Schoot Reineke A, Kremer Leontien C M, van de Wetering Marianne D, van Ommen Cornelia H
Department of Paediatric Oncology, Emma Children's Hospital / Academic Medical Center, PO Box 22660, Amsterdam, Netherlands, 1100 DD.
Cochrane Database Syst Rev. 2013 Sep 11(9):CD009160. doi: 10.1002/14651858.CD009160.pub2.
Venous thrombo-embolic events (VTEs) occur in 2.2% to 14% of paediatric cancer patients and cause significant morbidity and mortality. The malignant disease itself, the cancer treatment and the presence of central venous catheters (CVCs) increase the risk of VTE.
The primary objective of this review was to investigate the effects of preventive systemic treatments in paediatric cancer patients with tunnelled CVCs on (a)symptomatic VTE. Secondary objectives of this review were to investigate adverse effects of systemic treatments for the prevention of (a)symptomatic VTE in paediatric cancer patients with tunnelled CVCs; and to investigate the effects of systemic treatments in the prevention of (a)symptomatic VTE with CVC-related infection in paediatric cancer patients with tunnelled CVCs.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 8 2012), MEDLINE (1966 to August 2012) and EMBASE (1966 to August 2012). In addition, we searched reference lists from relevant articles and conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2006 to 2011), the American Society of Clinical Oncology (ASCO) (from 2006 to 2011), the American Society of Hematology (ASH) (from 2006 to 2011) and the International Society of Thrombosis and Haematology (ISTH) (from 2006 to 2011). We scanned the International Standard Randomised Controlled Trial Number (ISRCTN) Register and the National Institute of Health (NIH) Register for ongoing trials (www.controlled-trials.com) (August 2012), and we contacted the authors of eligible studies if additional information was required.
Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing systemic treatments to prevent venous thrombo-embolic events (VTEs) in paediatric cancer patients with tunnelled CVCs with a control intervention or no systemic treatment. For the description of adverse events, cohort studies were eligible for inclusion.
Two review authors independently selected studies, extracted data and performed risk of bias assessment of included studies. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.
Three RCTs and three CCTs (including 1291 children) investigated the prevention of VTE (low molecular weight heparin (LMWH) n = 134, antithrombin (AT) supplementation n = 37, low-dose warfarin n = 31, cryoprecipitate and/or fresh frozen plasma (FFP) supplementation n = 240, AT supplementation and LMWH n = 41). AT, cryoprecipitate and FFP were supplemented only in cases of AT or fibrinogen deficiency. Of the six included RCTs/CCTs, five investigated the prevention of VTE compared with no intervention (n = 737), and one CCT compared AT supplementation and LMWH with AT supplementation (n = 71). All studies had methodological limitations, and clinical heterogeneity between studies was noted.We found no significant effects of systemic treatments compared with no intervention in preventing (a)symptomatic VTE and no differences in adverse events (such as major and/or minor bleeding; none of the studies reported thrombocytopenia, heparin-induced thrombocytopenia (HIT), heparin-induced thrombocytopenia with thrombosis (HITT), death as a result of VTE, removal of CVC due to VTE, CVC-related infection, and post-thrombotic syndrome (PTS)) between experimental and control groups. Two studies with comparable participant groups and interventions were included for meta-analyses (n = 182). In the experimental group, 1/68 (1.5%) children were diagnosed with symptomatic VTE, as were 4/114 (3.5%) in the control group (best case scenario: risk ratio (RR) 0.65, 95% confidence interval (CI) 0.09 to 4.78). These studies also evaluated asymptomatic CVC-related VTE: In the experimental group, 22/68 (32.4%) were diagnosed with asymptomatic VTE, as were 35/114 (30.7%) in the control group (best case scenario: RR 1.02, 95% CI 0.40 to 2.55). Heterogeneity was substantial for this analysis: I(2) = 73%.The attribution of LMWH to AT supplementation resulted in a significant reduction in symptomatic VTE (Fisher's exact test, two-sided P = 0.028) without bleeding complications; asymptomatic VTE, thrombocytopenia, HIT, HITT, death as a result of VTE, removal of CVC due to VTE, CVC-related infection and PTS were not assessed.Four cohort studies were included for the evaluation of adverse events. Three studies provided information on bleeding episodes: One participant developed an ischaemo-haemorrhagic stroke. One study provided information on other adverse events: None occurred.
AUTHORS' CONCLUSIONS: We found no significant effects of systemic treatments compared with no intervention in preventing (a)symptomatic VTE in paediatric oncology patients with CVCs. However, this could be a result of the low number of included participants, which resulted in low power. In one CCT, which compared one systemic treatment with another systemic treatment, we identified a significant reduction in symptomatic VTE with the addition of LMWH to AT supplementation.All studies investigated the prevalence of major and/or minor bleeding episodes, and none found a significant difference between study groups. None of the studies reported thrombocytopenia, HIT, HITT, death as a result of VTE, removal of CVC due to VTE, CVC-related infection or PTS among participants.On the basis of currently available evidence, we are not able to give recommendations for clinical practise. Additional well-designed international RCTs are needed to further explore the effects of systemic treatments in preventing VTE. Future studies should aim for adequate power with attainable sample sizes. The incidence of symptomatic VTE is relatively low; therefore, it might be necessary to select participants with thrombotic risk factors or to investigate asymptomatic VTE instead.
