Methods

This study was a substudy to the Drug Elution and Distal Protection in Acute Myocardial Infarction (DEDICATION) multicenter trial. All patients were in the midst of acute ischemia and only patients with STEMI were included and randomly assigned to have a DES or a BMS implanted in the infarct-related lesion.

The local ethics committee approved the study protocol. All patients were ≥18 years of age and gave their informed consent in writing. We enrolled patients with chest pain lasting >30 minutes and <12 hours and who had a cumulated ST-segment elevation of 4 mm in ≥2 contiguous leads on electrocardiogram. Exclusion criteria were previous MI in the target vessel area, development of cardiogenic shock before enrollment, culprit lesions in an unprotected left main coronary artery, gastrointestinal bleeding within 1 month, pregnancy, known renal failure, life expectancy <1 year, and linguistic problems. Patients were pretreated with aspirin 300 to 500 mg, clopidogrel 300 to 600 mg, and unfractionated heparin 10,000 IU as soon as transportation to the catheterization laboratory was arranged. A β blocker was administered at the discretion of the transportation team according to blood pressure and heart rate. If there was no contraindication, patients were treated with a glycoprotein IIb/IIIa receptor blocker on arrival at the catheterization laboratory. Coronary angiography was performed, and the culprit lesion was identified. A guidewire was advanced through the highly stenosed or occluded lesion, and if the peripheral vascular bed was not visible, dilatation with a 1.5- to 2.0-mm-diameter balloon was allowed to visualize the coronary artery distal to the lesion. Central telephone (simple) randomization was performed by computerized assignment stratified according to gender and presence of diabetes. Patients were randomly assigned to treatment with or without distal protection and to receive a DES or BMS in the infarct-related lesion. All stents were implanted under high pressure (12 atm). Implantation of >1 stent of the same kind was allowed to cover the entire lesion. The operator and patient were aware of the assigned treatment.

Only patients included at our center had blood drawn for hs-CRP analysis immediately before primary percutaneous coronary intervention (pPCI). We retrospectively analyzed blood samples from 301 patients with STEMI referred to our invasive center. Four patients treated with balloon angioplasty only were excluded, yielding hs-CRP levels from 297 patients. All 297 had stents implanted according to the randomization protocol.

According to the low-grade inflammation concept, for this analysis we chose to focus on patients with preprocedure hs-CRP levels <10 mg/L because infections, trauma, and acute illness have been associated with increases in hs-CRP levels. Therefore, 39 patients with levels >10 mg/L were excluded. In the remaining population of 258 patients, we divided the population at the median value achieved (2 mg/L). We then repeated the same statistical analyses for all 297 patients using the same 2 mg/L value as a cutpoint because this value was previously described to predict adverse outcomes in several trials.

The primary end point of this study was the rate of a composite of death and MI within 36 months of pPCI. Secondary end points were definite stent thrombosis, all recurrent MIs, recurrent MI in an infarct-related artery, clinically driven target lesion revascularization, and target vessel revascularization. Definite stent thrombosis was characterized according to the Academic Research Consortium definition. MI was defined as a total creatine kinase increase ≥2 times the upper normal limit with a concomitant increase in creatine kinase-MB mass blood concentration in the presence of an acute coronary syndrome, and recurrent MI in an infarct-related artery was considered present if the recurrent MI could be related (by electrocardiography or angiography) to the target vessel. Clinically driven target lesion revascularization was defined as revascularization of the target lesion in the presence of recurrent angina and significant stenosis/occlusion of the infarct-related lesion, and target vessel revascularization was defined as any revascularization in the same coronary artery. The clinical events committee adjudicated all serious events and stent thromboses blinded to treatment sequence. Follow-up of clinical end points was conducted at 36 months.

Blood samples for analysis of hs-CRP were drawn from the sheath immediately before pPCI. Hs-CRP analysis was conducted by immunoturbidimetric analysis (Tina-quant hs-CRP latex assay, Roche/Hitachi, Cobas, Mannheim, Germany).

