Abstract: Background. Serial changes in strut coverage of drug-eluting stents (DESs), which are placed across side-branch vessels, remain unclear. Methods. The changes in strut coverage of DESs crossing side-branch vessels (size ≥2.0 mm) were serially evaluated by optical coherence tomography (OCT) in 30 patients at 9 months and 2 years after the index DES implantation. DESs were paclitaxel-eluting stents (PESs), sirolimus-eluting stents (SESs), and zotarolimus-eluting stents (ZESs), each in 10 patients. Measured neointimal hyperplasia (NIH) thickness of 0 μm on OCT was defined as an uncovered strut. Results. The percentage of uncovered side-branch struts significantly decreased from 55.7 ± 39.9% to 36.6 ± 32.0% (P<.0001) on serial follow-up: PES, 93.4 ± 10.5% to 67.6 ± 24.2%, P=.018; SES, 47.5 ± 34.4% to 29.6 ± 24.1%, P=.036; and ZES, 26.2 ± 34.8% to 12.4 ± 19.0%, P=.028. Among covered side-branch struts, the overall percentage of struts with NIH thickness more than 30 µm significantly increased from 36.3 ± 37.4% to 51.0 ± 36.0% (P<.0001). However, compared to other DES types, a significant increase in relatively thin NIH (0 to 30 µm) was observed in PESs (1.6 ± 3.4% to 17.4 ± 16.0%; P=.018). Conclusion. Serial follow-up OCT examination showed a significant decrease in the percentage of uncovered side-branch struts, and the coverage pattern differed with DES type.
J INVASIVE CARDIOL 2012;24(11):569-573
Key words: optical coherence tomography, stent
The attachment of stent struts to vessel walls allows migration and proliferation of smooth muscle cells from the media. However, because stent struts positioned across side-branch vessels are not intrinsically attached to the vessel wall, neointimal coverage on these struts may be expected to be poor or absent. Although drug-eluting stents (DESs) have reduced the rate of restenosis compared to bare-metal stents, safety concerns over the occurrence of late stent thrombosis have been raised.1-3 Several pathological studies have suggested that late stent thrombosis may be predominantly associated with delayed arterial healing, characterized by incomplete or absent neointimal coverage over DES struts.4,5 Therefore, DES struts positioned across side-branch vessels, which are theoretically typical examples of struts with poor neointimal coverage, may be a potential nidus for late stent thrombosis. Using optical coherence tomography (OCT), we previously showed that different patterns of strut coverage were observed on side-branch struts depending on DES type.6 However, to date, there are no published data about the natural course of uncovered side-branch DES struts in vivo. We thus investigated serial changes in strut coverage over side-branch DESs using OCT.
Study patients. From the OCT registry database of our institute, we identified 250 patients who underwent follow-up OCT examination at 9 months (± 3 months) after DES implantation between November 2007 and August 2009. A second follow-up OCT examination was performed at 2 years (± 3 months) after stent implantation as planned follow-up angiography for other stented segments in 60 patients with 63 stented lesions. Thirty of the 60 patients who underwent DES implantation across side-branch vessels were selected using the following inclusion criteria: (1) de novo lesions with >50% diameter stenosis; (2) main vessel diameter ≥2.5 mm; (3) side-branch vessel diameter ≥2.0 mm; and (4) no target lesion revascularization procedure between 9-month and 2-year follow-up. An offline quantitative coronary angiography analysis system (CASS system; Pie Medical Instruments) was used to determine the dimensions of the main and side-branch vessels for inclusion in the study. DESs used were sirolimus-eluting stent (SES; Cypher, Cordis Corporation) in 10 patients, paclitaxel-eluting stent (PES; Taxus, Boston Scientific) in 10 patients, and zotarolimus-eluting stent (ZES; Endeavor Sprint, Medtronic) in 10 patients. DES selection at the time of coronary intervention was at the physician’s discretion. General inclusion and exclusion criteria for the follow-up OCT procedures have been previously reported.7 Specifically, patients with in-stent restenotic lesions treated with repeat target lesion revascularization before 2-year follow-up were excluded from this study. The study protocol was approved by the institutional review board of our institutes, and informed written consent was obtained from all patients before the procedure. DES implantation was performed using conventional techniques, and most patients received dual (aspirin and clopidogrel) antiplatelet therapy for at least 12 months.
