Comparison of Neointimal Coverage by Optical Coherence Tomography of a Sirolimus-Eluting Stent Versus a Bare-Metal Stent Three Months After Implantation

Comparison of Neointimal Coverage by Optical Coherence Tomography of a Sirolimus-Eluting Stent Versus a Bare-Metal Stent Three Months After Implantation Yong Xie, MDa, Masamichi Takano, MD, PhDa,*, Daisuke Murakami, MDb, Masanori Yamamoto, MDb, Kentaro Okamatsu, MDb, Shigenobu Inami, MDb, Koji Seimiya, MDb, Takayoshi Ohba, MDb, Yoshihiko Seino, MD, PhDb, and Kyoichi Mizuno, MD, PhDa No detailed data regarding neointimal coverage of bare-metal stents (BMSs) at 3 months after implantation was reported to date. This investigation was designed to evaluate the neointimal coverage of BMSs compared with sirolimus-eluting stents (SESs) using optical coherence tomography. A prospective optical coherence tomographic follow-up examination was performed 3 months after stent implantation for patients who underwent BMS (n ⴝ 16) or SES implantation (n ⴝ 24). Neointimal hyperplasia (NIH) thickness on each stent strut and percentage of NIH area in each cross section were measured. Malapposition of stent struts to the vessel wall and the existence of in-stent thrombi were also evaluated. There were 5,076 struts of SESs and 2,875 struts of BMSs identified. NIH thickness and percentage of NIH area in the BMS group were higher than in the SES group (351 ⴞ 248 vs 31 ⴞ 39 ␮m; p <0.0001; 45.0 ⴞ 14% vs 10.0 ⴞ 4%; p <0.0001, respectively). The frequency of uncovered struts was higher in the SES group than the BMS group (15% vs 0.1%; p <0.0001). Malapposed struts were observed more frequently in the SES group than the BMS group (15% vs 1.1%; p <0.0001). In conclusion, there was no difference in incidence of in-stent thrombus between the 2 groups (14% vs 0%; p ⴝ 0.23). The present study showed almost all BMS struts to be well covered at a 3-month follow-up, suggesting that patients receiving BMS stents may not require dual-antiplatelet therapy >3 months after implantation. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;102: 27–31)

There were reports that neointimal coverage over a sirolimus-eluting stent (SES) evaluated using optical coherence tomography (OCT) was incomplete at 3 to 6 months after implantation.1,2 Although some angioscopic studies suggested that completion of neointimal coverage of bare-metal stents (BMSs) required approximately 3 to 6 months,3,4 no detailed information for neointimal coverage over BMSs evaluated using OCT 3 months after implantation was reported to date. This study was designed to evaluate the neointimal coverage of SESs in comparison to BMSs 3 months after implantation using OCT. Methods Twenty-four patients (24 lesions) undergoing implantation of an SES (Cypher; Cordis Corp., Miami Lakes, a Division of Cardiology, Nippon Medical School, Tokyo; and bCardiovascular Center, Chiba-Hokusoh Hospital, Nippon Medical School, Chiba, Japan. Manuscript received December 10, 2007; revised manuscript received and accepted February 26, 2008. This work was supported in part by the Japan-China Sasakawa Medical Fellowship, Tokyo, Japan. *Corresponding author: Tel.: ⫹81-03-3822-2514; fax: ⫹81-03-5685-0987. E-mail address: [email protected] (M. Takano).

