The Prognostic Significance of Carotid Intima-Media Thickness in Patients Who Underwent Percutaneous Coronary Intervention

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1 Original ORIGINAL Article ARTICLE Korean Circulation J 2007;37: ISSN c 2007, The Korean Society of Circulation The Prognostic Significance of Carotid Intima-Media Thickness in Patients Who Underwent Percutaneous Coronary Intervention Taek-Geun Kwon, MD, Ki-Hong Kim, MD, Hyun-Ju Yoon, MD, Dae-Woo Hyun, MD and Jang-Ho Bae, MD Cardiology Division, Heart Center, Konyang University Hospital, Deajeon, Korea ABSTRACT Background and Objectives:Increased carotid intima-media thickness (IMT) is known to be associated with adverse cardiovascular events in the patients with risk factors or established atherosclerosis. However, the prognostic importance of carotid IMT is uncertain in the patients who underwent percutaneous coronary intervention (PCI). We sought to evaluate the association of carotid IMT with major adverse cardiovascular events (MACE) and restenosis in the patients who underwent PCI. Subjects and Methods:The study population consisted of 308 consecutive patients who underwent PCI, and they were followed up for mean of 30.6±13.3 months. Base on the median values of carotid IMT, which was measured in the right common carotid artery at the time of PCI with using high-resolution ultrasound and a semiautomatic method, the subjects were divided into the thick (n=156, 1.003±0.14 mm) and thin IMT (n=152, 0.748±0.07 mm) groups, and they were followed up for at least 1 year. Results:Patients with thick carotid IMT were older (61±9 years vs. 57±10 years, respectively, p=0.001), had a higher body mass index (25.0±3.0 vs. 23.9±4.0, respectively, p=0.017), a history of previous myocardial infarction (20% vs. 9%, respectively, p=0.008), more multivessel disease and more restenosis (34.6% vs. 23.0%, respectively, p=0.025) than those patients with a thin carotid IMT. However other MACEs such as death, myocardial infarction, stroke, heart failure and target lesion revascularization did not show any significant differences between the two groups. Multivariate Cox regression analysis showed that carotid IMT was an independent predictor of restenosis (odds ratio: 1.754, 95% confidence interval: to 2.726, p=0.012). Conclusion:An increased carotid IMT is associated with restenosis, but it does not have clinical prognostic importance for the patients who underwent PCI during a mean follow up period of 31 months. (Korean Circulation J 2007;37: ) KEY WORDS:Carotid arteres;angioplasty, transluminal, percutaneous coronary;prognosis. Introduction The carotid intima-media thickness(imt) is increased in patients who are at risk for cardiovascular disease and in those patients with atherosclerotic disease such as coronary artery disease(cad), and IMT is well known as a noninvasive surrogate marker of atherosclerosis. 1-8) Carotid IMT has also been reported to be associated with the extent or severity of CAD. 9-12) Furthermore, O Leary et al. 13) reported that an increased carotid IMT is associated with a higher risk of stroke and acute myocardial infarction(ami) in an elderly population and it Received:January 9, 2007 Accepted:February 21, 2007 Correspondence:Jang-Ho Bae, MD, Cardiology Division, Heart Center, Konyang University Hospital, 685 Gasoowon-dong, Seo-gu, Daejeon , Korea Tel: , Fax: janghobae@yahoo.co.kr is also a more powerful predictor of cardiovascular disease than the conventional risk factors for atherosclerosis. The Framingham heart study showed that carotid IMT is independently associated with the 10-year coronary heart disease risk, which supports its usefulness as a prognostic marker. 14) However, the prognostic significance of carotid IMT in patients underwent percutaneous coronary intervention (PCI) has not been reported. The aim of this study was to evaluate the association of carotid IMT with major adverse cardiovascular events(mace) and restenosis in the patients underwent PCI. Methods Study population We enrolled a total of 308 consecutive patients who underwent PCI at the catheterization laboratory at Konyang University Hospital, Daejeon, Korean, from

