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Serial angiographic findings and prognosis of stent fracture site without early restenosis after sirolimus-eluting stent implantation
Serial angiographic findings and prognosis of stent fracture site without early restenosis after sirolimus-eluting stent implantation Yasushi Ino, MD, a Yasuaki Toyoda, MD, PhD, a Atsushi Tanaka, MD, PhD, b Shuuta Ishii, MD, a Yoshio Kusuyama, MD, PhD, a Takashi Kubo, MD, PhD, b Shigeho Takarada, MD, PhD, b Hironori Kitabata, MD, b Takashi Tanimoto, MD, b Kumiko Hirata, MD, PhD, b Masato Mizukoshi, MD, PhD, b Toshio Imanishi, MD, PhD, b and Takashi Akasaka, MD, PhD b Wakayama, Japan
Background Stent fracture is one of the possible causes of in-stent restenosis after sirolimus-eluting stent (SES) implantation. However, long-term prognosis including late restenosis in stent fracture site without early restenosis remains unknown. The aim of this study is to investigate the risk of late restenosis at the stent fracture site without early restenosis after SES implantation. Methods
We divided 366 patients with 490 lesions into 2 groups with or without stent fracture based on the first scheduled follow-up coronary angiography (fracture group, 21 lesions; nonfracture group, 469 lesions). The second scheduled follow-up coronary angiography (N15 months after SES implantation) was performed in 83 patients with 124 lesions.
Results Target lesion revascularization due to late restenosis at the stent fracture site did not occur in the fracture group, but occurred in 5 lesions in the nonfracture group. At the first follow-up, minimal luminal diameter was significantly smaller and percentage diameter stenosis was significantly larger in the fracture group (1.98 ± 0.41 vs 2.52 ± 0.49 mm, P = .001 and 30.5% ± 13.1% vs 13.0% ± 8.8%, P b .0001, respectively). These differences were also present at the second follow-up (P = .01 and P = .007, respectively). In each group, there were no significant changes in minimal luminal diameter, percentage diameter stenosis, and late lumen loss between the first and second follow-up. Conclusions Late restenosis was not observed in stent fracture sites without early restenosis during the midterm follow-up after SES implantation. (Am Heart J 2010;160:775.e1-775.e9.) Sirolimus-eluting stents (SESs) have been shown to dramatically reduce in-stent restenosis (ISR)1,2; however, they do not completely resolve this problem.3-5 Several studies have reported that stent fracture, seen in 1.6% to 7.7% of lesions after SES implantation, was one of the possible causes of ISR.5-12 Recently, several studies have demonstrated that late restenosis associated with the late catch-up phenomenon was seen in lesions after drugeluting stent (DES) implantation.13-17 However, the longterm prognosis including late restenosis at the stent fracture site without early restenosis remains unknown. The aim of the present study is to investigate the risk of late restenosis at the stent fracture site without early restenosis after SES implantation.
From the aDivision of Cardiology, Wakayama National Hospital, Wakayama, Japan, and bDepartment of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan. Submitted January 9, 2010; accepted July 9, 2010. Reprint requests: Takashi Akasaka, MD, Department of Cardiovascular Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan. E-mail: [email protected] 0002-8703/$ - see front matter © 2010, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2010.07.010
Methods Study population From September 2004 to August 2007, 455 patients with 594 lesions underwent SES (Cypher; Cordis/Johnson and Johnson, Miami, FL) implantation into de novo and ISR lesions at Wakayama National Hospital. These did not include patients with STelevation myocardial infarction who underwent primary percutaneous coronary intervention (PCI), as well as those with planned surgery requiring antiplatelet therapy withdrawal, those with intolerance to aspirin or ticlopidine, or those with inappropriate vessel size for SES. The first scheduled follow-up coronary angiography (CAG) (69 months after PCI) was performed in 387 (85.1%) of the 455 patients with 517 lesions. We excluded 21 patients with 27 lesions because of the requirement for target lesion revascularization (TLR) for ISR (including 8 lesions with stent fracture). We divided the remaining 366 patients with 490 lesions into 2 groups: those with or without stent fracture, according to the first scheduled follow-up CAG findings. The fracture group consisted of 21 lesions, and the nonfracture group consisted of 469 lesions. All patients were followed clinically for a minimum of 16 months (range, 16-59 months) after SES implantation. Long-term clinical follow-up data were obtained from outpatient record reviews or telephone interviews. In the fracture group, we lost no clinical follow-up data and obtained those of all 21 patients without ISR (clinical follow-up rate was 100%). On the
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Figure 1
Flow diagram of study population.
other hands, in the nonfracture group, we lost clinical follow-up data in 5 of 345 patients because of their removal to another prefectures from 18 to 30 months after SES implantation (clinical follow-up rate was 98.5%). We then judged these patients as event-free for 18 to 30 months after SES implantation and analyzed the clinical follow-up data. In our hospital, the approach to asymptomatic fracture without significant stenosis was not performing TLR but following closely with dual-antiplatelet therapy. Furthermore, the second scheduled follow-up CAG (N15 months after SES implantation) was performed without recourse to the presence of ischemic sign if approval of patients was obtained (16 of 21 patients). In the nonfracture group, it was performed in asymptomatic patients with positive results of stress test (silent ischemia) or symptomatic patients during the long-term followup after the first scheduled follow-up CAG (67 patients with 108 lesions) (Figure 1). This study complied with the Declaration of Helsinki regarding investigations in humans and was approved by the Ethics Committee of Wakayama National Hospital. All patients provided written informed consent.
(V-form), III (complete separation without displacement), and IV (complete separation with displacement) according to the classification of Popma et al.19 With the guiding catheter for magnification-calibration and an online system (QCA-CMS version 5.0; Medis, Leiden, the Netherlands), minimal luminal diameter (MLD) and diameters of the reference segments were measured at baseline (prestenting), poststenting, and first and second follow-up CAG. The target lesion MLD included the stent as well as 5-mm margins proximal and distal to the stent. In the fracture group, MLD was measured at the fracture site in all patients except for 1 case with late restenosis not at the fracture site but at the proximal site of the SES because the smallest in-stent MLD was located at the fracture site in all patients except for that case. Late lumen loss was defined as the difference between the MLD at poststenting and that at follow-up. Binary restenosis was defined as stenosis of N50% of the luminal diameter in the target lesion at follow-up.
Definition and classification of stent fracture, and quantitative coronary angiographic analysis
Major adverse cardiac events (MACEs) after the first scheduled follow-up CAG were defined as death of cardiac origin, very late stent thrombosis, and late restenosis. Stent thrombosis was defined as the angiographic confirmation of thrombotic stent occlusion with at least one of the following: (1) continuous chest pain for ≥20 minutes, (2) ischemic electrocardiographic changes, and (3) typical rise and fall of cardiac biomarkers, according to the definitions suggested by the Academic Research Consortium.20 Target lesion revasculariza-
Stent fracture was defined as complete or partial separation of the stent on plain fluoroscopy without contrast injection on the first scheduled follow-up CAG according to previous reports.12,18,19 The diagnosis of stent fracture required an independent review and agreement by 2 of the authors (Y. I. and Y. T.). Stent fracture was classified into type I (minor), II
Definition of major adverse cardiac events, late restenosis, and stent thrombosis
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Table I. Baseline clinical characteristics
Age, y Male gender, n (%) Hypertension, n (%) Dyslipidemia, n (%) Diabetes mellitus, n (%) Cigarette smoking, n (%) Prior MI, n (%) Prior PCI, n (%) Prior CABG, n (%) Acute coronary syndrome, n (%) No. of diseased vessels, n (%) 1 2 3 Multivessel disease, n (%) LVEF (%) Duration of the clinical follow-up after PCI, m
Table II. Angiographic and procedural characteristics
Fracture group (n = 21)
Nonfracture group (n = 345)
P value
66 ± 10 18 (86) 17 (81) 13 (62) 13 (62) 12 (57) 7 (33) 5 (24) 1 (5) 2 (10)
67 ± 10 274 (79) 274 (79) 238 (69) 151 (44) 165 (48) 153 (44) 175 (51) 28 (8) 82 (24)
.471 .588 .99 .478 .118 .502 .372 .023 .99 .182 .091
7 (33) 11 (52) 3 (14) 14 (67) 62 ± 9 35 ± 12
196 (57) 125 (36) 24 (7) 149 (44) 59 ± 11 34 ± 11
.042 .216 .728
MI, Myocardial infarction; LVEF, left ventricular ejection fraction.
