推荐收藏 | 高位结扎+激光消融+泡沫硬化联合加压与单纯加压治疗下肢静脉性溃疡的效果比较:一项回顾性队列研究 / 四六文摘

Scientific Reports

(2019) 9:14021

高位结扎+激光消融+泡沫硬化联合加压与单纯加压治疗下肢静脉性溃疡的效果比较:一项回顾性队列研究

刘小春*，郑国富，叶波，陈伟清，谢海亮，张滕

【赣州人民医院(南昌大学附属赣州医院)江西省赣州市红旗大道17号血管疝外科；如需索取资料，请与通讯作者刘小春联系(邮箱:lxcmail8@163.com)】

摘要：

我们的目的是通过与单纯的压力治疗比较评估高结扎-静脉内激光消融-泡沫硬化疗法(HL-EVLA-FS)联合压力治疗(CT)治疗下肢静脉性溃疡愈合时间和复发率。我们对2013年至2017年我院行HL-EVLA-FS+压力治疗或单纯压力治疗的活动性VLUs患者350例进行回顾性队列研究。主要结果为溃疡愈合时间;次要结果为12个月的溃疡复发率、复发与静脉回流的关系以及两种治疗方式的并发症。总计193例(200条肢体)接受压力+ HL-EVLA-FS治疗, 157例(177条肢体)仅行压力治疗。HL-EVLA-FS+压力组溃疡愈合时间较单纯CT组短[溃疡愈合风险比(HR)1.845（95% CI, 1.474-2.309），P = 0.0001]。压力+ HL-EVLA-FS组12个月溃疡复发率明显降低[溃疡复发率HR, 0.418 (95% CI, 0.258-0.677)，P = 0.0001 ]。小腿穿支静脉回流(CPVR)和孤立浅表静脉回流(ISVR)是溃疡复发的危险因素。与单纯压力治疗相比，联合手术治疗的VLUs愈合更快，溃疡复发率更低，VCSS值更低。

文献编号：

https://doi.org/10.1038/s41598-019-50617-y

引言

下肢活动性静脉溃疡(active venous leg ulcers, VLUs)在下肢静脉功能不全的临床分期为最高级别C6级[1]，症状重，愈合慢，容易复发，患病率随年龄的增长而增长[2]；另外因病程长治疗费用巨大[3]，已被认为是危害公共健康的常见病之一。静脉返流造成的持续性浅静脉高压是VLUs的主要病理基础[4,5]。压力治疗[6,7]和包括各种手术（传统手术、超声引导下的泡沫硬化剂化学消融(ultrasound-guided foam sclerotherapy, UGFS)[8,9]、激光腔内闭合(endovenous laser ablation, EVLA)[10,11]和射频消融(Radiofrequency Ablation, RA)[12]等）在内的治疗方式对消除或降浅静脉高压促进溃疡愈合具有良好的效果。在手术和压力治疗对溃疡愈合和复发(ESCHAR)的影响研究中[13、14]，CT联合手术被认为有较低的溃疡复发率。然而，研究发现两组溃疡愈合时间没有差异。最近，另一项临床试验(EVRA ulcer trial)[3]得出结论，CT联合早期静脉内消融治疗可促进溃疡愈合，减少溃疡复发，延长患者干预后1年内无溃疡的时间。CT联合HL-EVLA-FS的目标是消除浅表静脉回流，治愈活动性VLUs，但鲜有报道。我们的目的是比较两种治疗方法：压力+HL-EVLA-FS和单纯压迫治疗在活动性VLUs患者的溃疡愈合时间和复发率。

病例和方法

本院医学伦理委员会批准同意收集病案资料用于临床回顾性队列研究。将2013年到2017年5年间就诊于我院主诊断为下肢活动性静脉溃疡（C6）患者纳入研究，采用连续入组的方式入组。

病例入选标准

1. 年龄≥18岁;

2. 下肢活动性静脉性溃疡;

3. 超声检查提示静脉回流;

4. 未接受过压力疗法的VLUs患者。

病例排除标准

1. 其他原因引起的腿部溃疡，如动脉性溃疡、糖尿病性溃疡、营养不良性溃疡、恶性溃疡，踝肱指数< 0.8;

2. 愈合期溃疡(C5);

3. 静脉曲张手术史;

4. 曲张静脉直径≥1cm;

5. 严重系统性疾病;

6. 不能忍受压迫疗法的病人;

7. 选择其他治疗方法的VLUs患者。

符合条件的患者的个人资料和临床资料，包括性别、年龄、体重指数(BMI)、糖尿病史、吸烟史、静脉曲张病程、溃疡部位、溃疡持续时间、溃疡直径、静脉返流情况、术前VCSS (静脉临床严重程度评分) [16]等记录在基线特征表内。

方法

治疗方式的选择 根据病案中知情同意书提供的信息，治疗方式的选择是根据经治医生的建议和患者的意愿进行的。选择的治疗方式包括：复合手术联合压力治疗和单独压力治疗。

符合纳入标准的患者被充分告知两种治疗方式，并书面同意接受何种治疗。

静脉返流定义 大/小隐静脉和穿通静脉的返流时间>500ms，股静脉和腘静脉的返流时间>1s定义为异常静脉返流[17]。

根据回流部位的不同，将静脉回流分为孤立性浅表静脉回流(ISVR)、浅表静脉回流(SVR)、节段性深静脉回流(SDVR)、全长深静脉回流(FLDVR)和小腿穿支静脉回流(CPVR)[4,18]。

