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NDT Advance Access originally published online on April 23, 2007
Nephrology Dialysis Transplantation 2007 22(9):2563-2570; doi:10.1093/ndt/gfm206
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Impact of haemoglobin concentration and chronic kidney disease in patients with coronary heart disease undergoing percutaneous coronary interventions

Wibke Husemann1, Manfred Fobker2, Michele Pohlen1, Christian Bruch1, Martin Hausberg3, Günter Breithardt1 and Holger Reinecke1

1Medizinische Klinik und Poliklinik C (Department of Cardiology and Angiology), 2Institut für Klinische Chemie und Laboratoriumsmedizin (Institute of Clinical Chemistry and Laboratory Medicine) and 3Medizinische Klinik und Poliklinik D (Department of Nephrology), University Hospital, Münster, Germany

Correspondence and offprint requests to: Dr H. Reinecke, Ludwig-Teleky-Str 3, D-59071 Hamm, Germany. Email: hreinecke{at}gmx.net



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. A few recent studies suggested that anaemia has a marked impact on the survival of patients with coronary heart disease (CHD). However, all of these analyses did not take into consideration that chronic kidney disease (CKD) plays an important role in erythropoiesis and anaemia. Therefore, we assessed in this study whether anaemia is an independent predictor of mortality or if its impact was confounded by CKD, which is known to have itself a marked impact on outcomes of patients with CHD.

Methods. In a retrospective cohort study, we analysed 709 patients with symptomatic and significant CHD who underwent percutaneous coronary interventions. Patients were classified as anaemic using the WHO definition; renal function was classified by the estimated glomerular filtration rate (eGFR).

Results. In comparison with non-anaemic patients, anaemic patients had a significantly higher in-hospital mortality (4.9 vs 0.5%, P < 0.001). Moreover, 1-year mortality rates of anaemic patients were significantly higher regardless of whether they had a normal eGFR (22 vs 2.8%, P = 0.029), an eGFR of 60–89 ml/min (14 vs 4.2%, P < 0.001), an eGFR of 30–59 ml/min (21 vs 3.7%, P < 0.001) or an eGFR <30 ml/min (26 vs 0%, NS). When cumulative mortality was analysed by haemoglobin concentrations in steps of 1 g/dl from <11.0 g/dl to >16.9 g/dl, 1-year mortality rates were 28, 18, 15, 5.5, 3.8, 5.7, 1.5 and 0%, respectively (P < 0.001, log rank). Even after adjustment for comorbidities by multivariable Cox regression models, haemoglobin remained a significant predictor of long-term mortality (hazard rate ratio 0.77, 95% confidence interval (CI): 0.62–0.82, P < 0.001) while eGFR was not (hazard rate ratio 1.0, 95% CI: 0.99–1.01).

Conclusions. Anaemia was found to be a strong and independent predictor of acute and long-term mortality in patients with symptomatic CHD, regardless of the presence of CKD.

