that the
outcomes were biased by knowledge that the patient was receiving iron therapy
rather than a placebo. Second, the cause ofthe anemia cannot be determined by the
report. It is likely that some patients had anemia of chronic inflammation, and it is
not possible to determine if only patients with iron deficiency responded to iron
therapy. Third, no objective measures of cardiac function (ie, ejection fraction)
were made on follow-up to determine if symptomatic improvement was from
better cardiac function or for another cause, such as skeletal muscle function.
Finally, most patients had normal or near-normal hemoglobin concentrations; so,
it is unclear if this effect differs, depending on the hemoglobin concentration.10
This study demonstrates that intravenous administration of iron sucrose to
patients with CHF and anemia results in a significant increase in Hb, a reduction
in symptoms, and an improvement in exercise capacity. These effects were
achieved without simultaneous EPO therapy. Iron deficiency is present when
transferrin saturation is 16% and ferritin 30 ng/ml . Seven patients (44%) in this
study were iron deficient by these criteria, and they had the greatest response to
iron sucrose (increase in Hb 2.1 1.3 g/dl vs. 0.9 1.0 g/dl in the iron replete group,
p 0.06). Iron status is also the leading determinant of EPO responsiveness in
patients with chronic renal failure, and concomitant intravenous iron is an
essential adjunct in this context. We found no association between GI pathology
and iron deficiency or response to iron, suggesting dietary factors or
malabsorption may also influence iron status in patients with CHF. Given that the
risk of death in CHF increases with small reductions in Hb , modest increases in
Hb should confer significant clinical benefits. This is supported by the
observations that peak oxygen consumption in CHF correlates with Hb levels ,
and the correction of anemia improves this measure of exercise capacity . The
mean increase in Hb in this study was 1.4 _ 1.3 g/dl (range: _0.7 to _3.1g/dl) for a
treatment phase of just 5 to 17 days encompassing only 4 or 6 hospital visits.
Others have recorded mean increases of 2.6 g/dl and 3.3 g/dl using a combination
of EPO and iron in similar CHF groups.11
Although the EPO/iron combination may result in a greater response than
iron alone, there are clearly individuals who have a dramatic hematologic and
clinical response to the latter. The fact that we recorded no adverse events relating
to the administration of iron sucrose or during follow-up is consistent with other
safety data concerning the use of this drug. After a total of 2,297 injections of iron
sucrose in 657 patients with renal failure, Macdougall and Roche reported adverse
events in only 2.5%. All were short-lived, and no patient required hospitalization.
Furthermore, iron sucrose appears safe in patients with known intolerance of other
parenteral iron preparations . Intravenous iron sucrose, without concomitant EPO,
is a simple and safe therapy that increases Hb, reduces symptoms, and improves
exercise capacity in anemic patients with CHF. Further assessment of its efficacy
should be made in multicenter, randomized, placebocontrolled trials.12
2.4.2 Erythropoietin therapy
Another possible explanation for the improved cardiac function in this study
may be the direct effect that EPO itself has on improving cardiac muscle function
and myocardial cell growth unrelated to its effect of the anemia. In fact EPO may
be crucial in the formation of the heart muscle in utero. It may also improve
endothelial function. Erythropoietin may be superior to blood transfusions not
only because adverse reactions to EPO are infrequent, but also because EPO
causes the production and release of young cells from the bone marrow into the
blood. These cells have an oxygen dissociation curve that is shifted to the right of
the normal curve, causing the release of much greater amounts of oxygen into the
tissues than occurs normally. On the other hand, transfused blood consists of older
red cells with an oxygen dissociation curve that is shifted to the left, causing the
release of much less oxygen into the tissues than occurs normally .8
The use of IV Fe along with EPO has been found to have an additive effect,
increasing the Hb even more than would occur with EPO alone while at the same
time allowing the dose of EPO to be reduced (10 –13). The lower dose of EPO
will be cost-saving and also reduce the chances of hypertension developing. We
used iron sucrose (Venofer) as our IV Fe medication because, in our experience, it
is extremely well tolerated and has not been associated with any serious side
effects in more than 1,200 patients over six years.8
A major advance was made by Silverberg et al. who corrected the anaemia
of HF patients by subcutaneous (s.c.) erythropoietin and intravenous (i.v.) iron. In
their first and second reports, which included 26 patients and 179 patients ,
respectively, the functional capacity improved by 34% and the hospitalization
numbers dropped dramatically by 96%. In their randomized trial, which included
only 16 treated and 16 control patients, the improvement in exercise capacity,
quality of life and renal function was nevertheless remarkable. The functional
class improved by 42% in the treated patients and worsened by 11% in the control
group. In the first 26 treated patients, an increase in LVEF from 27.7 to 35.4%
was observed. The majority of these patients had advanced renal failure with a
mean serum creatinine of 2.59 mg%.11
Wexler et al. (this supplement) suggest that treatment of anaemia in the HF
patient can break the vicious cycle of the cardio renal anaemia syndrome which in
their opinion is crucial to the improvement in response to the treatment of HF. If
the anaemia is not corrected, the extent of improvement, even with an optimal
treatment of HF, is limited. The beneficial effect of the correction of anaemia is
