2017 Volume 81 Issue 10 Pages 1514-1521
Background: Stent fracture (SF) and peri-stent contrast staining (PSS) after sirolimus-eluting stent implantation are reported to be risk factors of adverse events. However, the effect of these after everolimus-eluting stent (EES) implantation on long-term outcomes remains unclear.
Methods and Results: The study sample comprised 636 patients (1,081 lesions) undergoing EES implantation in 2010 and follow-up angiography within 1 year. The 5-year cumulative rates of target lesion revascularization (TLR) and major adverse cardiac events (MACE: a combination of all-cause death, myocardial infarction, and TLR) were compared between patients with and without SF or PSS. SF was observed in 2.7%, and PSS in 3.0%. The cumulative rates of MACE and TLR were significantly higher in the SF group than in the non-SF group (51.7% vs. 27.5% and 48.3% vs. 13.4%, respectively), but showed no significant differences between the PSS and non-PSS groups. In a landmark analysis, the rate of TLR within 1 year was significantly higher in the SF group than in the non-SF group (44.8% vs. 7.2%), but beyond 1 year showed no significant difference (6.3% vs 6.7%).
Conclusions: The 5-year clinical outcomes suggested that SF after EES implantation is related to increased risk of MACE and TLR, especially within 1 year after the procedure, but PSS after EES implantation is unrelated.
First-generation drug-eluting stents (DES) have resulted in a substantial reduction in in-stent restenosis and the need for subsequent target lesion revascularization (TLR) compared with bare-metal stents.1,2 Everolimus-eluting stents (EES) are a second-generation DES, designed to improve safety, efficacy, and device performance with a newer antiproliferative drug, a durable polymer, improved stent design, and thinner struts. Compared with bare-metal stents and first-generation DES, EES have reduced adverse events as reported in randomized control trials and meta-analyses.3–7 Recently, stent fracture (SF) after DES implantation has become a concern because of its association with adverse events such as in-stent restenosis (ISR), stent thrombosis (ST), and subsequent TLR.8–10 Previous studies have reported that SF after sirolimus-eluting stent (SES) implantation is associated with ISR and higher cardiac event rates.11–13 This association is reported even in patients treated with second-generation DES.14 Peri-stent contrast staining (PSS) is contrast staining outside stent struts after stent implantation. Although PSS occurs at a low frequency, it has been reported as a risk factor for ST and TLR after first-generation DES implantation and a potential risk factor of adverse events after second-generation DES implantation.15–17 We aimed to investigate the effect of SF and PSS on 5-year clinical outcomes after EES implantation.
This study was a retrospective single-center study. A total of 1,013 consecutive patients (1,716 lesions) undergoing EES (Xience V, Abbott Vascular, Santa Clara, CA, USA) implantation between January and December 2010 were enrolled. The exclusion criteria were repeat EES implantation and the combined use of EES and other types of stent. Finally, we analyzed 636 patients (1,081 lesions) exclusively treated using EES and undergoing follow-up angiography within 1 year (Figure 1). Clinical outcomes were compared between the groups of lesions with and without a diagnosis of PSS and SF at follow-up angiography at 8 months. Informed consent was given by all patients for both the procedure and subsequent data collection and analysis for research purposes, and the study was approved by the institutional ethics committee.
Flow chart of patient inclusion. CAG, coronary angiography; EES, everolimus-eluting stent.
The procedures were performed according to standard clinical guidelines. Decisions regarding therapeutic strategies such as adjunctive devices, pharmacotherapy, and stent expansion pressure were left to the discretion of each operator.
