Scandinavian Cardiovascular Journal, 2015; Early Online: 1–6
ORIGINAL ARTICLE
Excellent very early neointimal coverage of bioactive stents by optical coherence tomography
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PASI P. KARJALAINEN & WAIL NAMMAS Heart Center, Satakunta Central Hospital, Pori, Finland
Abstract Objectives. In a prospective study, we explored the extent of neointimal coverage of stent struts by optical coherence tomography 14 days following the implantation of bioactive stents in an unselected cohort. Design. We enrolled 15 consecutive patients who underwent bioactive stent implantation. Optical coherence tomography images were obtained at 14-day follow-up. Morphometric analysis, strut coverage, strut apposition, neointimal hyperplasia, and possible thrombosis were evaluated at 1-mm intervals. Binary stent strut coverage was defined as the percentage of covered struts of all analyzed struts. Results. Patients underwent optical coherence tomography examination at an average of 14.5 ⫾ 2.3 days following stent implantation. Mean age was 62 ⫾ 11 years; 86.7% were males; 26.7% diabetic. Three-hundred eighteen cross-sections were analyzed, including 2935 struts, an average of 9.2 ⫾ 3 struts per cross-section. Binary stent strut coverage was 96.3%; the prevalence of malapposed struts 1.8%. No thrombi were detected. Mean neointimal hyperplasia thickness was 71.5 ⫾ 53.7 μm. Conclusions. In the current evaluation by optical coherence tomography at 14-day follow-up after bioactive stent implantation in an unselected cohort, binary stent strut coverage was fairly adequate, and the prevalence of malapposed struts was low. Key words: bioactive stents, neointimal coverage, optical coherence tomography, titanium
Introduction Vascular healing response to coronary stent implantation is a key determinant of long-term angiographic and clinical outcome. In autopsy analysis, incomplete endothelial coverage of stent struts was the most powerful predictor of late stent thrombosis following first-generation drug-eluting stent (DES) implantation (1). Neointimal healing response can be evaluated in vivo by optical coherence tomography (OCT) with an axial resolution of 12–15 μm that enables fairly adequate assessment of stent strut coverage. Evidence supports that stent strut coverage revealed by OCT correlates with histological neointimal healing after stenting in animal models (2,3). Recently, OCT has become the state-of-the-art for evaluation of neointimal strut coverage in randomized controlled trials that compare different stent designs (4). The safety of titanium-nitride-oxide-coated bioactive stents (BAS) was established in several reports
from real-world unselected populations (5,6), as well as from randomized controlled trials in patients presenting with acute coronary syndrome (7–9). OCT demonstrated adequate neointimal coverage following BAS implantation in an unselected nondiabetic cohort at 30-day follow-up; and in nondiabetic patients with acute coronary syndrome from a randomized trial at 9-month follow-up (10,11). Yet, the vascular healing response very early after BAS implantation remains unclear. We sought to evaluate the extent of neointimal coverage of stent struts by OCT 14 days following the implantation of BAS in an unselected cohort.
Materials and methods Patient selection and study design Prospectively, we enrolled 15 consecutive patients with symptomatic coronary artery disease amenable
Correspondence: Dr. Pasi P. Karjalainen, Heart Center, Satakunta Central Hospital, Sairaalantie 3, FIN-28100, Pori, Finland. Tel: ⫹ 358 2 6277755. Fax: ⫹ 358 2 6277757. E-mail: [email protected] (Received 12 June 2015 ; accepted 7 July 2015) ISSN 1401-7431 print/ISSN 1651-2006 online © 2015 Informa Healthcare DOI: 10.3109/14017431.2015.1071495
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for percutaneous coronary intervention, who received titanium-nitride-oxide-coated BAS (Titan2®, Hexacath, Paris, France). Eligible patients were above 18 years old, with at least one significant coronary lesion (defined as ⱖ 50% diameter stenosis by visual estimation) in a native coronary artery. The main exclusion criteria included unprotected left main or aorto-ostial lesions, in-stent restenosis, required stent length ⬎ 28 mm, and contraindication to aspirin, clopidogrel, or heparin. All patients underwent follow-up coronary angiography with OCT examination of the index stented segment at an average of 2 weeks. Treatment of more than one vessel was permissible. Before inclusion, informed written consent was obtained from each patient after full explanation of the study protocol. The study protocol was reviewed and approved by our Institutional Human Research Committee and it conforms to the ethical guidelines of the 1964 Declaration of Helsinki, as revised in 2013. Device description BAS (Titan2®, Hexacath, Paris, France) is a thinstrut (91 μm) balloon-expandable stent, made of stainless steel, and coated with titanium-nitrideoxide. The stent platform has a unique helicoidal design providing flexibility and conformability. Titanium-nitride-oxide is coated on all the surfaces of the stent, both inside and outside, through a patented process which results in nitride-oxide particles on the stent surface. This coating is extremely dense and hard, making the stent well adapted for direct stenting. In addition, the titanium-nitride-oxide coating adds strength to the stainless-steel substrate, making possible the use of thinner struts. The stent was used in the study in diameters ranging from 2.5 to 4.0 mm, and in lengths ranging from 7 to 28 mm. Optical coherence tomography image acquisition OCT images were obtained with the C7-XR frequency-domain system (LightLab Imaging Inc., Westford, MA, USA) employing the non-occlusive technique as described elsewhere (11,12). OCT images were analyzed off-line in an independent laboratory by a single experienced investigator (P.P.K.) blinded to patient baseline, angiographic, and procedural data, employing the proprietary software (OCT system software B.0.1, LightLab Imaging Inc., Westford, MA, USA) Optical coherence tomography image analysis Morphometric analysis, strut coverage, strut apposition, neointimal hyperplasia (NIH), and possible
