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Comparison of Effects of Drug-Eluting Stents Versus Bare Metal Stents on Plasma C-Reactive Protein Levels
Comparison of Effects of Drug-Eluting Stents Versus Bare Metal Stents on Plasma C-Reactive Protein Levels Jong-Youn Kim, MD, Young-Guk Ko, MD*, Chi Young Shim, MD, Sungha Park, MD, Ki-Chul Hwang, PhD, Donghoon Choi, MD, PhD, Yangsoo Jang, MD, PhD, Namsik Chung, MD, PhD, Won-Heum Shim, MD, PhD, and Seung-Yun Cho, MD, PhD After coronary stenting, inflammatory mechanisms play a crucial role in the pathogenesis of neointimal proliferation and in-stent restenosis. Drug-eluting stents (DESs) have been shown to decrease in-stent restenosis in different studies. We compared plasma C-reactive protein (CRP) levels after DES implantation with levels after bare metal stent (BMS) implantation. We performed percutaneous coronary intervention with a single stent in 67 patients (54 men; 59 ⴞ 9 years of age; n ⴝ 21 in the BMS group, n ⴝ 46 in the DES group) who had stable angina. Plasma CRP levels were determined before intervention and at 48 hours, 72 hours, and 2 weeks after coronary stenting. There was no difference in clinical and angiographic baseline characteristics except that the DES group had more patients with diabetes (34.8% vs 9.5%, p ⴝ 0.04), smaller reference vessels (2.95 ⴞ 0.53 vs 3.29 ⴞ 0.53 mm, p ⴝ 0.02), and smaller stent diameters (3.0 ⴞ 0.4 mm vs 3.4 ⴞ 0.5 mm, p <0.01). Plasma CRP levels at 48 hours (13.4 ⴞ 14.7 vs 5.9 ⴞ 4.9 mg/L, p <0.01) and 72 hours (16.7 ⴞ 19.8 vs 5.4 ⴞ 3.9 mg/L, p <0.01) after stent implantation were significantly higher in the BMS than in the DES group. In conclusion, DESs showed significantly lower plasma CRP levels after coronary stenting compared with BMSs. This may reflect the potent effects of DESs on acute inflammatory reactions induced by coronary intervention. © 2005 Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96:1384 –1388)
Few clinical data on the extent to which drug-eluting stents (DESs) influence acute phase inflammatory reactions after coronary stenting are currently available. Therefore, we investigated plasma levels of C-reactive protein (CRP) after DES insertion and compared these levels with those after bare metal stent (BMS) implantation.
Methods Patients: The study group consisted of 67 consecutive patients who had clinically consistent stable angina pectoris, single-vessel disease (defined as a decrease ⱖ70% in luminal diameter in the major epicardial coronary artery), left ventricular ejection fraction ⬎50%, and elective and successful percutaneous coronary intervention using a single coronary stent. Exclusion criteria included total occlusion, saphenous vein graft lesions, restenosis lesions, creatinine level ⬎2.0 mg/dl, aspartate aminotransferase and alanine aminotransferase levels ⬎2 times the upper limit of normal,
The Cardiology Division, Yonsei Cardiovascular Center and Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. Manuscript received April 13, 2005; revised manuscript received and accepted June 30, 2005. This research was supported by an Internal Medicine Research Grant (2004), Yonsei University College of Medicine, Seoul, Korea. *Corresponding author: Tel: 82-2-2228-8460; fax: 82-2-393-2041. E-mail address: [email protected] (Y.-G. Ko). 0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.07.042
CRP levels ⱖ3 mg/L before coronary intervention, and any identifiable condition that was related to infectious, active allergic, connective tissue-related, or other chronic inflammatory diseases. In addition, patients whose creatine kinase-MB level was 3 times the upper limit of normal, who developed groin hematoma after coronary artery intervention, or who took corticosteroids or other anti-inflammatory drugs, except low-dose aspirin, were excluded. Selection of stent type was carried out at the operator’s discretion. Overall, patients who had lesions and had a higher restenotic risk tended to be treated with DES. Patients were allocated to the BMS group (n ⫽ 21) or the DES group (n ⫽ 46). Coronary angiography and percutaneous coronary intervention: All patients received a daily dose of 100 mg of aspirin and 75 mg of clopidogrel for ⱖ3 days or a