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J Am Coll Cardiol, 2002; 39:1780-1786 © 2002 by the American College of Cardiology Foundation |
,*
* Department of Medicine, University of California, Los Angeles, USA
Ahmanson–University of California Cardiomyopathy Center, Los Angeles, USA
Cedars–Sinai Health System, Los Angeles, California, USA
Manuscript received December 28, 2001; revised manuscript received March 4, 2002, accepted March 11, 2002.
* Reprint requests and correspondence: Dr. Gregg C. Fonarow, Ahmanson–UCLA Cardiomyopathy Center, UCLA Division of Cardiology, 47-123 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095-1679, USA.
gfonarow{at}mednet.ucla.edu
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Abstract |
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BACKGROUND: Although it is known that chronic diseases, including HF, may be associated with anemia, the impact of hemoglobin (Hb) level on symptoms and survival in HF has not been fully defined.
METHODS: We analyzed a cohort of 1,061 patients with advanced HF (New York Heart Association [NYHA] functional class III or IV and left ventricular ejection fraction [LVEF] <40%) referred to a single center for evaluation and management. The Hb level was drawn at time of initial evaluation. Patients were divided into quartiles of Hb: Hb <12.3; Hb 12.3 to 13.6; Hb 13.7 to 14.8; Hb >14.8 g/dl.
RESULTS: Mean Hb was 13.6, and values ranged from 7.1 to 19.0 g/dl. The Hb groups were similar in age, medication profile, LVEF, hypertension, diabetes, smoking status and serum sodium. Lower Hb was associated with an impaired hemodynamic profile, higher blood urea nitrogen and creatinine, and lower albumin, total cholesterol and body mass index. Patients in the lower Hb quartiles were more likely to be NYHA functional class IV (p < 0.0001) and have lower peak oxygen consumption (PKVO2) (p < 0.0001). Survival at one year was higher with increased Hb quartile (55.6%, 63.9%, 71.4% and 74.4% for quartiles 1, 2, 3 and 4, respectively). On multivariate analysis adjusting for known HF prognostic factors, low Hb proved to be an independent predictor of mortality (relative risk 1.131, confidence interval 1.045 to 1.224 for each decrease of 1 g/dl).
CONCLUSIONS: In chronic HF, relatively mild degrees of anemia are associated with worsened symptoms, functional status and survival.
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Recent reports have suggested that mild to moderate anemia is a prevalent condition in the HF patient population (2,3), and severe, chronic anemia has been associated with the de novo development of HF (4). However, the impact of the anemic state on symptoms and prognosis in patients with established HF has not been well-described in the medical literature. Current guidelines and reviews do not include anemia as a prognostic factor or treatment goal in HF (5,6).
The effect of hemoglobin (Hb) level on HF outcomes has been studied in certain patient populations. Anemia was a risk factor for development of HF as well as rehospitalization for HF in patients with end-stage renal disease (ESRD) (7). In patients with asymptomatic left ventricular dysfunction or mild to moderate HF, a recent analysis of patients enrolled in the Studies Of Left Ventricular Dysfunction (SOLVD) identified low Hb as a predictor of mortality independent of renal insufficiency (2). However, in HF patients who present the most significant management challenge to physicians, those with New York Heart Association (NYHA) functional class III and class IV, the interaction among Hb level, symptoms and prognosis is unknown.
Recently, several small clinical studies have investigated the correction of anemia with erythropoietin and iron as a treatment for HF. These initial studies have shown favorable results including improvement in left ventricular ejection fraction (LVEF), NYHA functional class and exercise capacity (8–10). Before larger trials are undertaken, it is necessary to have a more complete understanding of anemia’s role in the progression of advanced HF. To explore this issue further, we examined the relationship among Hb level, HF patient characteristics and symptoms, and HF survival in a cohort of NYHA functional class III and class IV HF patients of multiple etiologies.
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Methods |
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Baseline data. Both Hb and hematocrit (Hct) levels were determined at time of initial presentation. All specimens were analyzed in Centers for Disease Control-approved laboratories. The NYHA functional class was assessed at the time of initial presentation. Medical treatments recorded were those implemented after baseline hemodynamic evaluation. Hemodynamic variables utilized in the analyses were the optimal values recorded after pulmonary artery catheter-tailored medical therapy, as these hemodynamic measurements have been shown to best correlate with survival (12). Laboratory testing, electrocardiography, echocardiography and cardiopulmonary exercise tests all occurred within three months of initial referral; later values were excluded from our analysis. Creatinine clearance was calculated by the Cockcroft-Gault formula using the patient’s "dry" weight after hemodynamically guided therapy. Hypertension, diabetes and smoking histories were based on medical record review.
