Anemia Management in Cardiorenal Disease

anemia is common in congestive heart failure (CHF) and is associated with increased mortality, morbidity, and progressive renal failure. The two most common causes of the anemia are associated renal failure, which causes depression of erythropoietin production in the kidney, and excessive cytokine production, which can also cause depression of erythropoietin production in the kidney as well as depression of the erythropoietic response in bone marrow.

Cytokines can induce iron deficiency by increasing hepcidin production from the liver, which both reduces gastrointestinal iron absorption and reduces iron release from iron stores located in the macrophages and hepatocytes. Many studies of anemia in CHF with erythropoiesis stimulating agents (ESA) and oral or IV iron—but also with IV iron without ESA—have shown positive effects on the anemia as well as on hospitalization, fatigue and shortness of breath, cardiac and renal function, quality of life, exercise capacity, and reduced beta natriuretic peptide. These studies have not demonstrated an increase in cardiovascular damage related to the therapy. Adequately powered, long-term placebo-controlled studies of ESA and of IV iron in CHF are still needed to examine hard cardiovascular endpoints.

Prevalence and significance of anemia in CHF

In a recent meta-analysis of 34 studies of anemia in CHF (1) including a total of 153,180 patients, 37.2 percent were anemic (using the authors’ own criteria), and the adjusted hazard ratio (HR) for death was 1.46. In these anemic CHF patients, there was no difference between systolic or diastolic CHF in prevalence of anemia or mortality.

Another recent meta-analysis looked at 21 prospective clinical studies of anemia in CHF that studied 97,699 patients (2) (Table 1).

Table:1
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In the six studies that considered mortality, anemia was linked to a significantly higher risk of death (rr 1.66, p < 0.001). In three of the four studies that looked at CHF hospitalization rates, the rates were higher among anemic patients. In the five studies that evaluated left ventricular ejection fraction (LVEF), anemic patients had a 0.53 percent lower LVEF than nonanemic patients, p < 0.001. In 16 of the 21 studies that used multivariate analysis, an independent relationship between anemia and all outcomes in CHF was found.

These studies suggest but do not prove that anemia plays a causal role in the worsening of CHF.

What causes the anemia in CHF?

Anemia associated with CHF is most likely due to a combination of several factors (3,4).

Chronic kidney disease (CKD)

CKD is associated with reduced production of erythropoietin (EPO) in the kidney. The renal damage seen in many cases of CHF is probably mainly a result of reduced renal blood flow caused by the reduced cardiac output leading to hypoxic renal damage. Perhaps the most dramatic evidence of the role of CHF in renal failure is the improvement of renal function seen after successful cardiac resynchronization therapy when cardiac function is improved. Treatment of CHF with beta blockers is associated with an improvement in CHF and with an improvement in renal function and anemia (5). These data suggest that the better CHF is treated, the slower will be the progression of renal failure.

Elevated cytokines causing abnormalities in EPO and iron metabolism

Cytokines elaborated in CHF, especially tumor necrosis factor alpha (TNF α) and interleukin-6 (IL-6), can cause four hematological abnormalities (6):
  • reduced EPO production in the kidney leading to inappropriately low levels in the blood for the degree of anemia present

  • reduced erythropoietic response of the bone marrow to ESA

  • hepcidin-induced failure of iron absorption from the gut

  • hepcidin-induced trapping of iron in iron stores in the macrophages and hepatocytes

Hepcidin (6) is a protein released from the liver by IL-6. It inhibits the protein ferroportin, which is found in the gastrointestinal tract and in macrophages and hepatocytes. Ferroportin is responsible for the release of iron from these three types of cells into the blood. If ferroportin is inhibited, gastrointestinal iron absorption is diminished, and iron is not released from its storage in macrophages and hepatocytes. This results in a low serum iron, leading to decreased delivery of iron to bone marrow and therefore iron deficiency anemia, even in the presence of adequate total iron stores—the so-called functional iron deficiency. Since hepcidin is filtered and removed in the kidney, its levels increase in CKD, which also partly explains the iron deficiency in CKD and CHF.

Compared to hemodialysis patients taking EPO alone, those taking EPO and IV iron had lower proinflammatory TNF α levels and higher anti-inflammatory cytokine IL-4 levels as well as lower levels of total peroxide (a marker of free radical concentration) (7) suggesting that iron may be anti-inflammatory.

Use of angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARBs), and beta blockers

ACE-I and ARBs can each cause a fall in hemoglobin (Hb) of about 0.5–1g/dL due to reduced production of EPO and reduced activity of EPO in the bone marrow, because angiotensin is a stimulator of erythropoiesis (8). ACE-I can also increase the levels of erythropoietic inhibitors in the blood, further inhibiting erythropoiesis. ACE-Is and ARBs are additive and equal in their effect on reducing the Hb. They are often used together, and can therefore cause a fall in Hb of about 1–2 g/dL (8).