tion was defined as repeat percutaneous or surgical intervention of the stented lesion. Late restenosis was defined as in-stent binary restenosis in a lesion without restenosis at the first scheduled follow-up CAG.
Statistical analysis Statistical analysis was performed using Stat View 5.0 software (SAS Institute Inc, Cary, NC). Categorical data are presented as frequencies and were compared with χ2 statistics or Fisher exact test. Continuous variables are expressed as mean ± SD and were compared with the paired and unpaired Student t test or Mann-Whitney U test. The MACEs during follow-up were analyzed by the Kaplan-Meier method. The log-rank test was used to evaluate differences between the event-free survival curves for the 2 groups. A probability value b .05 was considered statistically significant.
Lesions (n = 490) Target vessel LAD, n (%) LCX, n (%) RCA, n (%) LMCA, n (%) SVG, n (%) Lesion type A, n (%) B1, n (%) B2, n (%) C, n (%) ISR, n (%) Bifurcation lesion, n (%) Calcification, n (%) CTO, n (%) Stent diameter, mm Total stent length, mm Stent per lesion, n Maximal pressure, atm Stent overlap, n (%) Use of size up balloon, n (%) Aorta ostium stenting, n (%) QCA results Reference vessel diameter (mm) Pre-MLD (mm) Pre-%DS (%) Post-MLD (mm) Post-%DS (%)
Fracture group (n = 21)
Nonfracture group (n = 469)
8 (38) 3 (14) 10 (48) 0 (0) 0 (0)
188 (40) 140 (30) 135 (29) 4 (0.9) 2 (0.4)
1 (5) 0 (0) 6 (29) 14 (67) 1 (5) 3 (14)
20 (4) 73 (16) 306 (65) 70 (15) 50 (11) 145 (31)
.713 .144
3 (14) 8 (38) 2.82 ± 0.36 41 ± 15 2.0 ± 0.7 19 ± 2 15 (71) 4 (19) 1 (5)
136 (29) 40 (9) 2.91 ± 0.38 25 ± 12 1.2 ± 0.5 19 ± 3 89 (19) 47 (10) 7 (1.5)
.215 .0004 .301 b.0001 b.0001 .913 b.0001 .259 .297
2.68 ± 0.33
2.76 ± 0.47
.402
0.35 87 2.62 7.7
0.66 ± 77 ± 2.71 ± 6.8 ±
.0005 .0006 .353 .516
.359
b.0001
± ± ± ±
0.33 13 0.42 5.9
0.40 13 0.44 5.8
LAD, Left anterior descending; LCX, left circumflex; RCA, right coronary artery; LMCA, left main coronary artery; SVG, saphenous vein graft; CTO, chronic total occlusion.
Figure 2.
Sources of funding No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents.
Results Clinical, angiographic, and procedural characteristics Of the 21 lesions in the fracture group, none were type I fractures, 9 were type II, 7 were type III, and 5 were type IV. Baseline clinical characteristics in the fracture and nonfracture groups are shown in Table I. The 2 groups had no significant differences in almost all variables for the baseline clinical characteristics. Prior PCI was more common in the nonfracture group (P = .023), and multivessel disease was more common in the
P value
Survival free from MACEs.
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Table III. Characteristics of stent fracture patients without restenosis Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Age, y/gender
Indication of PCI
Location
ISR
CTO
No. of stents
Stent length/ diameter, mm
63/F 55/M 79/M 70/M 65/M 78/M 54/M 73/M 74/M 61/M 64/M 75/M 63/M 55/M 79/M
SCAD SCAD SCAD SCAD SCAD ACS ACS SCAD SCAD SCAD SCAD SCAD SCAD SCAD SCAD
LCX LAD LAD LAD LCX RCA RCA LAD LAD RCA RCA RCA RCA LAD LAD
− − − − − − − − − − − − − − −
− − − − − − − − + + + − + + +
2 2 1 1 1 1 2 2 2 3 2 3 2 2 2
31/2.5 43/2.5 18/2.5 28/2.5 18/2.5 18/3.5 38/3.5 32/2.5 43/2.5 63/3.0 39/3.0 54/2.5 44/2.5 47/3.0 59/3.0
16 56/M SCAD RCA 17 76/M SCAD RCA 18 47/M SCAD RCA 19 62/F SCAD LCX 20 45/M ACS RCA 21 79/M SCAD RCA Popma et al Duration of the 2nd DS at 1st SCAD, Stable coronary artery disease; ACS, acute coronary syndrome. classification follow-up CAG, m CAG, %
− + − − − − DS at 2nd CAG, %
− 2 − 3 + 3 + 1 − 3 − 1 Dual-antiplatelet therapy
44/3.5 64/2.5 58/3.0 28/2.5 74/3.0 33/3.0 Clinical outcome
Table IV. Characteristics of stent fracture patients with restenosis Patient no.
Age, y/gender
Indication of PCI
1 2 3 4 5 6 7 8 Stent length/ BA, Balloon angioplasty. diameter, mm
80/F 81/M 61/M 64/M 70/M 65/M 67/M 54/F Popma et al classification
ACS ACS SCAD SCAD SCAD SCAD SCAD SCAD %DS at 1st follow-up CAG
fracture group (P = .042). The angiographic and procedural characteristics of both groups are shown in Table II. Significant differences between the fracture and the nonfracture groups were demonstrated in the rate of type C and chronic total occlusion lesions, total stent length, number of stents per lesion, the rate of stent overlap lesion, pre-MLD, and preimplantation percentage diameter stenosis (%DS).
