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Long-Term Vascular Changes After Drug-Eluting Stent Implantation Assessed by Serial Volumetric Intravascular Ultrasound Analysis
Long-Term Vascular Changes After Drug-Eluting Stent Implantation Assessed by Serial Volumetric Intravascular Ultrasound Analysis Soo-Jin Kang, MD, PhDa,†, Duk-Woo Park, MD, PhDa,†, Gary S. Mintz, MDb, Seung-Whan Lee, MD, PhDa, Young-Hak Kim, MD, PhDa, Cheol Whan Lee, MD, PhDa, Ki-Hoon Han, MD, PhDa, Jae-Joong Kim, MD, PhDa, Seong-Wook Park, MD, PhDa, and Seung-Jung Park, MD, PhDa,* Using serial volumetric intravascular ultrasonography, we evaluated the predictors of late intimal hyperplasia (IH) increases after drug-eluting stent implantation. All eligible patients who underwent 6-month angiography without visual restenosis were requested to undergo a 2-year follow-up examination. Complete serial (after stenting and early [6-month], and late [2-year] follow-up) angiographic and intravascular ultrasound data were available for 135 patients with 143 lesions: 99 sirolimus-eluting stents and 44 paclitaxel-eluting stents. The external elastic membrane, stent, lumen, and peri-stent plaque volumes (external elastic membrane minus stent) were normalized by stent length. The percentage of IH volume was calculated as IH volume/stent volume ⴛ 100. The early reduction in the minimum lumen area was greater than the late reduction in the minimum lumen area (ⴚ0.8 ⴞ 0.8 vs ⴚ0.2 ⴞ 0.5 mm2, p <0.001). A progressive increase occurred in the percentage of IH volume: 8.1 ⴞ 7.1% from baseline to 6 months and 2.4 ⴞ 3.9% from 6 months to 2 years (p <0.001, between the early and late increases in the percentage of IH). The use of paclitaxel-eluting stents was the only independent predictor for the percentage of IH volume at 6 months ( ⴝ 0.419, p <0.001). The use of paclitaxel-eluting stents ( ⴝ 0.365, p <0.001, 95% confidence interval 3.7 to 9.7) and the post-stenting normalized plaque and media volume ( ⴝ 0.195, p ⴝ 0.020, 95% confidence interval 0.1 to 1.6) were the only independent predictors for the percentage of IH volume at 2 years. However, when the percentage of IH at 6 months was forced into the model, the percentage of IH at 6 months and the post-stenting normalized plaque and media volume, not paclitaxel-eluting stent use, predicted the 2-year percentage of IH. In conclusion, although IH continued to increase beyond 6 months, the growth rate of intima and luminal loss attenuated with time. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105: 1402–1408) Drug-eluting stents (DESs) reduce the rate of restenosis and the need for repeat revascularization compared to bare metal stents. Although delayed arterial healing, characterized by impaired endothelization and persistent fibrin deposition, has been suggested as a potential mechanism for late “catch-up” of neointimal growth after DES implantation,1–3 few long-term follow-up data have demonstrated late (after 1 year) DES-related vascular changes, including intimal hyperplasia (IH), stent–vessel wall apposition, and remodeling and their effect on late clinical prognosis.4 –7 Although quantitative coronary angiography has been used to assess late loss of minimal lumen diameter, 3-dimensional intravascular ultrasound volumetric analysis can proa Department of Cardiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; and bCardiovascular Research Foundation, New York, New York. Manuscript received October 20, 2009; revised manuscript received and accepted December 22, 2009. *Corresponding author: Tel: (82) 2-3010-4812; fax: (82) 2-475-6898. E-mail address: [email protected] (S.-J. Park). †
Drs. S.-J. Kang and D.-W. Park contributed equally to this article.
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.12.064
vide more detail and reliable information on the extent and distribution of intimal tissue and the nature and extent of vascular remodeling. We report the long-term, serial (baseline and early [6-month], and late [2-year] follow-up) intravascular ultrasound findings in patients treated with DES who did not experience clinical events between implantation and late follow-up. Methods The data were derived from the Serial Angiographic Analysis after Drug-Eluting Stent Placement by Six-month and Two-year Angiographic Follow-Up (DES-FU) study that included patients who had undergone DES implantation with sirolimus-eluting stents (SES Cypher stent, Cordis, Johnson & Johnson, Miami Lakes, Florida) and paclitaxeleluting stents (PES Taxus stent, Boston Scientific, Natick, Massachusetts) at the Asan Medical Center (Seoul, Korea). The patients in this cohort had undergone stent implantation from March 2003 to August 2004. From the present analysis, we excluded patients with serious co-morbid diseases, graft lesions, restenosis on the 6-month angiogram, and www.AJConline.org
Coronary Artery Disease/Long-Term Vascular Effects of DES Table 1 Baseline clinical characteristics Variable Age (years) Men Smoking Hypertension* Hypercholesterolemia† Diabetes mellitus Left ventricular ejection fraction (%) Previous percutaneous coronary intervention Previous coronary bypass surgery Clinical presentation Stable angina pectoris Unstable angina pectoris Acute myocardial infarction No. of narrowed coronary arteries 1 2 3 Isolated left main disease
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Table 2 Angiographic data and procedural characteristics of 143 lesions Total 57 ⫾ 10 98 (73%) 41 (30%) 72 (53%) 32 (24%) 24 (18%) 59 ⫾ 8 15 (11%) 2 (2%) 63 (47%) 57 (42%) 15 (11%) 54 (40%) 39 (29%) 41 (30%) 1 (1%)
* Defined as receiving antihypertensive treatment or having systolic blood pressure ⱖ140 mm Hg or diastolic blood pressure of ⱖ90 mm Hg. † Defined as total cholesterol ⬎200 mg/dl or receiving antilipidemic treatment.
those who had experienced adverse cardiac events, including death, myocardial infarction, stent thrombosis, or target vessel revascularization, before the late angiographic follow-up examination. In this registry, 531 patients with 766 lesions had undergone ⱖ2 scheduled follow-up angiograms, one at 4 to 12 months (6-month or early follow-up) and another at 13 to 46 months (2-year or late follow-up). As an intravascular ultrasound substudy, complete serial (after stenting and 6-month and 2-year follow-up) qualitative angiographic and volumetric intravascular ultrasound data were available for 135 patients (25.4%) with 143 lesions. All patients provided written informed consent. All procedures were performed using standard techniques. The choice of DES (i.e., SES or PES) and the use of predilation, intra-aortic balloon pump, debulking atherectomy, or postdilation strategies were at the operator’s discretion. Heparin was administered during the procedure according to standard practice. The patients who had not previously been taking antiplatelet agents were pretreated with a 300- to 600-mg loading dose of clopidogrel or 500 mg of ticlopidine, followed by clopidogrel (75 mg/day) or ticlopidine (250 mg/day) for ⱖ6 months after PCI and aspirin (100 to 200 mg/day) indefinitely. The duration of clopidogrel was also dependent on the operator’s discretion. Similarly, cilostazol 200 mg/day was prescribed for ⱖ1 month in patients with high-risk clinical profiles or who had undergone complicated procedures. All eligible patients who had undergone early 6-month angiography without restenosis were requested to return for a late 2-year angiographic follow-up examination. Qualitative angiographic measurements were done using standard techniques with automated edge-detection algorithms (CASS-5, Pie-Medical, Maastricht, The Netherlands) in the angiographic analysis center of the CardioVascular Research Foundation (Seoul, Korea).8 –11 Angiographic image
Variable
Total
Cypher
Taxus
Lesions (n) 143 99 44 6-Month follow-up duration (mo) 7.0 ⫾ 2.1 7.2 ⫾ 2.3 6.7 ⫾ 1.7 2-Year follow-up duration (mo) 25.1 ⫾ 3.6 25.0 ⫾ 3.3 25.2 ⫾ 4.1 Procedural findings Direct stenting 26 (18%) 17 (17%) 9 (21%) Stent in side branch 8 (6%) 4 (4%) 4 (9%) Maximal balloon size used (mm) 3.5 ⫾ 0.4 3.5 ⫾ 0.4 3.5 ⫾ 0.5 No. of drug-eluting stents/lesion 1.2 ⫾ 0.5 1.3 ⫾ 0.5 1.2 ⫾ 0.5 Stent length (mm) 29 ⫾ 15 29 ⫾ 15 29 ⫾ 15 Angiographic findings Chronic total occlusion 7 (5%) 6 (6%) 1 (2%) In-stent restenosis 6 (4%) 5 (5%) 1 (2%) Severe calcification 11 (8%) 8 (8%) 3 (7%) Thrombolysis In Myocardial 9 (6%) 7 (7%) 2 (5%) Infarction grade 0 Thrombus 9 (6%) 4 (4%) 5 (11%) Coronary lesion site Left anterior descending 51 (36%) 35 (35%) 16 (36%) Left circumflex 38 (27%) 30 (30%) 8 (18%) Right 44 (31%) 29 (29%) 15 (34%) Left main 10 (7%) 5 (5%) 5 (11%) Proximal reference diameter (mm) 3.2 ⫾ 0.4 3.2 ⫾ 0.4 3.2 ⫾ 0.5 Distal reference diameter (mm) 2.6 ⫾ 0.4 2.6 ⫾ 0.4 2.5 ⫾ 0.5 Minimal lumen diameter (mm) Before intervention 0.9 ⫾ 0.5 0.9 ⫾ 0.5 1.0 ⫾ 0.5 After intervention 2.6 ⫾ 0.4 2.6 ⫾ 0.4 2.5 ⫾ 0.5 6-Month follow-up 2.5 ⫾ 0.5 2.5 ⫾ 0.4 2.3 ⫾ 0.5 2-Year follow-up 2.3 ⫾ 0.6 2.4 ⫾ 0.5 2.1 ⫾ 0.6 Coronary restenosis at 2 years 5 (3%) 2 (2%) 3 (7%)
Figure 1. Serial changes in percentage of IH volume over 2 years. Overall, percentage of IH at 6 months measured 8.1 ⫾ 7.1% and increased to 10.5 ⫾ 8.5% (p ⫽ 0.010) at 2 years. This pattern was also seen in subset of lesions treated with SESs (from 6.1 ⫾ 5.8% at 6 months to 7.9 ⫾ 6.9% at 2 years, p ⫽ 0.046) and with PESs (from 12.6 ⫾ 7.8% at 6 months to 16.3 ⫾ 9.1% at 2 years, p ⫽ 0.049).
acquisition was performed at target sites using ⱖ2 angiographic projections of the stenosis at baseline, after stenting, and at 6 months and 2 years after stenting. Angiographic
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Table 3 Volumetric intravascular ultrasound measurements after stenting and at 6 months and 2 years of follow-up Variable
* p ⬍0.05 versus after stenting. † p ⬍0.05 versus 6-month follow-up.