Patients were categorized according to level of hs-CRP (median, quartiles) and according to the combination of hs-CRP level (>2 or <2 mg/L) and type of stent implanted: BMS + CRP ≤2 mg/L, DES + CRP ≤2 mg/L, DES + CRP >2 mg/L, and BMS + CRP >2 mg/L. In univariate analysis, data were divided in quartiles and by median for presentation of events. Differences in event rates for hs-CRP quartiles and 4 categories of stent type and hs-CRP were tested for significance by chi-squared linear trend tests. For nominal data event rates were tested by chi-square test in a 2 × 2 cross table. Event rates for continuous data were presented by their mean value and tested by t test for equality of means of independent samples and natural logarithmic values were used when variables were not normally distributed. We adjusted for confounders in multivariable analysis with Cox proportional hazard model. Survival was presented in Kaplan–Meier plots and tested for equality of survival distributions for different levels of hs-CRP and stent type by log-rank (Mantel-Cox) test. A p value <0.05 was considered statistically significant. Continuous hs-CRP levels, median hs-CRP value, hs-CRP quartiles, and ln(hs-CRP) were plotted into Cox proportional hazard models to find the strongest predictor of the primary end point by chi-square value, which was then tested for interaction between hs-CRP levels and stent type. Interaction between hs-CRP and stent type was tested in multivariable regression analysis including the interaction variable. We used SPSS 15 (SPSS, Inc., Chicago, Illinois) for data analysis.

Results

Baseline characteristics are presented in Table 1 . Graphs and tables are presented for patients with preprocedure hs-CRP levels <10 mg/L. In these patients, the median value was 2.0 mg/L with quartiles 0 to 1.2, 1.3 to 2.0, 2.1 to 3.7, and 3.8 to 10. Univariate analysis demonstrated that the median value of hs-CRP ( Figure 1 ) and hs-CRP quartiles ( Figure 2 ) significantly predicted the occurrence of all nonfatal recurrent MIs (p <0.001), recurrent MI in an infarct-related artery (p = 0.009), definite stent thrombosis (p = 0.025), and the combination of death and MI (p = 0.001) at 36-month follow-up and trends for stroke (p = 0.057) and clinically driven target lesion revascularization (p = 0.051). The upper hs-CRP quartile had an event rate of 39.1% for all adverse events (all MIs, any death, stroke, and all target vessel revascularization), which compared significantly to the 3 lower quartiles taken together (21.3%, p = 0.005).

Adverse events by median high-sensitivity C-reactive protein level ≤2 mg/L (blue bars) and >2 mg/L (red bars) . re-MI IRA = recurrent infarction in infarct-related artery; ST = stent thrombosis; TLR = target lesion revascularization; TVR = target vessel revascularization.

Adverse events by high-sensitivity C-reactive protein quartiles 1 (blue bars) , 2 (red bars) , 3 (green bars) , and 4 (purple bars) . Abbreviations as in Figure 1 .

In multivariable analyses we adjusted for age, gender, diabetes, body mass index, hypertension, hypercholesterolemia, smoking, left ventricular ejection fraction, maximum troponin T and creatine kinase-MB, pain to balloon time (minutes), vessel size, length of lesion, length of stented segment (millimeters), number of stents implanted, multivessel disease, use of distal protection, and Thrombolysis In Myocardial Infarction grade 3 flow at the end of the PCI procedure. Hs-CRP >2 mg/L was an independent predictor of the primary composite end point of death and all nonfatal recurrent MIs (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.3 to 5.6, p = 0.007) but not for the single variables of MI, stent thrombosis, target lesion revascularization, and target vessel revascularization. Other significant independent predictors of death and MI were age (HR 1.045 per year, 95% CI 1.016 to 1.075, p = 0.002) and multivessel disease (HR 2.1, 95% CI 1.4 to 3.2, p = 0.001; Table 2 ).