thrombosis were evaluated at 1-mm intervals (every fifth frame) in cross-sectional images. All crosssectional images were initially screened for quality assessment, and if the image quality was insufficient to allow reliable measurements, the preceding (or subsequent) cross-section with adequate quality was evaluated. Insufficient image quality was defined when any portion of the region of interest was out of screen, or if the image had poor quality caused by residual blood or artifact. Lumen and stent contours were traced manually or semi-automatically and the NIH area was calculated by subtracting the lumen area from the stent area. The percent NIH area was calculated by dividing the NIH area by the stent area multiplied by 100. If the lumen or stent area were not measurable, they were omitted. Struts were classified as uncovered if any part of the strut was exposed to the lumen with no visible tissue coverage, or covered if a layer of tissue was visible over the reflecting surfaces. For covered struts, the NIH thickness was measured. Struts overlaying an ostium of a side branch were labeled as nonapposed side-branch struts and excluded from the analysis. Binary stent strut coverage was defined as the percentage of covered struts of all analyzed struts. Incomplete stent apposition (ISA) distance was measured for protruding struts as previously described (11,12). Apposition was assessed strut by strut, by measuring the distance between the strut marker and the lumen contour. The strut marker was placed on the endoluminal leading edge, at the mid-point of its long axis, and the distance was measured following a straight line connecting it with the center of gravity of the vessel. A margin of 18 μm was added as a correction for half the blooming. The average blooming thickness was derived from previous studies (13). We adopted an ISA distance of 110 μm as the threshold to define strut malapposition (91-μm strut thickness of BAS ⫹ 18-μm margin of correction). Thrombus was defined as an irregular high- or low-backscattering (red or white thrombus) mass protruding into the vessel lumen discontinuous from the surface of the stent struts. Statistical analysis As the current study was an observational one, there was no formal statistical hypothesis. No formal power calculation was performed. Continuous variables were presented as mean ⫾ SD, whereas categorical variables were described with absolute and relative (percentage) frequencies. The primary endpoint of the study was binary stent strut coverage at 14-day follow-up. Statistical analysis was performed using SPSS statistical software (SPSS v. 16.0.1, SPSS Inc., Chicago, IL, USA).
Vascular healing after bioactive stents
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Results A total of 15 patients (18 stents) underwent OCT examination at an average of 14.5 ⫾ 2.3 days following BAS implantation. The mean age was 62 ⫾ 11 years; 86.7% were males; 26.7% diabetic. Eighty percent of the patients presented with acute coronary syndrome; complex lesions were treated in 86.7%; post-dilatation was performed in 93.3%. The other baseline clinical, angiographic, and procedural data are summarized in Table I. No clinical events occurred during the period from stent implantation to the time of follow-up. Three-hundred eighteen cross-sections were analyzed, including 2935 struts, an average of 9.2 ⫾ 3 struts per cross-section. Lumen area was measurable Table I. Baseline clinical, angiographic, and procedural data. Variable
(N ⫽ 15)
Age (years) Male gender Risk factors Diabetes mellitus Family history of CAD Hypertension Hypercholesterolemia Current smoking Medical history prior Myocardial infarction prior PCI prior CABG Indication for PCI Unstable angina NSTEMI STEMI Stable angina Index procedure LAD LCX RCA B or C type lesion Bifurcation lesion Calcified lesion Thrombus present Reference vessel diameter Lesion length Thrombectomy Stent diameter Stent length Number of stents per lesion Post-dilatation Medication at discharge Aspirin Clopidogrel
62 ⫾ 11 13 (86.7) 4 13 14 14 4
(26.7) (86.7) (93.3) (93.3) (26.7)
4 (26.7) 3 (20) 1 (6.7) 3 8 1 3
(20) (53.3) (6.7) (20)
9 (60) 2 (13.3) 4 (26.7) 13 (86.7) 8 (53.3) 10 (66.7) 3 (20) 3.01 ⫾ 0.34 12.8 ⫾ 6.6 1 (6.7) 3.08 ⫾ 0.34 19.8 ⫾ 8.9 1.2 ⫾ 0.3 14 (93.3) 15 (100) 15 (100)
CABG, coronary artery bypass grafting; CAD, coronary artery disease; LAD indicates left anterior descending; LCx, left circumflex; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; RCA, right coronary artery; STEMI, ST-elevation myocardial infarction. Continuous variables are presented as mean ⫾ SD, whereas categorical variables are presented as frequency (percentage).
