Comparison of Vascular Remodeling in Patients Treated With Sirolimus-Versus Zotarolimus-Eluting Stent Following Acute Myocardial Infarction

Authors


Abstract

Background:

The differences in the vascular response to stent implantation or in the incidence of late acquired stent malapposition among different types of drug-eluting stents are not well known in patients with acute myocardial infarction (MI).

Hypothesis:

The pattern of vascular remodeling and degree of neointimal proliferation were different depending on the different types of drug-eluting stents.

Methods:

This study used intravascular ultrasound (IVUS) to investigate vascular remodeling in patients treated with implantation of sirolimus-eluting stents (SESs) vs zotarolimus-eluting stents (ZESs) following acute MI. The study population consisted of 100 patients with acute MI who were treated either with SES (n = 41) or ZES (n = 59) and underwent both poststenting and 9-month follow-up IVUS examination. Serial vascular changes surrounding stented segments were compared between SES- and ZES-treated lesions.

Results:

Percentage of neointimal volume obstruction at follow-up was significantly smaller in SES-treated compared to ZES-treated lesions (2.8 ± 7.1% vs 18.1 ± 15.7%, respectively; P < 0.001). However, positive vascular remodeling, which was defined as greater than 10% increase in external elastic membrane volume index (31.7% vs 10.2%, respectively, P = 0.007), and late acquired stent malapposition (12.0% vs 0%, respectively, P = 0.006 ) occurred more frequently in SES-treated than in ZES-treated lesions.

Conclusions:

The pattern of vascular remodeling, including positive remodeling, late acquired stent malapposition, and degree of neointimal proliferation might be different depending on the different types of drug-eluting stents in patients with acute MI. © 2011 Wiley Periodicals, Inc.

Ki-Woon Kang, MD, and Young-Guk Ko, MD, contributed equally to this manuscript.

This study was partly supported by grants of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (No. A085012 and A102064); the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (0412-CR02-0704-0001 and No. A085136); and the Cardiovascular Research Center, Seoul, Republic of Korea. The authors have no other funding, financial relationships, or conflicts of interest to disclose.

Additional supporting information may be found in the online version of this article.

Introduction

Drug-eluting stents (DESs) have shown efficacy in reducing neointimal hyperplasia. The use of DESs is associated with reduced rates of restenosis and target lesion revascularization compared with bare metal stents.1–3 However, wider use of the DES has raised concerns about the safety of DESs because of increased occurrence of stent thrombosis after their implantation.4,5 Although the precise mechanism of stent thrombosis has not been completely understood, impaired endothelial healing, late stent malapposition (LSM), and prothrombotic properties of the DES itself may play a role in the development of stent thrombosis.6,7 Previous studies have shown that positive vascular remodeling is an important mechanism underlying LSM.8,9 Although neointimal hyperplasia has been the main focus of interest after stent implantation, few data have been reported on the vascular responses to stent implantation. Recently, LSM was reported more frequently in patients with ST-segment elevation myocardial infarction (MI) who were treated with paclitaxel-eluting stent compared to bare metal stent.10 However, whether there are differences in the vascular response to stent implantation or in the incidence of LSM among different types of DESs is not well known. The purpose of this study was to compare vascular remodeling between zotarolimus-eluting stent (ZES) (Endeavor Sprint; Medtronic Vascular, Santa Rosa, CA) and sirolimus-eluting stent (SES) (Cypher; Cordis Corporation, Miami Lakes, FL) in patients with acute MI.

Methods

From the acute MI registry database in our institute, we found 244 consecutive acute MI patients who were treated with SES (n = 114) or ZES (n = 130) implantation at infarct-related lesions from March 2007 to November 2008. Exclusion criteria for this study were as follows: old age (>75 years,n = 13), poor renal function (serum creatinine >2.0 mg/dL, n = 6), combined systemic illness or cancer (n = 3), hemodynamically unstable conditions including cardiogenic shock (n = 5) and implantation of ≥2 stents at the infarct-related artery (n = 22). Among the remaining 195 patients, a total of 100 patients (SES,n = 41;ZES,n = 59) who underwent both postintervention and 9-month follow-up intravascular ultrasound (IVUS) were included in this study. Reasons for further exclusion were as follows: patient or physician refusal of follow-up angiogram (n = 49), no postintervention IVUS (n = 41), no follow-up IVUS (n = 2), and loss to clinical follow-up (n = 3). Baseline clinical and angiographic characteristics among the 100 patients included in this study and 95 patients who were not selected for the study are shown in Table 1. There were no statistically significant differences in clinical and angiographic variables between the 2 groups. This study was approved by our institutional review board, and written informed consent was obtained from each patient.