Clinical outcomes after the first follow-up CAG Stent fracture patients without early restenosis are listed in Table III. In the fracture group, there was 1 case with late restenosis requiring TLR, not at the fracture site but at the proximal site of the SES. This group had no case with very late stent thrombosis or death of cardiac origin
Location LAD RCA LCX LCX RCA RCA RCA LAD Procedures of TLR
ISR
CTO
− − − + − − − − Dual-antiplatelet therapy
− − − − + − + −
No. of stents 2 1 1 1 4 1 3 3 Clinical outcome
at midterm follow-up after the first scheduled follow-up CAG. On the other hand, the nonfracture group had 5 late restenosis cases, 2 very late stent thrombosis cases, and 5 deaths due to cardiac failure. The event-free survival rate did not differ significantly between the 2 groups (log-rank probability value = .564) (Figure 2). For the 5 late restenosis cases in the nonfracture group, all the patients had recurrent angina pectoris at 19 to 49 months after initial SES implantation. Coronary angiography showed severe stenosis in the proximal edge of the stent in 2 cases, the midpoint in 2 cases, and the distal edge in 1 case. The additional SES implantation was performed in 3 cases, and coronary artery bypass grafting (CABG) was performed in 2 cases. In the nonfracture group, very late stent thrombosis occurred in 2 cases at 13 and 14 months after initial SES
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Table III (continued) Popma et al classification
Duration of the 2nd follow-up CAG, m
DS at 1st CAG, %
DS at 2nd CAG, %
Dual-antiplatelet therapy
Clinical outcome
III II III II III II II IV II II III IV IV II II
16 16 24 19 − − 16 17 16 22 19 21 − 24 −
48 42 29 20 39 20 26 28 30 37 27 49 19 14 35
47 43 27 20 − − 27 29 28 43 38 47 − 16 −
+ + + + + + + + + + + + + + +
III II IV III IV III
15 − 29 16 22 22
23 40 25 50 25 30
22 − 22 45 25 28
+ + + + + +
Event-free Event-free Event-free Event-free Event-free Event-free Event-free Event-free Event-free Event-free Event-free Event-free Event-free Event-free Late restenosis at nonfracture site Event-free Event-free Event-free Event-free Event-free Event-free
Table IV (continued) Stent length/ diameter, mm
Popma et al classification
%DS at 1st follow-up CAG
Procedures of TLR
Dual-antiplatelet therapy
Clinical outcome
34/2.5 18/3.0 23/2.5 23/3.0 94/3.0 33/3.0 83/3.0 56/3.0
III III II III III II III IV
88 74 70 90 68 72 75 56
PES implantation SES implantation SES implantation CABG SES implantation PES implantation PES implantation BA
+ + + − + + + +
Re-restenosis (−) re-TLR with PES Re-restenosis (−) Event-free Re-restenosis (−) Re-restenosis (−) Re-restenosis (−) re-TLR with PES
implantation. In 1 of 2 cases, ticlopidine was discontinued 9 months after SES implantation; and only aspirin had been continued. In the other case, dual-antiplatelet therapy had been continued. Emergent CAG revealed occlusion with thrombus at the site of the prior SES in both cases. Both cases underwent emergent PCI and had an additional bare-metal stent (BMS) implantation at that time. Patients with stent fracture having TLR at the first follow-up angiogram are listed in Table IV. In all 8 restenosis lesions with stent fracture, restenosis was located in fracture site; and the angiographic pattern of restenosis was focal type. Target lesion revascularization was performed in all patients, 3 patients had an additional SES implantation, 3 patients were implanted with paclitaxel-eluting stents (PESs), 1 patient was treated with balloon angioplasty, and 1 patient underwent CABG.
One patient with an additional SES implantation and 1 patient undergoing balloon angioplasty had recurrent restenosis with clinical symptoms, and both patients underwent PES implantation. Another 5 patients with reimplantation of a DES had no recurrent restenosis. Recurrent stent fracture was not observed in all 7 patients with reimplantation of a DES.
Serial quantitative coronary angiography results and late lumen loss The mean duration of the second follow-up CAG after SES implantation was 19.8 ± 4.9 and 20.5 ± 4.9 months in the fracture and nonfracture group, respectively (P = .778). Serial quantitative coronary angiography (QCA) results are shown in Figure 3. At the first
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Figure 3
Serial results of MLD (A) and %DS (B) at prestenting, poststenting, first follow-up, and second follow-up.
Figure 4
fracture group, P = .069 and P = .073 in the nonfracture group, respectively). Late lumen loss is shown in Figure 4. Late lumen loss at the first and second follow-up was significantly larger in the fracture group (P b .0001 and P b .0001, respectively). In each group, no significant changes in late lumen loss occurred between the first and second follow-up (P = .802 in the fracture group and P = .069 in the nonfracture group). Figures 5 and 6 demonstrate 2 representative serial angiographies with stent fracture.
Discussion
Late lumen loss at first follow-up and second follow-up.
follow-up, MLD was significantly smaller and %DS was significantly larger in the fracture group than in the nonfracture group (1.87 ± 0.50 vs 2.58 ± 0.52 mm, P b .0001 and 34% ± 13% vs 12% ± 10%, P b .0001, respectively). These differences were maintained at the second follow-up (1.85 ± 0.48 vs 2.47 ± 0.64 mm, P b .0001 and 34% ± 12% vs 14% ± 16%, P b .0001, respectively). However, in each group, no significant changes occurred in MLD and %DS between the first and second follow-up (P = .576 and P = .777 in the
The main findings of the present study were as follows: (1) There were no cases of late restenosis at the stent fracture site in the fracture group, whereas there were 5 cases in the nonfracture group. (2) At the first follow-up, MLD was significantly smaller and %DS and late loss were significantly larger in the fracture group. (3) These differences were maintained at the second follow-up. (4) In each group, no significant changes in MLD, %DS, and late lumen loss occurred between the first and second follow-up. According to previous reports, the frequency of ISR in stent fracture lesions is 33% to 80%.7-12 In the present study, 8 of 29 lesions in the fracture group and 19 of 488 lesions in the nonfracture group had restenosis requiring TLR by the initial angiogram (28% vs 3.9%, P b .0001), which is similar to the previous reports. Therefore, some
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Figure 5
A, Right CAG showed chronic total occlusion with bridge collateral in the midportion of the RCA (white arrow). B, Three Cypher stents (2.5/ 23, 3.0/18, and 3.0/23 mm) were deployed in the mid to distal portion of the RCA without gap (white lines), and another Cypher stent (3.5/18 mm) was deployed in the proximal portion (black line). C, Angiography at 9-month follow-up demonstrated mild stenosis with stent fracture (white arrow). D, Stent fracture on plain fluoroscopy (white arrow, fracture site; white line, stents). E, Progression of stenosis at the fracture site was not seen in angiography at 29-month follow-up (white arrow, fracture site; black arrow, late stent malapposition).
