Kahale Lara A, Hakoum Maram B, Tsolakian Ibrahim G, Matar Charbel F, Terrenato Irene, Sperati Francesca, Barba Maddalena, Yosuico Victor Ed, Schünemann Holger, Akl Elie A
Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
Cochrane Database Syst Rev. 2018 Jun 19;6(6):CD006650. doi: 10.1002/14651858.CD006650.pub5.
Cancer increases the risk of thromboembolic events, especially in people receiving anticoagulation treatments.
To compare the efficacy and safety of low molecular weight heparins (LMWHs), direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) for the long-term treatment of venous thromboembolism (VTE) in people with cancer.
We conducted a literature search including a major electronic search of the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1), MEDLINE (Ovid), and Embase (Ovid); handsearching conference proceedings; checking references of included studies; use of the 'related citation' feature in PubMed and a search for ongoing studies in trial registries. As part of the living systematic review approach, we run searches continually, incorporating new evidence after it is identified. Last search date 14 May 2018.
Randomized controlled trials (RCTs) assessing the benefits and harms of long-term treatment with LMWHs, DOACs or VKAs in people with cancer and symptomatic VTE.
We extracted data in duplicate on study characteristics and risk of bias. Outcomes included: all-cause mortality, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia, and health-related quality of life (QoL). We assessed the certainty of the evidence at the outcome level following the GRADE approach (GRADE handbook).
Of 15,785 citations, including 7602 unique citations, 16 RCTs fulfilled the eligibility criteria. These trials enrolled 5167 people with cancer and VTE.Low molecular weight heparins versus vitamin K antagonistsEight studies enrolling 2327 participants compared LMWHs with VKAs. Meta-analysis of five studies probably did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on mortality up to 12 months of follow-up (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.88 to 1.13; risk difference (RD) 0 fewer per 1000, 95% CI 45 fewer to 48 more; moderate-certainty evidence). Meta-analysis of four studies did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on major bleeding (RR 1.09, 95% CI 0.55 to 2.12; RD 4 more per 1000, 95% CI 19 fewer to 48 more, moderate-certainty evidence) or minor bleeding (RR 0.78, 95% CI 0.47 to 1.27; RD 38 fewer per 1000, 95% CI 92 fewer to 47 more; low-certainty evidence), or thrombocytopenia (RR 0.94, 95% CI 0.52 to 1.69). Meta-analysis of five studies showed that LMWHs probably reduced the recurrence of VTE compared to VKAs (RR 0.58, 95% CI 0.43 to 0.77; RD 53 fewer per 1000, 95% CI 29 fewer to 72 fewer, moderate-certainty evidence).Direct oral anticoagulants versus vitamin K antagonistsFive studies enrolling 982 participants compared DOACs with VKAs. Meta-analysis of four studies may not rule out a beneficial or harmful effect of DOACs compared to VKAs on mortality (RR 0.93, 95% CI 0.71 to 1.21; RD 12 fewer per 1000, 95% CI 51 fewer to 37 more; low-certainty evidence), recurrent VTE (RR 0.66, 95% CI 0.33 to 1.31; RD 14 fewer per 1000, 95% CI 27 fewer to 12 more; low-certainty evidence), major bleeding (RR 0.77, 95% CI 0.38 to 1.57, RD 8 fewer per 1000, 95% CI 22 fewer to 20 more; low-certainty evidence), or minor bleeding (RR 0.84, 95% CI 0.58 to 1.22; RD 21 fewer per 1000, 95% CI 54 fewer to 28 more; low-certainty evidence). One study reporting on DOAC versus VKA was published as abstract so is not included in the main analysis.Direct oral anticoagulants versus low molecular weight heparinsTwo studies enrolling 1455 participants compared DOAC with LMWH. The study by Raskob did not rule out a beneficial or harmful effect of DOACs compared to LMWH on mortality up to 12 months of follow-up (RR 1.07, 95% CI 0.92 to 1.25; RD 27 more per 1000, 95% CI 30 fewer to 95 more; low-certainty evidence). The data also showed that DOACs may have shown a likely reduction in VTE recurrence up to 12 months of follow-up compared to LMWH (RR 0.69, 95% CI 0.47 to 1.01; RD 36 fewer per 1000, 95% CI 62 fewer to 1 more; low-certainty evidence). DOAC may have increased major bleeding at 12 months of follow-up compared to LMWH (RR 1.71, 95% CI 1.01 to 2.88; RD 29 more per 1000, 95% CI 0 fewer to 78 more; low-certainty evidence) and likely increased minor bleeding up to 12 months of follow-up compared to LMWH (RR 1.31, 95% CI 0.95 to 1.80; RD 35 more per 1000, 95% CI 6 fewer to 92 more; low-certainty evidence). The second study on DOAC versus LMWH was published as an abstract and is not included in the main analysis.Idraparinux versus vitamin K antagonistsOne RCT with 284 participants compared once-weekly subcutaneous injection of idraparinux versus standard treatment (parenteral anticoagulation followed by warfarin or acenocoumarol) for three or six months. The data probably did not rule out a beneficial or harmful effect of idraparinux compared to VKAs on mortality at six months (RR 1.11, 95% CI 0.78 to 1.59; RD 31 more per 1000, 95% CI 62 fewer to 167 more; moderate-certainty evidence), VTE recurrence at six months (RR 0.46, 95% CI 0.16 to 1.32; RD 42 fewer per 1000, 95% CI 65 fewer to 25 more; low-certainty evidence) or major bleeding (RR 1.11, 95% CI 0.35 to 3.56; RD 4 more per 1000, 95% CI 25 fewer to 98 more; low-certainty evidence).