治疗方法

高位结扎-激光腔内消融（HL-EVLA.）

所有的静脉曲张在术前都做了标记。高结扎在隐股静脉汇合处[19]进行。在内踝处穿刺GSV主干，将激光纤维插入GSV主干。使用810nm激光仪器(AngioDynamics, Germany) 1次/秒的脉冲来关闭大隐静脉主干。对那些无法顺行置入导丝,比如那些与穿刺点局部感染或静脉狭窄,我们选择从腹股沟切口向下逆行插入导丝或分段使用激光烧灼GSV。对位于外踝的溃疡患者行小隐静脉的HL-EVLA。所有手术均在硬膜外或全身麻醉下进行。

泡沫硬化疗法（FS.）

对小腿曲张浅静脉作多点穿刺，非超声引导下曲张静脉内分别注射聚桂醇注射液（陕西天宇制药有限公司：SHAANXI TIANYU PHARMACEUTICAL.LCO.,LTD.）泡沫硬化剂（1ml聚桂醇注射液+4ml CO2 配置成4ml泡沫硬化剂），每点注射泡沫硬化剂约4ml左右，每条肢体不超过10ml的聚桂醇注射液。

压力治疗（CT）

压力治疗由经治医生和接受过训练的护士或社区护理人员协助进行。

溃疡清理后，创面覆盖凡士林纱块。患肢以3-4层弹力绷带加压包扎，保证足踝部压力达40mmHg，向上压力逐渐递减。3天后改用二级医用长筒弹力袜。最初的两周内持续性压力治疗，2周后白天穿弹力袜活动，夜间休息时解除弹力压迫，但要抬高患肢。

随访

活动性溃疡的患者接受干预后每月在门诊接受随访，直到溃疡愈合，并留下了图片。如果临床需要，检查次数更多。干预后，患者分别在1个月、6个月和1年接受复查，复查的方式为体检，部分患者接受了超声检查。如果溃疡复发，病人会被邀请立即到医院复诊。随访的过程中某些患者可能改变了治疗方式如追加手术。

结果指标

主要指标：主要终点指标为溃疡愈合的时间。溃疡的愈合时间是指从接受干预开始后到溃疡愈合的时间。溃疡愈合是指腿部溃疡的完全再上皮化。溃疡愈合的评估贯穿于整个1年的随访期间，由护理团队和研究人员共同完成(至少每月一次)。

次要指标：干预后1个月、6个月和1年的VCSS的变化；1年溃疡的复发率及其与静脉返流的关系；两组治疗方式的并发症。溃疡复发的时间从干预后溃疡愈合后开始算起，因此，溃疡复发分析仅包括溃疡愈合的患者。溃疡复发是指在治愈的溃疡部位再次出现溃烂，表现为上皮不完整。

统计方法

使用IBM SPSS Statistics 22.0 软件对数据进行分析。两样本的连续型变量使用均数±标准差 (SD) 描述，独立样本的T 检验比较其差异；计数资料使用百分比描述和卡方检验比较；我们使用Kaplan-Meier寿命表、log-rank比较两组溃疡愈合和复发的时间。采用Cox回归分析计算两组干预对溃疡愈合时间和复发的风险因素。使用多因素Cox回归分析溃疡复发与静脉返流的关系，并使用log-rank对曲张静脉返流中溃疡复发的危险因素进行比较。p < .05为差异有统计学意义。

结果

患者的一般资料

总共有539名有慢性腿部溃疡患者被纳入研究。共排除189例患者(图.1)，其中42例为其他原因引起的腿部溃疡，56例溃疡愈合，28例有VVs手术史，14例有严重的全身性疾病，33例不能坚持CT, 16例选择其他治疗。符合资格的病例为350例。根据经治医生的建议和患者的意愿，根据患者或临床医生的偏好，193例患者(200条肢体)接受压迫+ HL-EVLA-FS治疗, 157例患者(177条肢体)仅接受压迫治疗。他们中的许多人来自农村。两组的基线特征相似(表1)。被认为是影响溃疡愈合的因素如患者的性别、年龄、BMI、静脉曲张病程、溃疡持续时间、溃疡直径、静脉返流情况、干预前VCSS在两组间没有差异。

图 1. 两组患者入选流程图

表1. 两组研究患者的基线特征表.

*independent-sample t-test, §Pearson Chi-Square. HL-EVLA-FS high ligation-endovenous laser ablation-foam sclerotherapy, BMI body mass index, ISVR isolated superfcial venous refux, SVR superfcial venous refux, SDVR segmental deep venous refux, FLDVR full-length deep venous refux, CPVR Calf perforator veins refux.