Angiographic AnalysisQuantitative coronary angiography (QCA) analysis was performed using QCA-CMS (Medis Medical Imaging Systems, Leiden, The Netherlands). Coronary angiograms were obtained in multiple views after intracoronary nitrate administration. Reference diameter, minimal lumen diameter, percentage diameter stenosis, and lesion length were measured before and after the procedure and at follow-up. SF was defined as the complete separation of stent segments or stent struts confirmed by follow-up angiography and was evaluated in multiple views.16 PSS was defined as contrast staining outside the stent contour extending over 20% of the stent diameter measured by QCA and was classified into 4 patterns according to our previous report.16 The timing of PSS was classified as: resolved (PSS observed at post-stenting but not at follow-up), persistent (PSS observed at both post-stenting and at follow-up), and late acquired (PSS not observed at post-stenting but at follow-up). An independent view and the agreement of 2 independent cardiologists who were blinded to the clinical and procedural data were required for the angiographic diagnosis of SF, to assess the interobserver variability. In cases of disagreement, the evaluation of a third observer was obtained, and the final decision on the diagnosis of SF and PSS was made by consensus.
Definitions and Study EndpointsMajor adverse cardiac events (MACE) were defined as a combination of all-cause death, any type of myocardial infarction (MI), and clinically indicated TLR. ST was defined as definite or probable according to the Academic Research Consortium definitions.18 MI was defined according to the WHO extended definitions.19 Target vessel revascularization was defined as any revascularization in the stented vessels. TLR was defined as any repeat percutaneous coronary intervention (PCI) or aortocoronary bypass surgery because of restenosis (diameter stenosis >50%) or thrombosis of the target lesion. Furthermore, clinically indicated TLR was defined as TLR performed because of symptoms or objective signs of ischemia (at rest, or on stress ECG or myocardial perfusion imaging). Even in the absence of clinical or functional ischemia, TLR was considered as clinically indicated if the lesion diameter stenosis was ≥70% by QCA. Events related to non-EES-implanted lesions were not included in the evaluation of ST and TLR.
Follow-upTwo serial angiographic follow-ups were routinely scheduled at 8 and 20 months after the procedure. The clinical follow-up information was obtained at the time of the office visit or by telephone contact with primary care physicians or patients. If any revascularization procedure was performed at other hospitals, we obtained the medical records and angiograms in order to analyze the target lesion. Scheduled staged PCI procedures performed within 3 months after the index procedure were not regarded as follow-up events.
Antiplatelet TherapyAll the patients were pretreated with aspirin (100 mg daily) and ticlopidine (200 mg daily)/clopidogrel (75 mg daily). Dual antiplatelet therapy (DAPT) for at least 8 months was recommended after the index procedure. The duration of antiplatelet therapy was left to the discretion of each physician. The status of antiplatelet therapy was evaluated throughout the follow-up period, and persistent discontinuation of DAPT was defined as withdrawal of aspirin or thienopyridine for at least 2 office visits or telephone contacts.
Statistical AnalysisCategorical variables were compared using the chi-square test. Continuous variables are expressed as mean±SD and compared using Student’s t-test or the Wilcoxon rank-sum test based on the distributions. The cumulative incidence was estimated using the Kaplan-Meier method, and differences were assessed using the log-rank test. Clinical follow-up was considered to be achieved with an allowance of 2 months. Patients with individual endpoint events before 1 year after EES implantation were excluded from the landmark analysis. A multivariate logistic regression model was used to identify the independent risk factors of TLR instead of a Cox proportional hazard model because TLR is well known to be a time-related phenomenon, and the timing of TLR can be highly influenced by physicians’ and patients’ decisions. Continuous variables were dichotomized by clinically meaningful reference values. The variables used in the multivariate analysis were selected when they were shown to affect significantly dependent variables in the univariate analysis. Independent variables are expressed as odds ratios with 95% confidence intervals. Each clinical endpoint was evaluated on a per-patient basis, and risk factors of TLR were evaluated on a per-lesion basis. All P-values <0.05 were considered to be significant. Statistical analyses were performed using JMP 9.0 (SAS Institute, Cary, NC, USA).
SF was observed in 2.7% (29/1,081 lesions) and PSS in 3.0% (32/1,049 lesions) of the study group. Morphological patterns of PSS were as follows: monofocal, 34.3% (11 lesions); multifocal, 18.8% (6 lesions), segmental smooth contour, 28.1% (9 lesions); and segmental irregular contour, 18.8% (6 lesions). PSS was present in 2 lesions at the index procedure: 1 with resolved PSS and the other with persistent PSS. Late-acquired PSS at 8 month follow-up was observed in 31 lesions. SF was not observed at the index procedure. At 8-month follow-up, SF was observed in 29 lesions (Figure S1).
