CLINICAL PERSPECTIVE

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(Circulation. 2006;113:986-994.)
© 2006 American Heart Association, Inc.

Heart Failure

Clinical Correlates and Consequences of Anemia in a Broad Spectrum of Patients With Heart Failure

Results of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program

Eileen O’Meara, MD, FRCPC; Tim Clayton, BSc, MSc; Margaret B. McEntegart, MB, MRCP; John J.V. McMurray, MD; Chim C. Lang, MD; Simon D. Roger, MD, FRACP; James B. Young, MD; Scott D. Solomon, MD; Christopher B. Granger, MD; Jan Östergren, MD, PhD; Bertil Olofsson, PhD; Eric L. Michelson, MD; Stuart Pocock, BA, MSc, PhD; Salim Yusuf, DPhil, FRCPC; Karl Swedberg, MD, PhD; Marc A. Pfeffer, MD, PhD, for the CHARM Committees and Investigators

From the Western Infirmary, Glasgow, UK (E.O., M.B.M., J.J.V.M.); Montreal Heart Institute, Montreal, Quebec, Canada (E.O.); London School of Hygiene and Tropical Medicine, London, UK (T.C., S.P.); Ninewells Hospital & Medical School, Dundee, UK (C.C.L.); Gosford Hospital, Gosford, New South Wales, Australia (S.D.R.); Cleveland Clinic Foundation, Cleveland, Ohio (J.B.Y.); Brigham & Women’s Hospital, Boston, Mass (S.D.S, M.A.P.); Duke University Medical Center, Durham, NC (C.B.G.); Karolinska University Hospital Solna, Stockholm, Sweden (J.O.); AstraZeneca, R&D, Mölndal, Sweden (B.O.); AstraZeneca LP, Wilmington, Del (E.L.M.); HGM-McMaster Clinic, Hamilton, Ontario, Canada (S.Y.); and Sahlgrenska University Hospital/Östra, Göteborg, Sweden (K.S.).

Correspondence to Professor John J.V. McMurray, Department of Cardiology, Western Infirmary, Glasgow, G11 6NT, United Kingdom. E-mail j.mcmurray{at}bio.gla.ac.uk

Received August 11, 2005; revision received December 14, 2005; accepted December 22, 2005.

	Abstract

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Background— We wished to determine the prevalence of, potential mechanistic associations of, and clinical outcomes related to anemia in patients with heart failure and a broad spectrum of left ventricular ejection fraction (LVEF).

Methods and Results— In multivariable analyses, we examined the associations between hemoglobin and baseline characteristics, laboratory variables, and outcomes in 2653 patients randomized in the CHARM Program in the United States and Canada. Anemia was equally common in patients with preserved (27%) and reduced (25%) LVEF but was more common in black and older patients. Anemia was associated with ethnicity, diabetes, low body mass index, higher systolic and lower diastolic blood pressure, and recent heart failure hospitalization. More than 50% of anemic patients had a glomerular filtration rate <60 mL · min^–1 · 1.73 m^–2 compared with <30% of nonanemic patients. Despite an inverse relationship between hemoglobin and LVEF, anemia was associated with an increased risk of death and hospitalization, a relationship observed in patients with both reduced and preserved LVEF. There were 133 versus 69 deaths and 527 versus 352 hospitalizations per 1000 patient-years of follow-up in anemic versus nonanemic patients (both P<0.001). The effect of candesartan in reducing outcomes was independent of hemoglobin.

Conclusions— Anemia was common in heart failure, regardless of LVEF. Lower hemoglobin was associated with higher LVEF yet was an independent predictor of adverse mortality and morbidity outcomes. In heart failure, the causes of anemia and the associations between anemia and outcomes are probably multiple and complex.