Keywords: anaemia; angioplasty; mortality; PCI; renal function



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Anaemia is a relatively frequent condition in the general population which remains often underdiagnosed and untreated [1]. The underlying causes of anaemia may include various diseases such as iron, folate or B12 deficiency, malnutrition, cancer-induced blood losses, bone marrow depression, cytokine induction due to chronic diseases and especially chronic kidney disease (CKD) as an emerging cause [2]. For a long time, anaemia was considered to be at first a haematological disorder which had little interference with cardiovascular diseases. In contrast, some recent studies demonstrated that chronic anaemia has a marked impact on the cardiovascular system due to tissue hypoxia, endothelial dysfunction, sympathetic activation, heart failure and other factors [3,4]. Moreover, there is evidence that anaemia acts as an independent cardiovascular risk factor. Thus, one recent prospective epidemiological study in a general population found anaemia in healthy subjects without coronary heart disease (CHD) to be associated with a significantly higher rate of cardiovascular events during the following 6 years [5]. This impact on cardiovascular outcomes appears to be even more pronounced in patients with already manifested CHD [6,7] who were found to suffer from excessive acute and long-term mortality rates depending on their haemoglobin concentrations. However, at present it remains unclear whether the high rates of adverse outcomes are independently related to low haemoglobin concentrations or whether they are confounded by CKD which frequently coexists and is well known to markedly effect both erythropoiesis and cardiovascular events [8–10], especially in patients with manifest CHD [11–13]. Therefore, this study aimed to examine the influence of haemoglobin concentrations on the outcomes of patients with symptomatic CHD undergoing percutaneous coronary interventions (PCI) with special regard to the impact of different stages of CKD.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
Patients treated by PCI from 1 January 2001 to 31 December 2001 were retrospectively chosen for analysis using the institutional clinical computer database, in which the data of all patients are stored that have been treated with heart catheterization. In this database, apart from information concerning the PCI intervention, also additional data about concomitant diseases and drug use were stored. During the period of data collection, all patients admitted to our institution for emergency or elective PCI were included in the analysis.

Cardiovascular risk factors
Cardiovascular risk factors were assessed at presentation for PCI and were defined as follows: history of smoking was assumed if the patients had smoked within the last 10 years; hypertension if blood pressure >140/90 mmHg had been documented; hyperlipidaemia was assumed if total cholesterol or triglyceride levels were >200 mg/dl, or lipoprotein (a) (a variant form of low denisty lipoprotein that contains apolipoprotein-a) >20 mg/dl; family history of cardiovascular disease if stroke, myocardial infarction (MI), or coronary intervention occurred in a first-degree relative.

Haemoglobin concentrations
Haemoglobin concentrations were gathered using the database of the Institute for Clinical Chemistry. Only haemoglobin concentrations which were recorded 1–3 days ‘before’ the procedure were included for the following analyses. Patients were classified to be anaemic or not based on pre-procedural haemoglobin levels using the World Health Organization (WHO) definition (<12.0 g/dl in women and <13.0 g/dl in men) [14].

Renal function
End-stage renal failure was assumed if the patient had ever required temporary or ongoing maintenance haemodialysis.

Since end-stage renal failure is well known to be associated with excessive mortality, these few patients were not considered for further examination.

Currently, there are several reliable equations for estimation of glomerular filtration rates (eGFRs) available; because of its known greater preciseness in patients with mild to moderately reduced renal function which represent the majority in our study, the Cockroft–Gault equation was primarily used to calculate eGFRs:


Formula 1

(1)

Then, renal function was classified into five stages of CKD depending on the eGFR in accordance to the National Kidney Foundation [15].

For some key interpretations, the analyses were additionally performed with an eGFR calculated by the simplified Modification of Diet in Renal Disease (MDRD) equation to avoid any systematic error due to the use of the Cockroft–Gault equation:


Formula 2

(2)
Each of these alternative analyses was presented in the text. However, in summary, results were always very similar, regardless if the eGFR was calculated by the Cockroft–Gault or the MDRD equation.

Interventional procedures
PCIs were performed using arterial access from the femoral or brachial arteries. The coronary segment, the type of coronary stenosis dilated and angiographic success were classified according to the revised classification of the American Heart Association (AHA) and the American College of Cardiology (ACC). Angiographic success after PCI was assumed if a residual stenosis in the vessel diameter of <30% could be achieved. Left ventricular ejection fraction (EF) was assessed from 30° right anterior oblique projections of the pre-PCI angiograms and classified as normal, moderately or severely impaired in accordance to the ACC/AHA guidelines [16].

Follow-up
A questionnaire was developed, asking for repeat interventions and adverse events. The follow-up was conducted by telephone calls with patients, relatives or referring physicians.

If a follow-up questioning by phone was not possible, the questionnaire was sent by mail. The follow-up questioning was conducted in March 2004 and was 100% complete.

