Early vascular healing with rapid breakdown biodegradable polymer sirolimus-eluting versus durable polymer everolimus-eluting stents assessed by optical coherence tomography

doi:10.1016/j.carrev.2012.12.003

Cardiovascular Revascularization Medicine

Volume 14, Issue 2, March–April 2013, Pages 84-89

https://doi.org/10.1016/j.carrev.2012.12.003 Get rights and content

Abstract

Background

Differences in early arterial healing patterns after stent implantation between biodegradable and durable polymer based new generation drug-eluting stents are not well understood. The aim of this study was to compare the healing patterns of a novel rapid breakdown (≤ 8 weeks) biodegradable polymer sirolimus-eluting stent (BP-SES) with a durable polymer everolimus-eluting stent (EES) using intravascular optical coherence tomography (OCT) at 4 months.

Methods

A total of 20 patients were randomly assigned to stenting with BP-SES (n = 11) or EES (n = 9). Overall intravascular imaging was available for 15 (75%) patients. The primary endpoint was the difference in rate of uncovered struts between BP-SES and EES. To account for strut-level clustering, the results in both treatment groups were compared using a generalized linear mixed model approach.

Results

Regarding the primary endpoint, BP-SES as compared to EES showed similar rates of uncovered struts (37 [6.8%] versus 167 [17.5%], odds ratio (OR) 0.45 (95% CI 0.09-2.24), p = 0.33). There were no malapposed struts in BP-SES group and 14 malapposed struts in EES group (p = 0.97). No difference in percent neointimal volume (14.1 ± 8.2% vs. 11.4 ± 6.4%, p = 0.56) was observed.

Conclusions

Although rapid-breakdown BP-SES as compared to EES showed signs of improved early tissue coverage, after adjustment for strut-level clustering these differences were not statistically significant. No differences in ability to suppress neointimal hyperplasia after stent implantation between 2 stents were observed.

Introduction

First-generation drug-eluting stents (DES) deliver high clinical efficacy at the collateral cost of delayed healing of the stented arterial segment [1]. Pathological studies have suggested that the absence of stent strut tissue coverage and the persistence of fibrin deposition are the pathological hallmarks of delayed arterial healing and mechanistically underlie the slight excess of very late stent thrombosis seen with these devices.

The ITRIX biodegradable polymer sirolimus-eluting stent (BP-SES) is a novel device coated with an ultra-thin layer (5 μm) of rapid breakdown biodegradable polymer designed to degrade completely in approximately 8 weeks. It is hypothesized that both the faster release kinetics of the antiproliferative drug and the early loss of biodegradable polymer coating may be associated with an earlier vascular healing response expressed by a higher degree of stent strut coverage. In addition, the durable polymer everolimus-eluting stent (EES) has shown signs of improved early vessel healing in preclinical study [2] and recently has received approval in Europe for implantation with shorter duration (3 months) of dual antiplatelet therapy [3].

High-resolution intracoronary optical diagnostics allow precise assessment of stent coverage and stent apposition permitting insights into vascular healing patterns in vivo [4], [5]. However few studies have examined vessel healing at an early time point after stenting. Accordingly we compared rapid breakdown BP-SES with the durable polymer EES using optical coherence tomography (OCT) at 4 months.

Section snippets

Study population, devices, randomization and intervention protocol

The Polymer Degrading-Sirolimus Eluting-Coronary Stent Trial (PILOT) was a prospective, multi-center pilot trial, enrolling a total of 20 patients, who were randomly assigned to treatment with either BP-SES or EES. Eligible patients (age, ≥ 18 years and < 80 years) had angina pectoris and/or objective signs of ischemia, in the presence of a ≥ 50% diameter stenosis de novo native coronary artery lesion. Key exclusion criteria included patients with cardiogenic shock, left ventricular function < 40%,

Baseline patient, lesion and procedural characteristics

Patient study flow is shown in Fig. 1. A total of 11 patients were allocated to BP-SES and 9 patients allocated to EES. Baseline characteristics of the patients, procedure, and lesions are shown in Table 1. There were no significant differences between two groups.

Clinical outcomes

One patient in EES group underwent revascularization for restenosis at the proximal stent margin. Otherwise there were no clinical events in either group at 4 months follow-up.

OCT results

Fifteen patients returned for intravascular imaging surveillance; 4 patients in the BP-SES and 1 in the EES group declined.