loading dose of 200 mg of aspirin and 300 mg of clopidogrel before the procedure. Coronary angiography was performed with 5Fr catheters through the femoral artery. Percutaneous coronary interventions were performed with 6Fr catheters and conventional techniques. Coronary stents were implanted after predilation of the lesions. In the DES group (n ⫽ 46), a sirolimus-eluting stent (Cypher, Johnson & Johnson, Cordis Unit, Miami Lakes, Florida) was implanted in 29 patients and a paclitaxel-eluting stent (TAXUS, Boston Scientific, Watertown, Massachusetts) was implanted in 17 patients. In the BMS group, the Express (Boston Scientific; n ⫽ 11), BX Velocity (Johnson & Johnson, Cordis Unit; www.AJConline.org
Coronary Artery Disease/CRP After Drug-Eluting Stent Implantation Table 2 Procedural and follow-up data
Table 1 Baseline characteristics Variable Men Age (yrs) Hypertension Diabetes mellitus* Current smoking Hyperlipidemia† Statin medication Coronary artery affected Left main Left anterior descending Left circumflex Right Type of lesion B C
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BMS (n ⫽ 21)
DES (n ⫽ 46)
17 (81.0%) 59.3 ⫾ 10.8 10 (47.6%) 2 (9.5%) 2 (9.5%) 4 (19.0%) 16 (76.2%)
37 (80.4%) 59.1 ⫾ 8.9 17 (37.0%) 16 (34.8%) 9 (19.6%) 12 (26.1%) 24 (52.2%)
0 (0%) 12 (52.2%) 5 (21.7%) 6 (26.1%)
2 (3.6%) 35 (63.6%) 11 (20.0%) 7 (12.7%)
13 (62%) 8 (38%)
32 (70%) 14 (30%)
Data are presented as mean ⫾ 1 SD or numbers of patients (percentages). * p ⬍0.05. † Total cholesterol level ⬎220 mg/dl.
n ⫽ 3), Driver (Medtronic AVE, Minneapolis, Minnesota; n ⫽ 3), BeStent2 (Medtronic AVE; n ⫽ 2), and Vision (Guidant, Santa Clara, California; n ⫽ 1) stents were implanted. A successful procedure was defined as residual stenosis of ⬍20% in the worst of 2 orthogonal views, normal runoff of medium contrast in the stented artery, and no significant increase in markers of myocardial necrosis. Vascular sheaths were removed at the end of the procedure, and vascular closure devices were used in all patients. No patient received abciximab or thrombolytic drugs before or during the procedure. In all patients, aspirin and clopidogrel were maintained during follow-up after the procedure. Blood sampling and measurements of CRP: Peripheral blood samples were obtained immediately before the procedure and at 48 hours, 72 hours, and 2 weeks after the procedure. Blood samples were collected in serum separation tubes. Serum was separated by centrifugation at 3,000g for 10 minutes and frozen at ⫺40°C for subsequent analyses. High-sensitivity CRP level was measured with latexenhanced immunonephelometry on a Behring BN-ProSpec Nephelometer (Dade Behring, Marburg, Germany). Statistical analysis: For continuous variables, results are presented as mean ⫾ SD. Within groups of patients, changes in CRP level before and after intervention were analyzed by Wilcoxon’s signed rank test. Differences in CRP level between groups were evaluated by the MannWhitney U statistic test. A p value ⬍0.05 was considered statistically significant. All statistical analyses were performed with SPSS 11.0 (SPSS, Inc., Chicago, Illinois). Results Baseline characteristics: All clinical and angiographic baseline characteristics of the study population are presented in
Variable Procedural data Reference vessel diameter (mm) Minimal lumen diameter (mm) Diameter stenosis (%) Lesion length (mm) Stent diameter (mm) Stent length (mm) Balloon-to-vessel ratio Post-stent luminal diameter (mm) Post-stent residual stenosis (%) Follow-up data at 6 mo Minimal lumen diameter (mm) Diameter stenosis (%) Late loss (mm) In-stent restenosis (%) Major adverse cardiac event* (%)
BMS (n ⫽ 21)
DES (n ⫽ 46)
p Value
3.29 ⫾ 0.53
2.95 ⫾ 0.53
0.02
0.95 ⫾ 0.41
0.68 ⫾ 0.34
⬍0.01
71.1 ⫾ 10.9 18.30 ⫾ 5.45 3.40 ⫾ 0.51 20.38 ⫾ 4.73 1.10 ⫾ 0.14 3.18 ⫾ 0.51
77.1 ⫾ 10.7 18.85 ⫾ 8.15 2.97 ⫾ 0.40 21.76 ⫾ 5.99 1.10 ⫾ 0.10 2.83 ⫾ 0.60
0.04 NS ⬍0.01 NS NS 0.03
2.66 ⫾ 10.71
5.30 ⫾ 8.55
NS
2.35 ⫾ 0.70
2.58 ⫾ 0.55
NS
25.1 ⫾ 14.9 0.86 ⫾ 0.57 1/14 (7.1) 0/21 (0)
8.4 ⫾ 15.6 0.32 ⫾ 0.65 0/38 (0) 1/46 (2.2)†
⬍0.01 ⬍0.01 NS NS
Data are presented as mean ⫾ 1 SD. * Death, myocardial infarction, or target lesion revascularization. † One case of myocardial infarction due to subacute thrombosis.