HL-EVLA分别应用于200例肢体的GSV和20例肢体的SSV。对200例肢体VVs进行N-UGFS注射聚桂醇泡沫硬化剂。聚桂醇溶液平均(9.5±1.0)ml/条肢体。两组患者均接受了早期的3天3-4层的弹力绷带的压力治疗，后期的弹力袜治疗。干预后1个月、6个月、12个月的失访肢体数，其中联合手术治疗组分别为2、3、5例，压力治疗组分别为2、3、3例；两组中愈合的溃疡在愈合后12个月分别有4和6条肢体失访。在愈合和复发率的生存分析中，18例和10例失访患者分别作为删失病例处理。另外接受单独压力治疗组中，由于患者认为效果不佳，随访到1个月、6个月时发现分别有3、7条肢体接受了复合手术治疗（为克服基线偏倚，这部分患者仍保留在单独压力治疗组分析）。在干预后的观察期12个月内，联合治疗组和单独压力治疗组分别有6和16条肢体仍然未愈合(表. 1)。

主要结果

干预12个月后，联合复合手术治疗组中，186条肢体溃疡愈合，愈合时间中位数为1.08月 (95% CI, 1.02-1.36)，单独压力治疗组中153条肢体溃疡愈合，愈合时间中位数为2.15月(95% CI, 1.92-2.45)。联合复合手术治疗组较单独压力治疗组的愈合时间明显偏短[溃疡愈合的风险比（HR）, 1.845（95% CI, 1.474-2.309）, P=0.0001](图. 2).通过校正了年龄、BMI、静脉曲张时间、溃疡持续时间、溃疡直径等因素后，结果是一致的，联合治疗组溃疡的愈合也是更快的[HR溃疡愈合的HR值, 1.938 (95% CI, 1.544-2.434), P=0.0001]。

图2. 两组腿部溃疡愈合情况的Kaplan-Meier曲线分析

图3. Kaplan-Meier分析两组愈合的小腿溃疡12个月内复发情况

图4. 以CPVR返流模式Kaplan-Meier法分析两组溃疡的复发风险

图5. 以ISVR返流模式Kaplan-Meier分析两组溃疡复发风险

Figure 2. (a) Kaplan-Meier analysis of ulcer healing for all legs. (b) Kaplan-Meier analysis of ulcer12-month recurrence for all healed legs. (c) Kaplan-Meier analysis of ulcer recurrence by the refux pattern of CPVR. (d) Kaplan-Meier analysis of ulcer recurrence by the refux pattern of ISVR.

次要结果

两组患者在随访1个月、6个月和1年的VCSS值均具有明显差异，复合治疗组具有更低的VCSS值(表 2)。

表2. 干预后1个月、6个月和12个月两组患者VCSS的变化

* independent-sample t-test

溃疡愈合后继续随访12个月，联合治疗组中溃疡复发肢体数（愈合肢体）为26(186)，而单独压力治疗组为45(153)，联合治疗组比单独压力治疗组具有明显低的溃疡复发率[溃疡愈合的HR值为0.418 (95% CI, 0.258-0.677),P=0.0001](图. 3).

将静脉返流模式纳入多因素Cox 回归分析，发现小腿穿静脉返流(HR for ulcer recurrence, 7.734 [95% CI, 1.513-39.532],P=0.014)和单独浅静脉返流(HR for ulcer recurrence, 4.070 [95% CI, 1.229-13.478],P=0.0022)是溃疡复发的危险因素（表 3）。使用Log-rank comparison分别对小腿穿静脉返流(图. 4)和单独浅静脉返流(图. 5)的危险因素在两组溃疡复发中的影响比较，结果P值均小于0.0001。

表3. 多因素COX回归分析与溃疡复发的静脉返流模式

recurrence.HR hazard ratio, CI confidence interval, ISVR isolated superficial venous reflux, SVR superficial venous reflux, SDVR segmental deep venous reflux, FLDVR full-length deep venous reflux, CPVR Calf perforator veins reflux

复合手术组的并发症中DVT发生2条（1.0 %），经抗凝治疗和压力治疗，血栓分别在3个月和半年消失；激光皮肤烧伤发生6条（3.0%），症状轻微，均于1周内痊愈；隐神经的损伤11条（5.5%），表现为小腿内侧皮肤发麻，3个月后症状不同程度缓解，半年症状消失；血栓性浅静脉炎发生15条（7.5%），经压力治疗、抬高患肢，外用多磺酸粘多糖乳膏，均在3个月内症状消失。压力治疗并发症发生最多的是皮肤对弹力袜接触的过敏反应，共发生35条肢体，发生率为9.3%，经抗过敏治疗均能好转。

讨论

通过回顾性病例对照分析发现复合手术联合压力治疗比单独的压力治疗对下肢活动性静脉性溃疡具有较短的溃疡愈合时间，较低的溃疡复发率和较好的干预后VCSS值改善。

下肢静脉性溃疡治疗的原理是通过各种方法消除或减少静脉返流，降低浅静脉高压，促进溃疡愈合。根据病变程度，为追求更好的治疗效果，不断出现了多种治疗方式的复合治疗模式[21]，如激光+硬化剂[23,24],高位结扎+硬化剂[25]，还有高位结扎+激光[26]。复合治疗方式可以发挥各自的优势，取长补短，达到最佳的效果，特别适用于严重的下肢静脉曲张的治疗[24,25,27]。但是使用HL-EVLA-FS复合治疗方式联合压力治疗下肢活动性静脉性溃疡却鲜见报道。

