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The prognostic significance of early and late anaemia in acute coronary syndrome

Donald S.C. Ang, Michelle P.C. Kao, A. Noman, C.C. Lang, A.D. Struthers
DOI: http://dx.doi.org/10.1093/qjmed/hcr258 445-454 First published online: 30 December 2011

Abstract

Background and aim: Anaemia in acute coronary syndrome (ACS) is a common and strong independent risk factor but it is unknown whether early anaemia is transient or whether it persists over the subsequent weeks. We also sought to evaluate whether late anaemia carries the similar prognostic significance as baseline anaemia. Another unknown is whether haemoglobin improves risk stratification over and above the GRACE score.

Design and methods: Haemoglobin levels were prospectively measured in 448 consecutive patients presenting with ACS and at 7-weeks follow-up. Cardiovascular endpoints were defined as death or acute myocardial infarction (AMI) over a median duration of 30 months (range 1–50).

Results: The prevalence of anaemia on admission was 20% and this increased to 40% at 7-weeks follow-up. New anaemia occurred in 31% of patients. Baseline anaemia predicted CV endpoints independent of the admission GRACE (Global Registry of Acute Coronary Events) score [adjusted RR 2.54 (95% CI 1.73–3.71)]. Anaemia at 7-weeks follow-up was also a strong predictor of adverse outcomes [adjusted RR 1.67 (95% CI 1.04–2.69)]. Patients with persistent anaemia at 7 weeks were at an increased risk of death or AMI compared to those with persistently normal haemoglobin [unadjusted RR 3.58 (95% CI 2.04–6.29)].

Conclusion: In ACS, the prevalence of anaemia doubles from admission to 7-weeks follow-up (40%). Not only did baseline anaemia predict long-term prognosis independent of the admission GRACE score, but haemoglobin at 7-weeks post-ACS was also a simple independent predictor of adverse prognosis.

Introduction

Anaemia appears to be present in 10–18% of acute coronary syndrome (ACS) patients.1–3 Recent studies have demonstrated that anaemia on admission is an independent predictor of in-hospital, short- and long-term mortality in patients presenting with ACS.1,4–6 Nevertheless, the natural history of early anaemia in the context of ACS is unknown i.e. is early anaemia a transient phenomenon or does it persist or does it even increase in frequency over the next few weeks. We decided to answer this question. A second and perhaps more important question is whether late anaemia is also an indicator of a poor prognosis or whether the prognostic significance of anaemia is limited to the acute phase of ACS only. We also sought to address this question and to establish whether or not serial measures of haemoglobin (or anaemia) would be a better prognostic indicator than a single baseline measure. Another issue is that, despite the strong correlation between baseline anaemia and adverse prognosis, clinical risk scores like GRACE (Global Registry of Acute Coronary Events) does not include haemoglobin. Therefore, a key third question is whether a simple test like haemoglobin would improve risk stratification over and above the GRACE score.

Methods

Study population

A total of 448 patients with the diagnosis of ACS (between August 2004 and November 2006) were prospectively and consecutively recruited from the coronary care unit (CCU) or the cardiology ward, Ninewells Hospital, Dundee. To avoid possible confounding effects, patients were excluded if they had known malignancy, inflammatory disease, surgery or trauma within the last one month. Ethical approval was obtained from the Tayside Committee of Medical Research Ethics and all participating subjects gave written, informed consent.

Patients were classified into the following groups:

  1. ST elevation MI (STEMI): ST elevation >1 mm in 2 limb leads or >2 mm in leads V1–V6 or new left bundle branch block.

  2. Non-ST segment elevation MI (NSTEMI): no ST elevation on ECG despite elevated Troponin-T >0.03 ug/ml.7

  3. Unstable angina: ischaemic chest pain lasting >30 min with no evidence of myocyte necrosis or ST elevation but evidence of ST depression >1.0 mm on ECG.

During the ACS admission, the patients underwent the following:

  1. Clinical history: age, sex, cardiac risk factors, history of ischaemic heart disease or MI and smoking status.

  2. ECG: presence or absence of ST deviation (>1.0 mm)

  3. Admission haemoglobin level: anaemia was defined according to the criteria of the World Health Organization (WHO), i.e. haemoglobin level of <12 g/dl in women and haemoglobin of <13 g/dl in men.8

  4. Laboratory tests: Estimated glomerular filtration rate (eGFR) using the modification of diet in renal disease (MDRD4) and serum Troponin-T level.

