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Impact of the Metabolic Syndrome on Angiographic and Clinical Events After Coronary Intervention Using Bare-Metal or Sirolimus-Eluting Stents
Impact of the Metabolic Syndrome on Angiographic and Clinical Events After Coronary Intervention Using Bare-Metal or Sirolimus-Eluting Stents Rainer Hoffmann, MDa,*, Ekaterina Stellbrink, MDa, Jörg Schröder, MDa, Armin Grawe, MDa, Gunter Vogel, MDa, Rüdiger Blindt, MDa, Malte Kelm, MDa, and Peter W. Radke, MDb Patients with metabolic syndrome (MS) are at increased risk for cardiovascular events. Although the number of patients with MS requiring coronary revascularization is increasing rapidly, the impact of MS on clinical events and restenosis in patients who undergo stent placement is not well defined. Seven hundred thirty-four consecutive patients with 734 de novo coronary lesions (<50 mm lesion length, reference vessel diameter <3.5 mm) were enrolled in this study. Four hundred thirty-seven patients were treated with baremetal stents, and 297 patients were treated with sirolimus-eluting stents. Patients with bifurcation lesions, left main lesions, and ST-segment-elevation myocardial infarctions were excluded from the study. Patients were categorized into 3 groups: those with (1) diabetes mellitus (DM), (2) MS without DM, and (3) no MS and no DM. MS was defined according to American Heart Association and National Heart, Lung, and Blood Institute criteria (the presence of >3 of the following criteria: obesity, hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol, and increased fasting glucose). Clinical follow-up was performed for >1 year (mean 27.5 ⴞ 18.1 months). One hundred sixty-four patients (22%) had DM, 180 patients (25%) had MS without DM, and 390 patients (53%) had no MS and no DM. Baseline clinical and angiographic parameters were comparable among the 3 groups, including lesion length and reference vessel diameter. In patients treated with bare-metal stents, the rates of major adverse cardiac events (MACEs) at 12 months were 14% in patients without DM or MS, 18% in those with MS but no DM, and 33% in those with DM (p ⴝ 0.046). In patients treated with sirolimus-eluting stents, the MACE rates were 3% in patients without DM or MS, 4% in those with MS, and 13% in those with DM (p ⴝ 0.034). DM (odds ratio 2.14, 95% confidence interval 1.48 to 3.07, p <0.001) and bare-metal stent (odds ratio 2.51, 95% confidence interval 1.49 to 4.22, p <0.001) implantation were independent predictors of MACEs during follow-up, whereas MS was not predictive. Similarly, MS was not a predictor of target lesion revascularization. In conclusion, patients with MS did not have an increased risk for target lesion revascularization or a greater MACE rate compared with control patients during a 12 month follow-up period after bare-metal or drug-eluting stent placement. In contrast, DM is associated with significantly increased event rates. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:1347–1352)
Hyperinsulinemia and insulin resistance have been suggested to be stimuli for intimal hyperplasia.1 The impact of metabolic syndrome (MS) and its components on restenosis and clinical outcomes after percutaneous coronary intervention has not been well defined. In particular, it has not been clarified whether MS has a different impact on clinical event rates after the implantation of sirolimus-eluting stents (SES) compared with bare-metal stents (BMS). Thus, the aim of this study was to examine the impact of MS on clinical and angiographic restenosis using BMS and SES.
a
Medical Clinic I, University RWTH Aachen, Aachen; and bMedical Clinic, University Lübeck, Lübeck, Germany. Manuscript received March 10, 2007; revised manuscript received and accepted June 3, 2007. *Corresponding author: Tel: 49-241-8088468; fax: 49-241-8082303. E-mail address: [email protected] (R. Hoffmann). 0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.06.021
Methods Patients: A total of 734 consecutive patients were included in this retrospective analysis. Four hundred thirtyseven patients received BMS, and 297 patients received SES. Only patients with 1 coronary lesion to be treated during the interventional procedure were included in the analysis. Lesion length had to be ⬍50 mm length, and reference vessel diameter had to be ⬍3.5 mm. Patients were treated with BMS from June 1997 to July 1999 and with SES from June 2003 to June 2005. Patients were considered eligible if they presented with angina pectoris or had positive stress test results, or met both of these criteria, and had clinically significant angiographic stenosis in a native coronary vessel. Exclusion criteria included acute ST-segment elevation myocardial infarction, a target lesion in the left main trunk, a bifurcation lesion, and in-stent restenosis. www.AJConline.org
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Table 1 Baseline clinical characteristics Variable Men Age (yrs) Multivessel coronary disease Smokers Systemic hypertension Fasting glucose ⬎110 mg/dl* Low HDL† Hypertriglyceridemia (fasting triglycerides ⱖ1.7 mmol/L)* Obesity (body mass index ⬎28.8 kg/m2) Previous myocardial infarction
No MS, No DM (n ⫽ 390)
MS, No DM (n ⫽ 180)
DM (n ⫽ 164)
p Value
343 (88%) 60 ⫾ 10 230 (59%) 156 (40%) 238 (61%) 43 (11%) 51 (13%) 179 (46%)
131 (73%) 59 ⫾ 10 122 (68%) 68 (38%) 149 (83%) 77 (43%) 76 (42%) 154 (86%)
121 (74%) 63 ⫾ 9 121 (74%) 44 (27%) 131 (80%) 164 (100%) 66 (40%) 102 (62%)
0.006 0.004 0.036 0.037 0.102 ⬍0.001 ⬍0.001 ⬍0.001
59 (15%) 90 (23%)
63 (35%) 63 (35%)
57 (35%) 52 (32%)
0.045 0.034
* Or medically treated. HDL ⬍40 mg/dl in men and ⬍50 mg/dl in women.