We then combined hs-CRP levels (>2 or <2 mg/L) and type of stent implanted (BMS or DES): BMS + CRP ≤2 mg/L, DES + CRP ≤2 mg/L, DES + CRP >2 mg/L, and BMS + CRP >2 mg/L. Analysis for hs-CRP and stent type with the dependent variable of the composite end point of death and MI demonstrated a significant interaction between hs-CRP and stent type (p = 0.006). In univariate analysis hs-CRP >2 mg/L + BMS significantly predicted recurrent MI (p <0.001), recurrent MI in an infarct-related artery (p = 0.020), and the composite end point of death and MI (p <0.001; Figure 3 ). Hs-CRP >2 mg/L + BMS was an independent predictor of the composite end point of death and nonfatal recurrent MI (HR 2.56, 95% CI 1.2 to 5.6, p = 0.019). Although to a lesser extent, age and multivessel disease also predicted the occurrence of the composite end point ( Table 2 ).

Adverse events according to bare metal stent plus high-sensitivity C-reactive protein level ≤2 mg/L (blue bars) , drug-eluting stent plus high-sensitivity C-reactive protein level ≤2 mg/L (red bars) , drug-eluting stent plus high-sensitivity C-reactive protein level >2 mg/L (green bars) , and bare metal stent plus high-sensitivity C-reactive protein level >2 mg/L (purple bars) (p <0.001). Abbreviations as in Figure 1 .

Kaplan–Meier curve for event-free survival demonstrated significantly different levels of occurrence of death and MI according to combinations of hs-CRP and stent type: 3 events (4.8%) in patients with BMS + CRP ≤2 mg/L, 8 events (11.9%) in those with DES + CRP ≤2 mg/L, 12 events (17.6%) in patients with DES + CRP >2 mg/L, and 17 (27.9%) in those with BMS + CRP >2 mg/L ( Figure 4 ).

Kaplan–Meier for event-free survival (log function) demonstrated significant differences (p = 0.004) for occurrence of myocardial infarction and death, where the following order was increasingly detrimental: bare metal stent plus high-sensitivity C-reactive protein ≤2 mg/L (blue line) , drug-eluting stent plus high-sensitivity C-reactive protein ≤2 mg/L (green line) , drug-eluting stent plus high-sensitivity C-reactive protein >2 mg/L (yellow line) , bare metal stent plus high-sensitivity C-reactive protein >2 mg/L (purple line) .

Considering patients with hs-CRP >2 mg/L only, rate of recurrent MI was increased in those who had a BMS implanted (p = 0.032) as was the composite end point of death, MI, and clinically driven target vessel revascularization (p = 0.031; Table 3 ). During the follow-up period 14 (5.4%) stent thromboses occurred. Compared to patients with DESs, no stent thromboses were found in patients with hs-CRP ≤2 mg/L + BMS (p = 0.028; Tables 4, 5, and 6 ).

Table 4

Adverse events in patients with ST-segment elevation myocardial infarction and high-sensitivity C-reactive protein ≤2 mg/L according to implanted stent type (drug-eluting or bare metal stent)

Variable	DES + hs-CRP ≤2 mg/L	BMS + hs-CRP ≤2 mg/L	p Value
	(n = 67)	(n = 62)
All recurrent myocardial infarctions	3 (4.5%)	0	0.092
All deaths	5 (7.5%)	3 (4.8%)	0.537
Cardiac death	4 (6%)	2 (3.2%)	0.460
Recurrent myocardial infarction in infarct-related artery	2 (3%)	0	0.170
Definite stent thrombosis	1 (1.5%)	0	0.334
Any stent thrombosis	5 (7.5%)	0	0.028 ⁎
Clinically driven target lesion revascularization	3 (4.5%)	4 (6.5%)	0.621
Clinically driven target vessel revascularization	6 (9%)	6 (9.7%)	0.888
Stroke	3 (4.5%)	1 (1.6%)	0.348
Death + myocardial infarction	8 (11.9%)	3 (4.8%)	0.149
Death + myocardial infarction + clinically driven target lesion revascularization	10 (14.9%)	6 (9.7%)	0.366
Death + myocardial infarction + clinically driven target vessel revascularization	12 (17.9%)	8 (12.9%)	0.432

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