JACC
HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK
QUICK SEARCH:   [advanced]


     

J Am Coll Cardiol, 2003; 41:1933-1939, doi:10.1016/S0735-1097(03)00425-X
© 2003 by the American College of Cardiology Foundation
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mozaffarian, D.
Right arrow Articles by Levy, W. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mozaffarian, D.
Right arrow Articles by Levy, W. C.

CLINICAL RESEARCH: CLINICAL TRIAL

Anemia predicts mortality in severe heart failure

The prospective randomized amlodipine survival evaluation (PRAISE)

Dariush Mozaffarian, MD, MPH*{dagger},*, Regina Nye, MPH{ddagger} and Wayne C. Levy, MD{dagger}

* Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
{dagger} Division of Cardiology, University of Washington, Seattle, USA
{ddagger} Pfizer PGRD, New London, Connecticut, USA

Manuscript received September 23, 2002; revised manuscript received February 6, 2003, accepted February 20, 2003.

* Reprint requests and correspondence: Dr. Dariush Mozaffarian, VA Puget Sound Health Care System, 1660 South Columbian Way, MS 152, Seattle, Washington 98108, USA.
darymd{at}hotmail.com


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: Our aim was to examine the relationships between serum hematocrit (Hct) and risk of all-cause mortality among patients with severe heart failure (HF).

BACKGROUND: Anemia occurs with increased frequency in severe HF. However, few studies have examined the impact of anemia on mortality in this population.

METHODS: Using a prospective cohort design, we evaluated the relationships between baseline serum Hct and mortality among 1,130 patients with left ventricular EF <30% and New York Heart Association functional class IIIB or IV HF treated with angiotensin-converting enzyme inhibitors, diuretics, and digitalis. Mortality was ascertained by centralized adjudication.

RESULTS: The mean Hct was 41.8% (range 25.4% to 58.8%). Over 15 months of mean follow-up, there were 407 deaths (29 per 100 person-years). After adjustment for potential confounders, those in the lowest quintile of Hct (range 25.4% to 37.5%) had a 52% higher risk of death (hazard ratio 1.52, 95% confidence interval 1.11 to 2.10), compared with the highest quintile (range 46.1% to 58.8%). Within the lowest quintile of Hct, each 1% decrease in Hct was associated with an 11% higher risk of death (p < 0.01), whereas within the four higher quintiles of Hct, Hct was not associated with total mortality. Evaluation of different causes of death indicated that a lower Hct was strongly associated with death from progressive HF, rather than sudden death or other deaths.

CONCLUSIONS: Among patients with severe HF, anemia is a significant independent risk factor for death, with a progressively higher risk with increasing severity of anemia. Further investigation of the etiologies, prevention, and treatment of anemia in severe HF is warranted.

Abbreviations and Acronyms
  CI
  confidence interval
  EF
  ejection fraction
  Hct
  hematocrit
  HF
  heart failure
  HR
  hazard ratio
  MI
  myocardial infarction
  NYHA
  New York Heart Association
  PRAISE
  Prospective Randomized Amlodipine Survival Evaluation

While mortality from coronary artery disease and stroke has been declining, the incidence and health burden of congestive heart failure (HF) continue to rise (1). In the U.S., nearly 5 million people have HF and more than half a million new cases are diagnosed each year; HF is the most common cause of hospitalization among persons age ≥65 years; and health care costs for HF exceed $20 billion annually (1,2). Despite advances in medical treatment, HF patients have high mortality rates, and HF deaths have increased 145% over the last two decades (1). People with severely reduced left ventricular systolic function and severe HF symptoms are at particular risk, with mortality rates approaching 30% per year. These trends, mirrored in other industrialized nations (3–5), accentuate the importance of identifying and treating novel risk factors for poor outcomes in HF.

Accumulating evidence suggests that anemia may be an independent risk factor for mortality among patients with HF (6–9). Additionally, clinical studies among small numbers of HF patients (n = 26 [10] and n = 32 [11]) indicate that treatment of anemia with erythropoietin and iron improves symptoms and the ejection fraction (EF) and decreases hospitalizations and the need for diuretics, suggesting that anemia may be a modifiable risk factor in HF with a causal role in clinical outcomes. However, few previous studies have characterized the impact of anemia on HF mortality, such as the magnitude of risk, threshold of risk, or associations with different causes of death, and only one previous study (9) has examined patients with severe HF, the population at highest risk for both anemia and death.