†
Coronary intervention: Heparin was administered during the procedure according to standard practice. Aspirin (100 mg/day) and clopidogrel (300-mg loading dose) were started before the procedure. After the procedure, clopidogrel (75 mg/day) was administered in addition to aspirin for 1 month after elective stenting with a BMS, for 6 months after elective stenting using a SES, and for 9 months after stenting for acute coronary syndromes. Glycoprotein IIb/ IIIa inhibitors were given only to patients with acute coronary syndromes. BMS used consisted of Multilink stents (Guidant Corporation, Indianapolis, Indiana) in 202 patients, Velocity stents (Cordis Corporation, Miami Lakes, Florida) in 134 patients, and GFX stents (Medtronic AVE, Santa Rosa, California) in 101 patients. Stents were available in lengths of 8 to 33 mm and diameters of 2.5 to 4.0 mm. SES (Cypher; Cordis Corporation) were available in lengths of 8 to 33 mm and diameters of 2.5 to 3.5 mm. Follow-up protocol: Procedural success was defined as ⬍30% final diameter stenosis in the treated lesion and the absence of major clinical complications (in-hospital death, Q-wave myocardial infarction, or emergency coronary bypass surgery). All patients were followed for ⱖ12 months after the procedure by telephone interviews for any major adverse cardiac event (MACE), defined as death, Q-wave myocardial infarction, or need for target lesion revascularization. Patients treated with BMS were followed for a mean of 36 ⫾ 19 months, and patients treated with SES were followed for a mean of 15.1 ⫾ 6.7 months. Baseline clinical demographics, in-hospital complications, and the occurrence of death, myocardial infarction, and late recurrent coronary intervention during follow-up were verified by independent hospital chart review and source documentation or the records of family physicians. Angiography was performed routinely at 6-month follow-up after BMS implantation or earlier if symptoms of angina occurred. In patients treated with SES, the first 150 patients were scheduled for follow-up angiography 6 to 8 months after their procedures, or earlier if symptoms of angina occurred. Quantitative coronary angiography: Baseline, postprocedural, and follow-up coronary angiograms were
digitally recorded and analyzed offline at the angiographic core laboratory of University Aachen using a validated quantitative angiographic system (CAAS II System; Pie Medical Imaging, Maastricht, The Netherlands) by experienced personnel unaware of the clinical status of the patients. The contrast-filled catheter tip was used as the calibration standard. All measurements were performed on cine angiograms recorded after the intracoronary administration of nitroglycerin. Quantitative measurements included reference diameter, lesion length, and minimal luminal diameter in lesion (defined as the in-stent segment plus proximal and distal 5-mm edge segments) and in stent (without adjacent edge segment). Late loss (defined as the reduction in minimum luminal diameter from immediately after the procedure to 6-month follow-up), acute gain (defined as the increase in minimal luminal diameter immediately after percutaneous transluminal coronary angioplasty), net gain (the difference between acute gain and late loss), and loss index (the ratio of late loss to acute gain) were calculated. Study end points and definitions: The primary end point of the study was survival at 12 months free of MACEs. Secondary end points were survival free of need for revascularization of the target lesion because of narrowing of the lumen in the presence of symptoms or objective signs of ischemia and angiographic restenosis (in-segment stenosis ⬎50% on follow-up angiography). Patients were categorized into 3 groups: those with (1) no MS and no DM, (2) MS and no DM, and (3) DM with or without MS. The presence of MS was analyzed considering the presence of the following criteria: (1) hypertension, defined as blood pressure ⱖ130/85 mm Hg or taking antihypertensive medication; (2) fasting glucose ⱖ110 mg/dl; (3) reduced high-density lipoprotein (HDL) cholesterol (⬍40 mg/dl in men, ⬍50 mg/dl in women) or pharmacologic treatment for reduced HDL cholesterol; (4) a fasting triglyceride level ⱖ1.7 mmol/L (150 mg/dl) or pharmacologic treatment for hypertriglyceridemia; and (5) central obesity (body mass index ⬎28.8 kg/m2). A body mass index ⬎28.8 kg/m2 was used as substitute for a waist circumference ⱖ102 cm in men or ⱖ88 cm in women, as shown in a
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Table 2 Angiographic and procedure-related characteristics Variable
No MS, No DM (n ⫽ 390)
MS, No DM (n ⫽ 180)
DM (n ⫽ 164)
p Value
230 (59%) 94 (24%) 66 (17%)
102 (57%) 47 (26%) 31 (17%)
93 (57%) 46 (28%) 25 (15%)
0.823 0.610 0.862
12.6 ⫾ 7.5 2.68 ⫾ 0.60 1.04 ⫾ 0.52 16.4 ⫾ 8.2 2.81 ⫾ 0.45 14.5 ⫾ 2.1 12 (9%) 148 (38%)
12.9 ⫾ 7.8 2.72 ⫾ 0.66 0.96 ⫾ 0.59 16.0 ⫾ 6.1 2.82 ⫾ 0.44 14.7 ⫾ 2.2 8 (9%) 76 (42%)
12.9 ⫾ 6.1 2.63 ⫾ 0.60 0.97 ⫾ 0.47 16.4 ⫾ 6.8 2.79 ⫾ 0.43 14.7 ⫾ 2.6 5 (6%) 75 (46%)
0.918 0.102 0.108 0.852 0.185 0.243 0.824 0.219
2.71 ⫾ 0.62 2.52 ⫾ 0.43 2.38 ⫾ 0.46
2.74 ⫾ 0.63 2.52 ⫾ 0.44 2.39 ⫾ 0.48
2.70 ⫾ 0.59 2.46 ⫾ 0.45 2.32 ⫾ 0.41
0.311 0.273 0.265
Coronary pathology Left anterior descending Right Left circumflex Before intervention Lesion length (mm) Reference luminal diameter (mm) Minimal luminal diameter (mm) Stent length (mm) Stent diameter (mm) Implantation pressure (atm) Multistent placement Drug-eluting stent placement After intervention Reference luminal diameter (mm) Minimal luminal diameter in stent (mm) Minimal luminal diameter in lesion (mm)
Table 3 Clinical follow-up at 12 months Variable
Myocardial infarction (%) Mortality (%) Target lesion revascularization (%) Stent thrombosis (%) MACE (%)
BMS
SES
No MS, No DM (n ⫽ 242)
MS, No DM (n ⫽ 102)
DM (n ⫽ 93)
No MS, No DM (n ⫽ 148)
MS, No DM (n ⫽ 78)
DM (n ⫽ 71)
10 (4) 5 (2) 29 (12) 3 (1) 34 (14)
4 (4) 2 (2) 14 (14) 2 (2) 18 (18)
5 (5) 4 (4) 23 (25) 3 (3) 31 (33)*
0 (0) 3 (2) 1 (1) 1 (1) 4 (3)
2 (3) 3 (4) 1 (1) 0 (0) 5 (4)
1 (1) 5 (7) 5 (7)† 2 (3) 10 (13)‡
* p ⫽ 0.046 among all groups, p ⬍0.001 between patients without MS or DM and those with DM; † p ⫽ 0.036 among all groups, p ⫽ 0.024 between patients without MS or DM and those with DM; ‡ p ⫽ 0.034 among all groups, p ⫽ 0.004 between patients without MS or DM and those with DM.
study of Scottish men2 and in the Women’s Health Study.3 Patients were considered to have MS in the presence of ⱖ3 of these criteria, according to the definition proposed by the American Heart Association in conjunction with the National Heart, Lung, and Blood Institute.4 DM was defined as fasting glucose ⱖ126 mg/dl. Statistical analysis: Statistical analysis was performed using SPSS version 12.0 (SPSS, Inc., Chicago, Illinois). Categorical data were compared using Pearson’s chisquare test and are presented as frequencies. Continuous data were compared using Student’s t test or analysis of variance as adequate and are presented as mean ⫾ SD. Post hoc analysis (with Bonferroni’s correction) was performed for multiple comparisons. Cox proportional-hazards regression analysis was performed to identify predictors of target lesion revascularization and MACEs after the use of BMS or SES. Included variables were reference vessel diameter, lesion length, minimal luminal diameter before intervention, minimal luminal diameter after intervention, age, DM, MS, and stent type (BMS or SES). To consider the different follow-up periods for BMS and SES patients, Kaplan-Meier curves for freedom from MACEs were analyzed only up to 18 months after intervention. The impact of DM and MS on freedom from
Figure 1. MACE rates during an 18-month follow-up period in patients without DM or MS (solid line), patients with MS and no DM (dashed line), and patients with DM (dotted line). Event curves for patients treated with a SES are gray, and event curves for patients treated with BMS are black.
MACEs during the follow-up period was evaluated with the log-rank test. A p value ⬍0.05 was considered statistically significant.