6 Months of Follow-up
2 Years of Follow-up
Total
Cypher
Taxus
Total
Cypher
Taxus
Total
Cypher
Taxus
143
99
44
143
99
44
143
99
44
15.6 ⫾ 4.0 9.2 ⫾ 2.6 6.4 ⫾ 2.7
14.8 ⫾ 3.8 9.2 ⫾ 2.3 5.6 ⫾ 2.4
17.3 ⫾ 3.9 9.1 ⫾ 3.0 8.2 ⫾ 2.4
15.8 ⫾ 3.9 9.0 ⫾ 2.6 7.0 ⫾ 3.1
15.1 ⫾ 3.8 9.2 ⫾ 2.5 6.1 ⫾ 2.7
17.2 ⫾ 3.7 8.6 ⫾ 2.8 9.0 ⫾ 3.0
15.6 ⫾ 3.9 8.7 ⫾ 2.8 6.9 ⫾ 3.0
14.9 ⫾ 3.7 9.0 ⫾ 2.7 6.0 ⫾ 2.7
17.1 ⫾ 3.9 8.2 ⫾ 2.9 8.9 ⫾ 2.7
6.5 ⫾ 1.8 215 ⫾ 105 215 ⫾ 105 0⫾0 0⫾0 391 ⫾ 186 176 ⫾ 91 7.9 ⫾ 1.9 7.9 ⫾ 1.9 0⫾0 14.3 ⫾ 3.1 6.4 ⫾ 1.9
6.6 ⫾ 1.7 209 ⫾ 110 209 ⫾ 110 0⫾0 0⫾0 364 ⫾ 190 155 ⫾ 88 8.0 ⫾ 1.9 8.0 ⫾ 1.9 0⫾0 13.8 ⫾ 3.0 5.8 ⫾ 1.7
6.3 ⫾ 1.8 227 ⫾ 91 227 ⫾ 91 0⫾0 0⫾0 451 ⫾ 165 223 ⫾ 80 7.8 ⫾ 1.9 7.8 ⫾ 1.9 0⫾0 15.6 ⫾ 3.0 7.7 ⫾ 1.5
5.8 ⫾ 1.7* 217 ⫾ 14 199 ⫾ 97 17.9 ⫾ 20.0 8.1 ⫾ 7.1 430 ⫾ 204 213 ⫾ 107* 8.0 ⫾ 1.9 7.4 ⫾ 1.9* 0.6 ⫾ 0.6 15.8 ⫾ 3.2* 7.8 ⫾ 1.9*
6.0 ⫾ 1.8* 212 ⫾ 111 200 ⫾ 105 12.4 ⫾ 15.3 6.1 ⫾ 5.8 412 ⫾ 214 199 ⫾ 110* 8.1 ⫾ 1.8 7.6 ⫾ 2.0 0.5 ⫾ 0.4 15.6 ⫾ 3.4* 7.5 ⫾ 1.9*
5.1 ⫾ 1.4* 227 ⫾ 88 197 ⫾ 76 30.2 ⫾ 23.5 12.6 ⫾ 7.8 470 ⫾ 175 243 ⫾ 95 7.8 ⫾ 1.9 6.8 ⫾ 1.6* 1.0 ⫾ 0.8 16.2 ⫾ 2.9 8.4 ⫾ 1.6*
5.5 ⫾ 1.7* 217 ⫾ 104 194 ⫾ 95 23.2 ⫾ 25.0† 10.5 ⫾ 8.5† 446 ⫾ 208* 225 ⫾ 113* 8.0 ⫾ 1.9 7.2 ⫾ 1.9* 0.8 ⫾ 0.7 16.4 ⫾ 3.5* 8.3 ⫾ 2.2*,†
5.8 ⫾ 1.8* 213 ⫾ 111 197 ⫾ 105 15.7 ⫾ 17.1 7.9 ⫾ 6.9† 436 ⫾ 223* 219 ⫾ 121* 8.1 ⫾ 1.9 7.5 ⫾ 2.0 0.6 ⫾ 0.5 16.6 ⫾ 3.7* 8.3 ⫾ 2.4*,†
4.9 ⫾ 1.4* 228 ⫾ 88 187 ⫾ 69 40.0 ⫾ 31.2 16.3 ⫾ 9.1† 467 ⫾ 171 238 ⫾ 90 7.9 ⫾ 1.9 6.5 ⫾ 1.5* 1.3 ⫾ 0.8 16.1 ⫾ 2.9 8.2 ⫾ 1.6
10.5 ⫾ 3.6 6.8 ⫾ 2.3 3.7 ⫾ 1.9
10.4 ⫾ 3.6 6.9 ⫾ 2.2 3.5 ⫾ 1.8
10.7 ⫾ 3.7 6.6 ⫾ 2.7 4.2 ⫾ 2.0
10.8 ⫾ 3.5 6.9 ⫾ 2.2 3.9 ⫾ 1.9
10.7 ⫾ 3.6 7.1 ⫾ 2.2 3.6 ⫾ 1.9
10.9 ⫾ 3.2 6.4 ⫾ 2.1 4.5 ⫾ 1.8
10.9 ⫾ 3.6 6.7 ⫾ 2.2 4.1 ⫾ 2.2
10.9 ⫾ 3.6 7.0 ⫾ 2.3 3.8 ⫾ 2.0
11.0 ⫾ 3.6 6.1 ⫾ 1.8 4.9 ⫾ 2.3
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Lesions (n) Proximal reference Mean external elastic membrane area (mm2) Mean lumen area (mm2) Mean plaque and media area (mm2) Stented segment Minimum lumen area (mm2) Stent volume (mm3) Lumen volume (mm3) Intimal hyperplasia volume (mm3) Intimal hyperplasia volume (%) External elastic membrane volume (mm3) Plaque and media volume (mm3) Normalized stent volume (mm2) Normalized lumen volume (mm2) Normalized Intimal hyperplasia volume (mm2) Normalized external elastic membrane volume (mm2) Normalized plaque and media volume (mm2) Distal reference Mean external elastic membrane area (mm2) Mean lumen area (mm2) Mean plaque and media area (mm2)
After Stenting
Coronary Artery Disease/Long-Term Vascular Effects of DES
restenosis was defined as diameter stenosis of ⬎50% at follow-up angiography. Intravascular ultrasonography was performed after intracoronary administration of 0.2 mg nitroglycerin using a motorized transducer pull back (0.5 mm/s) and a commercial scanner (Boston Scientific/SCIMED, Minneapolis, Minnesota) consisting of a rotating 30- or 40-MHz transducer within a 3.2Fr imaging sheath. Quantitative volumetric intravascular ultrasound analysis was performed as previously described.12–13 Using computerized planimetry (EchoPlaque, version 2.7, Indec Systems, MountainView, California). The stent and reference segments were assessed every 1 mm. The reference segment external elastic membrane, lumen, and plaque and media (external elastic membrane minus lumen) areas were measured over a 5-mm length adjacent to each stent edge and averaged. In-stent measurements were also obtained every 1 mm and included the external elastic membrane, stent, lumen (intrastent lumen bounded by the borders of the stent and IH), peri-stent plaque and media (external elastic membrane minus stent), and IH (stent minus intrastent lumen) areas and volumes. The percentage of IH was defined as the IH volume divided by the stent. All volumes were calculated using Simpson’s rule and then normalized for analysis length (normalized volume). Late stent malposition (LSM) was defined as the separation of at least one stent strut not in contact with 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 speckling behind the strut.7 Within the LSM sections, the LSM and plaque and media (external elastic membrane minus stent minus LSM) volumes (and normalized volumes) were calculated using Simpson’s rule. All statistical analyses were conducted using Statistical Package for Social Sciences software (SPSS, Chicago, Illinois). Categorical data are presented as numbers and percentages and compared using chi-square statistics or Fisher’s exact test. Continuous variables are presented as the mean ⫾ SD and compared using the unpaired or paired Student t test. All p values were 2-sided, and p ⬍0.05 indicated statistical significance. Results Complete serial (after stenting and 6-month and 2-year follow-up) qualitative angiographic and volumetric intravascular ultrasound data were available for 135 patients with 143 lesions (99 SES-treated lesions and 44 PES-treated lesions). The point of early and late follow-up was 7.0 ⫾ 2.1 months (range 4.6 to 11.7) and 25.1 ⫾ 3.6 months (range 21.7 to 30), respectively. The baseline clinical and procedural characteristics are summarized in Tables 1 and 2. Overall, 143 lesions were assessed with serial (baseline, early follow-up, and late follow-up) intravascular ultrasound examinations. The percentage of IH volume at 6 months was 8.1 ⫾ 7.1%; this was followed by an increase of 2.4 ⫾ 3.9% from 6 months to 2 years (p ⬍0.001 vs 6-month percentage of IH), with no correlation between the early and late increases in the percentage of IH. Also, no relation was found between the late percentage of IH and the overall duration of follow-up. However, 122 lesions
