Article Text

PDF
Original article
Long-term (8–10 years) outcomes after biodegradable polymer-coated biolimus-eluting stent implantation
  1. Masanobu Ohya,
  2. Shunsuke Kubo,
  3. Akimune Kuwayama,
  4. Katsuya Miura,
  5. Takenobu Shimada,
  6. Hidewo Amano,
  7. Yusuke Hyodo,
  8. Suguru Otsuru,
  9. Seiji Habara,
  10. Takeshi Tada,
  11. Hiroyuki Tanaka,
  12. Yasushi Fuku,
  13. Harumi Katoh,
  14. Tsuyoshi Goto,
  15. Kazushige Kadota
  1. Department of Cardiology, Kurashiki Central Hospital, Kurashiki, Okayama, Japan
  1. Correspondence to Dr Masanobu Ohya, Department of Cardiology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, Okayama 710-8602, Japan; masanobu.ohya{at}gmail.com

Abstract

Objective Efficacy and safety data on biodegradable polymer-coated biolimus-eluting stent (BP-BES) are currently limited to 5 years. We evaluated longer term (8–10 years) clinical and angiographic outcomes after BP-BES implantation.

Methods Between 2005 and 2008, 243 patients (301 lesions) underwent BP-BES implantation. The primary clinical outcome measure was defined as any target lesion revascularisation (TLR). Absolute serial angiographic studies without any concomitant TLR within 2 years after the procedure were performed in 55 patients (65 lesions) at postprocedure, mid-term (within 1 year), late term (between 1 and 2 years) and very late term (beyond 2 years).

Results The median follow-up duration was 9.4 years (IQR 8.2–10.2 years). The 8-year cumulative incidence of any TLR was 20.3%. The increase rate was approximately 7% per year in the first 2 years, but decelerated to approximately 1.2% per year beyond 2 years after the procedure. The minimal lumen diameter significantly decreased from postprocedure (2.63±0.44 mm) to mid-term (2.43±0.59 mm, p=0.002) and from late term (2.27±0.63 mm) to very late term (1.98±0.73 mm, p=0.002). The 8-year cumulative incidences of definite or probable stent thrombosis (ST) and major bleeding (Bleeding Academic Research Consortium (BARC) ≥3) were 0.5% and 12.0%, respectively. Definite ST was none within 10 years in the entire cohort.

Conclusions The long-term clinical outcomes after BP-BES implantation were favourable, although angiographic late progression of luminal narrowing did not reach a plateau. The incidence of ST remained notably low, whereas that of major bleeding gradually increased.

Statistics from Altmetric.com

Introduction

The use of drug-eluting stents (DES) has emerged as a standard practice for patients with coronary artery disease because DES significantly reduced the rates of restenosis and subsequent target lesion revascularisation (TLR) compared with bare-metal stents.1 ,2 Nevertheless, late restenosis and very late stent thrombosis (ST) still occur due to their mechanisms such as delayed healing, neointimal proliferation and neoatherosclerosis.3 In particular, the risk of late-term ischaemic events after first-generation DES implantation remains high.4

BioMatrix (Biosensors, Morges, Switzerland), a type of biodegradable polymer-coated biolimus-eluting stent (BP-BES) using biolimus A9, was designed to improve those efficacy and safety profiles. Its platform has a flexible quadrature link design with a strut width of 120 µm. The lipophilicity of biolimus A9 is as high as that of sirolimus, which prevents inflammatory reaction and smooth muscle proliferation. Moreover, the simultaneous release of the drug and polylactic acid enables biodegradable polymer to dissolve into carbon dioxide and water after 6–9 months.5 Several randomised controlled trials demonstrated the efficacy and safety of BP-BES showing the risk of late TLR and very late ST lower than durable polymer sirolimus-eluting stents and equivalent to durable polymer everolimus-eluting stents.6–9 The prevention of incomplete endothelialisation and ongoing inflammatory response to permanent polymer might have brought better clinical outcomes.10–12 At present, the efficacy and safety of BP-BES are confirmed only for 5 years after the procedure and those beyond 5 years remain to be investigated.13 Moreover, limited data are available on the incidence and risk of bleeding in patients after BP-BES implantation, which has relatively low risk of ST. Therefore, we aimed to investigate longer term (8–10 years) clinical (ischaemic and haemorrhagic) and angiographic outcomes after BP-BES implantation.