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Table 4 Results of follow-up angiography BMS
Minimal luminal diameter in lesion (mm) Diameter stenosis (%) Late loss (mm) Restenosis
SES
No MS, No DM (n ⫽ 194)
MS, No DM (n ⫽ 77)
DM (n ⫽ 63)
No MS, No DM (n ⫽ 58)
MS, No DM (n ⫽ 40)
DM (n ⫽ 34)
1.82 ⫾ 0.63 32 ⫾ 16 0.69 ⫾ 0.61 35 (18%)
1.84 ⫾ 0.66 32 ⫾ 18 0.72 ⫾ 0.59 17 (22%)
1.54 ⫾ 0.62 38 ⫾ 19 1.03 ⫾ 0.63 21 (33%)
2.17 ⫾ 0.53 17 ⫾ 10 0.10 ⫾ 0.33 0 (0%)
2.19 ⫾ 0.53 18 ⫾ 12 0.10 ⫾ 0.20 1 (2%)
1.95 ⫾ 0.73 26 ⫾ 14 0.36 ⫾ 0.66* 4 (12%)†
* p ⫽ 0.009 among all groups, p ⬍0.001 between patients without MS or DM and those with DM; † p ⫽ 0.045 among all groups, p ⫽ 0.047 between patients without MS or DM and those with DM.
Results One hundred sixty-four patients (22%) had DM, 180 patients (25%) had MS and no DM, and 390 patients (53%) had no MS and no DM. In patients treated with BMS, 93 had DM, 102 had MS, and 242 had neither MS nor DM. In patients treated with SES, 71 had DM, 78 had MS, and 148 had no DM and no MS. Baseline clinical characteristics are listed in Table 1. Patients with MS more frequently had hypertension, low HDL, hypertriglyceridemia, obesity, elevated fasting glucose, and histories of myocardial infarctions than patients without DM or MS. Diabetic patients were older than those in the other 2 groups. Lesion characteristics for each of the 3 patient subgroups are listed in Table 2. Baseline angiographic parameters were comparable in all 3 groups with regard to lesion length, reference vessel diameter, minimal lesion diameter, and lesion location. Procedural characteristics: Procedural data are listed in Table 2. There were no differences among the 3 groups with regard to stent length, stent diameter, the use of multiple stents, and the number of stents per lesion. There was a slight trend toward the use of more SES in patients with MS or DM. Clinical results: Clinical follow-up at 12 months was obtained in all patients. Clinical event rates at 12 months are listed separately for patients with BMS and SES implantation in Table 3. After BMS implantation, MACE rates during 12-month follow-up were significantly higher for patients with DM than for patients with MS or patients without DM and without MS. Similarly, after SES implantation, MACE rates during 12-month follow-up were significantly higher for patients with DM than for the other 2 patient groups and comparable for patients with MS and patients without MS or DM. Thus, the impact of MS on MACEs was similar with BMS and SES. Figure 1 shows MACE rates for the different patient groups during follow-up. In the BMS patients, MACE rates were in particular driven by target lesion revascularization. Stent thrombosis rates tended to be higher in patients with DM compared with the other 2 patient groups after BMS and SES implantation (Table 3). Target lesion revascularization rates for the 3 patient groups after BMS and SES implantation are listed in Table 3. There was a strong trend toward higher target lesion revascularization rates for patients with DM after BMS implantation. After SES implantation, target lesion
revascularization rates were significantly higher in patients with DM than in the other 2 groups. The frequencies of myocardial infarction and death were not different among the 3 groups considering BMS and SES. The MACE rate in patients with DM and/or MS was significantly higher than in patients without MS and without DM, in BMS patients (25% vs 14%, p ⫽ 0.005), and in SES patients (10% vs 3%, p ⫽ 0.021). Among the 164 patients with DM, 92 had DM and MS and 72 had DM but no MS. Twenty-five patients with DM and MS (27%) and 16 patients with DM but no MS (22%) developed MACEs during follow-up (p ⫽ 0.588). Predictors of MACEs and target lesion revascularization: DM, the implantation of a BMS, and minimal luminal diameter after stent implantation were univariate predictors of MACEs during the total follow-up period. In the multivariate analysis, only DM (odds ratio [OR] 2.14, 95% confidence interval [CI] 1.48 to 3.07, p ⬍0.001) and the implantation of a BMS (OR 2.51, 95% CI 1.49 to 4.22, p ⬍0.001) remained independent predictors of MACEs during the total follow-up period. In contrast, MS was not a predictor of MACEs. Similarly, DM, the implantation of a BMS, lesion length, and minimal luminal diameter before intervention and after stent implantation were univariate predictors of target lesion revascularization during 12-month followup. DM (OR 1.93, 95% 1.13 to 3.36, p ⫽ 0.017), the implantation of a BMS (OR 2.98, 95% CI 1.82 to 4.95, p ⬍0.001), lesion length (OR 1.04, 95% CI 1.01 to 1.06, p ⫽ 0.010), and minimal luminal diameter after intervention (OR 0.41, 95% CI 0.20 to 0.82, p ⫽ 0.010) remained independent predictors of target lesion revascularization at 12-month follow-up, whereas MS was not a predictor of target lesion revascularization. Considering only the diabetic patients, fasting glucose level was found in a univariate logistic regression analysis to be a significant predictor of MACEs during follow-up (OR 1.002, 95% CI 1.001 to 1.004, p ⫽ 0.042). Angiographic results: Six-month follow-up angiography was performed in 334 patients after BMS placement and in 135 patients after SES placement (Table 4). The frequency of repeat angiography was similar for patients with DM, those with MS, and those without DM and MS. The results of angiographic follow-up are listed in Table 4. In-lesion late loss and restenosis rate tended to be higher in patients with DM after BMS implantation. There was no
Coronary Artery Disease/Coronary Intervention in Metabolic Syndrome
difference in BMS patients between those without DM or MS and those with MS (Table 4). In the SES patients, at angiographic follow-up, in-lesion late loss was 0.10 ⫾ 0.33 mm in the group with no MS and no DM, 0.10 ⫾ 0.20 mm in the group with MS but no DM, and 0.36 ⫾ 0.66 mm in the group with DM (analysis of variance p ⫽ 0.009). The binary in-lesion restenosis rate was higher in patients with DM than in nondiabetic patients. There was no difference in restenosis rate between patients without MS and those with MS (Table 4). Discussion The major findings of this study were that (1) MS without DM had no impact on angiographic restenosis and clinical events during a follow-up period of 1 year after the use of BMS and SES; (2) the relative risks for target lesion revascularization and MACEs were similarly decreased in all patient groups using SES compared with BMS; and (3) DM and BMS implantation are predictors of target lesion revascularization and MACEs during 12-month follow-up, whereas MS is not predictive. DM has been shown to be a major risk factor for CAD and restenosis after the implantation of coronary stents.5–11 Scheen et al11 showed in a meta-analysis that DM is equivocally associated with a twofold risk for restenosis after BMS and drug-eluting stent implantation. Similarly, DM was a significant predictor of MACEs in the RapamycinEluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry of drug-eluting stent use in the real world (OR 1.62, 95% CI 1.09 to 2.43, p ⫽ 0.02), especially because of clinically driven target vessel revascularization (OR 1.81, 95% CI 1.10 to 2.99, p ⫽ 0.02).12 The impact of noninsulin-dependent DM in