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Original article
Optical coherence evaluation of everolimus-eluting stents 8 months after implantation
  1. Takumi Inoue1,
  2. Junya Shite1,
  3. Junghan Yoon2,
  4. Toshiro Shinke1,
  5. Hiromasa Otake1,
  6. Takahiro Sawada1,
  7. Hiroyuki Kawamori1,
  8. Hiroki Katoh1,
  9. Naoki Miyoshi1,
  10. Naoki Yoshino1,
  11. Amane Kozuki1,
  12. Hirotoshi Hariki1,
  13. Ken-ichi Hirata1
  1. 1Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe, Japan
  2. 2Yonsei University, Wonju Christian Hospital, South Korea
  1. Correspondence to Associate Professor Junya Shite, Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan; shite{at}med.kobe-u.ac.jp

Abstract

Objective The aim of this study was to evaluate detailed vessel response after everolimus-eluting stents (EES) implantation in human de novo coronary lesions by optical coherence tomography (OCT).

Design, setting and patients Between November 2008 and October 2009, 25 patients (14 men, 65.5±8.6 years) with de novo native coronary artery lesions were implanted with 30 EES, and OCT was performed at 8 months post-implantation.

Main outcome measures Neointimal thickness (NIT) on each strut, strut apposition to the vessel wall, the frequency of struts surrounded by low intensity area and the incidence of intra-stent thrombus were analysed. To evaluate the radial unevenness of NIT, the difference between the maximum and minimum NIT (dNT) was calculated for each cross-section.

Results At 236±39 days after implantation, there were no major adverse cardiac events, nor target vessel revascularisation. A total of 5931 struts was evaluated by OCT. The median NIT was 80 μm (25th and 75th percentile 50 μm and 140 μm) and average NIT was 100±74 μm. The number of neointima-covered struts was 5834 (98.4%), and 31 (0.52%) struts showed malapposition without neointimal coverage. The number of struts surrounded by low intensity area was 452 (7.62%). Eleven EES (37%) showed full neointimal coverage. No intra-stent thrombus was detected. The average dNT was 108±77 μm.

Conclusions Most EES struts were covered with uniform and thin neointima. The frequency of low-intensity neointima was very low, which may be a result of promoted vessel healing. These results may support improved clinical outcomes with EES in clinical trials.

  • Coronary angioplasty (PCI)
  • coronary stenting
  • everolimus-eluting stents
  • neointimal coverage
  • optical coherence tomography
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Recent clinical trials have demonstrated improved safety and efficacy of everolimus-eluting stents (EES). In the prospective randomised clinical evaluation of the Xience V everolimus-eluting coronary stent system (Abbott Vascular, Inc, Santa Clara, California, USA) in the treatment of patients with de novo native coronary artery lesions (SPIRIT) III trial, EES has shown a significant reduction in 8 months angiographic late loss1 and 2-year target vessel failure and major adverse cardiac event rate compared with the first-generation paclitaxel-eluting stents (PES; TAXUS Express2; Boston Scientific Corp, Natick, Massachusetts, USA).2 In addition, a recent single-centre second-generation EES and PES in real-life practice (COMPARE) trial showed that EES were better than the second-generation PES (TAXUS Liberté; Boston Scientific Corp) in real-world patients in terms of safety and efficacy (all-cause mortality, myocardial infarction and target vessel revascularisation) at 12 months.3

The PROMUS/Xience V EES features a biocompatible polymer with a relatively low dose of everolimus coated on a thin strut (81 μm), flexible, cobalt-chromium stent platform,4 which is expected to provide minimal inflammatory reaction and good neointimal coverage. Optical coherence tomography (OCT) is an imaging modality that can visualise the intracoronary features with high axial resolution (10–20 μm), which is approximately 10 times greater than the resolution of intravascular ultrasound (100–150 μm).5 The mid-term OCT results in a consistent series of patients with EES have not yet been reported. The aim of the present study was to analyse OCT findings on neointimalisation, strut apposition and the presence of thrombus with EES at 8 months.

Methods

Study population and methods

Between November 2008 and October 2009, patients aged 18 years and older with one or two de novo lesions in a native coronary artery were implanted with the PROMUS EES (Boston Scientific Corp) and prospective 8-month follow-up angiography with OCT was performed at Yonsei University, Wonju Christian Hospital in South Korea. Target lesions had to comply with the following inclusion criteria: a reference vessel diameter between 2.4 and 4.0 mm by visual estimation, a target lesion length of 28 mm or less, and a visually estimated stenosis of more than 75% of the luminal diameter. Patients could be enrolled if the myocardial infarction occurred more than 6 months before enrolment. All patients provided written informed consent for their inclusion into this study and for follow-up OCT examination at Yonsei University, Wonju Christian Hospital.