Baseline Patient and Lesion CharacteristicsTable 1 and Table 2 show the baseline patient and lesion characteristics. The SF group had a significantly larger proportion of stable angina cases than the non-SF group (89.7% vs. 62.9%, P=0.001) and had significantly longer lesion length and total stent length (37.9±23.4 mm vs. 22.1±13.1 mm, P=0.0001 and 48.0±26.3 mm vs. 27.1±15.1 mm, P<0.0001) than the non-SF group. Right coronary lesions were more frequently observed in the SF group. Percentage diameter stenosis before the procedure was significantly greater in the SF group (84.3±18.7% vs. 77.0±18.8%, P=0.04) and in the PSS group than in non-PSS group (84.6±19.9% vs. 76.9%±18.8%, P=0.02).
| Overall | SF | Non-SF | P value | PSS | Non-PSS | P value | |
|---|---|---|---|---|---|---|---|
| n | 636 | 29 | 607 | 28 | 608 | ||
| Age, years | 69.6±10.9 | 66.8±14.0 | 69.7±10.7 | 0.16 | 71.0±11.5 | 69.6±10.9 | 0.51 |
| Male | 466 (73.3) | 20 (69.0) | 446 (73.5) | 0.59 | 18 (64.3) | 448 (73.8) | 0.27 |
| BMI, kg/m2 | 24.2±3.6 | 24.1±4.3 | 24.3±3.6 | 0.79 | 23.3±2.9 | 24.3±3.62 | 0.16 |
| Hypertension | 483 (75.9) | 23 (79.3) | 460 (75.8) | 0.66 | 20 (71.4) | 463 (76.1) | 0.57 |
| Diabetes mellitus | 253 (39.8) | 11 (37.9) | 242 (39.9) | 0.83 | 9 (32.1) | 244 (40.0) | 0.4 |
| Insulin therapy | 71 (11.1) | 2 (6.9) | 69 (11.4) | 0.46 | 1 (3.6) | 70 (11.5) | 0.19 |
| Dyslipidemia | 395 (62.1) | 22 (75.9) | 373 (61.5) | 0.17 | 19 (67.9) | 376 (61.9) | 0.69 |
| Current smoker | 79 (12.4) | 5 (17.2) | 74 (12.2) | 0.39 | 5 (17.9) | 74 (12.2) | 0.37 |
| eGFR (mL/min/1.73 m2) | 60.2±24.7 | 62.5±23.0 | 60.1±24.8 | 0.62 | 55.0±24.3 | 60.4±24.7 | 0.25 |
| Hemodialysis | 40 (6.3) | 1 (3.5) | 39 (6.4) | 1.00 | 3 (10.7) | 37 (6.1) | 0.41 |
| Clinical diagnosis | 0.001 | 0.005 | |||||
| STEMI | 105 (16.5) | 3 (10.3) | 102 (16.8) | 10 (35.7) | 95 (15.7) | ||
| NSTEMI/UAP | 123 (19.3) | 0 (0) | 123 (20.3) | 1 (3.6) | 122 (20.1) | ||
| Stable angina | 408 (64.2) | 26 (89.7) | 382 (62.9) | 17 (60.7) | 391 (64.3) | ||
| Previous MI | 226 (35.5) | 15 (51.7) | 211 (34.8) | 0.07 | 8 (38.6) | 218 (35.8) | 0.43 |
| Previous cerebral infarction | 50 (7.9) | 3 (10.3) | 47 (7.7) | 0.49 | 4 (14.3) | 46 (7.6) | 0.2 |
| Peripheral artery disease | 38 (6.0) | 3 (10.3) | 35 (5.8) | 0.25 | 0 (0) | 38 (6.3) | 0.4 |
| Previous PCI | 294 (46.2) | 14 (48.3) | 280 (46.1) | 0.82 | 11 (39.3) | 283 (46.5) | 0.46 |
| Previous CABG | 24 (3.8) | 2 (6.9) | 22 (3.6) | 0.3 | 0 (0) | 24 (4.0) | 0.61 |
