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Incidence and predictors of the late catch-up phenomenon after drug-eluting stent implantation
International Journal of Cardiology 168 (2013) 2588–2592
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Incidence and predictors of the late catch-up phenomenon after drug-eluting stent implantation Raisuke Iijima ⁎, Tadashi Araki, Yoshinori Nagashima, Kenji Yamazaki, Makoto Utsunomiya, Masaki Hori, Hideki Itaya, Hideo Shinji, Masanori Shiba, Hidehiko Hara, Masato Nakamura, Kaoru Sugi Division of Cardiovascular Medicine, Ohashi hospital, Toho University Medical Center, Japan
a r t i c l e
i n f o
Article history: Received 4 June 2012 Received in revised form 5 November 2012 Accepted 17 March 2013 Available online 8 April 2013 Keywords: Drug-eluting stent Late catch-up phenomenon Late in-stent restenosis Very late stent thrombosis Percutaneous coronary intervention
a b s t r a c t Background: Although clinical restenosis within 1 year after percutaneous coronary intervention has been remarkably reduced with the advent of drug-eluting stents (DES), the late catch-up (LCU) phenomenon remains an issue despite medical advances. The aim of this study was to investigate the incidence and predictive factors of the LCU phenomenon in an unselected population treated with first-generation DES. Methods: A total of 923 patients treated with DES between June 2004 and August 2008 were analyzed. The LCU phenomenon was defined as secondary revascularization 1 year after index stenting. Retreatment for very late stent thrombosis was considered as part of the LCU phenomenon. Results: Incidence of the LCU phenomenon was seen in 33 patients (3.6%). Very late stent thrombosis was observed in 5 patients (0.6%) and very late in-stent restenosis was observed in 28 patients (3.0%). At the 12-month landmark analysis, the cumulative rate of cardiac death was significantly higher in patients with the LCU phenomenon than in those without any target lesion revascularization (9.0% vs. 0.9%, p b 0.001). In the multivariate analysis, hemodialysis [odds ratio (OR) 6.07, p = 0.003], number of stents (OR 1.58, p = 0.02), and coronary bifurcation lesions (OR 2.06, p = 0.048) were identified as independent predictors of the LCU phenomenon. Conclusion: The LCU phenomenon is associated with serious consequences and adverse events and remains an important issue in modern practice, despite medical advances. DES should be deployed with a minimum number of stents, and special consideration must be given to patients on hemodialysis and those with coronary bifurcation lesions. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction In-stent restenosis (ISR) due to intimal hyperplasia was a significant clinical problem in the era of bare metal stents (BMS) [1]. Angiographic study demonstrated that intimal hyperplasia peaked at 6 months after BMS implantation [2]. The advent of drug-eluting stents (DES) remarkably reduced intimal hyperplasia after stent implantation. Pivotal trials have demonstrated single-digit rates of restenosis in selected patients; [3] however, these trials were conducted during the BMS era. Since then anecdotal clinical experience has provided some evidence of late ISR 1 year after DES implantation [4]. However, the temporal course of neointimal formation after DES implantation remains unclear. Very late stent thrombosis (VLST) also remains a troublesome issue for practitioners performing percutaneous coronary intervention (PCI)
⁎ Corresponding author at: Division of Cardiovascular Medicine, Ohashi hospital, Toho University Medical Center, 2-17-6 Ohashi Meguro-ku, 153-8515, Tokyo, Japan. Tel.: +81 3 3468 1251; fax: +81 3 3468 1269. E-mail address: [email protected] (R. Iijima). 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.03.046
[3]. The course of VLST may be related to that of late ISR. In the BMS era, myocardial infarction was frequently observed in the clinical presentation of ISR [5]. VLST and ISR are manifestations of the late catch-up (LCU) phenomenon. This study investigated the incidence and predictive factors of the LCU phenomenon in an unselected population treated with first-generation DES. 2. Methods 2.1. Study population At our institution, from June 2004 to August 2008, DES were successfully implanted in 1103 patients with coronary artery disease, who were prospectively followed for 3 years. All lesions were implanted in de novo lesions using either sirolimus-eluting stent (Cypher; Cordis, Johnson & Johnson, Miami Lakes, FL, USA) or paclitaxel-eluting stent (Taxus; Boston Scientific, Boston, MA, USA). Because the LCU phenomenon was defined as a cardiac event requiring retreatment 1 year after DES implantation, patients in whom revascularization or death from any cause that occurred within 1 year after DES implantation and those who could not be followed up were excluded from this study (Fig. 1). Thus, 923 patients were enrolled in the study. Complete clinical follow-up data for 88% of these patients at 2-year follow-up and 78% at 3-year follow-up were available. Follow-up angiography after PCI was performed in 722 patients (78%) between 8 and 12 months.
R. Iijima et al. / International Journal of Cardiology 168 (2013) 2588–2592
Study Flow Chart
2589
angiography was performed as previously reported [7]. All patients provided written informed consent.