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(86%) had an increase in the percentage of IH from 6 months to 2 years, and 21 lesions (15%) had a decrease in the percentage of IH from 6 months to 2 years. Although the overall percentage of IH volume at 2 years was 10.5 ⫾ 8.5%, it was much greater in the PES-treated lesions than in the SES-treated lesions (16.3 ⫾ 9.1% vs 7.9 ⫾ 6.9%, respectively, p ⬍0.001; Figure 1). The IH volume in the 25 patients with diabetes mellitus was not different from that of the 110 patients without diabetes at 6 months (17.2 ⫾ 15.9 vs 18.0 ⫾ 20.8 mm3, p ⫽ 0.9) or 2 years (20.6 ⫾ 18.5 vs 23.8 ⫾ 26.2 mm3, respectively, p ⫽ 0.6). Similarly, the percentage of IH volumes in those with diabetes versus those without were virtually identical at 6 months (8.8 ⫾ 6.9% vs 8.0 ⫾ 7.2%, respectively, p ⫽ 0.6) and 2 years (10.5 ⫾ 7.9% vs 10.5 ⫾ 8.7%, p ⫽ 1.0). Finally, no significant difference was found in the late increase in the percentage of IH volume between those with (1.7 ⫾ 3.1%) and without (2.5 ⫾ 4.1%) diabetes (p ⫽ 0.4). Univariate analysis demonstrated that PES use, acute coronary syndrome, and normalized post-stenting peri-stent plaque and media volume correlated with the percentage of IH volume at 6 months and at 2 years. These variables were entered into a multivariate model predicting the percentage of IH at 6 months and 2 years. Stepwise linear regression analysis identified PES use as the only independent predictor for the percentage of IH volume at 6 months ( ⫽ 0.419, p ⬍0.001, 95% confidence interval [CI] 4.1 to 8.8). Additionally, the percentage of IH volume at 2 years was independently determined by PES use ( ⫽ 0.365, p ⬍0.001, 95% CI 3.7 to 9.7) and the post-stenting normalized plaque and media volume ( ⫽ 0.195, p ⫽ 0.020, 95% CI 0.1 to 1.6). However, when the percentage of IH at 6 months was forced into the model, the independent predictors of neointimal hyperplasia at 2 years were the percentage of IH at 6 months and the post-stenting normalized plaque and media volume, not PES use. Finally, among the variables of normalized plaque and media volume, PES use, and acute coronary syndrome, the only independent determinant for the late increase in the percentage of IH volume (between 6 months and 2 years) was the immediate post-stenting normalized plaque and media volume ( ⫽ 0.262, p ⫽ 0.002, 95% CI 0.2 to 0.8). Overall, the in-stent minimum lumen area decreased from 6.5 ⫾ 1.8 mm2 after stenting to 5.8 ⫾ 1.7 mm2 at 6 months (p ⫽ 0.001), with no subsequent reduction in minimum lumen area at 2 years of follow-up (5.5 ⫾ 1.7 mm2, p ⫽ 0.3 vs at 6 months). The minimum lumen area changes in SES-treated and PES-treated lesions were similar in that a significant decrease in the minimum lumen area was noted only in the early follow-up phase (Table 3). The in-stent minimum lumen area at 2 years of follow-up correlated negatively with the early increase in the percentage of IH volume at 6 months (r ⫽ ⫺0.422, p ⬍0.001) and also with the late percentage of IH volume increase (r ⫽ ⫺0.293, p ⬍0.001) and showed a positive relation with the baseline minimum stent area (r ⫽ 0.848, p ⬍0.001). No significant change was found in the normalized stent volume from baseline to 6 months or 2 years, but the normalized lumen volume decreased from 7.9 ⫾ 1.9 mm2 after intervention to 7.4 ⫾ 1.9 mm2 at 6 months (p ⫽ 0.017). The normalized external elastic membrane volume
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Table 4 Serial changes in intravascular ultrasound parameters over 2 years Variable Lesions (n) Between post-stenting and 6 months Proximal reference ⌬Mean external elastic membrane area (mm2) ⌬Mean lumen area (mm2) ⌬Mean plaque area (mm2) Stented segment ⌬Minimum lumen area (mm2) ⌬Stent volume (mm3) ⌬Lumen volume (mm3) ⌬Intimal hyperplasia volume (mm3) ⌬Intimal hyperplasia volume (%) ⌬External elastic membrane volume (mm3) ⌬Plaque and media volume (mm3) ⌬Normalized stent volume (mm2) ⌬Normalized lumen volume (mm2) ⌬Normalized external elastic membrane volume (mm2) ⌬Normalized plaque and media volume (mm2) Distal reference ⌬Mean external elastic membrane area (mm2) ⌬Mean lumen area (mm2) ⌬Mean plaque and media area (mm2) Between 6 months and 2 years Proximal reference ⌬Mean external elastic membrane area (mm2) ⌬Mean lumen area (mm2) ⌬Mean plaque area (mm2) Stented segment ⌬Minimum lumen area (mm2) ⌬Stent volume (mm3) ⌬Lumen volume (mm3) ⌬Intimal hyperplasia volume (mm3) ⌬Intimal hyperplasia volume (%) ⌬External elastic membrane volume (mm3) ⌬Plaque and media volume (mm3) ⌬Normalized stent volume (mm2) ⌬Normalized lumen volume (mm2) ⌬Normalized external elastic membrane volume (mm2) ⌬Normalized plaque and media volume (mm2) Distal reference ⌬Mean external elastic membrane area (mm2) ⌬Mean lumen area (mm2) ⌬Mean plaque and media area (mm2)
Total
Cypher
Taxus
143
99
44
0.2 ⫾ 2.0 ⫺0.2 ⫾ 1.5 0.6 ⫾ 1.9
0.3 ⫾ 0.5 0.0 ⫾ 0.9 0.5 ⫾ 1.2
⫺0.1 ⫾ 3.3 ⫺0.5 ⫾ 2.2 0.9 ⫾ 2.8
⫺0.8 ⫾ 0.8 1.9 ⫾ 5.8 ⫺15.8 ⫾ 21.5 17.8 ⫾ 20.0 8.1 ⫾ 7.1 39.1 ⫾ 32.2 36.5 ⫾ 30.8 0.1 ⫾ 0.2 ⫺0.5 ⫾ 0.6 1.5 ⫾ 1.0 1.4 ⫾ 0.9
⫺0.6 ⫾ 0.8 2.9 ⫾ 3.7 ⫺9.2 ⫾ 15.8 12.4 ⫾ 15.3 6.1 ⫾ 5.8 47.8 ⫾ 30.8 44.1 ⫾ 29.7 0.1 ⫾ 0.1 ⫺0.3 ⫾ 0.4 1.8 ⫾ 0.8 1.7 ⫾ 0.8
⫺1.2 ⫾ 0.8 ⫺0.3 ⫾ 8.5 ⫺30.6 ⫾ 25.0 30.2 ⫾ 23.6 12.5 ⫾ 7.8 19.4 ⫾ 26.4 19.7 ⫾ 26.7 0.0 ⫾ 0.3 ⫺1.0 ⫾ 0.8 0.6 ⫾ 0.9 0.7 ⫾ 1.0
0.2 ⫾ 1.4 0.0 ⫾ 1.0 0.2 ⫾ 0.9
0.2 ⫾ 0.4 0.1 ⫾ 0.3 0.1 ⫾ 0.2
0.2 ⫾ 2.4 ⫺0.2 ⫾ 1.8 0.3 ⫾ 1.5
⫺0.1 ⫾ 1.3 ⫺0.2 ⫾ 1.0 ⫺0.1 ⫾ 1.8*
0.0 ⫾ 0.5* ⫺0.1 ⫾ 0.3 ⫺0.1 ⫾ 0.9*
⫺0.1 ⫾ 2.1 ⫺0.3 ⫾ 1.6 ⫺0.1 ⫾ 2.7
⫺0.2 ⫾ 0.5* 0.5 ⫾ 4.6* ⫺5.0 ⫾ 11.0* 5.3 ⫾ 10.1* 2.4 ⫾ 3.9* 16.7 ⫾ 39.2* 12.7 ⫾ 31.8* 0.0 ⫾ 0.1* ⫺0.2 ⫾ 0.4* 0.6 ⫾ 1.5* 0.5 ⫾ 1.1*
⫺0.2 ⫾ 0.4* 0.4 ⫾ 3.1* ⫺3.2 ⫾ 6.7* 3.3 ⫾ 4.8* 1.8 ⫾ 2.7* 24.2 ⫾ 43.2* 20.3 ⫾ 33.8* 0.0 ⫾ 0.1* ⫺0.1 ⫾ 0.3* 0.9 ⫾ 1.7* 0.8 ⫾ 1.2*
⫺0.3 ⫾ 0.7* 0.8 ⫾ 7.0 ⫺9.0 ⫾ 16.6* 9.8 ⫾ 16.0* 3.7 ⫾ 5.7* ⫺3.5 ⫾ 16.9* ⫺4.4 ⫾ 17.6* 0.0 ⫾ 0.2 ⫺0.3 ⫾ 0.5* ⫺0.1 ⫾ 0.6* ⫺0.1 ⫾ 0.6*
0.1 ⫾ 1.6 ⫺0.1 ⫾ 1.0 0.2 ⫾ 1.0
0.1 ⫾ 0.7 ⫺0.1 ⫾ 0.3* 0.1 ⫾ 0.5
0.1 ⫾ 2.7 ⫺0.3 ⫾ 1.7 0.4 ⫾ 1.6
* p ⬍0.05 versus change between post-stenting and 6 months.
