Kayssi Ahmed, Al-Jundi Wissam, Papia Giuseppe, Kucey Daryl S, Forbes Thomas, Rajan Dheeraj K, Neville Richard, Dueck Andrew D
Division of Vascular Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Room H287, 2075 Bayview Avenue, Toronto, ON, Canada, M4N 3M5.
Cochrane Database Syst Rev. 2019 Jan 26;1(1):CD012510. doi: 10.1002/14651858.CD012510.pub2.
Stents are placed in the femoropopliteal arteries for numerous reasons, such as atherosclerotic disease, the need for dissection, and perforation of the arteries, and can become stenosed with the passage of time. When a stent develops a flow-limiting stenosis, this process is known as "in-stent stenosis." It is thought that in-stent restenosis is caused by a process known as "intimal hyperplasia" rather than by the progression of atherosclerotic disease. Management of in-stent restenosis may include performing balloon angioplasty, deploying another stent within the stenosed stent to force it open, and creating a bypass to deliver blood around the stent. The role of drug-eluting technologies, such as drug-eluting balloons (DEBs), in the management of in-stent restenosis is unclear. Drug-eluting balloons might function by coating the inside of stenosed stents with cytotoxic chemicals such as paclitaxel and by inhibiting the hyperplastic processes responsible for in-stent restenosis. It is important to perform this systematic review to evaluate the efficacy of DEB because of the potential for increased expenses associated with DEBs over uncoated balloon angioplasty, also known as plain old balloon angioplasty (POBA).
To assess the safety and efficacy of DEBs compared with uncoated balloon angioplasty in people with in-stent restenosis of the femoropopliteal arteries as assessed by criteria such as amputation-free survival, vessel patency, target lesion revascularization, binary restenosis rate, and death. We define "in-stent restenosis" as 50% or greater narrowing of a previously stented vessel by duplex ultrasound or angiography.
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to November 28, 2017. Review authors also undertook reference checking to identify additional studies.
We included all randomized controlled trials that compared DEBs versus uncoated balloon angioplasty for treatment of in-stent restenosis in the femoropopliteal arteries.
Two review authors (AK, WA) independently selected appropriate trials and performed data extraction, assessment of trial quality, and data analysis. The senior review author (AD) adjudicated any disagreements.
Three trials that randomized a combined total of 263 participants met the review inclusion criteria. All three trials examined the treatment of symptomatic in-stent restenosis within the femoropopliteal arteries. These trials were carried out in Germany and Austria and used paclitaxel as the agent in the drug-eluting balloons. Two of the three trials were industry sponsored. Two companies manufactured the drug-eluting balloons (Eurocor, Bonn, Germany; Medtronic, Fridley, Minnesota, USA). The trials examined both anatomical and clinical endpoints. We noted heterogeneity in the frequency of bailout stenting deployment between studies as well as in the dosage of paclitaxel applied by the DEBs. Using GRADE assessment criteria, we determined that the certainty of evidence presented was very low for the outcomes of amputation, target lesion revascularization, binary restenosis, death, and improvement of one or more Rutherford categories. Most participants were followed up to 12 months, but one trial followed participants for up to 24 months.Trial results show no difference in the incidence of amputation between DEBs and uncoated balloon angioplasty. DEBs showed better outcomes for up to 24 months for target lesion revascularization (odds ratio (OR) 0.05, 95% confidence Interval (CI) 0.00 to 0.92 at six months; OR 0.24, 95% CI 0.08 to 0.70 at 24 months) and at six and 12 months for binary restenosis (OR 0.28, 95% CI 0.14 to 0.56 at six months; OR 0.34, 95% CI 0.15 to 0.76 at 12 months). Participants treated with DEBs also showed improvement of one or more Rutherford categories at six and 12 months (OR 1.81, 95% CI 1.02 to 3.21 at six months; OR 2.08, 95% CI 1.13 to 3.83 at 12 months). Data show no clear differences in death between DEBs and uncoated balloon angioplasty. Data were insufficient for subgroup or sensitivity analyses to be conducted.
AUTHORS' CONCLUSIONS: Based on a meta-analysis of three trials with 263 participants, evidence suggests an advantage for DEBs compared with uncoated balloon angioplasty for anatomical endpoints such as target lesion revascularization (TLR) and binary restenosis, and for one clinical endpoint - improvement in Rutherford category post intervention for up to 24 months. However, the certainty of evidence for all these outcomes is very low due to the small number of included studies and participants and the high risk of bias in study design. Adequately powered and carefully constructed randomized controlled trials are needed to adequately investigate the role of drug-eluting technologies in the management of in-stent restenosis.