Methods

Study sample and protocol

A total of 3460 consecutive patients (5922 lesions) underwent DES implantation in Kurashiki Central Hospital between February 2005 and December 2008. Of these patients, this study sample included 243 consecutive patients (301 lesions) undergoing BP-BES implantation and excluded 3217 patients undergoing other types of DES implantation, which consisted of 2582 patients implanted with sirolimus-eluting stents (Cypher, Cordis; Johnson & Johnson, Miami, Florida, USA) and 635 patients implanted with paclitaxel-eluting stents (Taxus; Boston Scientific, Natick, Massachusetts, USA). BP-BES was privately imported because it was off-label in Japan during the study period. The choice of BP-BES was left to each physician's discretion, especially in the case of bifurcation or severely angulated lesions, expecting improved clinical outcomes compared with sirolimus-eluting and paclitaxel-eluting stents. Clinical outcomes were collected either from hospital charts or by contacting patients, their family members or referring physicians. Patients who were lost to follow-up were censored on the last day with any follow-up information. The median follow-up duration was 9.4 years (IQR 8.2–10.2 years). Of the 243 patients, clinical follow-up was completed in 98% (239 patients) at 2 years, 98% (239 patients) at 4 years, 96% (234 patients) at 6 years and 88% (215 patients) at 8 years.

All the patients were advised to continue dual antiplatelet therapy with aspirin (100 mg/day) and thienopyridine (ticlopidine, 200 mg/day or clopidogrel, 75 mg/day) for at least 8 months after the procedure. However, the actual duration of dual antiplatelet therapy was left to each physician's discretion. When a patient discontinued at least one antiplatelet drug for more than 2 months between two successive surveys, the status of their dual antiplatelet therapy was considered persistent discontinuation.14 When their physician intended to discontinue dual antiplatelet therapy permanently, dates related to the resumption of medications after discontinuation were not confirmed.

The study was done in accordance with the provisions of the Declaration of Helsinki and the guidelines for epidemiological studies issued by the Ministry of Health, Labour and Welfare of Japan. Informed consent was provided for both the procedure and subsequent data collection and analysis for research purposes. The study was approved by the institutional ethics committee.

Clinical outcome measures

The primary clinical outcome measure was defined as any TLR. The other clinical outcome measures included all-cause death, cardiac death, myocardial infarction, ST, stroke, clinically driven TLR, ischaemic driven TLR, any coronary revascularisation, new lesion revascularisation and bleeding. Cardiac death included any kind of death, except for obviously non-cardiac death. Myocardial infarction was defined as ischaemic symptoms and/or ischaemic changes of electrocardiogram along with elevated cardiac enzymes (troponin or creatine kinase-MB fraction) greater than the upper limit of normal. ST was defined based on the Academic Research Consortium definitions.15 ST was classified according to the occurrence time as early (≤30 days), late (31 days to 1 year) and very late (>1 year). Stroke consisted of ischaemic and haemorrhagic stroke. TLR was defined as either repeat percutaneous coronary intervention or coronary bypass grafting for restenosis or thrombosis of the target lesion involving the proximal and distal edge segments detected by coronary angiography. Clinically driven TLR was defined as TLR for typical chest pain and/or objective evidence of ischaemia (either electrocardiographic changes during a spontaneous episode of pain or abnormal results of exercise electrocardiography or stress nuclear perfusion scan). Ischaemia-driven TLR included TLR for restenosis with per cent diameter stenosis >70% in addition to clinically driven TLR. New lesion revascularisation was defined as revascularisation for de novo lesions. Bleeding events were confirmed based on the Bleeding Academic Research Consortium (BARC) classification.16 Major bleeding was defined as BARC ≥3.