Table 1. Baseline Clinical and Angiographic Characteristics of Included and Excluded Patients
 Excluded, n = 95Included, n = 100P
  1. Abbreviations: MI, myocardial infarction; MLD, minimal lumen diameter.

  2. Data are expressed as number (%) or mean ± standard deviation.

Clinical variables
 Age, y60 ± 962 ± 80.111
 Male67 (70.5)63 (63.0)0.265
 Diabetes mellitus35 (36.8)41 (41.0)0.552
 Hypertension52 (54.7)61 (61.0)0.376
 Hypercholesterolemia46 (48.3)41 (41.0)0.297
 Current smoker34 (35.8)26 (26.0)0.139
 Left ventricular ejection fraction <40%10 (10.5)5 (5.0)0.148
 ST-elevation MI22 (23.2)15 (15.0)0.146
 Non–ST-elevation MI73 (76.8)85 (85.0) 
Angiographic variables
 Target vessel  0.388
 Left anterior descending artery61 (64.2)72 (72.0) 
 Left circumflex artery14 (14.7)9 (9.0) 
 Right coronary artery20 (21.1)19 (19.0) 
 Vessels involved  0.101
 1-vessel56 (58.9)68 (68.0) 
 2-vessel26 (27.4)27 (27.0) 
 3-vessel13 (13.7)5 (5.0) 
 Lesion length, mm21 ± 621 ± 60.191
 Stent diameter, mm3.1 ± 0.33.1 ± 0.30.621
 Stent length, mm24 ± 624 ± 60.163
 Stent implanted  0.104
 Sirolimus-eluting stent50 (52.6)41 (41) 
 Zotarolimus-eluting stent45 (47.4)59 (59) 
 Quantitative coronary angiographic analysis
 Reference vessel size2. 9 ± 0.42.9 ± 0.40.985
 Preintervention MLD, mm0.5 ± 0.10.5 ± 0.20.101
 Postintervention MLD, mm3.0 ± 0.43.0 ± 0.40.774

Methods for dual antiplatelet treatment and stenting procedure were described in the Supplementary material. Postintervention and 9-month follow-up IVUS examinations were performed in the same manner after intracoronary administration of 0.2 mg nitroglycerin using a motorized transducer pullback system (0.5 mm/s) and a commercial scanner (Boston Scientific Corp./SCIMED, Natick, MA) consisting of a rotating 30- or 40-MHz transducer within a 3.2- or 2.6-Fr imaging sheath. Quantitative and qualitative analyses were performed using planimetry software (EchoPlaque; Indec Systems Inc, Santa Clara, CA) by 2 experienced analysts blinded to clinical and procedural data according to criteria of the clinical expert consensus document on IVUS.11 Volumetric analysis at the stented segment included external elastic membrane (EEM) and lumen and stent volumes. Neointima (NI) volume was calculated as stent minus lumen volume, and percentage of NI volume obstruction was calculated as NI volume divided by stent volume. Volume indices (VI) were obtained by dividing volumes by stent length (mm3/mm). Positive or negative vascular remodeling was arbitrarily defined as >10% increase or decrease in EEM VI from the postintervention to follow-up, respectively. Postintervention planar analysis was performed at the stented segments with minimum lumen cross-sectional area and proximal and distal reference segments. Reference segments were defined as the most normal-looking cross-sections within 10 mm proximal and distal to the lesions. Acquired LSM was defined as a separation of at least 1 stent strut from the intimal surface of the arterial wall that was not overlapping a side branch, was not present immediately after stent implantation, and had evidence of blood flow (speckling) behind the strut.8,9 Postintervention incomplete stent apposition (ISA) was classified into 2 groups: (1) resolved ISA, in which incomplete apposition presents after the procedure, but no longer presents at follow-up; and (2) persistent ISA, in which incomplete apposition presents both after the procedure and at follow-up.12

Coronary angiography was performed after the administration of 0.2 mg intracoronary nitroglycerin. Angiographic results were analyzed by 2 independent angiographers. Quantitative coronary angiography analysis was performed using the guiding catheter for magnification-calibration and an offline quantitative coronary angiographic system (CMS; Medis Medical Imaging System, Nuenen, The Netherlands). Minimal luminal diameter (MLD) of treated coronary segments and diameters of the reference segments were measured before and after stenting and at follow-up from diastolic frames in a single, matched view showing the smallest MLD. The in-lesion MLD included the stent as well as 5-mm margins proximal and distal to the stent. The reference vessel diameter was the average of the proximal and distal reference lumen diameters. Angiographic restenosis was defined as a diameter stenosis ≥50% at follow-up. Late loss was calculated as postintervention MLD minus follow-up MLD.