Coverage and apposition of the stent struts were analyzed with strut- and patient-level. The spread-out-vessel graphics showing the spatial distribution and coverage of individual analyzed struts are shown in Fig. 2. There were fewer total struts analyzed in the BP-SES compared with the EES group (545 struts in 7 patients in BP-SES group versus 954 struts in 8 patients in

Discussion

The main findings of the current pilot study are that (1) although a novel rapid breakdown biodegradable polymer sirolimus-eluting stents as compared to a durable polymer everolimus-eluting stent showed evidence of higher strut-level coverage as evaluated by OCT at 4 months follow-up, these differences were not significant when adjustment was made for intra-patient clustering; (2) heterogeneity analysis revealed no difference in strut coverage patterns between the 2 stents; and (3) there was no

Conclusions

A novel rapid-breakdown BP-SES as compared to durable polymer EES showed similar degree of early stent strut coverage as assessed by OCT at 4 months, though coverage patterns were more homogeneous with BP-SES. No differences in ability to suppress neointimal hyperplasia after stent implantation between the 2 stents were observed.

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Randomised comparison of vascular response to biodegradable polymer sirolimus eluting and permanent polymer everolimus eluting stents: An optical coherence tomography study
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In-stent restenosis was defined as per cent diameter stenosis of > 50% within the stent segment at the time of follow-up angiography. The methods of OCT image acquisition were described in a previous report [15]. Following administration of intravenous heparin and intracoronary nitrates OCT was performed using frequency domain OCT (C7XR system, LightLab Imaging, Westford, MA, USA) allowing acquisition at 100 frames per second with non-occlusive imaging technique.
Drug-eluting stents with biodegradable polymer coatings have shown promising outcomes in randomised studies.
We compared neointimal healing patterns including strut coverage and assessed neointimal maturity using a novel algorithm in coronary lesions treated with sirolimus-eluting stents with biodegradable polymer coating (BP-SES) or everolimus eluting stents with permanent polymer coating (PP-EES) using optical coherence tomography after 6 months.
A total of 39 patients were randomised to BP-SES (n = 19) or PP-EES (n = 20) for the treatment of coronary lesions. Of those, 29 patients (14 BP-SES and 15 PP-EES) underwent optical coherence tomography (OCT) and angiography at 6-month follow-up. Tissue coverage and apposition were assessed in a total of 6162 struts (BP-SES, n = 2889; PP-EES, n = 3273). Neointimal maturity was assessed in 3672 neointimal regions above struts using grey scale intensity analysis. OCT analysis showed neointimal coverage of 2433 (BP-SES) vs. 2702 (PP-EES) struts (84.2% vs. 82.6%, p = 0.70), whereas the remainder was uncovered after 6 months. Mean neointimal thickness did not differ significantly between groups (54.3 ± 7.8 μm vs. 80 ± 14.6 μm, p = 0.12). The rate of malapposed struts was comparable between groups (1.3% vs. 2.2%, p = 0.27). Grey scale signal intensity analysis showed mature tissue coverage of struts in 46.2% in BP-SES vs. 31.8% in PP-EES (p = 0.31) of neointimal regions.
The present study showed comparable early vascular healing response characterised by neointimal coverage with mainly immature neointima in both BP-SES and PP-EES.
Time-related changes in neointimal tissue coverage of a novel Sirolimus eluting stent: Serial observations with optical coherence tomography
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Neointimal hyperplasia was calculated as the average of thickness of the tissue coverage of the luminal side of each strut. Coverage and apposition of the stent struts were analysed with strut- and cross section-level [10,11]. Struts were classified as malapposed if protruding into the lumen at a distance greater than the sum of the strut and polymer thickness (71 μm and 91 μm for the 2.25, 2.5 and 3.0 stent diameter and 3.5, 4.0 stent diameter respectively) plus the minimal axial OCT resolution (20 μm) Fig. 2.
DES has reduced rates of restenosis compared with BMS but it has been associated with delayed healing and increase of stent thrombosis. The aim of our study was to evaluate the vascular time-related changes following implantation of a new SES coated with an amorphous silicon carbide that allows faster re-endothelisation (Orsiro-Biotronik).
This prospective registry enrolled STEMI-patients with multi-vessel disease, thus candidates for a two-step procedure. PCI of the culprit lesion was performed with at least one Orsiro stent that was OCT-analysed during the second-step procedure (deferred to 30,90 and 180-days).
16 of the 95 patients with MVD underwent an OCT evaluation of the study device implanted in the culprit lesion during the second-step staged procedure and were enrolled in the present Registry. A total of 3060-struts were analysed. The percentage of uncovered struts was 19.6% at30-days, 1.3% at90-days and 1.8% at180-days (p < 0.001). The percentage of cross section with ≥ 1 uncovered struts were 51.3% at30-days, 6.5% at90-days and 5.7% at180-days (p < 0.001). The percentage of cross sections containing thrombus was 6.2% at30-days while no thrombus was detected both at90 and 180-days.