We therefore investigated, using a prospective cohort design, the relationships between baseline serum hematocrit (Hct) and mortality among 1,130 subjects enrolled in the Prospective Randomized Amlodipine Survival Evaluation (PRAISE), a randomized trial of amlodipine versus placebo among patients with severe HF. Our primary hypothesis was that a lower Hct would be associated with a higher risk of all-cause mortality among these patients with severe HF.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Study design and population.   We used baseline information and follow-up data from PRAISE, a multicenter, randomized clinical trial of amlodipine versus placebo among 1,153 men and women with left ventricular EF <30% and New York Heart Association (NYHA) functional class IIIB or IV HF symptoms treated with angiotensin-converting enzyme inhibitors, diuretics, and digitalis. Patients with both ischemic and nonischemic HF were enrolled. The design, inclusion and exclusion criteria, and primary results have been previously described (12). The protocol was approved by the institutional review boards of all 105 participating institutions, and informed written consent was obtained from all subjects. Laboratory analyses, including Hct, were performed at a central laboratory (Hct normal range = 41% to 50% in men and 33% to 46% in women). We excluded 23 participants with missing baseline Hct measurements, resulting in 1,130 participants included in this analysis.

Ascertainment and classification of mortality.   All deaths were reviewed and classified by a centralized adjudication committee based on information from hospital and emergency room records, electrocardiograms, chest X-rays, autopsy reports, death certificates, and statements from witnesses (12,13). Cardiac deaths were categorized as sudden death, pump failure death, or fatal myocardial infarction (MI). Sudden death was defined as death from cardiac or unknown causes that was unexpected and occurred after an abrupt loss of consciousness in a previously stable patient. Pump failure death was defined as progressive HF culminating in death not due to acute MI or observed or suspected life-threatening arrhythmia; heart transplantations (n = 8) were included as pump failure deaths. Deaths >60 min from the onset of symptoms for hospitalized acute MI were classified as fatal MI. The primary outcome of this analysis was all-cause mortality. We also evaluated different causes of death, such as pump failure death. No patients were lost to follow-up.

Statistical analysis.   Hematocrit was evaluated as an indicator variable (dummy variable) in quintiles and deciles, and as a continuous variable. Baseline characteristics were compared across quintiles of Hct using regression, with the characteristic as the dependent variable and Hct quintile as the independent variable. Kaplan-Meier estimates were used to evaluate survival over time, with differences evaluated using the log-rank test for equality of survivor functions. Cox proportional hazards models were used to evaluate risk, with multivariate Cox models evaluated to assess for confounders. Age, gender, HF etiology, and NYHA functional class were included in an initial multivariate Cox model. Other characteristics were added, both individually and in groups, and retained in the final model based on clinical interest or an appreciable change (±5%) in the hazard ratio (HR) associated with Hct. In addition to the characteristics in the final model (age, gender, diabetes, smoking, HF etiology, EF, NYHA functional class, systolic blood pressure, white blood cell count, and creatinine), we also evaluated for potential confounding by race, heart rate, diastolic blood pressure, cardiothoracic ratio, furosemide use and dose, metolazone use and dose, potassium-sparing diuretic use, treatment assignment (amlodipine or placebo), allopurinol use, uric acid, serum cholesterol, triglycerides, estimated creatinine clearance, blood urea nitrogen, sodium, and lymphocyte count. Likelihood ratio testing was used to assess for the effect modification by age, gender, diabetes, smoking, NYHA functional class, and etiology of HF. All p values were two-tailed. Analyses were performed using Stata version 6.0 (Stata Corp., College Station, Texas).


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Baseline characteristics overall and according to quintiles of Hct are presented in Table 1. The mean Hct was 41.8% (range 25.4% to 58.8%). The average age of the participants was 65 years at baseline. Three-quarters of participants were male, and more than one-third were diabetic. The mean EF was 21%, with 81% of participants with NYHA functional class IIIB and 19% with class IV symptoms. A higher Hct value was associated with younger age, male gender, more prevalent smoking, slightly lower EF, and higher blood pressure. Hematocrit was also positively associated with the white blood cell count, mean corpuscular volume, indexes of liver function, and serum cholesterol and inversely associated with blood urea nitrogen and creatinine.