0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.02.091

Florida) from December 2005 to March 2006 and 16 patients (16 lesions) treated using a BMS (Multilink Vision; Guidant Corp., Santa Clara, California; Liberté; Boston Scientific Corp., Natick, Massachusetts; or Sstent; Biosensors Int., Newport Beach, California) from April 2007 to July 2007 in native coronary arteries were identified as the SES and BMS groups, respectively. We previously reported part of the SES data.1 Exclusion criteria for optical coherence tomographic examination were (1) unprotected left main coronary artery disease, (2) restenotic lesions, (3) chronic renal failure (serum creatinine ⱖ2.5 mg/dl) without regular hemodialysis, (4) severely decreased left ventricular systolic function (ejection fraction ⬍30%), and (5) large vessel diameter (ⱖ4.5 mm). All patients received dual-antiplatelet therapy (ticlopidine 200 mg/day and aspirin 100 mg/day) before coronary intervention. During this study period, clopidogrel had not been approved for clinical use in Japan. The Medical Ethics Committee at Chiba-Hokusoh Hospital (Chiba, Japan) approved this study, and written informed consent was obtained from all patients. Patient demographics were obtained using hospital chart review. Acute myocardial infarction was defined as typical increase and decrease in cardiac biochemical markers (troponin-T) with electrocardiographic changes indicative of www.AJConline.org

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The American Journal of Cardiology (www.AJConline.org) Table 1 Clinical demographics

Figure 1. Optical coherence tomographic images at 3 months after stent implantation. (A) Intracoronary thrombus. At 9:00 o’clock of the image, a protruding mass (arrows) was clearly visualized beyond the SES struts into the lumen. (B) Typical cross-sectional image of a BMS. The stent struts appear to be well apposed and covered by thick neointima. (C) Typical cross-sectional image of an SES shows incomplete neointimal coverage over the struts. The optical coherence tomographic image shows the stent struts to be exposed to the lumen (arrows) or covered by thin neointima. (D) Malapposed struts of an SES. Twelve stent struts with shadowing were clearly visualized in a SES cross-section. From 10:00 o’clock to 1:00 o’clock, 4 stent struts seemed to float into the lumen with an extrastent area and then were uncovered by neointima (arrows).

ischemia and/or ischemic symptoms. Unstable angina was defined as electrocardiogram ST-segment depression or prominent T-wave inversion without increase in cardiac biochemical markers in a clinical setting (chest discomfort or anginal equivalents). Patients with unstable angina and acute myocardial infarction were categorized as having acute coronary syndrome.5,6 Stable coronary artery disease was defined as episodic precordial chest discomfort typically provoked by stress or exertion that rapidly resolved with rest or nitrates. There was no change in frequency or severity for ⱖ2 months. All angiograms were analyzed using a computer-assisted automated edge-detection algorithm (CMS; Medis, Nuenen, The Netherlands) by an investigator blinded to patient information using standard qualitative definitions and quantitative coronary angiographic measurements. In-stent restenosis was defined as ⱖ50% diameter stenosis at follow-up. The OCT system used in this study consisted of a computer, monitor display, interface unit (Model M2 Cardiology Imaging System; LightLab Imaging, Inc., Westford, Massachusetts), and a 0.014-inch wire-type imaging catheter (ImageWire; LightLab Imaging, Inc.). With the help of a 6- or 7-Fr guiding catheter, an overthe-wire type occlusion balloon catheter (Helios; Avantec Vascular Corp., Sunnyvale, California) with the flush lumen and lumen for the imaging catheter was advanced into the coronary artery and positioned proximal to the stent. To remove blood from the field of view and allow clear images, the occlusion balloon was inflated to 0.4 to 0.6 atm and Ringer’s lactate was infused at 0.5 to 1.0 ml/s. The image

Variable

SES (n ⫽ 24)

BMS (n ⫽ 16)

p Value

Age (yrs) Men Diabetes mellitus Dyslipidemia* Hypertension Smoker Obesity† Reason for SES implantation Acute coronary syndrome Stable coronary artery disease‡ Medication Aspirin Ticlopidine Dual-antiplatelet therapy Warfarin Coronary artery with SES Right Left anterior descending Left circumflex Reference vessel diameter Lesion length (mm) Length of stent segment (mm) No. of stents Multiple overlapping stents Bifurcating stent Restenosis

64 ⫾ 12 21 (88%) 8 (33%) 19 (79%) 18 (75%) 9 (38%) 11 (46%)

67 ⫾ 9 10 (63%) 5 (31%) 13 (81%) 13 (81%) 5 (31%) 8 (50%)

