内容概述： 介入心脏病学领域最显著的进步是药物洗脱支架（DES）的问世，但DES减少再狭窄率的最初优势，受到晚期支架血栓和TLR 率晚期追赶现象的困扰。药物洗脱球囊（DEB）技术基本上属于球囊成形术的升级，输送药物抑制细胞生长减少新内膜增生，减少支架相关的问题。这项技术的发展刚刚起步，相关研究试图完善器械和规定其应用范围，有许多问题需要研究，例如，最好的洗脱药物、理想剂量、载体基质等。本文通过回顾最新文献，阐述DEB 在支架内再狭窄和小血管病变中的应用，并论及在分叉病变、特定情况下如糖尿病患者和与BMS 联用等的研究数据。

    Introduction

    One of the most significant disruptive technologies in the era of interventional cardiology was the introduction of drug eluting stents (DES). The initial promise of DES in reducing re-stenosis rate was tampered by concerns of late stent thrombosis and late 'catch-up' phenomenon in TLR rates.

    The drug eluting balloon (DEB) technology basically used an upgraded version of the old angioplasty balloon that allowed delivery of cytostatic drug to reduce neo-intimal hyperplasia and doing away with issues related to stents.

    This technology is still in its infancy. Active research are ongoing to try to refine the device and define its application. There are still many issues that need to be learnt eg. what is the best drug ,optimal dosage, carrier matrix to use, etc.

    There are many DEB systems available today (For examples, see table ):   

    Each of these individual system needs to prove its worth. This manuscript describes the available literature supporting the use of DEB in coronary circulation. The main indications for DEB are for in-stent restenosis and small vessel disease. Application of DEB for bifurcation disease and specific clinical conditions eg. diabetes mellitus and use in conjunction with stents will also be discussed.

    In-stent restenosis

    One of the strongest indication for DEB is for in-stent restenosis. The first clinical data to suggest benefit was the Paccocath study. Paclitaxel-based DEB therapy significantly reduced insegment late lumen loss [(0.03±0.48)mm vs. (0.74±0.86) mm; P= 0.002] and binary restenosis(5% vs. 43%; P =0.002) when compared to uncoated balloon therapy.

    Combining data from Paccocath I & II studies, the benefits of reduced insegment late loss was shown to be sustained up to 2 years.

    Direct comparison between TAXUS stent(DES) and the paclitaxel-eluting Sequent Please balloon for the treatment of bare metal stent(BMS) in-stent restenosis was investigated in the PEPCAD-II trial. DEB clearly trumped DES in its ability to reduce in-segment late-loss [(0.17±0.42) mm vs. (0.38±0.61)mm;P=0.03] and binary restenosis (7.0% vs. 20.3%; P=0.04).

    Newer DEB platforms were also fairly consistent in its efficacy for the treatment of both BMS or DES –related ISR.

    For example, PEPPER Registry of the Panthera Lux^TM DEB announced its first 45 patients results at TCT 2010 demonstrating significant benefit in angiographic and clinical outcomes. The VALENTINES trial, investigating the DIOR-II DEB system, was announced at CRT 2011. This international multi-centre registry showed effective treatment of ISR with single-digit TLR-rate at 8 months. As the DEB platforms are being further refined, a lower dosed MOXY^TM (Lutonix) paclitaxel-eluting balloon (2μg/mm²) showed similar efficacy with the other higher dosed DEBs (eg. Paccocath and Sequent Please systems- 3μg/mm²) in reducing in-segment late-loss in the PERVIDEO-I Registry.

    Such consistent and impressive results with DEB had led to the recommendation of the 2010 Guidelines on myocardial revascularization from The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) –ie. the consideration of DEB for the treatment of bare-metal in-stent restenosis with a grade IIa recommendation and B level of clinical evidence.

    Small vessel coronary disease

    Suggestion of the benefit of DEB for treatment of small vessel disease was seen in the Spanish Registry of DIOR (paclitaxel-eluting) balloon.

    DEB treatment of vessels with a mean reference diameter of (1.9±0.3) mm had only (0.27±0.07)mm in-segment late loss and corresponding 13.3% binary restenosis rate.

    The PEPCAD-I data investigating effects of the Sequent Please DEB balloon in vessels ≤ 2.8mm were similarly impressive with DEB-alone strategy . However, in the event that a bare-metal stent had to be implanted as a bail-out strategy eg. for flow-limiting dissection,the outcome was significantly compromised.The late-loss in a DEB+BMS treatment strategy was 0.73mm, much higher than 0.18mm when only DEB treatment was applied.

