International Journal of Cardiology 186 (2015) 117–124

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Review

Is anemia a new cardiovascular risk factor? Georgia Kaiafa a, Ilias Kanellos a, Christos Savopoulos a, Nikolaos Kakaletsis a, George Giannakoulas b, Apostolos I. Hatzitolios a,⁎ a b

1st Propaedeutic Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece Cardiology Department, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece

a r t i c l e

i n f o

Article history: Received 9 October 2014 Received in revised form 20 January 2015 Accepted 15 March 2015 Available online 17 March 2015 Keywords: Anemia Acute coronary syndromes (ACS) Acute myocardial infarction (AMI) Heart failure (HF) Chronic heart failure (CHF)

a b s t r a c t Anemia is frequent in patients with cardiovascular disease and is often characterized as the fifth cardiovascular risk factor. It is considered to develop due to a complex interaction of iron deficiency, cytokine production and impaired renal function, although other factors, such as blood loss, may also contribute. Unfortunately, treatment of anemia in cardiovascular disease lacks clear targets and specific therapy is not defined. Treatment with erythropoietin-stimulating agents in combination with iron is the basic strategy but clear guidelines are not currently available. This review aims to clarify poorly investigated and defined issues concerning the relation of anemia and cardiovascular risk – in particular in patients with acute coronary syndromes and chronic heart failure – as well as the current therapeutic strategies in these clinical conditions. © 2015 Elsevier Ireland Ltd. All rights reserved.

Cardiovascular disease is a significant health issue around the world and accounts for a majority of deaths each year in westernized countries. In the United States cardiovascular disease accounts for one of every two deaths [1]. This increased death rate, despite advances in medical treatment, points to the importance of identifying factors related to poor outcomes and developing new treatment and prevention modalities. Anemia is common in patients with cardiovascular disease and is a multifactorial problem especially in the elderly population [2]. The odds ratio of mortality, morbidity and hospitalization in patients with anemia is similar to those of four other common cardiovascular risk factors, such as smoking, diabetes mellitus (DM), arterial hypertension and hypercholesterolemia. Consequently, anemia has lately been characterized as “the fifth cardiovascular risk factor” [2]. The purpose of the present review is to investigate most of the related issues and treatment options in the management of cardiovascular risk in anemic patients. In specific, the relationship of anemia with acute coronary syndromes (ACS) and CHF is sought.

Abbreviations: ACS, acute coronary syndromes; AMI, acute myocardial infarction; CHF, chronic heart failure; CHOIR trial, Correction of Hb and Outcomes in Renal Insufficiency; CPG, Committee for Practice Guidelines; DM, diabetes mellitus; EAS, European Atherosclerosis Society; ESAs, erythropoiesis-stimulating agents; ESC, European Society of Cardiology; HMW, high molecular weight; LDL, low density lipoproteins; PCI, percutaneous coronary intervention; RDW, red celldistribution width; STEMI, ST-elevation myocardial infarction; sTfR, soluble transferrin receptor; TSAT, transferrin saturation. ⁎ Corresponding author at: 1st Propaedeutic Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Stilp, Kiriakidi 1, Thessaloniki 546 36, Greece. E-mail address: [email protected] (A.I. Hatzitolios).

http://dx.doi.org/10.1016/j.ijcard.2015.03.159 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.

1. Definitions According to WHO criteria, anemia is defined as a concentration of Hb b13 g/dl in men and b 12 g/dl in women [3]. In general, risk factor is defined as any biological condition, substance, or behavior which has an association with, but has not been proven to cause an event or disease. Furthermore, cardiovascular risk is defined as the ten-year risk of cardiovascular disease occurrence and is divided into low, moderate, high and very high additional risk [3]. According to Framingham, the low cardiovascular risk is b 15%, moderate is 15–20%, high is 20–30% and very high is N 30%, while according to the European cardiovascular disease risk assessment model (SCORE) which concerns ten-year risk of fatal cardiovascular disease, the low is b1%, moderate is 1–5%, high is 5–10% and very high is N10% [4]. 2. Anemia & acute coronary syndromes Anemia is present in one third of patients with ACS; in particular, in 12.8% of patients with acute myocardial infarction (AMI), in 43% of the elderly patients with ST-elevation myocardial infarction (STEMI) and in 5–10% of non-ST elevation ACS patients [5]. Patients without coronary heart disease have a tremendous ability to compensate for diseases in coronary arterial oxygen content, while those with coronary artery disease have a limited ability to compensate for or to tolerate uncompensated decreases in myocardial oxygen delivery. At the coronary level, ischemia causes a critical imbalance in oxygen supply and demand to the myocardium. Protracting this condition induces necrosis since, when the heart surpasses certain limits, it is incapable of modulating