1513 patients with successful PCI 2.4. Statistical analysis
311 underwent BMS and BA 99 with in-stent restenosis lesion 1103 patients with DES implantation 83 any form of revascularization 34 all cause death 63 lost follow-up 923 eligible patients at 1 year following index PCI
810 patients (88%) at 2 year
Analyses were performed on a patient-by-patient basis. Data are presented as means ± SDs or percentages (%). Categorical variables were compared using the chi-squared test or Fisher's exact test when cell values were b5. Continuous variables were compared using the two-tailed unpaired t test. Event-free survival analyses were performed using the Kaplan–Meier method. For the main analysis, to identify independent predictors of the LCU phenomenon, a 2-step method was used as follows. (1) Univariate analysis was used to identify the clinical, angiographic, or procedural factors influencing the LCU phenomenon. Continuous variables were transformed into binary data, with 1 representing the presence of the assumed risk factor and 0 otherwise. The median value for each factor was used as the cut-off point for this division to avoid arbitrary influences. (2) Univariate predictors significant at a level of p b 0.05 were then entered into a stepwise multivariate logistic regression model. The odds ratio (OR) and 95% confidence intervals (CI) were calculated for the final multivariate model. Statistical significance was set at p b 0.05.
722 patients (78%) at 3 year
3. Results Fig. 1. Study flow chart: PCI indicates percutaneous coronary intervention; DES indicates drug-eluting stent; BMS indicates bare metal stent; BA indicates balloon angioplasty.
2.2. Stent and postprocedural management A bolus of heparin (100 IU/kg) was administered after sheath insertion and titrated to maintain an activated clotting time of >250 s throughout the procedure in all patients. DES were used in our hospital during this period, and its use was contraindicated in patients with malignancies or those scheduled for surgery. Target lesions were predilated with conventional balloon angioplasty. After stent implantation, highpressure balloon inflation procedure was performed to achieve satisfactory angiographic results of b25% residual stenosis by visual estimate. All patients received aspirin 100 mg and clopidogrel 75 mg per day for at least 12 months. Other cardiac medications were prescribed at the physician's discretion. 2.3. Definitions and follow-up The LCU phenomenon was defined as retreatment due to ISR or VLST 1 year after index stent implantation. Target lesion revascularization (TLR) was defined as retreatment with coronary intervention or coronary artery bypass grafting. Based on the Academic Research Consortium definition, only definite stent thrombosis was defined as VLST [6]. Retreatment for VLST was considered as part of the LCU phenomenon. However, retreatment for new lesions in another vessel and lesions remote from the originally stented site were not considered part of the LCU phenomenon. Cardiac death was considered as any fatal event not attributed to a noncardiac cause. Patients were followed up for at least 3 years after index stent implantation. Follow-up angiography was scheduled at 8 months after DES implantation. Quantitative coronary
In the present study involving 923 patients treated with firstgeneration DES, the LCU phenomenon was observed in 33 patients (3.6%). As shown in Fig. 2, VLST occurred in 5 patients (0.6%) and late ISR in 28 patients (3.0%). The mean interval time between index stent implantation and LCU was 47 ± 17 months. Acute coronary syndrome was the clinical presentation pattern in 74% of patients in whom retreatment for the LCU phenomenon was necessary. Single anti-platelet therapy was administered in 6 patients (18.2%). Table 1 displays the angiographic findings of serial angiograms at 4 time points evaluated from the index procedure to the time of cardiac events due to the LCU phenomenon. No significant lumen narrowing was observed in these 33 patients on follow-up angiography at 8 months after DES implantation. At the 8-month follow-up time point, stent fracture and peri-stent contrast staining were observed in 10 patients (30%) and 4 patients (12%), respectively. Angiographic thrombus was observed in 5 patients at the time of LCU phenomenon. Patterns of stent restenosis included focal ISR (76%) and diffuse ISR (24%). Evaluation of the influence of the LCU phenomenon at the 12-month landmark analysis revealed 3 cardiac deaths (2 due to VLST and 1 due to late ISR) associated with the LCU phenomenon. As shown in Fig. 3, the cumulative rate of cardiac death was significantly higher in patients with LCU phenomenon than in those
33 patients with LCU (3.6 %)
5 very late stent thrombosis (0.6%)
96.4 %
28 late in-stent restenosis (3.0%)
2-A. Incidence of LCU phenomenon
2-B. Distribution of ICU phenomenon
Fig. 2. Incidence of the late catch-up phenomenon (A). The distribution of definite very late stent thrombosis and late in-stent restenosis (B). LCU indicates late catch-up phenomenon.
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Table 1 Serial angiographic finding in 33 patients with late catch-up phenomenon. Before PCI Reference vessel size, mm Minimum lumen diameter, mm Diameter stenosis, % Lesion length, mm Stent fracture, n Type of stent restenosis Focal in-stent restenosis, n Diffuse in-stent restenosis, n Angiographic thrombus, n Peri-stent contrast staining, n
After PCI
Table 2 Baseline and procedural characteristics between late catch-up and TLR free patients.
8 months after PCI
Late catch up
2.80 ± 0.58
3.20 ± 0.52
2.99 ± 0.49
2.97 ± 0.47
0.79 ± 0.40
2.79 ± 0.49
2.40 ± 0.69
1.10 ± 0.49
72 ± 13 26.2 ± 18.5 – – –
14 ± 8 – – – –
21 ± 18 – 10 (30) – –
64 ± 14 12.9 ± 13.1 11 (33) 25 (76)
–
–
–
8 (24)
–
–
–
5 (15)
–
–
4 (12)
–
Age, years Male Hypertension Diabetes mellitus Dyslipidemia e-GFR, ml/min Chronic kidney disease Hemodialysis Acute coronary syndromes Prior coronary artery bypass surgery Left ventricular ejection fraction, % Multivessel disease Target of left main coronary artery Target of left anterior descending Type B2/C lesions Bifurcated lesion Chronic total occluded lesion Vessel size, mm MLD, mm Diameter stenosis, % Lesion length, mm MLD after intervention, mm Diameter stenosis after intervention, % Sirolimus-eluting stent Paclitaxel-eluting stent Stent diameter, mm Number of stents Stent length, mm
PCI indicates percutaneous coronary intervention.
