Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism: Results of the Select-D™ Pilot Trial
Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism: Results of the Select-D™ Pilot Trial
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有静脉血栓栓塞复发风险的特定癌症患者的抗凝治疗：Select-D™ 试点试验的结果
DOI：
10.1182/blood.v130.suppl_1.625.625
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
O. Chapman
中科院分区：
文献类型：
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作者：
A. Young;A. Marshall;Jenny Thirlwall;C. Hill;Danielle Hale;J. Dunn;A. Lokare;A. Kakkar;M. Levine;O. Chapman
简介：静脉血栓栓塞（VTE）在癌症患者是一个重要的和日益频繁的临床挑战。在英国，达尔特帕林是一种获得许可的低分子肝素（LMWH），皮下给药，用于癌症患者急性静脉血栓栓塞的延长治疗和预防复发，在试验开始前被认为是标准治疗。利伐沙班是一种高选择性的直接Xa因子抑制剂，具有口服生物利用度；直接口服抗凝剂（DOAC）。比较低分子肝素和doac在静脉血栓栓塞癌症患者中的作用的数据有限。方法：Select-d是一项前瞻性、随机、开放标签、多中心的先导试验，比较达尔特帕林（200 IU/kg每日，第1个月和150 IU/kg， 2-6个月）；和利伐沙班（15mg每日两次，连续3周，然后20mg每日一次，共6个月）用于VTE[症状性或偶然肺栓塞（iPE）或症状性下肢近端深静脉血栓形成（DVT）]的癌症患者。在6个月的试验治疗后，通过压缩超声检测残余静脉血栓形成（RVT）阳性的DVT患者和出现PE的患者可以随机分配到安慰剂组或利伐沙班组再治疗6个月。最初的样本量为530例患者，为第二次随机化（每组150例）提供了足够的数据来评估抗凝治疗的持续时间。当第二次随机化结束时，由于高损耗率，试验样本量减少。每组200例患者的修订样本量提供了主要结局（静脉血栓栓塞复发）估计在+/- 4.5%以内（即95%置信区间（CI）宽度为9%），假设6个月静脉血栓栓塞复发率为10%。次要结局包括大出血和临床相关的非大出血（CRNMB）[包括导致非计划接触医生或中断或停止研究药物的明显出血]、可接受性、生存和健康经济学。结果：2013年10月至2016年12月，从英国58个地点招募了406名患者；203名患者随机分配到每组。患者的中位年龄为67岁（22-87岁）；214例（53%）为男性；白人血统386人（95%）。患者表现为早期或局部晚期疾病（n=156, 38%）、转移性疾病（n=240, 59%）或血液系统恶性肿瘤（n=10, 3%）。超过一半的患者有iPE (n=214; 53%)；47% （n=192）有症状性PE或DVT。280例（69%）患者在静脉血栓栓塞发生时正在接受抗癌治疗；大多数接受化疗（n=232, 83%）或靶向治疗（n=41, 15%）。达特帕林组6个月静脉血栓栓塞复发率为11% (95% CI 7-17%)，利伐沙班组为4% （95% CI 2-9%）。各试验组的大出血情况相似[6例患者中有6例出血（3%；95% CI为1-6%）；利伐沙班组8例患者9例出血（4%;95% CI 2-8%）。利伐沙班组有更多的crnmb；使用达特帕林的5例患者中有5例出血（2%；95% CI为1-6%），而使用利伐沙班的27例患者中有28例出血（13%；95% CI为9-19%）。总共有11名患者（5%;95% CI 3-9%）在达特帕林组出血被归类为大出血或crnmb，而在利伐沙班组有34名患者（17%;95% CI 12-22%）出血。208例（54%）患者完成了6个月的试验治疗[100例（52%）患者使用达特帕林；108例（55%）服用利伐沙班。达特帕林组6个月总生存率为70% (95% CI 63-76%)，利伐沙班组为74% （95% CI 68-80%）。第二次随机化只招募了要求的300名患者中的92名；pe 82例（iPE 61例，有症状者21例），dvt 10例。由于死亡或停药（50%），患者没有继续进行第二次随机化；RVT阴性（12%）；不符合其他资格标准（24%）或减少随机化（14%）。结论：Select-d是一项用于静脉血栓栓塞治疗的大型随机试验，研究了DOAC与低分子肝素在癌症患者中的作用。利伐沙班治疗导致6个月静脉血栓栓塞复发率非常低，各试验组报告的大出血数量相似，但利伐沙班组观察到更多的crnmb。一项大型III期试验将证实使用利伐沙班治疗静脉血栓栓塞癌症患者。杨：利奥制药：酬金；拜耳：研究经费；Helsinn:谢礼。Kakkar：拜耳：荣誉，研究经费；詹森:谢礼;赛诺菲:谢礼;Daiichi Sankyo：您好。
Introduction: Venous thromboembolism (VTE) in cancer patients is an important and increasingly frequent clinical challenge. In the UK, dalteparin is a licensed low molecular weight heparin (LMWH), administered subcutaneously, for the extended treatment and prevention of recurrence of acute VTE in cancer patients, considered standard treatment prior to the trial starting. Rivaroxaban is a highly selective direct Factor Xa inhibitor with oral bioavailability; a direct oral anticoagulant (DOAC). Data comparing LMWH and DOACs in cancer patients with VTE are limited. Methods: Select-d is a prospective, randomised, open label, multicentre pilot trial comparing dalteparin (200 IU/kg daily, month 1 and 150 IU/kg, months 2-6); and rivaroxaban (15mg twice daily for 3 weeks then 20mg once daily, for 6 months in total) for cancer patients with VTE [symptomatic or incidental pulmonary embolism (iPE) or symptomatic lower extremity proximal deep vein thrombosis (DVT)]. After 6 months of trial treatment, DVT patients who were residual vein thrombosis (RVT) positive by compression ultrasound and patients with PE at