a Medizinische Klinik und Poliklinik C (Department of Cardiology and Angiology), Hospital of the University of Münster, Münster, Germany
b Institut für Epidemiologie und Sozialmedizin (Institute for Epidemiology und Social Medicine), Hospital of the University of Münster, Münster, Germany
c Institut für Klinische Chemie und Laboratoriumsmedizin (Institute of Clinical Chemistry and Laboratory Medicine), Hospital of the University of Münster, Münster, Germany
d Medizinische Klinik und Poliklinik D (Department of Nephrology), Hospital of the University of Münster, Münster, Germany
e Department of Biochemistry, Southwestern Medical Center, Dallas, USA
* Correspondence to: Dr H. Reinecke, Medizinische Klinik und Poliklinik C, Universitätsklinikum Münster, D-48129 Münster, Germany. Tel: +49 251 834 7617; Fax: +49 251 834 7864
E-mail address: reinech{at}uni-muenster.de
Received 7 February 2003; revised 16 July 2003; accepted 11 September 2003
Abstract
Aims It has recently been proposed that anaemia is an independent risk factor for development of cardiovascular disease in the general population. The impact of anaemia on long-term survival of patients with manifest coronary heart disease (CHD) has not been assessed so far. In this study, we examined the influence of haemoglobin concentrations on the outcome after percutaneous coronary interventions (PCI).
Methods and results In a retrospective cohort study, we analysed in-hospital and long-term mortality in all male patients admitted to our institution for elective PCI from 1998 to 1999. In 689 cases, complete follow-up information could be obtained (98.4%). Depending on their baseline haemoglobin, patients were divided in quintiles. In all subgroups, angiographic success after PCI (9094%) was comparably high and in-hospital mortality was low (00.7%). During follow-up (median 697 days), patients in the lowest haemoglobin quintile (12.9g/dl) were significantly more likely to suffer from all-cause death (22.2%) than those of the other quintiles (3.712.1%; estimated mortality rates from KaplanMeier models, P<0.0001, log rank test). In more detail, we found a U-shaped relationship between mortality and haemoglobin strata in steps of 1g/dl (P<0.0001, log rank test). After adjustment for potential co-variates, patients of the lowest haemoglobin quintile showed in Cox regression analysis a markedly higher risk for death (adjusted hazard rate ratio (HRR) 4.09, 95% confidence interval (CI) 1.5211.05) compared to the quintile with a haemoglobin concentration of 14.615.2g/dl.
Conclusion These results indicate that anaemia is associated with markedly reduced survival in patients with CHD after elective PCI. Since PCI is a common intervention and anaemia is a frequent condition in the general population, strategies for the management of anaemic PCI patients and treatment of anaemic patients with CHD should be developed.
Key Words: Anaemia Angioplasty Percutaneous coronaryintervention Mortality
1. Introduction
Anaemia is a relatively frequent condition in the general population with many possible underlying causes such as iron, folate or B12 deficiency, malnutrition, cancer-induced blood losses, bone marrow depression, renal failure with decreased production of erythropoeitin and/or renal loss of erythropoeitin.1
A few recent studies provided evidence that chronic anaemia may also be an independent cardiovascular risk factor. In a prospective study in the general population with healthy subjects without coronary heart disease (CHD), anaemia was found to be associated with a significantly higher rate of cardiovascular events during the following 6 years.2It had previously been shown that anaemia is a risk factor in patients with kidney disease and in patients with heart failure, and that these patients may benefit from treatment with iron and erythropoeitin.3Finally, a recent study revealed the profound impact of anaemia on in-hospital mortality in CHD patients undergoing coronary bypass surgery.4
There are no data available about the long-term survival of patients with manifest CHD and anaemia. Therefore, we analysed the impact of pre-procedural haemoglobin concentrations on all-cause and cardiac mortality in patients undergoing percutaneous coronary interventions (PCI).
2. Methods
2.1. Patients
All patients patients who underwent PCI from 1 March 1998 to 31 December 1999 were identified from a computer database in which data of all patients are stored who undergo heart catheterization at our institution.5In this database, apart from information about the intervention, data about concomitant diseases were stored since 1 March 1998. During the period mentioned above, all patients admitted to our institution for elective PCI were included in the analysis if no previous treatment with thrombolytic substances or glycoprotein IIb/IIIa-inhibitors was performed which might have otherwise influenced baseline haemoglobin levels. Thus, a total of 901 patients could be identified (78% male, 22% female). Since haemoglobin levels in females are influenced by menstruation, the subsequent analyses were only performed for male patients. From 11 men, no baseline haemoglobin concentration could be retrieved, therefore these cases were excluded from analysis. Co-morbidities at presentation for PCI of the patients who died during follow-up were identified from the files.