lesions with stent fractures do not result in TLR. The long-term prognosis of these patients is still unknown. Doi et al18 reported that half of the patients with stent fracture and ISR presented N1 year after SES implantation. Mehrle et al21 reported late restenosis 18 months after SES implantation. In the present study, 16 of 21 patients without TLR at the first scheduled follow-up CAG in the fracture group underwent a second followup CAG; and no patients had late restenosis requiring late TLR due to the late catch-up phenomenon in the fracture site. These results may be explained as follows. First, fracture cases in the present study excluded TLR cases at the first scheduled follow-up CAG. In contrast, in the reports of Doi et al and Mehrle et al, information was not provided as to whether the first scheduled follow-up CAG was performed or not. These other reports suggested that neointimal hyperplasia at the stent fracture site may be caused by local mechanical stimulation of the vessel wall with the broken struts.7,22 However, in our study, local mechanical stimulation of
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the vessel wall may have been less pronounced than in fracture cases with early restenosis at the first scheduled follow-up CAG. Second, other studies suggested that local drug delivery may be decreased in the fracture site.7,9,10,22 It was reported that the neointimal tissue volume after BMS implantation peaked at 6 months and, after this, often regressed.23,24 Because of decreased local drug delivery, the growth patterns of neointima at the fracture site might be similar to those after BMS implantation. Finally, animal studies have shown that late neointimal growth after DES implantation was larger than that after BMS implantation. Farb et al25 reported that PESs showed not only dose-dependent reduction in neointimal hyperplasia but also histologic signs of delayed healing and local toxicity after high-dose paclitaxel exposure. In addition, some clinical reports described late restenosis after PES implantation.13,14,26 On the other hand, several studies reported that delayed neointimal growth was rare in lesions after SES implantation27-30; and the results of the present study were similar to those of previous studies. Delayed neointimal growth may vary with different drugs, polymers, and/or stent platforms. In this study, not every patient underwent routine second follow-up CAG. Especially, it was performed only in patients with symptoms or a positive exercise test result in the nonfracture group; and the rate of it in that group was low, creating a selection bias. On the other hand, in the fracture group, it was performed in most patients who had no ischemic sign. Therefore, it is no surprise that numerically more restenosis occurred in the nonfracture group; and the comparison between the fracture and nonfracture groups after the first follow-up may be problematic. It is ideal that all patients without stent fracture would also be requested to have the second follow-up CAG regardless of clinical status. However, the aggressive second follow-up CAG for patients without clinical symptom is problematic ethically because several studies reported the long-term efficacy of SES in suppressing ISR.27-30 The aim of the present study is to investigate the risk of late restenosis at the stent fracture site without early restenosis after SES implantation. In the fracture group, the second scheduled follow-up CAG was recommended in all patients without recourse to the presence of ischemic sign; and it was performed in 16 (76%) of 21 patients. We could confirm that late restenosis in stent fracture site was not observed at 19.8 ± 4.9 months in those 16 patients and that clinical driven late TLR was not observed for 35 months after SES implantation in all 21 stent fracture patients without early restenosis except for 1 patient with late restenosis away from the fracture site. Furthermore, the analysis in all 366 patients showed that the event-free survival rate including clinically driven late TLR did not differ significantly between the 2 groups (Figure 2).
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Figure 6
A, Left CAG showed a moderate stenosis in the distal portion of the LAD (white arrow). B, Cypher stent (2.5/18 mm) deployment without predilatation. C, Final angiography after stent deployment (white line, stent). D, Angiography at 9-month follow-up demonstrates mild stenosis with stent fracture (white arrow). E, Stent fracture on plain fluoroscopy (white line, stent). F, Progression of stenosis at the fracture site was not seen in angiography at 24-month follow-up (white arrow, fracture site).
Nakazawa et al6 reported the relationship between stent fracture and stent thrombosis after DES implantation in autopsy registry. All stent thromboses associated with fracture site occurred in complete separation with displacement type fracture in their study. In addition, 2 cases of stent thrombosis associated with SES fracture occurred during the early phase (11 and 60 days after SES implantation). Lee et al9 reported a case of very late stent thrombosis at the stent fracture site 20 months after SES implantation. In this case, clopidogrel had been discontinued 12 months after SES implantation. Doi et al18 reported a similar case at the stent fracture site 20 months after SES implantation. In this case, the stent fracture was located in the midportion of a coronary aneurysm; and it was unclear whether dual-antiplatelet therapy was continued or not. In the present study, very late stent thrombosis did not occur in the fracture group. This may be explained as follows. First, dual-antiplatelet therapy with aspirin and ticlopidine had been continued in all patients in the fracture group for N12 months after SES implantation. Second, the population in our study did not include patients with severe stenosis at the fracture site because TLR had been performed at the first scheduled follow-up CAG. Third, type IV stent fracture (complete separation with displacement) was present in only 5 of 21 patients in the present study.
Study limitations There are several limitations in the present study. First, it is difficult to detect stent fracture after SES implantation in a prior ISR. In this study, 47 patients with 50 lesions had SES placed in a prior ISR in the nonfracture group.
Therefore, stent fracture might have been missed in those 47 patients. Furthermore, because intravascular ultrasound at the first follow-up CAG was not performed in all patients, small stent fractures, such as a single strut fracture, were difficult to detect with fluoroscopy. However, the incidence of stent fracture in the present study was 5.6%, which was similar to those in previous studies (1.6%-7.7%).7-12 Furthermore, although early ISR was observed in 3 patients with 3 lesions of those 47 patients, stent fracture was not observed in those 3 cases on intravascular ultrasound analysis. Second, the timing of the second follow-up CAG varied; and the duration of the interval after SES implantation may have affected the degree of intimal hyperplasia. In most of the lesions, however, no significant changes occurred in QCA parameters between the first and second follow-up. Third, the durations of second follow-up CAG and clinical follow-up after SES implantation in the fracture group were 19.8 ± 4.9 and 35 ± 12 months, respectively; and those were not so long. Fourth, there were significant differences in several characteristics of the lesion and/or PCI procedure between the fracture and nonfracture groups, which might affect the initial results. Finally, this was an observational analysis from a single center with a small number of patients with stent fractures; therefore, the present results should be viewed as preliminary and require confirmation with larger clinical trials.
Conclusions Late restenosis was not observed in stent fracture site without early restenosis during the midterm follow-up after SES implantation. The risk of very late stent
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thrombosis in stent fracture sites after this period is sill unknown, and close follow-up should be performed in patients with stent fracture.
References 1. Morice MC, Serruys PW, Sousa JE, et al, for the RAVEL Study Group. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346: 1773-80. 2. Moses JW, Leon MB, Popma JJ, et al, for the SIRIUS Investigators. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315-23. 3. Colombo A, Orlic D, Stankovic G, et al. Preliminary observations regarding angiographic pattern of restenosis after rapamycin-eluting stent implantation. Circulation 2003;107:2178-80. 4. Lemos PA, Saia F, Ligthart JM, et al. Coronary restenosis after sirolimus-eluting stent implantation: morphological description and mechanical analysis from a consecutive series of cases. Circulation 2003;108:257-60. 5. Takebayashi H, Mintz GS, Carlier SG, et al. Nonuniform strut distribution correlates with more neointimal hyperplasia after sirolimus-eluting stent implantation. Circulation 2004;110:3430-4. 6. Nakazawa G, Fin AV, Vorpahl M, et al. Incidence and predictors of drug-eluting stent fracture in human coronary artery. J Am Coll Cardiol 2009;54:1924-31. 7. Lee SH, Park JS, Shin DG, et al. Frequency of stent fracture as a cause of coronary restenosis after sirolimus-eluting stent implantation. Am J Cardiol 2007;100:627-30. 8. Aoki J, Nakazawa G, Tanabe K, et al. Incidence and clinical impact of coronary stent fracture after sirolimus-eluting stent implantation. Catheter Cardiovasc Interv 2007;69:380-6. 9. Lee MS, Jurewitz D, Aragon J, et al. Stent fracture associated with drug-eluting stents: clinical characteristics and implications. Catheter Cardiovasc Interv 2007;69:387-94. 10. Okumura M, Ozaki Y, Ishii J, et al. Restenosis and stent fracture following sirolimus-eluting stent (SES) implantation. Circ J 2007;71: 1669-77. 11. Umeda H, Gochi T, Iwase M, et al. Frequency, predictors and outcome of stent fracture after sirolimus-eluting stent implantation. Int J Cardiol 2009;133:321-6. 12. Ino Y, Toyoda Y, Tanaka A, et al. Predictors and prognosis of stent fracture after sirolimus-eluting stent implantation. Circ J 2009;73: 2036-41. 13. Liistro F, Stankovic G, Mario CD, et al. First clinical experience with a paclitaxel derivate-eluting polymer stent system implantation for instent restenosis: immediate and long-term clinical and angiographic outcome. Circulation 2002;105:1883-6. 14. Virmani R, Liistro F, Stankovic G, et al. Mechanism of late in-stent restenosis after implantation of a paclitaxel derivate-eluting polymer stent system in humans. Circulation 2002;106:2649-51.