HL-EVLA-FS的综合方法治疗下肢静脉性溃疡是可行的，因为该方法符合下肢静脉曲张的治疗原理。首先通过大/小隐静脉及其属枝结扎，阻断了大隐静脉和属枝的返流；其次激光腔内闭合大/小隐静脉，就是阻断了大/小隐静脉本身；再次硬化剂栓塞曲张浅静脉，就是处理了犯罪血管，同时消灭了穿静脉返流的靶血管，缩小了穿静脉，甚至硬化剂直接作用于穿静脉的内皮细胞，造成了穿静脉的闭塞；最后续以压力治疗。所有这些均有助于消除静脉返流，降低浅静脉压力，促使溃疡愈合。曾有人使用多种方式消除下肢所有浅静脉返流，治疗下肢静脉性溃疡，取得了良好的效果[28]。

早期有临床研究（ESCHAR study）根据慢性静脉性溃疡肢体静脉返流特征进行随机分组，通过比较单独的压力治疗和压力治疗联合在全麻或者局麻下浅静脉的抽剥或者离断手术的治疗效果，认为联合手术治疗并不能加快溃疡的愈合，但可以减少溃疡的复发[13,14]。这与我们的结论有所不同，可能与干预的手术方式有关。但该临床研究得出静脉返流的模式如独立的浅静脉返流与静脉溃疡的复发有关。本文通过静脉返流模式的Cox回归分析，也发现溃疡的复发与穿静脉返流和独立的浅静脉返流有关。

近来，另一项临床试验（EVRA ulcer trial）比较早期和延迟的静脉内消融干预浅表静脉回流联合压力治疗慢性静脉溃疡，同时也与单独的压力治疗进行比较[15]。消融方式包括腔内激光或射频消融，超声引导下泡沫硬化治疗等，认为压力治疗与静脉内消融的复合治疗方式可以促进溃疡的愈合、降低溃疡的复发、延长了干预后1年内患者无溃疡生存时间。我们的临床回顾性分析与此结论相近。然而随访过程中VCSS值的变化两组没有差异。

下肢静脉性溃疡的压力治疗一般都是使用弹力绷带或者弹力袜。是选择弹力绷带还是弹力袜目前也没有定论[29]。有临床研究专门对弹力绷带和弹力袜在治疗腿部静脉性溃疡做了临床随机对照研究，表明在足踝处提供40mm Hg压力的双层袜子是四层压缩绷带的有效替代品。双层袜有额外的好处就是减少溃疡复发和降低成本。然而，与绷带组相比，袜子组参与者的治疗变化率更高，并不是所有的人都适合弹力袜[7]。弹力绷带必须是由经过专门训练的医师或者护士使用，才能达到合适的压力；另外患者活动后，弹力绷带往往容易移位，每2-3天需要从新调整。压力袜使用较为方便，由患者本人、家属协助或者社区护士协助既可完成。所有我们的选择是在溃疡的早期处理3天内使用弹力绷带，3天后包括出院在家均使用弹力袜。

另外我们泡沫硬化剂的注射过程中并没有使用超声或导管的引导，而是直接注入曲张的浅静脉，但也没有引起肺梗等严重的并发症。Bush等人[30]采用经皮穿刺的方法非超声引导下将泡沫硬化剂直接注射到溃疡周围的曲张浅静脉中去，闭合溃疡周围的曲张浅静脉及其周围可能的穿静脉，从而达到溃疡愈合的目的。在我们的早期手术过程中，发现注入浅表静脉的硬化剂可以通过离断的大隐静脉远侧端流出，我们认为这是由于这类患者深静脉的高压、穿静脉的返流导致注入浅静脉的硬化剂几乎都是通过大隐静脉向上回流进入深静脉系统；也在术中通过超声证实了这一点。所以大隐静脉高位结扎有助于防止泡沫硬化剂通过大隐静脉流入到深静脉，这有助于支持我们大隐静脉高位结扎的必要性和术中不用超声引导注射硬化剂的安全性。关于直接注射泡沫硬化剂的方式未来还需要有更大的样本量和更长时间的随访结果来验证。

虽然CT联合手术干预后溃疡愈合时间较短，溃疡复发率较低，但仍存在相应的并发症。下肢DVT 2例(1.0%);激光烧伤6例(3.0%);11例发生隐神经损伤(5.5%);15条肢体发生浅表静脉炎(7.5%)。CT常见并发症为袜子皮肤过敏35例(9.3%)。所有这些并发症都是通过相应的过程恢复的。我们还发现，小腿激光功率的降低可降低皮肤烧伤和隐神经损伤的比率[31]。CT的并发症是袜子的接触性皮肤过敏，可能与袜子的材质有关。

本研究存在一定的局限性。首先，这不是一个随机对照试验，因此容易产生偏见，这可能会削弱我们结论的说服力。第二，我们的治疗组中三种手术方式同时使用，虽然治疗方式上具有较好的统一性，但仍然存在过渡干预的嫌疑，如某些不必要闭合的浅静脉可能被闭合了。第三，我们使用的压力袜并没有规定同一的品牌，而是由患者自行购买（因为弹力袜不是医保报销范围内的）。第四, 随访时间短，需要更长时间的随访。

总之，在下肢活动性静脉性溃疡的治疗上，复合手术联合压力治疗与单独的压力治疗比较，前者能够缩短溃疡愈合时间。

Scientific Reports

(2019) 9:14021

Comparison of combined compression and surgery with high ligation-endovenous laser ablation-foam sclerotherapy with compression alone for active venous leg ulcers