Statistics
Depending on their baseline haemoglobin before PCI, patients were divided into subgroups of 1 g/dl. Differences in basic clinical characteristics between the subgroups were tested by ANOVA F-test for continuous variables, and overall chi-square test for categorical variables. The P-values for all of these tests are given in the tables. All endpoint analyses were made by log rank tests or Cox regression analysis. Univariate predictors of mortality during follow-up were analysed by Cox regression analyses (hazard rate ratios, HRR), with 95% confidence intervals (95% CI). Multivariable analyses were performed by Cox regression analyses with confounding covariates (adjusted HRR). As covariates for adjustment, those parameters were chosen which were found to have a P-value <0.1 in univariate analyses of mortality. All tests were performed two-sided, and P-values <0.05 were taken as significant. All statistical tests were performed with SPSS 11.5 for Windows.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Acknowledgements
 References
 
During the study period, 770 patients were treated by PCI at our institution. Due to end-stage renal failure or missing baseline haemoglobin or creatinine values, only 709 of the cases were included in the following analysis (92%). Follow-up data was 100% complete for all of these patients.

The baseline characteristics of the patients are shown in Table 1. Depending on their baseline haemoglobin values before PCI, the patients were separated into eight subgroups. According to the definition of the WHO, anaemia was present in 18.1% of the whole cohort (17.1% of men, 21.5% of women). The mean haemoglobin concentration was 13.5 ± 1.7 g/dl in the whole study cohort, 13.9 ± 1.7 g/dl in men and 12.6 ± 1.5 g/dl in women. Significant differences were found regarding age and eGFR: in the groups with lower haemoglobin concentrations, patients were significantly older (Table 1) and had lower eGFRs (Figure 1, upper panel). Apart from some significant differences concerning hyperlipidaemia and smoking habits, cardiovascular comorbidities and previous events were similar at baseline between the different groups.


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  		Table 1. Baseline clinical data and cardiovascular risk factors at presentation for PCI

 

Figure 1
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  		Fig. 1. The upper panel (A) (light grey bars) shows a clear and significant association between a decreased renal function and lower haemoglobin concentrations (P < 0.001, tested by the ANOVA F-test). In the medium panel (B) (dark grey bars), a U-shaped relation between the proportion of patients presenting with acute coronary syndromes (ACS) and haemoglobin become overt: patients with lowest and highest haemoglobin concentrations were significantly more likely to present with an ACS (P = 0.027, chi-square test). Long-term mortality rates of the distinct subgroups of haemoglobin concentrations are shown in the lower panel (C) (black bars). Thus, the patients with lower haemoglobin concentrations had the highest mortality rates (P < 0.001, log rank test).

 
Angiographic characteristics during the index PCI are presented in Table 2. Thus, acute coronary syndromes (ACS) were more frequently present in patients with low (<11.0 g/dl) and high (>16.0 g/dl) haemoglobin concentrations suggesting a U-like association between haemoglobin concentrations and admission due to an ACS (Figure 1, medium panel). Furthermore, with increasing haemoglobin concentrations the probability also increased to receive an intervention of more than one coronary segment.


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  		Table 2. Angiographic characteristics and PCI data

 
Acute and long-term outcomes
The rates of in-hospital mortality and infarctions, as well as the necessity for redo-PCI in the separate subgroups are shown in Table 3. Since the number of occurring in-hospital events were low overall, there were no significant differences between the subgroups.