View this table:
[in this window]
[in a new window]
  		Table 1 Baseline Characteristics According to Quintiles of Hematocrit and Overall

 
Over 15 months of mean follow-up, there were 407 deaths (29 deaths per 100 person-years). Cardiac deaths accounted for the vast majority (87%) of fatalities, including 182 sudden deaths, 162 pump failure deaths, and 12 fatal MIs. In Kaplan-Meier survival analyses, those in the lowest quintile of Hct had significantly poorer survival, whereas survival in the four higher quintiles was relatively similar (Fig. 1). After adjustment for age, gender, diabetes, smoking, HF etiology, EF, NYHA functional class, systolic blood pressure, white blood cell count, and creatinine, those in the lowest quintile of Hct (range 25.4% to 37.5%) had a 52% higher risk of death (HR 1.52, 95% confidence interval [CI] 1.11 to 2.10), compared with the highest quintile of Hct (range 46.1% to 58.8%) (Table 2). In contrast, subjects in the second, third, and fourth quintiles of Hct did not have significantly different mortality compared with those in the highest quintile (Table 2). When Hct was evaluated in deciles, there was significantly higher mortality only in the lowest decile (Hct <35.4%) and no significant associations in the second to ninth deciles, compared with the highest decile (Hct >48.3%) as the reference group (Fig. 2).



View larger version (17K):
[in this window]
[in a new window]
  		Figure 1 Kaplan-Meier survival according to quintiles of hematocrit. *p = 0.004 for equality of survivor functions.

 

View this table:
[in this window]
[in a new window]
  		Table 2 Total Mortality According to Quintiles of Hematocrit

 


View larger version (16K):
[in this window]
[in a new window]
  		Figure 2 Mortality rates according to deciles of hematocrit (Hct). Compared with the reference group (tenth decile, Hct >48.3%), higher mortality was only present in the first decile (Hct <35.4%), in which there was a 72% higher risk of death (hazard ratio 1.72, 95% confidence interval 1.13 to 2.62) after adjustment for potential confounders (Table 2, footnote).

 
There also appeared to be a threshold of risk when Hct was evaluated continuously. After adjustment for potential confounders (Table 2, footnote), each 1% decrease in Hct was associated with a 3% higher risk of death (HR 1.03, 95% CI 1.01 to 1.05, p < 0.01) in the overall cohort. However, this association was entirely due to a higher risk in the lowest quintile of Hct (range 25.4% to 37.5%), within which each 1% decrease in Hct was associated with an 11% higher risk of death (HR 1.11, 95% CI 1.02 to 1.20, p < 0.01). In contrast, there was no association between each 1% decrease in Hct and total mortality (HR 1.01, 95% CI 0.98 to 1.04, p = 0.58) within the four higher quintiles (Hct >37.5%).

Because women normally have lower Hct values than men, we also evaluated associations with quintiles of Hct derived separately for men versus women (Table 3). After adjustment for potential confounders, both men and women in the lowest quintile of Hct had an approximately 60% higher risk of mortality, compared with those in the highest quintile, although the power was limited to confirm this finding among women because of fewer numbers of female participants.


View this table:
[in this window]
[in a new window]
  		Table 3 Total Mortality According to Quintiles of Hematocrit Among Men and Women

 
When we evaluated different causes of death, there was a strong inverse association between Hct and pump failure death, with a significantly higher risk as Hct decreased across quintiles (p for trend <0.001) (Table 4, Fig. 3). In similar analyses with Hct evaluated continuously, each 1% decrease in Hct was associated with an 8% higher risk of pump failure death (HR 1.08, 95% CI 1.05 to 1.12, p < 0.001). In contrast, there was a suggestion of a U-shaped relationship with other causes of death (e.g., sudden death and other deaths), with trends toward a higher risk among those in the lowest and highest quintiles of Hct (Table 4, Fig. 3). We evaluated this possible U-shaped relationship by adding a squared Hct term to the model: both the term (p = 0.03) and the likelihood ratio test (p = 0.04) were significant. In continuous analyses, the risk of these non-pump failure deaths was greatest for each 1% decrease in Hct below 36% (HR 1.18, 95% CI 1.01 to 1.37, p = 0.04; n = 138) and each 1% increase in Hct above 47% (HR 1.12, 95% CI 1.00 to 1.26, p = 0.06; n = 180); there was no relationship with non-pump failure deaths when Hct was between 36% and 47% (HR 1.00, 95% CI 0.94 to 1.05, p = 0.88; n = 812). Evaluation of sudden deaths and other deaths separately did not greatly alter these results, although the CIs were broader due to fewer total events.


