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Original article
Long-term clinical outcomes of overlapping heterogeneous drug-eluting stents compared with homogeneous drug-eluting stents
  1. Sung-Ho Her,
  2. Ki Dong Yoo,
  3. Chul-Soo Park,
  4. Dong-Bin Kim,
  5. Jong-Min Lee,
  6. Pum Joon Kim,
  7. Hee-Yeol Kim,
  8. Kiyuk Chang,
  9. Doo Soo Jeon,
  10. Wook Sung Chung,
  11. Ki-Bae Seung,
  12. Jae-Hyung Kim
  1. Division of Cardiology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
  1. Correspondence to Dong-Bin Kim, St. Paul's Hospital, Jeonnong-Dong, Dongdaemoon-Gu, Seoul 130-709, Republic of Korea; dbkimmd{at}catholic.ac.kr

Abstract

Objectives To evaluate long-term clinical outcomes of overlapping heterogeneous drug-eluting stents (DES) compared with homogeneous DES.

Design and setting The catholic medical centre coronary intervention database is a multicentre database of percutaneous coronary intervention with DES. This database contains data on consecutive patients from eight coronary intervention centres in Korea.

Patients Overlapping homogeneous DES were used in 940 patients and overlapping heterogeneous DES in 140 patients between January 2005 and June 2010.

Intervention The study enrolled patients with one-vessel disease treated with two overlapping DES in one lesion.

Main outcome measures The study end point was the occurrence of major adverse cardiac events (MACE), defined as cardiac death, myocardial infarction (MI) or target lesion revascularisation (TRL).

Results The two patient groups had similar baseline clinical and angiographic characteristics. MACE, cardiac death, MI and TRL rates, were not significantly different between the homogeneous and heterogeneous DES groups (9.9% vs 11.4%, p=0.574; 2.7% vs 3.6%, p=0.578; 1.5% vs 1.4%, p=1.000; 5.7% vs 6.4%, p=0.747, respectively). In addition, it was found that overlap with second-generation DES may be safe and effective, and the sirolimus-eluting stent (SES)+SES group had higher rate of MACE-free survival than the paclitaxel-eluting stent (PES)+PES group (p=0.014).

Conclusions Overlapping heterogeneous DES and overlapping homogeneous DES had similar long-term safety and efficacy outcomes.

  • Prognosis
  • coronary disease
  • stent
  • overlap
  • coronary angioplasty (PCI)
  • coronary stenting
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Introduction

The use of drug-eluting stents (DES) has greatly attenuated the relationship between stent length and restenosis.1–3 Moreover, the implantation of long or multiple overlapping DES in patients with a diffuse long coronary lesion is relatively safe and associated with good clinical outcomes.4–6 However, the safety and efficacy outcomes of overlapping with a different type of DES remain unknown. Furthermore, the results of overlap with second-generation DES have not been well established.

The objective of this study was to compare long-term clinical outcomes of overlapping heterogeneous DES with those of overlapping homogeneous DES.

Patients and methods

Patients

The catholic medical centre coronary intervention database is a multicentre database of percutaneous coronary intervention (PCI) with DES. It contains data on consecutive patients from eight coronary intervention centres in Korea. We included patients with two overlapping DES on one lesion in one-vessel disease between January 2005 and June 2010. We excluded patients with more than two stents, previous PCI, previous coronary artery bypass graft surgery, chronic renal failure requiring haemodialysis or peritoneal dialysis, presence of cardiogenic shock and life expectancy <1 year. The local institutional review board approved this study.

PCI

Implantation of the DES was performed following the practice of fully covering the diseased segment according to the current standard procedures. The treatment strategy and selection of DES type were left to the operator's discretion. Before, or at the time of, the procedure, patients received at least 100 mg of aspirin, a loading dose 300 mg or 600 mg of clopidogrel or 500 mg ticlopidine and unfractionated heparin (70–100 U/kg body weight). After the procedure, all patients were prescribed lifelong aspirin treatment and clopidogrel or ticlopidine for at least 12 months. The stent types were the sirolimus-eluting stent (SES; Cordis Corporation, Miami, Florida, USA), paclitaxel-eluting stent (PES; Boston Scientific, Natick, Massachusetts, USA), zotarolimus-eluting stent (ZES; Medtronic, Minneapolis, Minnesota, USA), everolimus-eluting stent (EES; Abbott Vascular Inc, Santa Clara, California, USA), and others (Coroflex (Braun, Berlin, Germany) and pico-elite (AMG International GmbH, Raesfeld-Erle, Germany) stents.