Hemodilution

It has been suggested that the anemia in CHF in many cases is partly due to hemodilution. In one study (9), investigators found that a true red cell deficit was present in 88 percent of CHF patients with anemia and diastolic CHF and 59 percent of those with anemia and systolic CHF. All the systolic CHF patients and 71 percent of the diastolic CHF patients also had expanded plasma volume. All these studies suggest that there is a true red cell deficit in the majority of anemic CHF patients but that hemodilution is also very common.

Diabetes

The EPO-producing cells in the kidney may be damaged early by glycosylation, which can explain why, for the same degree of renal function, diabetics have a lower Hb than nondiabetics.

Gastrointestinal problems

These include bleeding from aspirin, clopidogrel, warfarin-like agents, malignant tumors, polyps, esophagitis, or reduced iron absorption resulting from atrophic gastritis (in some cases caused by Helicobacter pylori, which can also cause Vitamin B12 deficiency), or from CHF-induced edema and damage to the intestinal wall. It has also been found that proton pump inhibitors such as omeprazole, which are widely used, reduce iron absorption.

Effect of correcting anemia in CHF patients with ESA

The studies of patients with CHF in whom the anemia has been treated have used either ESAs such as EPO or its derivative, the longer acting DA, along with the addition of either oral or intravenous (IV) iron. Such treatment has been reported in uncontrolled studies, non-placebo-controlled studies, small single-blind and small double-blind, placebo-controlled studies, or larger double-blind placebo-controlled studies (10). A recent Cochrane review (10) of ESA in CHF identified 11 RCTs with 793 participants comparing ESA with control. Nine of the studies were placebo-controlled, but only five were double blind. ESA treatment compared to control treatment was associated with an increase in Hb of about 2 g/dL, and the treatment was significantly associated with
  • fewer heart failure-related hospitalizations: rr 0.70 (0.5–0.93)

  • lower all-cause mortality: rr 0.59 (0.36–0.96)

  • improved exercise duration: 96.8 s

  • improved walk distance: 69.3 meters

  • increased peak exercise oxygen consumption: 2.29 mL/kg/min

  • improved NYHA class by a mean of 0.73

  • improved ejection fraction: +5.8 percent

  • reduced BNP: 236.6 pg/mL

  • improved quality of life indicators

However, no meta analysis can take the place of adequately powered long-term placebo-controlled studies with solid and not just surrogate endpoints, and no such study has as yet been completed for ESA in CHF.

Other effects of ESAs in CHF

Several studies have shown that correction of the anemia with ESA improved renal function, reduced diuretic dose, reduced heart rate, improved caloric intake, improved depression, and improved sleep apnea. Correction of the anemia also reduced plasma volume, increased red cell volume, improved left ventricular systolic and diastolic function, reduced left ventricular hypertrophy and dilation, reduced pulmonary artery pressure and severity of mitral regurgitation, reduced oxidative and nitrosative stress, reduced inflammatory factors such as IL-6 and C-reactive Protein (CRP), and improved adhesive and proliferative properties of circulating endothelial progenitor cells (3,4).

Adverse effects

A pooled analysis of three placebo-controlled DA studies (1115) (which had a target Hb of 14±1 g/dL) consisting of 516 patients found no differences in the rate of adverse effects or death compared to placebo. No significant differences occurred in mortality or in the incidence of hypertension, venous thrombosis, pulmonary embolus, cerebrovascular disorder, myocardial infarction, or other cardiovascular events. This held true even in those with more severe renal failure or more severe heart failure (15). Similarly, in the Cochrane meta-analysis of ESA in CHF mentioned above (10), no increase in adverse effects was observed. However, the studies examined were small and of limited duration.

The nonhematopoetic biological effects of erythropoietin

The value of ESAs in CHF has been shown in animal studies where its use after a myocardial infarction or after production of cardiac damage by other means—with or without improving the Hb—has improved endothelial dysfunction, increased neovascularization of heart muscle, reduced apoptosis of cardiomyocytes, reduced oxidative stress and inflammation, reduced fibrosis, reduced hypoxic damage, and prevented functional impairment of the heart (16). At least some of these effects are due to the increase in number and activity of endothelial progenitor cells from the bone marrow.

The effect of IV iron alone in the anemia of CHF

Experimental studies in animals have shown that severe iron deficiency can cause diastolic dysfunction and heart failure with pulmonary congestion, left ventricular hypertrophy and dilation, cardiac fibrosis, a reduction in EPO levels, and a worsening of the molecular signaling pathways (as measured by cardiac STAT 3 phosphorylation), an increase in the inflammatory cytokine TNFα, and proteinuria (17). In addition, iron deficiency in rat hearts causes mitochondrial ultrastructural aberrations, irregular sarcomere organization, and release of cytochrome C (18).

