Introduction

The use of drug-eluting stents (DES) has dramatically reduced in-stent restenosis compared with bare metal stents (BMS) in percutaneous coronary intervention (PCI) [1–4]. A higher rate of in-stent restenosis in BMS than that in DES is associated with small vessel diameter, long lesion, and diabetes, among other factors [5–7]. Under these conditions, the advantage of DES in small-size coronary arteries has been shown in several studies [8–10].

In contrast, it remains controversial whether we should choose DES even for large-size coronary lesions that are >3.5 mm in diameter, because the DES has unsolved problems such as late or very late stent thrombosis [11–14] and late catch-up phenomenon. So far, some studies have analyzed the clinical outcome of DES and BMS in large-size coronary arteries, but follow-up periods in these studies seem too short to conclusively address the problem [15–18]. Although recent studies demonstrate that clinical outcomes were not significantly different between BMS and DES in large-vessel lesions [19, 20], few data exist regarding the impact of stent type on clinical outcomes in terms of both short- and long-term prognoses. Particularly, it is important to determine the use of stents in the left main coronary lesions [21]. Therefore, we analyzed the clinical data of patients who underwent stent implantation in large-size coronary lesions using DES or BMS, and evaluated the clinical outcomes over a 2-year follow-up.

Methods

Patients and treatments

The study protocol was approved by the medical ethics committee of the Toyama Red Cross Hospital. Consecutive patients who underwent PCI in the Toyama Red Cross Hospital with large stents with a diameter of >3.5 mm were enrolled from January 2004 to December 2007. Indications for PCI included stable angina or acute coronary syndrome with elective or emergent procedures. Among them, we analyzed patients whose outcome was followed up for at least 2 years after intervention. Patients with both BMS and DES of diameter of >3.5 mm during this follow-up period were excluded from this study. The patients with large stent in a bypass graft were also excluded in the present study.

Device selection of guidewires, balloon catheters, and coronary stents was made at the discretion of the PCI operator. During PCI with DES or BMS, a bolus infusion of heparin (200 U/kg) was administered to maintain an activated clotting time of more than 200 s. Intravascular ultrasound was used at the operator’s discretion. As a standard, dual antiplatelet therapy with aspirin 100–200 mg and clopidogrel 50–75 mg or ticlopidine 200 mg was employed [22]. The duration of dual antiplatelet therapy was at least 12 months.

Clinical follow-up, definitions, and outcome

Patients were evaluated clinically during a follow-up period by visits to outpatient clinics. In patients who did not show up at the outpatient clinic, we mailed questionnaires to them to inquire about any post-PCI events, medications, and other relevant information. The initial follow-up coronary angiography was commonly performed at 8 months after stent implantation. Additional coronary angiography was performed when patients had chest pain, or when the attending cardiologists recommended it as needed for the particular lesion type or clinical background of the patient.

Procedural success was defined as residual stenosis of <25 %. Binary restenosis was defined as stenosis of >50 %. We investigated patients’ backgrounds and characteristics such as sex, age, smoking, the presence of obesity (BMI > 25), hypertension (blood pressure > 140/90 mmHg or use of hypotensive drug), hypercholesterolemia (total cholesterol > 220 mg/dl or low-density lipoprotein cholesterol > 140 mg/dl or use of cholesterol lowering medicine), diabetes mellitus (hemoglobin A1c determined by the JDS (Japan Diabetes Society) method > 6.5 %, or use of hypoglycemic medication), and lesion characteristics [23]. Then, we evaluated the occurrence of target lesion revascularization (TLR) and major adverse cardiac events (MACE) defined as cardiac death and nonfatal myocardial infarction. TLR was defined as clinically driven TLR performed when the patient had ischemic symptoms, ischemic electrocardiographic changes at rest, or positive stress test results. In addition, even in the absence of clear ischemia, revascularization for stenosis of ≥70 % which the operator clinically judged an indication of PCI was also considered clinically driven TLR. Cardiac death was defined as any death without a clear noncardiogenic cause. An incidence of in-stent thrombosis in the 2 groups was evaluated according to Academic Research Consortium definitions [24].

Statistical analysis

Continuous variables were expressed as mean ± SD and were compared using Student’s t test and analysis of variance. Categorical data were compared using the χ2 test or Fisher’s exact test. Cumulative incidences of TLR were estimated by the Kaplan–Meier method and compared with the log-lank test. Logistic regression analysis was used to assess independent predictors of TLR. Variables with p < 0.2 by univariate analysis were included in multivariate logistic regression analysis model. The p values were two sided, and a p < 0.05 was considered statistically significant. All data analyses were performed using StatMate IV software (ATMS Institute, Tokyo, Japan).

