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© 2005 European Society of Cardiology
Anaemia is an independent predictor of mortality in patients with left ventricular systolic dysfunction following acute myocardial infarction
a Department of Cardiology, Rigshospitalet, Copenhagen Denmark
b University of Glasgow Glasgow, United Kingdom
c Department of Cardiology, Bispebjerg Hospital Copenhagen, Denmark
* Corresponding author. Sponnecksvej 15, st., 2820 Gentofte, Denmark. Tel.: +45 45870331. Email address: nvaleur{at}dadlnet.dk (N. Valeur).
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Abstract |
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 TopNotes Abstract 1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Background: In patients with chronic heart failure (HF), mortality is inversely related to haemoglobin (hgb) concentration. We investigated the prognostic importance of anaemia in patients with acute myocardial infarction (AMI) and left ventricular systolic dysfunction (LVSD) with and without HF.
Methods and results: We studied 1731 patients with AMI and left ventricular ejection fraction 
35% from the TRAndolapril Cardiac Evaluation (TRACE) study. Mild anaemia (110 g/L hgb < 120 g/L in women and 120 g/L hgb < 130g/L in men) was present in 264 patients (15%), 114 (7%) had moderate (100 g/L hgb < 110 g/L in women and 110 g/L hgb < 120g/L in men) and 59 (3%) had severe (hgb < 100 g/L in women and < 110g/L in men) anaemia. According to the WHO criteria (hgb 120g/L in women and < 130g/L in men), 25% had anaemia. Anaemia was associated with increasing age, higher serum creatinine, lower body mass index, history of chronic HF, and worse NYHA class. In multivariable analyses including other prognostic factors only severe anaemia was associated with increased mortality, hazard ratio 1.59 (1.20–2.11). Anaemia was of prognostic importance in patients with HF, but not without HF. In HF patients the hazard ratios were 1.73 (1.26–2.36), 1.20 (0.93–1.56) and 1.05 (0.88–1.25) for severe, moderate and mild anaemia, respectively.
Conclusion: Anaemia is an independent predictor of mortality in patients with AMI and LVSD, but prognostic importance of anaemia is confined to the first year following AMI. The increased risk is driven by patients with severe anaemia and HF.
Key Words: Anaemia • Myocardial infarction • Prognosis • Heart failure
Received July 30, 2005; Revised October 16, 2005; Accepted November 28, 2005
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1. Introduction |
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TopNotesAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Anaemia is a relatively common finding in patients with chronic congestive heart failure (HF) due to left ventricular systolic dysfunction (LVSD). The described prevalence varies considerably from 17% up to 61% because of heterogeneous definitions of anaemia and different study cohorts [1-6]. Also, the prevalence of anaemia increases with NYHA class in patients with HF [2,4,7,8].
The prognosis of patients with chronic HF is poor and anaemia has been demonstrated to be an independent predictor of morbidity and mortality in several studies [2,4,6,8].
The prevalence and prognostic importance of anaemia in patients with LVSD, heart failure or both complicating acute myocardial infarction (AMI) is unknown. Also, the importance of different definitions of anaemia has not previously been studied. Therefore, we examined these questions in a large cohort of patients with AMI and LVSD randomised in the TRAndolapril Cardiac Evaluation (TRACE) study.
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2. Materials and methods |
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TopNotesAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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2.1. Patients
TRACE was a randomised, double-blind, placebo-controlled trial which examined the effect of the ACE-inhibitor trandolapril in patients with LVSD shortly after myocardial infarction. Details of the TRACE study have been published previously [9].
Between 1990 and 1992, 1749 patients were recruited from 27 Danish hospitals. In brief, patients were eligible for entering the TRACE study if LVSD was present two to six days after an enzyme-verified AMI. Prior medical history and concomitant medications were recorded. Blood chemistry, haematology (including the haemoglobin used for analyses) and weight was measured at the day of randomisation. Laboratory measurements were made at a single central laboratory. Left ventricular systolic function was assessed by echocardiography performed locally and subsequently analysed centrally prior to randomisation by two members of the study group [10]. The criterion for LVSD was a wall motion index (WMI) 1.2, corresponding to an ejection fraction (EF) 0.35. The most frequent reasons for exclusion were mandatory need for ACE inhibition, cardiogenic shock, death during screening, renal failure (creatinine above 200 µmol/L (2.3 mg/dL) and lack of informed consent. Patients with known or suspected malignant disease were excluded.