Tables 1 and 2. Patients who had diabetes were more frequently found in the DES group (34.8% vs 9.5%, p ⫽ 0.04), and the reference vessel diameter was larger in the BMS group (3.29 ⫾ 0.53 vs 2.95 ⫾ 0.53 mm, p ⫽ 0.02). Except for these factors, there was no other statistically significant difference in clinical and angiographic characteristics between groups. Further, there was no significant difference in baseline characteristics between patients who received sirolimus-eluting stents and those who received paclitaxel-eluting stents. Percutaneous coronary intervention and CRP levels: The coronary artery stenting procedure was successful in all patients. Overall, plasma levels of CRP were high after the procedure. For the combined dataset, mean plasma CRP levels were 1.3 ⫾ 0.8 mg/L at baseline; after coronary stenting, the mean CRP level increased to 7.1 ⫾ 7.2 mg/L (p ⬍0.01) at 48 hours and to 6.6 ⫾ 7.4 mg/L (p ⬍0.01) at 72 hours. Two weeks later, mean CRP level was near the baseline level. However, in a comparison between the DES and BMS groups, the DES group showed significantly lower CRP levels at 48 hours (5.9 ⫾ 4.9 vs 13.4 ⫾ 14.7 mg/L, p ⬍0.01) and at 72 hours (5.4 ⫾ 3.9 vs 16.7 ⫾ 19.8 mg/L, p ⬍0.01) after coronary stenting (Figure 1). Moreover, the increase in CRP levels from baseline to 48 hours (4.7 ⫾ 4.7 vs 11.9 ⫾ 14.2 mg/L, p ⬍0.01) and to 72 hours (4.2 ⫾ 3.8 vs 15.1 ⫾ 19.2 mg/L, p ⬍0.01) was significantly lower in the DES group (Figure 2). At 2 weeks after coronary intervention, CRP levels decreased to 1.5 ⫾ 2.8 mg/L in the DES group and 2.5 ⫾ 3.0 mg/L in the BMS group, with no statistically
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Figure 1. Changes in plasma CRP levels before and at 48 hours, 72 hours, and 2 weeks after coronary artery stenting. (A) BMS versus DES. (B) Sirolimus-eluting stent (Cypher) versus paclitaxel-eluting stent (TAXUS). Values are plasma CRP levels ⫾ 1 SD (numbers). Means (lines within boxes), interquartile ranges (25th to 75th percentiles) (box spans), and 10th to 90th percentiles (whiskers) are shown. *p ⬍0.05 for BMS versus DES.
significant difference. Between the sirolimus- and paclitaxeleluting stents, there were no significant difference in CRP levels at 48 hours (6.0 ⫾ 5.0 vs 5.8 ⫾ 5.0 mg/L) and 72 hours (4.8 ⫾ 3.2 vs 6.0 ⫾ 4.7 mg/L; Figure 1). Follow-up data: During the 6-month clinical follow-up, only 1 patient who received a paclitaxel-eluting stent developed nonfatal myocardial infarction due to subacute thrombosis after discontinuation of antiplatelet agents for noncardiac surgery. Follow-up angiograms, which were obtained in 14 patients in the BMS group and 38 patients in the DES
group, showed in-stent restenosis in only 1 patient in the BMS group; however, diameter stenosis (25.1 ⫾ 14.9% vs 8.4 ⫾ 15.6%, p ⬍0.01) and late loss (0.86 ⫾ 0.57 vs 0.32 ⫾ 0.65 mm, p ⬍0.01) were greater in the BMS group than in the DES group (Table 2). Discussion The present study confirms that a systemic inflammatory marker, plasma CRP, increases after balloon angioplasty
Coronary Artery Disease/CRP After Drug-Eluting Stent Implantation
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Figure 2. Changes in plasma CRP levels from baseline to 48 and 72 hours after coronary artery stenting in the BMS and DES groups. Values are mean plasma CRP levels ⫾ 1 SD (numbers). Means (lines within boxes), interquartile ranges (25th to 75th percentiles) (box spans), and 10th to 90th percentiles (whiskers) are shown. *p ⬍0.05 for BMS versus DES.