  5. Echocardiography: LV systolic dysfunction (LVSD) defined as LV ejection fraction <45% (Simpson's biplane method) or the presence of regional wall motion abnormality.

  6. Calculation of the ‘GRACE score’ based on clinical history, ECG and laboratory values upon first arrival to the CCU or the Acute Medical Admissions Unit9

At 7-weeks post-ACS, the patients underwent the following:

  1. Electrocardiography

  2. Routine blood tests including ‘repeat haemoglobin’ level.

  3. Repeat ‘transthoracic echocardiography’.

Left ventricular systolic function assessment

Quantitative assessment of left ventricular systolic function was made using the modified biplane Simpson's method to calculate a left ventricular ejection fraction.10 Three measurements from successive cardiac cycles were made in the two chamber and four chamber views. Left ventricular systolic dysfunction (LVSD) was defined as an LVEF < 45%. A 7-weeks follow-up period was used in this study to allow us to detect any changes that might have taken place due to LV remodelling.

End points

The composite end point of death from any cause or acute myocardial infarction (AMI) was evaluated over a median duration of 30 months. AMI was defined as an admission to the hospital with ischaemic sounding chest pain and Troponin-T >0.03 ug/ml.7 Information on end points was collected from telephone interviews with patients or patient relatives, hospital database and patients case notes. The researcher who was responsible for collection of the individual endpoints was blinded to the haemoglobin level and admission GRACE score.

Statistical analyses

Patients were classified into two groups (normal haemoglobin or anaemia) according to their admission and 7-weeks follow-up haemoglobin levels. The mean values and proportion of baseline variables were compared with ANOVA for continuous variables and chi-square test for categorical variables. Univariate cox regression analysis was carried out to look at predictors of death/AMI. Significant univariate predictors were subsequently entered into a multivariate cox regression analysis using the backward stepwise method was used to look at the independent predictors of composite endpoints. We compared the predictive accuracy of the GRACE score, presence of anaemia and combined GRACE/anaemia using receiver operating characteristic (ROC) curves, analysing the C-statistic. To do a ROC curve analysis using the presence/absence of baseline anaemia and GRACE score together, we had to calculate weighted scores for each as follows: (β1 × GRACE score) + (β2 × anaemia) where β1 and β2 denote estimates of beta coefficient for the GRACE score and baseline anaemia obtained from the multivariate cox regression model. Event rates for clinical outcomes were also determined using the Kaplan–Meier method and compared using log rank test. All statistical analyses were performed using SPSS for windows version 13.0. A value of P < 0.05 was considered to be statistically significant.

Results

The study population consisted of 448 patients initially: 120 patients had presented with STEMI, 235 patients with NSTEMI and 93 patients with unstable angina. The admission haemoglobin levels ranged from 7.1 g/dl to19.3 g/dl with a mean (±SD) of 13.9 ± 1.9 g/dl. The prevalence of anaemia on admission was 20%. At 7-weeks follow-up (n = 380), the prevalence of anaemia increased to 40%. New anaemia occurred in 31% of those with normal haemoglobin at baseline. At 7-weeks follow-up, none of the patients reported any significant bleeding episodes which necessitated re-hospitalization. Sixty-eight patients failed to attend the 7-weeks follow-up visit. Patients who failed to attend were significantly older with more co-morbidities as evidenced by a higher admission GRACE score (150 points vs. 134 points, P = 0.002). However, mean baseline haemoglobin levels were not significantly different in both groups (13.8 g/dl vs. 14.0 g/dl, P = 0.337).

The GRACE risk score was calculated from presentation characteristics. The GRACE score ranged from 49 points to 288 points (mean 139 ± 39 points). Of the 448 patients, 149 patients were in the low-risk group [first GRACE tercile (<119 points)], 149 in the medium-risk group [second GRACE tercile (120–151 points)] and 150 in the high-risk group [third GRACE tercile (>151 points)]. A significant but only weak correlation existed between the GRACE score and haemoglobin level (R −0.259, P < 0.001).