The mean follow-up time was 26 months, ranging from 24 to 50 months in the randomised study, but patients were followed for 10 to 12 years since randomisation. The primary end point was death from any cause. Information on survival status was available for all but 6 patients who emigrated. HF was defined as a history of heart failure requiring medical treatment or new onset HF (Killip class greater than 1) during the hospitalisation for the index infarction.
2.2. Definition of anaemia
Anaemia was defined in several ways. Firstly, we selected the cut-off values using the World Health Organisation definition: a hgb lower than 120 g/L (corresponding to 7.5 mmol/L) in women and 130 g/L (corresponding to 8.0 mmol/L) in men denoted as WHO-anaemia throughout the manuscript. In order to examine if the prognostic importance of anaemia was driven by the group of patients with most severe anaemia, the cut-off level of hgb was decreased with 10 and 20 g/L, respectively, resulting in a second and third definition of anaemia. The second definition, corresponding for the lowest decile in each gender, was used with a hgb lower than 110 g/L (6.8 mmol/L) in women, and lower than 120 g/L in men. This is denoted as lowest decile anaemia in this study. Severe anaemia was defined as hgb <100 g/L (6.2 mmol/L) in women and <110 g/L in men.
Secondly, anaemia was defined as mutually exclusive groups: mild anaemia (110 g/Lhaemoglobin concentration (hgb)<120 g/L in women and 120 g/Lhgb<130 g/L in men), moderate anaemia (100 g/Lhgb<110 g/L in women and 110 g/Lhgb<120 g/L in men) and severe anaemia (hgb <100 g/L in women and <110 g/L in men) as defined above.
2.3. Statistics
Continuous variables are presented as medians with 5th and 95th percentiles, and discrete variables as percentages. Baseline characteristics were compared using the continuity-adjusted Chi-square test for discrete variables and rank sum tests for continuous variables. Independent predictors of anaemia were identified by performing a multiple regression. Time-to-event curves were generated with the use of Kaplan-Meier estimates. Comparisons of time-to-event curves were performed with a log-rank test. Comparisons of mortality were made using the Cox proportional hazards models. Hazard ratios were obtained from Cox proportional-hazards regression using all variables listed in Table 1. Model assumptions (proportional hazard, linearity of continuous variables and no interaction) were tested and found valid unless otherwise reported. Interaction analysis was made in Cox proportional-hazard models with inclusion of the interaction variable. A p value <0.05 was considered significant. All calculations were made using SAS software (SAS Institute, Cary, NC, USA).
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2.4. Ethics
The TRACE study was approved by all Danish regional ethics committees. All patients gave their informed consent before inclusion in the randomised trial.
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3. Results |
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TopNotesAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Haemoglobin measurements were missing in 18 patients, leaving 1731 patients for analysis. For all patients, mean haemoglobin was 137 g/L (±16 g/L). Mean haemoglobin was 140 g/L (±16 g/L) in the 1238 men, and 129 g/L (±15 g/L) in the 493 women, respectively.
According to the exclusive groups, 1294 (75%) patients had no anaemia, 264 (15%) had mild, 114 (7%) had moderate and 59 (3%) had severe anaemia. According to the WHO criteria, 437 patients (25%) had anaemia and lowest decile anaemia was present in 173 patients (10%). The prevalence of anaemia according to gender and different haemoglobin cut-off values are shown in Fig. 1.
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Baseline characteristics for the exclusive definitions of anaemia are shown in Table 1. Anaemia was associated with increasing age, higher serum creatinine, lower body mass index, history of chronic HF, and worse NYHA class. The lower hgb is, the higher age, creatinine, NYHA class and frequency of chronic HF and the lower BMI would be. Anaemic patients were more likely to have been taking "ulcer healing drugs" and less likely to have received Aspirin or a fibrinolytic drug.
3.1. Anaemia in relation to HF
Baseline characteristics of the mutually exclusive groups according to the presence of HF or not are shown in Tables 2 and 3, respectively. Among patients with HF anaemic patients were older, had a higher creatinine, a lower body mass index and had more often NYHA class III-IV. They received less often fibrinolysis and aspirin than patients without anaemia.
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Among patients without HF, anaemic patients were older and more likely to have atrial fibrillation, and had a higher serum creatinine. Anaemic patients were more likely to have been taking "ulcer healing drugs".