without any TLR (9.0% vs. 0.9%, p b 0.001). An analysis was performed to identify the predictive factors of the LCU phenomenon. Table 2 compares baseline characteristics between patients in whom LCU phenomenon was observed and those in whom no TLR was performed. Patients with the LCU phenomenon were more likely to have poor kidney function, such as chronic kidney disease and were more likely to require hemodialysis. Moreover, acute coronary syndrome was more common in patients with the LCU phenomenon. In the evaluation of lesion characteristics, significant differences were observed in the location of the coronary bifurcated lesions, type of DES, and the number of stents. Finally, the multivariate analysis identified hemodialysis (OR, 6.07; 95%CI, 1.85–19.96; p = 0.003), the number of stents (OR, 1.58; 95%CI, 1.09–2.29; p = 0.02), and coronary bifurcation lesions (OR, 2.06; 95%CI, 1.01–4.21; p = 0.048) as independent predictors of the LCU phenomenon (Table 3).
Late catch-up
TLR free
(n = 33)
(n = 890)
67 ± 12 82 84 55 61 54 ± 40 45 33 58 3 60 ± 9 70 8 36 70 55 15 2.80 ± 0.55 0.87 ± 0.38 69 ± 13 26.7 ± 18.2 2.80 ± 0.49 13 ± 10 82 18 3.2 ± 0.3 1.9 ± 0.9 40 ± 22
69 ± 10 76 70 40 59 77 ± 31 24 8 39 4 59 ± 14 66 11 45 75 36 13 2.80 ± 0.57 0.79 ± 0.51 72 ± 16 23.9 ± 16.3 2.75 ± 0.49 11 ± 9 61 39 3.1 ± 0.3 1.5 ± 0.8 34 ± 19
p value
0.14 0.54 0.11 0.09 0.86 b0.0001 0.007 b0.0001 0.04 0.76 0.78 0.85 0.16 0.43 0.54 0.04 0.60 0.99 0.38 0.29 0.33 0.58 0.25 0.02 0.14 0.007 0.08
Data are presented as number of patients (%) or mean ± SD. e-GFR: Estimated glomerular filtration rate, MLD: Minimal lumen diameter.
first-generation DESs. The main findings are summarized as follows: The LCU phenomenon occurred in 3.6% of patients treated with firstgeneration DES; late ISR and definite VLST were observed in 3.0% and 0.6% of patients, respectively. Furthermore, the LCU phenomenon was significantly associated with cardiac death beyond 1 year after the index procedure. Strong associations were found between the LCU phenomenon and reduced renal function (especially in hemodialysis patients), coronary bifurcation lesions, and the number of stents.
4. Discussion The present study investigated the incidence and predictive factors of the LCU phenomenon in an unselected population treated with 20
15
Late catch-up
P < 0.001
10 100
Cumulative incidence (%)
5
TLR free
80 0 60
365
40
730
1095
1460
1825
No.at risk Late catch up
33
32
29
20
11
TLR free
890
776
692
430
189
20
0 0
365
730
1095
1460
1825 (day)
Fig. 3. Influence of the LCU phenomenon at the 12-month landmark analysis. Cumulative rates of cardiac death are shown for the period following 1 year after index PCI between the LCU phenomenon and TLR-free groups.
R. Iijima et al. / International Journal of Cardiology 168 (2013) 2588–2592 Table 3 Predictive factors of late catch-up phenomenon.
Hemodialysis Number of stents Bifurcated lesion Acute coronary syndrome chronic kidney disease Sirolimus-eluting stent
Uni-variate
Multi-variate
p value
Odd ratio
95%Cl
p value
b0.0001 0.008 0.04 0.04 0.006 0.02
6.07 1.58 2.06
1.85–19.96 1.09–2.29 1.01–4.21
0.003 0.02 0.048
Cl: confidence intervals.