ST-segment elevation MI was defined as the presence of clinical symptoms with ST-segment elevation ≥0.2 mV in 2 or more contiguous leads or new-onset left bundle branch block on electrocardiogram or abnormal imaging findings of MI combined with an increase in creatine kinase-MB fraction or troponin T/troponin I more than the 99th percentile of the upper normal limit that was not related to an interventional procedure. Non–ST-segment elevation MI was defined as MI without ST-segment elevation. Clinical events were defined according to the Academic Research Consortium.13 Major adverse cardiac event is defined as a composite of cardiac death, MI, and target vessel revascularization. All deaths were considered cardiac deaths unless a definite noncardiac cause could be established. Definite, probable, and possible stent thrombosis was defined according to the recommendation of the Academic Research Consortium.

Statistical analysis was performed using the Statistical Analysis System software (SAS 9.1.3.; SAS Institute, Cary, NC). Data are expressed as number (%) or mean ± standard deviation. Categoric data were compared with χ2 statistics or the Fisher exact test. Continuous data were compared using the Student t test. If the distributions were skewed, a nonparametric test was used. Univariate and multivariate logistic regression analyses were performed to determine the risk factors of acquired LSM. Variables with P < 0.2 in the univariate analysis were included in the multivariate analysis. A value of P < 0.05 was considered statistically significant.

Results

Baseline clinical characteristics between the 2 groups are presented in Table 2. There were no significant differences in clinical variables between the 2 groups. Angiographic data are also summarized in Table 2. Follow-up MLD was significantly larger in SES-treated lesions (2.7 ± 0.4 mm vs 2.3 ± 0.5 mm, P < 0.001). Postintervention planar and serial volumetric IVUS data are shown in Tables 3 and 4, respectively. Percentages of NI volume obstruction and NI VI were significantly smaller among SES-treated lesions (2.8 ± 7.1% vs 18.1 ± 15.7%, P < 0.001; and 0.2 ± 0.4 mm3/mm vs 1.5 ± 1.4 mm3/mm, P < 0.001, respectively). Positive vascular remodeling was more frequently observed in SES-treated lesions than in ZES-treated lesions (31.7% vs 10.2%, P = 0.007, respectively). Postintervention ISA resolved in two-thirds (4 of 6 ISAs) of SES-treated lesions and all (11 of 11 ISAs) of ZES-treated lesions. Acquired LSM occurred more frequently in the SES group than the ZES group (12.2% vs 0%, P = 0.006, respectively). Multivariate logistic regression analysis revealed that use of SES was the only independent risk factor of acquired LSM (odds ratio: 10.07, 95% confidence interval: 1.08-93.47, P = 0.042, Supplementary Table). Representative cases of positive remodeling and acquired LSM after implantation of SES are shown in the Supplementary Figure that can be viewed online. Long-term clinical outcomes are shown in Table 5. The mean follow-up duration was 35 ± 7 months after stent implantation (34.4 ± 5.8 months in SES-treated lesions vs 35.5 ± 4.9 months in ZES-treated lesions, P = 0.321). There were no significant differences in the major adverse cardiovascular events—death, MI, and target vessel revascularization—between the 2 groups.

Table 2. Clinical and Angiographic Characteristics
VariablesSirolimus-Eluting Stent, n = 41Zotarolimus-Eluting Stent, n = 59P
  1. Abbreviations: MI, myocardial infarction; MLD, minimal lumen diameter.