contrast to insulin-dependent DM on restenosis after coronary stent placement is less well defined. Abizaid et al6 demonstrated for BMS that patients with noninsulin-dependent DM had almost identical restenosis rates compared with nondiabetic patients, whereas insulin-dependent DM was associated with increased clinical and angiographic restenosis rates. In contrast, similarly increased luminal loss was reported after the implantation of paclitaxel-eluting stents in insulin- and noninsulin–requiring diabetic patients (0.44 ⫾ 0.46 and 0.41 ⫾ 0.20 mm, respectively).13 Patients with MS but without DM were found to have clinical restenosis and overall event rates similar to those of control patients without DM and MS in the BMS group and in the SES group. Patients with DM had significantly higher clinical restenosis and overall MACE rates. This finding indicates that the MS alone has a different impact on the proliferative response to stent implantation than DM. The major stimulus for increased intimal hyperplasia in diabetic patients may be hyperinsulinemia, as supported by the findings of several studies.7,14 –16 Consistent with the finding of hyperinsulinemia being a major stimulus for intimal hyperplasia, elevations of hemoglobin A1c and fasting glucose levels have been shown to relate to an increased risk for death and target vessel revascularization in undiagnosed diabetics who undergo percutaneous coronary intervention.17,18 The negative impact of impaired glucose tolerance has also been confirmed in intravascular ultrasound studies
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showing increased neointimal tissue proliferation after BMS implantation.16 Although an increased fasting glucose level may be a precursor of DM, it is only 1 of the components by which MS is defined. Iribarren et al19 reported fasting glucose levels ⬎110 mg/dl in 31% of patients defined to have MS. In this study, 43% of patients presented with elevated fasting glucose levels. The moderate rate of patients with increased fasting glucose levels is likely to go along with a moderate rate of hyperinsulinemia. Thus, most patients did not have hyperinsulinemia as a stimulus for intimal hyperplasia. In most patients, MS was defined by the presence of the other 4 components: obesity, hypertriglyceridemia, decreased HDL level, and increased blood pressure. However, these risk factors are likely not to have a stimulating effect on smooth muscle cell proliferation. The results of this study support those in a previous report by Rana et al,20 who did not observe an association between risk for target vessel revascularization and the presence of MS after BMS implantation. This study confirms these findings in a larger patient group and extends previous observations to patients treated with SES. Interestingly, neither MS nor any of the 5 components of the definition of MS were predictive of target lesion revascularization or MACE during follow-up. Only DM was predictive. We used body mass index as substitute for waist circumference to define obesity. This approach was found to be adequate, because body mass index is strongly related to waist circumference and predicts the development of DM and other metabolic disturbances as strongly as waist circumference, as shown in several studies.2,10,21,22 Only in a limited number of patients was angiographic follow-up performed. This particularly affected patients after SES implantation, whereas follow-up was more complete after BMS implantation. The overall higher angiographic follow-up rate after BMS implantation might have contributed to a considerably higher level of target lesion revascularization rate in the BMS patients. However, it is unlikely that the impact in patients with MS compared with control patients would have been different if a larger number of patients had obtained angiographic follow-up. Intravascular ultrasound imaging would have allowed a more precise analysis of potential differences in intimal hyperplasia among the 3 study groups. However, the near equivalence of clinical and angiographic restenosis rates between control patients and patients with MS but no DM almost excludes significant differences in intimal hyperplasia. Follow-up periods after BMS and SES implantation were different. However, the primary analysis focused on 1-year follow-up, which was available for all patients, and Cox proportional-hazards regression analysis to define predictors of MACEs and target lesion revascularization accounted for different follow-up periods. 1. Marroquin OC, Kip KE, Kelley DE, Johnson BD, Shaw LJ, Bairey Merz CN, Sharaf BL, Pepine CJ, Sopko G, Reis SE. Metabolic syndrome modifies the cardiovascular risk associated with angiographic coronary artery disease in women: a report from the Women’s Ischemia Syndrome Evaluation. Circulation 2004;109:714 –721. 2. Lean ME, Han TS, Morrison CE. Waist circumference as a measure for indicating need for weight management. BMJ 1995;311:158 –161.
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3. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14719 initially healthy American women. Circulation 2003;107:391–397. 4. Grundy SM, Cleeman JI, Daniels SR. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 2005;112:2735–2752. 5. Gilbert J, Raboud J, Zinman B. Meta-analysis of the effect of diabetes on restenosis rates among patients receiving coronary angioplasty stenting. Diabetes Care 2004;27:990 –994. 6. Abizaid A, Kornowski R, Mintz GS, Hong MK, Abizaid AS, Mehran R, Pichard AD, Kent KM, Satler LF, Wu H, et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol 1998;32:584 –589. 7. West NEJ, Ruygrok PN, Disco CMC, Webster MWI, Lindeboom WK, O’Neill WW, Mercado NF, Serruys PW. Clinical and angiographic predictors of restenosis after stent deployment in diabetic patients. Circulation 2004;109:867– 873. 8. Takagi T, Yoshida K, Akasaka T, Kaji S, Kawamoto T, Honda Y, Yamamuro A, Hozumi T, Moioka S. Hyperinsulinemia during oral glucose tolerance test is associated with increased neointimal tissue proliferation after coronary stent implantation in nondiabetic patients. J Am Coll Cardiol 2002;36:731–738. 9. Hong SJ, Kim MH, Ahn TH, Ahn YK, Bae JH, Shim WJ, Ro YM, Lim DS. Multiple predictors of coronary restenosis after drug-eluting stent implantation in diabetic patients. Heart 2006;92:1119 –1124. 10. Moussa I, Leon MB, Baim DS. Impact of sirolimus eluting stents on outcome in diabetic patients. A SIRIUS (Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients With De Novo Coronary Artery Lesions) substudy. Circulation 2004;109: 2273–2278. 11. Scheen AJ, Warze’e F, Legrand VMG. Drug-eluting stents: metaanalysis in diabetic patients. Eur Heart J 2004;25:2167–2168. 12. Lemos PA, Serruys PW, van Domburg RT. Unrestricted utilization of sirolimus-eluting stents compared with conventional bare stent implantation in the “real world.” The Rapamycin Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry. Circulation 2004;109:190 –195. 13. Dibra A, Kastrati A, Mehilli J, Pache J, Schuhlen H, von Beckerath N, Ulm K, Wessely R, Dirschinger J, Schomig A; ISAR-DIABETES Study Investigators. Paclitaxel-eluting or sirolimus-eluting stents to
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21.
22.
