Use of Everolimus-eluting Stent with a Bioresorbable Polymer Coating for Treatment of Recurrent In-stent Restenosis

In-stent restenosis (ISR) often limits the long-term success of percutaneous coronary intervention. A number of clinical trials have shown that drug-eluting stents are both safe and effective in preventing ISR in de novo lesions.^1,2,3 The use of drug-eluting stents for the treatment of in-stent restenosis has recently been reported and the sirolimus-eluting stent utilizing a biostable polymer coating has shown efficacy for focal ISR lesions in a small clinical trial.⁴ However, the efficacy of drug-eluting stents — especially for diffuse in-stent restenosis — has not been established,⁵ and the use of bioresorbable coatings to release drugs from stents for the treatment of in-stent restenosis has not been previously reported. Everolimus [40-O-(2-hydroxyethyl)-rapamycin] is a novel macrocyclic immunosuppressive agent with antifungal, antiproliferative properties. Everolimus is a semi-synthetic sirolimus (rapamycin) derivative. The efficacy and biocompatibility of the everolimus-eluting stent utilizing a bioresorbable polymer coating for the prevention of neointimal hyperplasia has been demonstrated in an experimental animal model.⁶ The use of a bioresorbable, polymer-coated, everolimus-eluting stent for de novo lesions has been recently reported,⁷ but the use of a bioresorbable, polymer-coated, everolimus-eluting stent for in-stent restenosis lesions has not been reported. We investigated the compassionate use of a bioresorbable, polymer-coated, everolimus-eluting stent (Biosensors International, Newport Beach, California; Figure 1) for the treatment of multiple, recurrent in-stent restenosis. Case report. A 63-year-old female who had a history of an old anterior myocardial infarction, percutaneous coronary intervention and coronary artery bypass graft (CABG) surgery, was referred to our institution for ISR at the proximal left circumflex (LCX). She had had a prior stent implanted in the left anterior descending (LAD) artery at the time of an anterior myocardial infarction treatment by the referring physician. As a result of clinical restenosis at this LAD stent concurrent with severe stenosis of the left main trunk, the patient underwent prior CABG surgery to the LAD and the distal LCX. She presented with chest pain post-CABG, and angiography again showed severe stenosis in the left main trunk and the proximal LCX. A 3.5 x 13 mm BX Velocity stent (Cordis, Johnson & Johnson, New Brunswick, New Jersey) was implanted at the left main trunk, and a 3.0 x 9 mm NIR stent (Boston Scientific, Natick, Massachusetts) was implanted in the proximal LCX by the referring physician. This proximal LCX lesion showed ISR and the patient was referred to our catheterization laboratory. The ISR was treated by cutting balloon (2.5 x 15 mm) dilatation (Figure 2A). One month after the procedure, the patient presented again with chest pain and the angiography showed a second ISR. The second ISR was treated by balloon (2.5 x 30 mm) dilatation followed by additional stent (3.0 x 9 mm S670, Medtronic) implantation at the distal lesion of the NIR stent in the LCX. Two months after the second procedure, she presented again with chest pain and the angiography showed a diffuse third ISR at proximal LCX. We performed rotational atherectomy (burr size 2.15 mm) followed by adjunctive balloon (3.5 x 30 mm) dilatation for this third ISR (Figure 2B). Two months after this third PCI procedure, the patient presented with a fourth diffuse ISR at the proximal LCX. We again performed rotational atherectomy (burr size 2.15 mm), followed by balloon dilatation (3.25 x 30 mm). Two months after the fourth procedure, she presented with Canadian Cardiovascular Society class IV angina pectoris. Angiography showed a diffuse fifth recurrent ISR in the proximal LCX segment (lesion length 22.1 mm; Figure 3), and the bypass graft to the LCX artery was occluded. The angiographic pattern of ISR was described and classified as “class diffuse proliferative” as described by Mehran et al.⁸ Since intracoronary radiation therapy for the treatment of ISR was not approved and not available in Japan, and the past four attempts to treat this ISR by cutting balloon, balloon dilatation and rotational atherectomy all resulted in diffuse ISR at the lesion site, we decided to use the drug-eluting stent for this recurrent, proximal LCX ISR lesion. However, both the sirolimus-eluting and the paclitaxel-eluting stents were neither approved nor availavle in Japan. We decided to use the 3.0 x 18 mm everolimus-eluting stent, as it was the only one of its kind available at our institution at the time of the procedure. After receiving a signed consent form from the patient, we performed the fifth coronary intervention to treat this fifth recurrent ISR lesion. Pre-procedure angiography showed a reference diameter of 3.04 mm, a minimal luminal diameter (MLD) of 0.54 mm, and a percent diameter stenosis (DS) of 81% at the lesion site. A 6 Fr Judkins Left short tip type 4 guiding catheter (Asahi Intec, Nagoya, Japan) was inserted via the left radial approach, and a 0.014 inch coronary guidewire was advanced through the BX Velocity stent strut in