Angiographic outcome measures

According to our institutional protocol, follow-up coronary angiography was scheduled 8 and 20 months after percutaneous coronary intervention. Coronary angiographic studies beyond 2 years were conducted based on the clinical indications. Serial angiographic studies without any concomitant TLR within 2 years after the procedure were classified into four terms: postprocedure, mid-term (within 1 year), late term (from 1 to 2 years) and very late term (beyond 2 years). Quantitative coronary angiography (QCA) analysis was independently conducted by the technicians of Kurashiki Central Hospital using QCA-CMS (Medis medical imaging systems, Leiden, the Netherlands). Angiographic measurements were obtained from multiple projections following intracoronary nitrate injection. Reference diameter, minimum lumen diameter and per cent diameter stenosis were measured before the procedure, after the procedure and at the index follow-up angiography.

Statistical analysis

Data are presented as mean±SD for continuous variables. Numbers and percentages were reported for categorical variables. Numerical data collected by serial angiographic studies were assessed by longitudinal analysis methods with generalised linear mixed-effects models and compared using 1-way repeated-measures analysis of variance or the Friedman test as appropriate. After these analyses, Wilcoxon's signed-rank test was applied as post hoc analysis, which was performed with the Bonferroni correction for multiple comparisons at four points (postprocedure, mid-term, late term and very late term). The cumulative incidences of clinical events were estimated by the Kaplan-Meier method. Data were analysed using the IBM SPSS statistical software (V.23; International Business Machines, Armonk, New York, USA). Two-tailed p values <0.05 were considered to be statistically significant.

Results

In baseline patient characteristics, the mean age was 69.1±10.1 years, the prevalence of diabetes mellitus was approximately 40% and the rate of patients on haemodialysis was approximately 5%. The majority of patients (92%) were diagnosed with stable coronary artery disease. At the time of hospital discharge, dual antiplatelet therapy was initiated in almost all the patients, whereas the use rates of statins, ß-blockers and inhibitors of the renin–angiotensin system were relatively low. The use rate of warfarin was approximately 9% (table 1).

Table 1

Baseline patient characteristics

In baseline lesion characteristics, the prevalence of culprit lesions in the left main coronary artery was almost one fourth. The majority of lesions were bifurcation lesions (90%) and B2 or C type in the American College of Cardiology/American Heart Association (ACC/AHA) classification (77%). The two-stenting strategy was performed in 94 (31%) of the 301 lesions (table 2).

Table 2

Baseline lesion, angiographic and procedural characteristics

The 8-year cumulative rate of any TLR was 20.3%, increasing approximately 7% per year in the first 2 years after the procedure, but decelerating to approximately 1.2% per year beyond 2 years after the procedure; that of clinically driven TLR was 14.3%, increasing approximately 4% per year in the first 2 years, but decelerating to approximately 1.2% per year beyond 2 years after the procedure; that of new lesion revascularisation was 37.2%, increasing throughout the study period (figure 1 and table 3).

Table 3

Cumulative incidences of clinical events through 8 years

Figure 1

Cumulative incidences of any coronary revascularisation, new lesion revascularisation, any target lesion revascularisation (TLR) and clinically driven TLR.

The median intervals of serial angiographic studies by quantitative analysis were as follows: mid-term, 8.3 (IQR 8.3–8.4) months; late term, 20.6 (IQR 20.4–21.0) months and very late term, 44.1 (IQR 36.6–64.5) months. The angiographic study at very late term was done only when clinical indications were present or follow-up for new lesion revascularisation was required. Absolute serial angiographic studies without concomitant TLR within 2 years after the procedure were performed in 55 patients (65 lesions). The decrease in the minimum lumen diameter was significant from postprocedure (2.63±0.44 mm) to mid-term (2.43±0.59 mm, p=0.002) and from late term (2.27±0.63 mm) to very late term (1.98±0.73 mm, p=0.002). The decrease from mid-term to late term had the same tendency (p=0.07) (figure 2A). Similarly, per cent diameter stenosis was progressive from postprocedure (16.7%±7.0%) to mid-term (24.4%±12.2%, p<0.001), from mid-term to late term (29.0%±14.2%, p=0.08) and from late term to very late term (35.8%±19.9%, p=0.04) (figure 2B).