Association between anaemia and clinical variables

Baseline and follow-up characteristics of the study population stratified by the presence or absence of anaemia are presented in Table 1. Patients with baseline anaemia were older and had lower BMI. They also had a higher prevalence of hypertension and type II Diabetes. They were more likely to present with non-ST elevation ACS, lower Troponin-T levels, clinical heart failure (Killip classes II, III and IV), renal impairment and LVSD. The presence of anaemia was significantly associated with a ‘higher admission GRACE score’. At 7-weeks follow-up, factors significantly related to anaemia included age, lower BMI, history of hypertension, aspirin use, recent thrombolysis, renal impairment and LVSD.

View this table:
Table 1

Baseline characteristics of the acute coronary syndrome population stratified by the World Health Organization definition of anaemia

Clinical variablesNormal Hb on admissionAnaemia on admissionP-valueNormal Hb at f/upAnaemia at f/upP-value
No of patients35791228152
Age (SD)63 (12)71 (10)<0.00161 (11)69 (10)<0.001
BMI (kg/m2)28 (5)26 (5)0.00529 (5)27 (4)<0.001
Sex: male, (%)69600.13370640.219
Medical history, (%)
    History of hypertension45550.07942560.009
    Type II diabetes11200.04011130.632
    Hypercholesterolaemia21180.56023150.066
    Previous MI17270.023
    Smoker (ex/current)66600.32668570.022
Medication (%)
    Aspirin3254<0.00196880.004
    Clopidogrel7100.37557540.529
    Statin3357<0.00197940.199
    Beta-blocker24370.01785790.211
    ACE-inhibitor19300.03068620.189
Index diagnosis/Treatment administered, (%)
    Non-ST elevation ACS70870.00168750.136
    Thrombolysis236<0.00116250.040
    Revascularization (CABG/PCI)28300.42331370.223
Clinical presentation (%)
    Killip classes II, III, IVa822<0.001
    ST deviationa52490.640
    Troponin-T (SD)a1.73 (3.24)0.75 (1.39)0.005
    Systolic BP (SD)133 (24)130 (25)0.231128 (18)128 (20)0.840
Diagnostic tests, (%)
    Haemoglobin (g/dl)14.7 (1.4)11.3 (1.3)<0.00114.0 (1.0)11.3 (1.0)<0.001
    MCV (fl)86.484.20.07085.882.30.010
    Total cholesterol (mmol/l) (SD)5.4 (1.4)4.3 (1.1)<0.0013.9 (1.)3.6 (0.9)0.005
    HDL cholesterol (mmol/l) (SD)1.3 (0.4)1.3 (0.3)0.9071.2 (0.5)1.3 (0.3)0.347
    EGFR (ml/min) (SD)67 (15)57 (22)<0.00167 (15)60 (16)<0.001
Echo parameters
    Left atrial diameter (cm) (SD)3.4 (0.6)3.6 (0.6)<0.0013.5 (0.6)3.6 (0.7)0.095
    LVSD, (%)23390.00314220.050
GRACE scorea132 (36)154 (43)<0.001
  • aRefers to variables which were only available on admission and not at 7-weeks follow-up.

  • PCI = Percutaneous coronary intervention.

Association between baseline anaemia, the GRACE score and clinical outcomes

Over a median follow-up of 30 months, 117 patients or 26% of the cohort developed ≥1 component of the composite end point of death or AMI (70 deaths and 74 fatal or non-fatal AMIs). Follow-up data on death/AMI were available for all 448 patients. As shown in Figure 1, anaemia adds to the prognostic value of the GRACE score and allowed further discrimination. Interestingly, ACS patients who were anaemic in the first GRACE tercile had comparable risk with third GRACE tercile patients without anaemia (31% vs. 32%). Patients in the high GRACE tercile and baseline anaemia were five times more likely to develop a CV event compared with those in the low-GRACE tercile and normal haemoglobin. Results of univariate analyses for the prediction of the composite outcome are presented in Table 2. In Table 3, the presence/absence of baseline anaemia and the admission GRACE score were entered in a backward stepwise multivariate cox regression analysis. As demonstrated, baseline anaemia independently predicted CV events over and above the GRACE score.

Figure 1.