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15. Fajadet J, Morice MC, Bode C, et al. Maintenance of long-term clinical benefit with sirolimus-eluting coronary stents: three-year results of the RAVEL trial. Circulation 2005;111:1040-4. 16. Hong MK, Mintz GS, Lee CW, et al. Late target lesion revascularization after implantation of sirolimus-eluting stent. Catheter Cardiovasc Interv 2008;71:299-303. 17. Cosgrave J, Corbett SJ, Melzi G, et al. Late restenosis following sirolimus-eluting stent implantation. Am J Cardiol 2007;100:41-4. 18. Doi H, Maehara A, Mintz GS, et al. Classification and potential mechanisms of intravascular ultrasound patterns of stent fracture. Am J Cardiol 2009;103:818-23. 19. Popma JJ, Tiroch K, Almonacid A, et al. A qualitative and quantitative angiographic analysis of stent fracture late following sirolimus-eluting stent implantation. Am J Cardiol 2009;103:923-9. 20. Cutlip DE, Windecker S, Mehran R, et al. Academic research consortium. clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344-51. 21. Mehrle A, Skelton T, Almonacid A. Stent fracture: an unusual cause of late restenosis after sirolimus-eluting stent placement. Catheter Cardiovasc Interv 2007;69:989-92. 22. Sianos G, Hofma S, Ligthart JM, et al. Stent fracture and restenosis in the drug-eluting stent era. Catheter Cardiovasc Interv 2004;61:111-6. 23. 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. 24. Kuroda N, Kobayashi Y, Nameki M, et al. Intimal hyperplasia regression from 6 to 12 months after stenting. Am J Cardiol 2002; 89:869-72. 25. Farb A, Heller PF, Shroff S, et al. Pathological analysis of local delivery of paclitaxel via a polymer-coated stent. Circulation 2001; 104:473-9. 26. Park DW, Hong MK, Mintz GS, et al. Two-year follow-up of the quantitative angiographic and volumetric intravascular ultrasound analysis after nonpolymeric paclitaxel-eluting stent implantation: late “catch-up” phenomenon from ASPECT Study. J Am Coll Cardiol 2006;48:2432-9. 27. Degertekin M, Serruys PW, Foley DP, et al. Persistent inhibition of neointimal hyperplasia after sirolimus-eluting stent implantation: long-term (up to 2 years) clinical, angiographic, and intravascular ultrasound follow-up. Circulation 2002;106:1610-3. 28. Sousa JE, Costa MA, Sousa AG, et al. Two-year angiographic and intravascular ultrasound follow-up after implantation of sirolimuseluting stents in human coronary arteries. Circulation 2003;107:381-3. 29. Sousa JE, Costa MA, Abizaid A, et al. Four-year angiographic and intravascular ultrasound follow-up of patients treated with sirolimuseluting stents. Circulation 2005;111:2326-9. 30. Aoki J, Abizaid AC, Serruys PW, et al. Evaluation of four-year coronary artery response after sirolimus-eluting stent implantation using serial quantitative intravascular ultrasound and computerassisted grayscale value analysis for plaque composition in event-free patients. J Am Coll Cardiol 2005;46:1670-6.
Background Stent fracture is one of the possible causes of in-stent restenosis after sirolimus-eluting stent (SES) implantation. However, long-term prognosis including late restenosis in stent fracture site without early restenosis remains unknown. The aim of this study is to investigate the risk of late restenosis at the stent fracture site without early restenosis after SES implantation. Methods
We divided 366 patients with 490 lesions into 2 groups with or without stent fracture based on the first scheduled follow-up coronary angiography (fracture group, 21 lesions; nonfracture group, 469 lesions). The second scheduled follow-up coronary angiography (N15 months after SES implantation) was performed in 83 patients with 124 lesions.
Results Target lesion revascularization due to late restenosis at the stent fracture site did not occur in the fracture group, but occurred in 5 lesions in the nonfracture group. At the first follow-up, minimal luminal diameter was significantly smaller and percentage diameter stenosis was significantly larger in the fracture group (1.98 ± 0.41 vs 2.52 ± 0.49 mm, P = .001 and 30.5% ± 13.1% vs 13.0% ± 8.8%, P b .0001, respectively). These differences were also present at the second follow-up (P = .01 and P = .007, respectively). In each group, there were no significant changes in minimal luminal diameter, percentage diameter stenosis, and late lumen loss between the first and second follow-up. Conclusions Late restenosis was not observed in stent fracture sites without early restenosis during the midterm follow-up after SES implantation. (Am Heart J 2010;160:775.e1-775.e9.) Sirolimus-eluting stents (SESs) have been shown to dramatically reduce in-stent restenosis (ISR)1,2; however, they do not completely resolve this problem.3-5 Several studies have reported that stent fracture, seen in 1.6% to 7.7% of lesions after SES implantation, was one of the possible causes of ISR.5-12 Recently, several studies have demonstrated that late restenosis associated with the late catch-up phenomenon was seen in lesions after drugeluting stent (DES) implantation.13-17 However, the longterm prognosis including late restenosis at the stent fracture site without early restenosis remains unknown. The aim of the present study is to investigate the risk of late restenosis at the stent fracture site without early restenosis after SES implantation.
From the aDivision of Cardiology, Wakayama National Hospital, Wakayama, Japan, and bDepartment of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan. Submitted January 9, 2010; accepted July 9, 2010. Reprint requests: Takashi Akasaka, MD, Department of Cardiovascular Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan. E-mail: [email protected] 0002-8703/$ - see front matter © 2010, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2010.07.010
Methods Study population From September 2004 to August 2007, 455 patients with 594 lesions underwent SES (Cypher; Cordis/Johnson and Johnson, Miami, FL) implantation into de novo and ISR lesions at Wakayama National Hospital. These did not include patients with STelevation myocardial infarction who underwent primary percutaneous coronary intervention (PCI), as well as those with planned surgery requiring antiplatelet therapy withdrawal, those with intolerance to aspirin or ticlopidine, or those with inappropriate vessel size for SES. The first scheduled follow-up coronary angiography (CAG) (69 months after PCI) was performed in 387 (85.1%) of the 455 patients with 517 lesions. We excluded 21 patients with 27 lesions because of the requirement for target lesion revascularization (TLR) for ISR (including 8 lesions with stent fracture). We divided the remaining 366 patients with 490 lesions into 2 groups: those with or without stent fracture, according to the first scheduled follow-up CAG findings. The fracture group consisted of 21 lesions, and the nonfracture group consisted of 469 lesions. All patients were followed clinically for a minimum of 16 months (range, 16-59 months) after SES implantation. Long-term clinical follow-up data were obtained from outpatient record reviews or telephone interviews. In the fracture group, we lost no clinical follow-up data and obtained those of all 21 patients without ISR (clinical follow-up rate was 100%). On the
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Figure 1
Flow diagram of study population.
other hands, in the nonfracture group, we lost clinical follow-up data in 5 of 345 patients because of their removal to another prefectures from 18 to 30 months after SES implantation (clinical follow-up rate was 98.5%). We then judged these patients as event-free for 18 to 30 months after SES implantation and analyzed the clinical follow-up data. In our hospital, the approach to asymptomatic fracture without significant stenosis was not performing TLR but following closely with dual-antiplatelet therapy. Furthermore, the second scheduled follow-up CAG (N15 months after SES implantation) was performed without recourse to the presence of ischemic sign if approval of patients was obtained (16 of 21 patients). In the nonfracture group, it was performed in asymptomatic patients with positive results of stress test (silent ischemia) or symptomatic patients during the long-term followup after the first scheduled follow-up CAG (67 patients with 108 lesions) (Figure 1). This study complied with the Declaration of Helsinki regarding investigations in humans and was approved by the Ethics Committee of Wakayama National Hospital. All patients provided written informed consent.