Data collection

Demographic, clinical, laboratory, angiographic and outcome data were collected using an internet-based reporting system. Additional information was obtained from the medical records of other hospitals and through telephone contact.

Study end points and definitions

The study end point was the occurrence of major adverse cardiac events (MACE), defined as cardiac death, myocardial infarction (MI) or target lesion revascularisation (TLR, either a percutaneous or surgical procedure with either a clinical or non-clinical indication).

All deaths were considered cardiac deaths unless a definite non-cardiac cause could be established. MI was defined as the presence of clinical signs of MI combined with a creatine kinase MB fraction or troponin-T/troponin-I increase more than the upper normal limit that was not related to an interventional procedure. TLR was defined as repeat PCI for a stenosis within the stent or within the 5 mm borders adjacent to the stent, or bypass graft surgery of the target vessel. Definite stent thrombosis (ST) was defined according to the ARC recommendations.7 The timing of ST was classified as early, late or very late (occurring within 1 month, 1 month to 1 year or more than 1 year after the index procedure, respectively). All events were reported at the participating centres.

Stent overlap was defined as the presence of two stents within a single treated lesion and an overlapping stent zone of at least 1 mm, as determined by angiography. Overlapping stent zones were identified based on the position of the stent balloon markers of the second stent relative to the first stent.

The reported stent length was based on the cumulative length of the adjacent stents.

Coronary angiography

Binary restenosis was defined as stenosis ≥50% in the target lesion at angiographic follow-up. All angiographic measurements of the target lesion were obtained within the stent and the areas 5 mm proximal and distal to the stent edge. All TLR cases were analysed using quantitative coronary angiography to determine the zone of restenosis triggering the repeat revascularisation and the site of minimal lumen diameter. Focal and diffuse restenoses were defined as a follow-up lesion length <10 mm and ≥10 mm, respectively.8

Digital angiograms were analysed with the use of an automated edge-detection system (CAAS II, Pie Medical Imaging, Maastricht, Netherlands). The restenosis pattern was analysed independently by two experienced interventionists.

Statistics

Continuous variables are presented as mean±SD or median with IQR. Categorical variables are presented as frequency with percentages. Continuous variables were analysed using the independent sample t test, and categorical variables were analysed with the χ2test or Fisher's exact test. The occurrence of adverse events during the follow-up period was analysed by the Kaplan–Meier method. Differences between event-free survival curves were compared by the log-rank test. Statistical significance was accepted for a two-sided value of p<0.05. All analyses were performed using the Statistical Analysis Software package (version 9.2, SAS Institute).

Results

Baseline characteristics

Of the 15 239 patients, 1080 were found to fulfil the study inclusion criteria. Overlapping homogeneous DES were used in 940 (87.0%) patients and overlapping heterogeneous DES were used in 140 (13.0%) patients. Median follow-up was 27 months (IQR 15–44) in the overlapping homogeneous DES group and 20 months (IQR 13–33) in the overlapping heterogeneous DES group. Patient baseline clinical and angiographic characteristics are presented in table 1. The overlapping homogeneous and heterogeneous DES groups were found to be similar for all baseline clinical and angiographic parameters. The mean ages were 68.04±10.35 years for the homogeneous DES group and 69.53±10.58 years for the heterogeneous DES group. For both groups, there was a higher proportion of men, the most common diagnosis was stable angina, and the left anterior descending artery was the most common location of the lesion. The two groups had similar total stent length and mean stent diameter.