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in all 318 cross-sections, whereas stent area was measurable in 309 out of 318 cross-sections. Binary stent strut coverage was 96.3%, and the prevalence of malapposed struts was 1.8%. No thrombi were detected. Mean NIH thickness was 71.5 ⫾ 53.7 μm; mean NIH area was 0.46 ⫾ 0.28 mm2; and mean percent NIH area was 6.3 ⫾ 4.2%. The other OCT measurements are summarized in Table II.
Discussion Major findings In the current short-term follow-up by OCT 14 days following BAS implantation in an unselected cohort, binary stent strut coverage was fairly adequate, and the prevalence of malapposed struts quite low. To the best of the authors’ knowledge, the current study presents the shortest follow-up interval to OCT analysis of strut neointimal coverage following coronary stent implantation. Neointimal stent strut coverage Vascular healing has always been a prime concern after coronary stent implantation. Impaired neointimal healing was a common autopsy finding in patients who had late stent thrombosis from a registry of human coronary stents (14). The most powerful histological morphometric predictor of late stent thrombosis was the ratio of uncovered to total stent struts (1). Such ratio was 0.86% at 1-month follow-up after implantation of currently available cobaltchromium-based bare-metal stents in a late-breaking randomized controlled trial (15). In the same trial, the percent uncovered struts in the comparator novel Table II. Optical coherence tomography measurements. Variable Total number of patients/stents Cross-sections analyzed Total number of struts analyzed Duration of follow-up (days) Struts per cross-section NIH thickness (μm) Stent CSA (mm2) Lumen CSA (mm2) NIH area (mm2) % NIH area (%) Binary stent strut coverage Uncovered stent struts Malapposed stent struts Presence of thrombi
Measurement (n ⫽ 20) 15/18 318 2935 14.5 ⫾ 2.3 9.2 ⫾ 3.0 71.5 ⫾ 53.7 7.25 ⫾ 1.91 6.79 ⫾ 1.89 0.46 ⫾ 0.28 6.3 ⫾ 4.2 2827 (96.3) 108 (3.7) 54 (1.8) 0 (0)
CSA, cross-sectional area; NIH, neointimal hyperplasia. Continuous variables are presented as mean ⫾ SD, whereas categorical variables are presented as frequency (percentage).
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polymer-free DES at 3-month follow-up was 1.59% (15). In another randomized trial comparing 2 novel polymer-coated sirolimus-eluting stents, the percent covered struts (binary stent strut coverage) at 3-month follow-up was 94.2% in the BuMA stent arm versus 90% in EXCEL stent arm (p ⬍ 0.01) (16). Yet, in a meta-analysis of studies reporting OCT-evaluated stent strut coverage post-DES implantation, the percent covered struts at 3-month follow-up associated with pooled studies of sirolimus-eluting stents was 86.9%; that associated with zotarolimus-eluting stents at the same time point was 99.3% (17). A similar prevalence (99.9%) was reported by a single-center observational study 3 months following zotarolimus-eluting stent implantation (18). However, in a serial analysis by OCT, binary stent strut coverage associated with zotarolimus-eluting stent implantation was 95.5% and 93.6% at follow-up intervals of 2 and 3 months, respectively; at 1-month follow-up, it was 88.4% (19). In comparison, the 1-month prevalence of covered struts associated with implantation of an endothelial progenitor cell capturing stent (Genus stent) was 95% (20). At a similar point of follow-up, binary stent strut coverage after BAS implantation was 97.2% (10). The current data support the figure reported previously in the latter study, and provide further insight into the adequacy of vascular healing very early after BAS implantation.