  2. Data are expressed as number (%) or mean ± standard deviation.

Clinical variables
 Age, y62 ± 963 ± 80.546
 Male27 (65.9)36 (61)0.626
 Diabetes mellitus16 (39)25 (42.4)0.741
 Hypertension23 (56.1)28 (47.5)0.407
 Hypercholesterolemia25 (61)37 (62.7)0.867
 Current smoker8 (19.5)18 (30.5)0.222
 Left ventricular ejection fraction <40%8 (19.5)12 (20.3)0.920
 ST-elevation MI8 (19.5)7 (11.9)0.292
 Non–ST-elevation MI33 (80.5)52 (88.1) 
Angiographic variables
 Time to follow-up angiogram, mo9.6 ± 0.99.4 ± 1.80.649
 Target vessel  0.530
 Left anterior descending artery32 (78.1)40 (67.8) 
 Left circumflex artery3 (7.3)6 (10.2) 
 Right coronary artery6 (14.6)13 (22) 
 Vessels involved  0.402
 1-vessel25 (61.0)43 (72.9) 
 2-vessel14 (34.1)13 (22) 
 3-vessel2 (4.9)3 (5.1) 
 Lesion length, mm22 ± 721 ± 60.191
 Stent diameter, mm3.1 ± 0.33.1 ± 0.50.621
 Stent length, mm25 ± 6.423 ± 6.40.163
 Quantitative coronary angiographic analysis
 Reference vessel size2.9 ± 0.42.9 ± 0.40.484
 Preintervention MLD, mm0.5 ± 0.50.5 ± 0.40.857
 Postintervention MLD, mm2.9 ± 0.33.0 ± 0.40.766
 Follow-up MLD, mm2.7 ± 0.42.3 ± 0.5<0.001
 Late loss, mm0.2 ± 0.30.7 ± 0.5<0.001
 Binary restenosis03 (5.1)0.131
Table 3. Comparison of Planar Intravascular Ultrasound Data Between the 2 Groups
Variables, mm2Sirolimus-Eluting Stent, n = 41Zotarolimus-Eluting Stent, n = 59P
  1. Abbreviations: CSA, cross-section area; EEM, external elastic membrane.

  2. Data are expressed as mean ± standard deviation.

Proximal reference segment
 EEM CSA15.2 ± 4.216.2 ± 4.70.315
 Lumen CSA9.5 ± 3.29.6 ± 3.30.906
Stented segment
 EEM CSA10.5 ± 3.910.2 ± 4.30.144
 Stent CSA6.4 ± 1.96.9 ± 1.90.145
 Lumen CSA6.4 ± 1.96.9 ± 1.90.133
Distal reference segment
 EEM CSA10.5 ± 3.910.2 ± 4.30.747
 Lumen CSA8.3 ± 3.87.6 ± 2.90.323
Table 4. Comparison of Volumetric Intravascular Ultrasound Data Between the 2 Groups
VariablesSirolimus-Eluting Stent, n = 41Zotarolimus-Eluting Stent, n = 59P
  1. Abbreviations: EEM, external elastic membrane; ISA, incomplete stent apposition; VI, volume index.

  2. Data are expressed as number (%) or mean ± standard deviation.

Postintervention
 EEM volume, mm3396.1 ± 149.3411.9 ± 106.20.670
 Stent volume, mm3210.1 ± 84.1214.1 ± 103.70.839
 Lumen volume, mm3210.1 ± 85.7214.1 ± 106.80.834
 EEM VI, mm3/mm14.6 ± 3.715.2 ± 4.10.420
 Stent VI, mm3/mm7.7 ± 2.17.9 ± 2.20.556
 Lumen VI, mm3/mm7.7 ± 2.17.9 ± 2.20.565
Follow-up
 EEM volume, mm3416.3 ± 161.9412.4 ± 211.90.787
 Stent volume, mm3210.2 ± 85.9214.2 ± 111.80.834
 Lumen volume, mm3204.2 ± 85.6173.8 ± 95.50.106
 Neointimal volume, mm36.0 ± 12.340.4 ± 34.4<0.001
 Neointimal volume obstruction, %2.8 ± 7.118.1 ± 15.7<0.001
 EEM VI, mm3/mm15.5 ± 3.615.2 ± 4.10.770
 Stent VI, mm3/mm7.7 ± 2.17.9 ± 2.10.537
 Lumen VI, mm3/mm7.5 ± 2.16.4 ± 2.10.015
 Neointima VI, mm3/mm0.2 ± 0.41.5 ± 1.4<0.001
Stent malapposition
 ISA6 (14.6)11 (18.6)0.600
 Persistent ISA2 (4.9)0 (0) 0.166
 Resolved ISA4 (9.7)11 (18.6)0.174
 Late acquired stent malapposition5 (12.2)0 (0) 0.006
Changes during follow-up
 ▵ EEM volume, mm320.2 ± 32.81.5 ± 15.90.001
 ▵ Stent volume, mm30.1 ± 0.90.1 ± 1.10.556
 ▵ Lumen volume, mm3−5.9 ± 12.3−40.3 ± 34.7<0.001
 ▵ EEM VI, mm3/mm0.9 ± 2.10.0 ± 1.4<0.001
 ▵ Stent VI, mm3/mm0.0 ± 0.80.0 ± 1.00.986
 ▵ Lumen VI, mm3/mm−0.2 ± 0.8−1.5 ± 1.9<0.001
Positive remodeling13 (31.7)6 (10.2)0.007
Negative remodeling2 (4.8)5 (8.4)0.488
Table 5. Comparison of 2-Year Clinical Outcomes Between the 2 Groups
VariablesSirolimus-Eluting Stent, n = 41Zotarolimus-Eluting Stent, n = 59P
  1. Data are expressed as number (%).