0.40 0.12 ⬎0.99 ⬎0.99 0.72 0.75 ⬎0.99

12 (50%) 12 (50%)

9 (56%) 7 (44%)

0.76 0.76

24 (100%) 24 (100%) 24 (100%) 1 (4%)

16 (100%) 14 (88%) 16 (100%) 0 (0%)

4 (17%) 14 (58%) 6 (25%) 2.8 ⫾ 0.3 26 ⫾ 12 30 ⫾ 11 1.6 ⫾ 0.8 9 (38%) 2 (8%) 1 (4%)

9 (56%) 7 (44%) 0 (0%) 3.1 ⫾ 0.3 20 ⫾ 10 23 ⫾ 10 1.1 ⫾ 0.4 2 (13%) 0 (0%) 3 (19%)

⬎0.99 0.15 ⬎0.99 ⬎0.99

0.12 0.004 0.11 0.048 0.01 0.15 0.51 0.28

Values expressed as number (percent) or mean ⫾ SD. * Total cholesterol ⱖ220 mg/dl, low-density lipoprotein cholesterol ⱖ140 mg/dl, triglycerides ⱖ150 mg/dl, or use of lipid-lowering agent. † Body mass index ⱖ25 kg/m2. ‡ Episodic precordial chest discomfort typically provoked by stress or exertion that rapidly resolved with rest or nitrates. There was no change in frequency or severity for ⱖ2 months.

wire was pulled from distal to proximal to the stent using a motorized pull-back system at 1.0 mm/s, and optical coherence tomographic images were acquired at 15 frames/s. Cross-sectional optical coherence tomographic images were analyzed at 1-mm intervals (every 15 frames). Neointimal hyperplasia (NIH) thickness inside all stent struts was measured. Stent area and lumen area in every image were measured using manual tracing, and percentage of NIH area was calculated as ([stent area ⫺ lumen area]/stent area) ⫻ 100. NIH thickness of 0 ␮m was defined as exposure (uncovered). In the SES group, a maximum distance ⬎160 ␮m (thickness of strut and polymer) between the inner strut surface and adjacent vessel surface was defined as malapposition. In the BMS group, a maximum distance between the inner strut surface and adjacent vessel surface greater than the thickness of the stent strut (Multilink Vision ⫽ 80 ␮m, Liberté ⫽ 95 ␮m, S-stent ⫽ 117.5 ␮m) was defined as malapposition. On an image of stent malapposition, lumen area was divided into in-stent lumen area and extrastent lumen area. Intracoronary thrombus was defined as a protruding mass beyond the stent strut into the lumen (Figure 1). Stents overlapping segments and bifurcation lesions with major side branches

Coronary Artery Disease/OCT Comparison of SES vs BMS Table 3 Optical coherence tomographic analysis for cross sections

Table 2 Optical coherence tomography analysis for stent struts

NIH thickness (␮m) Uncovered struts Malapposed struts Uncovered struts with malapposition

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SES (5,076 struts)

BMS (,2875 struts)

p Value

31 ⫾ 39 741 (15%) 777 (15%) 320 (6%)

351 ⫾ 248 3 (0.1%) 33 (1.1%) 3 (0.1%)

⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001

Values expressed as number (percent) or mean ⫾ SD.

No. of cross sections Stent area (mm2) Lumen area (mm2) Extastent lumen area (mm2) NIH area (mm2) NIH area (%) Cross sections with uncovered strut(s) Cross sections with uncovered strut ratio ⬎0.3

SES

BMS

632 8.9 ⫾ 2.2 8.0 ⫾ 2.1 1.1 ⫾ 0.6 (n ⫽ 98) 0.9 ⫾ 0.3 10.0 ⫾ 3.9 404 (63%) (n ⫽ 664) 116 (18%) (n ⫽ 664)

279 11.2 ⫾ 3.1 6.2 ⫾ 2.3 0.9 ⫾ 0.4 (n ⫽ 9) 5.03 ⫾ 2.1 45.0 ⫾ 13.9 3 (1%) (n ⫽ 288) 0 (0%) (n ⫽ 288)

p Value ⬍0.0001 ⬍0.0001 0.33 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001

Values expressed as number (percent) or mean ⫾ SD.