Percutaneous coronary intervention procedure

All patients received 100 mg of aspirin. All patients but one received 75 mg of clopidogrel. Two patients received triple antiplatelet therapy with cilostazol until 8 months follow-up. Except for one case, all of the percutaneous coronary intervention procedure for patients involved in this study were performed with intravascular ultrasound guidance using a mechanical ultrasound transducer (Boston Scientific Corp) or a dynamic-aperture ultrasound transducer (Volcano Corporation, Rancho Cordova, California, USA) to obtain optimal stent expansion and stent apposition. OCT analysis was performed by an independent core laboratory (Kobe University hospital, Kobe, Japan).

OCT examination

OCT examinations were performed according to the standard methods described in previous reports.6–8 Briefly, an over-the-wire type occlusion balloon catheter (Helios; Lightlab Imaging Inc, Westford, Massachusetts, USA) with lactated Ringer's solution infusion (0.5 ml/s) was applied to clear red blood cells from the imaging site. The entire stent was imaged with an automatic pullback device moving at 1 mm/s.

OCT analysis

OCT images were analysed by two independent observers using a proprietary off-line review system (LightLab Imaging Inc). All OCT cross-sectional image frames were evaluated to determine whether stent struts were covered with neointima and apposed to the vessel wall. In every 15th frame (1 mm), we evaluated each stent strut condition for classification into one of six categories: (1) well apposed to the vessel wall with neointimal coverage overlaying the strut; (2) well apposed to the vessel wall without neointimal coverage; (3) malapposed to the vessel wall with neointimal coverage; (4) malapposed to the vessel wall without neointimal coverage; (5) orifice branch site with neointima; and (6) orifice branch site without neointima. A malapposed strut was defined as a distance of more than 108 μm between the centre reflection of the strut to the vessel wall. This criterion was determined by adding the actual strut thickness and polymer thickness to the OCT resolution limit (81 μm+7 μm+20 μm=108 μm).9 If neointimal coverage on the strut was observed, neointimal thickness (NIT) was measured from the neointimal surface to the centre reflection of the strut.10 To evaluate the radial unevenness of NIT, the difference between the maximum and minimum NIT (dNT) was calculated for each cross-section. In addition, frequency of thrombus formation and low-density area surrounding the strut were recorded. A thrombus was defined as a mass protruding beyond the stent strut into the lumen with significant attenuation behind the mass.11 12 Low-density area was defined as a contrasting lower-intensity area compared with the adjacent surrounding neointimal tissue. Representative images of neointimal coverage in EES, malapposed struts, NIT measurement and low-density area are shown in figure 1. NIT of EES was compared post-hoc with historical data for TAXUS Express2 PES and Cypher sirolimus-eluting stents (SES; Cordis/Johnson & Johnson, Miami Lakes, Florida, USA) previously generated in our laboratory.13

Figure 1

Optical coherence tomography images. Stent strut condition for classification; (i) Well apposed with neointima; (ii) Well apposed without neointima; (iii) Malapposed with neointima; (iv) Malapposed without neointima. (A, B) Measurement of neointimal thickness. (C) The arrowhead shows low-intensity areas surrounding everolimus-eluting stent struts.

Statistical analysis

Qualitative data are presented as frequencies and quantitative data are shown as medians (25th, 75th percentiles) or mean values±SD, as indicated. Categorical data were compared using the χ2 test. Statistical differences in NIT between PROMUS EES and other DES were evaluated by Mann–Whitney's U test. Other quantitative data were analysed using an unpaired t test. A two-sided p value of less than 0.05 was considered statistically significant. Statistical analyses were performed using MedCalc version 10.3.1.0.

Results

A total of 25 patients (14 men, 65.5±8.6 years old) treated with 30 PROMUS EES were enrolled in this study. The patient characteristics are shown in table 1. Eighteen of 25 patients with unstable angina and two with previous myocardial infarction were enrolled. No patients had undergone previous coronary artery bypass graft surgery. The average interval of follow-up angiography was 236±39 days. The mean length of the PROMUS EES (n=30) was 23.0±5.0 mm and mean diameter was 2.92±0.34 mm. We evaluated 5931 struts of PROMUS EES. Stent apposition and neointimal coverage categories are shown in table 2. The number of neointima-covered struts was 5834 (98.4%), and 31 (0.52%) struts showed malapposition without neointimal coverage. The median NIT was 80 μm (25th 50 μm; 75th 140 μm) and average NIT was 100±74 μm. NIT distribution is shown in figure 2. Average dNT was 108±77 μm. No intra-stent thrombus was detected. The frequency of struts surrounded by low intensity area—a finding that is suggestive of disturbed neointimal maturation—was 7.62% (452 struts) in PROMUS EES. The frequency of stents fully covered with neointima was 37% (11/30 stents) (table 3).