(V-form), III (complete separation without displacement), and IV (complete separation with displacement) according to the classification of Popma et al.19 With the guiding catheter for magnification-calibration and an online system (QCA-CMS version 5.0; Medis, Leiden, the Netherlands), minimal luminal diameter (MLD) and diameters of the reference segments were measured at baseline (prestenting), poststenting, and first and second follow-up CAG. The target lesion MLD included the stent as well as 5-mm margins proximal and distal to the stent. In the fracture group, MLD was measured at the fracture site in all patients except for 1 case with late restenosis not at the fracture site but at the proximal site of the SES because the smallest in-stent MLD was located at the fracture site in all patients except for that case. Late lumen loss was defined as the difference between the MLD at poststenting and that at follow-up. Binary restenosis was defined as stenosis of N50% of the luminal diameter in the target lesion at follow-up.
Definition and classification of stent fracture, and quantitative coronary angiographic analysis
Major adverse cardiac events (MACEs) after the first scheduled follow-up CAG were defined as death of cardiac origin, very late stent thrombosis, and late restenosis. Stent thrombosis was defined as the angiographic confirmation of thrombotic stent occlusion with at least one of the following: (1) continuous chest pain for ≥20 minutes, (2) ischemic electrocardiographic changes, and (3) typical rise and fall of cardiac biomarkers, according to the definitions suggested by the Academic Research Consortium.20 Target lesion revasculariza-
Stent fracture was defined as complete or partial separation of the stent on plain fluoroscopy without contrast injection on the first scheduled follow-up CAG according to previous reports.12,18,19 The diagnosis of stent fracture required an independent review and agreement by 2 of the authors (Y. I. and Y. T.). Stent fracture was classified into type I (minor), II
Definition of major adverse cardiac events, late restenosis, and stent thrombosis
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Table I. Baseline clinical characteristics
Age, y Male gender, n (%) Hypertension, n (%) Dyslipidemia, n (%) Diabetes mellitus, n (%) Cigarette smoking, n (%) Prior MI, n (%) Prior PCI, n (%) Prior CABG, n (%) Acute coronary syndrome, n (%) No. of diseased vessels, n (%) 1 2 3 Multivessel disease, n (%) LVEF (%) Duration of the clinical follow-up after PCI, m
Table II. Angiographic and procedural characteristics
Fracture group (n = 21)
Nonfracture group (n = 345)
P value
66 ± 10 18 (86) 17 (81) 13 (62) 13 (62) 12 (57) 7 (33) 5 (24) 1 (5) 2 (10)
67 ± 10 274 (79) 274 (79) 238 (69) 151 (44) 165 (48) 153 (44) 175 (51) 28 (8) 82 (24)
.471 .588 .99 .478 .118 .502 .372 .023 .99 .182 .091
7 (33) 11 (52) 3 (14) 14 (67) 62 ± 9 35 ± 12
196 (57) 125 (36) 24 (7) 149 (44) 59 ± 11 34 ± 11
.042 .216 .728
MI, Myocardial infarction; LVEF, left ventricular ejection fraction.
tion was defined as repeat percutaneous or surgical intervention of the stented lesion. Late restenosis was defined as in-stent binary restenosis in a lesion without restenosis at the first scheduled follow-up CAG.
Statistical analysis Statistical analysis was performed using Stat View 5.0 software (SAS Institute Inc, Cary, NC). Categorical data are presented as frequencies and were compared with χ2 statistics or Fisher exact test. Continuous variables are expressed as mean ± SD and were compared with the paired and unpaired Student t test or Mann-Whitney U test. The MACEs during follow-up were analyzed by the Kaplan-Meier method. The log-rank test was used to evaluate differences between the event-free survival curves for the 2 groups. A probability value b .05 was considered statistically significant.
Lesions (n = 490) Target vessel LAD, n (%) LCX, n (%) RCA, n (%) LMCA, n (%) SVG, n (%) Lesion type A, n (%) B1, n (%) B2, n (%) C, n (%) ISR, n (%) Bifurcation lesion, n (%) Calcification, n (%) CTO, n (%) Stent diameter, mm Total stent length, mm Stent per lesion, n Maximal pressure, atm Stent overlap, n (%) Use of size up balloon, n (%) Aorta ostium stenting, n (%) QCA results Reference vessel diameter (mm) Pre-MLD (mm) Pre-%DS (%) Post-MLD (mm) Post-%DS (%)
Fracture group (n = 21)
Nonfracture group (n = 469)
8 (38) 3 (14) 10 (48) 0 (0) 0 (0)
188 (40) 140 (30) 135 (29) 4 (0.9) 2 (0.4)
1 (5) 0 (0) 6 (29) 14 (67) 1 (5) 3 (14)
20 (4) 73 (16) 306 (65) 70 (15) 50 (11) 145 (31)
.713 .144
3 (14) 8 (38) 2.82 ± 0.36 41 ± 15 2.0 ± 0.7 19 ± 2 15 (71) 4 (19) 1 (5)
136 (29) 40 (9) 2.91 ± 0.38 25 ± 12 1.2 ± 0.5 19 ± 3 89 (19) 47 (10) 7 (1.5)
.215 .0004 .301 b.0001 b.0001 .913 b.0001 .259 .297
2.68 ± 0.33
2.76 ± 0.47
.402
0.35 87 2.62 7.7
0.66 ± 77 ± 2.71 ± 6.8 ±
.0005 .0006 .353 .516
.359
b.0001
± ± ± ±
0.33 13 0.42 5.9
0.40 13 0.44 5.8
LAD, Left anterior descending; LCX, left circumflex; RCA, right coronary artery; LMCA, left main coronary artery; SVG, saphenous vein graft; CTO, chronic total occlusion.
Figure 2.
Sources of funding No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents.
Results Clinical, angiographic, and procedural characteristics Of the 21 lesions in the fracture group, none were type I fractures, 9 were type II, 7 were type III, and 5 were type IV. Baseline clinical characteristics in the fracture and nonfracture groups are shown in Table I. The 2 groups had no significant differences in almost all variables for the baseline clinical characteristics. Prior PCI was more common in the nonfracture group (P = .023), and multivessel disease was more common in the
P value
Survival free from MACEs.