Key Words: anemia • heart failure • kidney • mortality • hemoglobin

	Introduction

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Anemia is of interest in heart failure (HF) because it is common and is associated with reduced survival and because treatment with an erythropoietic agent might improve outcomes in HF.^1–14 Many questions about hemoglobin (Hb) in HF remain unresolved. Foremost is the relationship with left ventricular ejection fraction (LVEF), because most studies reported to date were clinical trials that included only patients with an LVEF <0.40. Similarly, few studies have been able to describe detailed associations between Hb and other patient characteristics, including etiology, comorbidity, signs and symptoms, and especially other hematologic and biochemical measures. Of particular interest, but poorly characterized, is the relationship between Hb and renal function. Similarly, little is known about the relationship between Hb and outcomes other than death and whether Hb remains an independent predictor of outcome when renal function is taken into account. The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program provides new information on these gaps in knowledge.

Clinical Perspective p 994

	Methods

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The CHARM Program
The design and key findings of the CHARM have been reported elsewhere.^15,16 CHARM consisted of 3 independent but related trials that randomized patients with NYHA class II to IV HF to placebo or candesartan. Patients with an LVEF 0.40 not taking an ACE inhibitor because of intolerance were enrolled in CHARM-Alternative; those taking an ACE inhibitor were enrolled in CHARM-Added; and patients with an LVEF >0.40 were randomized into CHARM-Preserved. There was no specific exclusion for anemia or level of Hb, but there was for creatinine 3 mg/dL. The overall follow-up was a median of 38 months and was similar in patients enrolled within and outside North America (United States and Canada). Ten patients (of 7599) were lost to follow-up in CHARM.

Blood was collected at baseline for hematologic and biochemical analyses in the 2743 patients enrolled in North America, 2653 of whom had an Hb measurement available.

Glomerular filtration rate (eGFR) was estimated from the simplified Modification of Diet in Renal Disease (MDRD) formula.^17,18

Statistical Analysis
The baseline characteristics were summarized and compared between patients who were anemic and those who were nonanemic using the World Health Organization definition (Hb <12g/dL in women and <13 g/dL in men).¹⁹ Linear regression was used to establish univariate and multivariable predictors of anemia and eGFR was added to that model to assess the impact of renal function on Hb. Subsequent analyses included other biochemical and hematologic measures considered a priori to be of particular importance in explaining the relationship between renal function and Hb. Variables with P<0.01 were included in the multivariable model in a stepwise fashion. Binary and categorical variables were entered using an appropriate number of indicator variables and quantitative variables as a single continuous measurement, as appropriate. If there was clear evidence of nonlinearity, cutoffs that reasonably represented the data and were clinically meaningful were used (eg, eGFR of 60 mL · min^–1 · 1.73 m^–2). Differences in baseline characteristics between those with and without anemia were compared by use of logistic regression.

Cox proportional-hazard models, using the risk factors established for the whole CHARM population (n=7599) with the addition of anemia, were fitted to assess the impact of anemia on the 2 main outcomes in CHARM, cardiovascular death or hospitalization for HF and all-cause mortality. The overall prognostic model has been described in detail, and data from the whole CHARM population were used to identify key prognostic factors more reliably.²⁰ Additional models also included eGFR to assess whether it affected the association between anemia and outcome. The assumptions of proportionality of the impact of anemia over time were assessed and found to be reasonable. All analyses were repeated in patients with reduced and preserved LVEF separately to assess whether there were substantial differences between the 2 populations.

The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.

	Results

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Hb and Baseline Characteristics
The baseline characteristics are summarized in Table 1. Table 2 shows the relationship between anemia and other laboratory measurements.

View this table: [in this window] [in a new window]   TABLE 1. Associations Between Anemia Status and Other Baseline Patient Characteristics

View this table: [in this window] [in a new window]   TABLE 2. Associations Between Anemia and Other Baseline Laboratory Measurements

Hb and Anemia
The mean±SD Hb in CHARM-Alternative was 13.5±1.7 g/dL, 13.8±1.5 g/dL in CHARM-Added, 13.4±1.6 g/dL in CHARM-Preserved, and 13.6±1.6 g/dL in the overall program. The proportion of anemic patients in each trial was 29%, 21%, and 27%, respectively, and 26% overall.