Figure 2

Serial angiographic outcomes of minimal lumen diameter (MLD), reference lumen diameter and per cent diameter stenosis. Serial changes of minimal and reference lumen diameter. Serial change of per cent diameter stenosis. We assessed 55 patients (65 lesions) undergoing complete serial coronary angiographic studies without target lesion revascularisation within 2 years after the procedure. Boxes and internal lines represent 25th and 75th percentiles and median and whiskers show range and outliers. Results are expressed as mean±SD. RD, reference diameter.

The 8-year cumulative incidences of other clinical outcome measures were as follows: all-cause death, 29.8%; cardiac death, 13.0%; myocardial infarction, 3.5%; definite or probable ST, 0.5%; stroke, 9.3% and major bleeding, 12.0% (figure 3 and table 3). Definite ST was none for the follow-up duration of this study and there was only one probable very late ST. On the other hand, the 8-year cumulative incidence of major bleeding gradually increased (figure 4). The characteristics of patients with major bleeding are shown in online supplementary table I. Seventeen of 24 patients with major bleeding continued dual antiplatelet therapy, 4 of whom additionally received anticoagulant therapy. Fourteen patients had intracranial bleeding, eight of whom fell into critical condition. The persistent discontinuation rates of dual antiplatelet therapy were 14.4% at 1 year, 36.4% at 5 years and 57.7% at 8 years (see online supplementary figure I).

Figure 3

Cumulative incidences of all-cause death, cardiac death, myocardial infarction and definite or probable stent thrombosis (ST).

Figure 4

Cumulative incidence of bleeding events according to the Bleeding Academic Research Consortium (BARC) classification.

supplementary table and figure

Discussion

The main findings of our study were as follows: (1) the cumulative clinical outcomes after BP-BES implantation remained favourable even beyond 5 years; (2) angiographic late progression of luminal narrowing did not reach a plateau after BP-BES implantation and (3) the incidence of ST after BP-BES implantation remained notably low, whereas that of major bleeding gradually increased throughout the study period.

In our study, the annual increase rate of TLR beyond 2 years after BP-BES implantation (1.2% per year) was numerically lower than those after sirolimus-eluting stent implantation in previous studies (approximately 2.0% per year),4 ,17 despite relatively high rates of complex lesions such as severely angulated and bifurcation lesions. It is probable that the clinical outcomes benefited from BP-BES because the presence of polymer can provoke delayed healing and inflammatory reaction. Nevertheless, angiographic late progression of luminal narrowing occurred and late TLR events involving severe angina pectoris continued to increase up to 10 years without reaching a plateau. The annual increase rate of TLR following late follow-up of BP-BES implantation was similar to that of bare-metal stent implantation in a very long-term follow-up study.18 It has been reported that the neoatherosclerotic change in lesions after DES implantation is associated with restenosis, TLR and ST.19 Even if the used polymer is biodegradable, metallic prostheses are permanently present inside the vessel and trigger neoatherosclerosis and inflammatory reaction.20 ,21 Therefore, late adverse events of culprit lesions after metallic stent implantations might not disappear on a permanent basis. Recently, Yamaji et al22 have reported that the annual rates of TLR and ST after first-generation DES implantation significantly declined beyond 5 years compared with those from 1 to 5 years, although the annual TLR rate beyond 5 years has not attenuated in our study. Despite our study sample including more complex patients and lesion characteristics compared with those of the randomised controlled trial, more intensive antiatherosclerotic drug therapy was not performed. The low penetration of antiatherosclerotic drug and the large portions of complex patient and lesion characteristics might affect the late term outcomes of our study.