静脉血栓栓塞事件（VTEs）在2.2%至14%的儿科癌症患者中发生，并导致显著的发病率和死亡率。恶性疾病本身、癌症治疗以及中心静脉导管（CVCs）的存在增加了VTE的风险。
本综述的主要目的是研究预防性全身治疗对置有隧道式CVC的儿科癌症患者发生（有）症状性VTE的影响。本综述的次要目的是研究全身治疗对预防置有隧道式CVC的儿科癌症患者发生（有）症状性VTE的不良反应；以及研究全身治疗对预防置有隧道式CVC的儿科癌症患者发生与CVC相关感染的（有）症状性VTE的影响。
我们检索了Cochrane对照试验中心注册库（CENTRAL）（《Cochrane图书馆》，2012年第8期）、MEDLINE（1966年至2012年8月）和EMBASE（1966年至2012年8月）。此外，我们检索了相关文章的参考文献列表以及国际儿科肿瘤学会（SIOP）（2006年至2011年）、美国临床肿瘤学会（ASCO）（2006年至2011年）、美国血液学会（ASH）（2006年至2011年）和国际血栓与止血学会（ISTH）（2006年至2011年）的会议论文集。我们查阅了国际标准随机对照试验编号（ISRCTN）注册库和美国国立卫生研究院（NIH）注册库以获取正在进行的试验（www.controlled-trials.com）（2012年8月），如有需要，我们还联系了符合条件的研究的作者。
比较全身治疗与对照干预或不进行全身治疗以预防置有隧道式CVC的儿科癌症患者发生静脉血栓栓塞事件（VTEs）的随机对照试验（RCTs）和对照临床试验（CCTs）。对于不良事件的描述，队列研究符合纳入条件。
两位综述作者独立选择研究、提取数据并对纳入研究进行偏倚风险评估。分析按照《Cochrane干预措施系统评价手册》的指南进行。
三项RCT和三项CCT（包括1291名儿童）研究了VTE的预防（低分子量肝素（LMWH）n = 134，抗凝血酶（AT）补充n = 37，低剂量华法林n = 31，冷沉淀和/或新鲜冰冻血浆（FFP）补充n = 240，AT补充和LMWH n = 41）。仅在AT或纤维蛋白原缺乏的情况下补充AT、冷沉淀和FFP。在纳入的六项RCT/CCT中，五项研究了与不干预相比预防VTE（n = 737），一项CCT比较了AT补充和LMWH与AT补充（n = 71）。所有研究均存在方法学局限性，且研究之间存在临床异质性。我们发现与不干预相比，全身治疗在预防（有）症状性VTE方面无显著效果，且实验组和对照组在不良事件（如严重和/或轻微出血；没有研究报告血小板减少、肝素诱导的血小板减少症（HIT）、肝素诱导的血小板减少症伴血栓形成（HITT）、VTE导致的死亡、因VTE拔除CVC、CVC相关感染和血栓后综合征（PTS））方面无差异。两项具有可比参与者组和干预措施的研究被纳入荟萃分析（n = 182）。在实验组中，1/68（1.5%）的儿童被诊断为有症状性VTE，对照组中有4/114（3.5%）（最佳情况：风险比（RR）0.65，95%置信区间（CI）0.09至4.78）。这些研究还评估了无症状的CVC相关VTE：在实验组中，22/68（32.4%）被诊断为无症状VTE，对照组中有35/114（30.7%）（最佳情况：RR 1.02，95% CI 0.40至2.55）。该分析的异质性很大：I² = 73%。将LMWH归因于AT补充导致有症状性VTE显著减少（Fisher精确检验，双侧P = 0.028）且无出血并发症；未评估无症状VTE、血小板减少、HIT、HITT、VTE导致的死亡、因VTE拔除CVC、CVC相关感染和PTS。四项队列研究被纳入评估不良事件。三项研究提供了出血事件的信息：一名参与者发生了缺血性出血性中风。一项研究提供了其他不良事件的信息：未发生。
我们发现与不干预相比，全身治疗在预防置有CVC的儿科肿瘤患者发生（有）症状性VTE方面无显著效果。然而，这可能是由于纳入的参与者数量较少导致检验效能较低。在一项将一种全身治疗与另一种全身治疗进行比较的CCT中，我们发现AT补充加用LMWH可使有症状性VTE显著减少。所有研究均调查了严重和/或轻微出血事件的发生率，且未发现研究组之间有显著差异。没有研究报告参与者中有血小板减少、HIT、HITT、VTE导致的死亡、因VTE拔除CVC、CVC相关感染或PTS。基于目前可得的证据，我们无法为临床实践提供建议。需要更多设计良好的国际RCT来进一步探索全身治疗在预防VTE方面的效果。未来的研究应旨在以可达到的样本量获得足够检验效能。有症状性VTE的发生率相对较低；因此，可能有必要选择具有血栓形成危险因素的参与者或研究无症状VTE。