Anemia and Baseline Demographics
The relationship between anemia and baseline characteristics was similar across all 3 trials. Anemic patients were more often elderly and black and had worse NYHA functional class and lower body mass index (Table 1). In the multivariable model (excluding laboratory measurements other than eGFR), female gender, lower diastolic blood pressure (BP), black ethnicity, and lower eGFR were the most powerful predictors of low Hb. The independent predictors of reduced Hb were similar in patients with reduced and preserved LVEF (Table 3).

View this table: [in this window] [in a new window]   TABLE 3. Independent Predictors of Hb in Patients in CHARM

Histories of HF hospitalization and diabetes were significant independent predictors of anemia in the multivariable analysis (Table 3).

Anemia, Symptoms, Signs, and Investigative Findings
On univariate analysis, anemic patients overall had a lower diastolic BP, more evidence of congestion, and a higher mean LVEF (Table 1). The proportion of patients with an LVEF <0.25 was lower in the anemic group. An inverse relationship between Hb and LVEF was seen in both the low and preserved LVEF trials. By Hb quintile, the mean LVEF was 0.42 (quintile I: median Hb, 11.5 g/dL; range, 10.8 to 12.5 g/dL), 0.39, 0.38, 0.38, and 0.35 (quintile V: median Hb, 15.5 g/dL; range, 15.2 to 16.1 g/dL; P<0.001). The proportion of patients with a LVEF <0.25 in each quintile was 13.7%, 18.4%, 20.7%, 21.7%, and 26.1% (P<0.001), and the proportion with an LVEF <0.50 was 65%, 70%, 73%, 75%, and 80% (P<0.001).

Lower diastolic BP, dependent edema, and higher LVEF remained independent predictors in the multivariable analysis (table 3).

Anemia and Other Hematologic and Biochemical Measures
Of laboratory measures significant in the univariate analysis (Table 2), 5 were selected as potential indicators of inflammation, bone marrow activity, hemodilution, malnutrition, and blood loss (white cell and platelet count, red cell distribution width, mean cell volume and albumin) and entered into the multivariable model. Each remained an independent predictor of anemia in both reduced and preserved LVEF HF (Table 3).

Anemia and Renal Function
Mean±SD eGFR was 67.5±26.7 mL · min^–1 · 1.73 m^–2 in CHARM-Alternative, 73.0±26.9 mL · min^–1 · 1.73 m^–2 in CHARM-Added, and 72.2±26.9 mL · min^–1 · 1.73 m^–2 in CHARM-Preserved. Mean eGFR was 14.5 mL · min^–1 · 1.73 m^–2 lower in anemic compared with nonanemic patients, a relationship apparent in all 3 trials. More than 50% anemic patients had stage III to IV chronic kidney disease, whereas <30% of nonanemic patients had an eGFR <60 mL · min^–1 · 1.73 m^–2. Conversely, 39% of patients with an eGFR <60 mL · min^–1 · 1.73 m^–2 were anemic compared with 17.9% of patients with an eGFR 60 mL · min^–1 · 1.73 m^–2.

Each 10–mL · min^–1 · 1.73 m^–2 reduction in eGFR below 60 mL · min^–1 · 1.73 m^–2 was associated with a reduction in Hb of 0.29 g/dL; this association was similar in patients with reduced and preserved LVEF.

Anemia and Clinical Outcomes
Anemia and Rates of Death and Hospitalization
The unadjusted rates of death and hospitalization from all (and specific) causes were significantly higher in anemic patients (Table 4), a relationship seen in both low and preserved LVEF patients (the Figure). Anemia was an independent predictor of both the composite of cardiovascular death or HF hospitalization and all-cause mortality.

View this table: [in this window] [in a new window]   TABLE 4. Rates of Death and Admission to Hospital per 1000 Patient-Years of Follow-Up by Anemia Status

View larger version (14K): [in this window] [in a new window]   Kaplan-Meier curves for the composite outcome of cardiovascular death or hospitalization for HF by anemia status (adjusted for other risk factors in the prognostic model): A, all patients; B, reduced LVEF patients; C, preserved LVEF patients.