| Multivessel disease | 257 (40.4) | 15 (51.7) | 242 (39.9) | 0.2 | 11 (39.3) | 246 (40.5) | 0.9 |
| Diseased vessel, n | 1.5±0.7 | 1.79±0.86 | 1.53±0.72 | 0.06 | 1.53±0.74 | 1.54±0.73 | 0.94 |
| Medication and hospital discharge | |||||||
| Antiplatelet therapy | |||||||
| Thienopyridine | 635 (99.8) | 28 (96.5) | 607 (100) | 0.04 | 28 (100) | 607 (99.8) | 0.89 |
| Aspirin | 632 (99.4) | 29 (100) | 603 (99.3) | 0.66 | 28 (100) | 604 (99.3) | 0.66 |
| Cilostazol | 35 (5.5) | 2 (6.9) | 33 (5.4) | 0.67 | 2 (7.1) | 33 (5.4) | 0.66 |
| Statins | 499 (79.3) | 23 (78.4) | 476 (78.4) | 0.93 | 22 (78.6) | 477 (78.8) | 0.74 |
| β-blockers | 215 (33.8) | 12 (41.4) | 203 (33.4) | 0.42 | 10 (35.7) | 205 (33.8) | 0.83 |
| ACEI/ARB | 439 (69.0) | 18 (62.1) | 421 (69.4) | 0.42 | 22 (78.6) | 417 (68.5) | 0.30 |
| Calcium-channel blockers | 279 (43.9) | 13 (44.8) | 266 (43.8) | 0.91 | 15 (53.6) | 264 (43.3) | 0.29 |
Values are mean±SD or n (%), unless otherwise specified. ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; BMI, body mass index; CABG, coronary artery bypass graft; eGFR, estimated glomerular filtration rate; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; PSS, peri-stent contrast staining; SF, stent fracture; STEMI, ST-elevation myocardial infarction; UAP, unstable angina.
| Overall | SF | Non-SF | P value | PSS | Non-PSS | P value | |
|---|---|---|---|---|---|---|---|
| Lesions, n | 1,081 | 29 | 1,052 | 32 | 1,049 | ||
| Lesion location | |||||||
| Left main trunk | 46 (4.26) | 1 (3.45) | 45 (4.3) | 0.001 | 0 (0) | 46 (4.4) | 0.01 |
| Left anterior descending | 382 (35.3) | 3 (10.3) | 379 (36.0) | 15 (46.9) | 367 (35.0) | ||
| Left circumflex | 245 (22.7) | 3 (10.3) | 242 (23.0) | 0 (0) | 245 (23.4) | ||
| Right coronary artery | 403 (37.2) | 21 (72.4) | 382 (36.3) | 17 (53.1) | 386 (36.8) | ||
| Graft | 5 (0.5) | 1 (3.5) | 4 (0.4) | 0 (0) | 5 (0.5) | ||
| Before index procedure | |||||||
| Lesion length, mm | 22.5±13.7 | 37.9±23.4 | 22.1±13.1 | 0.0001 | 26.9±16.7 | 22.4±13.6 | 0.06 |
| Lesion length >20 mm | 485 (45.4) | 23 (79.3) | 462 (44.4) | 0.0002 | 19 (59.4) | 466 (44.9) | 0.11 |
| Reference vessel diameter, mm | 2.93±0.49 | 3.21±0.56 | 2.92±0.48 | 0.002 | 3.19±0.46 | 2.92±0.49 | 0.002 |
| Minimum lumen diameter, mm | 0.65±0.58 | 0.49±0.61 | 0.65±0.57 | 0.13 | 0.47±0.62 | 0.62±0.57 | 0.07 |
| Diameter stenosis, % | 77.2±18.8 | 84.3±18.7 | 77.0±18.8 | 0.04 | 84.6±19.9 | 76.9±18.8 | 0.02 |