and implantation of a stent in coronary arteries. Further, implantation of a DES induces an increase in plasma CRP levels to a significantly lesser degree compared with a BMS. These are the first clinical data to indicate that DESs are capable of decreasing acute systemic inflammatory reactions that are induced by percutaneous coronary intervention using stents. Animal experiments and human pathology studies have demonstrated that stented coronary arteries show acute inflammatory reactions soon after implantation, especially when stenting is associated with medial injury or lipid core penetration; restenosis has been suggested to be associated with extent of vascular damage and inflammatory reactions.1– 4 Inflammatory mechanisms are generally considered to play a crucial role in the pathogenesis of neointimal proliferation and in-stent restenosis.5,6 Recent studies have documented a systemic inflammatory response as detected by an increase in CRP levels in peripheral blood after percutaneous coronary intervention, and a correlation between levels of CRP after coronary stenting and the cardiovascular event rate during follow-up has been suggested.7–11 Gaspardone et al7 reported that plasma CRP levels increased after coronary artery stenting and peaked at 48 hours after the procedure. Persistently increased plasma levels of CRP at ⬎48 hours after coronary stenting were associated with a higher incidence of cardiovascular events during follow-up. Similarly, Gottsauner-Wolf et al8 found that increased CRP levels that persisted ⬎48 hours were associated with a greater incidence of in-stent restenosis. Our study showed a pattern of increased plasma CRP after coronary artery stenting that was similar to that in previous studies. In the BMS and DES groups, plasma CRP
increased to peak levels at 48 hours after coronary stent implantation and decreased almost to baseline levels 2 weeks after coronary stenting. However, the DES versus the BMS induced a significantly lower increase in plasma CRP levels 48 and 72 hours after coronary stenting. Although all patients underwent coronary artery stenting using the same protocol, the intensity of the inflammatory response was highly variable among patients within a given group. This variability may be due to various factors, such as different compositions of coronary artery plaque, different extents of arterial wall damage caused by the procedure, and different patient susceptibilities to comparable inflammatory stimuli. In contrast to the results of our study, de la Torre-Hernandez et al12 recently reported no difference in CRP levels after coronary stenting in a comparison between BMSs and sirolimus-eluting stents. However, their study included CRP levels only within 20 hours after coronary interventions. Previous studies have suggested CRP levels that remain high for ⬎48 hours are more relevant to clinical significance and restenotic rates.7,8 1. Farb A, Sangiorgi G, Carter AJ, Walley VM, Edwards WD, Schwartz RS, Virmani R. Pathology of acute and chronic coronary stenting in humans. Circulation 1999;99:44 –52. 2. Carter AJ, Laird JR, Kufs WM, Bailey L, Hoopes TG, Reeves T, Farb A, Virmani R. Coronary stenting with a novel stainless steel balloonexpandable stent: determinants of neointimal formation and changes in arterial geometry after placement in an atherosclerotic model. J Am Coll Cardiol 1996;27:1270 –1277. 3. Van Beusekom HMM, Van der Geissen WJ, Van Suylen RJ, Bos E, Bosman FT, Serruys PW. Histology after stenting of human saphenous vein bypass grafts: observations from surgically excised grafts 3 to 320 days after stent implantation. J Am Coll Cardiol 1993;21: 45–54.
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4. Pietersma A, Kofflard M, de Wit LE, Stijnen T, Koster JF, Serruys PW, Sluiter W. Late lumen loss after coronary angioplasty is associated with the activation status of circulating phagocytes before treatment. Circulation 1995;91:1320 –1325. 5. Bennett MR. In-stent restenosis: pathology and implication for the development of drugs eluting stents. Heart 2003;89:218 –224. 6. Bhatia V, Bhatia R, Dhindsa M. Drug-eluting stents: new era and new concerns. Postgrad Med J 2004;80:13–18. 7. Gaspardone A, Crea F, Versaci F, Tomai F, Pellegrio A, Chiariello L, Gioffre PA. Predictive value of C-reactive protein after successful coronary-artery stenting in patients with stable angina. Am J Cardiol 1998;82:515–518. 8. Gottsauner-Wolf M, Zasmeta G, Hornykewycz S, Nikfardjam M, Stepan E, Wexberg P, Zorn G, Glogar D, Probst P, Maurer G, Huber K. Plasma levels of C-reactive protein after coronary stent implantation. Eur Heart J 2000;21:1152–1158.