increased from 14.3 ⫾ 3.1 mm2 after stenting to 15.8 ⫾ 3.2 mm2 at 6 months (p ⬍0.001). Late changes in the normalized lumen and external elastic membrane volumes were insignificant. The normalized plaque and media volume increased significantly during both the early follow-up period (from 6.4 ⫾ 1.9 mm2 after stenting to 7.8 ⫾ 1.9 mm2 at 6 months, p ⬍0.001) and the late follow-up period (from 7.8 ⫾ 1.9 mm2 at 6 months to 8.3 ⫾ 2.2 mm2 at 2 years, p ⫽ 0.041), although the late increases in the normalized plaque and media volume were less than the early increases (Table 4). Of the 22 lesions identified with LSM (15.4%), 17 LSMs were detected at 6 months and another 5 LSM at 2 years. Overall, 20 of 99 SES-treated lesions developed LSM compared to 2 of 44 PES-treated lesions (p ⫽ 0.031). No case of LSM found at 6 months had resolved at 2 years.
The overall duration of clinical follow-up for these 135 patients was 61 ⫾ 7 months. Overall, 4 patients (3.0%) died from noncardiac causes and 1 (0.7%) from sudden death. Stent thrombosis occurred in 1 patient (0.7%), and acute myocardial infarction occurred in 2 (1.5%). Target vessel revascularization was necessary in 10 patients (7.4%). Discussion The present study, with baseline, early follow-up, and late follow-up serial volumetric intravascular ultrasound analysis, has shown a significant increase in the percentage of IH volume only during the early phase. This was followed by only a modest increase in the percentage of IH from 6 months to 2 years, averaging 30% of the earlier
Coronary Artery Disease/Long-Term Vascular Effects of DES
neointimal proliferation, with no correlation in neointimal proliferation between the 2 points. The changes in minimum lumen area paralleled the changes in the percentage of IH volume because of the lack of late (after 6 months) chronic stent recoil. Therefore, despite concerns about long-term DES efficacy, the magnitude of IH increase and lumen decrease was less over time. Because the greatest neointimal proliferation and luminal renarrowing after DES implantation were confined to the first 6 months, the rate of clinical restenosis requiring target lesion revascularization in patients who avoided early repeat intervention was relatively low (3%) during the subsequent 18 months. The present study is one of only a few long-term intravascular ultrasound analyses of DES. We previously reported “late catch-up” of IH after DES implantation with nonpolymer-encapsulated PESs.3 Greater 6-month suppression of IH occurred within high-dose stents, paradoxically followed by a greater increase in IH at 2 years in the same high-dose stents. Late restenosis was explained by delayed healing and the local vascular toxic effect of high-dose paclitaxel.14 This was supported by preclinical animal studies showing delayed inflammation and cellular proliferation.1,15,16 In 26 patients in their first-in-humans study, Sousa et al17,18 reported serial intravascular ultrasound analysis of SES during a 4-year period that showed that the percentage of IH volume remained minimal at ⱕ4 years with no late catch-up. In our study, PES use was an independent predictor of the early increase in the percentage of IH volume at 6 months. This was consistent with the findings from many clinical trials and registries showing that PES implantation was associated with more neointimal proliferation than SES implantation.19,20 The present analysis has extended these observations by showing that this difference between PESs and SESs continues out to 2 years but did not increase. The difference between PESs and SESs at 2 years appeared to result entirely from the difference at 6 months; PES use was an independent predictor of the 2-year percentage of IH only when the 6-month neointimal hyperplasia was not in the model. In the present analysis, DES-dependent antiproliferative effects appeared to be eliminated beyond 6 months; thus, different mechanisms might be involved in determining late neointimal proliferation, however modest. Previous histologic studies in the bare metal stent era have indicated that the degree of in-stent neointimal proliferation correlated with the peri-stent plaque burden.21 This was one of a group of “minor” predictors of bare metal in-stent restenosis that included preintervention remodeling, among others; recent DES studies have reported inconsistent results relating residual peri-stent plaque burden to IH or angiographic restenosis.22,23 Although preintervention intravascular ultrasound data were not available for the present patient cohort and therefore preintervention remodeling could not be assessed, postintervention peri-stent plaque was a predictor of the percentage of IH increase from 6 months to 2 years, as well as of the percentage of IH at 2 years. Thus, when the differential, antiproliferative effects of PES versus SES decreased over time, the magnitude of peri-stent plaque appeared to re-emerge as a predictors of late DES neointimal hyperplasia. Other similar “minor” predictors of in-stent
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restenosis deserve repeat study as determinants of late neointimal proliferation. Alternatively, the potent antiproliferative action of DESs might have caused deleterious local effects on the vascular wall that occurred only late and that were mediated by the peri-stent plaque burden.13,14 The main reason for the high incidence of restenosis in patients with diabetes mellitus has been explained by the exaggerated IH in both stented and nonstented lesions.24 –26 Our data have indicated that the intimal growth at 6 months and the changes in the IH volume after 6 months were similar between those with and without diabetes. DESs appeared to effectively inhibit IH in patients with as well as without diabetes beyond the follow-up period, consistent with the findings from previous investigations.27 In our study, no patient showed late regression of LSM detected at 6 months, regardless of the stent type used, and 5 cases of LSM were newly detected at 2 years. One follow-up series of SES-treated patients revealed no change in LSM from 6 months to 2 years,28 and another study of selected patients treated with the Taxus-II stent showed that LSM tended to regress in the PES-treated patients.29 This was not a randomized comparison of SES versus PES. Pitfalls regarding the small sample size and potential for selection bias should be considered in the interpretation of these data. Most patients who were invited to return for late follow-up refused, and patients with restenosis at 6 months were excluded. 1. Liistro F, Stankovic G, Di Mario C, Takagi T, Chieffo A, Moshiri S, Montorfano M, Carlino M, Briguori C, Pagnotta P, Albiero R, Corvaja N, Colombo A. First clinical experience with a paclitaxel derivateeluting polymer stent system implantation for in-stent restenosis: immediate and long-term clinical and angiographic outcome. Circulation 2002;105:1883–1886. 2. Finn AV, Nakazawa G, Joner M, Kolodgie FD, Mont EK, Gold HK, Virmani R. Vascular responses to drug eluting stents: importance of delayed healing. Arterioscler Thromb Vasc Biol 2007;27:1500 –1510. 3. Park DW, Hong MK, Mintz GS, Lee CW, Song JM, Han KH, Kang DH, Cheong SS, Song JK, Kim JJ, Weissman NJ, Park SW, Park SJ. Two-year follow-up of the quantitative angiographic and volumetric intravascular ultrasound analysis after nonpolymeric paclitaxel-eluting stent implantation: late “catch-up” phenomenon from ASPECT study. J Am Coll Cardiol 2006;48:2432–2439. 4. Cook S, Wenaweser P, Togni M, Billinger M, Morger C, Seiler C, Vogel R, Hess O, Meier B, Windecker S. Incomplete stent apposition and very late stent thrombosis after drug-eluting stent implantation. Circulation 2007;115:2426 –2434. 5. Hong MK, Mintz GS, Lee CW, Kim YH, Lee SW, Song JM, Han KH, Kang DH, Song JK, Kim JJ, Park SW, Park SJ. Incidence, mechanism, predictors, and long-term prognosis of late stent malapposition after bare-metal stent implantation. Circulation 2004;109:881– 886. 6. Hong MK, Mintz GS, Lee CW, Park DW, Park KM, Lee BK, Kim YH, Song JM, Han KH, Kang DH, Cheong SS, Song JK, Kim JJ, Park SW, Park SJ. Late stent malapposition after drug-eluting stent implantation: an intravascular ultrasound analysis with long-term follow-up. Circulation 2006;113:414 – 419. 7. Shah VM, Mintz GS, Apple S, Weissman NJ. Background incidence of late malapposition after bare-metal stent implantation. Circulation 2002;106:1753–1755. 8. Ryan TJ, Faxon DP, Gunnar RM, Kennedy JW, King SB III, Loop FD, Peterson KL, Reeves TJ, Williams DO, Winters WL Jr, et al. Guidelines for percutaneous transluminal coronary angioplasty: A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee on Percutaneous Transluminal Coronary Angioplasty). Circulation 1988;78:486 –502. 9. Popma JJ, Leon MB, Moses JW, Holmes DR Jr, Cox N, Fitzpatrick M, Douglas J, Lambert C, Mooney M, Yakubov S, Kuntz RE; SIRIUS