Stent strut malapposition Early strut malapposition portends a higher risk of delayed coverage and late persistence of malapposition (21). Several studies reported the prevalence of malapposed struts at short intervals of follow-up after stent implantation. In a randomized trial by Prati et al. the percentage of malapposed struts associated with bare-metal stents was 1.2% at 1-month follow-up, compared with 4.1% with a novel DES at 3-month follow-up (15). In another randomized trial by Qian et al. the percentage of malapposed struts at 3-month follow-up was 1.28% with BuMA stent implantation, compared with 1.8% with EXCEL stent (16). Serial OCT analysis after zotarolimuseluting stent implantation revealed a percentage of malapposed struts of 1.9% and 3.1% at 2- and 3-month follow-up, respectively; at 1-month follow-up, it was 4.4% (19). Comparatively, the 1-month prevalence of malapposed struts following the implantation of the Genus endothelial progenitor cell capturing stent was 2.4% (20). In the current study, the prevalence of malapposed struts associated with BAS implantation at 14-day follow-up was 1.8%, quite comparable with the figures reported with
bare-metal stents at 1-month follow-up, and with DES at longer periods of follow-up. Clinical implications The current study provided reassuring data on the vascular healing properties very early following BAS implantation in a relatively high-risk unselected cohort (80% acute coronary syndrome and 86.7% complex lesions). Adequate neointimal coverage of stent struts at 14-day follow-up suggested excellent early healing characteristics, consistent with the prior report of OCT evaluation of BAS one month after implantation (10). Moreover, the low percentage of malapposed struts, comparable with that observed after DES at longer follow-up periods, further strengthened evidence of adequate early healing. Current evidence supports the clinical practice of short (one month) dual antiplatelet regimen following BAS implantation, similar to that needed after bare-metal stents. This is particularly important in patients who need long-term oral anticoagulation therapy, in those with active or potential bleeding (e.g., peptic ulcer), and in those liable to undergo surgery early following percutaneous coronary intervention. Based on data of the current report that revealed adequate neointimal strut coverage as early as 2 weeks post-procedural, we can consider an even shorter dual antiplatelet regimen following BAS implantation. A newer generation of bioactive stents is already available, based on a cobalt-chromium platform, with thinner stent struts (22). Study limitations Our data were based on a single-center study with a relatively small sample size; therefore, the conclusions based on these data should be taken with caution. Further studies with long-term clinical follow-up are required to evaluate the correlation of early stent endothelialization and clinical events. Second, the current OCT technology cannot detect tissue coverage ⬍ 10 μm, and thus cannot differentiate ultra-thin layers of neointima. Moreover, OCT data before and immediately after the index procedure were not available. Although the cohort included over 50% bifurcation lesions, non-apposed side branch struts were excluded from analysis. This might introduce selection bias. We performed strut-level analysis (the percentage of covered struts of all analyzed struts). Stent-level analysis performed at multilevel taking into consideration the heirarchical structure of the data would be better, given the abnormal distribution of variables. Finally, we performed image analy-
Vascular healing after bioactive stents sis at 1-mm longitudinal intervals, in contrast to some studies which reported image analysis at 0.6-mm longitudinal intervals. Although the methodology adopted in the current study was previously validated for the assessment of neointimal strut coverage and showed excellent reproducibility, it might have a lower sensitivity to detect uncovered struts than shorter-interval protocols.
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Conclusion In the current evaluation by OCT at 14-day follow-up after BAS implantation in an unselected cohort, binary stent strut coverage was fairly adequate, and the prevalence of malapposed struts was low.
Acknowledgments None.
Funding This research received no grant from any funding agency in the public, commercial, or not-for-profit sectors.
Declaration of interest: The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.
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7. Tuomainen PO, Ylitalo A, Niemelä M, Kervinen K, Pietilä M, Sia J, et al. Five-year clinical outcome of titanium-nitrideoxide-coated bioactive stents versus paclitaxel-eluting stents in patients with acute myocardial infarction: Long-term follow-up from the TITAX AMI trial. Int J Cardiol. 2013; 168:1214–9. 8. Karjalainen PP, Niemelä M, Airaksinen JK, Rivero-Crespo F, Romppanen H, Sia J, et al. A prospective randomised comparison of titanium-nitride-oxide-coated bioactive stents with everolimus-eluting stents in acute coronary syndrome: the BASE-ACS trial. EuroIntervention. 2012;8:306–15. 9. Romppanen H, Nammas W, Kervinen K, Airaksinen JK, Pietilä M, Rivero-Crespo F, et al. Stent-oriented versus patient-oriented outcome in patients undergoing early percutaneous coronary intervention for acute coronary syndrome: 2-year report from the BASE-ACS trial. Ann Med. 2013;45:488–93. 10. Annala AP, Lehtinen T, Kiviniemi TO, Ylitalo A, Nammas W, Karjalainen PP. Vascular healing early after titanium-nitrideoxide-coated stent implantation assessed by optical coherence tomography. J Invasive Cardiol. 2013;25:186–9. 11. Karjalainen P, Kiviniemi TO, Lehtinen T, Nammas W, Ylitalo A, Saraste A, et al. Neointimal coverage and vasodilator response to titanium-nitride-oxide-coated bioactive stents and everolimus-eluting stents in patients with acute coronary syndrome: insights from the BASE-ACS trial. Int J Cardiovasc Imaging. 