probably not related to protection from ischaemia, as silent ischaemia was as
common in 15 haemodialysis patients treated with erythropoietin and normalized
Hb compared wih 16 control haemodialysis patients.8
The main finding of the present study is that the correction of even mild
anemia in patients with symptoms of very severe CHF despite being on
maximally tolerated drug therapy resulted in a significant improvement in their
cardiac function and NYHA functional class. Therewas also a large reduction in
the number of days of hospitalization compared with a similar period before the
intervention. Furthermore, all this was achieved despite a marked reduction in the
dose of oral and IV furosemide. In the group in whom the anemia was not treated,
fourpatients died during the study. In all four cases the CHF was unremitting and
contributed to the deaths. In addition, for the group as a whole, the LVEF, the
NYHA class and the renal function worsened. There was also need for increased
oral and IV furosemide as well as increased hospitalization.6
Although erythropoietin levels are modestly elevated in patients with
CHF, the increase is less than that observed in other anemic populations.27,38,60
Accordingly, anemia in CHF may be responsive to exogenous erythropoietin
supplementation. The primary mechanism by which erythropoietin stimulates red
blood cell production is inhibition of apoptosis of bone marrow erythrocyte
progenitors. The erythropoietin receptor is a member of the cytokine class I
receptor superfamily.61 Ligand binding of erythropoietin to the homodimeric
erythropoietin receptor activates antiapoptotic signal transduction pathways. Bone
marrow erythroid progenitor cells escape from apoptosis and proliferate to result
inthe growth and maturation of proerythroblasts and normoblasts.
Subsequently, reticulocytosis occurs and hemoglobin concentration rises.
There are 3 currently available erythropoietic agents for treatment of anemia:
epoetin-_, epoetin-_ (both of which are recombinant human erythropoietin
[rHuEpo]), and darbepoetin-31 rHuEpo was first synthesized in 1985, 2 years
after the erythropoietin gene was cloned, and was approved by the US Food and
Drug Administration for clinical use for treatment of anemia in end-stage chronic
kidney disease in 1988. Early studies in dialysis-dependent patients with chronic
kidney disease showed that intravenous or subcutaneous administration of 150 to
200 IU/kg per week (in 1 to 3 divided doses) increased hemoglobin concentrations
to 10 to 12 g/dL in 83% to 90% of anemic patients with chronic kidney disease.
Plasma half-life of rHuEpo after intravenous dosing is 6 to 8 hours.11
Approximately 25% of the administered dose is absorbed after
subcutaneous dosing, but the plasma half-life is increased to 24 hours. The
amount of subcutaneous rHuEpo needed to achieve hemoglobin targets in patients
with chronic kidney disease is approximately 25% less than that needed for
intravenous dosing. Darbepoetin-_ is a long-acting, N-linked supersialylated
analog of human erythropoietin approved by the US Food and Drug
Administration for the treatment of anemia in patients with chronic kidney disease
in 2001.30 Compared with both native and recombinant erythropoietin, it has
stronger affinity for erythropoietin receptor and longer plasma half-life of
approximately 48 hours, with consequent longer dosing intervals of 1 to 2 weeks
during maintenance therapy. The effect of rHuEpo treatment on anemic patients
with CHF was first reported by Silverberg and his colleagues.1 In an open-label
study design, 26 anemic chronic HF patients (NYHA class III–IV and hemoglobin
12 g/dL) were treated with subcutaneous rHuEpo (mean dose, 5277 IU/wk) and
intravenous iron sucrose (mean dose, 185 mg/mo) with 4 to 15 months of follow-
up duration (mean, 7 months). rHuEpo therapy increased mean hemoglobin from
10.2 to 12.1 g/dL and was associated with improved NYHA function class (3.7
0.5 at baseline to 2.7 0.7, P_0.05), increased left ventricular ejection fraction
(28,5% at baseline to 35,8%, P_0.001), and reduced need for oral and intravenous
furosemide. The same investigators subsequently reported a randomized open-
label trial with a mean follow-up duration of 8 months to compare the effects of
partial correction of anemia with subcutaneous rHuEpo and intravenous iron
sucrose therapy versus usual care in 32 patients with severe CHF and anemia
(NYHA class III–IV and hemoglobin 11.5 g/dL).68 When compared with usual
care, the rHuEpo therapy (4000 IU 1 to 3 times weekly subcutaneously plus
intravenous iron sucrose 200 mg every 2 weeks) significantly increased the
hemoglobin level (10.3 to 12.9 g/dL versus 10.9 to 10.8 g/dL, P_0.0001),
improved NYHA functional class (rHuEpo 3.8_0.4 to 2.2_0.7 versus usual care
3.5_0.7 to 3.9_0.3, P_0.0001), and decreased hospitalization days (rHuEpo
13.8_7.2 to 2.9_6.6 days versus usual care 9.9_4.8 versus 15.5_9.8 days,
P_0.0001).11
An uncontrolled clinical series from the same investigators demonstrated
comparable clinical benefits of rHuEpo in 179 patients with CHF and concomitant
predialysis chronic kidney disease. Mancini and colleagues70 conducted a single-
blinded, randomized, placebo-controlled trial of rHuEpo therapy in 26 patients
with advanced CHF and anemia (hematocrit 35%). Patients received subcutaneous
rHuEpo 5000 IU 3 times per week adjusted to raise hematocrit to 45% for up to 3
months or a single subcutaneous injection of saline. Supplemental oral iron and
folate were also given to the patients who received rHuEpo therapy. Compared
with the placebo group, rHuEpo therapy was associated with significant increases
in hemoglobin (11.0 0.5 to 14.3 1.0 g/dL, P0.05), peak oxygen uptake (11.0 1.8 to
12.7 2.8 mL/min per kilogram, P 0.05), and treadmill exercise duration (590 107
to 657 119 seconds, P_0.004). The increases in hemoglobin levels were linearly
associated with the increase in peak oxygen uptake (r_0.53, P_0.02).