View this table:
[in this window]
[in a new window]
  		Table 4 Mortality by Different Causes According to Quintiles of Hematocrit

 


View larger version (17K):
[in this window]
[in a new window]
  		Figure 3 Mortality rates by cause of death, according to quintiles of hematocrit. Hematocrit was inversely associated with pump failure death (black bars) (p for trend <0.001). In contrast, there was a suggestion of a U-shaped relationship with sudden deaths (white bars) and other deaths (striped bars) (see text).

 
There was little evidence that the associations between Hct and mortality varied according to age, gender, diabetes, smoking, NYHA functional class, or etiology of HF (p > 0.05 by the likelihood ratio test for each interaction). All findings were similar if hemoglobin was used instead of Hct.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Among these patients with severe HF, we observed a significant and independent association between anemia and total mortality, with progressively higher mortality with increasing severity of anemia. Hematocrit was not associated with total mortality when values were within or near normal ranges, suggesting a potential threshold of risk rather than a linear or graded relationship. The results were similar whether Hct was evaluated in quintiles, in deciles, or continuously. The magnitude of the increased risk is striking, with a 52% higher risk of death in the lowest quintile of Hct compared with the highest quintile. This increased risk is more than twice the risk associated with diabetes, smoking, a decade of age, or a 10% difference in EF in this population.

Potential explanations.   There are several possible explanations for these findings. Although the associations persisted after adjustment for a wide variety of demographic, clinical, and laboratory characteristics, a lower Hct value may be a marker for some other factor that increases mortality among patients with severe HF. For example, anemia may be a marker for poor renal function or volume overload. However, there were only modest differences in blood urea nitrogen and serum creatinine associated with Hct, and no significant differences in NYHA functional class, diuretic use, or serum sodium. Moreover, the higher risk persisted after adjustment for these factors, suggesting that baseline differences in these characteristics did not entirely mediate the relationship between anemia and mortality.

Anemia may also be a marker for higher circulating cytokines and chemokines, which are associated with both anemia of chronic disease and higher mortality in HF (14–16). Lower Hct levels were associated with lower white blood cell counts, suggesting possible generalized bone marrow hypoproduction; decreased production may also extend to other organs, as suggested by liver function indexes. Systemic inflammation and immune activation in HF may be related to bacterial endotoxin translocation resulting from bowel wall edema and altered gut permeability (17); interestingly, from our clinical experience, HF patients with suspected bowel edema often show evidence of poor iron absorption, which may further exacerbate anemia.

There are also plausible biologic mechanisms for a causal relationship between anemia and mortality in HF. Myocardial ischemia may result from a reduced oxygen-carrying capacity combined with a low EF and increased wall stress. Among elderly patients with acute MI, blood transfusion is associated with lower mortality when the initial Hct is ≤33%, but not when the initial Hct is higher (18), consistent with a relative threshold of ischemia risk. Another plausible biologic mechanism is chronically increased myocardial work and adrenergic stimulation due to a diminished oxygen-carrying capacity of anemic blood, resulting in progressive HF. This hypothesis is supported by the strong inverse association between Hct and death due to progressive HF, rather than sudden death or other deaths. The resting cardiac output begins to increase with hemoglobin <10 g/dl ({approx} Hct <30 to 33%) (19), and this threshold is likely higher in the setting of abnormal states such as severe HF. Anemia independently predicts the development of HF among both renal failure patients and renal transplant recipients, independent of ischemic heart disease (20,21). Additionally, anemia is associated with elevated plasma catecholamines and alpha2-receptor densities among renal failure patients, proportional to the degree of anemia, and correction of anemia with erythropoietin reduces plasma noradrenaline and alpha2-receptor density (22). Correction of anemia reduces the cardiac output among renal failure patients (23,24), and improves the EF and reduces symptoms and hospitalizations among HF patients (10,11), further supporting the hemodynamic significance of anemia.