prevent restenosis in diabetic patients. N Engl J Med 2005;353: 663– 670. Piatti PM, Di Mario C, Monti L, Fragasso G, Sgura F, Caumo A, Setola E, Lucotti P, Galluccio E, Ronchi C, et al. Association of insulin resistance, hyperleptinemia and impaired nitric oxide release with in-stent restenosis in patients undergoing coronary stenting. Circulation 2003;108:2074 –2081. Radke PW, Voswinkel M, Reith M, Kaiser A, Haager PK, Hanrath P, Hoffmann R. Relation of fasting insulin plasma levels to restenosis after elective coronary stent implantation in patients without diabetes mellitus. Am J Cardiol 2004;93:639 – 641. Takagi T, Akasaka T, Yamamuro A, Honda Y, Hozumi T, Morioka S, Yoshida K. Impact of insulin resistance on neointimal tissue proliferation after coronary stent implantation: intravascular ultrasound studies. J Diabetes Complications 2002;16:50 –55. Muhlestein JB, Anderson JL, Horne BD, Lavasani F, Allen Maycock CA, Bair TL, Pearson RR, Carlquist JF; Intermountain Heart Collaborative Study Group. Effect of fasting glucose levels on mortality rate in patients with and without diabetes mellitus and coronary artery disease undergoing percutaneous coronary intervention. Am Heart J 2003;146:351–358. Corpus RA, O’Neill WW, Dixon SR, Timmis GC, Devlin WH. Relation of hemoglobin A1c to rate of MACEs in nondiabetic patients undergoing percutaneous coronary revascularization. Am J Cardiol 2003;92:1282–1286. Iribarren C, Go AS, Husson G, Sidney S, Fair JM, Quertermous T, Hlatky MA, Fortmann SP. Metabolic syndrome and early-onset coronary artery disease. J Am Coll Cardiol 2006;48:1800 –1807. Rana JS, Monraats PS, Zwinderman AH, de Maat MPM, Kastelein JJP, Doevendans PAF, de Winter RJ, Tio RA, Frants RR, van der Laarse A, et al. Metabolic syndrome and risk of restenosis in patients undergoing percutaneous coronary intervention. Diabetes Care 2005; 28:873– 877. Freeman DJ, Norrie J, Caslake MJ, Gaw A, Ford I, Lowe GD, O’Reilly DS, Packard CJ, Sattar N; West of Scotland Coronary Prevention Study. C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes 2002;51:1596 –1600. Han TS, Williams K, Sattar N, Hunt KJ, Lean ME, Haffner SM. Analysis of obesity and hyperinsulinemia in the development of metabolic syndrome: San Antonio Heart Study. Obes Res 2002;10: 923–931.
Hyperinsulinemia and insulin resistance have been suggested to be stimuli for intimal hyperplasia.1 The impact of metabolic syndrome (MS) and its components on restenosis and clinical outcomes after percutaneous coronary intervention has not been well defined. In particular, it has not been clarified whether MS has a different impact on clinical event rates after the implantation of sirolimus-eluting stents (SES) compared with bare-metal stents (BMS). Thus, the aim of this study was to examine the impact of MS on clinical and angiographic restenosis using BMS and SES.
a
Medical Clinic I, University RWTH Aachen, Aachen; and bMedical Clinic, University Lübeck, Lübeck, Germany. Manuscript received March 10, 2007; revised manuscript received and accepted June 3, 2007. *Corresponding author: Tel: 49-241-8088468; fax: 49-241-8082303. E-mail address: [email protected] (R. Hoffmann). 0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.06.021
Methods Patients: A total of 734 consecutive patients were included in this retrospective analysis. Four hundred thirtyseven patients received BMS, and 297 patients received SES. Only patients with 1 coronary lesion to be treated during the interventional procedure were included in the analysis. Lesion length had to be ⬍50 mm length, and reference vessel diameter had to be ⬍3.5 mm. Patients were treated with BMS from June 1997 to July 1999 and with SES from June 2003 to June 2005. Patients were considered eligible if they presented with angina pectoris or had positive stress test results, or met both of these criteria, and had clinically significant angiographic stenosis in a native coronary vessel. Exclusion criteria included acute ST-segment elevation myocardial infarction, a target lesion in the left main trunk, a bifurcation lesion, and in-stent restenosis. www.AJConline.org
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Table 1 Baseline clinical characteristics Variable Men Age (yrs) Multivessel coronary disease Smokers Systemic hypertension Fasting glucose ⬎110 mg/dl* Low HDL† Hypertriglyceridemia (fasting triglycerides ⱖ1.7 mmol/L)* Obesity (body mass index ⬎28.8 kg/m2) Previous myocardial infarction
No MS, No DM (n ⫽ 390)
MS, No DM (n ⫽ 180)
DM (n ⫽ 164)
p Value
343 (88%) 60 ⫾ 10 230 (59%) 156 (40%) 238 (61%) 43 (11%) 51 (13%) 179 (46%)
131 (73%) 59 ⫾ 10 122 (68%) 68 (38%) 149 (83%) 77 (43%) 76 (42%) 154 (86%)
121 (74%) 63 ⫾ 9 121 (74%) 44 (27%) 131 (80%) 164 (100%) 66 (40%) 102 (62%)
0.006 0.004 0.036 0.037 0.102 ⬍0.001 ⬍0.001 ⬍0.001
59 (15%) 90 (23%)
63 (35%) 63 (35%)
57 (35%) 52 (32%)
0.045 0.034
* Or medically treated. HDL ⬍40 mg/dl in men and ⬍50 mg/dl in women.
†
Coronary intervention: Heparin was administered during the procedure according to standard practice. Aspirin (100 mg/day) and clopidogrel (300-mg loading dose) were started before the procedure. After the procedure, clopidogrel (75 mg/day) was administered in addition to aspirin for 1 month after elective stenting with a BMS, for 6 months after elective stenting using a SES, and for 9 months after stenting for acute coronary syndromes. Glycoprotein IIb/ IIIa inhibitors were given only to patients with acute coronary syndromes. BMS used consisted of Multilink stents (Guidant Corporation, Indianapolis, Indiana) in 202 patients, Velocity stents (Cordis Corporation, Miami Lakes, Florida) in 134 patients, and GFX stents (Medtronic AVE, Santa Rosa, California) in 101 patients. Stents were available in lengths of 8 to 33 mm and diameters of 2.5 to 4.0 mm. SES (Cypher; Cordis Corporation) were available in lengths of 8 to 33 mm and diameters of 2.5 to 3.5 mm. Follow-up protocol: Procedural success was defined as ⬍30% final diameter stenosis in the treated lesion and the absence of major clinical complications (in-hospital death, Q-wave myocardial infarction, or emergency coronary bypass surgery). All patients were followed for ⱖ12 months after the procedure by telephone interviews for any major adverse cardiac event (MACE), defined as death, Q-wave myocardial infarction, or need for target lesion revascularization. Patients treated with BMS were followed for a mean of 36 ⫾ 19 months, and patients treated with SES were followed for a mean of 15.1 ⫾ 6.7 months. Baseline clinical demographics, in-hospital complications, and the occurrence of death, myocardial infarction, and late recurrent coronary intervention during follow-up were verified by independent hospital chart review and source documentation or the records of family physicians. Angiography was performed routinely at 6-month follow-up after BMS implantation or earlier if symptoms of angina occurred. In patients treated with SES, the first 150 patients were scheduled for follow-up angiography 6 to 8 months after their procedures, or earlier if symptoms of angina occurred. Quantitative coronary angiography: Baseline, postprocedural, and follow-up coronary angiograms were