2 104 Korean Circulation J 2007;37: March 2002 to 3 December All the patients had their carotid IMT measured at the time of PCI. The baseline demographic, clinical and angiographic characteristics were gathered by trained research technicians. Informed consent was obtained from all the participating patients. Those patients who were hemodynamically unstable, and those with life-threatening malignancy, other severe combined disease or poor quality of their carotid image, those lost to follow up or those who refused study procedures were excluded. The study protocol was approved by the hospital ethics committee. Carotid artery scanning Carotid artery scanning was performed with a highresolution ultrasonographic unit(hewlett-packard Sonos- 5500), equipped with a 7.5 MHz linear array transducer, and with the subjects in the supine position. An ECG signal was synchronized to the end of diastole for image analysis. All ultrasonographic examinations were performed by one specially trained technician, who was unaware of the study subjects clinical information. The carotid artery IMT was defined as the distance from the leading edge of the lumen-intima interface to the leading edge of the media-adventitia interface of the far wall. The IMT was measured in a 10 mm long segment just proximal to the carotid bulb in the common carotid artery with using a semi-automatic technique with MATH software(version 2.01, METRIS Co., Argenteuil, France). This computerized detection technique is 4 times more precise than ordinary calliper measurements for determining the carotid IMT. 15) Percutaneous coronary intervention Patients were premedicated with aspirin(at least 100 mg) and unfractionated heparin(5,000 to 10,000 IU). A loading dose of 300mg clopidogrel was administered before PCI. Coronary angiography(cag) was performed through the femoral or radial artery by using standard technique. Stent implantation was performed if the residual stenosis was over 50% after balloon angioplasty. Bare metal stents were mostly implanted(78.9%) during this study period(table 1). Angiographically successful results were achieved in all the patients without any significant complications in the catheterization room such as hypotension requiring intraaortic balloon pumping, myocardial infarction, loss of a side branch, stroke and death. Follow-up Clinical follow-up was performed for at least 1 year (mean: 30.6±13.3 months) and follow-up CAG was planned at 6 months. Combined antiplatelet therapy included daily administration of aspirin(100 mg) and clopidogrel(75 mg). Dual antiplatelet therapy was recommended for at least 6 months for the patients with bare metal stent and for at least 1 year for the patients with drug eluting stent. Adverse events were documented by making phone calls to the patients and by reviewing the hospital records. MACEs were defined as death from cardiovascular events, AMI, stroke, target lesion revascularization and hospitalization with congestive heart failure(chf). The definition of AMI included two of the following three criteria; prolonged chest pain of more than 20 minutes, elevation of cardiac enzymes(ck, CK-MB or the relative index) more than 2 times the normal levels and ST-T wave changes or new Q waves on serial ECGs that were indicative of myocardial damage. Stroke was Table 1. Characteristics of the patients Thin carotid IMT ( 0.84 mm, n=152) Thick carotid IMT (>0.84 mm, n=156) Age (years) 57.5± ± Men 198 (65%) 105 (67%) BMI (kg/m 2 ) 23.9± ± Previous MI 114 (09%) 131 (20%) Risk factors Hypertension 182 (54%) 185 (55%) Diabetes mellitus 138 (25%) 152 (33%) Dyslipidemia 145 (30%) 151 (33%) Smoker, current 151 (34%) 166 (42%) Lipid analysis Total cholesterol 185± ± Triglyceride 187± ± HDL cholesterol 40.5± ± LDL cholesterol 104± ± Carotid IMT (mm) 0.748± ±0.140 <0.001 Diagnosis Stable angina 181 (53.3%) 187 (55.8%) Unstable angina 129 (19.1%) 123 (14.7%) Acute MI 142 (27.6%) 146 (29.5%) Ejection fraction 61.3± ± Angiographic findings Mutivessel disease 165 (42.8%) 94 (60.3%) Angioplasty Balloon only 117 (14.6%) 119 (15.8%) Bare metal stent 126 (82.9%) 117 (75%).1 Drug eluting stent 119 (12.5%) 130 (19.2%) Medications ACE inhibitor 187 (57.2%) 192 (59.0%) Statins 104 (68.4%) 111 (71.2%) Beta-blockers 153 (34.9%) 157 (36.5%) Calcium channel blockers 162 (40.8%) 150 (32.3%) Values are means±sds. IMT: intima-media thickness, BMI: body mass index, MI: myocardial infration, ACE: angiotensin converting enzyme, HDL: high density lipoprotein, LDL: low density lipoprotein p