9. Azar RR, McKay RG, Kiernan FJ, Seecharran B, Feng YJ, Fram DB, Wu AH, Waters DD. Coronary angioplasty induces a systemic inflammatory response. Am J Cardiol 1997;80:1476 –1478. 10. Versaci F, Gaspardone A, Tomai F, Crea F, Chiariello L, Gioffre PA. Predictive value of C-reactive protein in patients with unstable angina pectoris undergoing coronary artery stent implantation. Am J Cardiol 2000;85:92–95. 11. Angioi M, Abdelmouttaleb I, Rodriguez RM, Aimone-Gastin I, Adjalla C, Gueant JL, Danchin N. Increased C-reactive protein levels in patients with in-stent restenosis and its implications. Am J Cardiol 2001;87:1189 –1193. 12. De la Torre-Hernandez JM, Sainz-Laso F, Burgos V, Perez T, Figueroa A, Zueco J, Colman T. Comparison of C-reactive protein levels after coronary stenting with bare metal versus sirolimus-eluting stents. Am J Cardiol 2005;95:748 –751.
Few clinical data on the extent to which drug-eluting stents (DESs) influence acute phase inflammatory reactions after coronary stenting are currently available. Therefore, we investigated plasma levels of C-reactive protein (CRP) after DES insertion and compared these levels with those after bare metal stent (BMS) implantation.
Methods Patients: The study group consisted of 67 consecutive patients who had clinically consistent stable angina pectoris, single-vessel disease (defined as a decrease ⱖ70% in luminal diameter in the major epicardial coronary artery), left ventricular ejection fraction ⬎50%, and elective and successful percutaneous coronary intervention using a single coronary stent. Exclusion criteria included total occlusion, saphenous vein graft lesions, restenosis lesions, creatinine level ⬎2.0 mg/dl, aspartate aminotransferase and alanine aminotransferase levels ⬎2 times the upper limit of normal,
The Cardiology Division, Yonsei Cardiovascular Center and Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. Manuscript received April 13, 2005; revised manuscript received and accepted June 30, 2005. This research was supported by an Internal Medicine Research Grant (2004), Yonsei University College of Medicine, Seoul, Korea. *Corresponding author: Tel: 82-2-2228-8460; fax: 82-2-393-2041. E-mail address: [email protected] (Y.-G. Ko). 0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.07.042
CRP levels ⱖ3 mg/L before coronary intervention, and any identifiable condition that was related to infectious, active allergic, connective tissue-related, or other chronic inflammatory diseases. In addition, patients whose creatine kinase-MB level was 3 times the upper limit of normal, who developed groin hematoma after coronary artery intervention, or who took corticosteroids or other anti-inflammatory drugs, except low-dose aspirin, were excluded. Selection of stent type was carried out at the operator’s discretion. Overall, patients who had lesions and had a higher restenotic risk tended to be treated with DES. Patients were allocated to the BMS group (n ⫽ 21) or the DES group (n ⫽ 46). Coronary angiography and percutaneous coronary intervention: All patients received a daily dose of 100 mg of aspirin and 75 mg of clopidogrel for ⱖ3 days or a loading dose of 200 mg of aspirin and 300 mg of clopidogrel before the procedure. Coronary angiography was performed with 5Fr catheters through the femoral artery. Percutaneous coronary interventions were performed with 6Fr catheters and conventional techniques. Coronary stents were implanted after predilation of the lesions. In the DES group (n ⫽ 46), a sirolimus-eluting stent (Cypher, Johnson & Johnson, Cordis Unit, Miami Lakes, Florida) was implanted in 29 patients and a paclitaxel-eluting stent (TAXUS, Boston Scientific, Watertown, Massachusetts) was implanted in 17 patients. In the BMS group, the Express (Boston Scientific; n ⫽ 11), BX Velocity (Johnson & Johnson, Cordis Unit; www.AJConline.org
Coronary Artery Disease/CRP After Drug-Eluting Stent Implantation Table 2 Procedural and follow-up data
Table 1 Baseline characteristics Variable Men Age (yrs) Hypertension Diabetes mellitus* Current smoking Hyperlipidemia† Statin medication Coronary artery affected Left main Left anterior descending Left circumflex Right Type of lesion B C
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BMS (n ⫽ 21)
DES (n ⫽ 46)
17 (81.0%) 59.3 ⫾ 10.8 10 (47.6%) 2 (9.5%) 2 (9.5%) 4 (19.0%) 16 (76.2%)
37 (80.4%) 59.1 ⫾ 8.9 17 (37.0%) 16 (34.8%) 9 (19.6%) 12 (26.1%) 24 (52.2%)
0 (0%) 12 (52.2%) 5 (21.7%) 6 (26.1%)
2 (3.6%) 35 (63.6%) 11 (20.0%) 7 (12.7%)
13 (62%) 8 (38%)
32 (70%) 14 (30%)
Data are presented as mean ⫾ 1 SD or numbers of patients (percentages). * p ⬍0.05. † Total cholesterol level ⬎220 mg/dl.