Although the LCU phenomenon occurred relatively infrequently 1 year after DES implantation in the study sample, it was significantly associated with an increased risk of cardiac death. Therefore, the LCU phenomenon was associated with serious consequences and adverse events, and it remains an important issue in modern clinical practice despite medical advances. In the present study, the LCU phenomenon was observed in the form of late ISR and VLST. Although the incidence of late ISR was higher than that of VLST, clear distinction between these manifestations of the LCU phenomenon may be difficult. In this study, retreatment was necessary in most patients with the LCU phenomenon due to acute coronary syndrome, even though some cases did not fully meet the criteria of the Academic Research Consortium [6]. In this study, a considerably lower rate of VLST was observed than that in the Bern and Rotterdam cohorts [8]. However, a steady rate of VLST of 0.2%–0.3% per year is consistent with other, more recent large studies [9,10]. For reducing intimal hyperplasia in stent segments, DES are superior to BMS [3]. However, the time course of restenosis in these two types of stents may be quite different. A serial angiographic study demonstrated luminal changes after BMS implantation. Intimal hyperplasia peaked in the first 6 months and lumen enlargement occurred from 6 months to 3 years after index stent implantation [2]. In contrast, Byrne et al. reported the results of angiographic data during 2-year follow-up in 1331 patients who were treated with DES [11]. They found that ongoing late lumen loss beyond 6–8 months post-index procedure was observed following DES implantation in these patients. In a 3-year follow-up study of patients in the J-Cypher registry, Nakagawa et al. reported incidences of TLR in sirolimus-eluting stent-treated lesions of 5.5% at 1 year, 8.1% at 2 years, and 10.0% at 3 years [12]. The late intimal growth in DES-treated patients in these studies lend support to the hypothesis of the LCU phenomenon occurring despite improvements in stent design since the era of BMS. In the present study, the late ISR rate of 3.0% was lower than in other studies. This discrepancy may be related to differences in the follow-up angiography protocol. In the J-Cypher registry, the timing of follow-up angiography varied among individual investigators. In addition, follow-up angiography >1 year after index PCI may increase the incidence of repeated procedures due to angiographically-driven TLR [12]. In contrast, scheduled follow-up angiography was performed within 1 year after stent implantation in the current study sample, and 83 patients (8.3%) underwent retreatment with PCI within 1 year. The cumulative TLR rate up to 3 years in the present study was 11.3%, which is similar to that in the J-Cypher registry (10.0%). However, the current study may offer more accurate data regarding the LCU phenomenon, because no significant lumen narrowing was observed in patients with the LCU phenomenon on follow-up angiography 8 months after DES implantation. Although multiple mechanisms are involved, the composition of DES might be associated in the development of the LCU phenomenon. Firstgeneration durable polymer DES are composed of antiproliferative agents, and the most frequently used carrier vehicles are polymers that are modified for drug release kinetics [13]. In some cases with DES implantation, these durable polymers provoke chronic eosinophilic infiltration of the stented vessel, suggesting an allergic reaction [14].
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This polymer-induced inflammation may play a role in the ongoing aggressive intimal proliferation in patients with late ISR. The development of neoatherosclerosis at the stent site may also result in the LCU phenomenon. In a recently published pathological study, neoatherosclerotic changes were observed more frequently and at earlier time points (median; 420 days) in patients with DES than in those with BMS [15]. The development of neoatherosclerosis is thought to be associated with instability and lack of a fully functional endothelialized luminal surface within the DES. Moreover, unstable characteristics in neoatherosclerosis were more frequently observed in patients treated with DES. These findings were consistent with that of the present study, in which retreatment was required in 74% of patients in whom the LCU phenomenon presented as acute coronary syndrome. Theoretically, a biodegradable polymer DES has a potential to overcome these limitations of durable polymer-DES. Recently published individual patients data from 3 large multicenter randomized trials comparing biodegradable polymer DES with durable polymer DES assessed clinical outcomes during 4 years after stenting [16]. The pooled analyses, which included 4062 patients reported that the risk of TLR and VLST was significantly lower among patients with biodegradable polymer DES than among those with durable polymer DES. Thus, the results of these analyses suggest that the use of biodegradable polymer DES may reduce the risk of the LCU phenomenon. The present study has several limitations. First, the study sample was relatively small and all data were obtained from a single center. Confounding factors may have influenced the results, for example, decisions regarding duration of dual antiplatelet therapy may have differed among the attending physicians. This factor may have influenced clinical outcomes in the patients included in this study, especially patients with stent thrombosis. Similarly, VLST was identified only in cases of angiographically documented stent thrombosis, which may have led to underestimation of the true incidence of VLST. Furthermore, sirolimus-eluting stent and paclitaxel-eluting stent were used in this study. The development of LCU phenomenon of two stents may be a different process. Finally, although a multivariate analysis was performed to identify the predictors of the LCU phenomenon, other hidden factors may be related with its development. In conclusion, the LCU phenomenon seemed to exist after DES implantation. The LCU phenomenon itself translated into the serious consequences of adverse event and is still an important issue in the modern practice. DES should be deployed with a minimum number of stent. Especially consideration must be given to the patients with hemodialysis and bifurcation lesion.
References [1] Komatsu R, Ueda M, Naruko T, Kojima A, Becker AE. Neointimal tissue response at sites of coronary stenting in humans: macroscopic, histological, and immunohistochemical analyses. Circulation 1998;98:224–33. [2] Kimura T, Yokoi H, Nakagawa Y, et al. Three-year follow-up after implantation of metallic coronary–artery stents. N Engl J Med 1996;334:561–6. [3] Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007;356:1030–9. [4] Wessely R, Kastrati A, Schömig A. Late restenosis in patients receiving a polymer-coated sirolimus-eluting stent. Ann Intern Med 2005;143:392–4. [5] Lee TT, Feinberg L, Baim DS, et al. Effect of diabetes mellitus on five-year clinical outcomes after single-vessel coronary stenting (a pooled analysis of coronary stent clinical trials). Am J Cardiol 2006;98:718–21. [6] Mauri L, Hsieh WH, Massaro JM, Ho KKL, D'Agostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007;356: 1020–9. [7] Iijima R, Ndrepepa G, Mehilli J, et al. Impact of diabetes mellitus on long-term outcomes in the drug-eluting stent era. Am Heart J 2007;154:688–93. [8] 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;369:667–78. [9] de la Torre-Hernández JM, Alfonso F, Hernández F, et al. ESTROFA Study Group. Drug-eluting stent thrombosis: results from the multicenter Spanish registry ESTROFA (Estudio ESpañol sobre TROmbosis de stents FArmacoactivos). J Am Coll Cardiol 2008;51:986–90.