Shape of risk.   We observed a threshold of risk for total mortality, due to a graded inverse relationship with pump failure death and a U-shaped relationship with other causes of death (largely sudden death). Among patients referred for heart transplant evaluation, Hct was inversely associated with total mortality, largely due to the risk of progressive HF (9). The relationships with non-pump failure deaths did not appear to be U-shaped (G. C. Fonarow, personal communication, September 2002), as suggested by our study. Further investigation is necessary to determine whether there is a threshold of risk, a graded relationship, or a U-shaped relationship between Hct and mortality in HF, taking into consideration that this relationship may differ depending on the cause of death, as suggested by our results.

Study strengths.   Our analysis has several strengths. Patients were enrolled from multiple centers, rather than from a single HF or transplant clinic, which increases the generalizability. All patients were receiving similar background medical therapy, including angiotensin-converting enzyme inhibitors, diuretics, and digitalis. Demographic, clinical, and laboratory characteristics were well characterized using standardized techniques, increasing the capacity to adjust for confounders. The predominant mortality end point was death (98%), rather than transplantation (2%). Comprehensive follow-up, review of events, and centralized adjudication minimized the potential for missed or misclassified outcomes.

Study limitations.   There are also potential limitations to our findings. Hematocrit was assessed at baseline and may have changed over time; such misclassification might cause underestimation of the associations between Hct and mortality. Also, although we adjusted for a wide variety of participant characteristics, residual confounding due to unmeasured or incompletely measured factors cannot be excluded. These patients were participants in a randomized clinical trial, so the results may not be generalizable to all patients with severe HF. We did not have information on levels of iron, erythropoietin, or cytokines and chemokines, so we could not differentiate etiologies of anemia. As this was a completed study and no further enrollment was possible, we did not calculate the power a priori; post hoc calculations showed >80% power to detect a 33% increase in mortality risk across the quintiles of Hct.

Conclusions.   Our findings indicate that anemia is a significant independent risk factor for death among patients with severe HF, particularly death due to progressive pump failure. If this association is causal, normalization of Hct in this population would be expected to reduce mortality by approximately 33% based on the magnitude of risk observed in our study, or one less annual death for every eight patients successfully treated. These results support the need for further investigation of the etiologies, prevention, and treatment of anemia in HF, including appropriately powered randomized clinical trials to determine whether prevention or treatment of anemia reduces mortality in severe HF.