2.2. Renal function
End-stage renal failure was assumed if the patient has ever required temporary or ongoing maintenance haemodialysis. Since end-stage renal failure is well known to have profound impact on haemoglobin concentrations, these patients were not included. Creatinine clearances for the other patients were calculated by the CockroftGault formula as follows: Creatinine clearance [ml/min]=((140age)xweight [kg])/(72xserumcreatinine [mg/dl]).
2.3. Cardiovascular risk factors
Cardiovascular risk factors were assessed at presentation for PCI and were defined as follows: history of smoking was defined if the patients has smoked within the last 10 years; hypertension if blood pressure >140/90mmHg has been documented; hyperlipidaemia if total cholesterol or triglycerides levels were higher than 200mg/dl, or levels of lipoprotein (a) higher than 20mg/dl; family history of cardiovascular disease if stroke, myocardial infarction (MI), or coronary intervention occurred in a first degree relative; diabetes was assumed if a patient was taking oral antidiabetic medication or insulin.
2.4. Haemoglobin
Haemoglobin values were retrieved from the computer database of the Institute for Clinical Chemistry. Only values which were determined 1 to 3 days before the procedure were considered for analyses.
2.5. Follow-up
A questionnaire asking for repeat interventions and adverse events was sent to all patients. If the patients did not return their questionnaire, a follow-up was performed by telephone calls with the patients, their relatives or referring physicians. This follow-up was performed from March to November 2001. From 50 patients, no information of repeat PCIs after index PCI could be retrieved. For patients who died during follow-up, the treating physicians were contacted to obtain information about causes of death.
2.6. Interventional procedures
Percutaneous coronary interventions 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 in accordance to the revised classification of the American Heart Association and the American College of Cardiology.6Thus, angiographic success after PCI was assumed if a residual stenosis in the vessel diameter of <50% could be achieved.6Left ventricular ejection fraction (EF) was assessed from the pre-PCI angiogram and determined from 30° right anterior oblique projections.
2.7. Statistics
Patients were divided in quintiles depending on their baseline haemoglobin before PCI. Since patients with identical haemoglobin level were assigned to the same group, the quintiles are slightly unbalanced. Differences in basic clinical characteristics between the quintiles were tested by ANOVA F-test for continuous variables, and overall chi-square test for dichotomous variables. The P-values for all of these tests are given in the tables. Correlation analyses were performed by two-sided Pearson test. Endpoint analyses were made by log rank tests or Cox regression analyses. Estimates of the mortality rates were taken from KaplanMeier models including 1200 days of follow-up since there were survival data and censored subjects in each subgroup for this time period. For a more detailed analysis of haemoglobin concentrations, patients were separated in strata of haemoglobin of 10.9g/dl, 11.011.9g/dl, 12.012.9g/dl, and so on in steps of 1g/dl until
18.0g/dl; 2-year all-cause mortality for these subgroups was compared by log rank test. Univariate predictors of mortality during follow-up were analysed by Cox regression, and calculation of hazard rate ratios (HRR) with 95% confidence intervals (95% confidence interval (CI)). Multivariate analysis was performed by Cox regression analyses for haemoglobin quintiles alone (crude HRR) and with potential covariates (adjusted HRR), taking quintile 4 as reference since it contains the largest proportion of patients within the reference/normal range of haemoglobin concentrations.7As covariates for adjustment, those parameters were chosen which were found to have a P-value lower than 0.1 in univariate analyses of death. Furthermore, family history of cardiovascular disease was added to the model, since it was significantly different between the quintiles. Alternatively, Cox regression models were calculated with both a linear term only, and a linear and quadratic term of haemoglobin together due to the U-shaped association of haemoglobin and mortality found in Fig. 1. These two models were compared by the likelihood ratio test.
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3. Results
Between 1 March 1998 and 31 December, 700 male patients without end-stage renal failure were scheduled for elective PCI. Due to missing haemoglobin values before PCI in 11 patients, 689 of them were included in the following analyses (98.4%). These patients were divided in quintiles depending on their baseline haemoglobin concentrations before PCI. Basic clinical parameters are given in Table 1. Significant differences were found between the quintiles regarding age, baseline haemoglobin concentrations, baseline serum creatinine and calculated creatinine clearance, and family history of cardiovascular disease.
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A more detailed analysis of mortality depending on the baseline haemoglobin concentration was performed in steps of haemoglobin concentrations of 1g/dl, and yielded a U-shaped curve for 2-year all-cause mortality in these subgroups (Fig. 1, P<0.0001, log rank).