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Table III. Characteristics of stent fracture patients without restenosis Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Age, y/gender
Indication of PCI
Location
ISR
CTO
No. of stents
Stent length/ diameter, mm
63/F 55/M 79/M 70/M 65/M 78/M 54/M 73/M 74/M 61/M 64/M 75/M 63/M 55/M 79/M
SCAD SCAD SCAD SCAD SCAD ACS ACS SCAD SCAD SCAD SCAD SCAD SCAD SCAD SCAD
LCX LAD LAD LAD LCX RCA RCA LAD LAD RCA RCA RCA RCA LAD LAD
− − − − − − − − − − − − − − −
− − − − − − − − + + + − + + +
2 2 1 1 1 1 2 2 2 3 2 3 2 2 2
31/2.5 43/2.5 18/2.5 28/2.5 18/2.5 18/3.5 38/3.5 32/2.5 43/2.5 63/3.0 39/3.0 54/2.5 44/2.5 47/3.0 59/3.0
16 56/M SCAD RCA 17 76/M SCAD RCA 18 47/M SCAD RCA 19 62/F SCAD LCX 20 45/M ACS RCA 21 79/M SCAD RCA Popma et al Duration of the 2nd DS at 1st SCAD, Stable coronary artery disease; ACS, acute coronary syndrome. classification follow-up CAG, m CAG, %
− + − − − − DS at 2nd CAG, %
− 2 − 3 + 3 + 1 − 3 − 1 Dual-antiplatelet therapy
44/3.5 64/2.5 58/3.0 28/2.5 74/3.0 33/3.0 Clinical outcome
Table IV. Characteristics of stent fracture patients with restenosis Patient no.
Age, y/gender
Indication of PCI
1 2 3 4 5 6 7 8 Stent length/ BA, Balloon angioplasty. diameter, mm
80/F 81/M 61/M 64/M 70/M 65/M 67/M 54/F Popma et al classification
ACS ACS SCAD SCAD SCAD SCAD SCAD SCAD %DS at 1st follow-up CAG
fracture group (P = .042). The angiographic and procedural characteristics of both groups are shown in Table II. Significant differences between the fracture and the nonfracture groups were demonstrated in the rate of type C and chronic total occlusion lesions, total stent length, number of stents per lesion, the rate of stent overlap lesion, pre-MLD, and preimplantation percentage diameter stenosis (%DS).
Clinical outcomes after the first follow-up CAG Stent fracture patients without early restenosis are listed in Table III. In the fracture group, there was 1 case with late restenosis requiring TLR, not at the fracture site but at the proximal site of the SES. This group had no case with very late stent thrombosis or death of cardiac origin
Location LAD RCA LCX LCX RCA RCA RCA LAD Procedures of TLR
ISR
CTO
− − − + − − − − Dual-antiplatelet therapy
− − − − + − + −
No. of stents 2 1 1 1 4 1 3 3 Clinical outcome
at midterm follow-up after the first scheduled follow-up CAG. On the other hand, the nonfracture group had 5 late restenosis cases, 2 very late stent thrombosis cases, and 5 deaths due to cardiac failure. The event-free survival rate did not differ significantly between the 2 groups (log-rank probability value = .564) (Figure 2). For the 5 late restenosis cases in the nonfracture group, all the patients had recurrent angina pectoris at 19 to 49 months after initial SES implantation. Coronary angiography showed severe stenosis in the proximal edge of the stent in 2 cases, the midpoint in 2 cases, and the distal edge in 1 case. The additional SES implantation was performed in 3 cases, and coronary artery bypass grafting (CABG) was performed in 2 cases. In the nonfracture group, very late stent thrombosis occurred in 2 cases at 13 and 14 months after initial SES
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Table III (continued) Popma et al classification
Duration of the 2nd follow-up CAG, m
DS at 1st CAG, %
DS at 2nd CAG, %
Dual-antiplatelet therapy
Clinical outcome
III II III II III II II IV II II III IV IV II II
16 16 24 19 − − 16 17 16 22 19 21 − 24 −
48 42 29 20 39 20 26 28 30 37 27 49 19 14 35
47 43 27 20 − − 27 29 28 43 38 47 − 16 −
+ + + + + + + + + + + + + + +
III II IV III IV III
15 − 29 16 22 22
23 40 25 50 25 30
22 − 22 45 25 28
+ + + + + +
Event-free Event-free Event-free Event-free Event-free Event-free Event-free Event-free Event-free Event-free Event-free Event-free Event-free Event-free Late restenosis at nonfracture site Event-free Event-free Event-free Event-free Event-free Event-free
Table IV (continued) Stent length/ diameter, mm
Popma et al classification
%DS at 1st follow-up CAG
Procedures of TLR
Dual-antiplatelet therapy
Clinical outcome
34/2.5 18/3.0 23/2.5 23/3.0 94/3.0 33/3.0 83/3.0 56/3.0
III III II III III II III IV
88 74 70 90 68 72 75 56
PES implantation SES implantation SES implantation CABG SES implantation PES implantation PES implantation BA
+ + + − + + + +
Re-restenosis (−) re-TLR with PES Re-restenosis (−) Event-free Re-restenosis (−) Re-restenosis (−) Re-restenosis (−) re-TLR with PES
implantation. In 1 of 2 cases, ticlopidine was discontinued 9 months after SES implantation; and only aspirin had been continued. In the other case, dual-antiplatelet therapy had been continued. Emergent CAG revealed occlusion with thrombus at the site of the prior SES in both cases. Both cases underwent emergent PCI and had an additional bare-metal stent (BMS) implantation at that time. Patients with stent fracture having TLR at the first follow-up angiogram are listed in Table IV. In all 8 restenosis lesions with stent fracture, restenosis was located in fracture site; and the angiographic pattern of restenosis was focal type. Target lesion revascularization was performed in all patients, 3 patients had an additional SES implantation, 3 patients were implanted with paclitaxel-eluting stents (PESs), 1 patient was treated with balloon angioplasty, and 1 patient underwent CABG.
One patient with an additional SES implantation and 1 patient undergoing balloon angioplasty had recurrent restenosis with clinical symptoms, and both patients underwent PES implantation. Another 5 patients with reimplantation of a DES had no recurrent restenosis. Recurrent stent fracture was not observed in all 7 patients with reimplantation of a DES.
Serial quantitative coronary angiography results and late lumen loss The mean duration of the second follow-up CAG after SES implantation was 19.8 ± 4.9 and 20.5 ± 4.9 months in the fracture and nonfracture group, respectively (P = .778). Serial quantitative coronary angiography (QCA) results are shown in Figure 3. At the first
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Figure 3
Serial results of MLD (A) and %DS (B) at prestenting, poststenting, first follow-up, and second follow-up.
Figure 4
fracture group, P = .069 and P = .073 in the nonfracture group, respectively). Late lumen loss is shown in Figure 4. Late lumen loss at the first and second follow-up was significantly larger in the fracture group (P b .0001 and P b .0001, respectively). In each group, no significant changes in late lumen loss occurred between the first and second follow-up (P = .802 in the fracture group and P = .069 in the nonfracture group). Figures 5 and 6 demonstrate 2 representative serial angiographies with stent fracture.