   Footnotes
 
Dr. Mozaffarian was supported by a VA Health Services Research and Development fellowship at the VA Puget Sound Health Care System. The data used in this analysis were collected by the PRAISE Study Group and provided by Pfizer PGRD; no funding support was provided by Pfizer PGRD for this analysis or manuscript.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. American Heart Association. 2002 Heart and Stroke Statistical Update. Dallas, TX: American Heart Association; 2001.
  2. Health Care Financing Administration. Heart Failure National Project Overview. http://www.hcfa.gov/quality/download/3s.pdf Accessed May 12, 2001
  3. McMurray J, McDonagh T, Morrison CE, Dargie HJ. Trends in hospitalization for heart failure in Scotland, 1980 to 1990. Eur Heart J. 1993;14:1158–1162[Abstract/Free Full Text]
  4. Reitsma JB, Mosterd A, de Craen AJ, et al. Increase in hospital admission rates for heart failure in the Netherlands, 1980 to 1993. Heart. 1996;76:388–392[Abstract/Free Full Text]
  5. Rodriguez-Artalejo F, Guallar-Castillon P, Banegas Banegas JR, del Rey Calero J. Trends in hospitalization and mortality for heart failure in Spain, 1980 to 1993. Eur Heart J. 1997;18:1771–1779[Abstract/Free Full Text]
  6. Kannel WB. Epidemiology and prevention of cardiac failure: Framingham Study insights. Eur Heart J. 1987;8(Suppl F):23–26
  7. Al-Ahmad A, Rand WM, Manjunath G, et al. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol. 2001;38:955–962[Abstract/Free Full Text]
  8. McClellan WM, Flanders WD, Langston RD, Jurkovitz C, Presley R. Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol. 2002;13:1928–1936[Abstract/Free Full Text]
  9. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Borenstein J. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol. 2002;39:1780–1786[Abstract/Free Full Text]
  10. Silverberg DS, Wexler D, Blum M, et al. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations. J Am Coll Cardiol. 2000;35:1737–1744[Abstract/Free Full Text]
  11. Silverberg DS, Wexler D, Sheps D, et al. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. J Am Coll Cardiol. 2001;37:1775–1780[Abstract/Free Full Text]
  12. the Prospective Randomized Amlodipine Survival Evaluation Study GroupPacker M, O’Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med. 1996;335:1107–1114[Abstract/Free Full Text]
  13. O’Connor CM, Carson PE, Miller AB, et al. Effect of amlodipine on mode of death among patients with advanced heart failure in the PRAISE trial. Prospective Randomized Amlodipine Survival Evaluation. Am J Cardiol. 1998;82:881–887[CrossRef][Medline]
  14. Means RT Jr. Advances in the anemia of chronic disease. Int J Hematol. 1999;70:7–12[Medline]
  15. Kapadia S, Dibbs Z, Kurrelmeyer K, et al. The role of cytokines in the failing human heart. Cardiol Clin. 1998;16:645–656[CrossRef][Medline]
  16. Blum A, Miller H. Pathophysiological role of cytokines in congestive heart failure. Annu Rev Med. 2001;52:15–27[CrossRef][Medline]
  17. Niebauer J, Volk HD, Kemp M, et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet. 1999;353:1838–1842[CrossRef][Medline]
  18. Wu WC, Rathore SS, Wang Y, Radford MJ, Krumholz HM. Blood transfusion in elderly patients with acute myocardial infarction. N Engl J Med. 2001;345:1230–1236[Abstract/Free Full Text]
  19. Metivier F, Marchais SJ, Guerin AP, Pannier B, London GM. Pathophysiology of anaemia: focus on the heart and blood vessels. Nephrol Dial Transplant. 2000;15(Suppl 3):14–18[Abstract/Free Full Text]
  20. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease. Am J Kidney Dis. 1996;28:53–61[Medline]
  21. Rigatto C, Parfrey P, Foley R, Negrijn C, Tribula C, Jeffery J. Congestive heart failure in renal transplant recipients: risk factors, outcomes, and relationship with ischemic heart disease. J Am Soc Nephrol. 2002;13:1084–1090[Abstract/Free Full Text]
  22. Muller R, Steffen HM, Brunner R, et al. Changes in the alpha adrenergic system and increase in blood pressure with recombinant human erythropoietin (rHuEpo) therapy for renal anemia. Clin Invest Med. 1991;14:614–622[Medline]
  23. Sikole A, Polenakovic M, Spirovska V, Polenakovic B, Masin G. Analysis of heart morphology and function following erythropoietin treatment of anemic dialysis patients. Artif Organs. 1993;17:977–984[Medline]
  24. Fellner SK, Lang RM, Neumann A, Korcarz C, Borow KM. Cardiovascular consequences of correction of the anemia of renal failure with erythropoietin. Kidney Int. 1993;44:1309–1315[Medline]



This article has been cited by other articles:


Home page
 J Am Coll CardiolHome page
H. F. Groenveld, J. L. Januzzi, K. Damman, J. van Wijngaarden, H. L. Hillege, D. J. van Veldhuisen, and P. van der Meer
Anemia and Mortality in Heart Failure Patients: A Systematic Review and Meta-Analysis
J. Am. Coll. Cardiol., September 2, 2008; 52(10): 818 - 827.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
W.H. W. Tang, W. Tong, A. Jain, G. S. Francis, C. M. Harris, and J. B. Young
Evaluation and long-term prognosis of new-onset, transient, and persistent anemia in ambulatory patients with chronic heart failure.
J. Am. Coll. Cardiol., February 5, 2008; 51(5): 569 - 576.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
J. K. Ghali, I. S. Anand, W. T. Abraham, G. C. Fonarow, B. Greenberg, H. Krum, B. M. Massie, S. M. Wasserman, M.-L. Trotman, Y. Sun, et al.
Randomized Double-Blind Trial of Darbepoetin Alfa in Patients With Symptomatic Heart Failure and Anemia
Circulation, January 29, 2008; 117(4): 526 - 535.
[Abstract] [Full Text] [PDF]