n ⫽ 3), Driver (Medtronic AVE, Minneapolis, Minnesota; n ⫽ 3), BeStent2 (Medtronic AVE; n ⫽ 2), and Vision (Guidant, Santa Clara, California; n ⫽ 1) stents were implanted. A successful procedure was defined as residual stenosis of ⬍20% in the worst of 2 orthogonal views, normal runoff of medium contrast in the stented artery, and no significant increase in markers of myocardial necrosis. Vascular sheaths were removed at the end of the procedure, and vascular closure devices were used in all patients. No patient received abciximab or thrombolytic drugs before or during the procedure. In all patients, aspirin and clopidogrel were maintained during follow-up after the procedure. Blood sampling and measurements of CRP: Peripheral blood samples were obtained immediately before the procedure and at 48 hours, 72 hours, and 2 weeks after the procedure. Blood samples were collected in serum separation tubes. Serum was separated by centrifugation at 3,000g for 10 minutes and frozen at ⫺40°C for subsequent analyses. High-sensitivity CRP level was measured with latexenhanced immunonephelometry on a Behring BN-ProSpec Nephelometer (Dade Behring, Marburg, Germany). Statistical analysis: For continuous variables, results are presented as mean ⫾ SD. Within groups of patients, changes in CRP level before and after intervention were analyzed by Wilcoxon’s signed rank test. Differences in CRP level between groups were evaluated by the MannWhitney U statistic test. A p value ⬍0.05 was considered statistically significant. All statistical analyses were performed with SPSS 11.0 (SPSS, Inc., Chicago, Illinois). Results Baseline characteristics: All clinical and angiographic baseline characteristics of the study population are presented in
Variable Procedural data Reference vessel diameter (mm) Minimal lumen diameter (mm) Diameter stenosis (%) Lesion length (mm) Stent diameter (mm) Stent length (mm) Balloon-to-vessel ratio Post-stent luminal diameter (mm) Post-stent residual stenosis (%) Follow-up data at 6 mo Minimal lumen diameter (mm) Diameter stenosis (%) Late loss (mm) In-stent restenosis (%) Major adverse cardiac event* (%)
BMS (n ⫽ 21)
DES (n ⫽ 46)
p Value
3.29 ⫾ 0.53
2.95 ⫾ 0.53
0.02
0.95 ⫾ 0.41
0.68 ⫾ 0.34
⬍0.01
71.1 ⫾ 10.9 18.30 ⫾ 5.45 3.40 ⫾ 0.51 20.38 ⫾ 4.73 1.10 ⫾ 0.14 3.18 ⫾ 0.51
77.1 ⫾ 10.7 18.85 ⫾ 8.15 2.97 ⫾ 0.40 21.76 ⫾ 5.99 1.10 ⫾ 0.10 2.83 ⫾ 0.60
0.04 NS ⬍0.01 NS NS 0.03
2.66 ⫾ 10.71
5.30 ⫾ 8.55
NS
2.35 ⫾ 0.70
2.58 ⫾ 0.55
NS
25.1 ⫾ 14.9 0.86 ⫾ 0.57 1/14 (7.1) 0/21 (0)
8.4 ⫾ 15.6 0.32 ⫾ 0.65 0/38 (0) 1/46 (2.2)†
⬍0.01 ⬍0.01 NS NS
Data are presented as mean ⫾ 1 SD. * Death, myocardial infarction, or target lesion revascularization. † One case of myocardial infarction due to subacute thrombosis.