Discussion
Late lumen loss at first follow-up and second follow-up.
follow-up, MLD was significantly smaller and %DS was significantly larger in the fracture group than in the nonfracture group (1.87 ± 0.50 vs 2.58 ± 0.52 mm, P b .0001 and 34% ± 13% vs 12% ± 10%, P b .0001, respectively). These differences were maintained at the second follow-up (1.85 ± 0.48 vs 2.47 ± 0.64 mm, P b .0001 and 34% ± 12% vs 14% ± 16%, P b .0001, respectively). However, in each group, no significant changes occurred in MLD and %DS between the first and second follow-up (P = .576 and P = .777 in the
The main findings of the present study were as follows: (1) There were no cases of late restenosis at the stent fracture site in the fracture group, whereas there were 5 cases in the nonfracture group. (2) At the first follow-up, MLD was significantly smaller and %DS and late loss were significantly larger in the fracture group. (3) These differences were maintained at the second follow-up. (4) In each group, no significant changes in MLD, %DS, and late lumen loss occurred between the first and second follow-up. According to previous reports, the frequency of ISR in stent fracture lesions is 33% to 80%.7-12 In the present study, 8 of 29 lesions in the fracture group and 19 of 488 lesions in the nonfracture group had restenosis requiring TLR by the initial angiogram (28% vs 3.9%, P b .0001), which is similar to the previous reports. Therefore, some
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Figure 5
A, Right CAG showed chronic total occlusion with bridge collateral in the midportion of the RCA (white arrow). B, Three Cypher stents (2.5/ 23, 3.0/18, and 3.0/23 mm) were deployed in the mid to distal portion of the RCA without gap (white lines), and another Cypher stent (3.5/18 mm) was deployed in the proximal portion (black line). C, Angiography at 9-month follow-up demonstrated mild stenosis with stent fracture (white arrow). D, Stent fracture on plain fluoroscopy (white arrow, fracture site; white line, stents). E, Progression of stenosis at the fracture site was not seen in angiography at 29-month follow-up (white arrow, fracture site; black arrow, late stent malapposition).
lesions with stent fractures do not result in TLR. The long-term prognosis of these patients is still unknown. Doi et al18 reported that half of the patients with stent fracture and ISR presented N1 year after SES implantation. Mehrle et al21 reported late restenosis 18 months after SES implantation. In the present study, 16 of 21 patients without TLR at the first scheduled follow-up CAG in the fracture group underwent a second followup CAG; and no patients had late restenosis requiring late TLR due to the late catch-up phenomenon in the fracture site. These results may be explained as follows. First, fracture cases in the present study excluded TLR cases at the first scheduled follow-up CAG. In contrast, in the reports of Doi et al and Mehrle et al, information was not provided as to whether the first scheduled follow-up CAG was performed or not. These other reports suggested that neointimal hyperplasia at the stent fracture site may be caused by local mechanical stimulation of the vessel wall with the broken struts.7,22 However, in our study, local mechanical stimulation of
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the vessel wall may have been less pronounced than in fracture cases with early restenosis at the first scheduled follow-up CAG. Second, other studies suggested that local drug delivery may be decreased in the fracture site.7,9,10,22 It was reported that the neointimal tissue volume after BMS implantation peaked at 6 months and, after this, often regressed.23,24 Because of decreased local drug delivery, the growth patterns of neointima at the fracture site might be similar to those after BMS implantation. Finally, animal studies have shown that late neointimal growth after DES implantation was larger than that after BMS implantation. Farb et al25 reported that PESs showed not only dose-dependent reduction in neointimal hyperplasia but also histologic signs of delayed healing and local toxicity after high-dose paclitaxel exposure. In addition, some clinical reports described late restenosis after PES implantation.13,14,26 On the other hand, several studies reported that delayed neointimal growth was rare in lesions after SES implantation27-30; and the results of the present study were similar to those of previous studies. Delayed neointimal growth may vary with different drugs, polymers, and/or stent platforms. In this study, not every patient underwent routine second follow-up CAG. Especially, it was performed only in patients with symptoms or a positive exercise test result in the nonfracture group; and the rate of it in that group was low, creating a selection bias. On the other hand, in the fracture group, it was performed in most patients who had no ischemic sign. Therefore, it is no surprise that numerically more restenosis occurred in the nonfracture group; and the comparison between the fracture and nonfracture groups after the first follow-up may be problematic. It is ideal that all patients without stent fracture would also be requested to have the second follow-up CAG regardless of clinical status. However, the aggressive second follow-up CAG for patients without clinical symptom is problematic ethically because several studies reported the long-term efficacy of SES in suppressing ISR.27-30 The aim of the present study is to investigate the risk of late restenosis at the stent fracture site without early restenosis after SES implantation. In the fracture group, the second scheduled follow-up CAG was recommended in all patients without recourse to the presence of ischemic sign; and it was performed in 16 (76%) of 21 patients. We could confirm that late restenosis in stent fracture site was not observed at 19.8 ± 4.9 months in those 16 patients and that clinical driven late TLR was not observed for 35 months after SES implantation in all 21 stent fracture patients without early restenosis except for 1 patient with late restenosis away from the fracture site. Furthermore, the analysis in all 366 patients showed that the event-free survival rate including clinically driven late TLR did not differ significantly between the 2 groups (Figure 2).
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Figure 6
A, Left CAG showed a moderate stenosis in the distal portion of the LAD (white arrow). B, Cypher stent (2.5/18 mm) deployment without predilatation. C, Final angiography after stent deployment (white line, stent). D, Angiography at 9-month follow-up demonstrates mild stenosis with stent fracture (white arrow). E, Stent fracture on plain fluoroscopy (white line, stent). F, Progression of stenosis at the fracture site was not seen in angiography at 24-month follow-up (white arrow, fracture site).
Nakazawa et al6 reported the relationship between stent fracture and stent thrombosis after DES implantation in autopsy registry. All stent thromboses associated with fracture site occurred in complete separation with displacement type fracture in their study. In addition, 2 cases of stent thrombosis associated with SES fracture occurred during the early phase (11 and 60 days after SES implantation). Lee et al9 reported a case of very late stent thrombosis at the stent fracture site 20 months after SES implantation. In this case, clopidogrel had been discontinued 12 months after SES implantation. Doi et al18 reported a similar case at the stent fracture site 20 months after SES implantation. In this case, the stent fracture was located in the midportion of a coronary aneurysm; and it was unclear whether dual-antiplatelet therapy was continued or not. In the present study, very late stent thrombosis did not occur in the fracture group. This may be explained as follows. First, dual-antiplatelet therapy with aspirin and ticlopidine had been continued in all patients in the fracture group for N12 months after SES implantation. Second, the population in our study did not include patients with severe stenosis at the fracture site because TLR had been performed at the first scheduled follow-up CAG. Third, type IV stent fracture (complete separation with displacement) was present in only 5 of 21 patients in the present study.
Study limitations There are several limitations in the present study. First, it is difficult to detect stent fracture after SES implantation in a prior ISR. In this study, 47 patients with 50 lesions had SES placed in a prior ISR in the nonfracture group.
Therefore, stent fracture might have been missed in those 47 patients. Furthermore, because intravascular ultrasound at the first follow-up CAG was not performed in all patients, small stent fractures, such as a single strut fracture, were difficult to detect with fluoroscopy. However, the incidence of stent fracture in the present study was 5.6%, which was similar to those in previous studies (1.6%-7.7%).7-12 Furthermore, although early ISR was observed in 3 patients with 3 lesions of those 47 patients, stent fracture was not observed in those 3 cases on intravascular ultrasound analysis. Second, the timing of the second follow-up CAG varied; and the duration of the interval after SES implantation may have affected the degree of intimal hyperplasia. In most of the lesions, however, no significant changes occurred in QCA parameters between the first and second follow-up. Third, the durations of second follow-up CAG and clinical follow-up after SES implantation in the fracture group were 19.8 ± 4.9 and 35 ± 12 months, respectively; and those were not so long. Fourth, there were significant differences in several characteristics of the lesion and/or PCI procedure between the fracture and nonfracture groups, which might affect the initial results. Finally, this was an observational analysis from a single center with a small number of patients with stent fractures; therefore, the present results should be viewed as preliminary and require confirmation with larger clinical trials.
Conclusions Late restenosis was not observed in stent fracture site without early restenosis during the midterm follow-up after SES implantation. The risk of very late stent
American Heart Journal Volume 160, Number 4
thrombosis in stent fracture sites after this period is sill unknown, and close follow-up should be performed in patients with stent fracture.
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