presentation, could be randomised to placebo or rivaroxaban for a further 6 months. The original sample size of 530 patients was large to provide sufficient numbers in the second randomisation (150 in each arm) to assess the duration of anticoagulation. The trial sample size was reduced when the second randomisation closed due to a high attrition rate. The revised sample size of 200 patients in each arm provides estimates of the primary outcome (VTE recurrence) to within +/- 4.5% (i.e. width of 95% confidence interval (CI) of 9%), assuming VTE recurrence rates of 10% at 6 months. Secondary outcomes included major bleeds and clinically relevant non-major bleeds (CRNMB) [including overt bleeds resulting in unscheduled contact with a physician or interruption or discontinuation of study drug], acceptability, survival and health economics. Results: 406 patients were recruited between October 2013 and December 2016 from 58 sites across the UK; 203 patients randomised to each arm. Patients had a median age of 67 years (range 22-87); 214 (53%) were males; 386 (95%) from white ethnic origin. Patients presented with either early or locally advanced disease (n=156; 38%), metastatic disease (n=240; 59%), or haematological malignancies (n=10; 3%). Over half of the patients had iPE (n=214; 53%); 47% (n=192) had symptomatic PE or DVT. 280 (69%) patients were receiving anticancer treatment at the time of their VTE; the majority receiving chemotherapy (n=232; 83%) or targeted therapy (n=41; 15%). The VTE recurrence rate at 6 months was 11% (95% CI 7-17%) for patients on dalteparin and 4% (95% CI 2-9%) for patients on rivaroxaban. Major bleeds were similar across trial arms [6 bleeds from 6 patients (3%; 95% CI 1-6%) on the dalteparin arm; 9 bleeds from 8 patients (4%; 95% CI 2-8%) on the rivaroxaban arm]. There were more CRNMBs on the rivaroxaban arm; 5 bleeds from 5 patients (2%; 95% CI 1-6%) on dalteparin compared with 28 bleeds from 27 patients (13%; 95% CI 9-19%) on rivaroxaban. In total, 11 patients (5%; 95% CI 3-9%) on the dalteparin arm had bleeds categorised as either major bleeds or CRNMBs compared to 34 patients (17%; 95% CI 12-22%) on the rivaroxaban arm. 208 (54%) patients completed 6 months of trial treatment [100 (52%) patients on dalteparin; 108 (55%) on rivaroxaban]. Overall survival at 6 months was 70% (95% CI 63-76%) on dalteparin and 74% (95% CI 68-80%) on rivaroxaban. The second randomisation only recruited 92 of the required 300 patients; 82 were PEs (61 iPE and 21 symptomatic) and 10 were DVTs. Patients did not continue to the second randomisation due to: death or withdrawal (50%); being RVT negative (12%); failing the other eligibility criteria (24%) or declining randomisation (14%). Conclusion: Select-d is a large pilot randomised trial for the treatment of VTE, investigating a DOAC versus a LMWH in patients with cancer. Treating with rivaroxaban resulted in a very low VTE recurrence rate at 6 months with a similar number of major bleeds reported across trial arms but more CRNMBs were seen with rivaroxaban. A large phase III trial will confirm the use of rivaroxaban for the treatment of VTE in cancer patients. Disclosures Young: Leo Pharma: Honoraria; Bayer: Honoraria, Research Funding; Helsinn: Honoraria. Kakkar: Bayer: Honoraria, Research Funding; Janssen: Honoraria; Sanofi: Honoraria; Daiichi Sankyo: Honoraria.