The 30-month composite endpoint of Death/AMI rates according to terciles of GRACE risk score and the presence of anaemia

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Table 2

Univariate cox proportional hazard analyses for the composite outcome of death or acute myocardial infarction at median of 30 months

Clinical variablesOn admission RR (95% CI)P-valueAt 7-weeks f/up RR (95% CI)P-value
No. of patients448380
Age (per year increase)1.05 (1.04–1.07)<0.0011.04 (1.02–1.06)0.001
Sex: male0.85 (0.58–1.23)0.3840.79 (0.50–1.27)0.334
Hypertension2.06 (1.41–2.99)<0.0011.90 (1.19–3.02)0.007
Type II diabetes2.43 (1.58–3.75)<0.0011.62 (0.89–2.95)0.112
Smoker1.17 (0.79–1.73)0.4281.25 (0.77–2.03)0.373
Non-ST-elevation ACS1.99 (1.22–3.27)0.0061.60 (0.92–2.77)0.097
Killip classes II, III, IVa2.88 (1.84–4.52)<0.001
ST-deviation on ECGa0.94 (0.65–1.35)0.730
eGFR (ml/min)0.97 (0.96–0.98)<0.0010.96 (0.95–0.98)<0.001
Haemoglobin (g/dl)0.76 (0.70–0.83)<0.0010.72 (0.63–0.83)<0.001
Anaemia2.74 (1.88–4.00)<0.0012.30 (1.46–3.65)<0.001
HDL cholesterol0.83 (0.49–1.40)0.4770.76 (0.39–1.45)0.398
Left atrial dilatation1.40 (1.03–1.90)0.0311.34 (0.96–1.86)0.087
LVSD1.69 (1.15–2.48)0.0071.73 (1.02–2.94)0.043
GRACE score (per point ↑)a1.01 (1.00–1.02)<0.001
GRACE score (Tercile 2)a1.81 (1.07–3.06)0.027
GRACE score (Tercile 3)a3.04 (1.86–4.97)<0.001
  • aRefers to variables which were only available on admission and not at 7-weeks follow-up.

View this table:
Table 3

Multivariate Cox for the composite of death or acute myocardial infarction at median of 30 months incorporating admission GRACE score and baseline haemoglobin levels

Variables at baselineRR (95% CI)P-value
Model 1 (AMI)
    GRACE score (Tercile 3)1.93 (1.06–3.50)0.031
    Anaemia (categorical variable)2.35 (1.44–3.83)0.001
Model 2 (AMI)
    GRACE score (per point increase)1.01 (1.00–1.01)0.032
    Haemoglobin (1 g/dl increase)0.80 (0.71–0.89)<0.001
Model 1 (Mortality)
    GRACE score (Tercile 2)2.78 (1.18–6.56)0.019
    GRACE score (Tercile 3)5.80 (2.58–13.02)<0.001
    Anaemia (categorical variable)2.66 (1.64–4.33)<0.001
Model 2 (Mortality)
    GRACE score (per point increase)1.02 (1.00–1.02)<0.001
    Haemoglobin (1 g/dl increase)0.79 (0.71–0.89)<0.001
Model 1 (AMI or death)
    GRACE score (Tercile 3)2.63 (1.60–4.33)<0.001
    Anaemia (categorical variable)2.54 (1.73–3.71)<0.001
Model 2 (AMI or death)
    GRACE score (per point increase)1.01 (1.00–1.02)<0.001
    Haemoglobin (1 g/dl increase)0.79 (0.73–0.88)<0.001

Predictive accuracy of the GRACE score, baseline haemoglobin, anaemia and their combination (ROC analysis)

We compared the predictive accuracy of the GRACE score, baseline haemogobin, anaemia and the combined use of GRACE score/anaemia by using ROC curves. Individual C-statistics were obtained for different combinations of clinical endpoints (Table 4). As expected, long-term risk prediction was improved when the combined use of the GRACE score/anaemia was employed.