Figure 2. Relations between distribution of NIH thickness and stent types. In the BMS group, percentages of struts with NIH thickness of 0, 10 to 50, 60 to 100, 110 to 150, 160 to 200, 210 to 250, and ⱖ260 ␮m were 0.1%, 6.2%, 8.6%, 8.3%, 8.5%, 9.8%, and 58.5%, respectively. Those in the SES group were 15%, 71%, 8%, 4%, 1%, 0%, and 1%, respectively.

were excluded from this analysis. Inter- and intraobserver variability was assessed by evaluation of 50 random cross-sectional images by 2 independent readers and the same reader at 2 separate times, respectively. Categorical variables were presented as frequencies and analyzed using either chi-square test or Fisher’s exact test. Continuous quantitative data were presented as mean ⫾ SD. Continuous data were compared using unpaired Student’s t test or Wilcoxon’s rank-sum test between different categories. A p value ⬍0.05 was considered statistically significant. Results Clinical characteristics of the study population are listed in Table 1. The BMS group had larger reference diameters, and accordingly, the stent diameter of the BMS (n ⫽ 18) was larger than that of the SES (n ⫽ 38; 3.3 ⫾ 0.4 vs 2.9 ⫾ 0.4 mm; p ⫽ 0.001). Stent segment length was shorter in BMS group than the SES group. The BMS group tended to show an increased rate of restenosis in comparison to the SES group. The rates were not statistically significant. There were no optical coherence tomographic procedure– related complications. Results of strut analysis are listed in Table 2. NIH thickness was greater in the BMS group than the SES group. Distributions of NIH thickness at intervals of 50 ␮m are shown in Figure 2. The ratio of the struts in which NIH thickness was ⱕ50 ␮m was higher in the SES group than the BMS group, whereas those ⱖ260 ␮m were

higher in the BMS group than the SES group. Only 3 struts (0.1%) in 3 patients (19%) in the BMS group were uncovered in comparison to 741 struts (15%) in 23 patients (96%) in the SES group. Malapposed struts and uncovered struts with malapposition were observed more frequently in the SES group than the BMS group. There were 24 cross sections in 11 overlapping segments, 8 cross sections located in a major branch in the SES group and 9 cross sections in 3 overlapping segments in the BMS group. These cross sections were excluded from the area analysis. Finally, area measurements were performed in 632 cross sections in the SES group and 279 cross sections in the BMS group. The BMS group had a larger stent area in comparison to the SES group. However, BMS lumen areas were much smaller than those for SESs. NIH area and percentage of NIH area were significantly lower in the SES group than the BMS group. Ninety-eight cross sections in the SES group and 9 cross sections in the BMS group were found to have extrastent lumens, and areas of the extrastent lumens were similar between the 2 groups. Significant differences existed between the 2 groups with regard to cross sections with uncovered struts and cross sections with an uncovered strut ratio ⬎0.3 (Table 3). Intraobserver variabilities in the measurement of thickness or distance and the measurement of area were 6 ⫾ 8 ␮m and 0.3 ⫾ 0.5 mm2, and interobserver variabilities were 8 ⫾ 8 ␮m and 0.2 ⫾ 0.4 mm2, respectively. Three thrombi were found in 3 patients with acute coronary syndrome in the SES group and none in the BMS group. The difference in rates of in-stent thrombi was not statistically significant between the 2 groups (14% vs 0%; p ⫽ 0.23). The 3 patients received dual-antiplatelet therapy and were found to have uncovered struts and a cross section with uncovered struts. Discussion Pathologic research showed that incomplete neointimal coverage of stent struts is the most powerful morphometric predictor of late stent thrombosis.7 Recent angioscopic studies also showed that thrombi were commonly seen in SESs with incomplete neointimal coverage.8,9 Therefore, to confirm complete neointimal coverage after stent implantation is clinically important.