Xiaochun Liu , Guofu Zheng, BoYe, WeiqingChen, HailiangXie & TengZhang

【Department of Vascular and Hernial Surgery, Ganzhou People’s Hospital (The Affiliated Ganzhou hospital of Nanchang University), No. 17, Red fag avenue, Ganzhou city, Jiangxi Province, 341000, PR China. Correspondence and requests for materials should be addressed to X.L. (email: lxcmail8@163.com)】

摘要：

We aimed to assess the ulcer healing time and recurrence rates after treatment with compression therapy (CT) with or without high ligation-endovenous laser ablation-foam sclerotherapy (HL-EVLA-FS) in people with active venous leg ulcers (VLUs). A retrospective cohort study was conducted with 350 patients with active VLUs treated by compression with or without HL-EVLA-FS in our hospital from 2013 to 2017. The primary outcome was the ulcer healing time; secondary outcomes were the 12-month recurrence rates, the relationship between recurrence and venous refux, and the complications of the two treatments. In total, 193 patients (200 limbs) underwent compression plus HL-EVLA-FS, and 157 patients (177 limbs) underwent CT alone. The ulcer healing time was shorter in the compression plus HL-EVLA-FS group than in the CT alone group (Hazard Ratio [HR] for ulcer healing, 1.845 [95% CI, 1.474–2.309], P=0.0001). The 12-month ulcer recurrence rates were signifcantly reduced in the compression plus HL-EVLA-FS group (HR for ulcer recurrence, 0.418 [95% CI, 0.258–0.677], P=0.0001). Calf perforator vein refux (CPVR) and isolated superfcial venous refux (ISVR) were risk factors for ulcer recurrence. The combined operation with CT resulted in faster healing of VLUs, a lower ulcer recurrence rate and lower VCSS values after intervention than CT alone.

文献编号：

https://doi.org/10.1038/s41598-019-50617-y

引言

An active VLU is the highest clinical stage of lower limb chronic venous insufciency (C6)1 . Its clinical characteristics are severe symptoms, slow healing, and a proneness to recurrence, and the prevalence increases with age2 . In addition, due to the high cost of treatment3 , VLUs have been considered as one of the common diseases endangering public health. Sustained superfcial venous hypertension caused by venous refux is the main pathological basis for VLUs4,5 . CT6,7 and various kinds of surgery (traditional surgery, ultrasound-guided foam sclerotherapy [UGFS]8,9 , EVLA10,11 and radiofrequency ablation [RA]12) have good efects on eliminating or reducing superfcial venous hypertension and promoting ulcer healing. In the Efect of Surgery and Compression on Healing and Recurrence (ESCHAR) study13,14, CT combined with surgery was thought to have a lower ulcer recurrence rate. However, the study found no diference in ulcer healing time between the two groups. Recently, another clinical trial (EVRA ulcer trial)3 concluded that CT combined with early endovenous ablation treatment could promote ulcer healing, reduce ulcer recurrence and prolong the patients’ ulcer-free time within 1 year afer the intervention. Te efect of compression combined use of HL-EVLA-FS is to eliminate superfcial venous refux and cure active VLUs, but it is rarely reported. We aimed to assess the ulcer healing time and recurrence rates afer treatment with compression with or without HL-EVLA-FS in people with active VLUs.

Patients and Methods

Patients.

Tis retrospective cohort study was approved by the medical ethics committee of Ganzhou People’s Hospital. Te methods were carried out in accordance with the approved guidelines. Te study was based on a consecutive inpatient population with active VLUs and was conducted in a single centre from 2013 to 2017.

Te inclusion criteria were as follows

1. Age≥18 years;

2. Active venous ulcer of the lower extremity;

3. Ultrasonographic examination indicating venous refux;

4. Patients with VLUs who had never received compression therapy.

Te exclusion criteria were as follows

1. Leg ulcers from other causes, such as arterial ulcers, diabetic ulcers, malnutrition ulcers, and malignant ulcers, and with an ankle–brachial index<0.8;

2. Healed ulcers (C5);

3. A history of surgery for VVs;

4. Diameter of VVs≥1 cm;

5. Serious systemic diseases;

6. Patients who could not tolerate compression therapy;

7. Patients with VLUs who had chosen other therapies.

Eligible patients’ personal and clinical details, including gender, age, body mass index (BMI), history of diabetes, smoking history, course of varicose veins, ulcer site, ulcer duration, ulcer diameter, venous refux pattern, and preoperative (Venous Clinical Severity Score)VCSS16, were recorded at baseline.

Methods.

Therapy options. According to the information provided in the informed consent form in the medical record, the therapy option was based on the preference expressed by either the patient or the treating clinician. Terapy options included CT with or without HL-EVLA-FS. Patients satisfying the inclusion criteria were fully informed about CT with or without HL-EVLA-FS and gave their written consent to undergo this specifc treatment.

Venous refux. A time of 500 ms was recommended as the cutof value for saphenous, deep femoral, and perforator vein incompetence, and 1 s, for femoral and popliteal vein incompetence17. Venous refux was identifed as isolated superfcial venous refux (ISVR), superfcial venous refux (SVR), segmental deep venous refux (SDVR), full-length deep venous refux (FLDVR) and calf perforator veins refux (CPVR) according to the location of refux4,18.