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(DiabeDES) Intravascular Ultrasound Trial. Eur Heart J 2008;29: 2733–2741. Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, Hong MK, Rhee KS, Chae JK, Ko JK, Park JH, Lee JH, Choi SW, Jeong JO, Seong IW, Cho YH, Lee NH, Kim JH, Chun KJ, Kim HS, Park SJ. A randomized comparison of sirolimus-versus paclitaxel-eluting stent implantation in patients with diabetes mellitus 2-year clinical outcomes of the DES-DIABETES trial. J Am Coll Cardiol 2009;53: 812– 813. Tanabe K, Serruys PW, Degertekin M, Guagliumi G, Grube E, Chan C, Munzel T, Belardi J, Ruzyllo W, Bilodeau L, Kelbaek H, Ormiston J, Dawkins K, Roy L, Strauss BH, Disco C, Koglin J, Russell ME, Colombo A; TAXUS II Study Group. Chronic arterial responses to polymer-controlled paclitaxel-eluting stents: comparison with bare metal stents by serial intravascular ultrasound analyses: data from the randomized TAXUS-II trial. Circulation 2004;109:196 –200. Lee CH, Zhang J, Kailasam A, Tai BC, Ye F, Low AF, Hou X, Hay ET, Teo SG, Lim YT, Chen S, Tan HC. An intravascular ultrasound study of Cypher, Taxus, and Endeavor stents on relation between neointimal proliferation and residual plaque burden. J Interv Cardiol 2008;21:519 –527. Kornowski R, Mintz GS, Kent KM, Pichard AD, Satler LF, Bucher TA, Hong MK, Popma JJ, Leon MB. Increased restenosis in diabetes mellitus after coronary interventions is due to exaggerated intimal hyperplasia: a serial intravascular ultrasound study. Circulation 1997; 95:1366 –1369. Maeng M, Jensen LO, Galloe AM, Thayssen P, Christiansen EH, Hansen KN, Helqvist S, Botker HE, Lassen JF, Thuesen L. Comparison of the sirolimus-eluting versus paclitaxel-eluting coronary stent in patients with diabetes mellitus: the diabetes and drug-eluting stent (DiabeDES) randomized angiography trial. Am J Cardiol 2009;103: 345–349. Jiménez-Quevedo P, Sabaté M, Angiolillo DJ, Costa MA, Alfonso F, Gómez-Hospital JA, Hernández-Antolín R, Bañuelos C, Goicolea J, Fernández-Avilés F, Bass T, Escaned J, Moreno R, Fernández C, Macaya C; DIABETES Investigator. Vascular effects of sirolimuseluting versus bare-metal stents in diabetic patients: three-dimensional ultrasound results of the Diabetes and Sirolimus-Eluting Stent (DIABETES) Trial. J Am Coll Cardiol 2006;6:2172–2179. Kumbhani DJ, Bavry AA, Kamdar AR, Helton TJ, Bhatt DL. The effect of drug-eluting stents on intermediate angiographic and clinical outcomes in diabetic patients: insights from randomized clinical trials. Am Heart J 2008;155:640 – 647. Degertekin M, Serruys PW, Tanabe K, Lee CH, Sousa JE, Colombo A, Morice MC, Ligthart JM, de Feyter PJ. Long-term follow-up of incomplete stent apposition in patients who received sirolimus-eluting stent for de novo coronary lesions: an intravascular ultrasound analysis. Circulation 2003;108:2747–2750. Aoki J, Colombo A, Dudek D, Banning AP, Drzewiecki J, Zmudka K, Schiele F, Russell ME, Koglin J, Serruys PW; TAXUS II Study Group. Peri-stent remodeling and neointimal suppression 2 years after polymer-based, paclitaxel-eluting stent implantation: insights from serial intravascular ultrasound analysis in the TAXUS II study. Circulation 2005;20:3876 –3883.
Drs. S.-J. Kang and D.-W. Park contributed equally to this article.
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.12.064
vide more detail and reliable information on the extent and distribution of intimal tissue and the nature and extent of vascular remodeling. We report the long-term, serial (baseline and early [6-month], and late [2-year] follow-up) intravascular ultrasound findings in patients treated with DES who did not experience clinical events between implantation and late follow-up. Methods The data were derived from the Serial Angiographic Analysis after Drug-Eluting Stent Placement by Six-month and Two-year Angiographic Follow-Up (DES-FU) study that included patients who had undergone DES implantation with sirolimus-eluting stents (SES Cypher stent, Cordis, Johnson & Johnson, Miami Lakes, Florida) and paclitaxeleluting stents (PES Taxus stent, Boston Scientific, Natick, Massachusetts) at the Asan Medical Center (Seoul, Korea). The patients in this cohort had undergone stent implantation from March 2003 to August 2004. From the present analysis, we excluded patients with serious co-morbid diseases, graft lesions, restenosis on the 6-month angiogram, and www.AJConline.org
Coronary Artery Disease/Long-Term Vascular Effects of DES Table 1 Baseline clinical characteristics Variable Age (years) Men Smoking Hypertension* Hypercholesterolemia† Diabetes mellitus Left ventricular ejection fraction (%) Previous percutaneous coronary intervention Previous coronary bypass surgery Clinical presentation Stable angina pectoris Unstable angina pectoris Acute myocardial infarction No. of narrowed coronary arteries 1 2 3 Isolated left main disease
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Table 2 Angiographic data and procedural characteristics of 143 lesions Total 57 ⫾ 10 98 (73%) 41 (30%) 72 (53%) 32 (24%) 24 (18%) 59 ⫾ 8 15 (11%) 2 (2%) 63 (47%) 57 (42%) 15 (11%) 54 (40%) 39 (29%) 41 (30%) 1 (1%)
* Defined as receiving antihypertensive treatment or having systolic blood pressure ⱖ140 mm Hg or diastolic blood pressure of ⱖ90 mm Hg. † Defined as total cholesterol ⬎200 mg/dl or receiving antilipidemic treatment.
those who had experienced adverse cardiac events, including death, myocardial infarction, stent thrombosis, or target vessel revascularization, before the late angiographic follow-up examination. In this registry, 531 patients with 766 lesions had undergone ⱖ2 scheduled follow-up angiograms, one at 4 to 12 months (6-month or early follow-up) and another at 13 to 46 months (2-year or late follow-up). As an intravascular ultrasound substudy, complete serial (after stenting and 6-month and 2-year follow-up) qualitative angiographic and volumetric intravascular ultrasound data were available for 135 patients (25.4%) with 143 lesions. All patients provided written informed consent. All procedures were performed using standard techniques. The choice of DES (i.e., SES or PES) and the use of predilation, intra-aortic balloon pump, debulking atherectomy, or postdilation strategies were at the operator’s discretion. Heparin was administered during the procedure according to standard practice. The patients who had not previously been taking antiplatelet agents were pretreated with a 300- to 600-mg loading dose of clopidogrel or 500 mg of ticlopidine, followed by clopidogrel (75 mg/day) or ticlopidine (250 mg/day) for ⱖ6 months after PCI and aspirin (100 to 200 mg/day) indefinitely. The duration of clopidogrel was also dependent on the operator’s discretion. Similarly, cilostazol 200 mg/day was prescribed for ⱖ1 month in patients with high-risk clinical profiles or who had undergone complicated procedures. All eligible patients who had undergone early 6-month angiography without restenosis were requested to return for a late 2-year angiographic follow-up examination. Qualitative angiographic measurements were done using standard techniques with automated edge-detection algorithms (CASS-5, Pie-Medical, Maastricht, The Netherlands) in the angiographic analysis center of the CardioVascular Research Foundation (Seoul, Korea).8 –11 Angiographic image
Variable
Total
Cypher
Taxus
Lesions (n) 143 99 44 6-Month follow-up duration (mo) 7.0 ⫾ 2.1 7.2 ⫾ 2.3 6.7 ⫾ 1.7 2-Year follow-up duration (mo) 25.1 ⫾ 3.6 25.0 ⫾ 3.3 25.2 ⫾ 4.1 Procedural findings Direct stenting 26 (18%) 17 (17%) 9 (21%) Stent in side branch 8 (6%) 4 (4%) 4 (9%) Maximal balloon size used (mm) 3.5 ⫾ 0.4 3.5 ⫾ 0.4 3.5 ⫾ 0.5 No. of drug-eluting stents/lesion 1.2 ⫾ 0.5 1.3 ⫾ 0.5 1.2 ⫾ 0.5 Stent length (mm) 29 ⫾ 15 29 ⫾ 15 29 ⫾ 15 Angiographic findings Chronic total occlusion 7 (5%) 6 (6%) 1 (2%) In-stent restenosis 6 (4%) 5 (5%) 1 (2%) Severe calcification 11 (8%) 8 (8%) 3 (7%) Thrombolysis In Myocardial 9 (6%) 7 (7%) 2 (5%) Infarction grade 0 Thrombus 9 (6%) 4 (4%) 5 (11%) Coronary lesion site Left anterior descending 51 (36%) 35 (35%) 16 (36%) Left circumflex 38 (27%) 30 (30%) 8 (18%) Right 44 (31%) 29 (29%) 15 (34%) Left main 10 (7%) 5 (5%) 5 (11%) Proximal reference diameter (mm) 3.2 ⫾ 0.4 3.2 ⫾ 0.4 3.2 ⫾ 0.5 Distal reference diameter (mm) 2.6 ⫾ 0.4 2.6 ⫾ 0.4 2.5 ⫾ 0.5 Minimal lumen diameter (mm) Before intervention 0.9 ⫾ 0.5 0.9 ⫾ 0.5 1.0 ⫾ 0.5 After intervention 2.6 ⫾ 0.4 2.6 ⫾ 0.4 2.5 ⫾ 0.5 6-Month follow-up 2.5 ⫾ 0.5 2.5 ⫾ 0.4 2.3 ⫾ 0.5 2-Year follow-up 2.3 ⫾ 0.6 2.4 ⫾ 0.5 2.1 ⫾ 0.6 Coronary restenosis at 2 years 5 (3%) 2 (2%) 3 (7%)
Figure 1. Serial changes in percentage of IH volume over 2 years. Overall, percentage of IH at 6 months measured 8.1 ⫾ 7.1% and increased to 10.5 ⫾ 8.5% (p ⫽ 0.010) at 2 years. This pattern was also seen in subset of lesions treated with SESs (from 6.1 ⫾ 5.8% at 6 months to 7.9 ⫾ 6.9% at 2 years, p ⫽ 0.046) and with PESs (from 12.6 ⫾ 7.8% at 6 months to 16.3 ⫾ 9.1% at 2 years, p ⫽ 0.049).