| Chronic total occlusion | 97 (9.0) | 10 (34.5) | 87 (8.3) | 0.001 | 5 (15.6) | 92 (8.8) | 0.18 |
| In-stent restenosis | 128 (11.8) | 6 (20.7) | 122 (11.6) | 0.14 | 2 (6.23) | 126 (12.0) | 0.32 |
| Bifurcation | 378 (35.0) | 5 (17.2) | 373 (35.5) | 0.05 | 10 (31.3) | 368 (35.1) | 0.71 |
| Ostial lesion | 129 (11.9) | 9 (31.0) | 120 (11.4) | 0.001 | 2 (6.3) | 127 (12.1) | 0.41 |
| AHA/ACC B2/C | 787 (72.8) | 25 (86.2) | 762 (72.4) | 0.14 | 20 (62.5) | 767 (73.2) | 0.18 |
| After index procedure | |||||||
| Stent diameter, mm | 2.83±0.38 | 2.93±0.43 | 2.82±0.37 | 0.13 | 2.94±0.35 | 2.82±0.38 | 0.09 |
| Total stent number per lesion, n | 1.29±0.58 | 2.1±0.94 | 1.3±0.55 | <0.0001 | 1.38±0.66 | 1.29±0.58 | 0.40 |
| Total stent length per lesion, mm | 27.7±15.9 | 48.0±26.3 | 27.1±15.1 | <0.0001 | 32.6±19.4 | 27.5±15.7 | 0.07 |
| Maximum stent inflation pressure, atm | 17.3±6.9 | 18.2±6.6 | 17.3±7.0 | 0.48 | 19.1±7.0 | 17.2±7.0 | 0.14 |
| Minimum lumen diameter, mm | 2.55±0.49 | 2.68±0.63 | 2.54±0.48 | 0.16 | 2.83±0.46 | 2.54±0.48 | 0.001 |
| Diameter stenosis, % | 15.4±8.3 | 18.4±10.9 | 15.3±8.2 | 0.05 | 12.5±6.3 | 15.5±8.4 | 0.05 |
| Follow-up angiographic results | |||||||
| Minimal lumen diameter, mm | 2.22±0.63 | 1.89±0.91 | 2.23±0.62 | 0.008 | 2.71±0.56 | 2.21±0.63 | <0.001 |
| Diameter stenosis, % | 26.0±15.3 | 42.8±24.3 | 25.6±14.8 | <0.0001 | 18.2±10.0 | 26.2±15.4 | 0.005 |
| Stent fracture | 29 (2.6) | 1 (3.5) | 28 (2.6) | 0.58 | |||
| Peri-stent contrast staining | 32 (3.0) | 1 (3.4) | 31 (3.0) | 0.58 | |||
Values are mean±SD or n (%), unless otherwise specified. ACC, American College of Cardiology; AHA, American Heart Association. Other abbreviations as in Table 1.
The proportion of patients on DAPT decreased over time, and no significant difference existed between the SF and non-SF groups (Figure 2) or between the PSS and non-PSS groups.
Persistent discontinuation of dual antiplatelet therapy: (A) SF vs. non-SF, (B) PSS vs. non-PSS. PSS, peri-stent contrast staining; SF, stent fracture.
At follow-up angiography, the SF group had smaller minimal lumen diameter and larger percentage diameter stenosis than the non-SF group (1.89±0.91 mm vs. 2.23±0.62 mm, P=0.008, and 42.8±24.3% vs. 25.6±14.8%, P<0.0001, respectively). In contrast, the PSS group had larger minimal lumen diameter and smaller percentage diameter stenosis than the non-PSS group (2.71±0.56 mm vs. 2.21±0.63 mm, P<0.0001 and 18.2±10.0% vs. 26.2±15.4%, P=0.005, respectively).