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There were reports that used OCT to show that neointimal coverage over an SES was incomplete 3 to 6 months after implantation.1,2 Previous postmortem research showed that the time needed to establish complete stent endothelialization with a BMS in humans probably was 3 to 4 months.10,11 Some angioscopic studies suggested that completion of neointimal coverage of BMSs in vivo required approximately 3 to 6 months.3,4 Although angioscopy provides direct visualization of the luminal surface, it cannot quantify the proportion and thickness of neointimal coverage. Intravascular ultrasound (IVUS) was also used to evaluate NIH after stent deployment.12 Nevertheless, the resolution of the IVUS may not be sufficient to provide detailed information about the neointima.13 OCT was recently introduced as a high-resolution imaging method. Axial resolution of OCT is approximately 10 to 20 ␮m, about 10 times higher than that of IVUS. The high resolution of OCT makes it an ideal method to identify vulnerable plaques and monitor structural changes after stent implantation.13,14 This imaging modality can clearly visualize Malapposed stent struts and neointima formation that could not be visualized completely using IVUS.13 In the present OCT study, most BMS struts (77%) were covered by neointima measuring ⬎150 ␮m in thickness, whereas the thickness of the NIH over most SES struts (86%) was ⬍50 ␮m at 3-month follow-up. In addition, although the SES group had a larger lumen area, frequencies of uncovered struts and cross sections with uncovered struts were much higher in the SES group in comparison to the BMS group. These findings verified the premise that SES not only inhibited hyperproliferation of neointima, resulting in restenosis, but also suppressed the endothelial healing process over the struts, thus leaving the metallic struts and polymer exposed to the lumen as thrombogenic components.15 Furthermore, in this series, uncovered struts existed in both the SES and BMS groups. In the SES group, uncovered struts were found in 63% of total cross sections in 96% of patients. Nevertheless, thrombi were found in only 14%. In other words, in this study, most uncovered struts were clinically harmless or innocent. This finding implies that formation of a late stent thrombus is a multifactorial process. Uncovered struts, especially those with a ratio ⬎0.3, may only provide an underlying substrate for thrombosis, which participates in the development of stent thrombus in combination with other clinical or procedural risk factors.16 Recent studies showed that stent malapposition had an important role in the pathogenesis of late stent thrombosis.17 In this OCT investigation, 15% of total stent struts in the SES group were malapposed, significantly more than that in the BMS group. These results correlated with those of a previous RAndomized study with the sirolimus-eluting Velocity balloon-expandable stent in the treatment of patients with de novo native coronary artery Lesions (RAVEL).18 Several speculative hypotheses were raised to explain this difference. First, antiproliferative and antimetabolic effects of the drug may prevent the growth of tissue in the space between the struts and vessel wall. Second, local arterial hypersensitivity reactions secondary to the polymer and drug can induce