Table 1

Baseline clinical and angiographic characteristics of the study population

Clinical outcomes

Complete clinical follow-up data were obtained in 97.1% of the study cohort. The reason for using overlapping heterogeneous DES was that same type of DES of an appropriate length and size were not available. The reasons for performing a stent overlap in the homogeneous and heterogeneous DES groups were, respectively, excessive lesion length in relation to maximal available stent length (603 patients (64.1%), 88 patients (62.9%)), incomplete target lesion coverage (252 patients (26.8%), 32 patients (22.9%)), dissections at the stent edges (78 patients (8.3%), 18 patients (12.9%)), and residual thrombi (5 patients (0.5%), 1 patient (0.7%)).

A total of 109 MACE (10.1%) and 43 deaths (4.0%) occurred in all patients during the follow-up period (median 26 months, IQR 15–43 months). Cardiac death, MI and TLR occurred, respectively, in 2.8%, 1.5% and 5.8% of all patients. The MACE, cardiac death, MI, and TRL rates were similar for both the homogeneous and heterogeneous DES groups (9.9% vs 11.4%, p=0.574; 2.7% vs 3.6%, p=0.578; 1.5% vs 1.4%, p=1.000; 5.7% vs 6.4%, p=0.747, respectively) (table 2 and figure 1). Definite ST was observed in nine (0.8%) of all the patients, comprising early ST in four patients, late ST in two patients, and very late ST in three patients in the homogeneous DES group, but no definite ST was noted in the heterogeneous DES group. However, statistical analysis showed that the incidence of definite ST was similar for both groups (table 2). No cardiac deaths occurred in patients who experienced definite ST.

Table 2

Long-term clinical outcomes between homogeneous and heterogeneous DES

Figure 1

Kaplan–Meier curves for clinical outcomes of overlapping drug-eluting stents. Kaplan–Meier curves show survival free from (A) major adverse cardiac events (MACE); (B) cardiac death; (C) myocardial infarction (MI) and (D) target lesion revascularisation (TLR). DES, drug-eluting stents.

Data for the dual antiplatelet treatment status was available in 97.7% of patients at 1 year after the index procedure. The median duration of thienopyridine use was similar in the two groups (20 months (IQR 13–25) in the homogeneous DES group vs 20 months (IQR 13–26) in the heterogeneous DES group, p=0.921). Of patients who had definite ST, the homogeneous DES group had seven receiving dual antiplatelet treatment and two receiving aspirin only.

Kaplan–Meier curves for MACE, cardiac death, MI, and TLR for both groups are presented in figure 1. There were no significant differences for those parameters between the two groups.

MACE according to stent type

The combinations of overlapping stents used in homogeneous DES group were, in descending order, SES+SES (43.6%), PES+PES (21.1%), ZES+ZES (12.4%), EES+EES (21.0%), and others (1.9%). The combinations of overlapping stents used in heterogeneous DES group were, in descending order, SES+PES (37.1%), SES+ZES (12.9%), PES+ZES (10.7%), SES+EES (12.9%), PES+EES (12.1%), ZES+EES (12.1%), and others (2.1%) (table 3).

Table 3

MACE according to combinations of overlapping stents

We analysed the difference in MACE between first-generation and second-generation DES. In overlapping homogeneous DES, the MACE rate was higher in the first-generation DES (SES+SES and PES+PES, n=608) than in the second-generation DES (ZES+ZES and EES+EES, n=314) (11.8% vs 7.0%. p=0.021). In overlapping heterogeneous DES, There was no difference in the MACE rate between first-generation DES (SES+PES, n=52) and other combination DES (SES+ZES, PES+ZES, SES+EES, PES+EES and ZES+EES, n=85) (13.5% vs 10.6%, p=0.597).

We analysed MACE in patients with SES+SES, PES+PES, and SES+PES. The SES+SES group had higher MACE-free survival than the PES+PES group (figure 2). MACE-free survival curves for SES+SES group and PES+PES group began diverging at 6–12 months. The cardiac death and MI rates were similar for the SES+SES and PES+PES groups (3.0% vs 2.8%, p=0.878; 1.4% vs 1.6%, p=0.724, respectively). The TLR rate was lower in the SES+SES group than in the PES+PES group (5.4% vs 11.7%, p=0.008). There were no significant differences between the other groups.