Tables 1 and 2. Patients who had diabetes were more frequently found in the DES group (34.8% vs 9.5%, p ⫽ 0.04), and the reference vessel diameter was larger in the BMS group (3.29 ⫾ 0.53 vs 2.95 ⫾ 0.53 mm, p ⫽ 0.02). Except for these factors, there was no other statistically significant difference in clinical and angiographic characteristics between groups. Further, there was no significant difference in baseline characteristics between patients who received sirolimus-eluting stents and those who received paclitaxel-eluting stents. Percutaneous coronary intervention and CRP levels: The coronary artery stenting procedure was successful in all patients. Overall, plasma levels of CRP were high after the procedure. For the combined dataset, mean plasma CRP levels were 1.3 ⫾ 0.8 mg/L at baseline; after coronary stenting, the mean CRP level increased to 7.1 ⫾ 7.2 mg/L (p ⬍0.01) at 48 hours and to 6.6 ⫾ 7.4 mg/L (p ⬍0.01) at 72 hours. Two weeks later, mean CRP level was near the baseline level. However, in a comparison between the DES and BMS groups, the DES group showed significantly lower CRP levels at 48 hours (5.9 ⫾ 4.9 vs 13.4 ⫾ 14.7 mg/L, p ⬍0.01) and at 72 hours (5.4 ⫾ 3.9 vs 16.7 ⫾ 19.8 mg/L, p ⬍0.01) after coronary stenting (Figure 1). Moreover, the increase in CRP levels from baseline to 48 hours (4.7 ⫾ 4.7 vs 11.9 ⫾ 14.2 mg/L, p ⬍0.01) and to 72 hours (4.2 ⫾ 3.8 vs 15.1 ⫾ 19.2 mg/L, p ⬍0.01) was significantly lower in the DES group (Figure 2). At 2 weeks after coronary intervention, CRP levels decreased to 1.5 ⫾ 2.8 mg/L in the DES group and 2.5 ⫾ 3.0 mg/L in the BMS group, with no statistically
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Figure 1. Changes in plasma CRP levels before and at 48 hours, 72 hours, and 2 weeks after coronary artery stenting. (A) BMS versus DES. (B) Sirolimus-eluting stent (Cypher) versus paclitaxel-eluting stent (TAXUS). Values are plasma CRP levels ⫾ 1 SD (numbers). Means (lines within boxes), interquartile ranges (25th to 75th percentiles) (box spans), and 10th to 90th percentiles (whiskers) are shown. *p ⬍0.05 for BMS versus DES.
significant difference. Between the sirolimus- and paclitaxeleluting stents, there were no significant difference in CRP levels at 48 hours (6.0 ⫾ 5.0 vs 5.8 ⫾ 5.0 mg/L) and 72 hours (4.8 ⫾ 3.2 vs 6.0 ⫾ 4.7 mg/L; Figure 1). Follow-up data: During the 6-month clinical follow-up, only 1 patient who received a paclitaxel-eluting stent developed nonfatal myocardial infarction due to subacute thrombosis after discontinuation of antiplatelet agents for noncardiac surgery. Follow-up angiograms, which were obtained in 14 patients in the BMS group and 38 patients in the DES
group, showed in-stent restenosis in only 1 patient in the BMS group; however, diameter stenosis (25.1 ⫾ 14.9% vs 8.4 ⫾ 15.6%, p ⬍0.01) and late loss (0.86 ⫾ 0.57 vs 0.32 ⫾ 0.65 mm, p ⬍0.01) were greater in the BMS group than in the DES group (Table 2). Discussion The present study confirms that a systemic inflammatory marker, plasma CRP, increases after balloon angioplasty
Coronary Artery Disease/CRP After Drug-Eluting Stent Implantation
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Figure 2. Changes in plasma CRP levels from baseline to 48 and 72 hours after coronary artery stenting in the BMS and DES groups. Values are mean plasma CRP levels ⫾ 1 SD (numbers). Means (lines within boxes), interquartile ranges (25th to 75th percentiles) (box spans), and 10th to 90th percentiles (whiskers) are shown. *p ⬍0.05 for BMS versus DES.