acquisition was performed at target sites using ⱖ2 angiographic projections of the stenosis at baseline, after stenting, and at 6 months and 2 years after stenting. Angiographic
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Table 3 Volumetric intravascular ultrasound measurements after stenting and at 6 months and 2 years of follow-up Variable
* p ⬍0.05 versus after stenting. † p ⬍0.05 versus 6-month follow-up.
6 Months of Follow-up
2 Years of Follow-up
Total
Cypher
Taxus
Total
Cypher
Taxus
Total
Cypher
Taxus
143
99
44
143
99
44
143
99
44
15.6 ⫾ 4.0 9.2 ⫾ 2.6 6.4 ⫾ 2.7
14.8 ⫾ 3.8 9.2 ⫾ 2.3 5.6 ⫾ 2.4
17.3 ⫾ 3.9 9.1 ⫾ 3.0 8.2 ⫾ 2.4
15.8 ⫾ 3.9 9.0 ⫾ 2.6 7.0 ⫾ 3.1
15.1 ⫾ 3.8 9.2 ⫾ 2.5 6.1 ⫾ 2.7
17.2 ⫾ 3.7 8.6 ⫾ 2.8 9.0 ⫾ 3.0
15.6 ⫾ 3.9 8.7 ⫾ 2.8 6.9 ⫾ 3.0
14.9 ⫾ 3.7 9.0 ⫾ 2.7 6.0 ⫾ 2.7
17.1 ⫾ 3.9 8.2 ⫾ 2.9 8.9 ⫾ 2.7
6.5 ⫾ 1.8 215 ⫾ 105 215 ⫾ 105 0⫾0 0⫾0 391 ⫾ 186 176 ⫾ 91 7.9 ⫾ 1.9 7.9 ⫾ 1.9 0⫾0 14.3 ⫾ 3.1 6.4 ⫾ 1.9
6.6 ⫾ 1.7 209 ⫾ 110 209 ⫾ 110 0⫾0 0⫾0 364 ⫾ 190 155 ⫾ 88 8.0 ⫾ 1.9 8.0 ⫾ 1.9 0⫾0 13.8 ⫾ 3.0 5.8 ⫾ 1.7
6.3 ⫾ 1.8 227 ⫾ 91 227 ⫾ 91 0⫾0 0⫾0 451 ⫾ 165 223 ⫾ 80 7.8 ⫾ 1.9 7.8 ⫾ 1.9 0⫾0 15.6 ⫾ 3.0 7.7 ⫾ 1.5
5.8 ⫾ 1.7* 217 ⫾ 14 199 ⫾ 97 17.9 ⫾ 20.0 8.1 ⫾ 7.1 430 ⫾ 204 213 ⫾ 107* 8.0 ⫾ 1.9 7.4 ⫾ 1.9* 0.6 ⫾ 0.6 15.8 ⫾ 3.2* 7.8 ⫾ 1.9*
6.0 ⫾ 1.8* 212 ⫾ 111 200 ⫾ 105 12.4 ⫾ 15.3 6.1 ⫾ 5.8 412 ⫾ 214 199 ⫾ 110* 8.1 ⫾ 1.8 7.6 ⫾ 2.0 0.5 ⫾ 0.4 15.6 ⫾ 3.4* 7.5 ⫾ 1.9*
5.1 ⫾ 1.4* 227 ⫾ 88 197 ⫾ 76 30.2 ⫾ 23.5 12.6 ⫾ 7.8 470 ⫾ 175 243 ⫾ 95 7.8 ⫾ 1.9 6.8 ⫾ 1.6* 1.0 ⫾ 0.8 16.2 ⫾ 2.9 8.4 ⫾ 1.6*
5.5 ⫾ 1.7* 217 ⫾ 104 194 ⫾ 95 23.2 ⫾ 25.0† 10.5 ⫾ 8.5† 446 ⫾ 208* 225 ⫾ 113* 8.0 ⫾ 1.9 7.2 ⫾ 1.9* 0.8 ⫾ 0.7 16.4 ⫾ 3.5* 8.3 ⫾ 2.2*,†
5.8 ⫾ 1.8* 213 ⫾ 111 197 ⫾ 105 15.7 ⫾ 17.1 7.9 ⫾ 6.9† 436 ⫾ 223* 219 ⫾ 121* 8.1 ⫾ 1.9 7.5 ⫾ 2.0 0.6 ⫾ 0.5 16.6 ⫾ 3.7* 8.3 ⫾ 2.4*,†
4.9 ⫾ 1.4* 228 ⫾ 88 187 ⫾ 69 40.0 ⫾ 31.2 16.3 ⫾ 9.1† 467 ⫾ 171 238 ⫾ 90 7.9 ⫾ 1.9 6.5 ⫾ 1.5* 1.3 ⫾ 0.8 16.1 ⫾ 2.9 8.2 ⫾ 1.6
10.5 ⫾ 3.6 6.8 ⫾ 2.3 3.7 ⫾ 1.9
10.4 ⫾ 3.6 6.9 ⫾ 2.2 3.5 ⫾ 1.8
10.7 ⫾ 3.7 6.6 ⫾ 2.7 4.2 ⫾ 2.0
10.8 ⫾ 3.5 6.9 ⫾ 2.2 3.9 ⫾ 1.9
10.7 ⫾ 3.6 7.1 ⫾ 2.2 3.6 ⫾ 1.9
10.9 ⫾ 3.2 6.4 ⫾ 2.1 4.5 ⫾ 1.8
10.9 ⫾ 3.6 6.7 ⫾ 2.2 4.1 ⫾ 2.2
10.9 ⫾ 3.6 7.0 ⫾ 2.3 3.8 ⫾ 2.0
11.0 ⫾ 3.6 6.1 ⫾ 1.8 4.9 ⫾ 2.3
The American Journal of Cardiology (www.AJConline.org)
Lesions (n) Proximal reference Mean external elastic membrane area (mm2) Mean lumen area (mm2) Mean plaque and media area (mm2) Stented segment Minimum lumen area (mm2) Stent volume (mm3) Lumen volume (mm3) Intimal hyperplasia volume (mm3) Intimal hyperplasia volume (%) External elastic membrane volume (mm3) Plaque and media volume (mm3) Normalized stent volume (mm2) Normalized lumen volume (mm2) Normalized Intimal hyperplasia volume (mm2) Normalized external elastic membrane volume (mm2) Normalized plaque and media volume (mm2) Distal reference Mean external elastic membrane area (mm2) Mean lumen area (mm2) Mean plaque and media area (mm2)
After Stenting
Coronary Artery Disease/Long-Term Vascular Effects of DES
restenosis was defined as diameter stenosis of ⬎50% at follow-up angiography. Intravascular ultrasonography was performed after intracoronary administration of 0.2 mg nitroglycerin using a motorized transducer pull back (0.5 mm/s) and a commercial scanner (Boston Scientific/SCIMED, Minneapolis, Minnesota) consisting of a rotating 30- or 40-MHz transducer within a 3.2Fr imaging sheath. Quantitative volumetric intravascular ultrasound analysis was performed as previously described.12–13 Using computerized planimetry (EchoPlaque, version 2.7, Indec Systems, MountainView, California). The stent and reference segments were assessed every 1 mm. The reference segment external elastic membrane, lumen, and plaque and media (external elastic membrane minus lumen) areas were measured over a 5-mm length adjacent to each stent edge and averaged. In-stent measurements were also obtained every 1 mm and included the external elastic membrane, stent, lumen (intrastent lumen bounded by the borders of the stent and IH), peri-stent plaque and media (external elastic membrane minus stent), and IH (stent minus intrastent lumen) areas and volumes. The percentage of IH was defined as the IH volume divided by the stent. All volumes were calculated using Simpson’s rule and then normalized for analysis length (normalized volume). Late stent malposition (LSM) was defined as the separation of at least one stent strut not in contact with 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 speckling behind the strut.7 Within the LSM sections, the LSM and plaque and media (external elastic membrane minus stent minus LSM) volumes (and normalized volumes) were calculated using Simpson’s rule. All statistical analyses were conducted using Statistical Package for Social Sciences software (SPSS, Chicago, Illinois). Categorical data are presented as numbers and percentages and compared using chi-square statistics or Fisher’s exact test. Continuous variables are presented as the mean ⫾ SD and compared using the unpaired or paired Student t test. All p values were 2-sided, and p ⬍0.05 indicated statistical significance. Results Complete serial (after stenting and 6-month and 2-year follow-up) qualitative angiographic and volumetric intravascular ultrasound data were available for 135 patients with 143 lesions (99 SES-treated lesions and 44 PES-treated lesions). The point of early and late follow-up was 7.0 ⫾ 2.1 months (range 4.6 to 11.7) and 25.1 ⫾ 3.6 months (range 21.7 to 30), respectively. The baseline clinical and procedural characteristics are summarized in Tables 1 and 2. Overall, 143 lesions were assessed with serial (baseline, early follow-up, and late follow-up) intravascular ultrasound examinations. The percentage of IH volume at 6 months was 8.1 ⫾ 7.1%; this was followed by an increase of 2.4 ⫾ 3.9% from 6 months to 2 years (p ⬍0.001 vs 6-month percentage of IH), with no correlation between the early and late increases in the percentage of IH. Also, no relation was found between the late percentage of IH and the overall duration of follow-up. However, 122 lesions