Table 1

Baseline characteristics

Table 2

Classification of stent strut conditions of EES

Figure 2

Distribution of neointimal thickness (NIT) of everolimus-eluting stent (EES).

Table 3

OCT measurements at 8-month follow-up

Discussion

This is the first report of OCT examination of 8-month follow-up of PROMUS EES. From our simple observational study, most of the PROMUS EES struts appeared to be covered with relatively uniform and thin neointima. Thirty-seven per cent of these stents were fully covered with neointima. There was no intra-stent thrombus, and the frequency of struts surrounded by low-intensity area was very low.

The PROMUS EES is a second-generation DES and have a thin strut (81 μm), flexible stent platform. The stent strut thickness of PROMUS EES is almost two-thirds that of first-generation DES (TAXUS Express2 PES 132 μm; Cypher SES 140 μm). This flexible strut may be more effectively apposed to the vessel wall, and thinner struts may be more effectively covered by neointima. This hypothesis may be supported by a previous human OCT study showing that the thinner struts of TAXUS Liberté PES (97 μm) were more likely to be embedded to the vessel wall compared with the thicker struts of Cypher SES (140 μm).14 Everolimus (100 μg/cm2) is an analogue of rapamycin, which is a proliferation signal inhibitor that acts in the late G1 phase of the cell cycle to inhibit cellular proliferation in a reversible manner (Novartis Corporation, Basel, Switzerland).4 In order to deliver the drug, PROMUS/Xience V EES utilise an ultrapure copolymer composed of vinylidene fluoride and hexafluoropropylene monomers that has good bioconformability.4 The polymer coating of the PROMUS/Xience V EES is specifically designed for the controlled release of everolimus and can maintain the therapeutic window of everolimus throughout three phases of vessel wound healing or the process of in-stent restenosis. These phases begin with platelet aggregation and deposition of the fibronectin extracellular matrix at the instant of vessel injury (the inflammatory phase), and is followed by migration of fibroblasts or smooth muscle cells for 1 to 2 weeks (the granulation phase), proteoglycan deposition and conversion of the extracellular matrix to type I collagen and elastin (the matrix remodelling phase), which largely complete at 90–120 days from the instant of vessel injury.15 In particular, 80% of the drug eluted is released in the first 30 days, and the elution is complete by approximately 120 days.4 These PROMUS/Xience V EES designs that incorporate a lipophilic limus and a biocompatible polymer may be effective for inhibiting excessive neointimal proliferation.

We previously conducted an OCT study comparing the first-generation, Cypher SES versus TAXUS Express2 PES with the same methodology of OCT analysis used in the present study. According to the study, the frequency of neointima-covered struts was 86.9% in Cypher SES and 93.2% in TAXUS Express2 PES13 (table 4). In addition, the median NIT and average NIT were 50 μm and 83±100 μm in Cypher SES, and 90 μm and 148±163 μm in TAXUS Express2 PES, respectively.13 Although there are several differences in baseline patient and lesion characteristics between the two studies (table 5), our results indicated that PROMUS EES appeared to show better neointimal coverage throughout the entire stented segment without increasing average NIT as compared with Cypher SES (percentage of neointima covered struts PROMUS EES 98.4% vs Cypher SES 86.9%; average NIT PROMUS EES 100±74 μm vs Cypher SES 83±100 μm). Also, when compared with TAXUS Express2 PES, average NIT with PROMUS EES seemed to be thinner than that of TAXUS Express2 PES with comparable neointimal coverage of the stented segment (percentage of neointima covered struts PROMUS EES 98.4% vs TAXUS Express2 PES 93.2%; average NIT PROMUS EES 100±74 μm vs TAXUS Express2 PES 148±163 μm). Furthermore, the distribution of NIT in the PROMUS EES group appeared to have a narrower range than those of NIT in the TAXUS Express2 PES and the Cypher SES group (figure 3), indicating a lesser variation of the efficacy of PROMUS EES compared with that of TAXUS Express2 PES and Cypher SES. In addition, average dNT in the PROMUS EES group (108±77 μm) was lower when compared with those in the TAXUS Express2 PES and the Cypher SES group (206±88 μm and 131±57 μm, respectively),13 supporting our speculation that EES offers more uniform suppression of neointimal proliferation than first-generation DES. Although detailed mechanisms are still speculative due to the lack of pathological analysis, we suggest that uniform drug distribution and less local injury due to thinner stent strut used in the platform of PROMUS EES may offer homogenous vessel healing after PROMUS EES implantation.