5-Year Clinical OutcomesComplete 5-year follow-up was achieved in 92.8% of the patients, and the mean follow-up period was 1,920±212 days. Table 3 shows the 5-year clinical outcomes after EES implantation. The event rates of MACE and TLR at 5 years were significantly higher in the SF group than in non-SF group (51.7% vs. 27.5%, P=0.001 and 48.3% vs. 13.4%, P<0.0001, respectively). Between the PSS and non-PSS groups, no significant difference existed in the event rates of MACE (21.4% vs. 28.9%; P=0.69) and TLR (7.1% vs. 15.4%; P=0.22). The rate of cardiac death was not significantly different between the SF and non-SF groups. The same result was observed between the PSS and non-PSS groups. Figure 3 shows the results of the landmark analysis. The rate of TLR within 1 year after the index procedure was significantly higher in the SF group than in the non-SF group (44.8% vs. 7.2%, P<0.0001), but beyond 1 year there was no significant difference between the groups (6.3% vs. 6.7%, P=0.90). During the follow-up period, definite ST was observed in 2 patients (Table 4); 1 had very late ST, in which PSS was identified at follow-up angiography; however, he had discontinued all antiplatelet drugs before the onset. Both SF and PSS were identified in only 1 patient, and no adverse events occurred during the follow-up period. Representative cases of TLR in the SF group and of VLST in the PSS group are shown in Figure S2 and Figure S3, respectively.
| Endpoint | Year | SF | Non-SF | P value | PSS | Non-PSS | P value |
|---|---|---|---|---|---|---|---|
| Major adverse cardiac events | 1 | 13 (44.8) | 68 (11.2) | <0.0001 | 1 (3.6) | 80 (13.1) | 0.15 |
| 5 | 14 (51.7) | 166 (27.5) | 0.001 | 6 (21.4) | 174 (28.9) | 0.69 | |
| All-cause death | 1 | 2 (4.7) | 14 (2.3) | 0.12 | 0 (0) | 16 (2.6) | 0.39 |
| 5 | 5 (17.2) | 94 (15.8) | 0.97 | 3 (10.7) | 96 (16.1) | 0.98 | |
| Cardiac death | 1 | 0 (0) | 5 (0.8) | 0.62 | 0 (0) | 5 (0.8) | 0.63 |
| 5 | 0 (0) | 19 (3.4) | 0.29 | 2 (7.3) | 17 (3.1) | 0.33 | |
| MI | 1 | 0 (0) | 16 (2.6) | 0.82 | 1 (3.6) | 15 (2.5) | 0.70 |
| 5 | 1 (3.7) | 21 (3.6) | 0.38 | 3 (11.0) | 19 (3.2) | 0.05 | |
| Target lesion MI | 1 | 0 (0) | 14 (2.3) | 0.42 | 1 (3.6) | 13 (2.1) | 0.59 |
| 5 | 0 (0) | 15 (2.5) | 0.80 | 2 (7.1) | 13 (2.1) | 0.13 | |
| TLR | 1 | 13 (44.8) | 43 (7.2) | <0.0001 | 0 (0) | 56 (9.4) | <0.001 |
| 5 | 14 (48.3) | 78 (13.4) | <0.0001 | 2 (7.1) | 90 (15.4) | 0.22 | |
| Clinically indicated TLR | 1 | 7 (27.4) | 26 (4.4) | <0.0001 | 0 (0) | 33 (5.6) | <0.0001 |
| 5 | 7 (27.4) | 46 (8.2) | <0.0001 | 1 (3.7) | 52 (9.2) | 0.29 | |
| Definite stent thrombosis | 1 | 0 (0) | 1 (0.2) | 0.82 | 0 (0) | 1 (0.2) | 0.82 |
| 5 | 0 (0) | 2 (0.3) | 0.02 | 1 (3.6) | 1 (0.2) | 0.02 | |
| Definite/probable stent thrombosis | 1 | 0 (0) | 2 (0.3) | 0.75 | 0 (0) | 2 (0.3) | 0.76 |
| 5 | 0 (0) | 3 (0.5) | 0.06 | 1 (3.6) | 2 (0.3) | 0.05 |
Values are n (%). Incidence was calculated by the Kaplan-Meier method. TLR, target lesion revascularization. Other abbreviations as in Table 1.
