C-reactive protein (CRP) elevation is associated with an adverse cardiovascular prognosis after bare metal stent implantation. Data have suggested a similar association between preprocedural CRP and adverse events after drug-eluting stent (DES) implantation. The present study was designed to address whether such a relation exists after DES placement. After excluding patients presenting with an acute coronary syndrome with troponin I elevation, we analyzed the data from 936 consecutive patients who had undergone DES implantation from 2003 to 2007 and had a preprocedural CRP measurement. The patients were divided into 3 groups according to the preprocedural CRP level (<1.31, 1.31–3.76, and >3.76 mg/L). The primary end point was the composite of death and Q-wave myocardial infarction (QWMI) at 2 years of follow-up. Target vessel revascularization was also assessed. The rate of death/QWMI was not significantly different statistically among the CRP tertiles during the in-hospital period (0.6% vs 0.0% vs 0.6%, p = 0.5) or at 1 year of follow-up (1.9% vs 2.9% vs 4.5%, p = 0.2). At 2 years, death/QWMI had occurred in 2.9% of patients in the lowest, 5.2% in the middle, and 8.8% in the highest tertile (p = 0.006). The incidence of target vessel revascularization was similar in the 3 groups at 2 years of follow-up (13.2% vs 14.9% vs 16.9%, p = 0.5). On multivariate analysis, the upper tertile of CRP was an independent predictor of death/QWMI at 2 years (hazard ratio 2.5, 95% confidence interval 1.1 to 5.4, tertile 3 vs tertile 1, p = 0.006). In conclusion, high preprocedural CRP levels are associated with an increased risk of death and QWMI after DES implantation at long-term follow-up but not acutely. The CRP levels were not related to target vessel revascularization. Thus, an elevated CRP level in this population appears to be more of a marker of global cardiovascular risk than a predictor of post–DES-related complications.
Inflammation plays a major role in the pathogenesis of atherosclerosis and its complications. Higher levels of C-reactive protein (CRP), a sensitive marker of inflammation, have been associated with poorer cardiovascular outcomes in both healthy populations and patients with coronary artery disease. Several studies have shown that higher preprocedural CRP levels are related to a greater risk of death and myocardial infarction after bare metal stent implantation. Additionally, an association between the preprocedural CRP level and an increased risk of bare metal stent restenosis has been suggested. Currently, the increased use of drug-eluting stent (DES) has resulted in a reduction of restenosis and the subsequent need for repeat revascularization. However, concern persists regarding a greater risk of very late stent thrombosis. Few data are available regarding the relation between preprocedural CRP levels and the long-term outcomes after DES implantation. In the present study, we investigated the value of preprocedural CRP levels on the long-term clinical outcomes of patients with stable coronary artery disease and unstable angina pectoris who underwent percutaneous coronary intervention with DES implantation.
Methods
An ongoing registry of catheter-based coronary procedures is maintained at our institution. All patients who underwent ≥1 coronary DES implantations at our center from January 2003 to December 2007 were considered. Those for whom both a preprocedure CRP measurement and 2-year follow-up information were available were included. Those presenting with either stable angina pectoris or unstable angina pectoris were considered, but those presenting with an acute coronary syndrome accompanied by troponin elevation before percutaneous coronary intervention were excluded. The cutoff value to define troponin elevation agreed with the new definition of infarction proposed by the American College of Cardiology and the European Society of Cardiology. All patients gave written consent for percutaneous coronary intervention, and the institutional review board approved the study. Blood samples were obtained just before percutaneous coronary intervention and then centrifuged; the serum was removed and stored at −80°C until the assay could be performed. Determinations of high-sensitive CRP were performed using nephelometry BNII (Siemens Health Care Diagnostics, Deerfield, Illinois).
Coronary stenting was performed using conventional techniques. The interventional strategy was left to the discretion of the operator. In >99%, a femoral approach was used. Two types of DESs were used: the paclitaxel-eluting stent (Taxus, Boston Scientific, Boston, Massachusetts) and the sirolimus-eluting stent (Cypher, Cordis/Johnson & Johnson, Miami, Florida). Intraprocedural anticoagulation was ensured using unfractionated heparin or bivalirudin. Glycoprotein IIb/IIIa inhibitors were used at the operator’s discretion. All patients received aspirin 325 mg/day ≥24 hours before the procedure and continued this regimen indefinitely. Additional antiplatelet therapy with clopidogrel 75 mg/day was instituted for all patients after a loading dose of 300 or 600 mg at percutaneous coronary intervention. In patients with unstable angina pectoris, clopidogrel was recommended for ≥12 months. For stable patients, clopidogrel maintenance therapy was recommended for ≥6 months after DES implantation.