3 Taek-Geun Kwon, et al:carotid IMT and Prognosis in Patients Who Underwent PCI 105 defined as a loss of neurological function caused by an ischemic event, and this loss persisted for more than 24 hours or it left residual signs, and hospitalization with CHF was defined as new symptoms of CHF or increased symptoms of CHF that required hospitalization. All deaths were considered to have been from cardiac causes unless a noncardiac cause could be identified. Restenosis was defined as stenosis of more than 50% of the luminal diameter on the follow-up CAG. Revascularization of the target lesion was defined as ischemia-driven PCI of the target lesion owing to restenosis or reocclusion within the stent or in the adjacent 5 mm of the distal or proximal segments. Statistical analysis The data is expressed as means±sds or as frequencies (percentages). Patient characteristics between the two groups were compared using the t-test for continuous variables and the chi-square test for categorical variables. Cumulative event rates were calculated according to the Kaplan-Meier method and the log-rank test. Cox regression analyses were performed to determine the variables that were independently associated with restenosis. A p<0.05 was considered statistically significant. All analyses were conducted with the use of statistical software (SPSS for Windows, version 11, SPSS Inc., Chicago, Illinois). Results Patient characteristics The study population consisted of 308 patients(203 males: 65.9%, mean age: 59.3±9.8 years. The carotid IMT ranged from 0.4 to 1.86 mm, with a mean(±sd) of 0.88±0.17 mm and a median of 0.85 mm. Base on the median values of carotid IMT, the subjects were divided into the thick(n=156, 1.003±0.14 mm) and thin IMT(n=152, 0.748±0.07 mm) groups. The patients with thick carotid IMT were older(61.1±9.1 vs. 57.5± 10.1, respectively, p=0.001), they had a higher body mass index(25.0±3.0 vs. 23.9±4.0, respectively, p= 0.017), and a higher prevalence of pervious myocardial infarction(20% vs. 9%, respectively, p=0.008), and multivessel disease(42.8% vs. 60.3%, respectively, p<0.001) than those patients with thin carotid IMT. The other coronary risk factors did not show any significant difference between the two groups. This may be explained as the study population consisted of patients with significant coronary artery disease that needed intervention. The baseline demographics of the study patients are summarized in Table 1. Follow up Clinical follow-up data were obtained from all the patients. During the 12 months of the clinical follow-up period, there was a total of 2 deaths, 5 acute myocardial infarctions, 59 target lesion revascularizations, 16 hospitalizations with CHF and 6 strokes. In all, 88 patients experienced at least one MACE. The Kaplan-Meier survival curve showed no significant difference in MACE (cardiac death, AMI, target lesion revascularization, stroke and hospitalization with CHF) between the two groups (Fig. 1). A total of 270 patients(87.7%) had follow-up CAG performed at a mean 6.0±1.4 months and the remaining 38 patients refused follow-up CAG because there Table 2. Predictors of restenosis by multivariate Cox regression analysis Beta RR 95% CI p Age (years) Male gender Carotid IMT Stent Length Diameter IMT: intima-media thickness, RR: relative risk, CI: confidence interval Cumulative survival Thick IMT Thin IMT Log rank, p= Months Fig. 1. Kaplan-Meier curves for event-free survival showed that MACEs (cardiac death, acute myocardial infarction, target lesion revascularization and stroke) were not associated with carotid intima-media thickness (Thin IMT group; patients whose carotid IMT 0.84 mm, Thick IMT group; patients whose carotid IMT>0.84 mm). MACEs: major adverse cardiovascular events, IMT: intima-media thickness. Event rate (%) Thin IMT Thick IMT Death Stroke AMI CHF TLR Restenosis Fig. 2. Major adverse cardiovascular events were not different between the thick carotid IMT group (carotid IMT>0.84 mm) and the thin carotid IMT group (carotid IMT 0.84 mm), except for restenosis. *: p<0.05. AMI: acute myocardial infarction, CHF: congestive heart failure, TLR: target lesion revascularization, IMT: intima-media thickness. * 14