Surgical therapy.

HL-EVLA.

All the varicose veins were marked before surgery. High ligation was performed at the SFJ19. Te trunk of the GSV was punctured at the medial malleolus, and the laser fbre was inserted into the trunk of the GSV. Te 810-nm laser instrument (AngioDynamics, Germany) was activated using a pulse of 1 time/second to close the trunk of the GSV. For those patients in whom the guidewire could not be inserted upward from the ankle, such as in those with local infection or stenosis of the GSV, we chose to downwardly insert the guidewire into the GSV at the inguinal incision and retrogradely or segmentally cauterize the GSV using a laser. HL and EVLA of the SSV were performed on patients with ulcers located on the lateral malleolus. All surgical interventions were performed under spinal or general anaesthesia19.

FS.

Multi-point punctures were made in the VVs of the calf. Sclerosing foam was injected into the VVs separately under non-ultrasound-guided foam sclerotherapy (N-UGFS) (foam was produced with the use of the Tessari technique at a ratio of 1ml of 1% lauromacrogol to 4ml of CO2). Approximately 4ml of sclerosing foam was injected at each point. Te total amount of lauromacrogol injected into each limb was no more than 10ml.

Compression therapy.

CT included the early treatment of compression bandages and the post-treatment of compression hosiery20.

CT was administered by therapists or trained community and hospital-based nursing teams. Following cleansing of the ulcer, the wound was covered with Vaseline gauze. Te limb was pressurized with a four-layer compression bandage, ensuring 40mm Hg of compression at the ankle, the leg pressure gradually diminishing up the leg. Afer 3 days, the bandages were replaced by level 2 compression hosiery. Te length of bed rest was 6 hours afer surgery. Continuous compressive therapy was administered during the frst two weeks. Afer 2 weeks, the patients were instructed to wear level 2 compression hosiery during the day and to remove the hosiery at night and elevate the limb.

Follow-up protocol.

Patients with active VLUs followed up monthly at outpatient visits afer the intervention, and the ulcers were photographed. If clinically necessary, patients would receive more outpatient follow-up visits. Te patients underwent reexamination at 1 month, 6 months and 12 months, respectively, afer the intervention. Te reexamination method was physical examination and duplex scanning. During the follow-up, some patients might have changed their treatment methods, such as adding surgery. Patients with ulcer healing continued to follow up for 12 months afer healing. If ulcers recurred, the patient would be admitted to the hospital immediately.

Outcomes.

Primary outcome. Te primary endpoint was time to ulcer healing. Ulcer healing time was the time from the beginning of the intervention to the time of ulcer healing. Ulcer healing was the complete epithelialization of the leg ulcer and was assessed throughout the 1-year follow-up period by the therapists or trained community and hospital-based nursing teams (at least once a month).

Secondary outcomes. Included the changes in VCSS at 1 month, 6 months and 12 months, the 12-month recurrence rates, ulcer recurrence correlations with venous refux patterns and complications in the two groups. Time zero for ulcer recurrence was at ulcer healing for those with open ulcers afer intervention; therefore, ulcer recurrence analyses only included patients with healed ulcers. Ulcer recurrence is the return of ulceration at the healed ulcer site, presenting as incomplete epithelium.

Statistical analysis.

Te continuous variables of the two samples were described by means±standard deviations (SDs), and their diferences were compared by independent-sample t-tests. Categorical data are presented as percentages. We analysed results with Kaplan-Meier life tables, with a log-rank test of the two groups for time to ulcer healing and recurrence. Te HR for time to ulcer healing and recurrence of the two interventions was calculated using Cox regression analysis. Multivariate Cox regression was used to analyse the relationship between ulcer recurrence and the venous refux patterns, and the log-rank test was used to compare the risk factors for ulcer recurrence in venous refux patterns.

All the tests were two-sided, with a signifcance level of 0.05, and were performed using SPSS sofware (ver. 22.0; IBM Corp; USA).

Results

General data of patients.

In total, 539 consecutive patients with a history of chronic leg ulceration were assessed for inclusion. A total of 189 patients were excluded (Fig. 1), of whom 42 had leg ulcers from other causes, 56 had healed ulcers, 28 had surgical history of VVs, 14 had serious systemic diseases, 33 were unable to adhere to CT, and 16 chose other treatments. Te number of eligible cases was 350. Based on the preference expressed by either the patient or the treating clinician, 193 patients (200 limbs) underwent compression plus HL-EVLA-FS, and 157 patients (177 limbs) underwent compression therapy alone. Many of whom came from countryside. Baseline characteristics were similar in the two groups (Table 1). Factors considered to afect ulcer healing, such as gender, age, BMI, course of varicose veins, ulcer duration, ulcer diameter, venous refux, and VCSS before intervention, did not difer between the two groups.

Table 1. Baseline Characteristics of the Study Patients According to Treatment Group. *independent-sample t-test, §Pearson Chi-Square. HL-EVLA-FS high ligation-endovenous laser ablation-foam sclerotherapy, BMI body mass index, ISVR isolated superfcial venous refux, SVR superfcial venous refux, SDVR segmental deep venous refux, FLDVR full-length deep venous refux, CPVR Calf perforator veins refux.