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  		Table 3. Acute and long-term outcome, and major adverse coronary events after PCI

 
The results of the long-term follow-up (mean duration 390 days, 95% CI 378–402 days) revealed that there was a substantial difference in all-cause mortality in the several haemoglobin subgroups (Table 3): patients with haemoglobin concentrations <11.0, 11.0–11.9 and 12.0–12.9 g/dl suffered from a 3- to 5-fold higher cumulative all-cause mortality compared with those with haemoglobin concentrations >12.9 g/dl (Figure 1, lower panel). Moreover, MIs trended to occur more often in patients with higher haemoglobin concentrations. There were no differences with regard to redo angiographies, PCIs or bypass surgery between the subgroups. The proportion of patients with known malignomas was higher in the subgroups of patients with lower haemoglobin concentrations, but these numbers of patients affected do not explain the increased rate of death within each subgroup. The need for chronic haemodialysis during follow-up was significantly higher in the patients with lower haemoglobin concentrations; however, it has to be kept in mind that eGFR was already at baseline significantly lower in these patients (Table 1).

Predictors of long-term mortality
A univariate analysis of significant predictors for mortality during follow-up is shown in Table 4. Besides other well-known predictors of long-term mortality as age, multivessel disease and left ventricular function, especially renal function indicated by eGFR (calculated by the Cockroft–Gault equation) and haemoglobin concentrations turned out to be significantly associated with long-term mortality. Additionally, the eGFR was also calculated for all patients by the MDRD equation. Thus, this eGFRMDRD was also found to be an independent predictor of long-term mortality in univariate analyses (HRR: 0.980; 95% CI: 0.967–0.993; P = 0.002)


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  		Table 4. Univariate predictors and risk estimates of long-term mortality during follow-up by Cox regression models

 
A multivariable Cox regression analysis of the parameters found to be significant in univariate analyses, identified haemoglobin concentrations and left-ventricular function as independent predictors of long-term mortality but not the eGFR (Table 5). The correlation coefficient between haemoglobin concentrations and the eGFR was –0.326. Again, if the eGFR was alternatively calculated by the MDRD equation, the results of the multivariable analysis remained unchanged and showed a strong and independent impact of haemoglobin (HRR: 0.709; 95% CI: 0.617–0.814; P < 0.001) but not the eGFRMDRD (HRR: 0.990; 95% CI: 0.997–1.005; P = 0.184).


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  		Table 5. Multivariable analysis by Cox regression of long-term mortality

 
The interaction of renal function and anaemia
The interaction of renal function and anaemia, and their impact on cumulative 1-year mortality are shown in Figure 2. This demonstrates that even the group of patients with normal renal function (eGFR >89 ml/min) showed a significantly higher number of deaths if anaemia was present. In the subgroups with manifest CKD, cumulative mortality rates of patients with anaemia were also markedly higher but similar to the survival rates of those with an eGFR >89 ml/min. Similar results regarding mortality rates were found for each subgroup of CKD if the eGFRMDRD was used (anaemic: 13, 20, 25 and 0%, respectively; non-anaemic: 6, 4, 6 and 0%, respectively).


Figure 2
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  		Fig. 2. Cumulative 1-year mortality rates (in %) for anaemic (black bars) and non-anaemic patients (grey bars) were plotted depending on the patient's baseline eGFR before PCI. At the top of each column, the number of patients in the group is noted. Differences between patients with and without anaemia were analysed with the log rank test and given above each pair of columns.

 
Cox regression models of long-term mortality including survival curves are shown in Figure 3. In Figure 3A, the crude survival rates depending on baseline haemoglobin concentrations were shown without adjustment for coexisting predictors of mortality and revealed the significant decrease in survival with lower haemoglobin concentrations. In Figure 3B, survival rates from an adjusted Cox regression model are shown which confirmed, that even after adjustment for other predictors of mortality survival rates significantly declined with lower haemoglobin concentrations. The results remained unchanged if the eGFRMDRD calculated by the MDRD equation was used.


Figure 3
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  		Fig. 3. Cumulative long-term survival was plotted using Cox regression models. Survival among the different subgroups depending on their baseline haemoglobin (Hb, in g/dl) is compared in panel (A); long-term survival was found to be reduced with lower haemoglobin concentrations (P < 0.001). In a second model (B), a Cox regression model adjusted by age, gender, number of diseased vessels, LV function and renal function (as indicated by the eGFR) was used; thus, also in this adjusted model, survival was significantly lower in the subgroups with lower haemoglobin (P = 0.001).