Results

Among consecutive 228 patients who underwent PCI with large stents, 183 patients (152 men, mean age 65.8 ± 10.5 years) and 238 lesions were eligible to enter our study (Fig. 1). The mean follow-up period was 3.8 ± 1.2 years. Administration of dual antiplatelet therapy with aspirin and clopidogrel or ticlopidine was confirmed in all patients.

Fig. 1
figure 1

Patient flowchart of this study population. PCI percutaneous coronary intervention, BMS bare metal stent, DES drug-eluting stent

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Baseline characteristics

The baseline characteristics of the enrolled patients are shown in Table 1. The frequency of acute coronary syndrome was significantly higher in the BMS group than in the DES group. There were no significant differences in the presence of diabetes, hypertension, active smoking, and obesity between the 2 groups. The lesions and stent characteristics are shown in Table 2. There were no significant differences in lesion types between the 2 groups. The mean diameter of BMS was greater than that of DES. In the DES group, sirolimus-eluting stents (Cypher, Johnson and Johnson, USA) accounted for 89.2 %, and paclitaxel-eluting stents (Taxus, Boston Scientific, USA) for 10.8 %. In the BMS group, Driver stents (Medtronic, USA) accounted for 31.0 %, Multi-link ZETA stents (Abbott, USA) for 13.8 %, and Multi-link VISION (Abbott, USA) for 13.1 %.

Table 1 Baseline patient characteristics
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Table 2 Lesion and stent characteristics
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Angiographic results

The rate of TLR in each period is shown in Fig. 2. TLR in the first 8-month follow-up period was significantly higher in the BMS group than in the DES group. Between the next 8 and 24 months, the rate of TLR was not significantly different between the 2 groups. Therefore, in a period of over 2 years after stent implantation, the overall TLR rate was higher in the BMS group than in the DES group (22.7 vs. 5.4 %; p = 0.0004). Interestingly, irrespective of lesion type, the TLR rate was significantly higher in the BMS group than in the DES group (19.4 vs. 3.1 % for types A and B1 lesions; p = 0.04, and 23.7 vs. 6.6 % for types B2 and C lesions; p = 0.005) (Fig. 3). Furthermore, in subgroups with or without diabetes, TLR rate was also significantly different between the BMS and DES groups (28.3 vs. 2.9 % for the presence of diabetes; p = 0.003, and 20.2 vs. 6.8 % for the absence of diabetes; p = 0.023). On the other hand, when subgroup analysis was performed in short lesion (stent length < 18 mm without stent overlap), there was a trend toward higher TLR rate in the BMS group compared with the DES group (16.7 vs. 4.5 %; p = 0.054).

Fig. 2
figure 2

Target lesion revascularization in each follow-up period. BMS bare metal stent, DES drug-eluting stent, TLR target lesion revascularization

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Fig. 3
figure 3

Target lesion revascularization in each lesion type. BMS bare metal stent, DES drug-eluting stent, TLR target lesion revascularization

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Because it is possible that the higher TLR rate for the BMS group in the early phase could be due to a higher number of patients with acute coronary syndrome, the same analysis was performed in patients who did not have ACS. Under these conditions, the TLR rate was also significantly higher in the BMS group than in the DES group at the 8-month follow-up (15.7 vs. 2.6 %; p = 0.005) and overall for the entire follow-up period (15.7 vs. 6.4 %; p = 0.0001) (Fig. 4). There were no statistical differences in TLR between BMS and DES in patients with ACS due to shortage of TLR.

Fig. 4
figure 4

Target lesion revascularization in non-acute coronary syndrome in each follow-up period. BMS bare metal stent, DES drug-eluting stent, TLR target lesion revascularization

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Long-term clinical outcomes

Cumulative incidence of TLR was significantly lower in the DES group than the BMS group (p < 0.001) (Fig. 5). There were no significant differences in the incidence of MACE between the BMS and DES groups (3.5 vs. 2.9 %; p = 0.80). However, 2 patients suffered from very late stent thrombosis in the BMS group, although there were no patients with such events in the DES group. One patient had elective gastroduodenal endoscopy with 1 week discontinuation of dual antiplatelet therapy at 2.8 years after stent implantation. In another patient, stent thrombosis occurred at 5.5 years after stenting while receiving aspirin.

Fig. 5
figure 5

Cumulative incidence of target lesion revascularization. BMS bare metal stent, DES drug-eluting stent, TLR target lesion revascularization

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Predictors of target lesion revascularization

Multiple logistic regression analysis, including BMS, acute coronary syndrome, and complex lesion (type B2 or C lesion), as covariates, confirmed that BMS was independently associated with TLR at the 8-month follow-up [p = 0.004, odds ratio 9.58, 95 % confidence interval (2.10–43.8)] (Table 3). In the present study, the incidence of ACS was more frequently found in BMS, thus resulting in some bias for the results. After excluding ACS, BMS was again found to be an independent factor for TLR (Supplemental Table).

