Methods

We studied 801 consecutive patients with STEMI treated with primary PCI within 12 hours of onset of symptoms in Chonnam National University Hospital (Gwangju, Republic of Korea) from November 2005 to June 2009. Patients with cardiogenic shock or underlying malignancy were excluded, and 739 patients (63 ± 13 years, 74% men) were included in the final analysis. Of these patients, numbers of patients at 1- and 6-month follow-up were 732 and 730, respectively. Clinical data from all patients were recorded in a Korean acute MI registry. CBC values were obtained just after admission and before a patient’s transfer to the catheter laboratory. It was possible to collect data from 99% of all patients.

STEMI was diagnosed based on an increase in troponin I level >1 ng/ml with a new ST-segment elevation in ≥2 contiguous leads measuring >0.2 mV in leads V ₁ to V ₃ or 0.1 mV in all other leads during the first 24 hours after onset of symptoms. All patients received aspirin ≥100 mg and a loading dose of clopidogrel 300 to 600 mg and unfractionated heparin 50 to 70 U/kg to maintain an activated clotting time of >250 to 300 seconds before or during the procedure. Primary PCI was performed using standard techniques if the coronary anatomy was suitable for angioplasty. Platelet glycoprotein IIb/IIIa receptor inhibition was at the discretion of the operator. All patients were prescribed lifelong aspirin and clopidogrel (75 mg/day) for 3 to 12 months depending on stent type. Automated analyzers were used for hematologic measurements. Anemia was defined according to the World Health Organization definition as admission hemoglobin (Hb) levels <13 mg/dl in men and <12 mg/dl in women. Left ventricular ejection fraction was determined by echocardiography. Impaired renal function was defined as an estimated glomerular filtration rate <60 ml/min/1.73 m ² calculated using the simplified Modification of Diet in Renal Disease formula including age, race, gender, and serum creatinine. Multivessel coronary disease was defined as >50% diameter stenosis by quantitative coronary angiography in ≥2 coronary arteries or a left main coronary artery lesion. Coronary artery lesion type was determined according to American College of Cardiology and American Heart Association classification. Successful PCI was defined as residual stenosis <50% in diameter with final Thrombolysis In Myocardial Infarction grade 3 flow. In-hospital complications included hypotension, cardiogenic shock, or arrhythmia requiring cardiopulmonary resuscitation or insertion of an intra-aortic balloon pump or temporary cardiac pacemaker. Major cardiac events included death, MI, repeat PCI, and coronary artery bypass grafting. Optimal evidence-based medical therapies were performed in all patients who had no contraindication to drugs.

For simplicity of analysis and presentation, all patients were categorized into 3 groups using the median value of N/L (3.86) and the presence of anemia; group I had low N/L and no anemia (n = 272), group II had low N/L and anemia, or high N/L and no anemia (n = 331), and group III had high N/L and anemia (n = 136). Categorical variables were presented as number of cases and percentage and continuous variables as mean ± SD. The relation between 2 continuous variables was assessed using bivariate correlation analysis. Comparative analysis was performed using Student’s t test or analysis of variance for continuous variables and Pearson chi-square test or Fisher’s exact test for categorical variables. Kaplan–Meier analysis of mortality data were performed using log-rank test in the entire population and particular subgroups including age ≥65 years (n = 347), diabetes mellitus (n = 181), multivessel coronary disease (n = 344), low left ventricular ejection fraction (<45%, n = 134), and impaired renal function (n = 118). Thrombolysis In Myocardial Infarction risk score, a well-known useful tool for early risk stratification in patients with STEMI undergoing primary PCI, was used to assess the prognostic discriminatory capacity of the combined use of Hb level and N/L in patients having higher mortality risk based on risk score. Risk factors included in Thrombolysis In Myocardial Infarction risk score were considered covariates in multivariate Cox regression analysis. The independent discriminatory capacity of the combined use of Hb level and N/L on short-term mortality was assessed by 2 stepwise multivariate Cox regression models using an Enter method. Candidate covariates for Cox regression analysis were chosen based on previous medical knowledge and independent of p value, namely age, gender, diabetes, hypertension, previous coronary artery disease, systolic blood pressure, heart rate, Killip class, body weight, anterior ST-segment elevation or left bundle branch block, time from symptom onset to PCI, left ventricular ejection fraction, creatinine clearance, multivessel coronary disease, and American College of Cardiology/American Heart Association class. All continuous variables were converted into categorical variables. Collinearity diagnostics were assessed among variables in Cox regression analysis. A 2-sided p value <0.05 was considered statistically significant for all analyses. All statistical analyses were performed using SPSS 17.0 (SPSS, Inc., Chicago, Illinois).