the left main artery to the proximal LCX ISR lesion. Next, a 2.5 x 30 mm balloon was advanced through the BX Velocity stent strut in the left main artery to the left LCX ISR lesion. Since the lesion was very diffuse and the lesion length was 22.1 mm, and the reference vessel diameter was 3.04 mm, we chose an undersized, longer balloon (2.5 x 30 mm) to avoid slipping during balloon dilatation. The undersized 2.5 x 30 mm balloon was dilated up to 12 atm without slipping or causing injury beyond the lesion. We then advanced the 3.0 x 18 mm everolimus-eluting stent through the BX velocity stent strut to the inside of proximal LCX ISR lesion. The lesion length prior to balloon dilatation was slightly longer than the stent length. A 3.0 x 18 mm everolimus-eluting stent was the only available size, thus we carefully positioned the 3.0 x 18 mm everolimus-eluting stent inside the 3.0 x 9 mm NIR stent and the 3.0 x 9 mm S670 in the LCX. The 3.0 x 18 mm everolimus-eluting stent was deployed to 12 atm. Final angiography showed a fully deployed everolimus-eluting stent inside the proximal LCX BX Velocity stent with a post-stent implantation MLD of 2.78 mm and a percent DS of 8.6% (Figure 4). Both aspirin 162 mg and ticlopidine 200 mg were given for one year. The patient remained symptom-free for one year for the first time after several repeat procedures to treat the proximal LCX lesion. A careful follow-up angiography was performed at three months, six months, and one year. Six-month follow-up angiography revealed a MLD of 2.27 mm and a percent DS of 25.3%. One-year long-term follow-up angiography revealed a MLD of 2.12 mm and a percent DS of 31.6%. Six-month follow-up angiography showed complete inhibition of neointimal hyperplasia inside the stent. One-year follow-up angiography revealed some neointimal hyperplasia inside the stent compared with the six-month follow-up angiography, but revealed inhibition of restenosis after everolimus-eluting stent implantation at the proximal LCX lesion (Figures 5 and 6). Discussion A recent study4 involving a small number of patients showed that sirolimus-eluting stents with biostable polymer coating were effective in treating ISR, but the efficacy of sirolimus-eluting stents has not yet been established for the treatment of ISR, especially for diffuse ISR lesions.⁵ Everolimus is a novel, semi-synthetic macrolide with immunosuppressive, antifungal, and antiproliferative properties. It has been shown to have similar immunosuppressive and toxicological profiles when compared with sirolimus.⁹ The mechanism of action of everolimus at the cellular and molecular levels may be similar to sirolimus. We have previously shown effective inhibition of neointimal hyperplasia in a pig coronary overstretch model after implantation of both low-dose and high-dose everolimus-eluting stents featuring a bioresorbable polymer coating to carry the drug.⁶ Histopathological analysis of stent cross-sections revealed that all everolimus-eluting stents had complete reendothelialization at thirty days. A first-in-man trial — the First Use To Underscore REduction in restenosis with everolimus (FUTURE) trial — compared the safety and efficacy of everolimus-sluting stents featuring a bioresorbable PLA coating to release the agent versus bare metal stents.⁷ In this study, there were no major adverse cardiac events (MACE), thirty-day and six-month angiographic follow-up showed no in-stent restenosis, and quantitative coronary angiography revealed a late loss of 0.17 mm. Everolimus-eluting stents in de novo lesions have been shown at six-month follow-up to be safe and effective in preventing restenosis. Following this clinical trial result, we decided to use an everolimus-eluting stent to treat this malignant ISR lesion case as a compassionate use of the device, since past procedures had failed to prevent recurrence of restenosis in the patient. This ISR lesion was located in the proximal LCX. To deliver the device, the stent had to cross through the stent strut of the BX Velocity stent located in the left main artery. This required superior flexibility, especially since we were using the 6 Fr transradial approach. The platform of the everolimus-eluting stent was the S-Stent (Biosensors International) — a highly flexible, deliverable, corrugated ring stent that is laser-cut from a stainless steel tube. Each corrugated ring has a total of six serially connected, S-shaped segments. Successive rings in the stent are connected by two short flexible links, with successive pairs of these links oriented in 90º quadrature around the circumference of successive rings (Quadrature Links™). The links increase the longitudinal flexibility and the deliverablity of the stent, while maintaining high hoop strength. We successfully delivered the device through the stent strut, which suggests the superior deliverability of the device. At one-year clinical and angiographic follow-up, this device proved to be safe and effective in preventing restenosis in this recurrent ISR lesion. Further follow-up will be necessary to confirm the long-term safety and efficacy of the device, and larger studies are warranted and planned to confirm this early finding.

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