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[10] Schulz S, Schuster T, Mehilli J, et al. Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period. Eur Heart J 2009;30:2714–21. [11] Byrne RA, Iijima R, Mehilli J, et al. Durability of antirestenotic efficacy in drug-eluting stents with and without permanent polymer. JACC Cardiovasc Interv 2009;2:291–9. [12] Nakagawa Y, Kimura T, Morimoto T, et al. j-Cypher Registry Investigators. Incidence and risk factors of late target lesion revascularization after sirolimuseluting stent implantation (3-year follow-up of the j-Cypher Registry). Am J Cardiol 2010;106:329–36. [13] Garg S, Serruys PW. Coronary stents: current status. J Am Coll Cardiol 2010;56:S1–S42.
[14] Virmani R, Guagliumi G, Farb A, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation 2004;109:701–5. [15] Nakazawa G, Otsuka F, Nakano M, et al. The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. J Am Coll Cardiol 2011;57:1314–22. [16] Stefanini GG, Byrne RA, Serruys PW, et al. Biodegradable polymer drug-eluting stents reduce the risk of stent thrombosis at 4 years in patients undergoing percutaneous coronary intervention: a pooled analysis of individual patient data from the ISAR-TEST 3, ISAR-TEST 4, and LEADERS randomized trials. Eur Heart J 2012;33:1214–22.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Incidence and predictors of the late catch-up phenomenon after drug-eluting stent implantation Raisuke Iijima ⁎, Tadashi Araki, Yoshinori Nagashima, Kenji Yamazaki, Makoto Utsunomiya, Masaki Hori, Hideki Itaya, Hideo Shinji, Masanori Shiba, Hidehiko Hara, Masato Nakamura, Kaoru Sugi Division of Cardiovascular Medicine, Ohashi hospital, Toho University Medical Center, Japan
a r t i c l e
i n f o
Article history: Received 4 June 2012 Received in revised form 5 November 2012 Accepted 17 March 2013 Available online 8 April 2013 Keywords: Drug-eluting stent Late catch-up phenomenon Late in-stent restenosis Very late stent thrombosis Percutaneous coronary intervention
a b s t r a c t Background: Although clinical restenosis within 1 year after percutaneous coronary intervention has been remarkably reduced with the advent of drug-eluting stents (DES), the late catch-up (LCU) phenomenon remains an issue despite medical advances. The aim of this study was to investigate the incidence and predictive factors of the LCU phenomenon in an unselected population treated with first-generation DES. Methods: A total of 923 patients treated with DES between June 2004 and August 2008 were analyzed. The LCU phenomenon was defined as secondary revascularization 1 year after index stenting. Retreatment for very late stent thrombosis was considered as part of the LCU phenomenon. Results: Incidence of the LCU phenomenon was seen in 33 patients (3.6%). Very late stent thrombosis was observed in 5 patients (0.6%) and very late in-stent restenosis was observed in 28 patients (3.0%). At the 12-month landmark analysis, the cumulative rate of cardiac death was significantly higher in patients with the LCU phenomenon than in those without any target lesion revascularization (9.0% vs. 0.9%, p b 0.001). In the multivariate analysis, hemodialysis [odds ratio (OR) 6.07, p = 0.003], number of stents (OR 1.58, p = 0.02), and coronary bifurcation lesions (OR 2.06, p = 0.048) were identified as independent predictors of the LCU phenomenon. Conclusion: The LCU phenomenon is associated with serious consequences and adverse events and remains an important issue in modern practice, despite medical advances. DES should be deployed with a minimum number of stents, and special consideration must be given to patients on hemodialysis and those with coronary bifurcation lesions. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction In-stent restenosis (ISR) due to intimal hyperplasia was a significant clinical problem in the era of bare metal stents (BMS) [1]. Angiographic study demonstrated that intimal hyperplasia peaked at 6 months after BMS implantation [2]. The advent of drug-eluting stents (DES) remarkably reduced intimal hyperplasia after stent implantation. Pivotal trials have demonstrated single-digit rates of restenosis in selected patients; [3] however, these trials were conducted during the BMS era. Since then anecdotal clinical experience has provided some evidence of late ISR 1 year after DES implantation [4]. However, the temporal course of neointimal formation after DES implantation remains unclear. Very late stent thrombosis (VLST) also remains a troublesome issue for practitioners performing percutaneous coronary intervention (PCI)
⁎ Corresponding author at: Division of Cardiovascular Medicine, Ohashi hospital, Toho University Medical Center, 2-17-6 Ohashi Meguro-ku, 153-8515, Tokyo, Japan. Tel.: +81 3 3468 1251; fax: +81 3 3468 1269. E-mail address: [email protected] (R. Iijima). 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.03.046
[3]. The course of VLST may be related to that of late ISR. In the BMS era, myocardial infarction was frequently observed in the clinical presentation of ISR [5]. VLST and ISR are manifestations of the late catch-up (LCU) phenomenon. This study investigated the incidence and predictive factors of the LCU phenomenon in an unselected population treated with first-generation DES. 2. Methods 2.1. Study population At our institution, from June 2004 to August 2008, DES were successfully implanted in 1103 patients with coronary artery disease, who were prospectively followed for 3 years. All lesions were implanted in de novo lesions using either sirolimus-eluting stent (Cypher; Cordis, Johnson & Johnson, Miami Lakes, FL, USA) or paclitaxel-eluting stent (Taxus; Boston Scientific, Boston, MA, USA). Because the LCU phenomenon was defined as a cardiac event requiring retreatment 1 year after DES implantation, patients in whom revascularization or death from any cause that occurred within 1 year after DES implantation and those who could not be followed up were excluded from this study (Fig. 1). Thus, 923 patients were enrolled in the study. Complete clinical follow-up data for 88% of these patients at 2-year follow-up and 78% at 3-year follow-up were available. Follow-up angiography after PCI was performed in 722 patients (78%) between 8 and 12 months.