and implantation of a stent in coronary arteries. Further, implantation of a DES induces an increase in plasma CRP levels to a significantly lesser degree compared with a BMS. These are the first clinical data to indicate that DESs are capable of decreasing acute systemic inflammatory reactions that are induced by percutaneous coronary intervention using stents. Animal experiments and human pathology studies have demonstrated that stented coronary arteries show acute inflammatory reactions soon after implantation, especially when stenting is associated with medial injury or lipid core penetration; restenosis has been suggested to be associated with extent of vascular damage and inflammatory reactions.1– 4 Inflammatory mechanisms are generally considered to play a crucial role in the pathogenesis of neointimal proliferation and in-stent restenosis.5,6 Recent studies have documented a systemic inflammatory response as detected by an increase in CRP levels in peripheral blood after percutaneous coronary intervention, and a correlation between levels of CRP after coronary stenting and the cardiovascular event rate during follow-up has been suggested.7–11 Gaspardone et al7 reported that plasma CRP levels increased after coronary artery stenting and peaked at 48 hours after the procedure. Persistently increased plasma levels of CRP at ⬎48 hours after coronary stenting were associated with a higher incidence of cardiovascular events during follow-up. Similarly, Gottsauner-Wolf et al8 found that increased CRP levels that persisted ⬎48 hours were associated with a greater incidence of in-stent restenosis. Our study showed a pattern of increased plasma CRP after coronary artery stenting that was similar to that in previous studies. In the BMS and DES groups, plasma CRP
increased to peak levels at 48 hours after coronary stent implantation and decreased almost to baseline levels 2 weeks after coronary stenting. However, the DES versus the BMS induced a significantly lower increase in plasma CRP levels 48 and 72 hours after coronary stenting. Although all patients underwent coronary artery stenting using the same protocol, the intensity of the inflammatory response was highly variable among patients within a given group. This variability may be due to various factors, such as different compositions of coronary artery plaque, different extents of arterial wall damage caused by the procedure, and different patient susceptibilities to comparable inflammatory stimuli. In contrast to the results of our study, de la Torre-Hernandez et al12 recently reported no difference in CRP levels after coronary stenting in a comparison between BMSs and sirolimus-eluting stents. However, their study included CRP levels only within 20 hours after coronary interventions. Previous studies have suggested CRP levels that remain high for ⬎48 hours are more relevant to clinical significance and restenotic rates.7,8 1. Farb A, Sangiorgi G, Carter AJ, Walley VM, Edwards WD, Schwartz RS, Virmani R. Pathology of acute and chronic coronary stenting in humans. Circulation 1999;99:44 –52. 2. Carter AJ, Laird JR, Kufs WM, Bailey L, Hoopes TG, Reeves T, Farb A, Virmani R. Coronary stenting with a novel stainless steel balloonexpandable stent: determinants of neointimal formation and changes in arterial geometry after placement in an atherosclerotic model. J Am Coll Cardiol 1996;27:1270 –1277. 3. Van Beusekom HMM, Van der Geissen WJ, Van Suylen RJ, Bos E, Bosman FT, Serruys PW. Histology after stenting of human saphenous vein bypass grafts: observations from surgically excised grafts 3 to 320 days after stent implantation. J Am Coll Cardiol 1993;21: 45–54.
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4. Pietersma A, Kofflard M, de Wit LE, Stijnen T, Koster JF, Serruys PW, Sluiter W. Late lumen loss after coronary angioplasty is associated with the activation status of circulating phagocytes before treatment. Circulation 1995;91:1320 –1325. 5. Bennett MR. In-stent restenosis: pathology and implication for the development of drugs eluting stents. Heart 2003;89:218 –224. 6. Bhatia V, Bhatia R, Dhindsa M. Drug-eluting stents: new era and new concerns. Postgrad Med J 2004;80:13–18. 7. Gaspardone A, Crea F, Versaci F, Tomai F, Pellegrio A, Chiariello L, Gioffre PA. Predictive value of C-reactive protein after successful coronary-artery stenting in patients with stable angina. Am J Cardiol 1998;82:515–518. 8. Gottsauner-Wolf M, Zasmeta G, Hornykewycz S, Nikfardjam M, Stepan E, Wexberg P, Zorn G, Glogar D, Probst P, Maurer G, Huber K. Plasma levels of C-reactive protein after coronary stent implantation. Eur Heart J 2000;21:1152–1158.
9. Azar RR, McKay RG, Kiernan FJ, Seecharran B, Feng YJ, Fram DB, Wu AH, Waters DD. Coronary angioplasty induces a systemic inflammatory response. Am J Cardiol 1997;80:1476 –1478. 10. Versaci F, Gaspardone A, Tomai F, Crea F, Chiariello L, Gioffre PA. Predictive value of C-reactive protein in patients with unstable angina pectoris undergoing coronary artery stent implantation. Am J Cardiol 2000;85:92–95. 11. Angioi M, Abdelmouttaleb I, Rodriguez RM, Aimone-Gastin I, Adjalla C, Gueant JL, Danchin N. Increased C-reactive protein levels in patients with in-stent restenosis and its implications. Am J Cardiol 2001;87:1189 –1193. 12. De la Torre-Hernandez JM, Sainz-Laso F, Burgos V, Perez T, Figueroa A, Zueco J, Colman T. Comparison of C-reactive protein levels after coronary stenting with bare metal versus sirolimus-eluting stents. Am J Cardiol 2005;95:748 –751.