There was no interaction between Hb concentration at baseline, treatment with candesartan, and outcomes.

	Discussion

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We have confirmed and extended the findings of previous studies of anemia in HF.^1–7 Anemia was equally prevalent in patients with preserved and reduced LVEF. It had similar prognostic import in both types of HF, despite an inverse relationship between Hb and LVEF, and was a predictor of hospitalization. Renal function was a powerful predictor of anemia, although our analyses suggested that the anemia of HF is probably multifactorial in origin.

The prevalence of anemia in our patients with low LVEF HF (25%) was similar to that in other clinical trials and more than twice that reported in persons 65 years of age in the general population.^1,4,7,9,21 The prevalence (27%) of anemia in patients with preserved LVEF HF, who were excluded from prior trials, was similar.

We could examine the clinical correlates of anemia in more detail and across a greater spectrum of patients than in previous reports. We found associations between low Hb and older age, female sex, worse functional status, and more comorbidity, although not all remained significant in the multivariable analyses.^1–9 Renal dysfunction was one of the strongest independent predictors of Hb, and mean eGFR was lower in anemic than in nonanemic individuals in all 3 trials. Hb declined little until the eGFR fell to <60 mL · min^–1 · 1.73 m^–2 but fell sharply thereafter, by 0.29 g/dL per 10–mL · min^–1 · 1.73 m^–2 decrease in eGFR. This was consistent with the relationship between eGFR and Hb in primary renal disease. Indeed, the mean eGFR in patients with anemia in CHARM (60.5 mL · min^–1 · 1.73 m^–2) corresponded to the threshold for stage III chronic kidney disease at which the risk of anemia increases.^18,22 Therefore, renal impairment may explain anemia in a substantial subset of patients with HF.

Diabetes remained an independent predictor of anemia, after taking renal function into account. The relationship between anemia and diabetes is complex, involving inflammation and nutritional factors, in addition to nephropathy. Erythropoietin concentration may also be inappropriately low in these patients, even without a significant reduction in GFR.^23,24

We found that black patients were more likely to be anemic than white ones, as has been noted before in the general population but not in patients with HF; its explanation is uncertain.²¹

Anemic patients had more evidence of congestion, suggesting that hemodilution might contribute to the anemia, a hypothesis supported by the associations between anemia and recent HF hospitalization and low serum albumin.²⁵ Low albumin could also suggest nutritional or inflammatory mechanisms, as could the relationship between Hb and body mass index, eg, as a result of cytokine activation, postulated to play a role in causing both anemia and cachexia.^26–28

The associations between anemia and higher red cell distribution width, lower mean cell volume, and higher platelet count also suggested that iron deficiency (or blood loss) may play a role in the anemia of HF. Although we do not have information on other factors that could contribute to the development of anemia in HF such as neurohumoral activation and inflammation, our new data on laboratory predictors suggest that the cause of anemia in HF is likely to be multifactorial.^26–28

Unexpectedly, we found an inverse relationship between Hb and LVEF, making the association between anemia and worse clinical status and outcome more remarkable. Although seemingly counterintuitive, in patients without HF, anemia increases cardiac output and reduces systemic vascular resistance (which may also account for the relationship we found between anemia and BP).^29,30 Patients with anemia may have more nitric oxide–mediated vasodilatation (Hb neutralizes nitric oxide), and the resulting reduction in afterload increases LVEF.^30,31 This mechanism may be exaggerated in HF in which excess cytokine production causing enhanced nitric oxide–mediated vasodilatation has been described.³²

As in prior studies, we found that anemia was associated with higher mortality, although this relationship also was seen in patients with preserved LVEF in CHARM.^1–9 Anemic patients had a higher risk of noncardiovascular and cardiovascular death (and all types of cardiovascular death). Our analysis of hospital admissions supports these findings and extends knowledge about the risks related to anemia. Importantly, we observed the relationship between anemia and outcome across a relatively normal range of Hb and in patients with preserved LVEF.