HL-EVLA was applied to the GSV of 200 limbs and to the SSV of 20 limbs. N-UGFS injection was performed on the VVs of 200 limbs. Te average amount of lauromacrogol solution was 9.5±1.0 ml/limb. Both groups received CT with 4-layer bandages for 3 days in the early stage and hosiery in the later stage. Te number of limbs lost to follow-up at 1, 6 and 12 months afer intervention was 2, 3 and 5, respectively, in the combined treatment group and 2, 3 and 3, respectively, in the CT alone group; in the two groups, 4 and 6 limbs, respectively, with healed ulcers were lost to follow-up 12 months afer ulcer healing. Te 18 and 10 patients lost to follow-up are shown as censored cases in the relevant healing and recurrence rate analyses, respectively. In addition, in the CT alone group, considering the possible poor outcomes, 3 and 7 limbs were found to have received combined treatment at 1 month and 6 months, respectively. Tese patients remained in the CT alone group for analysis to overcome baseline bias. At 12 months of observation afer the intervention, 6 and 16 limbs remained unhealed in the combined treatment group and the CT alone group, respectively (Fig. 1).

Primary outcome.

Afer 12 months of intervention, 186 limb ulcers healed in the combined treatment group with a median healing time of 1.08 months (95% CI, 1.02–1.36), while 153 limb ulcers healed in the CT alone group with a median healing time of 2.15 months (95% CI, 1.92–2.45). Te ulcer healing time was shorter in the combined treatment group than in the CT alone group (HR for ulcer healing, 1.845 [95% CI, 1.474–2.309], P=0.0001) (Fig. 2a). Afer adjusting for age, BMI, duration of varicose veins, ulcer duration, and ulcer diameter, the result was consistent. Ulcer healing was faster in the combined treatment group (HR for ulcer healing, 1.938 [95% CI, 1.544–2.434], P=0.0001).

Secondary outcomes.

Tere were signifcant diferences in VCSS values between the two groups at 1 month, 6 months and 1 year afer intervention. Te combined treatment group had lower VCSS values (Table 2).

Table 2. Te changes in VCSS at 1 month, 6 months and 12 months afer intervention. *independent-sample t-test.

Follow-up continued for 12 months afer ulcer healing. Te number of ulcer recurrent limbs (in previously healed limbs) in the combined treatment group was 26 (186), while it was 45 (153) in the CT alone group. Te combined treatment group had obviously lower ulcer recurrence than the CT alone group (HR for ulcer recurrence, 0.418 [95% CI, 0.258 to 0.677], P=0.0001) (Fig. 2b).

Te venous refux modes were taken into account in the multivariate Cox regression analysis. We found that CPVR (HR for ulcer recurrence, 7.734 [95% CI, 1.513 to 39.532], P=0.014) and ISVR (HR for ulcer recurrence, 4.070 [95% CI, 1.229 to 13.478], P=0.0022) were risk factors for ulcer recurrence (Table 3). Te log-rank test was used to compare the infuence of the risk factors of CPVR (Fig. 2c) and ISVR (Fig. 2d) on ulcer recurrence in the two groups, and the results showed that the P values were both less than 0.0001.

Table 3. Multivariate COX regression analysis the venious refux pattern related to the ulcer recurrence. HR hazard ratio, CI confdence interval, ISVR isolated superfcial venous refux, SVR superfcial venous refux, SDVR segmental deep venous refux, FLDVR full-length deep venous refux, CPVR Calf perforator veins refux.

For complications in the combined treatment group, DVT occurred in 2 limbs (1.0%), although the thrombus disappeared at 3 months and 6 months afer anticoagulation therapy and compression treatment, respectively; laser burn of the skin occurred in 6 limbs (3.0%), but the symptoms were mild and resolved within 1 week; and saphenous nerve injury occurred in 11 limbs (5.5%) and presented as skin numbness on the inner side of the calf. Afer 3 months, the symptoms gradually eased, and afer 6 months, they disappeared; superfcial phlebitis occurred in 15 limbs (7.5%), and the symptoms disappeared within 3 months afer compression treatment, elevation of limbs and application of mucopolysaccharide polysulfonate cream. Te common complication of CT was skin anaphylaxis to hosiery in 35 cases (9.3%). Afer anti-allergic treatment, all cases improved.

Discussion

Trough the retrospective cohort study, we found that combined surgery with CT had a shorter ulcer healing time, lower ulcer recurrence rate and better VCSS value improvement afer intervention than CT alone for lower extremity active VLUs.

Te principle of treating VLUs of lower limbs is to eliminate or reduce venous refux, reduce superfcial venous hypertension and promote ulcer healing by various methods21. According to the extent of the lesion and for better treatment efects, combined treatment modalities have been constantly appearing22. Combined treatments, such as EVLA-FS23,24, HL-FS25, and HL-EVLA26, have been introduced successively. Comprehensive treatments can draw on their respective strengths to achieve the best efect, especially when treating severe or recurrent VVs24,25,27. However, the combined treatment of active VLUs with HL-EVLA-FS plus CT has rarely been reported.