Cumulative incidence of target lesion revascularization within and beyond 1 year: (A) SF vs. non-SF, (B) PSS vs. non-PSS. PSS, peri-stent contrast staining; SF, stent fracture.
| Patient number | 1 | 2 |
| Age at index procedure, years | 74 | 47 |
| Type of stent thrombosis | Subacute | Very late |
| Sex | Female | Male |
| Diagnosis | UAP | STEMI |
| Lesion | LAD | LAD |
| Number of stents | 2 | 1 |
| Minimal stent size, mm | 2.5 | 3.0 |
| Ostial lesion | No | No |
| Bifurcation | No | Yes |
| In-stent restenosis | No | No |
| Chronic total occlusion | No | No |
| DAPT status | DAPT | None |
| Cessation status | Continuing | Disrupted |
| Stent fracture | No | No |
| Peri-stent contrast staining | No | Yes |
| Days from index procedure to events, day | 11 | 677 |
DAPT, dual antiplatelet therapy; LAD, left anterior descending; UAP, unstable angina. Other abbreviations as in Table 1.
Table 5 shows the results of univariate and multivariate analyses of the risk factors of TLR during the 5 years. Insulin-dependent diabetes mellitus, hemodialysis, chronic total occlusion, ISR, ostial lesion, total stent length >30 mm, and stent fracture were risk factors of TLR in the univariate analysis. Of these, hemodialysis, ISR, ostial lesion, total stent length >30 mm, and stent fracture were independent risk factors in the multivariate analysis.
| Univariate | Multivariate | |||
|---|---|---|---|---|
| OR (95% CI) | P value | OR (95% CI) | P value | |
| Age >80 years | 0.72 (0.39–1.32) | 0.29 | ||
| Male | 1.39 (0.86–2.25) | 0.18 | ||
| Hypertension | 1.04 (0.64–1.70) | 0.85 | ||
| Diabetes mellitus | 1.47 (0.98–2.19) | 0.06 | ||
| Insulin-dependent diabetes mellitus | 2.08 (1.22–3.53) | 0.006 | 1.61 (0.88–2.84) | 0.12 |
| Dyslipidemia | 1.16 (0.76–1.77) | 0.49 | ||
| Current smoker | 0.71 (0.36–1.40) | 0.33 | ||
| Hemodialysis | 3.81 (2.07–7.03) | 0.0001 | 3.73 (1.87–7.14) | 0.0003 |
| Chronic total occlusion | 2.48 (1.44–4.29) | 0.0008 | 1.80 (0.94–3.30) | 0.07 |
| In-stent restenosis | 3.48 (2.18–5.58) | 0.0001 | 3.50 (2.10–5.78) | <0.0001 |
| Bifurcation | 0.89 (0.58–1.37) | 0.61 | ||
| Ostial lesion | 2.24 (1.36–3.71) | 0.001 | 1.90 (1.08–3.24) | 0.03 |
| Total stent length >30 mm | 2.00 (1.31–3.08) | 0.001 | 1.80 (1.09–2.91) | 0.02 |
| Minimal stent size <3.0 mm | 1.16 (0.77–1.74) | 0.47 | ||
| Stent fracture | 8.28 (3.86–17.74) | 0.0001 | 5.39 (2.30–12.4) | 0.0002 |
| Peri-stent contrast staining | 0.29 (0.04–2.12) | 0.19 | ||
CI, confidence interval; OR, odds ratio.
The main findings of this study were as follows: (1) the incidence of SF and of PSS after EES implantation was 2.7% and 3.0%, respectively; (2) SF was associated with higher rates of MACE and TLR; (3) PSS was not associated with MACE and TLR; and (4) SF was associated with TLR within 1 year, but not beyond 1 year.
Some randomized control trials and meta-analyses have reported that EES reduce adverse events compared with bare-metal stents and first-generation DES in the long term.3–6 The EES was designed to improve safety and efficacy with a newer antiproliferative drug, a durable polymer, open-cell design with flexibility, and thinner struts, which were expected to prevent adverse events related to SF and PSS. However, the effect of SF and PSS after EES implantation on long-term clinical outcome remains unclear.