R. Iijima et al. / International Journal of Cardiology 168 (2013) 2588–2592
Study Flow Chart
2589
angiography was performed as previously reported [7]. All patients provided written informed consent.
1513 patients with successful PCI 2.4. Statistical analysis
311 underwent BMS and BA 99 with in-stent restenosis lesion 1103 patients with DES implantation 83 any form of revascularization 34 all cause death 63 lost follow-up 923 eligible patients at 1 year following index PCI
810 patients (88%) at 2 year
Analyses were performed on a patient-by-patient basis. Data are presented as means ± SDs or percentages (%). Categorical variables were compared using the chi-squared test or Fisher's exact test when cell values were b5. Continuous variables were compared using the two-tailed unpaired t test. Event-free survival analyses were performed using the Kaplan–Meier method. For the main analysis, to identify independent predictors of the LCU phenomenon, a 2-step method was used as follows. (1) Univariate analysis was used to identify the clinical, angiographic, or procedural factors influencing the LCU phenomenon. Continuous variables were transformed into binary data, with 1 representing the presence of the assumed risk factor and 0 otherwise. The median value for each factor was used as the cut-off point for this division to avoid arbitrary influences. (2) Univariate predictors significant at a level of p b 0.05 were then entered into a stepwise multivariate logistic regression model. The odds ratio (OR) and 95% confidence intervals (CI) were calculated for the final multivariate model. Statistical significance was set at p b 0.05.
722 patients (78%) at 3 year
3. Results Fig. 1. Study flow chart: PCI indicates percutaneous coronary intervention; DES indicates drug-eluting stent; BMS indicates bare metal stent; BA indicates balloon angioplasty.
2.2. Stent and postprocedural management A bolus of heparin (100 IU/kg) was administered after sheath insertion and titrated to maintain an activated clotting time of >250 s throughout the procedure in all patients. DES were used in our hospital during this period, and its use was contraindicated in patients with malignancies or those scheduled for surgery. Target lesions were predilated with conventional balloon angioplasty. After stent implantation, highpressure balloon inflation procedure was performed to achieve satisfactory angiographic results of b25% residual stenosis by visual estimate. All patients received aspirin 100 mg and clopidogrel 75 mg per day for at least 12 months. Other cardiac medications were prescribed at the physician's discretion. 2.3. Definitions and follow-up The LCU phenomenon was defined as retreatment due to ISR or VLST 1 year after index stent implantation. Target lesion revascularization (TLR) was defined as retreatment with coronary intervention or coronary artery bypass grafting. Based on the Academic Research Consortium definition, only definite stent thrombosis was defined as VLST [6]. Retreatment for VLST was considered as part of the LCU phenomenon. However, retreatment for new lesions in another vessel and lesions remote from the originally stented site were not considered part of the LCU phenomenon. Cardiac death was considered as any fatal event not attributed to a noncardiac cause. Patients were followed up for at least 3 years after index stent implantation. Follow-up angiography was scheduled at 8 months after DES implantation. Quantitative coronary
In the present study involving 923 patients treated with firstgeneration DES, the LCU phenomenon was observed in 33 patients (3.6%). As shown in Fig. 2, VLST occurred in 5 patients (0.6%) and late ISR in 28 patients (3.0%). The mean interval time between index stent implantation and LCU was 47 ± 17 months. Acute coronary syndrome was the clinical presentation pattern in 74% of patients in whom retreatment for the LCU phenomenon was necessary. Single anti-platelet therapy was administered in 6 patients (18.2%). Table 1 displays the angiographic findings of serial angiograms at 4 time points evaluated from the index procedure to the time of cardiac events due to the LCU phenomenon. No significant lumen narrowing was observed in these 33 patients on follow-up angiography at 8 months after DES implantation. At the 8-month follow-up time point, stent fracture and peri-stent contrast staining were observed in 10 patients (30%) and 4 patients (12%), respectively. Angiographic thrombus was observed in 5 patients at the time of LCU phenomenon. Patterns of stent restenosis included focal ISR (76%) and diffuse ISR (24%). Evaluation of the influence of the LCU phenomenon at the 12-month landmark analysis revealed 3 cardiac deaths (2 due to VLST and 1 due to late ISR) associated with the LCU phenomenon. As shown in Fig. 3, the cumulative rate of cardiac death was significantly higher in patients with LCU phenomenon than in those
33 patients with LCU (3.6 %)
5 very late stent thrombosis (0.6%)
96.4 %
28 late in-stent restenosis (3.0%)
2-A. Incidence of LCU phenomenon
2-B. Distribution of ICU phenomenon
Fig. 2. Incidence of the late catch-up phenomenon (A). The distribution of definite very late stent thrombosis and late in-stent restenosis (B). LCU indicates late catch-up phenomenon.
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Table 1 Serial angiographic finding in 33 patients with late catch-up phenomenon. Before PCI Reference vessel size, mm Minimum lumen diameter, mm Diameter stenosis, % Lesion length, mm Stent fracture, n Type of stent restenosis Focal in-stent restenosis, n Diffuse in-stent restenosis, n Angiographic thrombus, n Peri-stent contrast staining, n
After PCI
Table 2 Baseline and procedural characteristics between late catch-up and TLR free patients.