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Table 4

C-statistics (ROC curves) of baseline variable for the composite of death or acute myocardial infarction at median of 30 months

Baseline variableC-statistic95% CI of C-statisticP-value
Endpoint = AMI
    Anaemia0.5910.516–0.6670.014
    GRACE0.5860.518–0.6540.020
    Anaemia/GRACE0.6370.567–0.707<0.001
End point = Mortality
    Anaemia0.6200.542–0.6970.002
    GRACE0.7290.668–0.791<0.001
    Anaemia/GRACE0.7570.698–0.816<0.001
End points = AMI or mortality
    Anaemia0.6190.556–0.681<0.001
    GRACE0.6590.603–0.716<0.001
    Anaemia/GRACE0.7070.652–0.762<0.001

Reclassification of risk using baseline anaemia instead of GRACE score alone

Using GRACE [cut-off 140 (median value of study population)], 223 patients were classified as high risk and 225 patients as low. If we reclassify risk using baseline anaemia alone, 167 of the high-risk GRACE patients would become low risk whereas, 35 of the low-risk GRACE patients would become high risk i.e. a total of 202 patients will be reclassified representing 45% of the total ACS population. However, if we define the high-risk group as patients with both high GRACE score and baseline anaemia (n = 56), 167 of the 223 patients would be reclassified as low risk, representing 37% of the total population. Alternatively, if high risk is defined as either a high GRACE score or baseline anaemia, then the number of high-risk patients would increase from 223 to 258 i.e. 35 patients would be reclassified i.e. 8% of the total population.

Association between 7-weeks haemoglobin levels and clinical outcomes

Significant univariate variables (Table 2) at 7-weeks follow-up were entered into a multivariate cox regression analysis. GRACE score was only applicable on admission and hence GRACE is not used in this analysis of 7-weeks data. The presence of anaemia at 7-weeks follow-up independently predicted adverse clinical outcomes [RR 1.67 (95% CI 1.04–2.69) P = 0.034] (Table 5). The similar trend was observed with 7-weeks haemoglobin levels [RR 0.82 (95% CI 0.70–0.95) P = 0.008] (Table 5).

View this table:
Table 5

Multivariate Cox analyses for the composite of death or acute myocardial infarction at median of 30 months based on significant univariate predictors at 7-weeks follow-up

Variables at 7-weeks follow-upRR (95% CI)P-value
Model 1 (AMI)
    Anaemia (categorical variable)1.66 (1.02–2.73)0.043
    EGFR (ml/min)0.97 (0.96–0.99)<0.001
    History of hypertension1.67 (1.00–2.80)0.051
Model 2 (AMI)
    Haemoglobin (1 g/dl increase)0.85 (0.73–0.99)0.034
    EGFR0.97 (0.96–0.99)<0.001
    History of hypertension1.67 (1.00–2.80)0.050
Model 1 (Mortality)
    Age (per year increase)1.05 (1.01–1.09)0.012
    LVSD2.04 (1.04–4.01)0.039
    EGFR (ml/min)0.97 (0.95–0.99)0.004
    Anaemia (categorical variable)1.89 (0.97–3.70)0.063
Model 2 (Mortality)
    Age (per year increase)1.05 (1.01–1.09)0.012
    LVSD2.13 (1.08–4.18)0.029
    EGFR (ml/min)0.97 (0.95–0.99)0.013
    Haemoglobin (1 g/dl increase)0.77 (0.62–0.95)0.014
Model 1 (AMI or death)
    LVSD1.73 (1.02–2.96)0.043
    Anaemia (categorical variable)1.67 (1.04–2.69)0.034
    EGFR (ml/min)0.97 (0.95–0.98)<0.001
Model 2 (AMI or death)
    LVSD1.75 (1.03–2.99)0.008
    Haemoglobin (1 g/dl increase)0.82 (0.70–0.95)0.008
    EGFR (ml/min)0.97 (0.96–0.99)<0.001

Value of serial determination of haemoglobin levels

Among 380 patients with haemoglobin levels at baseline and at 7-weeks post-ACS, 55 patients (14%) had persistent anaemia and 213 patients (56%) had persistently normal haemoglobin levels and 97 patients (26%) developed anaemia at follow up. Patients with persistent anaemia at 7-weeks follow-up had a near 4-fold increase in sustaining death/AMI at 30 months compared to those with persistently normal haemoglobin levels [unadjusted RR 3.58 (95% CI 2.04–6.29)] (Figure 2). Those who developed new anaemia at follow up were also at increased risk [unadjusted RR 1.91 (95% CI 1.09–3.35)]. Figure 2 also suggests that low haemoglobin that normalized later identified early risk while normal haemoglobin which fell later identified later risk, as would be expected.