Te combined treatment of HL-EVLA-FS is feasible for the treatment of VLUs because it conforms to the treatment principle of VVs. First, the refux of the saphenous veins is blocked by high ligation of these vessels and their branches. Second, the saphenous veins are closed with EVLA, which blocks the veins themselves. Tird, FS is used to close the VVs, which addresses the ofending vessels, eliminates the refux target vessels of the PVs and narrows them. FS also directly acts on the endothelial cells of the PVs, causing their occlusion. Finally, compression can damage the endothelium by sclerosing agents adhering to each other and preventing the VVs from being re-opened by blood fow. All these strategies help to eliminate venous refux, reduce superfcial venous compression and promote ulcer healing. A variety of treatments have been used to eliminate total superfcial vein refux in treating venous ulcers, and good results have been achieved28.

In an early clinical study (the ESCHAR study) according to the venous refux characteristics of limbs with VLUs, patients were randomized into two groups, comparing CT alone and compression plus surgical treatment (disconnecting the saphenofemoral junction, stripping of the saphenous vein and avulsing calf varicosity) of the superfcial vein under general anaesthesia or local anaesthesia; the researchers concluded that combined treatments could not accelerate ulcer healing but could reduce ulcer recurrence13,14. Tis fnding was diferent from our conclusion and might be related to the surgical mode of intervention. However, the clinical study concluded that patterns of venous refux, such as ISVR, were associated with ulcer recurrence. In our study, Cox regression analysis of venous refux patterns also showed that ulcer recurrence was associated with ISVR and CPVR.

Recently, another clinical trial (the EVRA Current Controlled Trials number, ISRCTN02335796.) evaluating the role of early endovenous treatment of superfcial venous refux as an adjunct to compression therapy in patients with venous leg ulcers was performed15. In the trial, ablation methods included EVLA or RA, UGFS, etc. Te authors concluded that CT combined with early endovenous ablation treatment could promote ulcer healing, reduce ulcer recurrence and prolong the patients’ ulcer-free time within 1 year afer the intervention. Our conclusion of this retrospective analysis was similar to that of this trial. However, there was no diference in VCSS values between the two groups during their follow-up.

Compression therapy of the VLUs is usually done with bandages or hosiery, but it is still unclear which is the best option29. A randomized controlled study on the bandages and hosiery for the treatment of VLUs indicated that double hosiery could provide 40 mm Hg pressure at the ankle and was an efective alternative to the four-layer bandage. Te extra beneft of two-layer hosiery was to reduce ulcer recurrence and cost. However, compared with the bandages, the treatment changes with the hosiery were higher, but not all people were suitable for the hosiery7 . Te bandage must be used by a specially trained physician or nurse to achieve the right pressure. Afer patient activity, the bandage tends to be easily shifed. Terefore, every 2–3 days, the bandage needs to be adjusted. Te use of hosiery is convenient. Te patient, family members, or community nurse can accomplish appropriate maintenance. Our choice is to use bandages in the early treatment of VLUs for three days in hospital and then use hosiery afer three days.

Moreover, we directly injected foam sclerosing agent into VVs without ultrasound or catheter guidance with no resultant pulmonary embolism. To achieve ulcer healing, Bush et al. 30 used a percutaneous approach of non-ultrasound guided injection of foam sclerosing agent directly into the VVs around the ulcer to close the VVs and PVs surrounding the ulcer. During our early surgery, we found that the injection of foam sclerosing agent into the superfcial veins could discharge from the distal part of the detached GSV at the SFJ, which was also demonstrated by ultrasound during surgery. We speculate that the pressure of the deep veins or the refux of PVs of the patients led to the backfow of sclerosing agent injected into the VVs without reaching the deep veins. Consequently, HL of the GSV may help prevent the foam sclerosing agent from fowing back into the deep vein through the GSV, which supports the need for HL of the GSV and the safety of N-UGFS. In the future, the method of direct injection of foam sclerosing agent needs to be verifed with a larger sample and longer follow-up.

Although combined surgery with CT had a shorter ulcer healing time and lower ulcer recurrence rate afer the intervention, the combined operation still had corresponding complications. DVT occurred in 2 limbs (1.0%); laser burn of the skin occurred in 6 limbs (3.0%); saphenous nerve injury occurred in 11 limbs (5.5%); and superfcial phlebitis occurred in 15 limbs (7.5%). Te common complication of CT was skin anaphylaxis to hosiery in 35 cases (9.3%). All these complications recovered through corresponding processes. We also found that the reduction in laser power on the calf reduces the chance of skin burns and saphenous nerve injury31. Te complication of CT was the contact skin allergy of the hosiery, which might be related to the materials of the hosiery.

Tis study has some limitations. First, it is not a randomized controlled trial and is, therefore, more subject to bias, which may diminish the strength of our conclusions. Second, three surgical methods were performed simultaneously, which might be a good unity of intervention, but excessive intervention might exist, as some superfcial veins might be unnecessarily closed. Tird, the hosiery we applied might not be the same brand. Patients bought the hosiery according to a hosiery manual, which might afect the consistency of compression therapy. Te reason was that the cost of hosiery was not within the scope of the health care reimbursement. Further study of compression therapy should be provided with the same brand of hosiery. Fourth, the follow-up time was short, and a longer follow-up time is needed.

In conclusion, in the treatment of active VLUs, combined treatments can shorten the ulcer healing time and reduce the ulcer recurrence rate compared with CT alone.

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