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(86%) had an increase in the percentage of IH from 6 months to 2 years, and 21 lesions (15%) had a decrease in the percentage of IH from 6 months to 2 years. Although the overall percentage of IH volume at 2 years was 10.5 ⫾ 8.5%, it was much greater in the PES-treated lesions than in the SES-treated lesions (16.3 ⫾ 9.1% vs 7.9 ⫾ 6.9%, respectively, p ⬍0.001; Figure 1). The IH volume in the 25 patients with diabetes mellitus was not different from that of the 110 patients without diabetes at 6 months (17.2 ⫾ 15.9 vs 18.0 ⫾ 20.8 mm3, p ⫽ 0.9) or 2 years (20.6 ⫾ 18.5 vs 23.8 ⫾ 26.2 mm3, respectively, p ⫽ 0.6). Similarly, the percentage of IH volumes in those with diabetes versus those without were virtually identical at 6 months (8.8 ⫾ 6.9% vs 8.0 ⫾ 7.2%, respectively, p ⫽ 0.6) and 2 years (10.5 ⫾ 7.9% vs 10.5 ⫾ 8.7%, p ⫽ 1.0). Finally, no significant difference was found in the late increase in the percentage of IH volume between those with (1.7 ⫾ 3.1%) and without (2.5 ⫾ 4.1%) diabetes (p ⫽ 0.4). Univariate analysis demonstrated that PES use, acute coronary syndrome, and normalized post-stenting peri-stent plaque and media volume correlated with the percentage of IH volume at 6 months and at 2 years. These variables were entered into a multivariate model predicting the percentage of IH at 6 months and 2 years. Stepwise linear regression analysis identified PES use as the only independent predictor for the percentage of IH volume at 6 months ( ⫽ 0.419, p ⬍0.001, 95% confidence interval [CI] 4.1 to 8.8). Additionally, the percentage of IH volume at 2 years was independently determined by PES use ( ⫽ 0.365, p ⬍0.001, 95% CI 3.7 to 9.7) and the post-stenting normalized plaque and media volume ( ⫽ 0.195, p ⫽ 0.020, 95% CI 0.1 to 1.6). However, when the percentage of IH at 6 months was forced into the model, the independent predictors of neointimal hyperplasia at 2 years were the percentage of IH at 6 months and the post-stenting normalized plaque and media volume, not PES use. Finally, among the variables of normalized plaque and media volume, PES use, and acute coronary syndrome, the only independent determinant for the late increase in the percentage of IH volume (between 6 months and 2 years) was the immediate post-stenting normalized plaque and media volume ( ⫽ 0.262, p ⫽ 0.002, 95% CI 0.2 to 0.8). Overall, the in-stent minimum lumen area decreased from 6.5 ⫾ 1.8 mm2 after stenting to 5.8 ⫾ 1.7 mm2 at 6 months (p ⫽ 0.001), with no subsequent reduction in minimum lumen area at 2 years of follow-up (5.5 ⫾ 1.7 mm2, p ⫽ 0.3 vs at 6 months). The minimum lumen area changes in SES-treated and PES-treated lesions were similar in that a significant decrease in the minimum lumen area was noted only in the early follow-up phase (Table 3). The in-stent minimum lumen area at 2 years of follow-up correlated negatively with the early increase in the percentage of IH volume at 6 months (r ⫽ ⫺0.422, p ⬍0.001) and also with the late percentage of IH volume increase (r ⫽ ⫺0.293, p ⬍0.001) and showed a positive relation with the baseline minimum stent area (r ⫽ 0.848, p ⬍0.001). No significant change was found in the normalized stent volume from baseline to 6 months or 2 years, but the normalized lumen volume decreased from 7.9 ⫾ 1.9 mm2 after intervention to 7.4 ⫾ 1.9 mm2 at 6 months (p ⫽ 0.017). The normalized external elastic membrane volume
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Table 4 Serial changes in intravascular ultrasound parameters over 2 years Variable Lesions (n) Between post-stenting and 6 months Proximal reference ⌬Mean external elastic membrane area (mm2) ⌬Mean lumen area (mm2) ⌬Mean plaque area (mm2) Stented segment ⌬Minimum lumen area (mm2) ⌬Stent volume (mm3) ⌬Lumen volume (mm3) ⌬Intimal hyperplasia volume (mm3) ⌬Intimal hyperplasia volume (%) ⌬External elastic membrane volume (mm3) ⌬Plaque and media volume (mm3) ⌬Normalized stent volume (mm2) ⌬Normalized lumen volume (mm2) ⌬Normalized external elastic membrane volume (mm2) ⌬Normalized plaque and media volume (mm2) Distal reference ⌬Mean external elastic membrane area (mm2) ⌬Mean lumen area (mm2) ⌬Mean plaque and media area (mm2) Between 6 months and 2 years Proximal reference ⌬Mean external elastic membrane area (mm2) ⌬Mean lumen area (mm2) ⌬Mean plaque area (mm2) Stented segment ⌬Minimum lumen area (mm2) ⌬Stent volume (mm3) ⌬Lumen volume (mm3) ⌬Intimal hyperplasia volume (mm3) ⌬Intimal hyperplasia volume (%) ⌬External elastic membrane volume (mm3) ⌬Plaque and media volume (mm3) ⌬Normalized stent volume (mm2) ⌬Normalized lumen volume (mm2) ⌬Normalized external elastic membrane volume (mm2) ⌬Normalized plaque and media volume (mm2) Distal reference ⌬Mean external elastic membrane area (mm2) ⌬Mean lumen area (mm2) ⌬Mean plaque and media area (mm2)
Total
Cypher
Taxus
143
99
44
0.2 ⫾ 2.0 ⫺0.2 ⫾ 1.5 0.6 ⫾ 1.9
0.3 ⫾ 0.5 0.0 ⫾ 0.9 0.5 ⫾ 1.2
⫺0.1 ⫾ 3.3 ⫺0.5 ⫾ 2.2 0.9 ⫾ 2.8
⫺0.8 ⫾ 0.8 1.9 ⫾ 5.8 ⫺15.8 ⫾ 21.5 17.8 ⫾ 20.0 8.1 ⫾ 7.1 39.1 ⫾ 32.2 36.5 ⫾ 30.8 0.1 ⫾ 0.2 ⫺0.5 ⫾ 0.6 1.5 ⫾ 1.0 1.4 ⫾ 0.9
⫺0.6 ⫾ 0.8 2.9 ⫾ 3.7 ⫺9.2 ⫾ 15.8 12.4 ⫾ 15.3 6.1 ⫾ 5.8 47.8 ⫾ 30.8 44.1 ⫾ 29.7 0.1 ⫾ 0.1 ⫺0.3 ⫾ 0.4 1.8 ⫾ 0.8 1.7 ⫾ 0.8
⫺1.2 ⫾ 0.8 ⫺0.3 ⫾ 8.5 ⫺30.6 ⫾ 25.0 30.2 ⫾ 23.6 12.5 ⫾ 7.8 19.4 ⫾ 26.4 19.7 ⫾ 26.7 0.0 ⫾ 0.3 ⫺1.0 ⫾ 0.8 0.6 ⫾ 0.9 0.7 ⫾ 1.0
0.2 ⫾ 1.4 0.0 ⫾ 1.0 0.2 ⫾ 0.9
0.2 ⫾ 0.4 0.1 ⫾ 0.3 0.1 ⫾ 0.2
0.2 ⫾ 2.4 ⫺0.2 ⫾ 1.8 0.3 ⫾ 1.5
⫺0.1 ⫾ 1.3 ⫺0.2 ⫾ 1.0 ⫺0.1 ⫾ 1.8*
0.0 ⫾ 0.5* ⫺0.1 ⫾ 0.3 ⫺0.1 ⫾ 0.9*
⫺0.1 ⫾ 2.1 ⫺0.3 ⫾ 1.6 ⫺0.1 ⫾ 2.7
⫺0.2 ⫾ 0.5* 0.5 ⫾ 4.6* ⫺5.0 ⫾ 11.0* 5.3 ⫾ 10.1* 2.4 ⫾ 3.9* 16.7 ⫾ 39.2* 12.7 ⫾ 31.8* 0.0 ⫾ 0.1* ⫺0.2 ⫾ 0.4* 0.6 ⫾ 1.5* 0.5 ⫾ 1.1*
⫺0.2 ⫾ 0.4* 0.4 ⫾ 3.1* ⫺3.2 ⫾ 6.7* 3.3 ⫾ 4.8* 1.8 ⫾ 2.7* 24.2 ⫾ 43.2* 20.3 ⫾ 33.8* 0.0 ⫾ 0.1* ⫺0.1 ⫾ 0.3* 0.9 ⫾ 1.7* 0.8 ⫾ 1.2*
⫺0.3 ⫾ 0.7* 0.8 ⫾ 7.0 ⫺9.0 ⫾ 16.6* 9.8 ⫾ 16.0* 3.7 ⫾ 5.7* ⫺3.5 ⫾ 16.9* ⫺4.4 ⫾ 17.6* 0.0 ⫾ 0.2 ⫺0.3 ⫾ 0.5* ⫺0.1 ⫾ 0.6* ⫺0.1 ⫾ 0.6*
0.1 ⫾ 1.6 ⫺0.1 ⫾ 1.0 0.2 ⫾ 1.0
0.1 ⫾ 0.7 ⫺0.1 ⫾ 0.3* 0.1 ⫾ 0.5
0.1 ⫾ 2.7 ⫺0.3 ⫾ 1.7 0.4 ⫾ 1.6
* p ⬍0.05 versus change between post-stenting and 6 months.