The primary end point was defined as either all-cause mortality or nonfatal Q-wave myocardial infarction (QWMI) at 2 years of follow-up. QWMI was defined as new pathologic Q waves in ≥2 contiguous leads associated with creatinine kinase-MB ≥2 times the upper limit of normal and/or ischemic electrocardiographic changes, including ST-segment elevation of ≥1 mm. Non-QWMI was defined as creatinine kinase-MB of ≥3 times the upper limit of normal within 24 hours after percutaneous coronary intervention and, thereafter, as creatinine kinase-MB ≥2 times the upper limit of normal and/or ischemic electrocardiographic changes, including ST-segment elevation of ≥1 mm without new Q waves. Target vessel revascularization was characterized by ischemia-driven percutaneous or surgical revascularization of the treated vessel. Definite stent thrombosis was considered as defined by the Academic Research Consortium. Stent thrombosis was thus confirmed angiographically or by autopsy examination. Procedural success was defined as attainment of both Thrombolysis In Myocardial Infarction flow grade 3 and a residual stenosis of <30%. Major bleeding was defined as a decrease in hematocrit of ≥15% and/or the occurrence of a major hematoma and/or the occurrence of gastrointestinal bleeding. A major hematoma was defined as a hematoma measuring ≥4 cm or requiring transfusions or necessitating prolonged hospitalization. Gastrointestinal bleeding was defined as evidence of an upper (“coffee grounds” emesis or endoscopic findings demonstrating active bleeding) or lower (melena or endoscopic findings demonstrating active bleeding) gastrointestinal tract bleeding.
All data collection, management, and analyses were performed by a dedicated data coordinating center (Data Center, Cardiovascular Research Institute, Washington, DC). The data center staff, who were unaware of the study objectives, abstracted the demographic, clinical, and procedural information by hospital chart review. They also recorded the in-hospital outcomes. The data center staff obtained postdischarge follow-up information through telephone interviews with the patients or their referring physician. Source documentation for all reported clinical events was obtained, and their nature was adjudicated by independent physicians not involved in the study. Continuous variables are presented as the mean ± SD, except for laboratory characteristics, which are presented as the median (twenty-fifth to seventy-fifth percentiles) because of the nongaussian distribution. Categorical variables are expressed as percentages. Student’s t test, analysis of variance, or the Kruskal-Wallis test was used to compare continuous variables, and the chi-square test or Fischer’s exact test was used to compare categorical variables. The CRP levels were split into tertiles for the analyses.
Univariate Cox proportional hazard modeling followed by Cox multivariate analyses was used to determine the predictors of the primary end point at 2 years. The variables included in the univariate model were age, gender, diabetes mellitus, current smoker, chronic renal insufficiency, previous myocardial infarction, previous cardiac heart failure, unstable angina pectoris, type C lesion, and CRP as tertiles. p Values of 0.20 were used to determine the inclusion of variables in the multivariate model. Survival curves were constructed using the Kaplan-Meier method, and differences among CRP tertiles were tested using the log-rank test. All statistical analysis was performed using Statistical Analysis Systems, version 9.1 (SAS Institute, Cary, North Carolina). Statistical significance was assumed at p <0.05.
Results
The patients were divided into 3 groups according to the preprocedural CRP level: tertile 1, CRP ≤1.31 mg/L (n = 309); tertile 2, CRP 1.31 to 3.76 mg/L (n = 311); and tertile 3, CRP >3.76 mg/L (n = 316). The baseline characteristics, stratified according to the CRP tertile, are detailed in Table 1 . Patients with a higher CRP level were more often women and a current smoker, more often presented with a greater body mass index, and more often had chronic renal insufficiency. The baseline glucose and creatinine value were also greater in the patients in the upper CRP levels. The angiographic and procedural characteristics are summarized in Table 2 . No difference was found among the CRP tertiles in the angiographic and procedural characteristics, except for the target coronary vessel. Angiographic success was achieved in ≈98%. About 86% of the lesions were treated with DESs, and the mean number of DESs implanted was 1.46 ± 0.7 per patient. Medical therapy at discharge is summarized in Table 3 . No difference was found among the 3 groups in terms of discharge treatment.