2013;29:1693–703. 12. Lehtinen T, Nammas W, Airaksinen JK, Karjalainen PP. Feasibility and safety of frequency-domain optical coherence tomography for coronary artery evaluation: a single-center study. Int J Cardiovasc Imaging. 2013;29:997–1005. 13. Bezerra HG, Costa MA, Guagliumi G, Rollins AM, Simon DI. Intracoronary optical coherence tomography: a comprehensive review clinical and research applications. JACC Cardiovasc Interv. 2009;2:1035–46. 14. Farb A, Burke AP, Kolodgie FD, Virmani R. Pathological mechanisms of fatal late coronary stent thrombosis in humans. Circulation. 2003;108:1701–6. 15. Prati F, Romagnoli E, Valgimigli M, Burzotta F, De Benedictis M, Ramondo A, et al. Randomized comparison between 3-month Cre8 DES vs. 1-month Vision/Multilink8 BMS neointimal coverage assessed by OCT evaluation: the DEMONSTRATE study. Int J Cardiol. 2014;176:904–9. 16. Qian J, Zhang YJ, Xu B, Yang YJ, Yan HB, Sun ZW, et al. Optical coherence tomography assessment of a PLGApolymer with electro-grafting base layer versus a PLApolymer sirolimus-eluting stent at three-month follow-up: the BuMA-OCT randomised trial. EuroIntervention. 2014; 10:806–14. 17. Papayannis AC, Cipher D, Banerjee S, Brilakis ES. Optical coherence tomography evaluation of drug-eluting stents: a systematic review. Catheter Cardiovasc Interv. 2013;81: 481–7. 18. Kim JS, Jang IK, Fan C, Kim TH, Kim JS, Park SM, et al. Evaluation in 3 months duration of neointimal coverage after zotarolimus-eluting stent implantation by optical coherence tomography: the ENDEAVOR OCT trial. JACC Cardiovasc Interv. 2009;2:1240–7. 19. Hashikata T, Tojo T, Namba S, Kitasato L, Hashimoto T, Kameda R, et al. Neointimal coverage of zotarolimus-eluting stent at 1, 2, and 3 months’ follow-up: an optical coherence tomography study. Heart Vessels. 2014. [Epub ahead of print] 20. Lehtinen T, Kiviniemi TO, Ylitalo A, Mikkelsson J, Airaksinen JK, Karjalainen PP. Early vascular healing after endothelial progenitor cell capturing stent implantation. J Invasive Cardiol. 2012;24:631–5.
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21. Gutiérrez-Chico JL, Wykrzykowska J, Nüesch E, van Geuns RJ, Koch KT, Koolen JJ, et al. Vascular tissue reaction to acute malapposition in human coronary arteries: sequential assessment with optical coherence tomography. Circ Cardiovasc Interv. 2012;5:20–9.
22. Karjalainen PP, Mikkelsson J, Ylitalo A, Paana T, Nammas W. Mid-term clinical outcome of titanium-nitrideoxide-coated cobalt-chromium stents in patients with de novo coronary lesions: OPTIMAX first-in-man study. Rev Esp Cardiol. 2014;67:958–9.
ORIGINAL ARTICLE
Excellent very early neointimal coverage of bioactive stents by optical coherence tomography
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PASI P. KARJALAINEN & WAIL NAMMAS Heart Center, Satakunta Central Hospital, Pori, Finland
Abstract Objectives. In a prospective study, we explored the extent of neointimal coverage of stent struts by optical coherence tomography 14 days following the implantation of bioactive stents in an unselected cohort. Design. We enrolled 15 consecutive patients who underwent bioactive stent implantation. Optical coherence tomography images were obtained at 14-day follow-up. Morphometric analysis, strut coverage, strut apposition, neointimal hyperplasia, and possible thrombosis were evaluated at 1-mm intervals. Binary stent strut coverage was defined as the percentage of covered struts of all analyzed struts. Results. Patients underwent optical coherence tomography examination at an average of 14.5 ⫾ 2.3 days following stent implantation. Mean age was 62 ⫾ 11 years; 86.7% were males; 26.7% diabetic. Three-hundred eighteen cross-sections were analyzed, including 2935 struts, an average of 9.2 ⫾ 3 struts per cross-section. Binary stent strut coverage was 96.3%; the prevalence of malapposed struts 1.8%. No thrombi were detected. Mean neointimal hyperplasia thickness was 71.5 ⫾ 53.7 μm. Conclusions. In the current evaluation by optical coherence tomography at 14-day follow-up after bioactive stent implantation in an unselected cohort, binary stent strut coverage was fairly adequate, and the prevalence of malapposed struts was low. Key words: bioactive stents, neointimal coverage, optical coherence tomography, titanium
Introduction Vascular healing response to coronary stent implantation is a key determinant of long-term angiographic and clinical outcome. In autopsy analysis, incomplete endothelial coverage of stent struts was the most powerful predictor of late stent thrombosis following first-generation drug-eluting stent (DES) implantation (1). Neointimal healing response can be evaluated in vivo by optical coherence tomography (OCT) with an axial resolution of 12–15 μm that enables fairly adequate assessment of stent strut coverage. Evidence supports that stent strut coverage revealed by OCT correlates with histological neointimal healing after stenting in animal models (2,3). Recently, OCT has become the state-of-the-art for evaluation of neointimal strut coverage in randomized controlled trials that compare different stent designs (4). The safety of titanium-nitride-oxide-coated bioactive stents (BAS) was established in several reports
from real-world unselected populations (5,6), as well as from randomized controlled trials in patients presenting with acute coronary syndrome (7–9). OCT demonstrated adequate neointimal coverage following BAS implantation in an unselected nondiabetic cohort at 30-day follow-up; and in nondiabetic patients with acute coronary syndrome from a randomized trial at 9-month follow-up (10,11). Yet, the vascular healing response very early after BAS implantation remains unclear. We sought to evaluate the extent of neointimal coverage of stent struts by OCT 14 days following the implantation of BAS in an unselected cohort.