The occurrence of SF has been reported to range from <1% to >8%, and SF occurs more frequently in lesions treated with first-generation DES, especially SES.20–23 The poor flexibility and conformability of first-generation DES because of their closed cell design and stainless stent strut are considered to be the main cause of SF and the thinner struts and open-cell design of EES might contribute to the reduction of SF. In the present study, the incidence of SF after EES implantation was 2.7% of all lesions, which was in line with previous studies.14,24 Of note, SF was associated with TLR, especially within 1 year. The mechanism of restenosis in SF lesions can be associated with impaired local drug delivery at the SF site or mechanical damage to a vessel wall, which might cause rapid smooth muscle cell proliferation or stent recoil, and subsequent restenosis at the SF site.
The incidence of PSS after SES implantation has been reported to be 2.5–4.5% and associated with TLR and ST.25,26 The incidence of PSS after EES implantation in contrast to SF was higher in this study than in previous studies (1.2–1.5%).26,27 A possible explanation of this difference is that the proportion of chronic total occlusion, which has been reported as a risk factor of PSS,16 was higher in our study than in the other study.26 In this study, the proportion of ST-elevation MI was higher in the PSS group than in the non-PSS group, although the difference was not significant. Thrombus dissolution is one of the mechanisms of late-acquired stent malapposition, and acute coronary syndrome is reported to be a risk factor of stent malapposition.28 This result might be caused by the aforementioned mechanism. Although Tokuda et al reported that PSS after second-generation DES implantation was associated with TLR,17 the clinical effect of PSS on exclusively EES-implanted lesions is not fully elucidated.17 In the j-Cypher registry investigating 7,838 lesions with SES implantation, the cumulative rate of TLR was significantly higher in lesions with PSS than in those without PSS; however, that of TLR for restenosis (excluding the procedure for ST) was not significantly different between lesions with and without PSS.15 In the present study, the cumulative rate of TLR was not significantly different between the PSS and non-PSS groups, possibly because of the low rate of ST.
Imai et al reported that SF was more frequently observed in lesions with PSS after SES implantation.16 However, we identified only one patient with both SF and PSS in the same lesion, in whom no adverse events occurred. Therefore, the relationship between SF and PSS might differ between SES-implanted lesions and EES-implanted lesions.
A previous meta-analysis and an observational study have reported that EES use was associated with a reduction of ST, particularly VLST.3,29–32 In our study, definite ST occurred in only 2 patients (0.3%) during 5 years and the patient with VLST had discontinued all antiplatelet drugs, although PSS was observed in the culprit lesion. Therefore, SF and PSS after EES implantation might not be risk factors of ST under optimal antiplatelet therapy. Tada et al reported that PSS in lesions treated with SES implantation was associated with incomplete stent apposition and uncovered stent struts in their study using optical coherence tomography.33 We speculate that the characteristics of EES, such as thin stent strut and thromboresistic polymer, lessen the influence of unfavorable stent apposition.
The cumulative rate of persistent discontinuation of DAPT at 5 years was 49.7%, and there was a gradual increase from 1 year after the index procedure. This tendency might have been influenced by the fear of ST in the first-generation DES era, which lasted until this study period. There were no significant differences in discontinuation of DAPT between patients with lesions with and without SF or PSS. Therefore, identification of SF and PSS at follow-up angiography did not influence the clinical management of DAPT therapy.
Study LimitationsFirst, the study patients were not completely followed; it is possible that adverse events during the follow-up period were underestimated. Second, we identified SF based on an angiographic analysis, which might have led to underestimation of the incidence of SF. Third, the angiographic analysis was not performed in an independent laboratory, which might result in measurement bias. Finally, the number of lesions with SF or PSS was relatively small to detect differences in adverse events, especially those beyond 1 year. A larger study sample is necessary to confirm our findings.
The 5-year clinical outcomes after EES implantation suggested that SF is related to a higher risk of MACE and TLR, especially TLR within 1 year after the procedure, but PSS is unrelated.
We appreciate the assistance of Miho Kobayashi, Makiko Kanaike, and Yoshimi Sano with the manuscript.
None.
Supplementary File 1
Figure S1. Incidences of stent fracture and peri-stent contrast staining at the index procedure, 8 months, and 20 months.
Figure S2. Representative case of stent fracture and target lesion revascularization at follow-up.
Figure S3. Representative case of peri-stent contrast staining and very late stent thrombosis.
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-17-0236