Information on cause of death could be retrieved in 55 of the 62 patients who had died (89%). Forty-four patients (71%) died from cardiac causes (MI, congestive heart failure or sudden cardiac death), 19 of whom (43%) were in the lowest haemoglobin quintile (P=0.0016, log rank). Of these cardiac deaths, fatal MI confirmed by electrocardiography and laboratory markers occurred in 12 patients. Five patients (8.1%) died of cancer (three in the lowest quintile), and six patients died of other causes (four in the lowest quintile). Deaths from other causes were caused by bleeding (n=2), ruptured aortic aneurysm (n=1), and sepsis (n=1) in the lowest haemoglobin quintile; by sarcoidosis (n=1) in the second lowest haemoglobin quintile; and by pneumonia (n=1) in the quintile with the second highest haemoglobin concentration.
The cumulative survival of all patients was analysed by KaplanMeier curves (Fig. 2). Patients with the lowest haemoglobin quintile were compared to the pooled other quintiles and showed a significantly reduced survival (P<0.0001, log rank).
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A multivariate analysis was performed by Cox regression analysis. Thus, a crude HRR was calculated for the risk of death for each of the quintiles (Table 6). After adjustment for potential co-variates, a significant and markedly higher risk for death in patients of the lower quintile could be confirmed. In an alternative adjusted model, inclusion of a quadratic term of haemoglobin yielded a significant improvement in model fit (P=0.0059, likelihood ratio test) implicating a U-shaped (quadratic) relation between haemoglobin and mortality, as seen in Fig. 1.
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Chronic anaemia is an established risk factor for CVD outcomes in patients with kidney disease and in patients with heart failure.3,8,9Data of a recently performed prospective cohort study of 14 000 subjects (The Atherosclerosis Risk in Communities (ARIC) Study) suggest that anaemia may also be an independent cardiovascular risk factor in the general population.2This hypothesis is substantiated by previous results of the Framingham study demonstrating a U-shaped relation between haematocrit and mortality,10as similarly found in our analysis (Fig. 1). For the first time, we now analysed the impact of haemoglobin concentrations on long-term survival of patients with manifest CHD.
Although angiographic outcome and in-hospital mortality after PCI was comparable in all subgroups, we found a marked difference in survival with regard to both patients being divided in quintiles of haemoglobin (Table 6) as well as subgroups by haemoglobin strata in steps of 1g/d (Fig. 1). Remarkably, 48% of all deaths and 43% of all cardiac deaths occurred in the lowest haemoglobin quintile, which included only 21% of all PCI patients. This significant association between haemoglobin and death was confirmed by Cox regression models including potential co-variates, as age, cardiac status, classical coronary risk factors and creatinine.
Because of the retrospective data collection in our study, no firm conclusions on pathophysiologic background or therapeutical strategies can be drawn. We were interested in the fact, however, that the majority of patients in all haemoglobin quintiles died of cardiac reasons (44 of 62 patients) with a significantly increased cardiac mortality in the quintile with the lowest haemoglobin; and that only few patients (five of 62) died of cancer. Renal function may have influenced haemoglobin concentrations and outcome because creatinine levels were higher in the lowest haemoglobin quintiles. However, this inverse association of mortality and haemoglobin was also observed in patients with normal creatinine values, and in multivariate analysis afteradjustment for creatinine.
There are several potential mechanisms how chronic anaemia could increase cardiac mortality in patients with coronary heart disease. The presence of anaemia does result in ventricular remodelling and ventricular hypertrophy with higher oxygen consumption which is considerably unfavorable in CHD.9,11,12Moreover, chronic anaemia may pronounce myocardial ischemia. Thus, Wu et al. recently demonstrated that patients with acute MI and anaemia at admission had a significantly higher 30-day mortality than those with normal haemoglobin concentrations.13In contrast to this study by Wu et al. and one performed by Zindrou and coworkers about the higher in-hospital mortality of anaemic patients after bypass surgery,4we did not observe any impact of haemoglobin concentration on in-hospital mortality. This discrepancy might be due to the much lower acute haemodynamic stress and much shorter myocardial ischemia during PCI compared to bypass surgery and acute MI. On the other hand, almost all of the deaths in our study occurred within the first 600 days after the index PCI suggesting a more acute pathophysiological effect.
In summary, the most interesting and novel finding of this study is the markedly increased all-cause and cardiac mortality of anaemic patients within a relatively short time period after PCI. Since anaemia is a relatively frequent condition in the general population which remains often under-diagnosed and untreated as stated by others,14and in view of the high risk and large number of patients concerned, possible treatment options should be concerned and further evaluated.
Acknowledgments
The authors are indebted to Mr Ing. (grad.) Klaus Balkenhoff for establishing the PCI database. We thank all technicians and nurses in the catheterization laboratories for their ongoing support.
References