Home page
 Am J Health Syst PharmHome page
R. K. Spence
Medical and economic impact of anemia in hospitalized patients
Am. J. Health Syst. Pharm., August 15, 2007; 64(16_Supplement_11): S3 - S10.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
P. Ponikowski, S. D. Anker, J. Szachniewicz, D. Okonko, M. Ledwidge, R. Zymlinski, E. Ryan, S. M. Wasserman, N. Baker, D. Rosser, et al.
Effect of Darbepoetin Alfa on Exercise Tolerance in Anemic Patients With Symptomatic Chronic Heart Failure: A Randomized, Double-Blind, Placebo-Controlled Trial
J. Am. Coll. Cardiol., February 20, 2007; 49(7): 753 - 762.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
G. W. Dec
Anemia in Heart Failure: Time to Rethink Its Etiology and Treatment?
J. Am. Coll. Cardiol., December 19, 2006; 48(12): 2490 - 2492.
[Full Text] [PDF]

Home page
 HeartHome page
J D Newton and I B Squire
Glucose and haemoglobin in the assessment of prognosis after first hospitalisation for heart failure
Heart, October 1, 2006; 92(10): 1441 - 1446.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
A. P. Bolger, F. R. Bartlett, H. S. Penston, J. O'Leary, N. Pollock, R. Kaprielian, and C. M. Chapman
Intravenous Iron Alone for the Treatment of Anemia in Patients With Chronic Heart Failure
J. Am. Coll. Cardiol., September 19, 2006; 48(6): 1225 - 1227.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
A. S. Go, J. Yang, L. M. Ackerson, K. Lepper, S. Robbins, B. M. Massie, and M. G. Shlipak
Hemoglobin Level, Chronic Kidney Disease, and the Risks of Death and Hospitalization in Adults With Chronic Heart Failure: The Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study
Circulation, June 13, 2006; 113(23): 2713 - 2723.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
M. Komajda, S. D. Anker, A. Charlesworth, D. Okonko, M. Metra, A. Di Lenarda, W. Remme, C. Moullet, K. Swedberg, J. G.F. Cleland, et al.
The impact of new onset anaemia on morbidity and mortality in chronic heart failure: results from COMET
Eur. Heart J., June 2, 2006; 27(12): 1440 - 1446.
[Abstract] [Full Text] [PDF]

Home page
 HeartHome page
L Grigorian Shamagian, A Varela Roman, J M Garcia-Acuna, P Mazon Ramos, A Virgos Lamela, and J R Gonzalez-Juanatey
Anaemia is associated with higher mortality among patients with heart failure with preserved systolic function
Heart, June 1, 2006; 92(6): 780 - 784.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
Y.-D. Tang and S. D. Katz
Anemia in Chronic Heart Failure: Prevalence, Etiology, Clinical Correlates, and Treatment Options
Circulation, May 23, 2006; 113(20): 2454 - 2461.
[Full Text] [PDF]

Home page
 BloodHome page
B. F. Culleton, B. J. Manns, J. Zhang, M. Tonelli, S. Klarenbach, and B. R. Hemmelgarn
Impact of anemia on hospitalization and mortality in older adults
Blood, May 15, 2006; 107(10): 3841 - 3846.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
W. C. Levy, D. Mozaffarian, D. T. Linker, S. C. Sutradhar, S. D. Anker, A. B. Cropp, I. Anand, A. Maggioni, P. Burton, M. D. Sullivan, et al.
The Seattle Heart Failure Model: Prediction of Survival in Heart Failure
Circulation, March 21, 2006; 113(11): 1424 - 1433.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
E. O'Meara, T. Clayton, M. B. McEntegart, J. J.V. McMurray, C. C. Lang, S. D. Roger, J. B. Young, S. D. Solomon, C. B. Granger, J. Ostergren, et al.
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
Circulation, February 21, 2006; 113(7): 986 - 994.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
C. Opasich, M. Cazzola, L. Scelsi, S. De Feo, E. Bosimini, R. Lagioia, O. Febo, R. Ferrari, A. Fucili, R. Moratti, et al.
Blunted erythropoietin production and defective iron supply for erythropoiesis as major causes of anaemia in patients with chronic heart failure
Eur. Heart J., November 1, 2005; 26(21): 2232 - 2237.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
P. T. Vlagopoulos, H. Tighiouart, D. E. Weiner, J. Griffith, D. Pettitt, D. N. Salem, A. S. Levey, and M. J. Sarnak
Anemia as a Risk Factor for Cardiovascular Disease and All-Cause Mortality in Diabetes: The Impact of Chronic Kidney Disease
J. Am. Soc. Nephrol., November 1, 2005; 16(11): 3403 - 3410.
[Abstract] [Full Text] [PDF]