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Acknowledgements
 References
 
A few, but conclusive, reports demonstrated the impact of haemoglobin concentration on the survival of patients with CHD. Our study corroborates these previous findings as there was a significant deterioration of the outcome of patients with lower haemoglobin concentrations in comparison with patients without anaemia. The findings of this study regarding the impact of anaemia on in-hospital and long-term mortality of patients with CHD, especially the observed mortality rates, are in good accordance with those of the other trials who analysed the outcomes after PCI [6,7,17]. In this study as well as in more detail shown in a previous patient cohort [6], this excess mortality during follow-up in anaemic CHD patients was almost due to cardiovascular causes rather than cancer or other illnesses. However, all of the previous studies did not consider renal function as a confounding factor. Therefore, our study is the first to show in patients with CHD that the impact of anaemia was independent from coexisting CKD which is a frequent and increasing cause of anaemia.

In patients with chronic heart failure, one very recent study has investigated the effects of anaemia and renal failure [18]. This excellent and very large study found that both anaemia and renal failure were independent predictors for hospitalization and long-term mortality; as in our results, there was a markedly increased mortality risk with decreasing haemoglobin concentrations independent from eGFR. Chronic heart failure and CKD are often linked to each other and frequently show progression, even if they are treated with optimal medical therapy. Each of these three factors, Chronic heart failure, CKD and anaemia could cause or worsen one of the others, with anaemia appearing to be a key player being present in about one-third of the CHD patients [19]. Thus, a vicious circle exists between all these three conditions which has been named the cardio–renal–anaemia syndrome [20]. These relations and underlying mechanisms might not necessarily be identical in patients with manifest CHD, anaemia and renal failure. However, this analysis for the first time showed, that the presence of anaemia seems to be the most decisive factor influencing mortality in CHD patients regardless of renal function even if the cause of anaemia might be CKD. This conclusion is based on the univariate and multivariable Cox regression analyses and on the findings that even the group of patients with normal kidney function (>89 ml/min), when presenting with anaemia, showed an increased number of deaths (Figure 2).

This raises the question whether treatment of anaemia could improve survival. The very recently published CREATE trial investigated the impact of early correction of anaemia by epoietin beta in patients with stable CKD, with about 10% of the patients suffering from known CHD at randomization [21,22]. Although the functional status of the patients treated with epoietin beta improved significantly, there were no differences with regard to any cardiovascular endpoint. In the same issue of that journal, also the CHOIR study [23] was published which had similar treatment goals but a different patient population: the patients were markedly older and about one-third had significant coronary or peripheral arteriosclerotic disease (CABG, PCI, MI, stroke, amputation). Nevertheless, even in this setting the treatment group with a higher target haemoglobin concentration of 13.5 g/dl also showed no improvement in outcome but there was some evidence for potential harm. However, since there were no subgroup analyses of the patients with significant CHD in these trials, these negative results could not necessarily be transferred to patients with CKD ‘and’ manifest CHD as included in our analysis. A current survey reported that high endogenous erythropoietin levels were associated with smaller infarct sizes in patients with acute MI and successful primary PCI. These data provide some evidence that erythropoietin may have a protective effect against ischaemia [24] which might turn out to be relevant in patients with both CKD and CHD. Thus, it remains to be seen, whether future studies will recommend an employment of erythropoietin for the therapy of anaemia in patients with CHD or not, and if this leads to an improved long-term survival.



   Acknowledgements
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
References
 
The authors were indebted to Mr Ing. (grad.) Klaus Balkenhoff for establishing the PCI database. The authors would also like to thank all technicians and nurses in the catheterization laboratories for their ongoing support.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Received for publication: 21. 1.07
Accepted in revised form: 16. 3.07


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