increased from 14.3 ⫾ 3.1 mm2 after stenting to 15.8 ⫾ 3.2 mm2 at 6 months (p ⬍0.001). Late changes in the normalized lumen and external elastic membrane volumes were insignificant. The normalized plaque and media volume increased significantly during both the early follow-up period (from 6.4 ⫾ 1.9 mm2 after stenting to 7.8 ⫾ 1.9 mm2 at 6 months, p ⬍0.001) and the late follow-up period (from 7.8 ⫾ 1.9 mm2 at 6 months to 8.3 ⫾ 2.2 mm2 at 2 years, p ⫽ 0.041), although the late increases in the normalized plaque and media volume were less than the early increases (Table 4). Of the 22 lesions identified with LSM (15.4%), 17 LSMs were detected at 6 months and another 5 LSM at 2 years. Overall, 20 of 99 SES-treated lesions developed LSM compared to 2 of 44 PES-treated lesions (p ⫽ 0.031). No case of LSM found at 6 months had resolved at 2 years.
The overall duration of clinical follow-up for these 135 patients was 61 ⫾ 7 months. Overall, 4 patients (3.0%) died from noncardiac causes and 1 (0.7%) from sudden death. Stent thrombosis occurred in 1 patient (0.7%), and acute myocardial infarction occurred in 2 (1.5%). Target vessel revascularization was necessary in 10 patients (7.4%). Discussion The present study, with baseline, early follow-up, and late follow-up serial volumetric intravascular ultrasound analysis, has shown a significant increase in the percentage of IH volume only during the early phase. This was followed by only a modest increase in the percentage of IH from 6 months to 2 years, averaging 30% of the earlier
Coronary Artery Disease/Long-Term Vascular Effects of DES
neointimal proliferation, with no correlation in neointimal proliferation between the 2 points. The changes in minimum lumen area paralleled the changes in the percentage of IH volume because of the lack of late (after 6 months) chronic stent recoil. Therefore, despite concerns about long-term DES efficacy, the magnitude of IH increase and lumen decrease was less over time. Because the greatest neointimal proliferation and luminal renarrowing after DES implantation were confined to the first 6 months, the rate of clinical restenosis requiring target lesion revascularization in patients who avoided early repeat intervention was relatively low (3%) during the subsequent 18 months. The present study is one of only a few long-term intravascular ultrasound analyses of DES. We previously reported “late catch-up” of IH after DES implantation with nonpolymer-encapsulated PESs.3 Greater 6-month suppression of IH occurred within high-dose stents, paradoxically followed by a greater increase in IH at 2 years in the same high-dose stents. Late restenosis was explained by delayed healing and the local vascular toxic effect of high-dose paclitaxel.14 This was supported by preclinical animal studies showing delayed inflammation and cellular proliferation.1,15,16 In 26 patients in their first-in-humans study, Sousa et al17,18 reported serial intravascular ultrasound analysis of SES during a 4-year period that showed that the percentage of IH volume remained minimal at ⱕ4 years with no late catch-up. In our study, PES use was an independent predictor of the early increase in the percentage of IH volume at 6 months. This was consistent with the findings from many clinical trials and registries showing that PES implantation was associated with more neointimal proliferation than SES implantation.19,20 The present analysis has extended these observations by showing that this difference between PESs and SESs continues out to 2 years but did not increase. The difference between PESs and SESs at 2 years appeared to result entirely from the difference at 6 months; PES use was an independent predictor of the 2-year percentage of IH only when the 6-month neointimal hyperplasia was not in the model. In the present analysis, DES-dependent antiproliferative effects appeared to be eliminated beyond 6 months; thus, different mechanisms might be involved in determining late neointimal proliferation, however modest. Previous histologic studies in the bare metal stent era have indicated that the degree of in-stent neointimal proliferation correlated with the peri-stent plaque burden.21 This was one of a group of “minor” predictors of bare metal in-stent restenosis that included preintervention remodeling, among others; recent DES studies have reported inconsistent results relating residual peri-stent plaque burden to IH or angiographic restenosis.22,23 Although preintervention intravascular ultrasound data were not available for the present patient cohort and therefore preintervention remodeling could not be assessed, postintervention peri-stent plaque was a predictor of the percentage of IH increase from 6 months to 2 years, as well as of the percentage of IH at 2 years. Thus, when the differential, antiproliferative effects of PES versus SES decreased over time, the magnitude of peri-stent plaque appeared to re-emerge as a predictors of late DES neointimal hyperplasia. Other similar “minor” predictors of in-stent
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restenosis deserve repeat study as determinants of late neointimal proliferation. Alternatively, the potent antiproliferative action of DESs might have caused deleterious local effects on the vascular wall that occurred only late and that were mediated by the peri-stent plaque burden.13,14 The main reason for the high incidence of restenosis in patients with diabetes mellitus has been explained by the exaggerated IH in both stented and nonstented lesions.24 –26 Our data have indicated that the intimal growth at 6 months and the changes in the IH volume after 6 months were similar between those with and without diabetes. DESs appeared to effectively inhibit IH in patients with as well as without diabetes beyond the follow-up period, consistent with the findings from previous investigations.27 In our study, no patient showed late regression of LSM detected at 6 months, regardless of the stent type used, and 5 cases of LSM were newly detected at 2 years. One follow-up series of SES-treated patients revealed no change in LSM from 6 months to 2 years,28 and another study of selected patients treated with the Taxus-II stent showed that LSM tended to regress in the PES-treated patients.29 This was not a randomized comparison of SES versus PES. Pitfalls regarding the small sample size and potential for selection bias should be considered in the interpretation of these data. Most patients who were invited to return for late follow-up refused, and patients with restenosis at 6 months were excluded. 1. Liistro F, Stankovic G, Di Mario C, Takagi T, Chieffo A, Moshiri S, Montorfano M, Carlino M, Briguori C, Pagnotta P, Albiero R, Corvaja N, Colombo A. First clinical experience with a paclitaxel derivateeluting polymer stent system implantation for in-stent restenosis: immediate and long-term clinical and angiographic outcome. Circulation 2002;105:1883–1886. 2. Finn AV, Nakazawa G, Joner M, Kolodgie FD, Mont EK, Gold HK, Virmani R. Vascular responses to drug eluting stents: importance of delayed healing. Arterioscler Thromb Vasc Biol 2007;27:1500 –1510. 3. Park DW, Hong MK, Mintz GS, Lee CW, Song JM, Han KH, Kang DH, Cheong SS, Song JK, Kim JJ, Weissman NJ, Park SW, Park SJ. Two-year follow-up of the quantitative angiographic and volumetric intravascular ultrasound analysis after nonpolymeric paclitaxel-eluting stent implantation: late “catch-up” phenomenon from ASPECT study. J Am Coll Cardiol 2006;48:2432–2439. 4. Cook S, Wenaweser P, Togni M, Billinger M, Morger C, Seiler C, Vogel R, Hess O, Meier B, Windecker S. Incomplete stent apposition and very late stent thrombosis after drug-eluting stent implantation. Circulation 2007;115:2426 –2434. 5. Hong MK, Mintz GS, Lee CW, Kim YH, Lee SW, Song JM, Han KH, Kang DH, Song JK, Kim JJ, Park SW, Park SJ. Incidence, mechanism, predictors, and long-term prognosis of late stent malapposition after bare-metal stent implantation. Circulation 2004;109:881– 886. 6. Hong MK, Mintz GS, Lee CW, Park DW, Park KM, Lee BK, Kim YH, Song JM, Han KH, Kang DH, Cheong SS, Song JK, Kim JJ, Park SW, Park SJ. Late stent malapposition after drug-eluting stent implantation: an intravascular ultrasound analysis with long-term follow-up. Circulation 2006;113:414 – 419. 7. Shah VM, Mintz GS, Apple S, Weissman NJ. Background incidence of late malapposition after bare-metal stent implantation. Circulation 2002;106:1753–1755. 8. Ryan TJ, Faxon DP, Gunnar RM, Kennedy JW, King SB III, Loop FD, Peterson KL, Reeves TJ, Williams DO, Winters WL Jr, et al. Guidelines for percutaneous transluminal coronary angioplasty: A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee on Percutaneous Transluminal Coronary Angioplasty). Circulation 1988;78:486 –502. 9. Popma JJ, Leon MB, Moses JW, Holmes DR Jr, Cox N, Fitzpatrick M, Douglas J, Lambert C, Mooney M, Yakubov S, Kuntz RE; SIRIUS
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