Introduction

During percutaneous coronary intervention (PCI), metal stents are implanted in the coronary artery. However, stent fracture (SF) caused by metal fatigue remains a concern because of its association with restenosis, stent thrombosis (ST), and subsequent target lesion revascularization (TLR) [1, 2] even in the late periods [3]. Although pathological findings and their relevance to cardiovascular events of SF have been previously reported [4], data about repeat interventional treatment for restenotic lesions caused by SF after drug-eluting stent (DES) implantation are limited. Therefore, this study aimed to compare the outcomes between repeat newer-generation durable polymer DES implantation and drug-coated balloon (DCB) treatment for restenotic lesions caused by SF after DES implantation.

Methods

Ethical statements

Written informed consent was obtained from all patients in accordance with the Declaration of Helsinki. The institutional ethics committees approved the study protocol.

Study population, outcomes measurement, and procedural protocols

From April 2007 to April 2015, 9320 lesions were treated with a DES during PCI in our institution and were followed prospectively. Of 9320 lesions, 7549 lesions had a follow-up angiogram (follow-up rate: 81.0%), and 815 lesions were in-stent restenotic (ISR) lesions (binary restenosis rate 8.7%). Follow-up angiography was performed 8–12 months after primary PCI when patients were able to make regular clinical visits. TLR with PCI was performed when there were symptoms or signs of ischemia and the angiographic diameter of stenosis was ≥ 50%. Of 815 ISR lesions, 81 lesions (9.9%) were found to have SF. After excluding ISR lesions without TLR and angiographic follow-up after TLR, but with TLR with plain balloon angioplasty alone, bare-metal stent, and early-generation DES, 69 lesions (47 patients) had TLR for ISR lesion due to SF after DES implantation, and a newer-generation DES (DES group: 27 patients with 45 lesions) or DCB (SeQuent Please balloon catheter, B. Braun, Melsungen, Germany; DCB group: 20 patient with 24 lesions) was used (Fig. 1).

Fig. 1
figure 1

Study population

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Baseline demographic and outcomes were evaluated retrospectively between the DES and DCB groups. The primary outcome measure was 1-year repeat TLR after repeat DES implantation or DCB treatment. Coronary angiography was performed routinely at 8–12 months after the repeat intervention.

All interventions were performed using standard techniques. Selection of the type of DES and DCB used in the repeat PCI and use of intravascular imaging devices depended on the operator’s discretion. After the procedure, all patients were advised to continue aspirin (100 mg daily) for life, and either ticlopidine (200 mg daily) or clopidogrel (75 mg daily) was prescribed for at least 1 year after stent implantation. Aspirin and ticlopidine/clopidogrel treatment was recommended for at least 3 months in the DCB group, unless the patients had contraindications.

Definitions

Newer-generation DES was defined as a cobalt–chromium everolimus-eluting stent (CoCr-EES), platinum–chromium everolimus-eluting stent (PtCr-EES), slow-release zotarolimus-eluting stent (R-ZES), or thinner biocompatible polymer-coated limus-analog eluting stent. SF was detected in the ISR lesion and defined as complete or partial separation of the stent strut, as assessed by plain fluoroscopy. SF grading was defined according to a previous study: minor fracture (single strut), moderate fracture (multiple strut), and severe fracture (complete separation) [5]. Vessel tortuosity and hinge movement were defined according to previous studies [6, 7]. In all cases of ISR lesions, recurrent ISR lesions occurred in the stent margin and were defined as %diameter stenosis > 50% in the follow-up quantitative coronary analysis (QCA). Patterns of ISR lesions and recurrent ISR lesions were classified on the basis of the Mehran classification [8].

QCA

Coronary angiography was performed after intracoronary administration of 0.2 mg of nitroglycerin. The QCA was performed before and after stenting, and during follow-up angiography using a guiding catheter to calibrate the magnification and an automated edge detection algorithm validated by a cardiovascular measurement system (Medis and Heart version 2.0 Cathex, Leiden, The Netherlands). Two or more experienced observers who were blinded to the clinical information performed the QCA independently.

Statistical analysis

Data are presented as a value and percentage, mean, standard deviation, or median (interquartile range). Categorical variables were compared between groups using the v2 or Fisher’s exact test, as appropriate. Continuous variables were compared between groups using Student’s paired t test or Mann–Whitney’ test, according to the normality of data distribution. The primary outcome measure was estimated using Kaplan–Meier’s method, and the differences were evaluated with the log-rank test. All statistical analyses were two-tailed, and p < 0.05 was considered statistically significant. Statistical analyses were performed with the SPSS 11.0 software program (SPSS Inc., Chicago, IL).

A Cox proportional hazard model was used to determine the predictors for repeat TLR. Factors that were indicated by p < 0.05 in the univariate analysis were entered into the multivariate regression models. All baseline demographics were entered into the univariate model.

Results

There was no statistically significant difference in the clinical characteristics between the groups (Table 1). Table 2 shows the characteristics of the ISR lesions treated by either a newer-generation DES or DCB and predisposing factors associated with SF. The DCB group included a high number of lesions with vessel hinge movement. Procedural characteristics of repeat PCI for ISR lesions due to SF are shown in Table 3.