Home page
 Arch Intern MedHome page
J. L. Spivak
Anemia in the Elderly: Time for New Blood in Old Vessels?
Arch Intern Med, October 24, 2005; 165(19): 2187 - 2189.
[Full Text] [PDF]

Home page
 Arch Intern MedHome page
M. Kosiborod, J. P. Curtis, Y. Wang, G. L. Smith, F. A. Masoudi, J. M. Foody, E. P. Havranek, and H. M. Krumholz
Anemia and Outcomes in Patients With Heart Failure: A Study From the National Heart Care Project
Arch Intern Med, October 24, 2005; 165(19): 2237 - 2244.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
P. van der Meer, E. Lipsic, B. D. Westenbrink, R. M.A. van de Wal, R. G. Schoemaker, E. Vellenga, D. J. van Veldhuisen, A. A. Voors, and W. H. van Gilst
Levels of Hematopoiesis Inhibitor N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Partially Explain the Occurrence of Anemia in Heart Failure
Circulation, September 20, 2005; 112(12): 1743 - 1747.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
S. Philipp, H. Ollmann, T. Schink, R. Dietz, F. C. Luft, and R. Willenbrock
The impact of anaemia and kidney function in congestive heart failure and preserved systolic function
Nephrol. Dial. Transplant., May 1, 2005; 20(5): 915 - 919.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
A. Ishani, E. Weinhandl, Z. Zhao, D. T. Gilbertson, A. J. Collins, S. Yusuf, and C. A. Herzog
Angiotensin-converting enzyme inhibitor as a risk factor for the development of anemia, and the impact of incident anemia on mortality in patients with left ventricular dysfunction
J. Am. Coll. Cardiol., February 1, 2005; 45(3): 391 - 399.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
J. J.V. McMurray and M. A. Pfeffer
The year in heart failure
J. Am. Coll. Cardiol., December 21, 2004; 44(12): 2398 - 2405.
[Full Text] [PDF]

Home page
 The Annals of PharmacotherapyHome page
K. Caiola and J. W. Cheng
Use of Erythropoietin in Heart Failure Management
Ann. Pharmacother., December 1, 2004; 38(12): 2145 - 2149.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
G.M. Felker, K. F. Adams Jr, W. A. Gattis, and C. M. O'Connor
Anemia as a risk factor and therapeutic target in heart failure
J. Am. Coll. Cardiol., September 1, 2004; 44(5): 959 - 966.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
M. G. Shlipak, G. L. Smith, S. S. Rathore, B. M. Massie, and H. M. Krumholz
Renal Function, Digoxin Therapy, and Heart Failure Outcomes: Evidence from the Digoxin Intervention Group Trial
J. Am. Soc. Nephrol., August 1, 2004; 15(8): 2195 - 2203.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
I. Anand, J. J.V. McMurray, J. Whitmore, M. Warren, A. Pham, M. A. McCamish, and P. B.J. Burton
Anemia and Its Relationship to Clinical Outcome in Heart Failure
Circulation, July 13, 2004; 110(2): 149 - 154.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
P. van der Meer, A. A. Voors, E. Lipsic, T. D. J. Smilde, W. H. van Gilst, and D. J. van Veldhuisen
Prognostic value of plasma erythropoietin on mortality in patients with chronic heart failure
J. Am. Coll. Cardiol., July 7, 2004; 44(1): 63 - 67.
[Abstract] [Full Text] [PDF]

Home page
 Chronic Respiratory DiseaseHome page
C Nielson and D Wingete
Intensive care and invasive ventilation in the elderly patient, implications of chronic lung disease and comorbidities
Chronic Respiratory Disease, January 1, 2004; 1(1): 43 - 54.
[Abstract] [PDF]

Home page
 J Am Coll CardiolHome page
H. Taegtmeyer and S. Sharma
Anemia and energy depletion
J. Am. Coll. Cardiol., December 3, 2003; 42(11): 2030 - 2030.
[Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
D. Mozaffarian and W. Levy
Anemia and energy depletion: reply
J. Am. Coll. Cardiol., December 3, 2003; 42(11): 2030 - 2030.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow