Long-Term Clinical Outcome of Sirolimus-Eluting Stent Implantation in Metabolic Syndrome and Diabetes


Mohammad Almalla, MD, Jörg Schröder, MD, Verena Deserno, MS, Felix Vogt, MD,
Ralf Koos, MD, Karl-Christian Koch, MD, Nikolaus Marx, MD, Rainer Hoffmann, MD

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   ABSTRACT: Background. Patients with metabolic syndrome (MetS) are at increased risk of cardiovascular events. The long-term effectiveness of sirolimus-eluting stents (SES) in patients with MetS and in diabetic patients is not well defined. Methods. 563 consecutive patients with 629 de novo coronary lesions (

J INVASIVE CARDIOL 2010;22:317–321

Key words: diabetes, drugs, metabolic syndrome, restenosis, stent

   Metabolic syndrome (MetS) is rapidly increasing in frequency. Patients with MetS have an increased risk to develop coronary artery disease (CAD) as well as cardiovascular events.1,2 Even patients with MetS but no diabetes proved to have a higher prevalence of CAD, and the combination of both CAD and MetS has been associated with increased cardiovascular risks.3 Diabetes mellitus and insulin resistance have been shown to be strong independent predictors of restenosis after bare-metal stent (BMS) implantation.4–6 Even with the introduction of drug-eluting stents (DES), diabetes has remained a significant predictor of in-stent restenosis.7,8 The impact of MetS on restenosis and long-term clinical outcomes including stent thrombosis (ST) after percutaneous coronary intervention using sirolimus-eluting stents (SES) has not been well defined. Thus, the aim of this study was to examine the impact of MetS on clinical event rates during long-term follow up after implantation of SES.

   This was a single-center study which included consecutive patients treated with the Cypher® SES (Cordis Corp. Miami Lakes, Florida).

   Patients. A total of 563 patients with 629 de novo coronary lesions ( 50%) in a native coronary vessel. Patients were excluded if they had a bifurcation lesion, a left main lesion or an in-stent restenotic lesion. The study was approved by the ethical committee of the University Aachen.

   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 6 months after elective stenting using a SES, and for 9–12 months after stenting for acute coronary syndromes. Glycoprotein IIb/IIIa inhibitors were given at the discretion of the operator. Cypher SES were available in lengths of 8–33 mm and diameters of 2.5–3.5 mm.

   Follow-up protocol. Procedural success was defined as

   Quantitative coronary angiography. Baseline, post-procedural 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 an adjacent edge segment). Late loss was calculated as the reduction in minimal luminal diameter from immediately after the procedure to follow up.

   Study endpoints and definitions. The primary endpoint of the study was survival free of MACE. Secondary endpoints 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, angiographic restenosis (in-segment stenosis > 50% on follow-up angiography) and definite ST (stent thrombosis is angiographically documented as complete occlusion or flow-limiting thrombus of previously successfully treated artery). ST episodes are reported as early events up to 30 days post stent implantation, late events from 30 days to 1 year and very late events more than 1 year post-stent implantation. Patients were categorized into three groups: 1) controls, no MetS and no diabetes; 2) MetS, MetS and no diabetes; and 3) diabetics, diabetes with or without MetS. The presence of MetS was analyzed considering the presence of the following criteria: 1) hypertension, defined as blood pressure of at least 130/85 mmHg or patient taking antihypertensive medication; 2) fasting glucose ≥ 110 mg/dl; 3) reduced high-density lipoprotein (HDL) cholesterol ( 1.7 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 a substitute for a waist circumference ≥ 102 cm in men or ≥ 88 cm in women, as shown in a study of Scottish men and in the Women’s Health Study.9,10 Patients were considered to have MetS in the presence of three or more of these criteria according to the definition proposed by the American Heart Association in conjunction with the National Heart, Lung, and Blood Institute (AHA/NHLBI).11 Diabetes was defined as fasting glucose ≥ 126 mg/dl.

   Statistical analysis. Statistical analysis was performed using SPSS version 12.0 (SPSS, Inc., Chicago, Illinois). Categorical data were compared using Pearson’s chi-square test and are presented as frequencies. Continuous data were compared using the Student’s t-test or analysis of variance as adequate and are presented as mean ± standard deviation. Post hoc analysis (with Bonferroni’s correction) was performed for multiple comparisons. To consider the different follow-up periods for SES patients, Kaplan-Meier curves for freedom from MACEs were analyzed. The impact of diabetes and MetS on freedom from MACE during the follow-up period was evaluated with the log-rank test. A p-value

   A total of 284 patients (51%) with 318 lesions were in the control group, 148 patients (26%) with 163 lesions had MetS and 132 patients (23%) with 148 lesions were diabetics. Baseline clinical characteristics are summarized in Table 1. Patients with MetS were more frequently male and had more frequent hypertension. The diabetics were older than the other patient groups.

   Lesion characteristics for each of the three patient subgroups are shown in Table 2. Baseline angiographic parameters were comparable between the three groups with regard to lesion length, reference vessel diameter, minimal lesion diameter and lesion location.

   Procedural data are provided in Table 2. There were no differences between the three groups with regard to stent length, stent diameter and the number of stents used per lesion.

   Angiographic results. Follow-up angiography was performed for 294 patients with 329 lesions. One-hundred fifty control patients, 76 patients with MetS and 64 diabetics had angiographic follow up (Table 3). The frequency of repeat angiography was similar for the three groups (53.8%, 52.1% and 49.3%, respectively). The clinical and angiographic baseline characteristics of the patients with follow-up angiography were comparable to the total study group. In-lesion late loss was 0.19 ± 0.59 mm in the controls, 0.17 ± 0.44 mm in patients with MetS and 0.46 ± 0.81 mm in diabetics (p

   Clinical follow up. Clinical follow up was obtained in 95% of patients. Clinical event rates are given in Table 4. At follow up, target lesion revascularization (TLR) was required in 7.7% of controls and 5.4% of MetS patients. In contrast, TLR was necessary in 14.5% of diabetics (p = 0.041). Annual TLR rates were 2.2%, 1.6% and 4.9%, respectively (p = 0.038). Mortality rates were 4.2%, 9.4% and 15.3% (p = 0.042), with an annual mortality rate of 1.2%, 3.0% and 5.6%, respectively (p = 0.037). Mortality rates in MetS patients were significantly higher than in the control patients (p = 0.047) (Figure 1). During the follow-up period, total MACE rates for controls, MetS patients and diabetics were 14.1%, 19.5%, and 37.4%, respectively (p = 0.081). Annual MACE rates were 4.1%, 5.9% and 12.6%, respectively (p = 0.067) (Figure 2).
Early definite ST rates for controls, MetS patients and diabetics were 0.3%, 0.6% and 3%, respectively (p = 0.057). Definite late and very late ST were reported only in diabetic patients with a frequency of 1.5% and 1.5%, respectively. During the complete follow up, there were 10 cases with ST, resulting in frequencies of 0.3%, 0.6% and 6.1%, respectively (p = 0.037). Annual ST rates were 0.2%, 0.3% and 2.7%, respectively (p = 0.039) (Tables 4 and 5). Eight cases of ST occurred in diabetics, 1 in a noninsulin-dependent diabetic patient (1.3%) and 7 in insulin-dependent patients (12.0%).


   The major finding of this study is the lack of impact of MetS without diabetes on angiographic restenosis and target lesion-related clinical events during long-term follow up after use of SES. Diabetes mellitus has been shown to be a major risk factor for CAD and restenosis after implantation of coronary stents.4–8,12

   CAD is currently responsible for three-quarters of diabetes-related deaths.13 In a meta-analysis by Scheen et al, diabetes was associated with a high risk of restenosis after BMS and DES implantation.12 In a subanalysis of the SIRIUS study specifically devoted to the impact of diabetes on restenosis, the in-lesion restenosis rate was found to be significantly reduced with DES compared to BMS in the noninsulin-dependent diabetic patients (7.7% vs. 49.3%; p 8

   At 5-year follow up of patients included in the SIRIUS trial, diabetics had a higher frequency of clinical events compared to nondiabetic patients in the BMS and SES groups. Among the SES patients, diabetics had more frequent cardiac death than nondiabetic patients (9.9% vs. 4.2%; p = 0.0045).14 The impact of noninsulin-dependent versus insulin-dependent diabetes on restenosis after coronary stent implantation is less well defined. Abizaid et al demonstrated for BMS that insulin-dependent diabetes was associated with increased clinical and angiographic restenosis rates, while noninsulin-dependent diabetes had almost identical restenosis rates compared to nondiabetic patients.5 In contrast, Dibra et al reported for insulin- and noninsulin-requiring diabetics similar lumen loss measurements of 0.44 ± 0.46 and 0.41 ± 0.20 mm, respectively, after implantation of paclitaxel-eluting stents (PES).15 An increased proliferation of smooth muscle cells after stent implantation resulting in increased growth of neointimal tissue and restenosis rates has been described in diabetics. This mechanism does not seem to be effective in patients with MetS.

   ST is a dramatic clinical event associated with MI and frequent mortality. Recent publications including long-term follow up of trials and registries, as well as some meta-analyses, have indicated that DES are associated with increased rates of very late ST (after 1 year) compared with BMS.16–18 In this study, ST rates were significantly higher in diabetics compared to nondiabetic patients. Patients with MetS had no increase in ST rates.

   The Multicenter Spanish Registry ESTROFA19 was designed to assess the incidence, predictors and outcome of DES thrombosis (angiographically documented) in real-world clinical practice with 3 years of follow up. In a total of 23,500 patients treated with DES, the cumulative incidence of ST was 2% at 3 years. Antiplatelet treatment had been discontinued in 95 cases (31.6%) of ST. No differences in incidence were found among stent types.
Independent predictors for subacute ST analyzed in a subgroup of 14,120 cases were diabetes, renal failure, acute coronary syndrome, ST-elevation MI (STEMI), stent length and left anterior descending artery stenting, while predictors for late ST were STEMI, stenting in the left anterior descending artery and stent length. Daemen and colleagues20 performed a large multicenter cohort study assessing all angiographically documented ST after unrestricted use of SES and PES in 8,146 patients between 2002 and 2005. Their aim was to estimate the incidence and time course of ST with DES in routine clinical practice, to identify predictors of ST and differences between early ( 30 days) ST. They observed angiographically documented ST in 152 patients (cumulative incidence at 3 years 2.9%). Incidence of early ST was 1.2%. Late ST occurred steadily at a constant rate of 0.6% per year up to 3 years after stent implantation. At the time of ST, dual antiplatelet therapy was taken by 87% of early ST and 23% of late ST patients (p

   The increased risk of ST in diabetic patients may be related to the proinflammatory and prothrombotic status typical of this population, along with the more diffuse and aggressive nature of their atherosclerosis.21–24 The nonresponsiveness to antiplatelet therapy also has a role: diabetics have been considered less responsive to the cardioprotective effects of aspirin and clopidogrel.25 Patients with ST have high in vitro post-treatment platelet reactivity despite the dual antiplatelet treatment, suggesting that platelet aggregation nonresponsiveness to clopidogrel may be an important cause.26

   Buonamici and colleagues27 assessed whether nonresponsiveness to clopidogrel as revealed by high in vitro post-treatment platelet reactivity was predictive of DES thrombosis. In their interesting work, a total of 804 patients who had successful SES or PES implantation were assessed for post-treatment platelet reactivity after a loading dose of 600 mg of clopidogrel. Patients with platelet aggregation by 10 µmol adenosine 5-diphosphate > 70% were defined as nonresponders. All patients received dual-antiplatelet treatment (aspirin 325 mg and clopidogrel 75 mg daily) for 6 months. The primary endpoint was the incidence of definite/probable early, subacute and late ST at 6-month follow up. The incidence of 6-month definite/probable ST was 3.1%. All cases of ST were subacute or late. Of 804 patients, 105 (13%) were not responsive to clopidogrel. The incidence of ST was 8.6% in nonresponders and 2.3% in responders (p

   Study limitations. The study was not randomized and angiographic follow-up data were not obtained in all patients. However, the reduced angiographic follow-up rates are a result of systematic high follow-up rates during the start of the study and subsequent low rates. Thus, the findings are less likely affected by follow-up bias effects. Intravascular ultrasound imaging would have allowed better analysis of potential differences in intimal hyperplasia between the three groups. However, the near-equivalence of clinical and angiographic restenosis rates between the controls and patients with MetS almost excludes significant differences in intimal hyperplasia between these two groups. We used body mass index as a substitute for waist circumference to define obesity. This was found to be adequate, as body mass is strongly related to waist circumference and predicts diabetes development and other metabolic disturbances as strongly as waist circumference.9,10,28,29 We did not distinguish between diabetics with and without MetS. The distinction was abandoned in order to prevent too small patient numbers in the resulting groups.

   MetS without diabetes is not associated with increased target lesion revascularization or ST rates during long-term follow up after SES implantation. However, patients with MetS have a higher follow-up mortality rate compared to control patients. Annual event rates during long-term follow up including ST rates are significantly higher in diabetics as compared to nondiabetic patients.

From the Medical Clinic I, University RWTH Aachen, Aachen, Germany. The authors report no conflicts of interest regarding the content herein. Manuscript submitted February 26, 2010, provisional acceptance given
March 18, 2010, final version accepted April 8, 2010. Address for correspondence: Rainer Hoffmann, MD, Medical Clinic I, University RWTH Aachen, Pauwelsstraße 30, 52057 Aachen, Germany. E-mail: RHoffmann@ukaachen.de


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