BACKGROUND Early thrombus removal might prevent post-thrombotic syndrome by preserving venous function and restoring flow. Previous trials comparing additional catheter-directed thrombolysis to standard treatment showed conflicting outcomes. We aimed to assess the benefit of additional ultrasound-accelerated catheter-directed thrombolysis for the prevention of post-thrombotic syndrome compared with standard therapy in patients with iliofemoral deep-vein thrombosis. METHODS We did a multicentre, randomised, single-blind, allocation-concealed, parallel group, superiority trial in 15 hospitals in the Netherlands. Patients aged 18-85 years with a first-time acute iliofemoral deep-vein thrombosis and symptoms for no more than 14 days were randomly assigned (1:1) to either standard treatment with additional ultrasound-accelerated catheter-directed thrombolysis or standard treatment alone. Randomisation was done with a web-based automatic programme and a random varying block size (2-12), stratified by age and centre. Standard treatment included anticoagulant therapy, compression therapy (knee-high elastic compression stockings; 30-40 mmHg), and early ambulation. Additional ultrasound-accelerated catheter-directed thrombolysis was done with urokinase with a starting bolus of 250 000 international units (IU) in 10 mL NaCl followed by a continuous dose of 100 000 IU/h for a maximum of 96 h through the Ekos Endowave-system. Adjunctive percutaneous transluminal angioplasty, thrombosuction, or stenting was performed at the discretion of the physician who performed the intervention. The primary outcome was the proportion of patients with post-thrombotic syndrome at 12 months diagnosed according to the original Villalta criteria-a Villalta-score of at least 5 on two consecutive occasions at least 3 months apart or the occurrence of venous ulceration-and was assessed in a modified intention-to-treat population of all randomly assigned patients who passed screening and started treatment. The safety analysis was assessed in the same modified intention-to-treat population. This study is complete and is registered at ClinicalTrials.gov, NCT00970619. FINDINGS Between May 28, 2010, and Sept 18, 2017, 184 patients were randomly assigned to either additional ultrasound-accelerated catheter-directed thrombolysis (n=91) or standard treatment alone (n=93). Exclusion because of screening failure or early withdrawal of informed consent resulted in 77 patients in the intervention group and 75 in the standard treatment group starting allocated treatment. Median follow-up was 12·0 months (IQR 6·0-12·0). 12-month post-thrombotic syndrome occurred in 22 (29%) patients allocated to additional treatment versus 26 (35%) patients receiving standard treatment alone (odds ratio 0·75 [95% CI 0·38 to 1·50]; p=0·42). Major bleeding occurred in four (5%) patients in the intervention group, with associated neuropraxia or the peroneal nerve in one patient, and no events in the standard treatment group. No serious adverse events occurred. None of the four deaths (one [1%] in the intervention group vs three [4%] in the standard treatment group) were treatment related. INTERPRETATION This study showed that additional ultrasound-accelerated catheter-directed thrombolysis does not change the risk of post-thrombotic syndrome 1 year after acute iliofemoral deep-vein thrombosis compared with standard therapy alone. Although this trial is inconclusive, the outcome suggests the possibility of a moderate beneficial effect with additional ultrasound-accelerated catheter-directed thrombolysis. Further research is therefore warranted to better understand this outcome in the context of previous trials, preferably by combining the available evidence in an individual patient data meta-analysis. FUNDING The Netherlands Organisation for Health Research and Development (ZonMw), Maastricht University Medical Centre, BTG-Interventional Medicine.

中文翻译：

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超声加速导管定向溶栓与抗凝治疗预防血栓后综合症（CAVA）：一项单盲，多中心，随机试验。

背景技术早期的血栓清除可能会通过保留静脉功能和恢复血流来预防血栓形成后综合症。以前的试验比较了其他导管定向溶栓治疗与标准治疗的比较，结果相矛盾。我们的目的是评估与standard股深静脉血栓形成患者相比，采用超声加速导管定向溶栓治疗与标准治疗相比，预防血栓形成后综合征的益处。方法我们在荷兰的15家医院中进行了一项多中心，随机，单盲，隐藏分配，平行分组的优势试验。首次随机分配年龄在18-85岁之间的首次急性股深静脉血栓形成和症状不超过14天的患者（1：1）接受额外的超声加速导管定向溶栓治疗的标准治疗，或单独进行标准治疗。随机分组是通过基于网络的自动程序和按年龄和中心分层的随机变化的块大小（2-12）完成的。标准治疗包括抗凝治疗，加压疗法（膝盖高弹性加压袜； 30-40 mmHg）和早期下床活动。通过尿激酶进行超声辅助的导管定向溶栓，开始时在10 mL NaCl中推注250 000国际单位（IU），然后通过Ekos Endowave-连续剂量100 000 IU / h最多96 h。系统。经介入的内科医生酌情进行了经皮经皮腔内血管成形术，血栓抽吸或支架置入术。主要结局是根据最初的Villalta标准诊断为12个月时血栓后综合症患者的比例-连续两次至少间隔3个月或发生静脉溃疡的Villalta评分至少为5。在经过筛选并开始治疗的所有随机分配患者的改良意向治疗人群中进行评估。在相同的经过改良的意向性治疗人群中评估了安全性分析。该研究已经完成，并已在ClinicalTrials.gov上注册，NCT00970619。结果在2010年5月28日至2017年9月18日之间，将184例患者随机分配至其他超声加速导管定向溶栓治疗（n = 91）或单独进行标准治疗（n = 93）。由于筛查失败或早日撤回知情同意书而被排除在外，导致干预组77例患者和标准治疗组75例开始分配治疗。中位随访时间为12·0个月（IQR 6·0-12·0）。接受额外治疗的22名患者（29％）发生了12个月的血栓形成后综合征，而仅接受标准治疗的26名患者（35％）发生了（赔率0·75 [95％CI 0·38至1·50]； = 0·42）。干预组中有四名（5％）患者发生了大出血，其中一名患者伴有神经性神经萎缩或腓神经，在标准治疗组中未发生任何事件。没有发生严重的不良事件。4例死亡（干预组1例，标准治疗组3例[4％]）均与治疗无关。解释这项研究表明，与单独的标准疗法相比，急性股深静脉血栓形成后1年，额外的超声加速导管定向溶栓治疗不会改变血栓形成后综合征的风险。尽管该试验尚无定论，但结果提示，超声辅助导管定向溶栓治疗可能产生中度有益作用。因此，有必要进行进一步的研究以更好地了解先前试验中的结果，最好是将可用证据结合到单个患者数据的荟萃分析中。资金荷兰卫生研究与发展组织（ZonMw），马斯特里赫特大学医学中心，BTG-介入医学。