Materials and methods Patient selection and study design Prospectively, we enrolled 15 consecutive patients with symptomatic coronary artery disease amenable
Correspondence: Dr. Pasi P. Karjalainen, Heart Center, Satakunta Central Hospital, Sairaalantie 3, FIN-28100, Pori, Finland. Tel: ⫹ 358 2 6277755. Fax: ⫹ 358 2 6277757. E-mail: [email protected] (Received 12 June 2015 ; accepted 7 July 2015) ISSN 1401-7431 print/ISSN 1651-2006 online © 2015 Informa Healthcare DOI: 10.3109/14017431.2015.1071495
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for percutaneous coronary intervention, who received titanium-nitride-oxide-coated BAS (Titan2®, Hexacath, Paris, France). Eligible patients were above 18 years old, with at least one significant coronary lesion (defined as ⱖ 50% diameter stenosis by visual estimation) in a native coronary artery. The main exclusion criteria included unprotected left main or aorto-ostial lesions, in-stent restenosis, required stent length ⬎ 28 mm, and contraindication to aspirin, clopidogrel, or heparin. All patients underwent follow-up coronary angiography with OCT examination of the index stented segment at an average of 2 weeks. Treatment of more than one vessel was permissible. Before inclusion, informed written consent was obtained from each patient after full explanation of the study protocol. The study protocol was reviewed and approved by our Institutional Human Research Committee and it conforms to the ethical guidelines of the 1964 Declaration of Helsinki, as revised in 2013. Device description BAS (Titan2®, Hexacath, Paris, France) is a thinstrut (91 μm) balloon-expandable stent, made of stainless steel, and coated with titanium-nitrideoxide. The stent platform has a unique helicoidal design providing flexibility and conformability. Titanium-nitride-oxide is coated on all the surfaces of the stent, both inside and outside, through a patented process which results in nitride-oxide particles on the stent surface. This coating is extremely dense and hard, making the stent well adapted for direct stenting. In addition, the titanium-nitride-oxide coating adds strength to the stainless-steel substrate, making possible the use of thinner struts. The stent was used in the study in diameters ranging from 2.5 to 4.0 mm, and in lengths ranging from 7 to 28 mm. Optical coherence tomography image acquisition OCT images were obtained with the C7-XR frequency-domain system (LightLab Imaging Inc., Westford, MA, USA) employing the non-occlusive technique as described elsewhere (11,12). OCT images were analyzed off-line in an independent laboratory by a single experienced investigator (P.P.K.) blinded to patient baseline, angiographic, and procedural data, employing the proprietary software (OCT system software B.0.1, LightLab Imaging Inc., Westford, MA, USA) Optical coherence tomography image analysis Morphometric analysis, strut coverage, strut apposition, neointimal hyperplasia (NIH), and possible
thrombosis were evaluated at 1-mm intervals (every fifth frame) in cross-sectional images. All crosssectional images were initially screened for quality assessment, and if the image quality was insufficient to allow reliable measurements, the preceding (or subsequent) cross-section with adequate quality was evaluated. Insufficient image quality was defined when any portion of the region of interest was out of screen, or if the image had poor quality caused by residual blood or artifact. Lumen and stent contours were traced manually or semi-automatically and the NIH area was calculated by subtracting the lumen area from the stent area. The percent NIH area was calculated by dividing the NIH area by the stent area multiplied by 100. If the lumen or stent area were not measurable, they were omitted. Struts were classified as uncovered if any part of the strut was exposed to the lumen with no visible tissue coverage, or covered if a layer of tissue was visible over the reflecting surfaces. For covered struts, the NIH thickness was measured. Struts overlaying an ostium of a side branch were labeled as nonapposed side-branch struts and excluded from the analysis. Binary stent strut coverage was defined as the percentage of covered struts of all analyzed struts. Incomplete stent apposition (ISA) distance was measured for protruding struts as previously described (11,12). Apposition was assessed strut by strut, by measuring the distance between the strut marker and the lumen contour. The strut marker was placed on the endoluminal leading edge, at the mid-point of its long axis, and the distance was measured following a straight line connecting it with the center of gravity of the vessel. A margin of 18 μm was added as a correction for half the blooming. The average blooming thickness was derived from previous studies (13). We adopted an ISA distance of 110 μm as the threshold to define strut malapposition (91-μm strut thickness of BAS ⫹ 18-μm margin of correction). Thrombus was defined as an irregular high- or low-backscattering (red or white thrombus) mass protruding into the vessel lumen discontinuous from the surface of the stent struts. Statistical analysis As the current study was an observational one, there was no formal statistical hypothesis. No formal power calculation was performed. Continuous variables were presented as mean ⫾ SD, whereas categorical variables were described with absolute and relative (percentage) frequencies. The primary endpoint of the study was binary stent strut coverage at 14-day follow-up. Statistical analysis was performed using SPSS statistical software (SPSS v. 16.0.1, SPSS Inc., Chicago, IL, USA).