4 106 Korean Circulation J 2007;37: was no clinical evidence of restenosis. Restenosis was more common in the patients with thick carotid IMT than in the patients with thin carotid IMT(34.6% vs. 23%, respectively, p=0.025)(fig. 2). On multivariate Cox regression analysis, carotid IMT was an independent risk factor of restenosis even after adjustment for age, male gender, and the length and diameter of the stent(odds ratio: 1.754, 95% confidence interval: to 2.726, p=0.012)(table 2). Discussion The present study shows that an increased carotid intima-media thickness in patients who underwent PCI was not related to an increased risk of MACE, but it was related to restenosis. Carotid IMT has been recognized as a surrogate marker of atherosclerosis. It is associated with cardiovascular disease risk factors and CAD, and it is also associated with the outcomes of cardiovascular disease. 1-8) However, the role of carotid IMT in secondary prevention is currently undefined. But the relationship between carotid IMT and future cardiovascular events has been shown by several trials of patients with known coronary heart disease. In the Cholesterol Lowering Atherosclerosis Study trial, the risk of myocardial infarction or coronary death increased not only with increments of the carotid IMT, but also with the rate of progression of the carotid IMT. 16) Therefore, by attenuating the carotid IMT progression in patients with known CAD, therapies directed toward atherosclerosis such as statins, fibrates and niacin would improve the future cardiovascular risk ) In our study, the baseline carotid IMT didn t show any prognostic importance in patients who underwent PCI, except for restenosis. For secondary prevention, statins were prescribed not only to the patients with thick carotid IMT, but also to the patients with thin carotid IMT in our study(table 1). This probably contributed the apparent lack of association of adverse events with the baseline carotid IMT. Another main finding of this study was that carotid IMT is associated with restenosis. The incidence of angiographic restenosis varies from 10% to 50% and it depends on the absence or presence of several risk factors such as female gender, diabetes mellitus and/or unstable angina pectoris. The angiographic risk factors for restenosis are stenosis of a longer length, chronic total occlusions and angiographically identifiable thrombus. Disease in saphenous vein grafts and in small native vessels(<3.0 mm) is associated with higher rates of restenosis. One of the leading predictors of angiographic stenosis after angioplasty is the postprocedural diameter. 24) In our study, restenosis developed in 34.7% of the patients. The relatively high incidence of restenosis is explained that most of patients(78.9%) had bare metal stent implanted. When we analyzed the risk factors for restenosis in the patients with implanted bare metal stent, only carotid IMT was an independent risk factor of in-stent restenosis after adjustment for the length and diameter of the stent. This result suggests that a thick carotid IMT is another risk factor of in-stent restenosis after PCI. Inflammation is associated with in-stent restenosis 25)26) and with carotid IMT ) Although we did not evaluate inflammatory markers in the present study, an association between carotid IMT and in-stent restosis may be related to inflammation. In conclusion, the present study suggests that an increased carotid IMT is independently associated with restenosis, but not with MACE in the patients who underwent PCI. Thus, carotid IMT is useful for predicting in-stent restenosis in the patients who underwent PCI, in addition to its role as a marker of atherosclerosis. Study limitation One year was too short to evaluate the prognostic power of carotid IMT in the patients who undergo PCI; this needs more long-term follow up. We did not measure the carotid IMT on the follow-up study. Measurement of the regression of carotid IMT or attenuation of the carotid IMT progression may be better to evaluate the role of carotid IMT for secondary prevention. The response of carotid IMT to lipid lowering agents must be evaluated in a future study. REFERENCES 1) Bae JH, Seung KB, Jung HO, et al. Analysis of Korean carotid intima-media thickness in Korean healthy subjects and patients with risk factors: Korea multi-center epidemiological study. Korean Circ J 2005;35: ) O Leary DH, Polak JF, Kronmal RA, et al. Thickening of the carotid wall: a marker for atherosclerosis in the elderly? Stroke 1996;27: ) Mannami T, Konishi M, Baba S, Nishi N, Terao A. 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