在股腘动脉置入支架的原因众多，如动脉粥样硬化疾病、动脉夹层及穿孔等，且随着时间推移支架可能会出现狭窄。当支架出现限流性狭窄时，这一过程被称为“支架内狭窄”。一般认为，支架内再狭窄是由“内膜增生”过程引起，而非动脉粥样硬化疾病的进展所致。支架内再狭窄的治疗方法可能包括进行球囊血管成形术、在狭窄支架内再置入一个支架以撑开它，以及创建旁路以绕过支架输送血液。药物洗脱技术，如药物洗脱球囊（DEB），在支架内再狭窄治疗中的作用尚不清楚。药物洗脱球囊可能通过用细胞毒性化学物质（如紫杉醇）覆盖狭窄支架内部，并抑制导致支架内再狭窄的增生过程来发挥作用。由于与未涂层球囊血管成形术（也称为普通老式球囊血管成形术，即POBA）相比，DEB可能会增加费用，因此进行这项系统评价以评估DEB的疗效很重要。
通过无截肢生存、血管通畅、靶病变血运重建、二元再狭窄率和死亡等标准，评估药物洗脱球囊与未涂层球囊血管成形术相比，在股腘动脉支架内再狭窄患者中的安全性和疗效。我们将“支架内再狭窄”定义为经双功超声或血管造影显示，先前置入支架的血管狭窄50%或更严重。
Cochrane血管信息专家检索了Cochrane血管专业注册库、CENTRAL、MEDLINE、Embase、CINAHL数据库以及世界卫生组织国际临床试验注册平台和ClinicalTrials.gov试验注册库，检索截至2017年11月28日的数据。综述作者还进行了参考文献核对以识别其他研究。
我们纳入了所有比较药物洗脱球囊与未涂层球囊血管成形术治疗股腘动脉支架内再狭窄的随机对照试验。
两位综述作者（AK、WA）独立选择合适的试验，并进行数据提取、试验质量评估和数据分析。资深综述作者（AD）裁决任何分歧。
三项共纳入263名参与者的随机试验符合综述纳入标准。所有三项试验均研究了股腘动脉有症状支架内再狭窄的治疗。这些试验在德国和奥地利进行，药物洗脱球囊中使用的药物为紫杉醇。三项试验中有两项由行业赞助。两家公司生产了药物洗脱球囊（德国波恩的Eurocor公司；美国明尼苏达州弗里德利的美敦力公司）。试验同时考察了解剖学和临床终点。我们注意到各研究间补救性支架置入的频率以及药物洗脱球囊应用的紫杉醇剂量存在异质性。使用GRADE评估标准，我们确定，对于截肢、靶病变血运重建、二元再狭窄、死亡以及一个或多个卢瑟福分级改善等结果，所呈现证据的确定性非常低。大多数参与者随访至1年，但有一项试验对参与者随访长达2年。试验结果显示，药物洗脱球囊组与未涂层球囊血管成形术组在截肢发生率上无差异。在长达24个月的时间里，药物洗脱球囊在靶病变血运重建方面显示出更好的结果（6个月时比值比（OR）为0.05，95%置信区间（CI）为0.00至0.92；24个月时OR为0.24，95%CI为0.08至0.70），在6个月和12个月时二元再狭窄方面也有更好结果（6个月时OR为0.28，95%CI为0.14至0.56；12个月时OR为0.34，95%CI为0.15至0.76）。接受药物洗脱球囊治疗的参与者在6个月和12个月时，一个或多个卢瑟福分级也有改善（6个月时OR为1.81，95%CI为1.02至3.21；12个月时OR为2.08，95%CI为1.13至3.83）。数据显示药物洗脱球囊组与未涂层球囊血管成形术组在死亡方面无明显差异。数据不足以进行亚组分析或敏感性分析。
基于对三项共263名参与者的试验进行的荟萃分析，有证据表明，与未涂层球囊血管成形术相比，药物洗脱球囊在解剖学终点（如靶病变血运重建（TLR）和二元再狭窄）以及一个临床终点（干预后长达24个月的卢瑟福分级改善）方面具有优势。然而，由于纳入研究和参与者数量较少以及研究设计中存在高偏倚风险，所有这些结果的证据确定性都非常低。需要进行足够样本量且精心设计的随机对照试验，以充分研究药物洗脱技术在支架内再狭窄治疗中的作用。