| Variable | Total (n = 936) | C-Reactive Protein (mg/L) | p Value | ||
|---|---|---|---|---|---|
| Tertile 1 (≤1.31; n = 309) | Tertile 2 (1.31–3.76; n = 311) | Tertile 3 (>3.76; n = 316) | |||
| Cardiovascular risk factors | |||||
| Age (years) | 65.8 ± 11.0 | 66.0 ± 10.7 | 65.4 ± 11.1 | 65.9 ± 11.1 | 0.761 |
| Men | 660 (70.5%) | 244 (79.0%) | 217 (69.8%) | 199 (63.0%) | <0.001 |
| Family history of coronary artery disease ⁎ | 557 (60.1%) | 187 (61.1%) | 190 (61.7%) | 180 (57.5%) | 0.514 |
| Diabetes mellitus † | 288 (31.0%) | 88 (28.8%) | 92 (29.8%) | 108 (34.4%) | 0.269 |
| Systemic hypertension ‡ | 769 (82.4%) | 242 (78.6%) | 261 (84.5%) | 266 (84.2%) | 0.095 |
| Current smoker | 128 (13.7%) | 24 (7.8%) | 43 (13.8%) | 61 (19.3%) | <0.001 |
| Body mass index (kg/m 2 ) | 29.1 ± 5.4 | 27.8 ± 4.2 | 29.0 ± 4.9 | 30.5 ± 6.6 | <0.001 |
| Hypercholesterolemia § | 835 (89.4%) | 267 (86.7%) | 290 (93.2%) | 278 (88.3%) | 0.021 |
| Chronic renal insufficiency ¶ | 81 (8.7%) | 19 (6.2%) | 16 (5.2%) | 46 (14.7%) | <0.001 |
| Cardiac history | |||||
| Previous myocardial infarction | 242 (26.9%) | 77 (25.9%) | 98 (33.1%) | 67 (21.9%) | 0.007 |
| Previous coronary artery bypass surgery | 199 (21.4%) | 66 (21.6%) | 76 (24.6%) | 57 (18.1%) | 0.140 |
| Previous percutaneous coronary intervention | 323 (35.5%) | 114 (37.6%) | 116 (38.8%) | 93 (30.1%) | 0.051 |
| Previous congestive heart failure | 93 (10.6%) | 30 (10.2%) | 27 (9.5%) | 36 (12.1%) | 0.569 |
| Indication for percutaneous coronary intervention | |||||
| Stable coronary artery disease | 409 (43.7%) | 146 (47.2%) | 131 (42.1%) | 132 (41.8%) | 0.305 |
| Unstable angina pectoris | 527 (56.3%) | 163 (52.8%) | 180 (57.9%) | 184 (58.2%) | 0.305 |
| Severity of heart disease | |||||
| Left ventricular ejection fraction | 51 ± 1 | 52 ± 1 | 51 ± 1 | 50 ± 1 | 0.144 |
| No. of diseased vessels | 1.92 ± 0.8 | 1.91 ± 0.9 | 1.90 ± 0.8 | 1.95 ± 0.8 | 0.823 |
| Laboratory characteristics | |||||
| Baseline glucose (mg/dl) | 109 (97.0–142.0) | 107.0 (93.5–132.0) | 108.0 (97.0–142.0) | 113.5 (99.0–157.5) | 0.009 |
| Baseline creatinine (mg/dl) | 1.00 (0.90–1.20) | 1.00 (0.90–1.20) | 1.00 (0.80–1.20) | 1.00 (0.90–1.30) | 0.423 |
| C-reactive protein (mg/l) | 2.29 (0.96–5.22) | 0.66 (0.41–0.94) | 2.29 (1.76–2.94) | 7.98 (5.10–14.94) | — |
⁎ Defined as family history of coronary artery disease in first-degree relative; included myocardial infarction, angina pectoris, revascularization, and sudden unexplained death.
† Defined as any history of diabetes mellitus and/or use of hypoglycemic drugs; also included new diagnosis made during index hospitalization with fasting glucose level ≥1.26 g/L on ≥2 different occasions.
‡ History of hypertension diagnosed and/or treated with medication or currently treated with diet and/or medication by a physician.
§ Included patients with previously documented diagnosis of hypercholesterolemia treated with diet or medication; a new diagnosis could be made during hospitalization by elevated total cholesterol >160 mg/dl; did not include elevated triglycerides.