Results

Mean and median values of N/L in all patients were 5.07 ± 4.14 and 3.86, respectively. Mean and median values of Hb in all patients were 13.92 ± 1.98 and 14.10 mg/dl, respectively. Of the 739 patients, anemia was found in 182 patients (25%). The correlation between values of N/L and age was positive but weak. Hb level was correlated moderately with age and decreased with increasing age ( Figure 1 ).

Simple correlation analysis between age and (A) neutrophil-to-lymphocyte ratio (r = 0.153, p <0.001) and (B) hemoglobin level (r = −0.487, p <0.001).

Baseline characteristics of patient groups are listed in Table 1 . Patients in group III were older and more frequently women and had higher rates of hypertension, longer time from symptom onset to PCI, lower body weight, lower admission blood pressure, worse renal function, and more multivessel coronary disease. Other significant differences included lower rates of a history of smoking and lower low-density lipoprotein cholesterol levels.

During 6-month follow-up, we registered 143 in-hospital complications (19.4%), 51 composite major cardiac events at 1 month (7.0%), and 45 deaths at 6 months (6.2%). Clinical outcomes in hospital and 1 month and 6 months after PCI according to presence of anemia or N/L are listed in Table 2 . Patients with anemia or high N/L had worse clinical outcomes for major cardiac events and deaths at 1 month and 6 months. When patients were stratified by Hb level and N/L ( Figure 2 ), there was a stepwise association with 180-day mortality.

Mortality at 180 days stratified by hemoglobin level and neutrophil-to-lymphocyte ratio (no anemia and low neutrophil-to-lymphocyte ratio, n = 269; no anemia and high neutrophil-to-lymphocyte ratio, n = 231; anemia and low neutrophil-to-lymphocyte ratio, n = 97; anemia and high neutrophil-to-lymphocyte ratio, n = 133).

Clinical outcomes in hospital and 1 month and 6 months after PCI according to 3 groups based on Hb level and N/L are listed in Table 3 . There were significant differences in clinical outcomes among the 3 groups. Six-month mortality rate was roughly 12-fold higher in group III compared to group I; 180-day cumulative survival according to the 3 groups based on Hb level and N/L in all patients and particular subgroups are shown in Figure 3 . Group III showed significantly lower survival rates not only in the entire study population but also in high-risk subgroups such as patients with an advanced age, diabetes mellitus, multivessel coronary disease, and low ejection fraction, except for those with impaired renal function. Increased mortality risk of group III was particularly pronounced in combination with low left ventricular ejection fraction (<45%), with 180-day mortality approaching 38%.

Table 3

Clinical outcomes in hospital period and follow-up at six months according to three groups based on hemoglobin level and neutrophil-to-lymphocyte ratio

Variable	Group I (n = 272)	Group II (n = 331)	Group III (n = 136)	p Value
				Overall	Group I vs III	Linear ⁎
In-hospital outcomes (n = 739)
Success rate of percutaneous coronary intervention	271 (99.6%)	325 (98.2%)	133 (97.8%)	0.198	0.076	0.090
In-hospital complication	44 (16%)	60 (18%)	39 (29%)	0.008	0.003	0.006
1-month outcomes (n = 732)
Composite major cardiac events	9 (3%)	23 (7%)	19 (14%)	<0.001	<0.001	<0.001
Death	1 (0.4%)	18 (6%)	14 (10%)	<0.001	<0.001	<0.001
6-month outcomes (n = 730)
Composite major cardiac events	29 (11%)	54 (17%)	36 (27%)	<0.001	<0.001	<0.001
Death	3 (1.1%)	23 (7%)	19 (14%)	<0.001	<0.001	<0.001

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