digitally recorded and analyzed offline at the angiographic core laboratory of University Aachen using a validated quantitative angiographic system (CAAS II System; Pie Medical Imaging, Maastricht, The Netherlands) by experienced personnel unaware of the clinical status of the patients. The contrast-filled catheter tip was used as the calibration standard. All measurements were performed on cine angiograms recorded after the intracoronary administration of nitroglycerin. Quantitative measurements included reference diameter, lesion length, and minimal luminal diameter in lesion (defined as the in-stent segment plus proximal and distal 5-mm edge segments) and in stent (without adjacent edge segment). Late loss (defined as the reduction in minimum luminal diameter from immediately after the procedure to 6-month follow-up), acute gain (defined as the increase in minimal luminal diameter immediately after percutaneous transluminal coronary angioplasty), net gain (the difference between acute gain and late loss), and loss index (the ratio of late loss to acute gain) were calculated. Study end points and definitions: The primary end point of the study was survival at 12 months free of MACEs. Secondary end points were survival free of need for revascularization of the target lesion because of narrowing of the lumen in the presence of symptoms or objective signs of ischemia and angiographic restenosis (in-segment stenosis ⬎50% on follow-up angiography). Patients were categorized into 3 groups: those with (1) no MS and no DM, (2) MS and no DM, and (3) DM with or without MS. The presence of MS was analyzed considering the presence of the following criteria: (1) hypertension, defined as blood pressure ⱖ130/85 mm Hg or taking antihypertensive medication; (2) fasting glucose ⱖ110 mg/dl; (3) reduced high-density lipoprotein (HDL) cholesterol (⬍40 mg/dl in men, ⬍50 mg/dl in women) or pharmacologic treatment for reduced HDL cholesterol; (4) a fasting triglyceride level ⱖ1.7 mmol/L (150 mg/dl) or pharmacologic treatment for hypertriglyceridemia; and (5) central obesity (body mass index ⬎28.8 kg/m2). A body mass index ⬎28.8 kg/m2 was used as substitute for a waist circumference ⱖ102 cm in men or ⱖ88 cm in women, as shown in a
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Table 2 Angiographic and procedure-related characteristics Variable
No MS, No DM (n ⫽ 390)
MS, No DM (n ⫽ 180)
DM (n ⫽ 164)
p Value
230 (59%) 94 (24%) 66 (17%)
102 (57%) 47 (26%) 31 (17%)
93 (57%) 46 (28%) 25 (15%)
0.823 0.610 0.862
12.6 ⫾ 7.5 2.68 ⫾ 0.60 1.04 ⫾ 0.52 16.4 ⫾ 8.2 2.81 ⫾ 0.45 14.5 ⫾ 2.1 12 (9%) 148 (38%)
12.9 ⫾ 7.8 2.72 ⫾ 0.66 0.96 ⫾ 0.59 16.0 ⫾ 6.1 2.82 ⫾ 0.44 14.7 ⫾ 2.2 8 (9%) 76 (42%)
12.9 ⫾ 6.1 2.63 ⫾ 0.60 0.97 ⫾ 0.47 16.4 ⫾ 6.8 2.79 ⫾ 0.43 14.7 ⫾ 2.6 5 (6%) 75 (46%)
0.918 0.102 0.108 0.852 0.185 0.243 0.824 0.219
2.71 ⫾ 0.62 2.52 ⫾ 0.43 2.38 ⫾ 0.46
2.74 ⫾ 0.63 2.52 ⫾ 0.44 2.39 ⫾ 0.48
2.70 ⫾ 0.59 2.46 ⫾ 0.45 2.32 ⫾ 0.41
0.311 0.273 0.265
Coronary pathology Left anterior descending Right Left circumflex Before intervention Lesion length (mm) Reference luminal diameter (mm) Minimal luminal diameter (mm) Stent length (mm) Stent diameter (mm) Implantation pressure (atm) Multistent placement Drug-eluting stent placement After intervention Reference luminal diameter (mm) Minimal luminal diameter in stent (mm) Minimal luminal diameter in lesion (mm)
Table 3 Clinical follow-up at 12 months Variable
Myocardial infarction (%) Mortality (%) Target lesion revascularization (%) Stent thrombosis (%) MACE (%)
BMS
SES
No MS, No DM (n ⫽ 242)
MS, No DM (n ⫽ 102)
DM (n ⫽ 93)
No MS, No DM (n ⫽ 148)
MS, No DM (n ⫽ 78)
DM (n ⫽ 71)
10 (4) 5 (2) 29 (12) 3 (1) 34 (14)
4 (4) 2 (2) 14 (14) 2 (2) 18 (18)
5 (5) 4 (4) 23 (25) 3 (3) 31 (33)*
0 (0) 3 (2) 1 (1) 1 (1) 4 (3)
2 (3) 3 (4) 1 (1) 0 (0) 5 (4)
1 (1) 5 (7) 5 (7)† 2 (3) 10 (13)‡
* p ⫽ 0.046 among all groups, p ⬍0.001 between patients without MS or DM and those with DM; † p ⫽ 0.036 among all groups, p ⫽ 0.024 between patients without MS or DM and those with DM; ‡ p ⫽ 0.034 among all groups, p ⫽ 0.004 between patients without MS or DM and those with DM.
study of Scottish men2 and in the Women’s Health Study.3 Patients were considered to have MS in the presence of ⱖ3 of these criteria, according to the definition proposed by the American Heart Association in conjunction with the National Heart, Lung, and Blood Institute.4 DM was defined as fasting glucose ⱖ126 mg/dl. Statistical analysis: Statistical analysis was performed using SPSS version 12.0 (SPSS, Inc., Chicago, Illinois). Categorical data were compared using Pearson’s chisquare test and are presented as frequencies. Continuous data were compared using Student’s t test or analysis of variance as adequate and are presented as mean ⫾ SD. Post hoc analysis (with Bonferroni’s correction) was performed for multiple comparisons. Cox proportional-hazards regression analysis was performed to identify predictors of target lesion revascularization and MACEs after the use of BMS or SES. Included variables were reference vessel diameter, lesion length, minimal luminal diameter before intervention, minimal luminal diameter after intervention, age, DM, MS, and stent type (BMS or SES). To consider the different follow-up periods for BMS and SES patients, Kaplan-Meier curves for freedom from MACEs were analyzed only up to 18 months after intervention. The impact of DM and MS on freedom from
Figure 1. MACE rates during an 18-month follow-up period in patients without DM or MS (solid line), patients with MS and no DM (dashed line), and patients with DM (dotted line). Event curves for patients treated with a SES are gray, and event curves for patients treated with BMS are black.
MACEs during the follow-up period was evaluated with the log-rank test. A p value ⬍0.05 was considered statistically significant.
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Table 4 Results of follow-up angiography BMS
Minimal luminal diameter in lesion (mm) Diameter stenosis (%) Late loss (mm) Restenosis
SES
No MS, No DM (n ⫽ 194)
MS, No DM (n ⫽ 77)
DM (n ⫽ 63)
No MS, No DM (n ⫽ 58)
MS, No DM (n ⫽ 40)
DM (n ⫽ 34)
1.82 ⫾ 0.63 32 ⫾ 16 0.69 ⫾ 0.61 35 (18%)
1.84 ⫾ 0.66 32 ⫾ 18 0.72 ⫾ 0.59 17 (22%)
1.54 ⫾ 0.62 38 ⫾ 19 1.03 ⫾ 0.63 21 (33%)
2.17 ⫾ 0.53 17 ⫾ 10 0.10 ⫾ 0.33 0 (0%)
2.19 ⫾ 0.53 18 ⫾ 12 0.10 ⫾ 0.20 1 (2%)
1.95 ⫾ 0.73 26 ⫾ 14 0.36 ⫾ 0.66* 4 (12%)†
* p ⫽ 0.009 among all groups, p ⬍0.001 between patients without MS or DM and those with DM; † p ⫽ 0.045 among all groups, p ⫽ 0.047 between patients without MS or DM and those with DM.