¶ Included chronic renal insufficiency previously diagnosed or treated with medication, diet, or dialysis; diagnosis could be made at admission if baseline creatinine of >2.0 mg/dl was found.
| Variable Patient based | Total n = 936 | C-Reactive Protein (mg/L) | p Value | ||
|---|---|---|---|---|---|
| Tertile 1 (≤1.31; n = 309) | Tertile 2 (1.31–3.76; n = 311) | Tertile 3 (>3.76; n = 316) | |||
| No. of lesions dilated | 1.82 ± 2.0 | 1.72 ± 0.9 | 1.79 ± 1.0 | 1.94 ± 3.2 | 0.391 |
| No. of drug-eluting stents per patient | 1.46 ± 0.7 | 1.48 ± 0.7 | 1.49 ± 0.7 | 1.43 ± 0.7 | 0.535 |
| No. of bare metal stents per patient | 0.23 ± 059 | 0.25 ± 0.65 | 0.23 ± 0.57 | 0.23 ± 0.56 | 0.892 |
| Glycoprotein IIb/IIIa inhibitors | 58 (6.2%) | 18 (5.9%) | 19 (6.1%) | 21 (6.7%) | 0.913 |
| Bivalirudin | 762 (81.4%) | 254 (82.2%) | 255 (82.0%) | 253 (80.1%) | 0.750 |
| Lesion based | n = 1,704 | n = 557 | n = 563 | n = 584 | |
| Target coronary vessel | |||||
| Left main | 31 (1.8%) | 9 (1.6%) | 7 (1.2%) | 15 (2.6%) | 0.222 |
| Left anterior descending | 625 (36.7%) | 215 (38.6%) | 193 (34.3%) | 217 (37.2%) | 0.311 |
| Left circumflex | 433 (25.4%) | 163 (29.3%) | 122 (21.7%) | 148 (25.3%) | 0.014 |
| Right | 503 (29.5%) | 131 (23.5%) | 195 (34.6%) | 177 (30.3%) | <0.001 |
| Saphenous vein graft | 104 (6.1%) | 37 (6.6%) | 43 (7.6%) | 24 (4.1%) | 0.036 |
| Internal mammary | 8 (0.5%) | 2 (0.4%) | 3 (0.5%) | 3 (0.5%) | |
| ACC/AHA class C | 338 (21.2%) | 113 (21.6%) | 107 (20.5%) | 118 (21.6%) | 0.874 |
| Restenosis lesion | 129 (7.5%) | 35 (6.3%) | 47 (8.3%) | 47 (8.1%) | 0.369 |
| Ostial lesion | 106 (6.4%) | 36 (6.6%) | 31 (5.6%) | 39 (6.9%) | 0.644 |
| Procedure | |||||
| Angiographic success | 1,650 (97.8%) | 549 (98.4%) | 544 (97.1%) | 557 (98.1%) | 0.328 |
| Preprocedural diameter stenosis (%) | 84 ± 12 | 84 ± 12 | 83 ± 12 | 84 ± 11 | 0.533 |
| Postprocedural diameter stenosis (%) | 4 ± 13 | 4 ± 14 | 3 ± 11 | 4 ± 13 | 0.340 |
| Bare metal stent | 202 (13.3%) | 71 (14.1%) | 63 (12.5%) | 68 (13.4%) | 0.745 |
| Drug-eluting stent | 1,378 (85.9%) | 447 (85.3%) | 465 (86.6%) | 466 (85.8%) | 0.832 |
| Drug-eluting stent length (mm) | 20.6 ± 6.6 | 20.4 ± 6.6 | 20.7 ± 6.4 | 20.7 ± 6.7 | 0.877 |
| Drug-eluting stent diameter (mm) | 3.0 ± 0.5 | 3.0 ± 0.3 | 3.0 ± 0.7 | 3.0 ± 0.3 | 0.211 |
| Variable ⁎ | Total | C-Reactive Protein (mg/L) | p Value | ||
|---|---|---|---|---|---|
| Tertile 1 (≤1.31) | Tertile 2 (1.31–3.76) | Tertile 3 (>3.76) | |||
| Antiplatelet therapy | |||||
| Aspirin | 926/928 (99.8%) | 306/307 (99.7%) | 306/307 (99.7%) | 314/314 (100%) | 0.552 |
| Thienopyridine † | 907/913 (99.4%) | 302/303 (99.7%) | 300/302 (99.7%) | 305/308 (99.0%) | 0.628 |
| Other therapy | |||||
| β Blocker | 724/924 (78.4%) | 245/305 (80.3%) | 235/307 (76.5%) | 244/312 (78.2%) | 0.523 |
| Angiotensin-converting enzyme inhibitors | 397/871 (45.6%) | 128/286 (44.8%) | 128/285 (44.9%) | 141/300 (47.0%) | 0.830 |
| Angiotensin receptor blocker | 108/845 (12.8%) | 38/275 (13.8%) | 34/282 (12.1%) | 36/288 (12.5%) | 0.811 |
| Statin | 822/850 (96.7%) | 270/278 (97.1%) | 276/283 (97.5%) | 276/289 (95.5%) | 0.356 |
⁎ Data for available patients.