Figure 2.

Kaplan–Meier curves showing the cumulative incidence of death/AMI at median 30 months, according to the trend of haemoglobin. Each group is labelled by the haemoglobin levels on admission and at 7-weeks follow-up. At median of 30 month follow-up, the event rate (for death/AMI) was 52% in patients with persistent anaemia vs. 12% in the group with persistently normal haemoglobin (P < 0.001 by the Log-rank test).

Table 6 demonstrates the relationship between clinical/echo parameters at 7-weeks post-ACS and the four groups of patients divided according to different haemoglobin trends. Patients with persistent anaemia were older, were more likely to have renal impairment but surprisingly had lower BMI. The use of aspirin and previous administration of thrombolysis were also lower in the group with persistent anaemia. The use of dual anti-platelet regime did not significantly influence the outcome of haemoglobin levels.

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Table 6

Univariate association between 7-weeks follow-up clinical variables and the respective haemoglobin trends

Variables at 7-weeks follow-upNormal–normal (n = 213)Anaemia–normal (n = 15)Normal–anaemia (n = 97)Anaemia–anaemia (n = 55)P–value
Age (SD)60 (11)69 (7)69 (10)70 (10)<0.001
Male sex-no (%)715368560.113
BMI (kg/m2)29 (5)29 (6)27 (5)26 (4)0.005
History of hypertension (%)406756560.009
Type II diabetes (%)102711160.163
Smoker/x-smoker (%)696056580.107
Index diagnosis-NSTEACS (%)678070840.080
Aspirin (%)969392820.005
Clopidogrel (%)575753560.889
Dual anti-platelet regime (%)456255530.963
ACE-inhibitor (%)695765550.239
Thrombolysis (%)26132250.010
Revascularization (%)304036380.527
Systolic BP (mmHg)127 (18)137 (11)128 (19)127 (21)0.323
Total cholesterol3.9 (0.9)4.6 (1.1)3.5 (0.8)3.8 (1.0)<0.001
EGFR (ml/min) (SD)68 (15)56 (18)62 (14)55 (19)<0.001
LVSD (%)132921240.079
Left atrial diameter (cm) (SD)3.5 (0.6)3.5 (0.7)3.6 (0.6)3.6 (0.8)0.384

Discussion

Our study demonstrates three novel findings in ACS risk stratification. First, we found that the prevalence of anaemia doubled during a 7-weeks follow-up period from 20% to 40%. Importantly, new anaemia occurred in 31% of those who had normal haemoglobin levels at baseline. Secondly, baseline anaemia predicted long-term adverse clinical outcomes over and above the composite GRACE score. In fact, risk prediction in this patient population could be enhanced considerably if both parameters were utilized synergistically (Figure 1). Thirdly, individuals with persistence of anaemia at follow-up were at exceptionally high risk i.e. approximately four times more likely to develop death/AMI in the long term compared to those with persistently normal haemoglobin levels. Patients who developed new anaemia at follow up were also at increased risk [unadjusted RR 1.91 (95% CI 1.09–3.35)] (Figure 2).

Recent evidence suggests that baseline anaemia in ACS is an independent predictor of clinical outcomes. Nikolsky et al.3 studied patients with AMI undergoing primary PCI and found that those with baseline anaemia had higher in-hospital and 1-year mortality. Similarly, in 39 922 ACS patients enrolled in clinical trials, Sebastine et al.,4 showed that anaemia was a powerful and independent predictor of 30 day MACE. In a separate study that evaluated solely male patients with ACS referred for coronary angiography, baseline anaemia independently predicted death/AMI at 2-years follow-up.6 The only other study that assessed serial haemoglobin levels studied MI patients where Aronson et al.1 evaluated the changes in haemoglobin levels, but over only a short period of time (i.e. the hospital course). They demonstrated that development of anaemia during hospitalization is frequent and correlated with long-term mortality. Our present study extends our knowledge about anaemia for the first time to the post-hospitalization phase and showed that the adverse effect of anaemia is not solely due to factors operative in the acute phase during hospitalization. Other strengths of our study include the availability of echocardiographic LV function data at two separate time points. We deduce from our 7-weeks echo data that both anaemia and LVSD were independent predictors of adverse outcomes. Importantly, the presence of LVSD predicted mortality but had no predictive effect on future AMI.