8 months after PCI
Late catch up
2.80 ± 0.58
3.20 ± 0.52
2.99 ± 0.49
2.97 ± 0.47
0.79 ± 0.40
2.79 ± 0.49
2.40 ± 0.69
1.10 ± 0.49
72 ± 13 26.2 ± 18.5 – – –
14 ± 8 – – – –
21 ± 18 – 10 (30) – –
64 ± 14 12.9 ± 13.1 11 (33) 25 (76)
–
–
–
8 (24)
–
–
–
5 (15)
–
–
4 (12)
–
Age, years Male Hypertension Diabetes mellitus Dyslipidemia e-GFR, ml/min Chronic kidney disease Hemodialysis Acute coronary syndromes Prior coronary artery bypass surgery Left ventricular ejection fraction, % Multivessel disease Target of left main coronary artery Target of left anterior descending Type B2/C lesions Bifurcated lesion Chronic total occluded lesion Vessel size, mm MLD, mm Diameter stenosis, % Lesion length, mm MLD after intervention, mm Diameter stenosis after intervention, % Sirolimus-eluting stent Paclitaxel-eluting stent Stent diameter, mm Number of stents Stent length, mm
PCI indicates percutaneous coronary intervention.
without any TLR (9.0% vs. 0.9%, p b 0.001). An analysis was performed to identify the predictive factors of the LCU phenomenon. Table 2 compares baseline characteristics between patients in whom LCU phenomenon was observed and those in whom no TLR was performed. Patients with the LCU phenomenon were more likely to have poor kidney function, such as chronic kidney disease and were more likely to require hemodialysis. Moreover, acute coronary syndrome was more common in patients with the LCU phenomenon. In the evaluation of lesion characteristics, significant differences were observed in the location of the coronary bifurcated lesions, type of DES, and the number of stents. Finally, the multivariate analysis identified hemodialysis (OR, 6.07; 95%CI, 1.85–19.96; p = 0.003), the number of stents (OR, 1.58; 95%CI, 1.09–2.29; p = 0.02), and coronary bifurcation lesions (OR, 2.06; 95%CI, 1.01–4.21; p = 0.048) as independent predictors of the LCU phenomenon (Table 3).
Late catch-up
TLR free
(n = 33)
(n = 890)
67 ± 12 82 84 55 61 54 ± 40 45 33 58 3 60 ± 9 70 8 36 70 55 15 2.80 ± 0.55 0.87 ± 0.38 69 ± 13 26.7 ± 18.2 2.80 ± 0.49 13 ± 10 82 18 3.2 ± 0.3 1.9 ± 0.9 40 ± 22
69 ± 10 76 70 40 59 77 ± 31 24 8 39 4 59 ± 14 66 11 45 75 36 13 2.80 ± 0.57 0.79 ± 0.51 72 ± 16 23.9 ± 16.3 2.75 ± 0.49 11 ± 9 61 39 3.1 ± 0.3 1.5 ± 0.8 34 ± 19
p value
0.14 0.54 0.11 0.09 0.86 b0.0001 0.007 b0.0001 0.04 0.76 0.78 0.85 0.16 0.43 0.54 0.04 0.60 0.99 0.38 0.29 0.33 0.58 0.25 0.02 0.14 0.007 0.08
Data are presented as number of patients (%) or mean ± SD. e-GFR: Estimated glomerular filtration rate, MLD: Minimal lumen diameter.
first-generation DESs. The main findings are summarized as follows: The LCU phenomenon occurred in 3.6% of patients treated with firstgeneration DES; late ISR and definite VLST were observed in 3.0% and 0.6% of patients, respectively. Furthermore, the LCU phenomenon was significantly associated with cardiac death beyond 1 year after the index procedure. Strong associations were found between the LCU phenomenon and reduced renal function (especially in hemodialysis patients), coronary bifurcation lesions, and the number of stents.
4. Discussion The present study investigated the incidence and predictive factors of the LCU phenomenon in an unselected population treated with 20
15
Late catch-up
P < 0.001
10 100
Cumulative incidence (%)
5
TLR free
80 0 60
365
40
730
1095
1460
1825
No.at risk Late catch up
33
32
29
20
11
TLR free
890
776
692
430
189
20
0 0
365
730
1095
1460
1825 (day)
Fig. 3. Influence of the LCU phenomenon at the 12-month landmark analysis. Cumulative rates of cardiac death are shown for the period following 1 year after index PCI between the LCU phenomenon and TLR-free groups.
R. Iijima et al. / International Journal of Cardiology 168 (2013) 2588–2592 Table 3 Predictive factors of late catch-up phenomenon.
Hemodialysis Number of stents Bifurcated lesion Acute coronary syndrome chronic kidney disease Sirolimus-eluting stent
Uni-variate
Multi-variate
p value
Odd ratio
95%Cl
p value
b0.0001 0.008 0.04 0.04 0.006 0.02
6.07 1.58 2.06
1.85–19.96 1.09–2.29 1.01–4.21
0.003 0.02 0.048
Cl: confidence intervals.