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its metabolism in relation to the availability of energy substrates. The drop in circulating erythrocyte mass and the consequent decrease in hemoglobin and hematocrit represent obstacles to oxygen transport and delivery to tissues. Tachycardia secondary to anemia leads to a shorter diastolic phase and reduction in arterial pressure, phenomena which are particularly prominent in acute anemia. Such changes can result in serious repercussions for patients suffering from coronary disease, leading often to documentable myocardial damage [6]. The high risk for ACS in anemic patients is also probably associated with the low levels of high-molecular-weight adiponectin, which has anti-inflammatory and atherosclerotic effects [7]. Recent data also suggest that ACS patients with anemia demonstrate a reduced number of peripheral endothelial progenitor cells with impaired function, possibly representing a lower capacity for vascular healing. These phenomena may partly explain the poor prognosis observed in anemic patients with ACS [8]. Furthermore, anemia may predispose patients to recurrent ischemia, which can be an important underlying mediator of worse outcomes [9]. Recent studies suggest that patients with anemia have a greater burden of necrotic core and thin-cap fibroatheroma, which may contribute to future adverse events including recurrent AMI. In one study, virtual histology intravascular ultrasound analysis demonstrated that anemia at the time of clinical presentation was associated with more vulnerable plaque component in patients with ACS [10]. Baseline anemia with lower admission Hb levels is associated with longer duration of symptoms in men with STEMI and inversely related to their admission inflammatory surrogate (CRP) levels [11]. It is known that CRP induces plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells and thus could have implications in the development of atherothrombosis. Elevated inflammatory levels in anemic patients might be a contributor to adverse clinical events [12]. Anemia on admission provides independent prognostic information on top of the GRACE score for the prediction of mortality or recurrent AMI in ACS patients at 1-month follow-up with a decrease of Hb of more than 0.9 g/dl indicating high-risk ACS [5]. Moderate and severe in-hospital acquired new-onset anemia, in patients admitted with normal hemoglobin, is a common complication during AMI, frequently persists after discharge and is associated with poor outcomes, namely a higher mortality rate and incidence of complications in comparison with patients who maintain normal Hb values [13]. It could be explained by in-hospital antithrombotic therapy, obscure bleeding, repeating blood withdrawal, as well as hemodilution due to iv fluid administration as preparation prior to coronary angiography. The incidence of in-hospital acquired anemia varies significantly across hospitals and this variability may reflect that different processes of inhospital care [14]. Anemia may be caused by bleeding episodes during invasive procedures and intensive anticoagulation in the setting of ACS, but it is also

