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.