Subjects with both hemodilution anemia and true anemia with reduced red
blood cell volume appeared to derive comparable improvement in exercise
capacity in response to rHuEpo therapy. In the hemodilution subgroup with
expanded plasma volume, the rise in measured hematocrit in response to rHuEPO
treatment was primarily due to a decrease in plasma volume. As diuretic dosing
did not change during the study, this finding suggests that erythropoietin has
direct or indirect effects on renal regulation of plasma volume. The
pharmacokinetic and pharmacodynamic profile of darbepoetin was compared in
33 anemic CHF patients (hemoglobin _12.5 g/dL) versus 30 healthy subjects.
Darbepoetin-_ administered once monthly at doses of 2.0 _g/kg or higher
produced a sustained increase in hemoglobin concentration in anemic patients
with CHF without severe drug-related adverse events. The effect of treatment with
darbepoetin-_ (0.7 _g/kg subcutaneously every 2 weeks for 26 weeks) on exercise
tolerance in 41 anemic patients with CHF (hemoglobin 9 to 12 g/dL) was
evaluated in a randomized placebo controlled trial.72 An abstract report of the
study findings indicates favorable effects of darbepoetin on exercise duration and
quality of life when compared with placebo. A larger double-blinded, placebo-
controlled, randomized trial, Studies of Anemia in Heart Failure Trial (STAMINA
HeFT), was undertaken to determine whether increased hemoglobin in response to
darbepoetin can improve exercise capacity and quality of life in 300 anemic
patients with CHF. The study has completed enrollment, but results have not yet
been published.11
2.4.3 Blood Tranfusion
The clinical utility of blood transfusion in anemic cardiovascular disease
populations is controversial. According to the guidelines from the American
College of Physicians and the American Society of Anesthesiology, the
“transfusion threshold” for patients without known risk factors for cardiac disease
is a hemoglobin level in the range of 6 to 8 g/dL.55 In 78 974 elderly patients
hospitalized with acute myocardial infarction, blood transfusion was associated
with a significantly lower 30-day mortality rate among patients with a hematocrit
_30% on admission. In 838 critically ill patients (26% with cardiovascular
disease), maintaining hemoglobin at 10 to 12 g/dL did not provide additional
benefits on 30-day mortality compared with maintaining hemoglobin at 7 to 9
g/dL. Blood transfusion may be associated with other adverse effects including
immunosuppression with increased risk of infection, sensitization to HLA
antigens, and iron overload. Given this profile of risks and benefits, transfusion
may be considered as an acute treatment for severe anemia on an individualized
basis but does not appear to be a viable therapeutic strategy for the long-term
management of chronic anemia in CHF.11
CHPATER III
Conclusion
More than half of community patients with heart failure arecurrently anemic
and the prevalence is increasing over time. Patients with heart failure with
preserved ejection fraction have an increased prevalence of anemia compared with
patients with reduced ejection fraction. Anemia is associated with increased
mortality, but hemoglobin follows a J-shaped curve, with increased mortality at
both low and very high hemoglobin levels. Further work is needed to investigate
the increasing prevalence of anemia in heart failure and to determine whether
treatment improves outcomes.
Intravenous iron treatment appears to improve subjective and objective
outcomes in patients with heart failure. The reported trials enrolled patients who
had iron deficiency or anemia of chronic inflammation. Most patients were not
anemic or only had mild anemia. After treatment, hemoglobin concentration rose
slightly. This suggests that the effect of iron was mediated by mechanisms other
than correction of anemia. Experimental evidence points to iron serving as a
cofactor for muscle function. In summary, anaemia is very common in HF
patients. It is frequently associated with renal failure and, when present, it affects
prognosis of these patients, their quality of life and their response to treatment.
Aggressive correction of the anaemia with s.c. erythropoietin and i.v. or p.o.
iron can improve the Hb levels of these patients, their quality of life, their
response to medical therapy and, hopefully, though not yet demonstrated, improve
their prognosis. While the level to which the anaemia should be corrected is not
clear, Hb probably should exceed 12 g/dl.