observed in AMI patients who are treated conservatively without bleeding complications [15], which suggests that mechanisms other than bleeding may play a role to the development of anemia. Tissue injury in AMI incites an acute inflammatory response that may persist for a long time [16]. The inflammation interacts with the hematopoietic system at various levels and results in reduced erythropoiesis, accelerated destruction of erythrocytes and erythropoietin resistance [17]. Preprocedural anemia is associated with increased adverse inhospital events after primary percutaneous coronary intervention (PCI) [18]. Patients with anemia undergoing primary PCI are at a higher risk of an adverse outcome. Although anemia does not appear to be an independent predictor of all-cause mortality or major adverse cardiac events after primary PCI on multivariate analysis, there appears to be a threshold value of Hb among men, below which there is an associated increased risk [19]. Another analysis from the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial demonstrated that baseline anemia was an independent predictor of in-hospital and 1-year mortality. Patients with anemia had more bleeding complications and blood transfusions along with increased 30-day and 1-year rates of disabling stroke [20]. Furthermore, an association between low serum iron concentration before primary PCI and impaired recovery of LV systolic function 6 months later has been found. The circulating concentration of IL-6 was increased after STEMI and negatively correlated with serum iron concentration. Thus serum iron concentration is associated with a cardioprotective phenotype and is a potential biomarker for complications after STEMI [21]. Although, there is a clear correlation between anemia and mortality in patients with ACS (Table 1), there is little clinical evidence that permits prediction of the critical hemoglobin or hematocrit at which significant ischemia will develop in any given patient [22]. According to Sabatin et al. [23], Hb levels b10 g/dl are related to a significant risk of cardiovascular death in patients with ACS (Fig. 1). The higher Ht is associated with a lower risk of cardiovascular death and it seems that for each Ht increase of 1% there is a 4% reduction of cardiovascular risk [24]. However, it is also worth mentioning that Hb N 17 g/dl brings about very serious risks [25]. 3. Anemia & chronic heart failure CHF is a complex clinical syndrome of symptoms and signs in which the efficiency of the heart as a pump is impaired. It is caused by cardiac dysfunction, generally resulting from any structural or functional impairment of ventricular ejection or filling of blood characterized by either LV dilation or hypertrophy or both. Whether the dysfunction is primarily systolic or diastolic or mixed, it leads to neurohormonal and circulatory abnormalities, usually resulting in characteristic symptoms such as dyspnea and fatigue, which may limit exercise tolerance, and fluid retention in the pulmonary and/or splanchnic circulation, and/or peripheral edema [26,27].

Table 1 The five main studies concerning occurrence of cardiovascular risk in anemic patients. Studies ARIC study [76] (Atherosclerosis Risk in Communities)

Results

14,410 people aged 45–64 years from the general population without cardiovascular disease. 1358 of them had low Hb. In 6.1 years cardiovascular–coronary events were observed at a rate of 3.8%. Anemia is an independent prognostic marker with regard to coronary disease risk. CADILLAC study [20] 2082 patients of any age with acute myocardial infarction. Anemia was present in 260 (12.8%) and is strongly (Controlled Abciximab and Device Investigation to Lower associated with adverse outcomes and increased mortality. Late Angioplasty Complications) Meneveau et al. [5] 1410 consecutive patients with acute coronary syndromes. Anemia was detected in 381 patients (27%). Anemia (Registre Franc Comtois des Syndromes Coronariens was an independent predictive factor of mortality and had incremental predictive value to the GRACE score Aigus) system for early clinical outcomes. NHANES II survey [77] 8896 persons from NHANES II survey. 1629 men and 1706 women were with Ht in the lower tertile. There is no (National Health And Nutrition Examination Survey) specific correlation between anemia and cardiovascular risk. SOLVD study [29,30] 6538 patients with depressed left ventricular function. After adjusting for possible confounders, including renal function, (Studies Of Left Ventricular Dysfunction) low Ht was associated with the risk of CV mortality, HF death, HF hospitalization and cardiac ischemic events. Abbreviations as in the text.

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Fig. 1. Unadjusted and adjusted ORs and 95% CIs for association between baseline hemoglobin concentration and cardiovascular mortality through 30 days in patients with STEMI (with written reuse license from Wolters Kluwer Health).

