Methods

The present study included 2,534 consecutive patients with ACS who underwent PCI in our hospitals from 2000 to 2011. These patients were obtained from an initial sample of 6,724 patients admitted and treated during the same period. To be included in the study, patients had to have clinical and angiography-proved ACS and baseline GGT activity measurements available. After exclusion of 2,967 patients with stable coronary artery disease (CAD) and patients with known hepatobiliary disease, malignancy, acute infection, alcohol abuse (n = 971), or cardiogenic shock (n = 252), 2,534 patients with ACS remained and were included in this study. By design, the study represents a retrospective analysis of prospectively collected data. The study conforms to the Declaration of Helsinki.

Unstable angina was diagnosed according to the Braunwald’s criteria. The diagnosis of non–ST-segment elevation myocardial infarction (NSTEMI) required clinical electrocardiographic criteria similar to those of unstable angina and elevation of cardiac troponin T level (measured with a conventional assay until October 2009 and a high-sensitivity assay thereafter). STEMI was diagnosed if the patient had chest pain lasting ≥20 min associated with ST-segment elevation of ≥0.1 mV in at least 2 limb leads or ≥0.2 mV in at least 2 contiguous precordial leads or complete left bundle branch block of new onset. Cardiovascular risk factors (arterial hypertension, diabetes, hypercholesterolemia, and smoking) were defined according to the accepted criteria. Body mass index was calculated using patient’s weight and height measured during the hospital stay. Renal function was assessed by calculating the creatinine clearance according to the Cockcroft–Gault formula.

The diagnosis of CAD was confirmed by coronary angiography in all patients and consisted in documentation of significant disease (defined as coronary stenoses ≥50% lumen obstruction in at least 1 of the main coronary arteries) or culprit lesions. Digital angiograms were analyzed in the core angiographic laboratory using an automated edge detecting system (CMS; Medis Medical Imaging Systems, Neuen, the Netherlands). Left ventricular ejection fraction was calculated with the area–length method on the left ventricular angiograms. PCI was performed as per standard practice and involved stent implantation after pretreatment with clopidogrel (600 mg as loading dose) and aspirin (325 to 500 mg).

Blood for the measurement of GGT was obtained on admission (before angiography). The GGT activity was measured in plasma at 37°C with an enzymatic-colorimetric assay on a Roche/Hitachi cobas c 501 analyzer. The measuring range in plasma is from 3 to 200 U/L (0.05 to 20 μkat/L), and the lower detection limit of the test is 3 U/L (0.05 μkat/L). The consensus value is <60 U/L (<1 μkat/L) in men and <40 U/L (<0.67 μkat/L) in women. C-reactive protein was measured using a fully automated latex-enhanced immunoturbidometric assay on a Cobas Integra analyzer (Roche Diagnostics, Mannheim, Germany). The analytical sensitivity of the assay is 0.085 mg/L. The measuring range is up to 160 mg/L. The upper reference limit in healthy adults is 5 mg/L. Serum creatinine was measured with a kinetic colorimetric assay based on the compensated Jaffe method. Other laboratory measurements were performed using standard laboratory methods.

The primary outcome measure was 3-year all-cause mortality. Cardiac mortality, noncardiac mortality, nonfatal myocardial infarction, and stroke were also assessed. Cardiac death was defined according to the Academic Research Consortium criteria. Information on deaths was obtained from the hospital records, phone contact with the patient’s relatives or referring physician, death certificates, insurance companies, and registration of address office. Myocardial infarction was diagnosed if electrocardiographic (new abnormal Q waves in at least 2 adjacent limb leads or at least 2 contiguous precordial leads) or enzymatic (elevation of creatine kinase myocardial band activity >2 times [>3 times within the first 48 hours after PCI] the upper limit of normal) criteria were met. Stroke was diagnosed if a focal deficit lasted for >24 hours. Neurologic deficits were consulted by a neurologist immediately after acute event and assessed by brain imaging tests.

Chronic antithrombotic therapy after PCI included clopidogrel 75 mg/day for at least 1 month in patients who were treated with bare-metal stents or at least 6 months in patients who were treated with drug-eluting stents and aspirin (200 mg/day continuously). Other medications were prescribed at the discretion of the treating physician.

The follow-up protocol after hospital discharge included phone interviews at 1 month, 6 months, 1 year, and yearly thereafter to ascertain vital status and occurrence of cardiovascular events. If patients developed symptoms any time during the follow-up, they underwent a complete clinical, electrocardiographic, and laboratory assessment. The follow-up information and advent adjudication were performed by medical personnel unaware of clinical diagnosis, received therapy or GGT activity.

Data are presented as median with 25th to 75th percentiles, number of patients (or events), and proportions (%). The distribution pattern of continuous data was assessed with the Kolmogorov–Smirnov test. Continuous data were compared with the Kruskal–Wallis rank-sum test. Categorical data were compared with the chi-square test. Survival analysis was performed with the Kaplan–Meier method, and the risk was estimated by univariate Cox proportional hazards model. Adjusted survival analysis was performed with the multivariate Cox proportional hazards model. All variables of Table 1 were entered into the model. Owing to the skewed distribution, GGT was entered into the model after logarithmic transformation, and the hazard related to this marker was calculated per SD increase in the logarithmic scale of GGT activity. The discrimination of the risk prediction models of mortality (ability of the model to predict who will die from those who will not die) without and with inclusion of GGT was evaluated by calculating the C-statistic in the multivariate Cox model adjusting for the same variables as for mortality. Bootstrapping (400 samples) was used to calculate the 95% CI of the C-statistic. This allows the comparison of C-statistics of the models before and after GGT inclusion. The R Statistical Package (the R foundation for Statistical Computing, Vienna, Austria) was used for analysis. A 2-sided p <0.05 was considered to indicate the statistical significance.

Results

The study included 2,534 patients with ACS. Patients were divided into 3 groups: the group with GGT in the first tertile (GGT <28 U/L; n = 848 patients), the group with GGT in the second tertile (GGT 28 to <50 U/L; n = 843 patients), and the group with GGT in the third tertile (GGT ≥50 U/L; n = 843 patients). Baseline demographic and clinical characteristics are listed in Table 1 . In patients presenting with unstable angina, NSTEMI, or STEMI, GGT activity values (median with 25th to 75th percentiles) were 36.1 (24.8 to 57.1) U/L, 40.0 (25.4 to 73.9) U/L and 37.0 (24.0 to 59.3) U/L, respectively (p <0.001). On admission, 894 patients (35.3%) were on chronic statin therapy. GGT activity level was 36.0 (25.0 to 59.0) U/L in patients receiving statins versus 37.9 (24.3 to 63.0) U/L in those not receiving statins (p = 0.540). Coronary stents were implanted in all patients. Overall, 4,308 lesions (1.7 lesions per patient) were stented. At discharge, statins were prescribed in 2,385 patients (94%).

The frequency of 3-year clinical events is listed in Table 2 . There were 250 deaths from all-causes over the 3-year follow-up: 70 deaths in patients in the first, 69 deaths in patients in the second; and 111 deaths in patients in the third GGT tertile (Kaplan–Meier estimates of mortality, 9.7%, 9.0%, and 14.8%, respectively; unadjusted hazard ratio [HR] 1.31, 95% CI 1.12 to 1.53; p <0.001; Figure 1 ).

Kaplan–Meier curves of 3-year all-cause mortality. Percentages show Kaplan–Meier estimates of mortality for patients in each of the GGT tertiles.

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