Results One hundred sixty-four patients (22%) had DM, 180 patients (25%) had MS and no DM, and 390 patients (53%) had no MS and no DM. In patients treated with BMS, 93 had DM, 102 had MS, and 242 had neither MS nor DM. In patients treated with SES, 71 had DM, 78 had MS, and 148 had no DM and no MS. Baseline clinical characteristics are listed in Table 1. Patients with MS more frequently had hypertension, low HDL, hypertriglyceridemia, obesity, elevated fasting glucose, and histories of myocardial infarctions than patients without DM or MS. Diabetic patients were older than those in the other 2 groups. Lesion characteristics for each of the 3 patient subgroups are listed in Table 2. Baseline angiographic parameters were comparable in all 3 groups with regard to lesion length, reference vessel diameter, minimal lesion diameter, and lesion location. Procedural characteristics: Procedural data are listed in Table 2. There were no differences among the 3 groups with regard to stent length, stent diameter, the use of multiple stents, and the number of stents per lesion. There was a slight trend toward the use of more SES in patients with MS or DM. Clinical results: Clinical follow-up at 12 months was obtained in all patients. Clinical event rates at 12 months are listed separately for patients with BMS and SES implantation in Table 3. After BMS implantation, MACE rates during 12-month follow-up were significantly higher for patients with DM than for patients with MS or patients without DM and without MS. Similarly, after SES implantation, MACE rates during 12-month follow-up were significantly higher for patients with DM than for the other 2 patient groups and comparable for patients with MS and patients without MS or DM. Thus, the impact of MS on MACEs was similar with BMS and SES. Figure 1 shows MACE rates for the different patient groups during follow-up. In the BMS patients, MACE rates were in particular driven by target lesion revascularization. Stent thrombosis rates tended to be higher in patients with DM compared with the other 2 patient groups after BMS and SES implantation (Table 3). Target lesion revascularization rates for the 3 patient groups after BMS and SES implantation are listed in Table 3. There was a strong trend toward higher target lesion revascularization rates for patients with DM after BMS implantation. After SES implantation, target lesion
revascularization rates were significantly higher in patients with DM than in the other 2 groups. The frequencies of myocardial infarction and death were not different among the 3 groups considering BMS and SES. The MACE rate in patients with DM and/or MS was significantly higher than in patients without MS and without DM, in BMS patients (25% vs 14%, p ⫽ 0.005), and in SES patients (10% vs 3%, p ⫽ 0.021). Among the 164 patients with DM, 92 had DM and MS and 72 had DM but no MS. Twenty-five patients with DM and MS (27%) and 16 patients with DM but no MS (22%) developed MACEs during follow-up (p ⫽ 0.588). Predictors of MACEs and target lesion revascularization: DM, the implantation of a BMS, and minimal luminal diameter after stent implantation were univariate predictors of MACEs during the total follow-up period. In the multivariate analysis, only DM (odds ratio [OR] 2.14, 95% confidence interval [CI] 1.48 to 3.07, p ⬍0.001) and the implantation of a BMS (OR 2.51, 95% CI 1.49 to 4.22, p ⬍0.001) remained independent predictors of MACEs during the total follow-up period. In contrast, MS was not a predictor of MACEs. Similarly, DM, the implantation of a BMS, lesion length, and minimal luminal diameter before intervention and after stent implantation were univariate predictors of target lesion revascularization during 12-month followup. DM (OR 1.93, 95% 1.13 to 3.36, p ⫽ 0.017), the implantation of a BMS (OR 2.98, 95% CI 1.82 to 4.95, p ⬍0.001), lesion length (OR 1.04, 95% CI 1.01 to 1.06, p ⫽ 0.010), and minimal luminal diameter after intervention (OR 0.41, 95% CI 0.20 to 0.82, p ⫽ 0.010) remained independent predictors of target lesion revascularization at 12-month follow-up, whereas MS was not a predictor of target lesion revascularization. Considering only the diabetic patients, fasting glucose level was found in a univariate logistic regression analysis to be a significant predictor of MACEs during follow-up (OR 1.002, 95% CI 1.001 to 1.004, p ⫽ 0.042). Angiographic results: Six-month follow-up angiography was performed in 334 patients after BMS placement and in 135 patients after SES placement (Table 4). The frequency of repeat angiography was similar for patients with DM, those with MS, and those without DM and MS. The results of angiographic follow-up are listed in Table 4. In-lesion late loss and restenosis rate tended to be higher in patients with DM after BMS implantation. There was no
Coronary Artery Disease/Coronary Intervention in Metabolic Syndrome
difference in BMS patients between those without DM or MS and those with MS (Table 4). In the SES patients, at angiographic follow-up, in-lesion late loss was 0.10 ⫾ 0.33 mm in the group with no MS and no DM, 0.10 ⫾ 0.20 mm in the group with MS but no DM, and 0.36 ⫾ 0.66 mm in the group with DM (analysis of variance p ⫽ 0.009). The binary in-lesion restenosis rate was higher in patients with DM than in nondiabetic patients. There was no difference in restenosis rate between patients without MS and those with MS (Table 4). Discussion The major findings of this study were that (1) MS without DM had no impact on angiographic restenosis and clinical events during a follow-up period of 1 year after the use of BMS and SES; (2) the relative risks for target lesion revascularization and MACEs were similarly decreased in all patient groups using SES compared with BMS; and (3) DM and BMS implantation are predictors of target lesion revascularization and MACEs during 12-month follow-up, whereas MS is not predictive. DM has been shown to be a major risk factor for CAD and restenosis after the implantation of coronary stents.5–11 Scheen et al11 showed in a meta-analysis that DM is equivocally associated with a twofold risk for restenosis after BMS and drug-eluting stent implantation. Similarly, DM was a significant predictor of MACEs in the RapamycinEluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry of drug-eluting stent use in the real world (OR 1.62, 95% CI 1.09 to 2.43, p ⫽ 0.02), especially because of clinically driven target vessel revascularization (OR 1.81, 95% CI 1.10 to 2.99, p ⫽ 0.02).12 The impact of noninsulin-dependent DM in contrast to insulin-dependent DM on restenosis after coronary stent placement is less well defined. Abizaid et al6 demonstrated for BMS that patients with noninsulin-dependent DM had almost identical restenosis rates compared with nondiabetic patients, whereas insulin-dependent DM was associated with increased clinical and angiographic restenosis rates. In contrast, similarly increased luminal loss was reported after the implantation of paclitaxel-eluting stents in insulin- and noninsulin–requiring diabetic patients (0.44 ⫾ 0.46 and 0.41 ⫾ 0.20 mm, respectively).13 Patients with MS but without DM were found to have clinical restenosis and overall event rates similar to those of control patients without DM and MS in the BMS group and in the SES group. Patients with DM had significantly higher clinical restenosis and overall MACE rates. This finding indicates that the MS alone has a different impact on the proliferative response to stent implantation than DM. The major stimulus for increased intimal hyperplasia in diabetic patients may be hyperinsulinemia, as supported by the findings of several studies.7,14 –16 Consistent with the finding of hyperinsulinemia being a major stimulus for intimal hyperplasia, elevations of hemoglobin A1c and fasting glucose levels have been shown to relate to an increased risk for death and target vessel revascularization in undiagnosed diabetics who undergo percutaneous coronary intervention.17,18 The negative impact of impaired glucose tolerance has also been confirmed in intravascular ultrasound studies