Many conditions or comorbidities are associated with an increased propensity for structural heart disease. A list of the most important potential causes of CHF appears in Table 2. 3.1. Prevalence and incidence of anemia in heart failure The frequency of anemia is constantly increasing in CHF. It is estimated that anemia approaches 53–58% of CHF patients in the USA [28]. According to the SOLVD study, up to 9.6% of patients with CHF will develop anemia in the first year [29,30]. According to Val-HeFT study, 16.9% of CHF patients will develop anemia [31], while according to COMET study patients will develop anemia in the first year at 14.2% and in a five-year period at 27.5% [32]. A number of prospective and retrospective studies (Val-HeFT, COMET, ELITE-II, RENAISSANCE, CHARM, Silverberg et al.) [31–36] revealed a 30% incidence for hospitalized patients and 20% for outpatients with CHF (Table 3). Table 2 Potential causes of chronic heart failure. Myocardial disease

Coronary artery disease Arterial hypertension Cardiomyopathy: • Familial (hypertrophic, dilated, arrhythmogenic right ventricular cardiomyopathy, restrictive, left ventricular non-compaction) • Acquired (myocarditis; infective/immune-mediated/ toxic, endocrine, nutritional, pregnancy, infiltration)

Valvular heart disease Pericardial disease Endocardial disease

Congenital heart disease Arrhythmias, conduction disorders High output states

Volume overload

Mitral, aortic, tricuspid, pulmonary Constrictive pericarditis Pericardial effusion Endomyocardial diseases with/without hypereosinophilia Endocardial fibroelastosis Tachyarrhythmia (atrial, ventricular) Bradyarrhythmia (sinus node dysfunction) Atrioventricular block Anemia Sepsis Thyrotoxicosis Paget's disease Arteriovenous fistula Renal failure Iatrogenic

3.2. Etiology and pathophysiologic mechanisms of anemia in CHF Current guidelines of the European Society of Cardiology for the management of CHF [37] recognize iron deficiency as a common comorbidity, which complicates the natural course of the disease and is an independent adverse prognostic factor, irrespectively of the presence of anemia. In a group of 546 patients with CHF of varying severity the prevalence of iron deficiency was 37% in the whole cohort, 57% in anemic patients and 32% in non-anemic ones [38]. Iron deficiency is not associated with the expected decrease in ferritin concentrations. This relative increase in ferritin concentrations may be the result of the inflammation that accompanies the CHF syndrome [39]. Iron controls the expression of the central citric acid cycle enzyme aconitase and because it is a central component in mitochondrial respiration complexes, it catalyzes the transfer of electrons in oxidation–reduction processes. Heart tissue is rich in mitochondria, making iron a particular important element for the cardiac function as it is an important co-factor in the production of free radicals, and there is evidence to suggest that these highly reactive molecules may play a crucial role in the process of cardiac remodeling and apoptosis in CHF [40]. The relatively low erythropoietin in CHF could be attributable to either cytokine inhibition of erythropoietic production on the kidney and/or to the associated renal failure. Interleukin-1 and TNF-a directly inhibit the in vitro production of erythropoietin in patients with inflammatory disorders who commonly exhibit a blunted response of erythropoietin to anemia [41]. Elevated plasma concentrations of TNF-a interfere with the peripheral effects of erythropoietin [42]. Anemia in patients with advanced CHF may also be caused by bone narrow suppression. Another mechanism of low Hb concentration may be the increased plasma volume with the presence of normal red blood cell volume. Androne et al. have reported a 46% prevalence of hemodilution in anemia patients with advanced CHF [43]. Other reasons for the increase in frequency and severity of anemia in patients with CHF are the increased patient age (the age itself is associated with lower Hb), increasing prevalence of renal deficiency and diabetes mellitus, and the optimal treatment of heart failure with the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These drugs depress erythropoietin synthesis by increasing N-acetyl-seryl-aspartyl-lysyl-proline, which is an inhibitor of erythropoiesis and cause an ≃0.5 g/dl decrease in Hb [44,45]. Fig. 2 and Table 4 summarize all possible pathophysiologic mechanisms of anemia in CHF [46–48].

