Objective

There have been concerns about the long term safety of paclitaxel coated devices in the lower limbs. A formal systematic review and meta-analysis of randomised controlled trials (RCTs) was performed to examine the long term risk of major amputation using paclitaxel coated balloons in peripheral arterial disease (PAD).

Method

This systematic review was registered with PROSPERO (ID 227761). A broad bibliographic search was performed for RCTs investigating paclitaxel coated balloons in the peripheral arteries (femoropopliteal and infrapopliteal) for treatment of intermittent claudication or critical limb ischaemia (CLI). The literature search was last updated on 20 February 2021 without any restrictions on publication language, date, or status. Major amputations were analysed with time to event methods employing one and two stage models. Sensitivity and subgroup analyses, combinatorial meta-analysis, and a multivariable dose response meta-analysis to examine presence of a biological gradient were also performed.

Results

In all, 21 RCTs with 3 760 lower limbs were analysed (52% intermittent claudication and 48% CLI; median follow up two years). There were 87 major amputations of 2 216 limbs in the paclitaxel arms (4.0% crude risk) compared with 41 major amputations in 1 544 limbs in the control arms (2.7% crude risk). The risk of major amputation was significantly higher for paclitaxel coated balloons with a hazard ratio (HR) of 1.66 (95% CI 1.14 – 2.42; p = .008, one stage stratified Cox model). The prediction interval was 95% CI 1.10 – 2.46 (two stage model). The observed amputation risk was consistent for both femoropopliteal (p = .055) and infrapopliteal (p = .055) vessels. Number needed to harm was 35 for CLI. There was good evidence of a significant non-linear dose response relationship with accelerated risk per cumulative paclitaxel dose (chi square model p = .007). There was no evidence of publication bias (p = .80) and no significant statistical heterogeneity between studies (I² = 0%, p = .77). Results were stable across sensitivity analyses (different models and subgroups based on anatomy and clinical indication and excluding unpublished trials). There were no influential single trials. Level of certainty in evidence was downrated from high to moderate because of sparse events in some studies.

Conclusion

There appears to be heightened risk of major amputation after use of paclitaxel coated balloons in the peripheral arteries. Further investigations are warranted urgently.

中文翻译：

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编辑选择 – 下肢动脉应用紫杉醇涂层球囊后发生大截肢的风险：随机对照试验的系统回顾和荟萃分析

 客观的

人们一直担心下肢紫杉醇涂层装置的长期安全性。对随机对照试验 (RCT) 进行了正式的系统评价和荟萃分析，以检查在外周动脉疾病 (PAD) 中使用紫杉醇涂层球囊导致大截肢的长期风险。

 方法

本系统评价已在 PROSPERO 注册（ID 227761）。对研究外周动脉（股腘动脉和腘下动脉）紫杉醇涂层球囊治疗间歇性跛行或严重肢体缺血（CLI）的随机对照试验进行了广泛的文献检索。文献检索的最新更新日期为 2021 年 2 月 20 日，对出版语言、日期或状态没有任何限制。采用一阶段和两阶段模型，通过时间事件方法对主要截肢进行了分析。还进行了敏感性和亚组分析、组合荟萃分析和多变量剂量反应荟萃分析，以检查生物梯度的存在。

 结果

总共分析了 21 项随机对照试验，涉及 3 760 名下肢（52% 为间歇性跛行，48% 为 CLI；中位随访时间为两年）。紫杉醇组有 2 216 条肢体发生 87 例大截肢（粗风险为 4.0%），而对照组有 1 544 条肢体有 41 例大截肢（粗风险为 2.7%）。紫杉醇涂层球囊的大截肢风险显着较高，风险比 (HR) 为 1.66（95% CI 1.14 – 2.42； p = .008，一阶段分层 Cox 模型）。预测区间为 95% CI 1.10 – 2.46（两阶段模型）。股腘血管 ( p = .055) 和腘下血管 ( p = .055) 观察到的截肢风险是一致的。对于 CLI，需要伤害的数量是 35。有充分的证据表明，紫杉醇累积剂量与加速风险之间存在显着的非线性剂量反应关系（卡方模型p = .007）。没有发表偏倚的证据 ( p = .80)，研究之间也没有显着的统计异质性 ( I ² = 0%， p = .77)。敏感性分析结果稳定（基于解剖学和临床指征的不同模型和亚组，不包括未发表的试验）。没有有影响力的单一试验。由于一些研究中事件稀疏，证据的确定性水平从高降为中。

 结论

在外周动脉中使用紫杉醇涂层球囊后，大截肢的风险似乎会增加。迫切需要进一步调查。