The GRACE score was developed initially to predict in hospital mortality11 across the entire spectrum of ACS patients but recently its predictive power has also been demonstrated for longer term risk of death and myocardial infarction in this same patient population.12,13 Meneveau et al.14 demonstrated that baseline anaemia when added to the GRACE risk score reclassified early risk (in-hospital and 30 day mortality) in a significant proportion of ACS patients. Our study confirms this and extends this observation to a much longer time frame (median of 30 months). We also included recurrent AMI as an additional endpoint along with mortality. In our study, the C-statistics for GRACE score in predicting mortality is lower than previously quoted in the literature. A possible explanation here is that while the GRACE score was validated to predict 30-day or 6-month mortality, the follow-up period of our study was substantially longer (median of 30 months). This may have weakened the predictive value of the GRACE score.

An intriguing message from this study is that the prevalence of anaemia doubled to 40% at 7-weeks follow-up. The underlying pathophysiology of this development of anaemia is not entirely clear. It is possible that contemporary ACS therapy that involves aggressive anticoagulation and anti-platelet regime may be associated with sub-clinical blood loss. In accord with this, in our study, thrombolysis was given significantly more frequently to follow-up patients who were anaemic even though thrombolysis had been given significantly less to those who became anaemic on admission. Another plausible mechanism to explain the high prevalence of anaemia is haemodilution: this possibility is strengthened by the strong correlation between anaemia and worsening admission Killip class.15 Thirdly, judging from the high proportion of patients with CKD stages III, IV and V (37%) in our population, pre-existing renal anaemia is another potential mechanism although it is worth noting that at 7 weeks, haemoglobin and eGFR were each independently predictive. Fourthly, erythropoiesis in the marrow may be suppressed by inflammatory cytokines or even by the use of ACE inhibitors in the longer term. Detailed studies could now be undertaken to assess the exact mechanisms that contribute to post-ACS anaemia, although it could well be multifactorial. Whatever its mechanism, haemoglobin has potential both during the acute phase and later for assessing prognosis after ACS. This obviously does not necessarily imply that anaemia is causal per se, but our study might one day prompt cautious trials to see if correction of persistent anaemia (e.g. by parenteral iron and erythropoietin) might be of benefit in anaemic-ACS patients. In a recent study, treatment with intravenous iron in patients with chronic heart failure and iron deficiency, with or without anaemia, improved symptoms, functional capacity and quality of life.16 The risks and benefits of blood transfusion in ACS currently remain unknown.4,17,18

There are multiple mechanisms that could account for the correlation between anaemia and poor prognosis in ACS. The most obvious possibility is that anaemia indicates lower oxygen delivery to tissue including the myocardium.19 The resulting myocardial oxygen deficit could in turn lead to increased myocardial ischaemia and to LV diastolic dysfunction.20 It could also trigger neuroendocrine activation. Evidence for anaemia being linked to neuroendocrine activation is reinforced by data that anaemia is associated with reduced heart rate variability and the latter is thought to be arrhythmogenic, which could be another contributing mechanism.21

Several limitations should be considered for this study. First, we do not have information on the number of patients who developed bleeding complications during their index ACS admission or data regarding iron studies/stores. Therefore, the explanation for a 2-fold increase in the prevalence of anaemia at follow up cannot be fully elucidated. Secondly, due to our modest population size, further work is required to confirm our findings. Thirdly, there was a 15% drop-out rate at 7-weeks follow-up. As mentioned earlier, patients who failed to attend follow-up were older and had substantially more co-morbidities. However, an important strength of our study is the unselected nature of our ACS cohort that closely reflects the real world scenario.

In conclusion, the prevalence of anaemia after ACS doubles after discharge. The presence of baseline anaemia independently predicted long-term adverse prognosis over and above the GRACE risk score. Furthermore, our study suggests that serial haemoglobin levels post-ACS are better predictors of adverse prognosis compared with a one-off haemoglobin level at baseline.

Funding

British Heart Foundation.

Conflict of interest: None declared.

Acknowledgements

The authors would like to thank the British Heart Foundation for generously funding this project.

References

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