Selected-Summaries - In-Stent Restenosis Treated With Stent-Based Delivery of Paclitaxel Incorporated in a Slow-Release Polymer Formulation, IHJ Jan-Feb 2003, Vol 55, No. 1

In-Stent Restenosis Treated With Stent-Based Delivery of Paclitaxel Incorporated in a Slow-Release Polymer Formulation

K Tanabe et al. TAXUS III Trial Investigators. Circulation 2003; 107: 559–564

Summary

The TAXUS III trial was a single-arm, 2-center study evaluating the feasibility and safety of a paclitaxel-eluting stent for the treatment of in-stent restenosis (ISR). It enrolled 28 patients with ISR with a lesion length of <30 mm, 50%–99% diameter stenosis in vessels with a diameter between 3 and 3.5 mm. Patients with acute myocardial infarction, poor ejection fraction (<30%), recent stroke, renal dysfunction, or contraindication to antithrombotics were excluded from the present study. The stent used was TAXUS NIRx paclitaxel-eluting stent (Boston Scientific Corporation, USA), with a total load of 1.0 µg/mm² of paclitaxel incorporated into a slow-release copolymer carrier system that gives biphasic release an early burst over the first 48 hours followed by slow release over the next 10 days. Predilatation was performed in all cases, and postdilatation was performed when necessary. All the stents were 15 mm long and 3–3.5 mm in diameter. During the procedure, ACT was kept at > 250 s, and standard antiplatelet regimen was followed post-procedure. Angiographic and intravascular ultrasonographic (IVUS) follow-up was performed at 6 months, and clinical followup at 6 months and 1 year. There were clinical, angiographic, and IVUS-based end-points. Angiographic follow-up was available in 25 patients, and IVUS follow-up in 17. The major adverse cardiac event (MACE) rate was 29% (8 patients; 1 non-Q-wave myocardial infarction, 1 coronary artery bypass grafting, and 6 target lesion revascularization [TLR]). Two patients underwent revascularization for restenosis in the gap between 2 paclitaxel-eluting stents, 1 for restenosis for a bare stent implanted at edge dissection, 1 for anginal symptoms but no restenosis (diameter stenosis of 32.5%), and in 2 patients not for restenosis but for incomplete stent apposition/ expansion as detected on IVUS study. One patient had target vessel occlusion but required no intervention as there were no symptoms. Binary angiographic restenosis occurred in 4 patients (16%). One patient had restenosis of a bare stent implanted to cover edge dissection due to implantation of a paclitaxel-coated stent, and 2 patients had restenosis in the gap between 2 paclitaxel-eluting stents. Thus, of the 4 restenoses, only 1 occurred in the area of paclitaxel delivery. The diameter stenosis at follow-up was 30.8%, with an average in-stent late loss of 0.54 mm. Late loss at the proximal and distal edges was 0.20 and 0.11 mm, respectively, Of 17 patients undergoing IVUS, the volume of neointimal hyperplasia was 20.3±23.1 mm³. There was no evidence of positive or negative remodeling in the 6 patients undergoing TLR. Thus, paclitaxel-eluting stent implantation appears to be safe and potentially effective in the treatment of ISR.

Comments

In the current era, use of stents has improved the safety and success of percutaneous-coronary interventions (PCI) and even reduced the restenosis rate (BENESTENT and STRESS trials). However, their use has also brought about the complex and difficult-to-manage problem of ISR and repeat TLR. Several pharmacologic and mechanical approaches have been tried to overcome the problem of ISR but they have limitations. Plain balloon angioplasty for ISR leads to a re-restenosis rate of 30%–85%, depending on whether it is a focal restenosis or diffuse ISR. Similarly, directional coronary atherectomy (re-restenosis rate 60%), and excimer laser (TLR 41%) have not been of much benefit. Rotablation and the use of cutting balloon may have some theoretical advantage but large studies to prove their efficacy are not available. Only radiation therapy has been found to be consistently useful till date. A number of double-blind clinical trials using gamma sources (SCRIPPS, WRIST, GAMMA-1) and a beta source (START, INHIBIT) have reported a striking efficacy in preventing re-restenosis in patients with established ISR (17%–34%). A major problem with brachytherapy, however, has been late stent thrombosis and late restenosis. Implantation of a new stent in the irradiated segment and withdrawal of clopidogrel/ticlopidine have been correlated with late thrombosis. Preliminary evidence from trials using prolonged antiplatelet regimens (>3 months) have suggested a marked reduction in this complication. Another major problem with brachytherapy is the edge effect. Careful analysis has suggested that these edge effects may represent a "geographic miss" of radiation and this problem can be substantially ameliorated with careful attention to registering adequate doses of radiation throughout the instrumented segment of the coronary artery. Furthermore, brachytherapy is less accessible, and its delivery requires special handling. In this context, stentbased local drug delivery have revolutionized the field of PCI. Smith et al. reported use of sirolimus-eluting stents in 15 patients with ISR; at 4 months, MACE occurred in 6.7% (1/15) cases. One patient died suddenly, and late occlusion occurred in another. In-stent late loss was 0.02 mm, and on IVUS, neointimal hyperplasia was 7.8±0.03 mm². In the present study using paclitaxel-coated stents, although the technical re-restenosis rate is 16%, actual restenosis occurred in only 1 patient. Similarly, the occurrence of late loss (0.54 mm) and neointimal hyperplasia (20.3 mm²) was low. However, these studies are too small and do not have a placebo arm. Nevertheless, it does seem that drug-eluting stents may be of use in the therapy of ISR.