vessel positive remodeling out of proportion to the increase in peristent intimal hyperplasia. There are several limitations to this study. First, this was not a randomized study, and the number of patients enrolled in the study was relatively small. Therefore, it was not the purpose of this study to identify clinical factors influencing neointimal coverage over the stent struts. Second, although OCT has higher resolution in comparison to other imaging modalities, it is still insufficient to make an accurate distinction between fibrin and NIH and also determine whether the neointima is covered by a layer of endothelial cells. Finally, because OCT examination was not performed immediately after the index procedure, it was not possible to identify when thrombosis occurred and whether malapposition of stent struts was late acquired or persistent. 1. Takano M, Inami S, Jang IK, Yamamoto M, Murakami D, Seimiya K, Ohba T, Mizuno K. Evaluation by optical coherence tomography of neointimal coverage of sirolimus-eluting stent three months after implantation. Am J Cardiol 2007;99:1033–1038. 2. Matsumoto D, Shite J, Shinke T, Otake H, Tanino Y, Ogasawara D, Sawada T, Paredes OL, Hirata K, Yokoyama M. Neointimal coverage of sirolimus-eluting stents at 6-month follow-up: evaluated by optical coherence tomography. Eur Heart J 2007;28:961–967. 3. Ueda Y, Nanto S, Komamura K, Kodama K. Neointimal coverage of stents in human coronary arteries observed by angioscopy. J Am Coll Cardiol 1994;23:341–346. 4. Sakai S, Mizuno K, Yokoyama S, Tanabe J, Shinada T, Seimiya K, Takano M, Ohba T, Tomimura M, Uemura R, Imaizumi T. Morphologic changes in infarct-related plaque after coronary stent placement: a serial angioscopy study. J Am Coll Cardiol 2003;42: 1558 –1565. 5. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE, Fesmire FM, Hochman JS, Levin TN, et al. ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non–ST-Elevation Myocardial Infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non–ST-Elevation Myocardial Infarction). Circulation 2007;116: e148 – e304. 6. Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Circulation 2007;116:2634 –2653. 7. Finn AV, Joner M, Nakazawa G, Kolodgie F, Newell J, John MC, Gold HK, Virmani R. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation 2007;115:2435–2441. 8. Takano M, Yamamoto M, Xie Y, Murakami D, Inami S, Okamatsu K, Seimiya K, Ohba T, Seino Y, Mizuno K. Serial long-term evaluation of neointimal stent coverage and thrombus after sirolimus-eluting stent implantation by use of coronary angioscopy. Heart 2007;93:1353– 1356. 9. Kotani J, Awata M, Nanto S, Uematsu M, Oshima F, Minamiguchi H, Mintz GS, Nagata S. Incomplete neointimal coverage of sirolimuseluting stents: angioscopic findings. J Am Coll Cardiol 2006;47:2108 – 2111. 10. Farb A, Burke AP, Kolodgie FD, Virmani R. Pathological mechanisms of fatal late coronary stent thrombosis in humans. Circulation 2003; 108:1701–1706. 11. Grewe PH, Deneke T, Machraoui A, Barmeyer J, Muller KM. Acute and chronic tissue response to coronary stent implantation: pathologic findings in human specimen. J Am Coll Cardiol 2000;35:157–163. 12. Hoffmann R, Mintz GS, Dussaillant GR, Popma JJ, Pichard AD, Satler LF, Kent KM, Griffin J, Leon MB. Patterns and mechanisms of in-stent restenosis. A serial intravascular ultrasound study. Circulation 1996;94:1247–1254.

Coronary Artery Disease/OCT Comparison of SES vs BMS 13. Kume T, Akasaka T, Kawamoto T, Watanabe N, Toyota E, Sukmawan R, Sadahira Y, Yoshida K. Visualization of neointima formation by optical coherence tomography. Int Heart J 2005;46:1133–1136. 14. Kubo T, Imanishi T, Takarada S, Kuroi A, Ueno S, Yamano T, Tanimoto T, Matsuo Y, Masho T, Kitabata H, et al. Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J Am Coll Cardiol 2007;50:933–939. 15. Joner M, Finn AV, Farb A, Mont EK, Kolodgie FD, Ladich E, Kutys R, Skorija K, Gold HK, Virmani R. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193–202. 16. Luscher TF, Steffel J, Eberli FR, Joner M, Nakazawa G, Tanner FC, Virmani R. Drug-eluting stent and coronary thrombosis: biological

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mechanisms and clinical implications. Circulation 2007;115: 1051–1058. 17. 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. 18. Serruys PW, Degertekin M, Tanabe K, Abizaid A, Sousa JE, Colombo A, Guagliumi G, Wijns W, Lindeboom WK, Ligthart J, de Feyter PJ, Morice MC; RAVEL Study Group. Intravascular ultrasound findings in the multicenter, randomized, double-blind RAVEL (RAndomized study with the sirolimus-eluting VElocity balloon-expandable stent in the treatment of patients with de novo native coronary artery Lesions) trial. Circulation 2002;106:798 – 803.