AUTHORS' CONCLUSIONS: For the long-term treatment of VTE in people with cancer, evidence shows that LMWHs compared to VKAs probably produces an important reduction in VTE and DOACs compared to LMWH, may likely reduce VTE but may increase risk of major bleeding. Decisions for a person with cancer and VTE to start long-term LMWHs versus oral anticoagulation should balance benefits and harms and integrate the person's values and preferences for the important outcomes and alternative management strategies.Editorial note: this is a living systematic review (LSR). LSRs offer new approaches to review updating in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.
癌症会增加血栓栓塞事件的风险，尤其是在接受抗凝治疗的人群中。
比较低分子肝素（LMWH）、直接口服抗凝剂（DOAC）和维生素K拮抗剂（VKA）对癌症患者静脉血栓栓塞（VTE）长期治疗的疗效和安全性。
我们进行了文献检索，包括对Cochrane对照试验中心注册库（CENTRAL；2016年第1期）、MEDLINE（Ovid）和Embase（Ovid）进行主要电子检索；手工检索会议论文集；检查纳入研究的参考文献；使用PubMed中的“相关引用”功能并在试验注册库中搜索正在进行的研究。作为实时系统评价方法的一部分，我们持续进行检索，在识别到新证据后将其纳入。最后检索日期为2018年5月14日。
评估LMWH、DOAC或VKA对癌症和有症状VTE患者长期治疗的益处和危害的随机对照试验（RCT）。
我们对研究特征和偏倚风险进行了重复数据提取。结局包括：全因死亡率、复发性VTE、大出血、小出血、血小板减少症以及健康相关生活质量（QoL）。我们按照GRADE方法（GRADE手册）在结局层面评估证据的确定性。
在15785条引用文献中，包括7602条独特引用文献，16项RCT符合纳入标准。这些试验纳入了5167例癌症和VTE患者。
低分子肝素与维生素K拮抗剂
八项纳入2327名参与者的研究比较了LMWH与VKA。五项研究的荟萃分析可能未排除LMWH与VKA相比在长达12个月随访期内对死亡率的有益或有害影响（风险比（RR）1.00，95%置信区间（CI）0.88至1.13；风险差（RD）每1000人少0例，95%CI少45例至多48例；中等确定性证据）。四项研究的荟萃分析未排除LMWH与VKA相比在大出血（RR 1.09，95%CI 0.55至2.12；RD每1000人多4例，95%CI少19例至多48例，中等确定性证据）或小出血（RR 0.78，95%CI 0.47至1.27；RD每1000人少38例，95%CI少92例至多47例；低确定性证据）或血小板减少症（RR 0.94，95%CI 0.52至1.69）方面的有益或有害影响。五项研究的荟萃分析表明，与VKA相比，LMWH可能降低了VTE的复发率（RR 0.58，95%CI 0.43至0.77；RD每1000人少53例，95%CI少29例至少72例，中等确定性证据）。
直接口服抗凝剂与维生素K拮抗剂
五项纳入982名参与者的研究比较了DOAC与VKA。四项研究的荟萃分析可能未排除DOAC与VKA相比在死亡率（RR 0.93，95%CI 0.71至1.21；RD每1000人少12例，95%CI少51例至多37例；低确定性证据）、复发性VTE（RR 0.66，95%CI 0.33至1.31；RD每1000人少14例，95%CI少27例至多12例；低确定性证据）、大出血（RR 0.77，95%CI 0.