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showing increased neointimal tissue proliferation after BMS implantation.16 Although an increased fasting glucose level may be a precursor of DM, it is only 1 of the components by which MS is defined. Iribarren et al19 reported fasting glucose levels ⬎110 mg/dl in 31% of patients defined to have MS. In this study, 43% of patients presented with elevated fasting glucose levels. The moderate rate of patients with increased fasting glucose levels is likely to go along with a moderate rate of hyperinsulinemia. Thus, most patients did not have hyperinsulinemia as a stimulus for intimal hyperplasia. In most patients, MS was defined by the presence of the other 4 components: obesity, hypertriglyceridemia, decreased HDL level, and increased blood pressure. However, these risk factors are likely not to have a stimulating effect on smooth muscle cell proliferation. The results of this study support those in a previous report by Rana et al,20 who did not observe an association between risk for target vessel revascularization and the presence of MS after BMS implantation. This study confirms these findings in a larger patient group and extends previous observations to patients treated with SES. Interestingly, neither MS nor any of the 5 components of the definition of MS were predictive of target lesion revascularization or MACE during follow-up. Only DM was predictive. We used body mass index as substitute for waist circumference to define obesity. This approach was found to be adequate, because body mass index is strongly related to waist circumference and predicts the development of DM and other metabolic disturbances as strongly as waist circumference, as shown in several studies.2,10,21,22 Only in a limited number of patients was angiographic follow-up performed. This particularly affected patients after SES implantation, whereas follow-up was more complete after BMS implantation. The overall higher angiographic follow-up rate after BMS implantation might have contributed to a considerably higher level of target lesion revascularization rate in the BMS patients. However, it is unlikely that the impact in patients with MS compared with control patients would have been different if a larger number of patients had obtained angiographic follow-up. Intravascular ultrasound imaging would have allowed a more precise analysis of potential differences in intimal hyperplasia among the 3 study groups. However, the near equivalence of clinical and angiographic restenosis rates between control patients and patients with MS but no DM almost excludes significant differences in intimal hyperplasia. Follow-up periods after BMS and SES implantation were different. However, the primary analysis focused on 1-year follow-up, which was available for all patients, and Cox proportional-hazards regression analysis to define predictors of MACEs and target lesion revascularization accounted for different follow-up periods. 1. Marroquin OC, Kip KE, Kelley DE, Johnson BD, Shaw LJ, Bairey Merz CN, Sharaf BL, Pepine CJ, Sopko G, Reis SE. Metabolic syndrome modifies the cardiovascular risk associated with angiographic coronary artery disease in women: a report from the Women’s Ischemia Syndrome Evaluation. Circulation 2004;109:714 –721. 2. Lean ME, Han TS, Morrison CE. Waist circumference as a measure for indicating need for weight management. BMJ 1995;311:158 –161.
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3. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14719 initially healthy American women. Circulation 2003;107:391–397. 4. Grundy SM, Cleeman JI, Daniels SR. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 2005;112:2735–2752. 5. Gilbert J, Raboud J, Zinman B. Meta-analysis of the effect of diabetes on restenosis rates among patients receiving coronary angioplasty stenting. Diabetes Care 2004;27:990 –994. 6. Abizaid A, Kornowski R, Mintz GS, Hong MK, Abizaid AS, Mehran R, Pichard AD, Kent KM, Satler LF, Wu H, et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol 1998;32:584 –589. 7. West NEJ, Ruygrok PN, Disco CMC, Webster MWI, Lindeboom WK, O’Neill WW, Mercado NF, Serruys PW. Clinical and angiographic predictors of restenosis after stent deployment in diabetic patients. Circulation 2004;109:867– 873. 8. Takagi T, Yoshida K, Akasaka T, Kaji S, Kawamoto T, Honda Y, Yamamuro A, Hozumi T, Moioka S. Hyperinsulinemia during oral glucose tolerance test is associated with increased neointimal tissue proliferation after coronary stent implantation in nondiabetic patients. J Am Coll Cardiol 2002;36:731–738. 9. Hong SJ, Kim MH, Ahn TH, Ahn YK, Bae JH, Shim WJ, Ro YM, Lim DS. Multiple predictors of coronary restenosis after drug-eluting stent implantation in diabetic patients. Heart 2006;92:1119 –1124. 10. Moussa I, Leon MB, Baim DS. Impact of sirolimus eluting stents on outcome in diabetic patients. A SIRIUS (Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients With De Novo Coronary Artery Lesions) substudy. Circulation 2004;109: 2273–2278. 11. Scheen AJ, Warze’e F, Legrand VMG. Drug-eluting stents: metaanalysis in diabetic patients. Eur Heart J 2004;25:2167–2168. 12. Lemos PA, Serruys PW, van Domburg RT. Unrestricted utilization of sirolimus-eluting stents compared with conventional bare stent implantation in the “real world.” The Rapamycin Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry. Circulation 2004;109:190 –195. 13. Dibra A, Kastrati A, Mehilli J, Pache J, Schuhlen H, von Beckerath N, Ulm K, Wessely R, Dirschinger J, Schomig A; ISAR-DIABETES Study Investigators. Paclitaxel-eluting or sirolimus-eluting stents to
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prevent restenosis in diabetic patients. N Engl J Med 2005;353: 663– 670. Piatti PM, Di Mario C, Monti L, Fragasso G, Sgura F, Caumo A, Setola E, Lucotti P, Galluccio E, Ronchi C, et al. Association of insulin resistance, hyperleptinemia and impaired nitric oxide release with in-stent restenosis in patients undergoing coronary stenting. Circulation 2003;108:2074 –2081. Radke PW, Voswinkel M, Reith M, Kaiser A, Haager PK, Hanrath P, Hoffmann R. Relation of fasting insulin plasma levels to restenosis after elective coronary stent implantation in patients without diabetes mellitus. Am J Cardiol 2004;93:639 – 641. Takagi T, Akasaka T, Yamamuro A, Honda Y, Hozumi T, Morioka S, Yoshida K. Impact of insulin resistance on neointimal tissue proliferation after coronary stent implantation: intravascular ultrasound studies. J Diabetes Complications 2002;16:50 –55. Muhlestein JB, Anderson JL, Horne BD, Lavasani F, Allen Maycock CA, Bair TL, Pearson RR, Carlquist JF; Intermountain Heart Collaborative Study Group. Effect of fasting glucose levels on mortality rate in patients with and without diabetes mellitus and coronary artery disease undergoing percutaneous coronary intervention. Am Heart J 2003;146:351–358. Corpus RA, O’Neill WW, Dixon SR, Timmis GC, Devlin WH. Relation of hemoglobin A1c to rate of MACEs in nondiabetic patients undergoing percutaneous coronary revascularization. Am J Cardiol 2003;92:1282–1286. Iribarren C, Go AS, Husson G, Sidney S, Fair JM, Quertermous T, Hlatky MA, Fortmann SP. Metabolic syndrome and early-onset coronary artery disease. J Am Coll Cardiol 2006;48:1800 –1807. Rana JS, Monraats PS, Zwinderman AH, de Maat MPM, Kastelein JJP, Doevendans PAF, de Winter RJ, Tio RA, Frants RR, van der Laarse A, et al. Metabolic syndrome and risk of restenosis in patients undergoing percutaneous coronary intervention. Diabetes Care 2005; 28:873– 877. Freeman DJ, Norrie J, Caslake MJ, Gaw A, Ford I, Lowe GD, O’Reilly DS, Packard CJ, Sattar N; West of Scotland Coronary Prevention Study. C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes 2002;51:1596 –1600. Han TS, Williams K, Sattar N, Hunt KJ, Lean ME, Haffner SM. Analysis of obesity and hyperinsulinemia in the development of metabolic syndrome: San Antonio Heart Study. Obes Res 2002;10: 923–931.