Major adverse cardiovascular events5 (12.2)6 (10.2)0.750
Death001.000
Myocardial infarction2 (4.9)1 (1.7)0.359
Definite or probable stent thrombosis2 (4.9)00.228
Target lesion revascularization1 (2.4)2 (3.4)0.507
Target vessel revascularization3 (7.3)5 (8.5)0.488

Discussion

This serial IVUS study in patients with acute MI showed that there might be more frequent positive vascular remodeling and acquired LSM and more prominent inhibition of NI proliferation in SES-treated lesions than in ZES-treated lesions.

Previous studies have reported the percentage of NI volume obstruction to be about 30% with bare metal stents and about 10% with DESs.14–17 In the ENDEAVOR III study, the percentage of NI volume obstruction was 2.7% ± 3.1% in the SES group and 16.1 ± 10.8% in the ZES group.14 The results of volumetric IVUS analysis in this study were similar to those of the ENDEAVOR III study.

A recent meta-analysis reported that the risk of acquired LSM in patients with DES implantation was 2.5 times higher than those with implantation of bare metal stents.18 In patients with acute MI, infarct-related lesions with increased number of inflammatory cells may be more prone to developing inflammatory reactions after DES implantation. In addition, thrombus lysis behind stent struts in the infarct-related lesions may partly contribute to the development of acquired LSM following acute MI. Although acquired LSM was observed with an incidence of 4% to 25% after SES implantation, it ranged from 0% to 7% in ZES-treated lesions in patients with coronary artery disease.8,10,14,15,19,20 In this study, serial IVUS examinations were performed to compare vascular remodeling directly between SES and ZES in the specific group of patients with acute MI. Acquired LSM was observed in 5 patients (12%) with SES-treated lesions, and none of the ZES-treated lesions showed acquired LSM. These differences in the incidence of acquired LSM might be related to different effects of SES and ZES on the vessel wall surrounding the stent struts. SES has a stainless steel stent platform with a strut thickness of 140 µm coated with polyethylene covinyl acetate and poly-n-butyl methacrylate polymers and sirolimus. The SES is designed to release 80% of the drug within 30 days of implantation.21 In contrast, the ZES uses a cobalt chromium stent platform with a strut thickness of 91 µm loaded with a biomimetic phosphorylcholine polymer and a sirolimus analogue, zotarolimus. ZES is designed to release >95% of the drug within 14 days of stent deployment.21

The presence of acquired LSM is generally associated with positive vascular remodeling and an increased vessel size in the stented segment.9,10 In this study, SES showed increased EEM volume at follow-up, whereas there was little change in EEM volume for ZES. The SES effectively suppresses NI hyperplasia; however, it induces expansion of plaque plus media layer. Data from various studies support the finding that acquired LSM is associated with increased risk of stent thrombosis.18,22,23 However, the impact of positive vascular remodeling in the stented segment on long-term clinical outcomes is not sufficiently known.24,25 Therefore, the clinical implications of different degrees of vascular remodeling on long-term clinical outcomes need to be clarified in large-scale clinical trials with long-term follow-up.

This study was limited by being a retrospective analysis of registry data from a single center, the small number of study patients, and the relatively short duration of clinical follow-up.

Conclusion

This study suggested that the pattern of vascular remodeling including positive remodeling, acquired LSM, and the degree of NI proliferation might be different depending on different types of DES in patients following acute MI.

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