End points. Death was the primary end point in this study. Deaths were classified as sudden death, HF death or death secondary to MI. Death was considered sudden if it was unexpected based on the patient’s clinical status and if it occurred out of the hospital within 15 min of the onset of unexpected symptoms or during sleep. Death during hospitalization for worsening congestive symptoms was considered an HF death. Urgent heart transplants (Status I) were analyzed as deaths, under the assumption that these patients would have died without a transplant. Nonurgent transplants (Status II) were considered a nonfatal end of follow-up.
Statistical analysis. Data are presented as mean ± SD for continuous variables and as frequencies for categorical variables. Patients were divided into quartiles of Hb. Differences in baseline characteristics among quartiles were analyzed using analysis of variance for continuous variables and Pearson’s chi-square test for categorical variables. To evaluate differences between survivors and nonsurvivors, we used an independent sample t test for continuous variables and Pearson’s chi-square test for categorical variables. Both one-year and five-year survival curves were calculated with the Kaplan-Meier method, and differences between the curves were evaluated with the log-rank statistic. We assessed the relationship between baseline variables and mortality using a Cox proportional hazards survival model (SPSS for Windows, version 10.0.5). Hazard ratios (relative risk [RR]) with 95% confidence intervals (CI) demonstrate the risk of death when a variable is present. The multivariate Cox model included the following variables seen to be predictors of mortality on univariate analysis as well as other known factors for HF mortality: age, gender, body mass index (BMI), left ventricular end diastolic dimension, hypertension history, diabetes history, smoking history, serum sodium, albumin, creatinine and HF etiology.
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Results |
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Mean Hb was 13.6 ± 1.9 g/dl and Hb ranged from 7.1 to 19.0 g/dl. The mean Hb level for women was 12.7 ± 1.8 g/dl and for men was 13.8 ± 1.9 g/dl. Of both men and women in the cohort, 30% were considered anemic when anemia was defined as Hb <13 g/dl in men and Hb <12 g/dl in women (13). Hemoglobin level >17 g/dl was seen in 3% of men and 1% of women.
Relationship between hb level and baseline characteristics. Differences among the Hb quartiles are detailed in Table 1. Age, past medical history, LVEF, etiology of HF, serum sodium and medication usage were similar among the Hb groups. Patients in the lower quartiles were more likely to be women. Lower Hb levels were associated with greater symptoms, as evident by more patients being NYHA functional class IV (75.3%, 68.0%, 56.7% and 59.1% for quartiles 1, 2, 3 and 4, respectively, p < 0.0001). Lower BMI and albumin and impaired renal function were seen in the lower Hb quartiles. The hemodynamic profile of the patients in the lower quartiles were characterized by lower blood pressure, but higher heart rate and pulmonary capillary wedge pressure (Table 1). Greater impairment in exercise capacity was demonstrated in HF patients with lower Hb concentrations. Peak oxygen consumption (PKVO2) on cardiopulmonary exercise testing was 12.8 ± 4.6, 12.4 ± 4.5, 13.8 ± 4.7 and 14.6 ± 5.4 ml/kg per min for quartiles 1, 2, 3 and 4, respectively, p < 0.0001.
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A low baseline Hb level in this cohort of advanced HF patients proved to be a significant predictor of subsequent mortality. The Hb level was significantly higher in patients alive at one year compared to those who had died or had undergone urgent transplant at one year. Table 2 details the differences in baseline characteristics between survivors and nonsurvivors at one year. On univariate Cox regression analysis, each 1 g/dl decrease in Hb was associated with a 16% increased risk of death. Hemoglobin was similarly predictive of mortality at five-year follow-up (data not shown). Survival rates steadily declined as Hb quartile decreased, as shown in the Kaplan-Meier survival curves for the four Hb quartiles (Fig. 1). This stepwise trend was preserved after the cohort was further subdivided by Hb deciles, with no evidence of a U-shaped relationship (Fig. 2).
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Discussion |
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A second point of emphasis is the relatively mild degrees of anemia associated with increased morbidity and mortality; significantly impaired survival was seen in women with Hb <11.6 g/dl and men with Hb <12.6 g/dl, values that may not be considered significant or associated with increased risk in clinical practice. Third, patients with decreased Hb were characterized by an unfavorable hemodynamic profile, worse symptoms of HF, as described by NYHA functional class, and greater impairment in exercise capacity, as quantified by PKVO2. Based on this analysis it would be predicted that correction of anemia would be associated with an improvement in exercise capacity of approximately 2 ml/kg/min, which has previously been shown to be clinically relevant (14). Interestingly, that was the magnitude of improvement in exercise capacity recently observed in a small trial of 12 weeks of erythropoietin therapy in patients with anemia and HF (10).
