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 ones 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 10fold 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 NTprobrain natriuretic peptide, C-reactive protein, ejection fraction (31.3% 35.7%), and a 6-minute walk (192.3240.1 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 (placebo15 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 Ganzonis 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 IIIIV 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 followup 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 openlabel 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 IIIIV 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 singleblinded, 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, placebocontrolled, 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.