    Subsequent analysis of this cohort showed geographic mis-match as probable explanation – seen in 10 out of the 13 cases of restenosis at 6 months. Geographic mis-match occured when the implanted stent was placed beyond the previously DEB pre-treated segment.

    The Piccoleto trial (EuroPCR 2009) from Italy showed contradicting results. Utilising the 1st. generation DIOR balloon in the treatment of small vessels (about 2.5mm), it failed to show equivalence to TAXUS stent with higher restenosis rates and trend toward higher TLR at 9 months. However, there were indications that the poor DEB result could be due to suboptimal techniques eg. lack of use of pre-dilation in the DEB cohort, lower balloon inflation pressures, etc.

    This trial raised the point that different DEB designs might have different efficacy. The first generation DIOR balloon
had paclitaxel coated on the balloon without a carrier matrix whereas the second generation DIOR balloon used shellac as its carrier. This carrier determined important issues eg. drug load, stability, retention during transit to lesion and transfer efficiency to the vessel wall.

    In summary, DEB could be useful for the treatment of small vessel disease especially as a stand-alone strategy. However, there might be a price to pay in terms of late-lumen loss and TLR when we need to perform bail-out stenting.

    This might be mitigated with attention paid to technical details eg. avoiding geographic mis-match, adequate predilatation, use of adequate balloon pressures and selection of proven DEB platforms.

    Bifurcation intervention

    The Sequent Please DEB use in coronary bifurcations was studied in the PEPCAD V study. Following DEB pre-treatment in both main and side branches, the main vessel was stented with a Coroflex BMS and a provisional BMS strategy in the side-branch. Fairly impressive late loss figures were seen both in the main and side branch (0.38mm and 0.21mm respectively).These were almost DES-like and TLR was only seen in 1 of the 28 patients. However, there was safety concern with 2 reported cases (7.1%) of late stent thrombosis in the main branch.

    The DEBIUT (Drug Eluting Balloon in bifurcation Trial) tested the DIOR balloon. This trial failed to achieve its primary
endpoints of defined improvements in late lumen loss for both main and side branches owing to unexpectedly good results in the BMS + uncoated POBA arm which was used as the comparator with the BMS + DEB arm. However, strong trends showing favourable outcome of BMS + DEB in the main branch and DEB in the side branch with regards to late loss and binary restenosis rates was seen.

    DEB use in diabetic patients

    The PEPCAD IV Asian multi-centre study compared the Sequent Please DEB + Cobalt Chromium BMS strategy with TAXUS DES device in the treatment of diabetics. The angiographic 9 months late loss and major adverse cardiovascular events (MACE) were no different between either strategy. There were 2 possible late stent thrombosis in the DEB arm.

    BMS premounted on DEB strategy

    In a comparison of BMS pre-mounted on a DEB –(Coroflex Blue platform) with Sirolimus coated Cypher stent (PEPCAD III trial), the intended non-inferiority criteria was not met. The former strategy was inferior in efficacy with greater late lumen loss, restenosis and TLR rates. There was once again a hint of harm with higher stent thrombosis rate in the BMS +
DEB arm (2.0 % vs. 0.3%).

    DEB + endothelial progenitor cell (EPC) capture stent (Genous® stent)

    It appeared that combining DEB with a BMS might not be a good option when compared to DEB alone strategy as the late lumen loss tended to be higher (eg. In PEPCAD I, III and V, and DEBIUT trials). In addition, there were concerns with late stent thrombosis as seen in PEPCAD III, IV and V.

    In view of these concerns, combination of DEB with an EPC-capture stent was studied in 2 trials – PERFECT trial (TCT
2010) and POTENT registry (EuroPCR 2010).
 
    The former study showed improved late loss and TLR (4.8%) rates compared to EPC capture stent alone. The latter registry showed comparable MACE (6%) and TLR rates (4%).Both these studies showed no concern of increased stent thrombosis rates.

    The on-going REMEDEE trial utilizing the GENOUS stent platform with EPC-capture antibody coating in the luminal stent aspect and Sirolimus elution in the abluminal aspect result is highly anticipated.

    Summary

    It is very clear from the available and rapidly evolving clinical data that DEB technology is here to stay. It will complement current percutaneous intervention strategies. The most established roles of DEB are in the management of in-stent restenosis and small vessel disease.

    Most of the evidence supporting DEB use comes from rather small studies and registries. As the technology evolves and
various clinical trial programs are completed, the indications for DEB use will be further refined and consolidated.（Gim-Hooi Choo 马来西亚国家心脏研究院）

    文章来源：《医心评论》