OCT image protocol and analysis. OCT examination using a conventional OCT system (Model M2 Cardiology Imaging System; Light Lab Imaging) with a motorized pull-back system at 1.0 mm/s was previously described.7 OCT analysis was performed by an independent investigator blinded to patient and procedural information. OCT examination into side-branch vessels through the stent struts was not performed. OCT cross-sectional still frames were selected at 0.067 mm intervals in the limited segments with stent struts crossing a side branch (Figure 1). Because of the possibility that proximal and distal ends of the side-branch ostium might not be well-matched for serial comparison using the current OCT system, stented segments were chosen where the side-branch vessel occupied more than 45° of the main vessel’s circumference at the take-off.6 Frames with image artifacts, such as motion artifacts, were excluded. For serial comparison, cross-sectional OCT images at 9-month and 2-year follow-up were manually and meticulously matched using the distance between the proximal and distal ends of the side-branch vessel for reference. Among 753 image sections, 716 image sections (95.1%) were analyzable in this study; 363/382 (95.0%) at initial follow-up and 353/371 (95.1%) at second follow-up. Stent and luminal cross-sectional areas (CSAs) were measured, and neointimal hyperplasia (NIH) CSA was calculated as stent CSA – luminal CSA. Percent NIH CSA was calculated as NIH CSA × 100/stent CSA. Thickness of NIH was measured as the distance between the endoluminal surface of the neointima and the luminal surface of the strut.8,9 An uncovered strut was defined as having an NIH thickness of 0 µm.8,9 The percentage of uncovered struts was calculated as (number of uncovered struts/total number of struts in the limited segments with stent struts crossing a side branch) × 100. In covered side-branch struts, NIH thickness pattern was divided into two groups: struts with relatively thin NIH thickness (0 to 30 µm); and those with NIH thickness >30 µm. One OCT study with 3-month follow-up after SES implantation showed that mean NIH thickness was 29 ± 41 µm.10 Another study reported that median NIH thickness was 52.5 µm, and the 25th percentile of NIH thickness was 28.0 µm on 6-month follow-up OCT after SES implantation.11 Based on these studies,10,11 NIH thickness under 30 µm may represent early strut coverage. Mean values are reported in this study. The results of inter- and intra-observer variability for the measurement of OCT variables have been previously reported.12
Statistical analysis. Statistical analysis was performed using Predictive Analytics SoftWare (PASW) for Windows, version 18.0.0 (SPSS, Inc). Data are expressed as number (%) or mean ± standard deviation. Comparisons of categorical data were made using χ-square statistics or Fisher’s exact test. Student’s t-test, paired t-test, or Wilcoxon signed-rank test were used to compare continuous variables. Comparisons among the three stent groups included were performed using one-way ANOVA or the Kruskal-Wallis test. A P-value <.05 was considered statistically significant.
Baseline clinical and angiographic characteristics are listed in Table 1. All imaging procedures were performed without any complications or adverse events. Table 2 shows the initial and follow-up OCT findings of stent struts on the main vessel and branch vessel side. Percentage of uncovered side-branch struts was highest with the PES on initial follow-up OCT (93.4 ± 10.5% vs 47.5 ± 34.4% for SES and 26.2 ± 34.8% for ZES; P=.0001). Similar results were seen on second follow-up OCT (67.6 ± 24.2% for PES vs 29.6 ± 24.1% for SES and 12.4 ± 19.0% for ZES; P<.0001). Serial changes in the percentage of uncovered struts in the main vessel and branch vessel side are shown in Table 3. The percentage of uncovered struts on the main vessel side decreased significantly from 5.6 ± 6.9% to 3.2 ± 3.6% (P=.009) at follow-up. It also decreased significantly from 55.7 ± 39.9% to 36.6 ± 32.0% (P<.0001) on the branch vessel side. The percentage of side-branch struts with NIH thickness over 30 µm increased significantly, from 36.3 ± 37.4% to 51.0 ± 36.0% (P<.0001; Figure 2). However, a significant increase in relatively thin NIH (0 µm < NIH thickness <30 µm) was seen in PES struts (1.6 ± 3.4% to 17.4 ± 16.0%; P=.018), but not in SES or ZES struts. The representative images about strut coverage are shown in Figure 3.
Compared to previous reports that showed that 21.9% of the side-branch struts were uncovered at 9- to13-month follow-up,13 the percentage of uncovered side-branch struts at 9-month follow-up was relatively high (55.7%) in the present study. The difference may be attributable to different OCT analysis methods and the enrolled DES types. PESs were not included, and OCT analysis was performed at 1 mm intervals in the previous study.13 In the current study, the percentage of uncovered side-branch struts was highest in PESs at 9-month follow-up OCT. This finding was consistent with a previous OCT study, which also showed the highest percentage of uncovered struts in side-branch ostium in lesions treated with PES at 6-month follow-up OCT (60.1% for PES vs 17.0% for SES and 13.2% for ZES; P<.0001).14
To the best of our knowledge, this is the first study to evaluate the status of uncovered side-branch struts at 2-year follow-up and document the serial change between 9 months and 2-year follow-up. This serial follow-up study showed that there was significant improvement in overall DES strut coverage over side-branch ostium from 44.3% at 9 months to 63.4% at 2-year follow-up. Although the percentage of uncovered side-branch struts significantly decreased during serial follow-up, PESs still showed the highest percentage of uncovered side-branch struts at 2 years (67.6%) compared to other DESs. In addition, struts with relatively thin NIH thickness of 0 to 30 µm comprised about 50% of covered struts in PES even at 2-year follow-up. The proportion of side-branch struts with relatively thin NIH was less than one-fifth or one-tenth in other DES-covered struts. These findings suggested that strut coverage over the side-branch ostium may be insufficient or significantly delayed even at 2-year follow-up in PES compared to SES or ZES. These findings may be partially related to the different drug release kinetics or distribution of each DES.6 The sirolimus in SESs is nearly completely released from the polymer within 30 days, and 95% of the zotarolimus in ZESs is eluted from the stent within 15 days of implantation.6,15,16 In contrast, paclitaxel is released from PESs as an initial burst from the polymer, followed by a constant slow release lasting more than 180 days.6,17 Thus, profound inhibition of the reparative response to arterial injury by the prolonged and inhomogeneous release of the antiproliferative drug paclitaxel6,18 may be partly involved in the delayed coverage over the side-branch struts up to 2 years in this study.