Although the LCU phenomenon occurred relatively infrequently 1 year after DES implantation in the study sample, it was significantly associated with an increased risk of cardiac death. Therefore, the LCU phenomenon was associated with serious consequences and adverse events, and it remains an important issue in modern clinical practice despite medical advances. In the present study, the LCU phenomenon was observed in the form of late ISR and VLST. Although the incidence of late ISR was higher than that of VLST, clear distinction between these manifestations of the LCU phenomenon may be difficult. In this study, retreatment was necessary in most patients with the LCU phenomenon due to acute coronary syndrome, even though some cases did not fully meet the criteria of the Academic Research Consortium [6]. In this study, a considerably lower rate of VLST was observed than that in the Bern and Rotterdam cohorts [8]. However, a steady rate of VLST of 0.2%–0.3% per year is consistent with other, more recent large studies [9,10]. For reducing intimal hyperplasia in stent segments, DES are superior to BMS [3]. However, the time course of restenosis in these two types of stents may be quite different. A serial angiographic study demonstrated luminal changes after BMS implantation. Intimal hyperplasia peaked in the first 6 months and lumen enlargement occurred from 6 months to 3 years after index stent implantation [2]. In contrast, Byrne et al. reported the results of angiographic data during 2-year follow-up in 1331 patients who were treated with DES [11]. They found that ongoing late lumen loss beyond 6–8 months post-index procedure was observed following DES implantation in these patients. In a 3-year follow-up study of patients in the J-Cypher registry, Nakagawa et al. reported incidences of TLR in sirolimus-eluting stent-treated lesions of 5.5% at 1 year, 8.1% at 2 years, and 10.0% at 3 years [12]. The late intimal growth in DES-treated patients in these studies lend support to the hypothesis of the LCU phenomenon occurring despite improvements in stent design since the era of BMS. In the present study, the late ISR rate of 3.0% was lower than in other studies. This discrepancy may be related to differences in the follow-up angiography protocol. In the J-Cypher registry, the timing of follow-up angiography varied among individual investigators. In addition, follow-up angiography >1 year after index PCI may increase the incidence of repeated procedures due to angiographically-driven TLR [12]. In contrast, scheduled follow-up angiography was performed within 1 year after stent implantation in the current study sample, and 83 patients (8.3%) underwent retreatment with PCI within 1 year. The cumulative TLR rate up to 3 years in the present study was 11.3%, which is similar to that in the J-Cypher registry (10.0%). However, the current study may offer more accurate data regarding the LCU phenomenon, because no significant lumen narrowing was observed in patients with the LCU phenomenon on follow-up angiography 8 months after DES implantation. Although multiple mechanisms are involved, the composition of DES might be associated in the development of the LCU phenomenon. Firstgeneration durable polymer DES are composed of antiproliferative agents, and the most frequently used carrier vehicles are polymers that are modified for drug release kinetics [13]. In some cases with DES implantation, these durable polymers provoke chronic eosinophilic infiltration of the stented vessel, suggesting an allergic reaction [14].
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This polymer-induced inflammation may play a role in the ongoing aggressive intimal proliferation in patients with late ISR. The development of neoatherosclerosis at the stent site may also result in the LCU phenomenon. In a recently published pathological study, neoatherosclerotic changes were observed more frequently and at earlier time points (median; 420 days) in patients with DES than in those with BMS [15]. The development of neoatherosclerosis is thought to be associated with instability and lack of a fully functional endothelialized luminal surface within the DES. Moreover, unstable characteristics in neoatherosclerosis were more frequently observed in patients treated with DES. These findings were consistent with that of the present study, in which retreatment was required in 74% of patients in whom the LCU phenomenon presented as acute coronary syndrome. Theoretically, a biodegradable polymer DES has a potential to overcome these limitations of durable polymer-DES. Recently published individual patients data from 3 large multicenter randomized trials comparing biodegradable polymer DES with durable polymer DES assessed clinical outcomes during 4 years after stenting [16]. The pooled analyses, which included 4062 patients reported that the risk of TLR and VLST was significantly lower among patients with biodegradable polymer DES than among those with durable polymer DES. Thus, the results of these analyses suggest that the use of biodegradable polymer DES may reduce the risk of the LCU phenomenon. The present study has several limitations. First, the study sample was relatively small and all data were obtained from a single center. Confounding factors may have influenced the results, for example, decisions regarding duration of dual antiplatelet therapy may have differed among the attending physicians. This factor may have influenced clinical outcomes in the patients included in this study, especially patients with stent thrombosis. Similarly, VLST was identified only in cases of angiographically documented stent thrombosis, which may have led to underestimation of the true incidence of VLST. Furthermore, sirolimus-eluting stent and paclitaxel-eluting stent were used in this study. The development of LCU phenomenon of two stents may be a different process. Finally, although a multivariate analysis was performed to identify the predictors of the LCU phenomenon, other hidden factors may be related with its development. In conclusion, the LCU phenomenon seemed to exist after DES implantation. The LCU phenomenon itself translated into the serious consequences of adverse event and is still an important issue in the modern practice. DES should be deployed with a minimum number of stent. Especially consideration must be given to the patients with hemodialysis and bifurcation lesion.
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[14] Virmani R, Guagliumi G, Farb A, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation 2004;109:701–5. [15] Nakazawa G, Otsuka F, Nakano M, et al. The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. J Am Coll Cardiol 2011;57:1314–22. [16] Stefanini GG, Byrne RA, Serruys PW, et al. Biodegradable polymer drug-eluting stents reduce the risk of stent thrombosis at 4 years in patients undergoing percutaneous coronary intervention: a pooled analysis of individual patient data from the ISAR-TEST 3, ISAR-TEST 4, and LEADERS randomized trials. Eur Heart J 2012;33:1214–22.