3.2. Multivariable associates of anaemia
In a multiple logistic regression analysis mild anaemia was associated to age with hazard ratio (1.03 [1.01-1.04], p<0.0001); body mass index (0.93 [0.90-0.96], p<0.0001) and creatinine (1.008 [1.004-1.012], p=0.0002), moderate anaemia was only associated with age (1.03 [1.01-1.05], p=0.0034) and body mass index (0.93 [0.89-0.97], p=0.0015), while severe anaemia was associated with creatinine (0.991 [0.983-0.999], p=0.031). The lower haemoglobin the higher creatinine.
3.3. Mortality analyses
During the 10 years of follow-up, 1268 patients died, of whom 331 had anaemia according to WHO limits (WHO-anaemia).
In univariable analysis, WHO-anaemia was found to be a significant prognostic predictor of mortality with a hazard ratio of 1.21 (1.06-1.37), 1.43 (1.19-1.70) for lowest decile anaemia, and 1.82 (1.37-2.41) for severe anaemia, respectively. Mild anaemia was associated with a hazard ratio of 1.04 (0.89-1.21) and moderate anaemia was associated with a hazard ratio of 1.23 (0.99-1.53). However, every increase of 1 g/dL in hgb was associated with a 7% decrease in mortality (HR=0.93 (0.90-0.96).
In order to test whether the different levels of haemoglobin for men and women were appropriate, separate analyses according to sex were also performed. Univariable hazard ratios for different haemoglobin levels and sex are shown in Fig. 1. Using the same haemoglobin levels for both sexes, resulted in a higher hazard ratio for men.
Survival of patients with mild, moderate and severe anaemia is shown in Fig. 2. Mortality increased with severity of anaemia (p<0.001). Survival of patients with and without WHO-anaemia in relation to HF is shown in Fig. 3. WHO-anaemia was associated with a higher mortality rate in patients with HF only. From the survival curves, it was apparent that the increased risk associated with anaemia was predominantly found during the first year. Restricting the analyses to a follow-up of 1 year showed increased risk associated with anaemia. For every increase of 1 g/dL in hgb mortality decreased by 19% (HR=0.81 (0.74-0.90); multivariable analysis). Similarly, repeating the analyses in patients surviving 1 year removed the associated risk of anaemia (p=ns for all anaemia groups). However, severe anaemia was of borderline significance (HR=1.40 (0.92-2.17); p=0.12).
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In multivariable analyses the prognostic importance of anaemia according to different criteria are shown in Table 4. Lowest decile and severe anaemia, but not mild, moderate or WHO-anaemia, were associated with a significant increase in the risk of death, with a hazard ratio of 1.24 (1.04-1.48) for lowest decile anaemia and 1.59 (1.20-2.11) for severe anaemia, respectively.
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There was a significant interaction between WHO-anaemia and HF (p=0.03). Thus, anaemia was more important in the group of HF patients compared to the patients without HF. The hazard ratio of death in patients with lowest decile anaemia and HF was 1.32 (1.08-1.61) and 1.65 (1.21-2.25) in patients with severe anaemia and HF (Table 4).
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4. Discussion |
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TopNotesAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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There are several new findings in this large study of patients with a myocardial infarction and LVSD. 25% had anaemia according to the criteria of the WHO, but WHO-anaemia was not an independent predictor of mortality, in contrast to lowest decile anaemia and severe anaemia, where the mortality risk increased by 24% and 59%, respectively. The risk associated to the lowest decile anaemia was driven by patients with severe anaemia. However, there appeared to be an increased risk associated with every decrease in haemoglobin. The prognostic importance of anaemia was confined to the first year following AMI, which is an important new finding. Lastly, an interaction with HF was found, whereby anaemia was only associated with death in patients with HF.
Our results show how the prevalence and hazard associated with anaemia depends on the cut-off value of haemoglobin used. The prevalence of anaemia decreases with lower cut-off values of haemoglobin, whereas the risk associated with anaemia increases. The WHO definition is commonly used, but our data suggest that the WHO criteria for anaemia are too wide to have prognostic importance in a post-AMI population. However, with the difference in hazard ratios for men and women at the same haemoglobin levels, it seems reasonable to use different cut-off values according to gender (Fig. 1). A decrease in haemoglobin of 1 g/dL results in the same prevalence of anaemia, as well as the same mortality risk for men and women. It is important that future studies give prevalence and outcome results based on different definitions, using different haemoglobin cut-off values in men and women.