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Table 3 A brief description of anemia — heart failure trials. Initial study

Population

Hypothesis being tested

Treatment

Conclusions

SOLVD study [29,30]

4174 patients with EF b35%

The impact of ACEIs on Ht in HF patients and the relationship between incident anemia and mortality

Enalapril vs placebo

Val-HeFT study [31]

5002 patients with symptomatic HF

The prognostic value of baseline Hb in HF, to relate changes in Hb over time to mortality and morbidity, and to identify factors related to changes in Hb, including the effect of valsartan

Valsartan vs placebo

COMET study [32]

3029 patients with CHF in NYHA II–IV and EF b35%

The predictors of new onset anemia and its long-term prognostic value, particularly in patients treated with beta-blockers

Carvedilol vs metoprolol

ELITE-II study [33]

The relationship between the concentration of Hb and survival in CHF

Losartan vs captopril

RENAISSANCE study [34]

3044 patients N60 years old, with CHF in NYHA II–IV and EF b40% 912 patients with CHF in NYHA II–IV and EF b30%

The relationship between anemia, severity of CHF, and clinical outcomes

Etanercept vs placebo

CHARM study [35]

2653 patients with CHF in NYHA II–IV

The prevalence of potential mechanistic Candesartan vs placebo associations and clinical outcomes related to anemia in patients with HF and a broad spectrum of LVEF

PRAISE study [49]

1130 patients with CHF in NYHA IIIB–IV and EF b30%

The relationships between serum Ht and risk of all-cause mortality among patients with severe HF

Amlodipine vs placebo

COPERNICUS study [50]

2,289 patients with CHF EF b25%

The importance of anemia in severe CHF and its ability to predict hospitalization

Carvedilol vs placebo

FAIR-HF [54]

459 patients with CHF in NYHA II–III and EF b40%

STAMINA-Heft study [69]

319 patients with symptomatic HF and EF b40%

The effects of i.v. ferric carboxymaltose in Ferric carboxymaltose CHF patients with iron deficiency seen vs placebo according to the presence or absence of anemia at baseline The effect of treating anemia in HF Darbepoetin alfa vs placebo

Incident anemia at 1 year is common in those with reduced left ventricular function (9.6%). Participants with anemia had an increased mortality risk compared with those that never develop anemia. Changes in Hb over 1 year were inversely associated with subsequent risk of mortality and morbidity (20%), independently of the effects of baseline anemia and other important predictors. Several factors were independently related to anemia at baseline and changes in Hb, suggesting multiple causes of anemia in patients with heart failure. In stable ambulatory CHF patients, development of new onset anemia is frequent and can be predicted by a set of clinical variables (14.2% at year 1 to 27.5% at year 5). Decreases in Hb over time relate to future increased morbidity and mortality. Hb is an independent predictor of mortality in CHF patients, with anemic and polycythemic patients having the worst survival. Anemia is frequently present in patients with CHF. Lower Hb is associated with greater disease severity, a greater left ventricular mass index, and higher hospitalization and mortality rates (14.2%). Anemia was common in HF, regardless of LVEF. Lower Hb was associated with higher LVEF yet was an independent predictor of adverse mortality and morbidity outcomes. In HF, the causes of anemia and the associations between anemia and outcomes are probably multiple and complex. Among patients with severe HF, anemia is a significant independent risk factor for death, with a progressively higher risk with increasing severity of anemia (11% for each 1% decrease in Ht). Levels of Hb b11 g/dl in patients with HF is correlated with annual risk of death or hospitalization 46.6%, while when Hb b16.5 g/dl the percentage of annual risk is reduced to 25.5%. Iron status should be assessed in symptomatic CHF patients both with and without anemia and treatment of iron deficiency should be considered.

RED-HF study [73]

2600 patients with CHF in NYHA II–IV and EF b40%

CONFIRM-HF study [55]

304 patients with CHF in NYHA II–III and EF b45%

IRON-HF study [56]

23 patients with CHF in NYHA II–IV and EF b40%

The effect of iv or oral iron supplementation alone in heart failure patients with anemia

iv vs oral iron

CREATE study [70]

603 patients with GFR; 15–35

sc EPO

CHOIR study [71] TREAT study [72]

1,432 participants with CKD and anemia 4,038 patients with diabetes, CKD and anemia

If the complete correction of anemia in patients with stage 3 or 4 CKD improves cardiovascular outcomes as compared with partial correction of anemia The impact of target Hb level on progression of kidney disease If in these patients, increasing Hb levels with the use of darbepoetin alfa would lower the rates of death, cardiovascular events, and end-stage renal disease

Silverberg et al. [36]

142 patients with congestive HF

The effect of the long-acting erythropoietin-stimulating agent darbepoetin on mortality and morbidity (and quality of life) in patients with HF and anemia The benefits and safety of long-term iv iron therapy in iron-deficient patients with HF

Darbepoetin alfa vs placebo

Ferric carboxymaltose (FCM) vs placebo

sc epoetin-alfa Darbepoetin alfa vs placebo

The prevalence and severity of anemia in Combination of sc EPO patients with congestive HF and the and iv iron effect of its correction on cardiac and renal function and hospitalization.

Treatment with darbepoetin alfa was not associated with significant clinical benefits. Darbepoetin alfa treatment was well tolerated and effectively raised hemoglobin. A trend of lower risk of morbidity and mortality was observed. Treatment with darbepoetin alfa did not improve clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia.

Treatment of symptomatic, iron-deficient HF patients with FCM over a 1-year period resulted in sustainable improvement in functional capacity, symptoms, and QoL and may be associated with risk reduction of hospitalization for worsening HF. iv iron seems to be superior in improving functional capacity of heart failure patients. However, correction of anemia seems to be at least similar between oral iron and iv iron supplementation. In patients with CKD, early complete correction of anemia does not reduce the risk of cardiovascular events. Hb target did not interact with estimated glomerular filtration rate, proteinuria, diabetes, or heart failure. The use of darbepoetin alfa in these patients did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. Anemia is very common in congestive HF and its successful treatment is associated with a significant improvement in cardiac function, functional class, renal function and in a marked fall in the need for diuretics and hospitalization.

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Table 3 (continued) Initial study

Population

Hypothesis being tested

Treatment

Conclusions

Nanas et al. [53]

37 consecutive patients with end-stage congestive HF and anemia

The causes of anemia in patients with end-stage congestive HF

–

Palazzuoli et al. [57]

51 patients with CHF in NYHA III–IV and EF b40%

The effect of β-EPO therapy and oral iron on left ventricular (LV) dimensions and function, pulmonary artery pressure (PAP), and B-type natriuretic peptide (BNP)

Subcutaneous EPO vs placebo

The iron status of patients with end-stage chronic congestive HF should be thoroughly evaluated and corrected before considering other therapeutic interventions. Correction of anemia with EPO and oral iron over 1 year lead to an improvement in LV systolic function, LV remodeling, BNP levels, and PAP compared with a control group in which only oral iron was used.

Abbreviations as in the text.

3.3. Prognostic implications of anemia The incidence of anemia increases with worsening functional class, from 9% for NYHA I to 79% for NYHA IV [34]. Additionally, anemia is considered as an independent risk factor for acute and CHF with left ventricular dysfunction and is associated with an ~20% increase in risk of morbidity and mortality [31]. According to the RENAISSANCE study, the annual risk of death was 28% in anemic patients with CHF and just 16% in patients with HF without anemia [34]. PRAISE study showed that a reduction of 1% in Ht was correlated with an 11% increase in the risk of death in patients with CHF [49]. Finally, according to COPERNICUS study, anemia was an independent risk factor for 1-year morbidity, CHF hospitalization and mortality outcomes [50]. There is some controversial data indicating that high levels of Ht are correlated with lower risk of death in patients with CHF. It is estimated that for every 1% increase in Ht, we expect a 2.4% reduction in the annual risk of death [36]. Also, a 1 g/dl increase in Hb concentration is associated with a 4.1 g/m2 decrease in left ventricular mass over a 24-week period [34]. However, a high Hb level may promote systemic vasoconstriction by trapping nitric oxide [51]. Therefore, both patients with polycythemia vera as well as anemic CHF patients present the worst prognosis [33]. It should be clarified that there are no specific recommendations for the optimal upper levels of hemoglobin in CHF patients. 4. Treatment of anemia in CHF Until recently the role of anemia in CHF has been underestimated and unrecognized resulting in undertreatment. In 2000 in the U.S.

only 527 (3.5%) out of 14.985 anemic CHF patients received EPO and only 22 (0.2%) received iv iron. In 2009 from 11.754 anemic CHF patients, only 38.4% performed blood test for iron in the course of one year, 8% received EPO and 21% iron supplements [52]. A reasonable question is up to which grade should anemia be corrected in CHF? There are advantages in the correction of anemia, such as improving tissue oxygenation, exercise tolerance and quality of life, potential antiapoptotic action of treatments and possible reducing the percentage of deaths and hospitalizations. On the other hand there are potential risks, such as increased risk of thrombosis, platelet activation, risk of hypertension and endothelial activation. 5. Iron therapy: oral or intravenous? Iron deficiency is the most common cause of anemia in patients with CHF. Three studies [Nanas et al., FAIR-HF (Ferinject Assessment in patients with iron deficiency and CHF) and CONFIRM-HF] [53–55] demonstrated that iron deficiency should be considered as a potential therapeutic target in symptomatic CHF patients and subsequently iron repletion improves functional capacity, symptoms and quality of life. IRON-HF study [56] showed that iv iron was superior in improving functional capacity of HF patients compared to oral supplementation. However in Palazzuoli study [57] correction of anemia in CHF patients with oral iron over 1 year did not lead to a clinical improvement unless they received a combination of oral iron and EPO. A large dose of oral iron is required for long-term period to full the iron stores, which might have a potential risk of dose-depending sideeffects, such as gastrointestinal (20–30%) and often results in poor

Fig. 2. Pathophysiologic relationship between anemia and chronic heart failure.

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Table 4 The etiology of anemia in chronic heart failure. Functional iron deficiency Malnutrition

Bone marrow Absolute iron deficiency

Impaired renal function, Diabetic nephropathy Medications Hemodilution Age

Chronic disease Inflammation Vitamin B12 (atrophic gastritis) Cardiac cachexia Folic acid EPO resistance Cytokines (TNF-a) Chronic blood loss (aspirin, warfarin, clopidogrel and novel P2Y12 platelet inhibitors) Iron malabsorption (damage of the intestinal wall or reduced absorption of iron from proton pump inhibitors) EPO production ACE-inhibitors Pseudo-anemia (50% of NYHA IV patients) The age itself is associated with lower Hb

Abbreviations as in the text.

compliance [58–60]. On the other hand, iv iron is associated with the risk of developing bacterial infections [61] and it can also increase oxidative stress, which in turn contributes to an increased risk for endothelial dysfunction and tissue damage [63]. Another possible negative effect of iron administration is that excess of iron catalyzes the modification of low density lipoproteins (LDL), inducing the formation of atherosclerotic plaques leading to an increase in the risk of coronary events [62]. Newer iv iron complexes (i.e., sucrosic Fe++, carboxymaltosic, low molecular weight dextran) are more secure, without side effects and can be easily administered with relatively low cost [63]. For a stronger recommendation of iron deficiency as a therapeutic target in CHF, additional well-designed and controlled studies with longer follow-up periods are needed to determine the exact mechanisms of benefit and long-term cardiovascular outcomes associated with supplemental iron therapy in patients with CHF. 6. Which patients will respond to intravenous iron administration? There is no way to predict which patients with CHF will respond to i.v. iron administration. It is difficult to answer this question because there are no specific criteria, examinations or markers for this purpose. The most reliable indicators for iron deficiency are: ferritin, sTfR (soluble transferrin receptor), TSAT (transferrin saturation), RDW (red cell distribution width with normal reference values ranging between 11– 14%). RDW is a measurement of the size of variation of erythrocyte volume; it has been identified as a strong independent predictor of increased morbidity and mortality in patients with ACS and CHF even in nonanemic ones and an increased RDW is associated with a poor prognosis. FAIR-HF data provided a unique opportunity to evaluate the link between high RDW and iron status [64] and showed that iron deficiency contributes to increased RDW values in CHF, regardless of the presence or absence of anemia (94% sensitivity), while iron treatment in iron deficient patients decreased RDW values, which confirms the association between iron deficiency and anisocytosis. Also, patients with increased RDW values had impaired exercise capacity and the observed improvement in 6MWT after 24 weeks was associated with a decrease in RDW [64]. 7. Blood transfusion A few studies which focused on RBC transfusion revealed the adverse effect of transfusion in patients with CHF. There is a narrow window of the optimal Hb or Ht level at which patients with cardiac disease have the better outcome; Ht values below 28% (irrespectively if the anemia is chronic or acute) or above 35% appear to be associated with increasing risk of morbidity and mortality. Based on these data, it seems prudent to transfuse patients with cardiovascular disease when