Table 3 Factors related to target lesion revascularization at around 8 months
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Discussion

In this study, we compared the short- and long-term results over 2 years between BMS and DES in lesions requiring large coronary stents >3.5 mm in diameter. Overall, TLR rates were significantly higher in the BMS group than in the DES group, although there were no significant differences in the incidence of MACE between the two groups. Interestingly, the incidence of short-term TLR, transiently observed within 8 months after stent implantation, was higher in the BMS group than in the DES group. These results demonstrate that we should choose DES even in a large-size coronary artery >3.5 mm in diameter.

A series of previous studies showed no significant differences in the rate of TLR and MACE between BMS and DES in patients requiring large coronary stents [15–18]. However, follow-up periods in these studies seemed to be relatively short to support their conclusions, because the late catch-up phenomenon and very late stent thrombosis could occur more than 1 year after stent implantation. In this study, the mean follow-up period in all patients was 3.8 ± 1.2 years. Under these conditions, the TLR rates were higher in BMS than in DES in the initial 8 months of follow-up, thus yielding overall higher TLR in BMS-implanted lesions.

Recent studies reported that there was no difference in TLR between BMS and DES in large coronary lesions [19, 20]. In this point of view, our results might be explained by the protocol in which follow-up coronary angiography at 8 months was routinely performed. Especially in diabetic patients, TLR might be even higher in BMS than in DES as reported by a previous study [4].

It might be important that the benefit from DES may differ between men and women [25]. In our study, there was no significant difference in gender between the BMS and DES group, although most patients were of male gender. However, we would suggest performing a further study to compare the advantage of DES in Japanese men and women.

Importantly, two patients suffered from very late stent thrombosis in the BMS group. Generally, BMS is superior to DES in terms of stent thrombosis. A previous study reported that the rate of stent thrombosis was 0.34 % at 30 days, 0.54 % at 1 year, and 0.77 % at 2 years after DES implantation in a Japanese cohort [14]. Another study reported that an increase in inflammatory cytokines in the late phase after implantation of DES was shown and this might result in abnormal wound healing [26], although the use of DES could suppress the excessive intimal proliferation in accordance with out-stent plaque suppression [27]. Nonetheless, late or very late stent thrombosis may occur in the BMS group in case of large coronary arteries as in our cases and another study [28]. Positive remodeling and rupture of neoatherosclerosis in-stent segment might have been associated with late or very late BMS thrombosis [29]. Moreover, in our cases, BMS thrombosis occurred in patients with diabetes, and long lesion required multiple overlapped stents. From these results, these conditions could promote stent thrombosis not only in DES, but also in BMS in large coronary arteries.

In the present study, TLR was higher in BMS than in DES for simple lesions as well as in complicated lesions in large coronary arteries, suggesting BMS implantation in large coronary arteries might be inferior to DES in every type of lesion. Furthermore, we previously reported that in terms of PCI for the left main coronary, which should be the largest vessel in the coronary tree, the incidence of TLR was much greater with BMS for complex lesions than that with DES for simple lesions [21]. A previous study had shown that atherosclerotic progression of neointimal proliferation inside a BMS was observed with intravascular ultrasound over the long term, and this would be the potential for adverse clinical events [30]. A higher inflation pressure and/or greater balloon size for post-dilatation may be responsible for excessive neointimal proliferation, possibly contributing to higher incidence of TLR in BMS in the larger coronary arteries. Therefore, DES may be superior to BMS in terms of neointimal suppression even in large coronary lesions.

There remain several limitations in the present study. First, the number of patients enrolled in this study was relatively small. However, clearly significant differences were observed in the overall TLR rates between BMS and DES in the early phase after implantation into large coronary artery lesions. Second, the retrospective and non-randomized study design implies some degree of selection bias. However, it should be noted that the outcome was demonstrated in consecutive patients in our hospital, and so these results might reflect a real-world population. A future large-scale trial will be necessary to confirm any definitive conclusions on this subject. Third, we presented only stent size instead of vessel size or plaque volume which might be related to the occurrence of TLR [27]. However, even under these conditions, there was significant difference in TLR in early phase after stent implantation. Fourth, the present study consisted of patients treated with first-generation stents. However, the present results provide an important clinical implication regarding the selection of the next-generation stents.

Conclusion

The present study demonstrates that even in coronary lesions requiring large-size stents, the rate of TLR in DES was significantly reduced compared with BMS in the early phase after stent implantation, and that there was no increased risk of unfavorable prognosis associated with DES during the follow-up period beyond 2 years. We would suggest that DES might be encouraged in the treatment of even large-size coronary lesions, if patients do not have any associated diseases that would preclude the use of these stents.