This is, to our knowledge, the first large study of the prognostic importance of anaemia in AMI patients with left ventricular systolic dysfunction. Other reports have described the prevalence and prognostic importance of anaemia in patients with AMI [5,11-14]. However, these studies comprised a very heterogeneous group of AMI patients with little information on the prevalence of LVSD. In the registry report by Al Falluji et al., 6.4% patients had a diagnostic code for anaemia in the pre-fibrinolytic period, and 10.2% in the fibrinolytic period, and anaemia had no prognostic significance [11]. The prevalence of HF was not reported, although LVSD was found in 50% of the anaemic patients versus 35% in the non-anaemic group. In another study of post-MI patients, 21.8% had a haematocrit between 30% and 39%, and 5.9% had a haematocrit lower than 30%. Anaemia was found to be an independent prognostic variable, with the lower haematocrit the higher the risk of death [15]. Only 61% of the patients had a LVEF reported and 35% of these had LVSD. In a recent study of the entire spectrum of acute coronary syndromes every decrease of haemoglobin of 1g/dL was associated a 21% increase in cardiovascular mortality at 30 days [14]. This is comparable to our 20% increase in all cause mortality at 1 year. During the first year, more than 75% of all deaths were cardiovascular in our study [9].
In our study, NYHA class was significantly higher in the patients with HF who were anaemic. This supports other studies, where low haemoglobin values directly relate to poor peak oxygen consumption, disabling symptoms, and impaired survival [4,7,16-18]. Our study cannot tell whether anaemia increases the risk of getting HF in acute myocardial infarction or whether HF induces anaemia, but an interaction was found between anaemia and HF (p=0.03).
In our study population, the aetiology of anaemia is unknown. Several mechanisms have been suggested in patients with HF. Most patients with HF have reduced renal function, which may result in depressed production of erythropoietin [19]. It is interesting that reduced renal function was only associated with more anaemia when using the WHO criteria. However, patients could only be included in the TRACE study if creatinine was below 200 µmol/L (2.3 mg/dL) limiting the possibility to demonstrate a relation between renal function and anaemia. Elevated plasma levels of erythropoietin were associated with the severity of HF, but poorly correlated to haemoglobin, suggesting a resistance to EPO in the bone marrow of HF patients [20]. This resistance could be mediated by high levels of proinflammatory cytokines. TNF-P and interleukin-6 are known to be present in chronic diseases such as chronic HF, and have been shown to suppress the bone marrow production resulting in anaemia [21,22]. In this study, patients with known or suspected cancer, or a chronic illness expected to reduce survival were excluded.
Haemodilution is common in HF patients and patients with haemodilution seem to do worse than patients with true anaemia [1]. Haemodilution could be an important factor in our population, but we do not know to what degree.
Malnutrition was suggested to cause anaemia in a study where anaemic patients had lower serum albumin, cholesterol and BMI [4]. Our finding of significantly lower BMI in anaemic patients supports this. Some studies have suggested an association between anaemia and the use of ACE inhibitors, but our entire study population received ACE inhibitors only after the measurement of haemoglobin. Since all patients in our study had coronary artery disease, anaemia could originate from gastrointestinal blood loss due to fibrinolysis, aspirin, NSAID or warfarin use. However, none of these medications were associated with anaemia. Also, fibrinolysis and aspirin were administered less often in the anaemic patients. This could contribute to the worse prognosis in this group, as these medications have shown beneficial effects on survival. However, as these treatment were included in multivariable analyses, it is not likely that this explains the excess mortality associated with anaemia.
4.1. Limitations
This is a retrospective study where only patients with LVSD were included, and no data to elucidate the cause or following treatment of anaemia were collected. Therefore the actual study can only be hypothesis generating. Patients were included in 1990-1992 and treatment regimens have changed since then. However, as anaemia is still frequent among post-MI patients it is not likely that the importance of anaemia should have changed considerably. The aetiologies of anaemia were not known, and the prognosis may vary according to this. The strengths of the study are that the population was large with long complete follow-up, free of malignant disease and well-characterised chronic diseases.
4.2. Perspectives
More attention should be paid to anaemia in patients with HF and AMI, and a study of treatment in a large population of patients is warranted. Recent pilot studies in HF patients have shown that correction of anaemia with erythropoietin and iron might lea d to improvement in symptoms and exercise capacity [7,23].
4.3. Conclusion
Anaemia is an independent predictor of mortality in patients with AMI and LVSD. The increased risk is driven by patients with more severe anaemia and HF, and the risk is most apparent in the first year.
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Notes |
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TopNotesAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Sponsors: TRACE was sponsored by a grant from Roussel-Uclaf and Knoll. 
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References |
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TopNotesAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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