Figure 2

Kaplan–Meier curves for major adverse cardiac events (MACE) according to stent type. Kaplan–Meier curves show survival free from MACE in sirolimus-eluting stent (SES)+SES and paclitaxel-eluting stent (PES)+PES (A); SES+SES and SES+PES (B); PES+PES and SES+PES (C).

Pattern of restenosis

Binary restenosis was observed in 88 lesions of 63 patients. We examined the location of restenoses across different zones of the treated lesions (figure 3). For analysis, we divided the treated lesion into three zones: proximal, overlap and distal. The proximal and distal zone included the proximal and distal stent regions and a distance of 5 mm adjacent to the stent, and did not include any of the overlapping region.

Figure 3

Pattern of restenosis in overlapping drug-eluting stents. Target lesion revascularisation was performed in 88 lesions of 63 patients. For analysis of restenosis location, stents were divided into three zones: proximal, overlap and distal. Proximal and distal zones included the proximal and distal stent regions plus 5 mm adjacent to the stent. The locations of binary restenoses are represented by black-coloured bars. DES, drug-eluting stents.

Of the 88 restenosis lesions, 28 (32%) were in the stent overlap zone, 28 (32%) were in the proximal stent zone, and 32 (36%) were in the distal stent zone. TLR was performed for 54 homogeneous DES group lesions. For those lesions, the regions of maximal restenosis within a treated lesion were located in the proximal zone for 19 lesions, in the overlap zone for 15 lesions and in the distal zone for 20 lesions. TLR was performed for nine heterogeneous DES group lesions, and maximal restenosis was observed in the overlap zone for two lesions, proximal zone for four lesions and distal zone for three lesions. In the homogeneous DES group, restenoses were classified as focal in 27 lesions, multifocal in nine lesions and diffuse in 18 lesions. In the heterogeneous DES group, restenoses were classified as focal in six lesions, multifocal in one lesion and diffuse in two lesions. Two focal restenosis lesions showed total occlusion.

Discussion

As far as we know, this study is the first to compare long-term outcomes between patients treated with overlapping homogeneous and heterogeneous DES. We found that overlapping heterogeneous DES were as safe and effective as homogeneous DES.

The use of DES has greatly attenuated the relationship between the stent length and restenosis. As a result, long DES tend to be used to obtain complete lesion coverage. If a residual segment of the lesion remains uncovered, additional stenting is considered. Overlapping stent regions are associated with higher concentrations of drug and polymer, and this had led to concerns about safety, mostly on the basis of animal study findings. Finn et al reported signs of incomplete and delayed endothelialisation and greater fibrin deposition as indicators of delayed healing, and reported increased inflammation at overlapping homogeneous DES sites in rabbit iliac arteries.9 However, a subanalysis of a large clinical trial has shown that overlapping homogeneous DES might be safe and effective.4 5

A few studies have reported findings for second-generation DES. Otake et al examined the 8–9 month intravascular ultrasound (IVUS) results in patients with overlapping EES (n=36) and PES (n=38).10 Overlapping EES were associated with greater neointimal suppression in the single-strut regions compared with overlapping PES, and there was a similar trend in the overlap region. There were no incidences of stent fracture or late incomplete stent apposition in the overlap region.

Few studies have examined outcomes following the use of overlapping heterogeneous DES. Lim et al used histopathology to examine overlapping homogeneous stents and heterogeneous stents at 4 weeks after stenting in pigs.11 They found that the SES+PES group had better histological outcomes than the SES+SES or PES+PES groups. They suggested that use of overlapping homogeneous DES increased the local concentration of the same drug, and this might result in worse inflammation and delayed endothelialisation than with use of overlapping heterogeneous DES.

A study by Burzotta et al demonstrated that in eight patients use of overlapping heterogeneous SES+PES was associated with no specific adverse event.12 Kang et al performed 9-month angiography and IVUS following the use of 14 overlapping SES+PES, 13 overlapping SES+SES and 20 overlapping PES+PES.13 They found that suppression of neointimal hyperplasia and side effects were similar in the overlapping heterogeneous DES and homogeneous DES. They observed no ST or aneurysmal formation. These findings are in agreement with our study results, but this study differed from that previous study in that it included more patients and second-generation DES, and had a long follow-up.