Study limitations. Our study has some limitations. Because it is a non-randomized, retrospective study, it has the potential risk of selection bias. The number of study participants was relatively small. This study did not have OCT data for bare-metal stent struts across the side-branch vessel and OCT analysis according to different rheological impacts on bifurcation lesions. Our study also lacked histopathological data to validate the OCT findings. Finally, with the current OCT techniques, a precise qualitative assessment of neointima remains challenging. For example, we could not differentiate fibrin deposition from neointimal formation on the stent struts.
This serial follow-up OCT study showed that strut coverage of side-branch DES, regardless of DES type, improved with time; however, PESs showed the highest percentage of uncovered side-branch struts on 2-year follow-up OCT. In addition, the NIH thickness pattern of covered struts in side-branch vessel side differed with each type of DES on serial follow-up.
Acknowledgments. This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (no. A085012 and no. A102064), a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (no. A085136), and the Cardiovascular Research Center, Seoul, Korea.
- Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293(17):2126-2130.
- Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet. 2007;369(9562):667-678.
- Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med. 2007;356(10):1020-1029.
- Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol. 2006;48(1):193-202.
- Finn AV, Joner M, Nakazawa G, et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation. 2007;115(18):2435-2441.
- Her A, Lee BK, Shim JM, et al. Neointimal coverage on the drug-eluting stent struts crossing the side-branch vessels using optical coherence tomography. Am J Cardiol. 2010;105(11):1565-1569.
- Kim U, Kim JS, Kim JS, et al. The initial extent of malapposition in ST-elevation myocardial infarction treated with drug-eluting stent: the usefulness of optical coherence tomography. Yonsei Med J. 2010;51(3):332-338.
- Kim JS, Hong MK, Fan C, et al. Intracoronary thrombus formation after drug-eluting stents implantation: optical coherence tomographic study. Am Heart J. 2010;159(2):278-283.
- Tearney GJ, Regar E, Akasaka T, et al. Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the international working group for intravascular optical coherence tomography standardization and validation. J Am Coll Cardiol. 2012;59(12):1058-1072.
- Takano M, Inami S, Jang IK, et al. Evaluation by optical coherence tomography of neointimal coverage of sirolimus-eluting stent three months after implantation. Am J Cardiol. 2007;99(8):1033-1038.
- Matsumoto D, Shite J, Shinke T, et al. Neointimal coverage of sirolimus-eluting stents at 6-month follow-up: evaluated by optical coherence tomography. Eur Heart J. 2007;28(8):961-967.
- Kim JS, Jang IK, Kim TH, et al. Optical coherence tomography evaluation of zotarolimus-eluting stents at 9-month follow-up: comparison with sirolimus-eluting stents. Heart. 2009;95(23):1907-1912.
- Gutirrez-Chico JL, Regar E, Nesch E, et al. Delayed coverage in malapposed and side-branch struts with respect to well-apposed struts in drug-eluting stents: in vivo assessment with optical coherence tomography. Circulation. 2011;124(5):612-623.
- Kyono H, Guagliumi G, Sirbu V, et al. Optical coherence tomography (OCT) strut-level analysis of drug-eluting stents (DES) in human coronary bifurcations. EuroIntervention. 2010;6(1):69-77.
- Klugherz BD, Llanos G, Lieuallen W. Twenty-eight-day efficacy and pharmacokinetics of the sirolimus-eluting stent. Coron Artery Dis. 2002;13(3):183-188.
- Nakazawa G, Finn AV, John MC, et al. The significance of preclinical evaluation of sirolimus-, paclitaxel-, and zotarolimus-eluting stents. Am J Cardiol. 2007;100(8B):36M-44M.
- Finn AV, Kododgie FD, Harnek J, et al. Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation. 2005;112(2):270-278.
- Nakazawa G, Ladich E, Finn AV, Virmani R. Pathophysiology of vascular healing and stent mediated arterial injury. EuroIntervention. 2008;4(Suppl C):C7-C10.
From the 1Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea and 2Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted May 4, 2012, provisional acceptance given May 14, 2012, final version accepted May 30, 2012.
Address for correspondence: Myeong-Ki Hong, MD, PhD, Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, 120-752 Seoul, South Korea. Email: email@example.com