Ht falls below 28%, but not to attempt achieving normal values (greater than 40%). The mechanism of the association between transfusion and mortality in patients with CHF is unclear. It has been speculated that platelet activation, activation of the coagulation cascade, reduction in tissue oxygen delivery, disruption of NO-mediated vasodilation and the risk of transmission of an infectious disease whether bacterial or viral, could contribute to a negative effect of transfusion on mortality [65]. 8. Therapy with EPO and other ESAs A few studies showed that in CHF, correction of anemia with EPO reduced heart rate, plasma volume, pressure of the pulmonary artery, hypertrophy and diastolic left ventricular function, severity of mitral regurgitation and anti-inflammatory agents (IL-6, CRP) [66,67]. It also improved renal function, depression, sleep apnea and skills for adhesion and proliferation of circulating endothelial progenitor cells. Furthermore, EPO receptors exist in myocardial cells of adult and administration of EPO reduces apoptosis of these cells [68]. However, a series of large randomized trials showed that the aggressive correction of the anemia in CHF patients with ESAs has either neutral or even negative effects on patients' prognosis. In particular, STAMINA-Heft study, a randomized double-blind trial of darbepoetin A in patients with symptomatic CHF and anemia, showed that treatment with this synthetic EPO was not associated with significant clinical benefits [69]. CREATE trial showed neutral effects on the occurrence of cardiovascular events at three years [70], while CHOIR trial (Correction of Hb and Outcomes in Renal Insufficiency) showed that EPO increased the occurrence of death and cardiovascular events at three years, without having a significantly beneficial effect on quality of life [71]. TREAT study (Trial to Reduce Cardiovascular Events with Aranesp Therapy) demonstrated an increase in the rate of stroke at three years in the darbepoetin arm [72], while RED-HF study (Reduction of Events With Darbepoetin in Heart Failure) demonstrated that there was no improvement, in patients who were under EPO treatment [73]. Recent oncology publications raise concern regarding EPO-treated patients, because of the potential increase in incidence of disease progression in the EPO group (6% vs 3% compared with placebo), as well as an increase in the incidence of thrombotic and vascular events in the EPO group, attributable to direct effects of EPO in platelets or vascular endothelial cells or effects of increased Hb levels on blood viscosity (1% vs 0.2% compared to placebo) [74]. Currently, the use of iron and ESAs is recommended in anemic patients with CHF only when chronic kidney disease coexists, actually in order to achieve Hb between 11.0–12.0 g/dl [75]. 9. Conclusion Anemia is a common phenomenon in patients with ACS and/or CHF and is associated with a worse prognosis. There is not enough evidence to suggest that anemia is either a simple independent indicator of disease severity or a secondary factor involved into deterioration of prognosis. The question whether treatment of anemia in these patients is associated with better outcome remains controversial. Treatment with iv iron has shown promising results, while the use of ESAs is recommended only in anemic patients with CHF and coexisting chronic kidney disease, with a target of Hb no more than 10.0–12.0 g/dl. However, large-scale, randomized controlled trials are required for assessing the potential benefits resulting from the correction of anemia in patients with cardiovascular disease and the targets of Hb that should be pursued as well as the rate of correction. Conflict of interest The authors report no relationships that could be construed as a conflict of interest.

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