The SIRTAX study was designed to compare the safety and efficacy of SES and PES. Recently, Raber et al used SIRTAX data to examine the impact of stent overlap on angiographic and long-term clinical outcome.14 They analysed 134 patients treated with overlapping homogeneous DES, 199 patients treated with multiple DES in a vessel without overlap and 679 patients treated with one DES per vessel. MACE (cardiac death, MI, ischaemic-driven TLR) were more common in patients treated with overlapping DES (34 events, 25.4%) than in the other groups (42 events, 21.1% and 95 events, 14.0%) at 3 years (p<0.01). In addition, both the risk of TLR (20.2% vs 16.1% vs 9.7%, p<0.01) and the composite of death or MI (17.2% vs 14.1% vs 9.1%, p<0.01) were increased in patients treated with overlapping DES compared with the other groups. All three groups had a similar risk of definite ST (4.5% vs 4.0% vs 3.2%, p=0.75). However, unlike our study, their study did not include an appropriate control group. Our study enrolled eight times more patients with overlapping DES than that study.

Our study found that during a median follow-up period of 26 months, the MACE rate was 10.1%, and the ST rate 0.8%. These rates are somewhat lower than those reported by the previous study.14 One reason for this may be that our study enrolled only patients with one-vessel disease, whereas approximately 70% of patients in the previous study had multivessel diseases. Another reason may be the prolonged use of thienopyridine in our study patients. Thienopyridine was used for a median 20 months compared with the previous study in which clopidogrel was used for 12 months. A third reason may be that systematic angiographic follow-up was not performed in the current patients. This prevented the ‘oculostenotic reflex’, which in turn prevented inflation of the TLR rate. Finally, ethnic differences might have contributed to the differences between the current and previous study findings. The TLR rate at 1 year after Cypher was only 1.4% in the recent ZEST trial,15 and the incidence of definite/probable ST was only 0.91% at 2 years in the j-Cypher registry.16 17 Regardless of the cause of variance between the current and previous studies, our registry demonstrates favourable long-term clinical outcomes following overlapping DES implantation for the treatment of coronary lesions.

There are limited data of comparisons between stent types in overlapping DES. Our study showed that second-generation DES had a lower MACE rate than first-generation DES in the overlapping homogeneous DES group, and combinations of second-generation DES with second-generation DES or first-generation DES had a similar MACE rate to first-generation DES in the overlapping heterogeneous DES group. These findings suggest that overlap with second-generation DES is safe and effective. In this study, we also demonstrated that use of SES+SES resulted in better long-term outcomes than use of PES+PES, primarily by decreasing the need for repeat revascularisation. Use of PES has shown comparable clinical outcomes to the use of SES in several studies,18–20 but SES may be better than the PES in an angiography follow-up and IVUS follow-up study.21 22 Other studies also showed that SES had better outcomes than PES in complex lesion subsets.23–25 Considering the complexity of diffuse long lesions, our findings that use of SES decrease the frequency of adverse outcomes seem to be relevant.

The analysis of the pattern of restenosis in TLR patients showed that the lumen narrowing occurred equally from the proximal to distal stent region, irrespective of overlapping type. However, considering that the area of the overlap zone was less than the area of the proximal and distal zones, this suggests that overlapping regions are associated with a greater risk of restenosis. This finding is in agreement with a substudy of the ODESSA trial.26

Limitation

Our study had several limitations. The study was non-randomised and observational in design. We enrolled a relatively small number of patients with overlapping heterogeneous DES. Furthermore, we included various stent types, so we should consider the different characteristics of individual stents. Systemic angiographic follow-up was not performed, so we could not evaluate late stent malapposition or aneurysmal formation.

Conclusion

We first evaluated long-term clinical outcomes of overlapping heterogeneous DES. We found that overlapping heterogeneous DES were as safe and effective as overlapping homogeneous DES. However, a larger clinical trial, especially with a greater number of overlapping heterogeneous DES, is necessary to confirm these findings.

References

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Footnotes

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the institutional review board of the Catholic Medical Center.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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