Epidemiologic evidence. Prior epidemiologic studies that have included Hb or Hct in their analyses provide supportive evidence for the significant relationship between anemia, HF and prognosis. Anemia was associated with an increased risk of death or HF rehospitalization in California patients hospitalized for HF between 1991 and 1992 (15). Furthermore, the Framingham Heart Study found Hct to be a significant risk factor for increased HF incidence (16).
Although the present study describes a remarkable association between anemia and HF mortality, the pathophysiologic relationship between Hb and HF progression requires further study. Hemoglobin may be a marker of poor prognosis in HF or, conversely, it may play a causative role in HF progression. Several potential explanations for the association between low Hb and poor prognosis deserve exploration.
Anemia of chronic disease. Increased levels of plasma cytokines such as tumor necrosis factor in HF patients are associated with higher NYHA functional class (17) and increased HF mortality (18). Anemia in advanced HF may be a marker of increased levels of circulating cytokines and cytokine receptors. It is known that anemia commonly seen in chronic inflammatory states, such as some infections, neoplasm and rheumatologic conditions, is mediated by inflammatory cytokines such as tumor necrosis factor, interleukin-1 and the interferons (19). It may be that the anemia in HF is similar to that seen in other chronic diseases and is likewise mediated by elevated circulating cytokines. As with anemia of other chronic disease states, increased erythropoietin levels have been found in patients with chronic heart failure (20).
Malnutrition. In our study, patients in the lower Hb quartiles were characterized by markers of malnutrition, such as lower levels of albumin and lower BMI (Table 1). Malnutrition is a common causative factor in the development of anemia in non-HF populations, such as the elderly (21). It is possible that the poor prognosis of anemia in HF stems from malnutrition due to cardiac cachexia, a catabolic state seen in advanced HF and associated with increased HF mortality (22). However, Hb was predictive of mortality independent of BMI and albumin levels.
Hemodilution. Low Hb may be a marker of volume overload in poorly compensated, high-risk HF patients. Previous studies have demonstrated that decreased Hb or Hct in HF is reflective of plasma volume expansion and not necessarily indicative of decreased red blood cell volume (23). Because Hb was predictive of mortality independent of pulmonary capillary wedge pressure after hemodynamically guided diuresis, hemodilution alone cannot fully account for these findings.
Anemia and ischemia. Although it has been shown that the resting, healthy human heart can withstand acute, severe anemia without sustaining myocardial ischemia (24), the presence of CAD may significantly impair the heart’s ability to tolerate low levels of Hb (25). A recent observational study showed reduction in 30-day mortality in patients with Hct <33% who received blood transfusion during hospitalization for MI compared to those who were not transfused (26). Anemia in HF patients may predispose to myocardial ischemia, repetitive stunning, apoptosis, and necrosis, thus contributing to the progression of ventricular dilation and clinical HF.
Renal insufficiency. The kidney and its related hormonal mechanisms play a fundamental role in the pathophysiology of HF. Impaired renal function is associated with both anemia and worse prognosis in patients with HF. Although lower Hb was associated with higher blood urea nitrogen and creatinine and lower creatinine clearance, the increased mortality risk seen remained after adjustment for renal function and other HF prognostic factors. Similarly, in the SOLVD analysis the increased mortality risk with anemia in HF was independent of renal function impairment (2). It should be noted, however, that in a randomized clinical trial involving patients with ESRD and HF, normalization of Hct (42%) with erythropoietin and intravenous (IV) iron dextran compared to maintaining lower Hct levels (30%) was associated with a trend for increased nonfatal MIs and mortality (RR 1.3; 95% CI 0.9 to 1.9, p = NS) (27).
Study limitations. Our study is retrospective and examines a selected population of HF patients with advanced disease referred for transplant evaluation. Hemoglobin levels were assessed at a single point in time, and thus we cannot comment on the importance in change in Hb over time. Treatment of anemia with transfusion or other medications during the time course of the study is also not documented or included in the analysis, though it was not routine to treat these patients with transfusions, iron or erythropoietin. Data on the use of beta-blockers or addition of medicines after the time of initial presentation are not included in the analysis. We also do not have data on cytokine or erythropoietin levels, or direct measures of plasma volume or red blood cell mass, information that would help in understanding the pathophysiologic role of anemia in HF progression.
Conclusions. Lower Hb is associated with greater functional impairment, worse exercise capacity, and increased mortality in this cohort of advanced HF patients of multiple etiologies. Further studies aimed at understanding the interaction between Hb and HF progression are needed. Initial studies suggest that treatment of anemia is beneficial in HF (8). Additional randomized, placebo-controlled studies are warranted to test the hypothesis that correction of anemia improves symptoms and exercise capacity in advanced HF and also to determine whether treatment of anemia has an impact on HF survival.
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Footnotes |
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20% secondary to ischemic or nonischemic dilated cardiomyopathy. Am J Cardiol. 1990;66:1348–1354[CrossRef][Medline]
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