Table 4

Classification of chronic stent strut conditions of EES, compared with PES and SES

Table 5

Patient characteristics of SES and PES (data cited from Miyoshi et al)13

Figure 3

Distribution of neointimal thickness (NIT) of everolimus-eluting stents (EES), paclitaxel-eluting stents (PES) and sirolimus-eluting stents (SES). Median NIT of ESS was 80 μm (25th 50 μm; 75th 140 μm), while that of PES was 90 μm (25th 40 μm; 75th 200 μm) and that of SES was 50 μm (25th 20 μm; 75th 140 μm). The distributions of NIT in EES appear to have a narrower range than those of NIT in PES and SES. *Data cited from Miyoshi et al.13

Struts with low-density area were observed less frequently with PROMUS EES in the current study than with TAXUS Express2 PES and Cypher SES in the previous study (7.62%, 30.9% and 17.0%, respectively).13 A pathological analysis of a recent animal study suggests the ‘peri-strut low intensity area’ on OCT images may represent the presence of fibrin surrounded by proteoglycan extracellular matrix.16 Wilson et al17 have reported that a high prevalence of diffuse granulomatous inflammation in porcine models—defined as inflammation consisting of macrophages, multinucleated giant cells, lymphocytes, granulocytes and many eosinophils adjacent to almost all struts—was seen with Cypher SES and TAXUS Liberté PES. Therefore, the low-intensity areas seemed to represent delayed arterial healing, possibly resulted from peri-strut inflammation. There are many factors that contribute to persistent inflammation and delayed vessel healing around stent struts, such as stent design, high drug concentration and polymer type.18 19 Among these, excessive local drug concentration may be one of the most important factors that induce delayed arterial healing. Finn et al18 demonstrated that overlapping stent segments, when the dose is presumed to be twice that of non-overlapping sites, exhibited a greater delayed healing process when compared with proximal and distal non-overlapping segments in rabbit iliac artery treated with Cypher SES and TAXUS Express2 PES. In this regard, PROMUS EES have a very low total dose of everolimus (100 μg/cm2), and have the lowest available limus-family drug load per unit.4 Also, previously mentioned, the fluorinated copolymer of PROMUS EES is biocompatible and is designed to elicit a less inflammatory reaction.4 Therefore, a relatively low incidence of struts with low intensity area seen around PROMUS EES struts may represent promoted vessel healing due to less local inflammation, which is presumably because of a very low total dose of everolimus and the use of biocompatible polymer.

The frequency of stents fully covered with neointima at 8 months was 37% in the PROMUS EES group. Therefore, PROMUS EES in this study was more likely to be fully covered with neointima than in the previous TAXUS Express2 PES and Cypher SES study (11% in the TAXUS Express2 PES group and 17% in the Cypher SES group).13 Based on pathological studies, incomplete neointimal stent coverage is the most important morphometric predictor of late stent thrombosis because it is the most powerful surrogate indicator of endothelialisation.20–22 Indeed, we did not detect any intra-stent thrombus in any PROMUS EES. In contrast, we previously reported that the incidence of mural thrombus was 33% (nine out of 27 stents) in TAXUS Express2 PES and 26% (seven out of 27 stents) in Cypher SES.13 These results may be supported by a recent large clinical trial, showing the lower incidence of stent thrombosis at 1 year in EES than in TAXUS Liberté PES.23

Study limitations

There were several limitations to this study. First, this is a single centre study based on relatively limited sample size, raising the possibility of selection bias. Therefore, the results of the study should be interpreted cautiously. Second, although we compared OCT findings among three types of DES in the discussion section, there are a few differences in patients and lesion characteristics. Therefore, a randomised head-to-head comparison needs to be undertaken to address more adequately and further clarify the differences among three types of DES.

Conclusions

In this small sample size study, the results show that NIT with PROMUS EES is thin and homogeneous at 8 months. The frequencies of uncovered struts, peri-strut low intensity tissue and mural thrombus were minimal. These results may suggest potentially improved clinical outcomes with PROMUS EES compared with other DES.

References

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Footnotes

  • See Editorial, p 1361

  • Linked articles 214825.

  • Competing interests Wonju Christian Hospital received a research grant from Boston Scientific Corporation, Inc (Natick, Massachusetts, USA).

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Yonsei University, Wonju Christian Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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