The prevalence of iron deficiency in CHF depends on how iron deficiency is defined. If merely defined as a percent transferrin saturation (percent TSAT) of <16 percent, it was found in one preliminary study in 78 percent of anemic and 61 percent of nonanemic CHF patients. If defined as a percent TSAT of <16 percent and a serum ferritin of 30–100 µg/L, it was found in only 15 percent of anemics and 15 percent of nonanemics (21).

In another study of anemia in CHF, about half the patients had serum iron below normal, and the great majority of anemic patients also had an elevated soluble transferrin receptor (a quite dependable measure of iron deficiency) (22). Markedly reduced iron stores were in the bone marrow in 73 percent of the cases in a study of anemia in severe CHF (23). Therefore pure iron deficiency (serum ferritin <100 µg/L and transferrin saturation <20 percent) or functional iron deficiency (serum ferritin >100 µg/L and percent TSAT <20 percent) are commonly seen in CHF patients with anemia or even without anemia.

Does IV iron improve iron-deficient CHF patients?

Three recent studies of IV iron in anemic CHF patients—two uncontrolled studies (24,25) and one double-blind placebo-controlled study (26)—have found improved Hb, hospitalization, LVEF, NYHA class, quality of life, left ventricular hypertrophy and dilation, exercise capacity, and renal function, as well as reduced heart rate, BNP, and CRP.

In another recent CHF controlled study of IV iron in patients with iron deficiency with or without anemia, there was an improvement in NYHA class, Patient Global Assessment, and oxygen consumption during exercise (27), even though the Hb did not improve significantly with IV iron. These changes were more pronounced in the anemic patients, suggesting that part of the effect of iron on the heart may be related not only to its causing improved oxygenation from the increased Hb but also to iron’s direct effects on improving mitochondrial function, resulting in increased oxygen utilization and increased ATP and energy production.

A multicenter double-blind, placebo-controlled study of 459 CHF patients with iron deficiency anemia using IV iron alone, the FAIR-HF study (28) has recently been published. In this study, an improvement was seen in the NYHA, patient global assessment, six-minute walk test, Quality of Life, and renal function with the use of IV iron alone. There was also a trend toward a lower rate of first hospitalization for any cardiovascular reason among those receiving the IV iron compared with those receiving placebo. These positive findings were similar in those with anemia and those without anemia.

In most studies comparing oral to IV iron in CKD, IV iron has been found to produce a greater Hb response with fewer side effects (29). No comparisons have been made between oral and IV therapy in CHF.

If iron is to be used in the anemia of CHF, in our opinion, it is probably best to use the IV form. But as in the case of ESA, there are no long-term placebo-controlled studies of IV iron with solid endpoints. Until these studies are done, there will be uncertainty about the value of iron therapy in CHF.

To what level should Hb be corrected in CHF?

U.S. FDA guidelines for ESA products are not available for CHF but are available for CKD. In light of safety concerns about raising Hb levels above 12 g/dL with ESA, the guidelines state that dosing should be individualized to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL and that higher doses of these agents should be avoided. It is hoped that the role of target Hb levels above 12 g/dL in CHF treated with ESA will be clarified by the long-term placebo-controlled study with more than 2000 patients, The Reduction of Events with Darbepoetin alfa in Heart Failure, the RED-HF study (30), due for completion in 2011.

Conclusions

Faced with patients who have both CHF and Hb levels below 12 g/dL, it may well be that ESA use should be considered to raise the Hb to 12 g/dL. If iron deficiency is present, as it often is, correction with IV iron even without ESA may also be a useful intervention and might even be used as the first therapy applied. Correction of iron deficiency even without the presence of anemia may also be indicated, but here again data is lacking.

It may well turn out that a combined approach of ESA and IV iron is the best approach for correcting the anemia in CHF. This will allow a lower dose of both agents to be used, which will reduce the chances of side effects caused by high doses of either agent, reduce the dose and cost of ESA, cause a more rapid and greater Hb response than that achieved with either agent alone, increase the chances of reaching the target hemoglobin, and reduce the chances of iron deficiency being induced by ESA. Clearly, the relative role of ESA and/or IV iron in the treatment of the anemia of CHF merits further investigation by long-term placebo-controlled studies with hard endpoints. Finally, it should be said that good treatment of CHF is associated with an improvement in renal function or a slowing in its progression. Therefore, cooperation between the nephrologist and cardiologist in the treatment of patients with CHF is crucial.

Notes

[1] Donald S. Silverberg, MD, Adrian Iaina, MD, and Doron Schwartz, MD, are with the department of nephrology, and Dov Wexler, MD, is with the department of cardiology at Tef Aviv Sourasky Medical Center in Tel Aviv, Israel.

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