Our data shows that the new Orsiro stent promotes early and persistent strut coverage with low peri-strut thrombus. This pilot OCT evaluation might suggest a low incidence of late adverse events and anticipate safe outcome after early withdrawal of dual antiplatelet therapy.
Cell viability of fibroblasts to pifenidone and sirolimus: A future concept for drug eluting stents
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However, there is still no long term drug eluting product on the market. Drug eluting stents were found to be responsible for early vessel wound healing (Abhyankar et al., 2013; Tada et al., 2013). Moreover, it was observed that when two sirolimus eluting stents were placed proximally they formed a fibrinous tissue membrane (Yamada and Takahashi, 2013).
Currently one of the major problems that interventional pulmonologists have to face is the increased proliferation of fibrinous tissue on the site of the stent placement, and usually at the two ends.
The drugs rapamycin and pirfenidone were chosen for our experiment. Fibroblasts were also cultured in order to administer pirfenidone and rapamycin in different concentrations. The following cell viability methods were used: (a) Senescence – Cell Titer Assay, (b) Necrosis – Cyto Tox Assay and (c) Apoptosis – Caspase-Glo 3/7 Assay.
Rapamycin has minimal to no effect on fibroblasts regarding apoptosis, senescence and necrosis. 0.1 to 1 μM. Pirfenidone concentrations lead to an elevated cell metabolism because cells try to evade the cytotoxic effect of the drug. Increasing Pirfenidone concentrations lead to higher apoptosis rates. 10 μM pirfenidone induces the highest apoptosis rates in this experiment and reduce cell viability to a minimum.
Necrosis is unaffected by the investigated drugs.
Long-term outcomes of biodegradable polymer versus durable polymer drug-eluting stents in patients with diabetes a pooled analysis of individual patient data from 3 randomized trials
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This is hypothesized to confer a lower risk of late stent thrombosis, an effect potentially magnified in patients with diabetes. Indeed a number of intravascular imaging studies show encouraging data regarding vessel healing after biodegradable polymer DES implantation in man [25,26]. Our study represents the first analysis of long-term outcomes in patients with diabetes treated with biodegradable polymer DES.
There is ongoing debate on the optimal drug-eluting stent (DES) in diabetic patients with coronary artery disease. Biodegradable polymer drug-eluting stents (BP-DES) may potentially improve clinical outcomes in these high-risk patients. We sought to compare long-term outcomes in patients with diabetes treated with biodegradable polymer DES vs. durable polymer sirolimus-eluting stents (SES).
We pooled individual patient-level data from 3 randomized clinical trials (ISAR-TEST 3, ISAR-TEST 4 and LEADERS) comparing biodegradable polymer DES with durable polymer SES. Clinical outcomes out to 4 years were assessed. The primary end point was the composite of cardiac death, myocardial infarction and target-lesion revascularization. Secondary end points were target lesion revascularization and definite or probable stent thrombosis.
Of 1094 patients with diabetes included in the present analysis, 657 received biodegradable polymer DES and 437 durable polymer SES. At 4 years, the incidence of the primary end point was similar with BP-DES versus SES (hazard ratio = 0.95, 95% CI = 0.74–1.21, P = 0.67). Target lesion revascularization was also comparable between the groups (hazard ratio = 0.89, 95% CI = 0.65–1.22, P = 0.47). Definite or probable stent thrombosis was significantly reduced among patients treated with BP-DES (hazard ratio = 0.52, 95% CI = 0.28–0.96, P = 0.04), a difference driven by significantly lower stent thrombosis rates with BP-DES between 1 and 4 years (hazard ratio = 0.15, 95% CI = 0.03–0.70, P = 0.02).
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^☆: Funding: This study was supported by AMG international GmbH, Germany.

^☆☆: Conflict of interest: Dr. Kastrati reports received lecture fees from Abbott, Biotronik, Cordis and Medtronic. The remaining authors report no conflicts of interest.

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ClinicalEarly vascular healing with rapid breakdown biodegradable polymer sirolimus-eluting versus durable polymer everolimus-eluting stents assessed by optical coherence tomography☆,☆☆

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Study population, devices, randomization and intervention protocol

Baseline patient, lesion and procedural characteristics

Clinical outcomes

OCT results

Discussion

Conclusions

J Am Coll Cardiol

JACC Cardiovasc Interv

Lancet

J Am Coll Cardiol

Lancet

Lancet

Am Heart J

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

JACC Cardiovasc Interv

Drug-eluting stents in percutaneous coronary intervention: a benefit-risk assessment

Drug Saf

Application of optical coherence tomography in percutaneous coronary intervention

Circ J

Clinical
Early vascular healing with rapid breakdown biodegradable polymer sirolimus-eluting versus durable polymer everolimus-eluting stents assessed by optical coherence tomography☆,☆☆