Vascular healing after bioactive stents
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Results A total of 15 patients (18 stents) underwent OCT examination at an average of 14.5 ⫾ 2.3 days following BAS implantation. The mean age was 62 ⫾ 11 years; 86.7% were males; 26.7% diabetic. Eighty percent of the patients presented with acute coronary syndrome; complex lesions were treated in 86.7%; post-dilatation was performed in 93.3%. The other baseline clinical, angiographic, and procedural data are summarized in Table I. No clinical events occurred during the period from stent implantation to the time of follow-up. Three-hundred eighteen cross-sections were analyzed, including 2935 struts, an average of 9.2 ⫾ 3 struts per cross-section. Lumen area was measurable Table I. Baseline clinical, angiographic, and procedural data. Variable
(N ⫽ 15)
Age (years) Male gender Risk factors Diabetes mellitus Family history of CAD Hypertension Hypercholesterolemia Current smoking Medical history prior Myocardial infarction prior PCI prior CABG Indication for PCI Unstable angina NSTEMI STEMI Stable angina Index procedure LAD LCX RCA B or C type lesion Bifurcation lesion Calcified lesion Thrombus present Reference vessel diameter Lesion length Thrombectomy Stent diameter Stent length Number of stents per lesion Post-dilatation Medication at discharge Aspirin Clopidogrel
62 ⫾ 11 13 (86.7) 4 13 14 14 4
(26.7) (86.7) (93.3) (93.3) (26.7)
4 (26.7) 3 (20) 1 (6.7) 3 8 1 3
(20) (53.3) (6.7) (20)
9 (60) 2 (13.3) 4 (26.7) 13 (86.7) 8 (53.3) 10 (66.7) 3 (20) 3.01 ⫾ 0.34 12.8 ⫾ 6.6 1 (6.7) 3.08 ⫾ 0.34 19.8 ⫾ 8.9 1.2 ⫾ 0.3 14 (93.3) 15 (100) 15 (100)
CABG, coronary artery bypass grafting; CAD, coronary artery disease; LAD indicates left anterior descending; LCx, left circumflex; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; RCA, right coronary artery; STEMI, ST-elevation myocardial infarction. Continuous variables are presented as mean ⫾ SD, whereas categorical variables are presented as frequency (percentage).
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in all 318 cross-sections, whereas stent area was measurable in 309 out of 318 cross-sections. Binary stent strut coverage was 96.3%, and the prevalence of malapposed struts was 1.8%. No thrombi were detected. Mean NIH thickness was 71.5 ⫾ 53.7 μm; mean NIH area was 0.46 ⫾ 0.28 mm2; and mean percent NIH area was 6.3 ⫾ 4.2%. The other OCT measurements are summarized in Table II.
Discussion Major findings In the current short-term follow-up by OCT 14 days following BAS implantation in an unselected cohort, binary stent strut coverage was fairly adequate, and the prevalence of malapposed struts quite low. To the best of the authors’ knowledge, the current study presents the shortest follow-up interval to OCT analysis of strut neointimal coverage following coronary stent implantation. Neointimal stent strut coverage Vascular healing has always been a prime concern after coronary stent implantation. Impaired neointimal healing was a common autopsy finding in patients who had late stent thrombosis from a registry of human coronary stents (14). The most powerful histological morphometric predictor of late stent thrombosis was the ratio of uncovered to total stent struts (1). Such ratio was 0.86% at 1-month follow-up after implantation of currently available cobaltchromium-based bare-metal stents in a late-breaking randomized controlled trial (15). In the same trial, the percent uncovered struts in the comparator novel Table II. Optical coherence tomography measurements. Variable Total number of patients/stents Cross-sections analyzed Total number of struts analyzed Duration of follow-up (days) Struts per cross-section NIH thickness (μm) Stent CSA (mm2) Lumen CSA (mm2) NIH area (mm2) % NIH area (%) Binary stent strut coverage Uncovered stent struts Malapposed stent struts Presence of thrombi
Measurement (n ⫽ 20) 15/18 318 2935 14.5 ⫾ 2.3 9.2 ⫾ 3.0 71.5 ⫾ 53.7 7.25 ⫾ 1.91 6.79 ⫾ 1.89 0.46 ⫾ 0.28 6.3 ⫾ 4.2 2827 (96.3) 108 (3.7) 54 (1.8) 0 (0)
CSA, cross-sectional area; NIH, neointimal hyperplasia. Continuous variables are presented as mean ⫾ SD, whereas categorical variables are presented as frequency (percentage).