Moreover, the rate of new lesion revascularisation continually increased to approximately two times higher than that of TLR. The association between in-stent and native coronary artery atherosclerotic changes has been reported.23 In a prospective study, the risk of cardiovascular events was nearly equivalent between culprit and non-culprit lesions.24 The risk of new lesion revascularisation was higher in our study than in the above-mentioned study, which might be attributed to our having higher rates of diabetes mellitus and multivessel disease. Intensive medications such as high-dose statin therapy could prevent late adverse clinical events, especially in patients with higher ischaemic risk after DES implantation.25

It is remarkable that there were no definite ST and only one probable ST up to 10 years in our study with a relatively high follow-up rate. Although the finding was underpowered due to the small sample size, it provided a reassuring evidence for the extremely low incidence of ST after BP-BES implantation.6–9 On the other hand, the cumulative incidence of major bleeding gradually increased in patients after BP-BES implantation. It has been reported that prolonged dual antiplatelet therapy significantly increased the risk of major bleeding.26 We could not assess the difference in the cumulative incidence of major bleeding by landmark analysis based on the duration of dual antiplatelet therapy due to its low incidence. However, the rate of patients continuing dual antiplatelet therapy after BP-BES implantation was considerably high in real-world settings. It might be because patients after stent implantation often need to undergo new lesion revascularisation afterwards, and consequently they cannot discontinue dual antiplatelet therapy. Furthermore, dual antiplatelet therapy might be continued to prevent ischaemic complications including myocardial infarction and ST caused by the treatment for relatively complicated lesions. According to two meta-analyses, an extended duration of dual antiplatelet therapy increases the risk of bleeding events, but is not associated with the risk of mortality.27 ,28 However, in our study with a longer follow-up duration, most of cerebral bleeding events became fatal, although it might be due to the patient characteristics such as Asian and elderly.29 In the current DES era, the risks of myocardial infarction and ST are relatively low.30 We should continuously reconsider whether we can discontinue dual antiplatelet therapy, particular in patients with high risk of bleeding, although the optimal duration of dual antiplatelet therapy remains controversial.

Several limitations of this study should be considered. First, this was a retrospective and observational study. Second, possible selection bias existed due to each physician's preference regarding the types of stent. It was particularly strong when selecting stents for patients with bifurcation lesions. Thus, our findings might be not applicable to all patients treated with BP-BES. Third, the number of patients receiving absolute serial follow-up angiographic studies was relatively small and the timings of the serial angiographic studies were not at regular intervals. Moreover, the QCA studies were not conducted in an independent core laboratory. Instead, a well-validated system of our hospital was used. Fourth, we could not confirm the change or accession of medications during the follow-up period. Finally, our study had no control group; however, our findings from a longer follow-up study after BP-BES implantation could be a practical yardstick for evaluating the long-term outcomes of treatment with current and future DES including biodegradable or durable polymer DES.

Conclusions

The long-term clinical outcomes after BP-BES implantation were favourable, although angiographic late progression of luminal narrowing did not reach a plateau. The incidence of ST remained notably low, whereas that of major bleeding gradually increased throughout the study period.

Key messages

What is already known on this subject?

  • The efficacy and safety of biodegradable polymer-based biolimus-eluting stents (BP-BES) for 5 years after the procedure are confirmed.

What might this study add?

  • Longer term (8–10 years) efficacy and safety were demonstrated, although angiographic late progression of luminal narrowing did not reach a plateau. The incidence of stent thrombosis remained notably low, whereas that of major bleeding gradually increased.

How might this impact on clinical practice?

  • The long-term outcomes appear to benefit from BP-BES, although late adverse events in both culprit and non-culprit lesions do not disappear. We should continuously pay attention to bleeding events in patients after stent implantation for coronary artery disease.

Acknowledgments

The authors appreciate the stuff members of the cardiac catheterisation laboratory and Miho Kobayashi, Makiko Kanaike and Yoshimi Sano for secretarial assistance.

References

View Abstract

Footnotes

  • Contributors MO, SK, KK: conception and design as well as analysis and interpretation of data and final approval of the manuscript submitted. MO: drafting of the manuscript. SK, KK: revising the manuscript critically for important intellectual content. KK: drafting of the manuscript and revising the manuscript critically for important intellectual content. The residual authors for conception and design, revising the manuscript critically for important intellectual content and final approval of the manuscript submitted.

  • Competing interests None declared.

  • Ethics approval The study was approved by the institutional ethics committee.

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

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.