Do these findings from CHARM help explain why anemia is associated with worse outcomes? Previously, unfavorable ventricular remodeling was suggested as a link, but this relationship seems more complex than originally appreciated.³² Although LVEF is higher in anemic patients (but still reduced from normal in many patients), anemia also is associated with left ventricular hypertrophy, and the combination of left ventricular dilatation, low LVEF, and left ventricular hypertrophy is ominous.³³ It also has been suggested that anemia leads to excessive myocardial work to compensate for reduced tissue oxygen delivery. Certainly, the clear increase in deaths and admissions resulting from HF (and perhaps the higher LVEF) in anemic patients is consistent with this hypothesis. There are other possible links between anemia and poor outcome. A particularly important one could be renal function.^4,34,35 However, only 9.0% patients with anemia in CHARM had severe renal dysfunction, and anemia remained an independent predictor of outcome in multivariate models including eGFR. Anemia also causes fluid retention, and we found a relationship between congestion (which is associated with a worse outcome) and anemia. In addition, anemia may be a marker of poor nutritional status, as discussed above, which is also a predictor of worse outcome. Consequently, anemia may be linked to a worse prognosis through multiple and overlapping mechanisms.

Our study had a number of limitations. As with all trials, the patients were relatively selected; in particular, patients with a creatinine 3 mg/dL were excluded. We did not have information on blood loss during the trial or on treatment of anemia (eg, transfusion or use of erythropoietin). Our analysis focused on baseline Hb, whereas Anand et al³⁶ have shown recently that change in Hb is also an independent predictor of outcome in HF. We also did not measure classic markers of causes of anemia (eg, measures of iron status) or novel biomarkers.³⁷

	Acknowledgments

 
Disclosures

The CHARM program was funded by AstraZeneca, which was responsible for data collection. The data analysis for this manuscript was performed independently by Tim Clayton and Dr Pocock. The Executive Committee (Drs Pfeffer, Swedberg, Granger, McMurray, and Yusuf) supervised the management of the study and were primarily responsible for the interpretation of the data and review, and approval of the manuscript. Drs Michelson and Olofsson are employees of AstraZeneca. All other authors have received research grants, honoraria for lectures and/or consulting fees from AstraZeneca. Drs McMurray, Pfeffer, Swedberg, and Young are involved in a trial or trials of correcting anemia in cardiovascular disease sponsored by Amgen Inc.

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CLINICAL PERSPECTIVE

We have shown that anemia was equally common in HF with preserved and reduced LVEF. Low Hb was more common in female, black, and older patients and was associated with recent hospitalization for HF, edema, worse renal function, diabetes, and low body mass index. Despite an inverse relationship with LVEF, low Hb concentration was associated with an increased risk of death and hospitalization, including cardiovascular death and hospitalization for HF. The beneficial effect of candesartan in reducing outcomes was independent of Hb. The causes of anemia in HF and the association between anemia and adverse outcomes in HF are likely to be multiple and complex. Recently, it has been recognized that anemia is common in HF with a low LVEF and in those patients is associated with an increased risk of death. We estimated the prevalence of anemia in HF patients with both reduced and preserved LVEF, its association with other patient characteristics and laboratory abnormalities, and both fatal and nonfatal outcomes. Anemia was as prevalent in patients with preserved EF (27%) as in those with reduced EF (25%). In both types of HF, it was associated with an increased risk of death and hospital admission for cardiovascular and noncardiovascular reasons. Female gender, diabetes, lower body mass index, and black ethnicity were associated with lower Hb. Reduced renal function, hematologic markers of bleeding/iron deficiency, higher white cell count, and reduced albumin also were associated with low Hb, suggesting that renal dysfunction, undernutrition, and inflammation might be involved in causing anemia. Anemia is common in all types of HF, is associated with increased risk of hospital admission and death from all causes, and is likely to be multifactorial in origin. It remains to be determined how best to treat anemia in HF and whether its treatment will improve outcome.

	Footnotes

 
Guest Editor for this article was Jay N. Cohn, MD.

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