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P. P. Karjalainen & W. Nammas
polymer-free DES at 3-month follow-up was 1.59% (15). In another randomized trial comparing 2 novel polymer-coated sirolimus-eluting stents, the percent covered struts (binary stent strut coverage) at 3-month follow-up was 94.2% in the BuMA stent arm versus 90% in EXCEL stent arm (p ⬍ 0.01) (16). Yet, in a meta-analysis of studies reporting OCT-evaluated stent strut coverage post-DES implantation, the percent covered struts at 3-month follow-up associated with pooled studies of sirolimus-eluting stents was 86.9%; that associated with zotarolimus-eluting stents at the same time point was 99.3% (17). A similar prevalence (99.9%) was reported by a single-center observational study 3 months following zotarolimus-eluting stent implantation (18). However, in a serial analysis by OCT, binary stent strut coverage associated with zotarolimus-eluting stent implantation was 95.5% and 93.6% at follow-up intervals of 2 and 3 months, respectively; at 1-month follow-up, it was 88.4% (19). In comparison, the 1-month prevalence of covered struts associated with implantation of an endothelial progenitor cell capturing stent (Genus stent) was 95% (20). At a similar point of follow-up, binary stent strut coverage after BAS implantation was 97.2% (10). The current data support the figure reported previously in the latter study, and provide further insight into the adequacy of vascular healing very early after BAS implantation.
Stent strut malapposition Early strut malapposition portends a higher risk of delayed coverage and late persistence of malapposition (21). Several studies reported the prevalence of malapposed struts at short intervals of follow-up after stent implantation. In a randomized trial by Prati et al. the percentage of malapposed struts associated with bare-metal stents was 1.2% at 1-month follow-up, compared with 4.1% with a novel DES at 3-month follow-up (15). In another randomized trial by Qian et al. the percentage of malapposed struts at 3-month follow-up was 1.28% with BuMA stent implantation, compared with 1.8% with EXCEL stent (16). Serial OCT analysis after zotarolimuseluting stent implantation revealed a percentage of malapposed struts of 1.9% and 3.1% at 2- and 3-month follow-up, respectively; at 1-month follow-up, it was 4.4% (19). Comparatively, the 1-month prevalence of malapposed struts following the implantation of the Genus endothelial progenitor cell capturing stent was 2.4% (20). In the current study, the prevalence of malapposed struts associated with BAS implantation at 14-day follow-up was 1.8%, quite comparable with the figures reported with
bare-metal stents at 1-month follow-up, and with DES at longer periods of follow-up. Clinical implications The current study provided reassuring data on the vascular healing properties very early following BAS implantation in a relatively high-risk unselected cohort (80% acute coronary syndrome and 86.7% complex lesions). Adequate neointimal coverage of stent struts at 14-day follow-up suggested excellent early healing characteristics, consistent with the prior report of OCT evaluation of BAS one month after implantation (10). Moreover, the low percentage of malapposed struts, comparable with that observed after DES at longer follow-up periods, further strengthened evidence of adequate early healing. Current evidence supports the clinical practice of short (one month) dual antiplatelet regimen following BAS implantation, similar to that needed after bare-metal stents. This is particularly important in patients who need long-term oral anticoagulation therapy, in those with active or potential bleeding (e.g., peptic ulcer), and in those liable to undergo surgery early following percutaneous coronary intervention. Based on data of the current report that revealed adequate neointimal strut coverage as early as 2 weeks post-procedural, we can consider an even shorter dual antiplatelet regimen following BAS implantation. A newer generation of bioactive stents is already available, based on a cobalt-chromium platform, with thinner stent struts (22). Study limitations Our data were based on a single-center study with a relatively small sample size; therefore, the conclusions based on these data should be taken with caution. Further studies with long-term clinical follow-up are required to evaluate the correlation of early stent endothelialization and clinical events. Second, the current OCT technology cannot detect tissue coverage ⬍ 10 μm, and thus cannot differentiate ultra-thin layers of neointima. Moreover, OCT data before and immediately after the index procedure were not available. Although the cohort included over 50% bifurcation lesions, non-apposed side branch struts were excluded from analysis. This might introduce selection bias. We performed strut-level analysis (the percentage of covered struts of all analyzed struts). Stent-level analysis performed at multilevel taking into consideration the heirarchical structure of the data would be better, given the abnormal distribution of variables. Finally, we performed image analy-
Vascular healing after bioactive stents sis at 1-mm longitudinal intervals, in contrast to some studies which reported image analysis at 0.6-mm longitudinal intervals. Although the methodology adopted in the current study was previously validated for the assessment of neointimal strut coverage and showed excellent reproducibility, it might have a lower sensitivity to detect uncovered struts than shorter-interval protocols.
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Conclusion In the current evaluation by OCT at 14-day follow-up after BAS implantation in an unselected cohort, binary stent strut coverage was fairly adequate, and the prevalence of malapposed struts was low.
Acknowledgments None.
Funding This research received no grant from any funding agency in the public, commercial, or not-for-profit sectors.
Declaration of interest: The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.
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