The in-hospital and 1- and 2-year outcomes are reported in Table 4 and shown in Figure 1 . No statistically significant difference among CRP tertiles was found during the in-hospital period (0.6% vs 0.0% vs 0.6%, p = 0.5) or at 1 year (1.9% vs 2.9% vs 4.5%, p = 0.2) for death/QWMI. However, at 2 years of follow-up, the primary end point, death/QWMI, and the composite of death, QWMI, and target vessel revascularization occurred more often in those patients within the upper CRP group (2.9% vs 5.2% vs 8.8% [p = 0.006] and 15.5% vs 19.3% vs 24.0% [p = 0.027] for tertile 1, 2, and 3, respectively). Figure 2 shows the freedom from death/QWMI in Kaplan-Meier curves according to CRP tertile. No difference was seen in the non-QWMI, target vessel revascularization, and stent thrombosis rates among the CRP groups at 2 years of follow-up.
| Outcome | Total (n = 936) | C-Reactive Protein (mg/L) | p Value | ||
|---|---|---|---|---|---|
| Tertile 1 (≤1.31; n = 309) | Tertile 2 (1.31–3.76; n = 311) | Tertile 3 (>3.76; n = 316) | |||
| In-hospital | |||||
| Death | 2 (0.2%) | 1 (0.3%) | 0 | 1 (0.3%) | 0.775 |
| QWMI | 2 (0.2%) | 1 (0.3%) | 0 | 1 (0.3%) | 0.849 |
| Non-QWMI | 65 (7.0%) | 22 (7.1%) | 19 (6.1%) | 24 (7.6%) | 0.751 |
| Target vessel revascularization | 8 (0.9%) | 3 (1.0%) | 2 (0.6%) | 3 (0.9%) | 0.913 |
| Death/QWMI | 4 (0.4%) | 2 (0.6%) | 0 | 2 (0.6%) | 0.479 |
| Death/QWMI/target vessel revascularization | 4 (0.4%) | 2 (0.6%) | 0 | 2 (0.6%) | 0.478 |
| Stent thrombosis | 2 (0.2%) | 0 | 1 (0.3%) | 1 (0.3%) | 1.000 |
| Major bleeding | 6 (0.6%) | 1 (0.3%) | 2 (0.6%) | 3 (1.0) | 0.876 |
| Cumulative 1-year outcome | |||||
| Death | 27 (2.9%) | 5 (1.6%) | 9 (2.9%) | 13 (4.2%) | 0.775 |
| QWMI | 3 (0.3%) | 1 (0.3%) | 0 | 2 (0.6%) | 0.663 |
| Non-QWMI | 76 (8.1%) | 27 (8.7%) | 21 (6.7%) | 28 (8.8%) | 0.557 |
| Target vessel revascularization | 91 (9.9%) | 28 (9.2%) | 32 (10.5%) | 31 (10.1%) | 0.860 |
| Death/QWMI | 29 (3.1%) | 6 (1.9%) | 9 (2.9%) | 14 (4.5%) | 0.179 |
| Death/QWMI/target vessel revascularization | 119 (12.7%) | 34 (11.0%) | 41 (13.2%) | 44 (13.9%) | 0.527 |
| Stent thrombosis | 5 (0.5%) | 2 (0.6%) | 1 (0.3%) | 2 (0.6%) | 0.875 |
| Cumulative 2-year outcome | |||||
| Death | 48 (5.2%) | 8 (2.6%) | 15 (4.9%) | 25 (8.2%) | 0.008 |
| QWMI | 5 (0.5%) | 1 (0.3%) | 1 (0.3%) | 3 (0.9%) | 0.628 |
| Non-QWMI | 78 (8.3%) | 28 (9.1%) | 22 (7.1%) | 28 (8.9%) | 0.614 |
| Target vessel revascularization | 136 (15.0%) | 40 (13.2%) | 45 (14.9%) | 51 (16.9%) | 0.446 |
| Death/QWMI | 52 (5.6%) | 9 (2.9%) | 16 (5.2%) | 27 (8.8%) | 0.006 |
| Death/QWMI/target vessel revascularization | 184 (19.6%) | 48 (15.5%) | 60 (19.3%) | 76 (24.0%) | 0.027 |
| Stent thrombosis | 6 (0.6%) | 2 (0.6%) | 1 (0.3%) | 3 (0.9%) | 0.791 |
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