Table 1 Baseline patient characteristics
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Table 2 Characteristics of ISR lesion
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Table 3 Procedure characteristics at TLR
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The binary recurrent ISR lesion rate and patterns of recurrent ISR lesions are shown in Table 4. The DES group tended to have more total occlusions (40%), whereas the DCB group tended to have more focal re-ISR lesions (67%). Comparisons of the QCA results during the PCI procedure (Table 5) revealed that the postprocedural minimum lumen diameter tended to be small in the DCB group, but there was no significant difference between the two groups.

Table 4 Binary re-ISR rate and patterns of re-ISR
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Table 5 QCA analysis
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The primary outcome measure was the cumulative incidence of repeat TLR, and there was no significant difference between the two groups (43.9% versus 31.9%, p = 0.31) (Fig. 2). Univariate and multivariate predictors of repeat TLR are shown in Table 6. In the multivariate analysis, severe SF (hazard ratio [HR] 3.18, 95% confidence interval [CI] 0.96–10.6, p = 0.06) and lesion with vessel hinge movement (HR 6.54, 95% CI 1.30–32.8, p = 0.02) were associated with repeat TLR.

Fig. 2
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Cumulative incidence of repeat TLR

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Table 6 Predictors of 12 months re-TLR
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Discussion

In this study, we mainly found that angiographic outcomes after additional interventional procedure for restenosis caused by SF were poor and did not differ in terms of treatment devices, i.e., DCB or newer-generation DES implantation.

Repeat revascularization of patients with ISR lesions is challenging [9]. Although several treatment options for ISR lesions after DES implantation exist, the preferred treatment option was reported to be repeat DES implantation instead of conventional angioplasty in the first-generation DES era. However, the 3-year efficacy and safety of the paclitaxel DCB were similar to the paclitaxel-eluting stent in a randomized trial [10]. With regard to the outcomes of CoCr-EES for ISR lesions after DES implantation, Alfonso et al. reported that CoCr-EES provides superior 1-year outcome, i.e., a decreased need for TLR compared with paclitaxel DCB [11].

Recently, the largest meta-analysis of patients with coronary ISR lesions treated with either a second-generation DES or DCB, which included ten studies (4 randomized control trials and 6 observational studies) and examined clinical and angiographic outcomes, demonstrated that a second-generation DES is equally effective and safe as a DCB for TLR, myocardial infarction, and prevention of ST [12].

The development of the DES has revolutionized the field of interventional cardiology, reducing the occurrence of severe neointimal proliferation, which is the main cause of restenosis after stent implantation [13]. SF and mechanical issues may be more prevalent in the current DES era. Based on bench test results, Ormiston et al. reported that a stent with cobalt alloys does not fracture easily compared with a stent with thick struts constructed from stainless steel [14]. Additionally, in an autopsy study, Otsuka et al. reported that CoCr-EES had the least incidence of SF compared with an early-generation durable polymer stainless steel DES [4]. Metal alloys or a stent platform resistant to fracture may be suitable for restenotic lesions due to SF. However, further investigation on newer-generation DESs and DCBs in the setting of restenotic lesions caused by SF is needed. An optical coherence tomography study revealed that the absence of a stent strut was the common morphological feature of SF, and its length was correlated with the neointimal area, suggesting that the loss of a stent strut is one of the important contributors to excessive neointimal growth [15]. Additionally, restenosis associated with DES fractures may reflect local trauma sustained by the vessel at the fracture site. To suppress neointimal growth in such a lesion, a DES and additional stent strut to cover the restenotic lesion to increase the lumen diameter was expected to be the ideal treatment. On the basis of the present study’s results, the selection of treatment devices did not lead to the outcomes of such lesions. Lesions with severe SF, which was affected by anatomical specificity such as vessel hinge movement, were predicted to be suitable for further interventional treatment. Regarding the result of recurrent ISR lesion patterns, the DES group tended to have more totally occluded recurrent ISR lesions. The stent-in-stent strategy for a restenotic lesion due to stent fracture might be associated with a high risk for stent thrombosis. However, among the entire study population, there was only one case of stent thrombosis in the DES group. Other totally occluded lesions were silently occluded. There was no case of stent thrombosis in the DCB group. The reason for total occlusion in the DES group might have been the luminal decrease because of the additional metal layer. The totally occluded lesion would become technically complicated and might have needed to be avoided. Considering the current state of interventional cardiology devices for ISR lesions caused by SF from the viewpoint of not adding another metal layer to the coronary artery, DCB treatment might be considered.

Study limitations

First, this study was not a randomized study, and this might have affected the results. The use of a DES or DCB was at the operator’s discretion. Second, there was no significant difference in the incidence of 12-month repeat TLR between the two groups. However, the sample size of the present study was small, and the result might be different in a larger population. Lastly, the DCB group included a high number of lesions with vessel hinge movement; however, the angiographic outcomes were similar between the DES group and DCB group, which may indicate that the DCB group showed similar angiographic outcomes in patients with a complicated lesion background.

Conclusions

The 12-month repeat TLR rate was high in both groups. After treating ISR lesions caused by SF after DES, mechanical stress leads to further interventional treatment regardless of the type of treatment devices used during TLR. Further investigation and newer devices are expected to improve angiographic outcomes to overcome ISR lesions due to SF.